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Library of Congress Cataloging-in-Publication Data

Urologic oncology / [edited by] Jerome P. Richie, Anthony D’Amico.

p.; cm.
Includes bibliographical references.
ISBN 0-7216-0003-4 (alk. paper)
1. Genitourinary organs–Cancer. I. Richie, Jerome P. II. D’Amico, Anthony V.
[DNLM: 1. Urologic Neoplasms–therapy. 2. Urologic Neoplasms–diagnosis.
WJ 160 U7844 2005]
RC280.U74U75 2005
616.99¢461–dc22
2004045390

Acquisitions Editor: Rebecca Schmidt Gaertner

Editorial Assistant: Suzanne Flint

Printed in the United States of America

Last digit is the print number: 9 8 7 6 5 4 3 2 1

 CONTRIBUTORS

SIDNEY C. ABREU, MD RICHARD BIHRLE, MD

Fellow, Section of Laparoscopic and Minimally Invasive Surgery Professor of Urology
Glickman Urological Institute Indiana University School of Medicine
Cleveland Clinic Foundation Indianapolis, Indiana
Cleveland, Ohio 38: Radical Orchiectomy and Retroperitoneal Lymph Node Dissection
13: Laparoscopic Radical and Partial Nephrectomy

ALEX F. ALTHAUSEN, MD FIONA C. BURKHARD, MD

Associate Clinical Professor (Urology), Department of Surgery Department of Urology
Harvard Medical School and Massachusetts General Hospital University of Bern
Cancer Center Bern, Switzerland
Boston, Massachusetts 24: Orthotopic Bladder Substitution in the Male and Female
22: Selective Bladder Preservation by Combined Modality Treatment
MICHAEL C. CARR, MD, PhD
GERALD L. ANDRIOLE, MD Assistant Professor of Urology
Professor, Department of Surgery
University of Pennsylvania School of Medicine
Chief, Division of Urologic Surgery
Philadelphia, Pennsylvania
Washington University School of Medicine;
Director, Prostate Study Center at Barnes-Jewish Hospital 46: Neuroblastoma
St. Louis, Missouri
43: Superficial Carcinoma of the Penis: Management and Prognosis PETER R. CARROLL, MD
Professor and Chair, Department of Urology
DARIUS J. BÄGLI, MD, CM, FRCSC, FAAP University of California, San Francisco
Associate Professor of Surgery, Division of Urology San Francisco, California
The University of Toronto Faculty of Medicine
Toronto, Ontario, Canada 23: Noncontinent and Continent Cutaneous Urinary Diversion
26A: Clinically Localized Adenocarcinoma of the Prostate: (Stage
49: Prepubertal Testicular Tumors T1a-T2c): Surgical Management and Prognosis
GLEN W. BARRISFORD, MD
Resident in Urology WILLIAM J. CATALONA, MD
Brigham and Women’s Hospital Professor of Urology
Harvard Medical School Northwestern University Feinberg School of Medicine
Boston, Massachusetts Chicago, Illinois
32: Complications of Surgical Treatment for Localized Prostatectomy 29: Anatomic Nerve-Sparing Radical Retropubic Prostatectomy
Cancer

JAY S. BELANI, MD XAVIER CATHELINEAU, MD

Resident, Division of Urologic Surgery Professor, Department of Urology
Washington University School of Medicine L’Institut Mutualiste Montsouris
St. Louis, Missouri Paris, France
43: Superficial Carcinoma of the Penis: Management and Prognosis 31: Laparoscopic Radical Prostatectomy

ARIE BELLDEGRUN, MD, FACS

Professor of Urology;
Chief, Division of Urologic Oncology
David Geffen School of Medicine at UCLA
Los Angeles, California
14: Treatment of Advanced Renal Cell Carcinoma
SAM S. CHANG, MD
Assistant Professor, Department of Urologic Surgery
Vanderbilt University School of Medicine
Nashville, Tennessee
19: Prognosis and Management of Invasive Transitional Cell Carcinoma

v
vi Contributors

RICHARD CHILDS, MD ANDREW J. DRESLIN, MD

Allogeneic Hematopoietic Cell Transplant Unit, Hematology Resident in Urology
Branch Brigham and Women’s Hospital
National Heart, Lung, and Blood Institute Boston, Massachusetts
National Institutes of Health 16: Management of Upper Urinary Tract Transitional Cell Carcinoma
Bethesda, Maryland
5: Immunotherapy: Basic Guidelines
MICHAEL J. DROLLER, MD
STEVEN J. CHMURA, MD, PhD Professor of Urology
Resident, Department of Radiation and Cellular Oncology Mount Sinai School of Medicine
The University of Chicago Hospitals New York, New York
Chicago, Illinois 17: Diagnosis and Staging of Bladder Cancer
3: Principles and Applications of Radiation Oncology

DONALD S. COFFEY, PhD VICTOR FERLISE, MD

Professor, Oncology, Pharmacology and Molecular Sciences; Instructor of Urology
Director, Research Laboratories University of Pennsylvania School of Medicine
James Buchanan Brady Urological Institution Philadelphia, Pennsylvania
The Johns Hopkins Medical Institutions 39: Retroperitoneal Tumors: Diagnosis, Staging, Surgery, Management,
Baltimore, Maryland and Prognosis
1: The Molecular and Cellular Biology of Urologic Cancers

MICHAEL S. COOKSON, MD ROBERT A. FIGLIN, MD, FACP

Associate Professor, Department of Urologic Surgery Professor of Medicine and Urology
Vanderbilt University School of Medicine David Geffen School of Medicine at UCLA
Nashville, Tennessee Los Angeles, California
19: Prognosis and Management of Invasive Transitional Cell Carcinoma 14: Treatment of Advanced Renal Cell Carcinoma

MAX J. COPPES, MD, PhD, MBA

Head, Division of Paediatric Oncology; ROBERT C. FLANIGAN, MD
Professor, Departments of Oncology and Paediatrics Albert J. Speh, Jr, and Clair R. Speh Professor and Chairperson
University of Calgary Faculty of Medicine Department of Urology
Calgary, Alberta, Canada Stritch School of Medicine
47: Wilms’ Tumor Loyola University
Maywood, Illinois
PATRICK J. CREAVEN, MBBS, PhD 40: Urethral Cancer
Research Professor
School of Medicine & Biomedical Sciences
SUNY Buffalo; RICHARD S. FOSTER, MD
Senior Investigator Professor of Urology
Roswell Park Cancer Institute Indiana University School of Medicine
Buffalo, New York Indianapolis, Indiana
4: Principles of Chemotherapy for Genitourinary Cancer 38: Radical Orchiectomy and Retroperitoneal Lymph Node Dissection

ANTHONY V. D’AMICO, MD, PhD

Professor, Department of Radiation Oncology YVES FRADET, MD, FRCSC
Harvard Medical School; Professor and Chairman, Department of Surgery
Chief, Genitourinary Radiation Oncology Faculty of Medicine
Dana-Farber Cancer Institute Université Laval
Brigham and Women’s Hospital Québec, Canada
Boston, Massachusetts 20: Transurethral Surgery of Bladder Tumors
25: Cancer of the Prostate: Detection and Staging

PHILLIPP DAHM, MD JUDSON R. GASH, MD

Associate Professor, Division of Urology Associate Professor of Radiology
Department of Surgery University of Tennessee
Duke University Medical Center Knoxville, Tennessee
Durham, North Carolina 10: Diagnosis and Staging of Renal Cell Cancer
30: Radical Perineal Prostatectomy

TRACY M. DOWNS, MD INDERBIR S. GILL, MD, MCH

Assistant Professor, Division of Urology Glickman Urological Institute
University of California, San Diego School of Medicine Cleveland Clinic Foundation
La Jolla, California Cleveland, Ohio
23: Noncontinent and Continent Cutaneous Urinary Diversion 13: Laparoscopic Radical and Partial Nephrectomy
 Contributors vii

MISOP HAN, MD FREDERICK A. KLEIN, MD

Assistant Professor, Department of Urology Professor and Chairman, Division of Urology
Feinberg School of Medicine Northwestern University University of Tennessee Medical Center
Chicago, Illinois Knoxville, Tennessee
29: Anatomic Nerve-Sparing Radical Retropubic Prostatectomy 10: Diagnosis and Staging of Renal Cell Cancer

J. MATTHEW HASSAN, MD ERIC A. KLEIN, MD

Resident Glickman Urological Institute
Vanderbilt University School of Medicine The Cleveland Clinic Foundation
Nashville, Tennessee Cleveland, Ohio
19: Prognosis and Management of Invasive Transitional Cell Carcinoma 37: Nongerm Cell Tumors of the Testis

BADRINATH R. KONETY, MD, MBA

NIALL M. HENEY, MD, Assistant Professor, Department of Urology
Clinical Assistant Professor of Surgery University of Iowa
Harvard Medical School and Iowa City, Iowa
Massachusetts General Hospital 15: Transitional Cell Carcinoma of the Renal Cell Pelvis and
Boston, Massachusetts Ureter: Evaluation and Treatment
22: Selective Bladder Preservation by Combined Modality Treatment
TRACEY KRUPSKI, MD
WERNER W. HOCHREITER, MD Clinical Instructor
Department of Urology David Geffen School of Medicine at UCLA
University Hospital of Bern Los Angeles, California
Bern, Switzerland 14: Treatment of Advanced Renal Cell Carcinoma
24: Orthotopic Bladder Substitution in the Male and Female
SANJAYA KUMAR, MD
Assistant Professor, Department of Surgery
AVRUM JACOBSON, MD, CM Harvard Medical School;
Urologist Division of Urology
Lakeshore General Hospital Brigham & Women’s Hospital
Montreal, Québec, Canada Boston, Massachusetts
34: Testis Tumors: Diagnosis and Staging 41: Urethrectomy

MICHAEL A.S. JEWETT, MD, FRCSC, FACS LOUIS LACOMBE, MD, FRCSC
Professor, Department of Surgery (Urology) Assistant Professor of Urology, Department of Surgery
University of Toronto Faculty of Medicine
Toronto, Ontario, Canada Université Laval
35: Seminoma: Management and Prognosis Québec, Canada
20: Transurethral Surgery of Bladder Tumors
MICHAEL W. KATTAN, PhD, MD
Associate Professor of Public Health and Biostatistics in Urology PAUL H. LANGE, MD
Cornell University Professor and Chairman
New York, New York Department of Urology
University of Washington Medical Center
25: Cancer of the Prostate: Detection and Staging Seattle, Washington
34: Testis Tumors: Diagnosis and Staging
DONALD S. KAUFMAN, MD
Clinical Professor of Medicine W. ROBERT LEE, MD, MS
Harvard Medical School; Associate Professor and Vice-Chairman
Director, The Claire and John Bertucci Center for Department of Radiation Oncology
Genitourinary Cancers Wake Forest University School of Medicine
Massachusetts General Hospital Winston-Salem, North Carolina
Boston, Massachusetts
26B: Clinically Localized Adenocarcinoma of the Prostate:
22: Selective Bladder Preservation by Combined Modality Treatment Radiation Therapy

HYUNG KIM, MD HOWARD S. LEVIN, MD

Assistant Professor, Department of Urology Staff, Department of Anatomic Pathology
Roswell Park Cancer Center The Cleveland Clinic Foundation
Buffalo, New York Cleveland, Ohio
14: Treatment of Advanced Renal Cell Carcinoma 37: Nongerm Cell Tumors of the Testis
viii Contributors

W. MARSTON LINEHAN, MD MAXWELL V. MENG, MD

Chief, Urologic Surgery Assistant Professor, Department of Urology
National Institutes of Health University of California, San Francisco
National Cancer Institute/Urologic Oncology Branch San Francisco, California
Bethesda, Maryland 23: Noncontinent and Continent Cutaneous Urinary Diversion; 26A:
5: Immunotherapy: Basic Guidelines Clinically Localized Adenocarcinoma of the Prostate: (Stage T1a-
T2c): Surgical Management and Prognosis
MARK S. LITWIN, MD, MPH
Professor of Urology and Health Services PETER D. METCALFE, MD
David Geffen School of Medicine at UCLA Resident in Urology
Los Angeles, California Dalhousie University
6: Health-Related Quality of Life Issues in Urologic Oncology Halifax, Nova Scotia, Canada
49: Prepubertal Testicular Tumors
KEVIN R. LOUGHLIN, MD, MBA
Professor of Surgery (Urology)
Harvard Medical School;
M. DROR MICHAELSON, MD, PhD
Instructor in Medicine
Senior Surgeon
Harvard Medical School
Brigham and Women’s Hospital
Boston, Massachusetts
Boston, Massachusetts
22: Selective Bladder Preservation by Combined Modality Treatment
42: Squamous Cell Carcinoma of the Penis: Diagnosis and Staging

DONALD F. LYNCH, Jr, MD AARON J. MILBANK, MD

Professor and Chairman, Department of Urology Glickman Urological Institute
Eastern Virginia Medical School and Jones Institute for The Cleveland Clinic Foundation
Reproductive Medicine Cleveland, Ohio
Norfolk, Virginia 37: Nongerm Cell Tumors of the Testis
45: Penectomy and Ilioinguinal Lymphadenectomy
MICHAEL E. MITCHELL, MD
S. BRUCE MALKOWICZ, MD Professor of Urology
Professor of Urology University of Washington School of Medicine;
University of Pennsylvania School of Medicine Chief, Division of Pediatric Urology
Philadelphia, Pennsylvania Children’s Hospital & Regional Medical Center
39: Retroperitoneal Tumors: Diagnosis, Staging, Surgery, Seattle, Washington
Management, and Prognosis 46: Neuroblastoma

MURUGESAN MANOHARAN, MD, FRCS ASHRAF MOSHARAFA, MD

Assistant Professor, Department of Urology Fellow in Urology
University of Miami School of Medicine Indiana University School of Medicine
Miami, Florida Indianapolis, Indiana
18: Superficial Transitional Cell Carcinoma of the Bladder: 38: Radical Orchiectomy and Retroperitoneal Lymph Node Dissection
Management and Prognosis
ANDREW C. NOVICK, MD
FRAY F. MARSHALL, MD Professor of Surgery
Chairman of Urology Cleveland Clinic Lerner College of Medicine;
Emory University School of Medicine Chairman, Glickman Urological Institute
Atlanta, Georgia Cleveland Clinic Foundation
11: Renal Cell Carcinoma: Localized Disease Cleveland, Ohio
12: Surgery of Renal Cell Carcinoma, Including Partial Nephrectomy
MARY FRANCES MCALEER, MD, PhD
Resident, Department of Radiation Oncology WILLIAM K. OH, MD
Thomas Jefferson University Assistant Professor of Medicine
Philadelphia, Pennsylvania Harvard Medical School
27: Regionally Advanced Adenocarcinoma of the Prostate: (T3-4N + Boston, Massachusetts
M0): Management and Prognosis 28: Metastatic Adenocarcinoma of the Prostate

W. SCOTT MCDOUGAL, MD MICHAEL P. O’LEARY, MD

Walter S. Kerr, Jr. Professor of Urology Assistant Professor, Department of Surgery
Harvard Medical School; Harvard Medical School;
Chief, Urology Service Division of Urology
Massachusetts General Hospital Brigham and Women’s Hospital
Boston, Massachusetts Boston, Massachusetts
44: Invasive Carcinoma of the Penis: Management and Prognosis 32: Management of Complications of Radical Prostatectomy Surgery
 Contributors ix

KENNETH OGAN, MD MARTIN G. SANDA, MD

Assistant Professor of Urology Visiting Associate Professor at Harvard Medical School,
Emory University School of Medicine Division of Urology;
Atlanta, Georgia Beth Israel Deaconess Medical Center
11: Renal Cell Carcinoma: Localized Disease Boston, Massachusetts
2: Gene Therapy for Urologic Cancer: Basic Principles, Prospects, and
RISHIKESH PANDYA, MCH, DNB, MS Limitations
Fellow, Division of Urology
University of Toronto WILLIAM U. SHIPLEY, MD
Toronto, Ontario, Canada Andres Soriano Professor of Radiation Oncology
35: Seminoma: Management and Prognosis Harvard Medical School;
Head, Genitourinary Oncology Unit
DAVID F. PAULSON, MD Department of Radiation Oncology
Professor of Urology Massachusetts General Hospital
Duke University Medical Center Boston, Massachusetts
Durham, North Carolina 22: Selective Bladder Preservation by Combined Modality Treatment
30: Radical Perineal Prostatectomy
WENDLA SILVERBERG, MD
DAVID F. PENSON, MD, MPH Resident, Department of Radiation and Cellular Oncology
Associate Professor of Urology and Preventive Medicine
The University of Chicago
Keck School of Medicine
Chicago, Illinois
University of Southern California
Los Angeles, California 3: Principles and Applications of Radiation Oncology
6: Health-Related Quality of Life Issues in Urologic Oncology
DONALD G. SKINNER, MD
DAVID I. QUINN, MD Professor and Chairman, Department of Urology
Assistant Professor of Medicine Hanson-White Chair in Medical Research
Keck School of Medicine Keck School of Medicine
University of Southern California University of Southern California
Los Angeles, California Los Angeles, California
4: Principles of Chemotherapy for Genitourinary Cancer 21: Partial and Radical Cystectomy

DEREK RAGHAVAN, MD, PhD JOSEPH A. SMITH, Jr, MD

Professor, Lerner College of Medicine;
Chairman and Director, Cleveland Clinic Taussig Cancer Center
The Cleveland Clinic Foundation
Cleveland, Ohio
4: Principles of Chemotherapy for Genitourinary Cancer
William L. Bray Professor and Chairman
Department of Urologic Surgery
Vanderbilt University School of Medicine
Nashville, Tennessee
19: Prognosis and Management of Invasive Transitional Cell Carcinoma

MICHAEL L. RITCHEY, MD HOWARD M. SNYDER, III, MD

Professor of Surgery and Pediatrics; Professor of Urology
Director, Division of Urology University of Pennsylvania School of Medicine
University of Texas Health Science Center Philadelphia, Pennsylvania
Houston Medical Center
Houston, Texas 48: Rhabdomyosarcoma of the Pelvis and Paratesticular Structures
47: Wilms’ Tumor
MARK S. SOLOWAY, MD
RONALD RODRIGUEZ, MD, PhD Professor and Chairman
Assistant Professor, Department of Urology Department of Urology
The Johns Hopkins University University of Miami School of Medicine
Baltimore, Maryland Miami, Florida
2: Gene Therapy for Urologic Cancer: Basic Principles, Prospects, 18: Superficial Transitional Cell Carcinoma of the Bladder:
and Limitations Management and Prognosis

RANDALL G. ROWLAND, MD, PHD GRAEME S. STEELE, MD

Professor and Chief, Division of Urology Assistant Professor of Surgery
University of Kentucky College of Medicine Harvard Medical School and
Lexington, Kentucky Brigham and Women’s Hospital
36: Nonseminomatous Germ Cell Tumors: Management and Boston, Massachusetts
Prognosis 16: Management of Upper Urinary Tract Transitional Cell Carcinoma
x Contributors

JOHN P. STEIN, MD PAMELA UNGER, MD

Associate Professor of Urology Associate Professor of Pathology
Keck School of Medicine Mount Sinai School of Medicine
University of Southern California New York, New York
Los Angeles, California 33: Seminal Vesicles: Diagnosis, Staging, Surgery, Management, and
21: Partial and Radial Cystectomy Prognosis

RICHARD G. STOCK, MD RICHARD K. VALICENTI, MD

Professor of Radiation Oncology Associate Professor of Radiation Oncology
Mount Sinai School of Medicine Thomas Jefferson University
New York, New York Philadelphia, Pennsylvania
33: Seminal Vesicles: Diagnosis, Staging, Surgery, Management, 27: Regionally Advanced Adenocarcinoma of the Prostate: (T3-4N +
and Prognosis M0): Management and Prognosis
NELSON N. STONE, MD
Professor of Urology and Radiation Oncology GUY VALLANCIEN, MD
Mount Sinai School of Medicine Head, Departments of Urology and Nephrology
New York, New York L’Institut Mutualiste Montsouris
33: Seminal Vesicles: Diagnosis, Staging, Surgery, Management, and Paris, France
Prognosis 31: Laparoscopic Radical Prostatectomy

URS E. STUDER, MD CELI VAROL, MD

Chairman Department of Urology
University of Bern; University Hospital of Bern
Director, Department of Urology Bern, Switzerland
University Hospital of Bern 24: Orthotopic Bladder Substitution in the Male and Female
Bern, Switzerland
24: Orthotopic Bladder Substitution in the Male and Female
E. DARRACOTT VAUGHAN, Jr, MD
AGNIESZKA SZOT BARNES, MD, MS Professor
Research Fellow in Prostate Image-Guided Therapy Program Weill Medical College of Cornell University
Department of Radiology New York, New York
Brigham and Women’s Hospital 8: Adrenal Tumors
Boston, Massachusetts
7: Image-Guided Minimally Invasive Therapy JOHANNES VIEWEG, MD
Associate Professor of Urology and Immunology
SHAHIN TABATABAEI, MD Duke University Medical Center
Instructor in Surgery Durham, North Carolina
Harvard Medical School 30: Radical Perineal Prostatectomy
Boston, Massachusetts
44: Invasive Carcinoma of the Penis: Management and Prognosis DONALD VINDIVICH, MD
Senior Researcher, James Buchanan Brady Urological Institution
MIAH-HIANG TAY, MBBS, MRCP The Johns Hopkins Medical Institutions
National Cancer Centre of Singapore Baltimore, Maryland
Singapore
1: The Molecular and Cellular Biology of Urologic Cancers
28: Metastatic Adenocarcinoma of the Prostate

CLARE M.C. TEMPANY, MB, BAO, BCh DAVID S. WANG, MD

Professor, Department of Radiology Assistant Professor of Urology
Harvard Medical School; Boston University School of Medicine
Director, Clinical Magnetic Resonance Imaging Boston, Massachusetts
Brigham and Women’s Hospital 9: Open and Laparoscopic Surgery of Adrenal Tumors
Boston, Massachusetts
7: Image-Guided Minimally Invasive Therapy PADRAIG WARDE, MB, BCh, BAO
Professor, Department of Radiation Oncology
RABI TIGUERT, MD University of Toronto;
Fellow, Urology–Oncology Associate Director, Radiation Medicine Program
Université Laval Princess Margaret Hospital
Québec, Canada Toronto, Ontario, Canada
20: Transurethral Surgery of Bladder Tumors 35: Seminoma: Management and Prognosis
 Contributors xi

W. BEDFORD WATERS, MD HSI-YANG WU, MD

Professor of Urology Assistant Professor of Urology
University of Tennessee University of Pittsburgh
Knoxville, Tennessee Pittsburgh, Pennsylvania
10: Diagnosis and Staging of Renal Cell Cancer 48: Rhabdomyosarcoma of the Pelvis and Paratesticular Structures

RALPH R. WEICHSELBAUM, MD JASON B. WYNBERG, MD, FRCSC

Chairman, Department of Radiation and Cellular Oncology Urologic Oncology Fellow
The University of Chicago National Cancer Institute
Chicago, Illinois Bethesda, Maryland
3: Principles and Applications of Radiation Oncology 5: Immunotherapy: Basic Guidelines

RICHARD D. WILLIAMS, MD ANTHONY L. ZIETMAN, MD

Professor and Head, Department of Urology Professor of Radiation Oncology
Rubin H. Flocks Chair Harvard Medical School;
University of Iowa Director of Residency Training for Radiation Oncology
Iowa City, Iowa Massachusetts General Hospital
15: Transitional Cell Carcinoma of the Renal Cell Pelvis and Ureter: Boston, Massachusetts
Evaluation and Treatment 22: Selective Bladder Preservation by Combined Modality Treatment

HOWARD N. WINFIELD, MD
Professor of Urology
Director of Endourology and Minimally Invasive Surgery;
University of Iowa
Iowa City, Iowa
9: Open and Laparoscopic Surgery of Adrenal Tumors
 PREFACE

Urologic cancer has become a major public health problem in the United States: an estimated 42%
of all new cancers in men and 16% of cancer deaths in men are a result of urologic cancers.
Although less common in women, bladder and kidney cancer still rank among significant causes
of morbidity and mortality. The impact of urologic cancers on the population and the far-reaching
advances in urologic oncology have provided the impetus for this new textbook, which covers all
aspects of urologic oncology in a concise yet focused fashion.
Major strides have been accomplished in the field of urologic oncology, particularly in the
area of prostate cancer, where an estimated 220,900 new cases were expected in 2003 and a
significant but decreasing number of deaths totaling 31,800. Three sentinel factors have cat-
alyzed the advances in the diagnosis and treatment of prostate cancer: the discovery and
application of serum prostate specific antigen and its isoforms for early detection of prostate
cancer, the development of effective surgical and radiotherapeutic approaches that increase
efficacy and reduce morbidity from prostate cancer, and the utilization of an increasing num-
ber of transrectal ultrasound spring loaded needle guided biopsies to more efficiently diag-
nose prostate cancer in an ambulatory setting.
Urologic oncology has matured from case studies to evidence-based medicine.
Randomized prospective studies in many arenas of urologic oncology have aided the clinician
in decision-making processes. The stratification of patients into various prognostic groups
based on pretreatment factors has allowed accurate comparisons of cancer control outcome
of different modalities of treatment. Urologic oncology has become a multidisciplinary spe-
cialty, with integration of medical oncology and radiation oncology specialists along with
urologic oncologist to provide the most comprehensive treatment options for the patient
with urologic malignancy.
This textbook provides basic principles of medical and surgical urologic oncology. Each
urologic cancer tumor type is reviewed with regard to incidence, etiology, clinical presenta-
tion, diagnosis and staging, treatment options, prognosis, and future directions. Common
surgical procedures for genitourinary cancers are discussed in terms of indications, preoper-
ative preparation, technique, efficacy, and side effects. Both adult and pediatric malignancies,
including neuroblastoma, Wilms’ tumor, testis tumors, and rhabdomyosarcoma, are reviewed
in detail.
Leading authorities in the field have contributed their knowledge and expertise to this
compendium of urologic oncology. The text is supplemented with tables and figures, as well
as a bibliography containing classic references and recent papers published in the urologic
and medical literature. We expect that this textbook will serve as a valuable resource to the
oncologist in need of pertinent information in every aspect of urologic oncology, from basic
principles to treatment to multidisciplinary approaches.

Jerome P. Richie, MD
Anthony V. D’Amico, MD, PhD

xiii
C H A P T E R
1 The Molecular and Cellular Biology
of Urologic Cancers
Donald S. Coffey, PhD, and Donald Vindivich, MD
The focus of this chapter is to provide an overview of
some of the important concepts and discoveries that have
recently revolutionized our understanding of cancer.
This will be accomplished by giving simple schematics
that show the complexity and elegance of the control
mechanisms involved in controlling life and how these
processes go astray when cancer develops. This will not
be an extensive review with detailed references but rather
an overview of the most important and complex medical
problems.
THE ENIGMAS OF GENITOURINARY CANCERS
All of our present molecular concepts of the role of
inherited genetics as the sole cause of cancers appear to
be challenged by the tissue specificity of the genitouri-
nary cancers. Each organ inherits the same genome, but
only certain organs, such as the prostate, bladder and
kidney, are highly prone to form cancers. In contrast,
other organs in close anatomic proximity are essentially
devoid of any historic presence of a reported cancer, such
as the epididymis, vas deferens, and bulbourethral glands.
All of these organs with vast differences in their cancer
risk can reside within the same human; thus, they have
the same inheritance, genome, environmental exposure,
and have aged to exactly the same time (Figure 1-1). For
example, the bulbourethral gland and the prostate are
both derived from the same developmental anlagen, the
urogenital sinus, and they both bud off as adjacent struc-
tures from the developing urethra. Both organs are
androgen responsive and have a similar blood supply and
nerve stimulation and reside within the same host, shar-
ing a common diet, carcinogenic intake, hormonal envi-
ronments, and identical aging. One would have
anticipated that whatever causes the multimillions of
accumulated cases of prostate cancers in the history of
the world should have produced at least a dozen bul-
bourethral cancers, but not one has ever been reported.
The same is true for the epididymis. No simple compar-
ative analysis of replication rates, DNA repair, acquired
mutation, inherited gene, or lifestyle and environments
seems appropriate to explain this paradox of such a
marked tissue specificity for cancer risk. Something
within the biologic and molecular contexts of the cell
type and differentiation would appear to be involved;
this nongenetic effect is termed an epigenetic event
(Figure 1-2).
EPIGENETIC EFFECTS
Since the same DNA sequence in two different cell types
can produce such drastic differences in cancer risk factors,
it is apparent that other factors besides just the DNA
sequence (genetics) may affect this carcinogenesis. This
epigenetic process is usually thought to be related to the
maturation of the stem cell to a specific cell type. What is
the molecular basis of epigenetics? The same gene
sequence can produce a different messenger RNA in dif-
ferent cell types due to alternative splicing of the RNA.
DNA rearrangements can also alter the message. Recent
attention has been focused on alterations in chromatin
structure, which changes the way DNA is wrapped around
the histone cores to form a nucleosome and alter gene
expression. One hundred and forty-seven base pairs (bp) of
DNA are coiled twice around each histone octamer that is
made up of two copies each of H2A, H2B, H3, and H4.
This tight interaction of the nucleosome with DNA can be
loosened by acetylation of the histone through the action
3
4 Part I Principles of Urologic Oncology
Figure 1-1 Within a human the prostate and bulbourethral
gland are similar, yet the risk of cancer is astronomically
different. Understanding the molecular basis of this tissue
specificity is one of the great riddles of cancer.
of histone acetyl transferases (HAT) or the DNA nucleo-
some can be tightened by histone deacetylation (HDAC).
In addition, some of these histones can be methylated,
which usually occurs on the lysine of histone H3. Histone
hypoacetylation and H3 methylation both tend to tighten
DNA and silent chromatin from being expressed. In addi-
tion, the DNA may be silenced by DNA methylation
through methylation of the cytosine in the five positions
(5 mC). These three types of regulations work closely in
coordination, and can be transferred during propagation
to the daughter cell, and, therefore, can act like pseudoge-
netic elements or as termed, an epigenetic event.
A fourth element modifying chromatin structure is
small molecular weight RNA, such as interference RNA
(RNAi). These and other small RNA molecules are not
read out into proteins but appear to have powerful regu-
latory abilities in directing chromatin structure, message
availability, cell function, and gene function. One of these
small RNAs that are not translated is termed DD3 and is
overexpressed in prostate cancer and may be an impor-
tant control factor or diagnostic agent.
DNA topology involves the winding and unwinding of
the double helix and can change the super helical density
through the actions of topoisomerases and helices that
can greatly alter chromatin structure. These factors are
usually attached at the base of 60,000 molecular weight
DNA loops that are attached to the fixed replication
complex on the nuclear matrix. The nuclear matrix is tis-
sue specific in its protein composition. This loop organ-
ization represents a much higher order structure of DNA
and chromatin and is cell type specific and represents one
of the frontiers of understanding epigenetic events.
Five to ten percent of the total proteins made within
the cell are transcription factors, and it is estimated that
Figure 1-2 An inherited gene that causes cancer is present
in every cell, but it only produces cancer in a specific type of
cell: this specificity is an epigenetic event dictated by the
context of the cell.
there are about 3000 different types of these transcrip-
tion factors within a human. It now appears that organ-
ism complexity, as well as cellular diversity, may arise
from the diversity of these transcription complexes that
form large cellular machinery in a tissue-specific manner
of self-assembly.1
Once a protein is formed by translation of a specific
gene, its turnover rate is regulated by a series of posttrans-
lational modifications, such as ubiquination and proteo-
some interactions, clipping or glycosylation, etc. Certainly,
folding of proteins into various dynamic structures is
essential for their proper action. Many of these proteins
are transported to specific cellular sites and can interact in
heterodimers with thousands of other proteins to form
complex networks. Understanding these self-assembling
networks has now become a major frontier of cell biology.2
CARCINOGENS
What causes genitourinary cancers? Is it mostly environ-
ment (nurture) or inheritance (nature)? Obviously it is
both, but environment has been understudied. In China,
prostate and breast cancer incidence is less than one-
tenth of the incidence rate in the U.S., and this is true of
many other parts of Asia. When Asian populations, with
low prostate cancer rates, migrate to the U.S., there is a
dramatic increase in their incidence of prostate cancer
that occurs by the second generation. This alteration risk
is different with migration and would appear to involve a
change in environmental exposure or a change in lifestyle
risk factors that are beyond a simple Mendelian model of
genetics. It now appears that genes and environment
interact in a system we have not resolved, but it can still
 Chapter 1 The Molecular and Cellular Biology of Urologic Cancers 5
only be an effective carcinogenic event when it occurs in
a specific type of cell within the body. It is still unclear
whether this migration to a higher cancer risk area
removes a protective agent that was in the Asian environ-
ment or has added a carcinogenic agent in the United
States’ environment.
With few exceptions, it has been extremely difficult to
induce prostate cancer in aging rats. However, if rats are
fed with burnt meat, both prostate cancer and breast can-
cer appear.3 A polycyclic hydrocarbon has been identified
from burnt meat and appears to make adducts to the
DNA and thus produces mutations. DNA repair cuts out
these aberrant bases, and they appear in the urine. The
production of these carcinogens in burnt meat is related
to the temperature and time of cooking and might easily
explain many cultural variations in food processing that
alter carcinogens. For example, the Chinese eat meat, but
they do not burn it excessively in the same way as we do
in the U.S. in our barbecuing and tendencies to sear to
the point of burning in the preparation of many of our
meats. Obviously, other cultural aspects of diet might
also be involved, such as the absence of milk and cheese
in the diet of Asia in contrast to its heavy use in the U.S.
and Northern Europe, or the addition of tea and soy in
the Asian diet.
INFLAMMATION
Chronic inflammation has recently received tremendous
interest as an etiologic factor associated with many dis-
eases appearing during aging, including arteriosclerosis,
arthritis, and now cancer. It has long been recognized
that schistosomiasis infections in Egypt were associated
with a high incidence of bladder cancer. Now a new
mechanism for inflammation in the formation of prostate
cancer is becoming evident.4 This new mechanism may
combine many aspects of genetics and epigenetics
defined by lifestyle and risks.
In the aging prostate, there appear to be many small
foci of atrophy. Usually, atrophy indicates a dormant
state or DNA synthesis that is often seen when andro-
gens are withdrawn. Following androgen ablation the
entire prostate becomes atrophied in relation to its
epithelial cells and DNA synthesis and replication essen-
tially cease.5 The paradox was that in some prostates in
humans these small foci of atrophy could be seen in jux-
taposition to acini with highly stimulated luminal epithe-
lial cells that appeared to be under strong androgen
stimulation. The paradox of atrophy next to stimulation
was resolved in part when it was observed that these atro-
phied epithelial cells seen in the small foci were actually
not dormant for DNA synthesis but were highly stimu-
lated and were undergoing rapid DNA synthesis. This
proliferative type of atrophy was often associated with
areas of prostate inflammation. Prostate inflammation is
very common and is often not associated with any symp-
toms, and it must be distinguished from prostatitis,
which frequently can be symptomatic. The cause of this
hidden prostate inflammation is unknown. It may be
related to pathogens, it could also be associated with
autoimmunity. Nevertheless, this close proximity of
highly replicating prostate cells in focal proliferative
atrophy juxtaposition with inflammatory cells that could
produce high levels of reactive oxygen species (ROS)
could be highly detrimental to the DNA of the prostate
epithelial cells unless they can protect themselves against
this oxidative onslaught. One of the common mecha-
nisms of protecting against this type of oxidative damage
is to induce a stress response that up-regulates glu-
tathione-S-transferase pi (GSTPi) that provides a strong
protection against carcinogens and ROS. These prostate
cells that are under stress near the inflammation have
indeed induced their defenses by the induction of this
GSTPi, however, a few isolated epithelial cells appear to
be unable to produce this protective effect. These cells
are highly prone to DNA damage, and when replicated
would then accumulate and be the early events in prosta-
tic interepithelial neoplasia (PIN), a precursor to
prostate cancer. This model has been proposed and
tested by Angelo De Marzo, and a recent review dis-
cusses details of the molecular mechanism.4 How is
GSTPi regulated? As stated, the DNA promoter region
of GSTPi is in a CpG-rich island domain located within
the promoter region. This promoter is silenced by the
methylation of the cytosine residues in these CpG
islands, thus turning off the expression protective effect
of GSTPi for the replicating cells located in the reactive
oxygen environment of the inflammation. The final
prostate cancer cells that form have a hypermethylated
CpG island region in the promoter of GSTPi, and this is
the most common molecular and genome change (>90%)
that has been reported to be associated with all forms of
prostate cancer. The cellular and molecular events that
can be correlated with the early pathology pathway to
prostate cancer have been defined and named prolifera-
tive inflammatory atrophy (PIA).4 It is also of interest
that in animal models of prostate inflammation in the rat,
that the inflammation can be suppressed by high levels of
soy in the diet; a possible clue to a protective factor in the
Asian diet.5
Two genes that have been implicated as candidates in
familial human prostate cancer studies and by microarray
studies are the macrophage scavenger receptor (MSR-1)
and RNASEL6 (Table 1-1). These genes have been shown
to increase infections in knock out animals devoid of these
genes. Thus, the role of pathogens might be implicated in
this process, but equal attention should be given at this
time to the possibility that this type of inflammation may
be produced by autoimmune reactions. Estrogen imprint-
ing in the early neonate life of the rat can result in later
6 Part I Principles of Urologic Oncology

Table 1-1 Selected Genes Proposed to be Involved in Prostate Cancer Initiation or Progression,
or in Modifying the Risk of Prostate Cancer Development
Gene Proposed Function

Mutations causing decreased activity

MS (MSR-1) Antiinfectious, macrophage scavenger receptor
RNASEL Antiinfectious, apoptosis, RNASE
ELAC2 Metal-dependent hydrolase

Promoter hypermethylation resulting in gene silencing

GSTP1 Carcinogen detoxification
EDNRB Endothelin receptor
ER (alpha and beta) Estrogen receptor

LOH and point mutation

PTEN Cell survival and proliferation, phosphatase
TP53 (also p53) Cell survival and proliferation, genome stability
LOH and haploinsufficiency
NKX3-1 Cell differentiation and proliferation
CDKN1B (P27KlP1) Cell proliferation, brake for proliferation

Point mutations
COPEB (also KLR6) Transcription regulation
Androgen receptor (AR) Cell proliferation, survival and differentiation
Amplification
AR Cell proliferation, survival, and differentiation

Overexpressed at mRNA and protein level

HTERT (telomerase) Cell immortality
HPN (Hepsin) Transmembrane protease
FASN Fatty-acid synthesis
AMACR (racemase) Fatty-acid metabolism, branched chain
EZH2 Transcription repressor, cell proliferation
MYC Cell proliferation
BCL2 Cell survival

Polymorphisms affecting prostate cancer risks

AR (CAG and GGC repeats) Cell proliferation, survival, and differentiation
CYP17 Androgen metabolism
SRD5A2 (5 Alpha reductase) Androgen metabolism

Metastasis suppressor (down-regulated)

KAI1 CD44
NME23 KISSI
BRMS1
MAP2K4

development of marked inflammation in the adult rat’s
prostate if they are carried out in strains that have a high
propensity for autoimmune disease.
The body’s defense against many infectious insults is
to produce reactive oxygen, which is primarily pro-
duced by macrophages. Reactive oxygen can also occur
from normal metabolism within the cell and has often
been suggested as part of the aging process. As hydro-
gen from food metabolism interacts with oxygen to
make water, they go through a series of oxidation states
involving single electron transfer resulting in free rad-
icals that can be highly deleterious to DNA resulting in
specific types of DNA oxidative damage. In addition,
nitric oxide (NO), which is formed by NO synthetase
activity in the metabolism of arginine, produces NO, a
powerful oxidizing agent when combined with ROS.
GSTPi is a powerful defender against these types of
oxidative agents produced by inflammation, as well as
protecting against adduct formation on the DNA
caused by carcinogens. These free radicals can also be
 Chapter 1 The Molecular and Cellular Biology of Urologic Cancers 7
squelched in the presence of vitamin E. Thus, vitamin
E as a free radical scavenger has received popularity as
a chemoprotective agent and is being tested in large
clinical trials. Lipid peroxidation is another mechanism
for protecting DNA, and it utilizes selenium in its
action.
Inflammation may be involved in the tissue specificity
of cancer. Seminal vesicles, which rarely get cancer, have
no inflammation like the prostates do. Furthermore,
inflammation is greatly reduced in the prostates of peo-
ple in Asia, and this reduction can be mimicked in ani-
mals fed diets high in soy. The role of estrogens in
inflammation is also an intriguing possibility, particularly
since the soy diet contains high levels of phytoestrogens
that could serve as antiestrogens and block these effects.5
Much is left to discover in these new developing fields of
carcinogenesis of the prostate, but there is little doubt
that major inroads have been realized in the last 4 years
by combining genetic and epigenetic concepts.4 We now
have models that might help explain why only humans
and dogs get prostate cancer, why the seminal vesicles are
not at risk, and why the risks are so different in Asia and
change with migration.5 Molecular targets are being
identified by new microarray techniques, and clinical
prevention trails are now underway in many centers.
FAMILIAL CANCER
Cancer clusters in some families could be the result of
inherited genetic alterations or shared environmental
factors. Single or multiple genes could be causing predis-
position to cancer. Sporadic occurrence suggests aggre-
gation by the adverse effects of the environment, such as
pollutants and carcinogens, as well as socioeconomic dif-
ferences and cultural habits, such as work, sexual, and
dietary factors. It is now possible to apply statistical
analysis to these inherited patterns, trying to correlate
these with the time of diagnosis in order to determine if
there is a genetic predisposition, inherited primarily
through genes from either the mother or the father,
termed autosomal. In this regard, Patrick C. Walsh and
his colleagues have reported that there is a hereditary
form of prostate cancer (HPC) with an early onset and a
3- to 9-fold increased incidence, depending on the num-
ber of first-degree relatives involved. Indeed, hereditary
prostate cancer appears to be inherited in a Mendelian
manner and is autosomal dominant, with a penetrance of
approximately 85%. Intense efforts have been underway
in many centers to find chromosomal linkage to this
hereditary form of cancer and to identify the gene(s)
involved in this increased cancer risk.7 It is hoped that
these high-risk genes can be sequenced as they have been
in breast cancer. In breast cancer, BRCA1 and BRCA2
have been identified as hereditary genes. Also, in colon
cancer, 4 genes have been identified and, 3 of which are
mismatch DNA repair genes, termed MSH2, MLH1,
PMS1, PMS2, as well as the APC tumor suppressor gene.
Two kidney cancer genes have been identified to be
WT1, in the Wilms’ tumor, and the VHL gene associ-
ated with von Hippel-Lindau syndrome, identified by
Marston Linehan and his colleagues.
It is most interesting that there is a familial tendency
in both prostate and renal cell cancers but no such famil-
ial tendency has yet been identified for bladder cancer.
However, only 10% of many types of cancers are inher-
ited through a predisposing gene or genes, but 90% of
cancers are acquired through living or by environmental
insults; these later types are termed sporadic cancers. It is
believed that if we identify the inherited genes that pre-
dispose to familial cancer, these genes will be the same
targets that are altered by carcinogens, aging, or biologic
damage in sporadic cancers. This is the basis for Knudson’s
hypothesis, which has been proven in retinoblastoma.
Since we inherit two genes, one each from our mother
and father, we therefore have two alleles for every gene
that can be slightly different in sequence (polymorphism)
or in methylation (imprinting). If both genes are required
to be knocked out to produce cancer, which is the case
when a suppressor gene is eliminated, then inheriting the
loss of one gene (loss of heterozygosity [LOH]) would
increase your chances of getting cancer, because now an
environmental insult only needs to eliminate the second
allele to inactivate the suppressor gene. This increase in
probability results in the early onset of cancer, because
one of the two suppressor genes had already been inacti-
vated at birth.
The similarity that approximately 10% of all colon,
breast, and prostate cancers are inherited, although the
overall frequency of these genes in the population is
about 0.3%, is one of the mysteries in cancer research. Is
this similarity by chance or does it have a meaning? In
addition, in each case when you inherit these predispos-
ing genes you have an approximately 85% chance of get-
ting the cancer, but 15% will not get cancer.
One of the difficulties in locating cancer-causing
genes is that once you have developed cancer, it is often
accompanied by a genetic instability, which produces a
series of changes in the genome that alter the cancerous
properties of the cell. This temporal change in the can-
cer cell clones is called progression and produces a
marked tumor cell heterogeneity. These genetic changes
that ensue because of this instability can produce a cell
with an increased growth rate, and then this clone will
expand and dominate in the tumor. This phenomenon is
termed “clonal selection,” and since it occurs with time,
it is called tumor progression. Ultimately, cells may be
selected with not only increased growth rate but also with
more aggressive properties, and alterations in many can-
cer genes, such as p53, appear to be related to more
aggressive tumors. Therefore, when a tumor is removed
8 Part I Principles of Urologic Oncology
from a patient and the karyotype or DNA is examined, it
is possible to see tremendous changes in the chromo-
somes. There are cases of chromosomal deletions, ampli-
fications, rearrangements, and duplications, which can
result in changes in ploidy and abnormal amounts of
DNA in the cancer cell nuclei. This was seen earlier in
what we call karyotyping, but this only looked at the
shapes and forms of chromosomes and their banding.
Later it was possible to differentially stain cancer and
normal DNA using either red or green markers as probes
to stain and differentially compare the chromosomes. By
looking at the presence or absence of the red and green
markers on cancer chromosomes, it is possible to visual-
ize changes in their karyotype. This technique has been
termed comparative genome hybridization (CGH).
Recently, all chromosomes can be painted a different
color; a process termed spectral karyotyping (SKY). With
this, it has been possible to find that in certain cancer
chromosomes there is a gain in areas on one arm, and a
simultaneous loss in areas on the other arm. In prostate
cancer, this occurs with loss of material in the short arm
(p) and a subsequent gain in the long arm (q) of the
eighth chromosome; this is not a simple transposition.
Some of these changes may be causal for cancer, but
many are just associated with the properties of the tumor
as it progresses and are simply epiphenomena. This pro-
duces the complex problems that the geneticists face when
analyzing tumor cell chromosomes and DNA. Therefore,
this requires the meticulous linking of the inherited chro-
mosome changes within the lineages of the families with
the tumor types. These linkage studies are most difficult
and usually require years of work. New molecular probes
and information from the Human Genome Project are
speeding this process, and certainly automated and high-
throughput systems are accelerating this search, which has
been a most difficult problem for cancer research.
Certainly, many candidate genes have been identified and
are being verified or eliminated by painstaking work.
The problem then will be to link specific sequences to
gene functions, gene control, and disease. There will be
much variation and polymorphism within the population,
genetic types, and races. Several different types of each
inherited cancer may exist. The genome can also change
through aging, replication errors, and failures in DNA
repair. This is a complex but critical problem in under-
standing genetic changes associated with cancer. Large pop-
ulations will be required in these studies to assure accuracy.7
CANCER GENES
Cancer susceptibility is driven primarily by six types of
genes:
1. Oncogenes. A series of over 60 genes have been
identified that are activated or overexpressed and that
have a positive effect in the induction of growth.
These constitutive genes have a prefix like c-myc. If
they are mutated and inserted by viruses this prefix
changes to v, like v-src.
2. Suppressor genes. Loss of the function of a suppressor
gene essentially removes a brake on cell growth, thus
permitting it to become up-regulated (examples are
p53, Rb, and p16).
3. DNA repair genes. Normal or induced errors in DNA
copying, DNA damage from the environment, or
oxidative damage must be corrected or the gene will
be mutated or silenced. In colon cancer, a group of
mismatch repair genes (MSH2, MLH1, PMS1, and
PMS2) have all been shown to be inherited and to
induce cancer by accumulation of DNA damage. We
know little about how telomere damage is repaired or
how repetitive DNA transposons are regulated.
4. DNA defense genes. These genes protect the DNA
from oxidative damage or electrophiles that can form
adducts to the bases that are detrimental. There are
enzymes that protect the cell against ROS that form
free radicals and produce oxidative damage to the
cell. As the mitochondria carry out their aerobic
oxidation, 4 electrons are required to reduce
molecular oxygen to water. In this process, partially
reduced intermediates of oxygen produce superoxide,
hydrogen peroxide, and hydroxyl radicals that are
collectively known as ROS. ROS can also be caused
by ionizing radiation, UV light, or certain chemicals
in the environment. ROS converts guanine in DNA
to 8-oxoguanine, which is highly mutagenic and
preferentially mispairs with adenine during
replication. There are enzymes, such as glutathione-
S-transferase (GST), glutathione reductase, quinone
reductase, superoxide dismutase, catalase, and other
protective enzymes that inactivate electrophiles,
carcinogens, and ROS. Carcinogens in our
environment are often in a pro-form and need to be
activated by type 1 enzymes or the active carcinogen
needs to be inactivated by type 2 enzymes. For
example, procarcinogens like benzpyrene are inactive
and must be metabolized by epoxidases to form the
active carcinogen that reacts with DNA; this
represents a type 1 reaction. Type 2 reactions are
represented by the family of glutathione transferases,
glucuronosyltransferases, and quinone reductases, all
of which can inactivate carcinogens or ROS. Types 1
and 2 enzymes can be induced or altered by
environment, diet, or inheritance, altering the rate of
cancer formation. There are several isoforms and
polymorphisms; for example, GST-M is related to
bladder and glutathione-S-transferase isoforms
(GST-π) methylation to prostate cancer.
5. Viral genes. Retroviruses, polyoma, adenoma, and
papilloma viruses can also introduce genes into the
 Chapter 1 The Molecular and Cellular Biology of Urologic Cancers 9
mammalian cell, which when expressed induce
malignant transformation. This includes large
T-antigen, E1, E6, and oncogenes.
6. DNA methylation genes. DNA methylation is altered
in many cancers and for unknown reasons.
Hypermethylation of CpG islands in promoter
regions can silence genes. DNA methylation can vary
in maternal and paternal genes, termed imprinting.
Loss of imprinting (LOI) is a common change in
cancers. At present, all of the above six mechanisms
are being studied to determine what causes urologic
cancers. At the moment, there is only definitive
evidence that the VHL gene is associated with von
Hippel-Lindau syndrome, and the WT1 gene is
associated with Wilms’ tumor. The p53 gene is
associated with bladder cancer but it may only be a
progression marker, as it is in prostate cancer. No
specific gene has yet been shown to be inherited in
prostate cancer, although practically all of these
tumors are associated with inactivation of one of the
GST-π. As stated, this inactivation of expression is
accomplished through methylation of the CpG
islands in the promoter region, which down-regulates
the gene. This genomic change is almost universal in
both familial and sporadic prostate cancers but is not
believed to be the inherited gene that causes the
cancer, but we do not know what controls DNA
methylation.
Since both aging and cancer produce heterogeneity in
the stability of various chromosomes, it is hard to elimi-
nate this form of noise in the system, without careful
study. In addition, many normal genes have different
DNA sequences, which are called polymorphism. These
polymorphisms are inherited and can produce different
types of isozymes or genetic patterns that may or may not
have effects on how these genes function. Some of these
polymorphisms are certainly going to increase tendencies
towards malignant transformation that would enhance
the chances of acquiring cancer, which will add to the
complexity. Many suppressor genes not only will be lost
through mutation or genetic inactivation but can also be
down-regulated and turned off by nongenetic or epige-
netic means, such as DNA methylation.
Many traits within the human body, resulting in spe-
cific phenotypes, do require many genes operating in
concert to produce their specific phenotype. This poly-
genic phenomenon can be operating in some cancers.
Indeed, there are multiple steps involved in the evolution
of cancer. It is well known that multiple hits are required,
resulting in multiple changes, which occur with time. It
has been estimated that 3 to 6 changes may be the mini-
mum requirement to produce a clone of cells with the
properties to propagate the cancer to a lethal stage. It has
been suggested that these hits are cumulative and may
not have to occur in a specific order, although this model
has not been completely confirmed. Certainly, just inher-
iting one familial cancer gene seems to guarantee the rest
of the hits, since there is often an 85% chance of devel-
oping cancer when an inherited gene is involved, an
effect termed penetrance.
How do the aforementioned oncogenes and suppres-
sor genes function within the cell to cause cancer? They
appear to regulate cell replication, death, and growth.
There are about 60 oncogenes of primarily four types:
1. Genes for growth factors or their receptors (e.g.,
platelet-derived growth factor [PDGF], erb-B, and
RET).
2. Genes affecting cell-signaling pathways, such as ras
and src.
3. Genes acting as transcription factors that activate
early growth genes, such as the myc oncogenes.
4. Genes affecting the cell cycle: Bcl-2 is an inhibitor of
cell death that when overexpressed, blocks apoptosis
and allows cells to survive and accumulate.
Overexpressing factors that bind to suppressors can
remove the brake. For example, MDM-2 removes
the suppressor brake p53 by binding to it and
inactivating it. Many virus proteins are expressed in
an infected cell, such as large T, E1A, and E7, and
have the ability to complex suppressor molecules,
such as p53 and Rb. In summary, turning these genes
on turns on cell growth. Suppressors are brake
molecules that turn growth off. Removing the brake,
of course, turns on the growth. These brakes can be
removed either by inheriting the loss of this gene, by
mutating the gene and activating it, or by turning off
the gene through regulation, which is the case when
the DNA in its promoter region is methylated.
How do the suppressor genes function as brakes?
Many of these genes are located in the nucleus and affect
the cell cycle regulation. The Rb gene is present in all
cells and codes for a master brake on the cell cycle that is
discussed in the following. The p53 is one of the best-
known suppressors and is abnormally regulated in most
cancers. It blocks the cell cycle by inducing a series of cell
cycle kinase inhibitors. This p53 protein is activated when
the cell detects damage, such as DNA breakage, and blocks
the cell cycle at the G1/S checkpoint to allow time for DNA
repair. If the damage is extensive the p53 induces abnormal
cells to undergo a suicide through apoptosis. The p53 can
also affect the mechanism of mitosis; abnormalities may
result in mitotic dysjunction (Figure 1-3).
MTS-1, also called p16, is another suppressor
involved in the braking components of the cell cycle.
Other suppressor genes function in the cytoplasm, such
as APC, which is involved in colon cancer. APC may affect
the cell adhesion molecule mechanisms by interacting
10 Part I Principles of Urologic Oncology
Figure 1-3 Schematic of how cyclin-dependent kinases
(CDKs) are activated or inactivated in the cell cycle. The
active kinases are bound to variable cyclins and
phosphorylate Rb, thus releasing the Rb brake on the cell
cycle.
with catenin-like molecules. DPC4 is involved in pancre-
atic cancer and interacts with the cell signaling mecha-
nisms.1 NF-1 and NF-2 are suppressor genes involved in
cell signaling pathways.
Of great interest to the urologist is the WT1 gene,
which is involved in the Wilms’ tumor of the kidney, and
the VHL gene, which is involved in renal cell cancer
accompanying von Hippel-Lindau syndrome. VHL can
either be lost by inheritance or inactivated by methylation
of the cytosine residues of the DNA located in the pro-
moter region of this gene. The VHL gene appears, at the
moment, to be involved in the regulation of transcription.
Transcription is the conversion of the information of
DNA into RNA through the action of RNA polymerase
II that forms messenger RNA (mRNA). An important
protein binds to the RNA polymerase II and controls the
elongation of the mRNA. This transcription and elonga-
tion factor is termed elongin or S III. It appears that in
normal cells, VHL forms a protein that binds to the elon-
gin and is involved in the control of transcription elonga-
tion. When the VHL gene is missing or mutated, it loses
its ability to complex to the elongin and, therefore, allows
elongin to interact with RNA polymerase II, deregulating
the process of mRNA elongation. VHL is the first sup-
pressor gene that has been identified to control the level
of transcriptional elongation. This raises the question:
Why does the elongation result in cancer? It is believed
that this may increase the expression of certain genes
involved in growth control, such as myc or fos.
In summary, the only two genes so far identified for uro-
logic cancers that can be inherited and increase our inci-
dence of cancer are VHL and WT1, which cause renal cell
cancers. In urologic cancers, other suppressors have been
implicated, such as Rb, p53, p16, and the oncogenes
PDGF, myc, and Bcl-2. However, none of these have been
shown to be involved in cancer as inherited factors. There
are many candidate genes for familial prostate cancer, such
as RNASEL for HPC-1 on 1q25-25; ELAC2 for HPC-2;
and MSR-1 but as yet none have been confirmed to a point
of certainty. Certainly these genes play a major role in uro-
logic cancers in controlling growth and progression, but
what is the inherited gene that sets off prostate cancer?
This will soon be resolved, as many groups are rapidly
mapping in on the target of candidate genes.6
MICROARRAYS AND PROTEOMICS
DNA expressed as RNA can be reversed transcribed to
obtain a c-DNA sample that can be hybridized to the
specific DNA of the gene that was transcribed to make
the original messenger RNA. By placing from 10,000 to
40,000 small snippets of DNA from identified genes onto
a chip or a microscope slide, it is possible to hybridize the
c-DNA made from the messenger RNA to the specific
genes it represents. The gene targets are located on each
small dot placed on the chip. With these high through-
put techniques, it is possible to analyze thousands of gene
expression patterns in one sample in a quantitative man-
ner. This is possible by coloring these gene (c-DNA)
expression products with red for the control cell, which
can be normal, or by coloring green for the cancer cell (c-
DNA) and then by combining the red and green messen-
ger RNA, the appearance of a red dot would indicate a
gene that was expressed only in the normal cell. Likewise,
the green dot would represent genes turned on only in
the cancer cell. The expression of both red and green
would form a yellow dot and would indicate expression in
both cell types. With this type of microarray or with
other forms of differential displays, it has been possible to
implicate a series of genes that are turned off or on that
may be involved in prostate cancer in comparison to nor-
mal as is shown in Table 1-1.6 Many of these genes have
been activated or knocked out in transgenic mice, and
their functions have been studied in many cases. For
example, NKX3-1 is expressed in normal prostates and is
decreased in prostate cancers. In mice that have lost one
or more of these NKX3-1 genes abnormal duct develop-
ment and hyperplasia occurs. It then goes on to form
PIN. Likewise PTEN on 10q23 mutated in about one-
third of human prostate cancers and correlates with high
Gleason grade. PTEN is a phosphatase that inactivates
PIP3 that is a signal of several growth factors, including
IGF-1. PIP3 activates protein kinase AKT, which leads to
inhibition of apoptosis causing increasing cell survival and
a tumor. Increasing both PTEN and NKX3-1 increases
the severity of high-grade PIN in animal models.
The most consistent of these genomic alterations
associated with cancer may be the GSTP1 gene, which is
inactivated by hypermethylation of the promoter region
 Chapter 1 The Molecular and Cellular Biology of Urologic Cancers 11
that occurs in over 90% of primary lesions of prostate
cancer. The functions of the other genes in Table 1-1 are
discussed in more detail in a recent review.6
Certainly the increased expression of a gene in the
form of messenger RNA does not necessarily reflect the
amount of protein or its posttranslational modification.
In this regard, rapid development of proteomic tech-
niques that give two-dimensional electrophoretic pat-
terns of protein content based on their molecular weight
and charge is providing additional means of identifying
proteins that change during various stages of cancer and
treatment. These isolated proteins can then be identified
in sequence using new techniques utilizing mass spec-
trometry. Time of flight and fragmentation of proteins in
mass spectrometers have been extremely useful especially
when the proteins are first trapped by baiting them to
specific binding elements on commercially developed
probes. Certainly as these techniques become defined
and standardized they will add a new armamentarium to
the identification of new markers and targets.
THE CONTROL OF THE CELL CYCLE, CELL
DEATH, AND TUMOR GROWTH
In normal tissues, the rate of cell replication and the rate
of cell death are in a tightly controlled balance, but it is
unknown how this balance is maintained. However, when
an imbalance occurs, either through an increase in cell
replication or a decrease in cell death, there is an accu-
mulation of cells that forms the tumor. This balance
involves growth factors, cell signaling, and control of the
cell cycle, as well as apoptosis. DNA damage, aging, and
senescence activate certain signals, which we believe to
be “death” genes that cause the cell to commit suicide.
Signaling of the cell cycle for growth and cell death is one
of the most active areas of science.
First we will review how the cell cycle functions. The
cell is usually quiescent in the nongrowing phase, which
is termed G0. Growth factors, steroids, and hormones
can stimulate the cell to grow and undergo an active
phase of biochemical events, termed G1 or the gap period
that occurs before DNA synthesis. After the biochemical
preparation in G1, the cell undergoes DNA synthesis,
termed the S phase. Following the replication of the
complete DNA, there is a second gap called G2, where
the cell prepares itself for mitosis. Then the mitosis (M
phase) ensues, in which the mitotic spindle separates the
two sets of chromosomes. Then the nucleus reorganizes
and the cell cycle is completed. Recently, there has been
a tremendous amount of research delineating the bio-
chemical controls of the cell cycle. There are specific
checkpoints at the interface between each of these
phases, in which the cell stops to determine its next deci-
sion. These decisions in the cycle are primarily con-
trolled by the interaction of regulatory proteins to form
heterodimers with kinases that are either active or inac-
tive. This in turn regulates their state of phosphorylation
of growth suppressors. A kinase is an enzyme that phos-
phorylates a protein. In the cell cycle, these kinases are
termed cyclin-dependent kinases (CDKs); there are
approximately 7 of these enzymes (CDK2, CDK4, etc.).
They are usually at a constant level and inactive as shown
in Figure 1-3. These CDKs are activated at specific
phases of the cell cycle by binding to a second type of
molecule, called cyclins (termed cyclin A to H). These
are termed cyclins because their concentration varies
through the cycle, and it is these transient molecules that
regulate the cell cycle. Therefore, you can activate cyclin
kinases in a controlled manner by turning on the synthe-
sis and degradation of the cyclins.
Once the CDKs are activated by binding cyclins, they
appear to regulate the cell cycle by phosphorylating and
turning off the brakes within the nucleus that prevent cell
growth. One of the primary brakes or suppressors in the
nucleus is Rb, which, when unphosphorylated, is a check-
point at G1/S and prevents the cycle from proceeding.
When the cyclin kinase is activated, it phosphorylates the
Rb, thus removing the brake and allowing the cell cycle
to initiate DNA synthesis and to continue to complete
growth to the daughter cell.
CDKs can also be inactivated by binding to a group of
CDK inhibitors (CDKIs). Examples of this type of
inhibitor are p16, p21, and p27. If these inhibitors are
induced, the cell cycle stops, growth is suppressed, and so
a checkpoint is formed. How are these inhibitors
induced? This occurs in part through the normal func-
tion of p53, which acts like an inducer and can up-
regulate these inhibitors. The p53 is usually turned on
when cells are damaged. In this case, the cell wishes to
make the decision not to proceed through cell cycle and
to repair itself. In summary, expression of p53 is
increased during cell and/or DNA damage and induces a
braking system on the cell cycle to prevent defective cells
from being made. If the p53 is damaged, lost, or down
regulated, this checkpoint is eliminated. This results in
damaged DNA proceeding and accumulating through
each cell cycle and may result in the large amount of
genetic instability and DNA damage that occur in cancer.
We have just discussed most briefly how the cell cycle
is regulated, but how does a cell determine to undergo
cell death or apoptosis? Damage to the DNA is detected
in part by a series of checkpoint including AMT, ATR,
KU 70, and poly-ADP ribosylation. Broken ends of the
DNA often bind KU 70 or have a special polymer added
to them that is made from a breakdown product of
nicotinamide-adenine dinucleotide (NAD). The poly-
ADP ribosylation of the ends of damaged DNA appears
to set off a signal that can induce cell death.
Other ways to induce cell death are to remove the cell
from its extracellular matrix (ECM) anchorage or to disturb
12 Part I Principles of Urologic Oncology
the cytoskeleton. This is termed anoikis; unknown sig-
nals from the cell periphery and integrin disruption are
being signaled to the nucleus to induce cell death. In
addition, there are large protein molecules like tumor
necrosis factor (TNF), Fas-ligand and trail ligands that
act conversely to growth factors and could be termed
death factor. Their action is cell type specific. The TNF
binds to two types of cell surface receptors and the Fas-
ligand binds to its receptor. These complexes then
involve the activation of a series of caspases (2, 3, 6, 7,
and 9) and the release of cytochrome c from the mito-
chondria all in dynamic concert with either proapoptotic
factor induction (Bid, Bad, Bax) or antiapoptotic factor
suppression (Bc1-2, Bcl-xl).
Sometimes growth factors can induce cell death in
certain cell types. For example, tumor growth factor-β
(TGF-β) can activate cell death in some epithelial cells.
Other growth factors appear to induce cell death when
they are absent; these include EGF and FGF2 and FGF7.
Of great importance to the urologist is the fact that the
absence of androgen on its receptor can induce cell death
in the prostate. Therefore, when the androgen with-
drawal occurs following castration, this absence of andro-
gens induces rapid cell death in the prostate epithelial
cells. This is, of course, the basis for the hormonal treat-
ment of prostate cancer.
In apoptosis, the fragmentation of the DNA produces
a characteristic pattern of small DNA fragments that can
be observed on gel electrophoresis to form the multiple
pieces of short DNA of 170 bp surrounding the nucleo-
somes. These multiples of 170 produces a stepladder
effect on DNA gel analysis. Once the DNA fragmenta-
tion occurs, it is irreversible and accompanied by the pro-
Figure 1-4 Examples of the types of cell signaling. (Adapted from Partin AW, Coffey DS: In
Walsh PC, Retik AB, Stamey TA, Vaughan ED Jr (eds): Campbell’s Urology, 7th edition.
Philadelphia, WB Saunders, 1997, with permission.)
teolytic degradation of the nuclear architecture, destroy-
ing the lamins around the nuclear periphery and the
internal nuclear matrix components. The cell then disin-
tegrates under protease activity, and phagocytosis of the
remaining components occurs, destroying the cell. This
entire event of cell death has been termed “apoptosis”
and is characterized by these morphologic and series of
biochemical events.
As there are brakes or suppressors of growth on the
cell cycle, such as p53 and Rb, there are also brakes to
stop cell death. One of the leading brakes, for example, is
Bcl-2. When Bcl-2 is available, it blocks the process of
cell death and therefore is termed a survival factor. How
is the brake Bcl-2 removed? It can bind to a series of pro-
teins and form a heterodimer. One of these Bcl-2-binding
molecules is termed Bax, and now a family of these death-
inducing molecules has been identified. Combining the
Bcl-2 with Bax removes the brake and allows cell death
to occur.
CELL GROWTH FACTORS
There is much direct and indirect signaling that occurs
between cells and organs. As shown in Figure 1-4, this
signaling can be broken down to various types or cate-
gories. Growth factors (GF) are of many types, and they
bind to specific transmembrane receptors on the cell sur-
face, setting off kinase cascades and structural informa-
tion to induce cell growth or death. If the growth factor
is made and operates on the cell in which it was manu-
factured, it is called an autocrine factor. Usually, the
autocrine factors are secreted from the cell and then
bind to their specific cell surface receptors. If the growth
 Chapter 1 The Molecular and Cellular Biology of Urologic Cancers 13

factor operates within the cell, it is called an intracrine
mechanism. If the growth factor diffuses to a neighbor-
ing cell, it is termed a paracrine stimulation. If the
growth factor is transported through the circulation to
distant cells, it is termed an endocrine effect. Other spe-
cial factors can be transported by the nerves (neurocrine),
or they may come from immune like cells (cytokine).
Cells can also signal by direct communication through
linkages of their structural elements. The ECM makes
direct contact with the cell by binding to integrins, which
are molecules that extend through the cellular membrane
and link to the cytoskeleton within the cell. Cells can also
“hold hands” with their neighbors by direct linkage of
the cell adhesion molecules (CAMS), which form
homodimers.
These direct structural linkages, which transfer infor-
mation in a vectral manner, allow the cell to sense its
neighbors. This linkage is like a telephone area code and
is one of the most active areas of research in cell biology.
These combined units of structural elements form a tis-
sue matrix system, as is shown in Figure 1-5. The CAMS
form a homopolymer with their neighbors. One of the
most prominent of these is E-cadherin, which is a cell
surface CAM and extends through the membrane of the
cell and organizes cytoskeleton components, such as
actin. It does that by interacting with an important mol-
ecule called catenin, which appears in several forms
called α and β. In cancers, there is aberration in the
expression of E-cadherin, whose expression can be regu-
lated by methylation of the DNA in the promoter region
for this gene. The linkage to actin can also be disrupted
by components that can bind to the catenin, such as the
suppressor APC, which has been delineated in colon can-
cer. The cytoskeleton can also be regulated in its organi-
zation by binding to receptors called integrins that detect
ECM components, such as fibronectin. Aberrations in
this linking system, which involves vinculin, tailin, and α-
actinin, disrupt the organization of the cytoskeleton
components, such as actin.
The cytoskeleton is made up of microtubules, actin,
and keratins, which give the shape to the cell and a differ-
ent structure to each cell type. The recognition of the cell

Figure 1-5 The dynamic tissue matrix system is composed of interlocking structural
components that hardwire the cell to the nucleus and DNA. The proteins of the matrix are
tissue specific.
14 Part I Principles of Urologic Oncology
structure, shape, and organization is the basis of histology.
The cytoskeleton links directly to the nuclear matrix,
which organizes the DNA into 50,000 loop domains,
termed replicons. These loops of about 60,000 bp of
DNA are anchored at their base onto the nuclear matrix,
where DNA synthesis and DNA methylation can occur.
Steroid hormone receptors bind to this nuclear matrix in
a tissue-specific manner dictated by the receptors dimer-
ization and interaction with coactivators on corepressors.
It is this nuclear matrix protein pattern that makes up the
tissue specificity. The nuclear matrix protein pattern is
altered in cancer. This dynamic tissue matrix system
is shown in its interactive form in Figure 1-5.
In summary, what a cell touches determines what a cell
does, and the disturbance in the tissue matrix system and
its dynamic components cause the variation in shape that
we term pleomorphism that is a hallmark of cancer. Only
the pathologist can diagnose cancer, which is done by
recognizing aberrations and variations in the nuclear
structure and in the tissues and cell structure. Cancer is a
disease of cell structure.
CELL SIGNALING
As mentioned, many factors can regulate cell growth and
cell death. They do so by interacting with specific trans-
membrane receptors on the cell surface. Their ligands
involve growth factors, cytokines, stress signals, ECM,
and death signals, such as TNF. Once these ligands bind
Figure 1-6 Brief example of 5 types of transmembrane receptor activating the
phosphorylation cascade to activate nuclear function. K, kinase; KK, kinase that
phosphorylates a kinase. See text for discussion.
to their cell surface receptors, which span the membrane
and activate a series of kinases on the cytoplasmic portion
of the receptor, they set off a cascade of phosphorylation
that proceeds to the nucleus. The kinases can either be
tyrosine kinases, which put phosphate groups on tyro-
sine, or serine kinases, which put phosphate groups on
the serine molecules of the target substrate. Many of
these kinases are opposed by phosphatases. Figure 1-6
demonstrates a few of these cascades of protein phospho-
rylations that are directed to the nucleus. Each large K
indicates a kinase that is activated as the receptor signals
down to the nucleus. A selection of five of the major
kinase cascades involve a series of phosphorylations of
kinase molecules that activate other kinase molecules to
phosphorylate, finally reaching phosphorylation of
nuclear factors. These four prominent kinase pathways
are the jak/stat, MAP kinase, and the jnk/erk path-
ways and the PI-3 kinase. These phosphorylation pathways
finally terminate in the nucleus to activate a series of
transcription factors that induce the expression of spe-
cific genes of either growth and death or survival and
senescence. The receptor tyrosine kinase receptor mole-
cule can also link itself to a series of G-protein systems to
activate these kinases or can act through another impor-
tant mechanism that converts the lipids of the membrane
into signaling molecules. For example, phospholipase C
(PLC) can hydrolyze the lipid molecules of the mem-
brane to become signals by making inositol phosphate
(IP-3) or diacylglycerol (DAG). The IP-3 activates calcium
 Chapter 1 The Molecular and Cellular Biology of Urologic Cancers 15

release in the cell that is a signal. The DAG activates pro-
tein kinase C, which is another major kinase system also
signaling to the nucleus.
One of the most important cell signal pathways in
prostate cancer is the PI-3 kinase that activates AKT and
cascades to block the proapoptotic factor Bax and thus
increases cell survival. The phosphorylation of AKT is
countered by the phosphatase PTEN that is inactivated
in many prostate cancers, thus increasing Bax phospho-
rylation and increasing cell survival. This has been only a
brief simplified glimpse at some cell signaling pathways
that are involved in cancer.
STROMAL EPITHELIAL INTERACTIONS
All of the aforementioned signaling mechanisms and
many more come together and are synchronized in the
cell organization forming the tissue that involves the
interaction of many stromal and epithelial signals. The
stroma talks to the epithelium and the epithelial cells talk
to the stroma, both types are nurtured by blood vessels
and nerves.
The interface between the stromal and epithelial cells
is conducted through the formation of the ECM, which
is formed by secretion and products made from both the
stromal and epithelial cells, such as fibronectin, collagen,
laminin, and proteoglycans. This structural support sys-
tem organizes the structure of the cell and polarizes it to
receive growth factors and signals that come from the
stroma, epithelium, and endocrine hormones diffusing
from the blood vessels.
This action of growth factors steroids, and the ECM
making the stromal–epithelial organization and cross-
talk is shown in Figure 1-7, which is a diagram of the
prostate, where the epithelium is composed of neuroen-
docrine, secretory epithelial, and basal cells. It is believed
that the basal cells are the stem cells that differentiate to
form both secretory and neuroendocrine cells. The
stroma is made up of smooth muscle, fibroblast, and
nerve cells. Threading their way through the stroma are
the capillaries, lined by endothelial cells, and the immune
cells, which can move in and out of the prostate. The
capillaries bring the steroids, androgens, estrogens, and
nutrients to the prostate. Testosterone is converted to the
more active dihydrotestosterone (DHT) by 5-α-reductase
in the stroma. In the stroma, the DHT stimulates fibrob-
last growth factor-7 (KGF), which then diffuses up and
activates the receptors on the epithelial cells in a

Figure 1-7 Stromal-epithelial interactions in the prostate mediated by DHT regulated growth
factors; +, stimulation; −, inhibition; NO, nitric oxide. (Adapted from Partin AW, Coffey DS: In
Walsh PC, Retik AB, Stamey TA, Vaughan ED Jr (eds): Campbell’s Urology, 7th edition.
Philadelphia, WB Saunders, 1997, with permission.)
16 Part I Principles of Urologic Oncology
paracrine manner. DHT also stimulates fibroblast
growth factor 2 (BFGF), which both feeds back in an
autocrine effect on the stroma and has a paracrine effect
on the epithelial cells. A similar stimulation is induced by
DHT on the production of insulin-like growth factor II
(IGF-II), which also has an autocrine and paracrine
effect. Insulin-like growth factors are bound to a family
of insulin-like growth factor binding proteins (IGFBP),
which are also made by the stroma. DHT can diffuse
from the smooth muscle into the epithelial cells, where it
induces the synthesis of epidermal growth factor and
TGF-α. In the epithelial cells, the androgen also induces
production of IGFBP, which complexes the insulin-like
growth factors and keeps it inactive. One of the main
secretory proteins made by the prostate is PSA, which
hydrolyzes the IGFBP to release active IGF-I and IGF-
II, which then can stimulate the growth of the epithelial
cells. PSA is a major secretory protein in the ejaculate.
This diagram shows some of the cross-talk between
the stroma and epithelial cells via the testosterone and
DHT induction of growth factors that can function in an
autocrine and paracrine way to these cell components. It
is also important to note that many neurotransmitters are
made in the prostate, such as NO. NO is produced by the
endothelial, immune, and nerve cells and can have a
strong stimulatory effect on stromal and epithelial com-
ponents how this entire system is organized in the
embryo, grows to adult size and then becomes dysregu-
lated to produce tumors with aging is the basis of much
research.
AGING AND TELOMERASE
Although aging is involved in cancer, we know very little
about what really brings about this irreversible and dete-
riorating effect. Certainly, accumulated damage from
free radicals from reactive oxygen, as well as cross-link-
ing and stiffening of collagen, are all key components in
how we age. Importantly, there is also a biologic clock
that counts each cell division; this brings about senes-
cence. At the end of each chromosome are repetitive
pieces of DNA called telomeres. When the cell divides
each time, it loses a small amount of these telomeres,
which is caused by the inability of the DNA synthesis
mechanism to fully replicate the last little bit of terminal
DNA. The loss of these repetitive pieces of DNA is
therefore accumulative and acts as a mitotic clock, count-
ing the cell cycles. After approximately 50 doublings, the
telomeres of the cell have been reduced to a critical
length, resulting in the cell’s senescence and death. Every
cell is limited by this mitotic clock except cells that have
learned how to become immortal. The immortal cells
stabilize their telomeres by activating the enzyme called
telomerase. Telomerase is an enzyme that carries its own
small template made of RNA that is copied into telomere
units that allow the cell to replace the telomeres that are
lost when the cell divides. In any cell in culture, telom-
erase has to be activated or the cells would not be immor-
tal. This is also the case only in the stem cells and the
germ cells. The other cells do not have telomerase activ-
ity and are subject to cell death as the mitotic clock ticks
down counting each cell cycle. In cancer cells, telomerase
is activated and the cells have become immortal.
We have reported that telomerase is one of the best
markers so far in denoting prostate cancer cells from nor-
mal and benign prostatic hypertrophy (BPH) cells. This
will be a new diagnostic marker when applied in an
appropriate manner. Telomerase is one of the most excit-
ing frontiers in understanding senescence, immortality,
and how the cancer cell has broken through this aging
barrier to become immortal.6 Telomere shortening is one
of the earliest molecular lesions in cancer and can initiate
genetic instability by altering chromosome structure.
OVERCOMING THE TUMOR CELL
HETEROGENEITY: APTAMERS AND IN VITRO
EVOLUTION
One of the major obstacles in the treatment of urologic
cancers is their tremendous heterogeneity. Although
clinically appearing as a homogeneous tumor, it actually
consists of a heterogeneous pool of cancer cell clones.
When we apply any treatment, such as chemotherapy or
radiotherapy, we select for subclones in the tumor that
are resistant to our treatment. This is not related to the
response of the tumor cells to our treatment but to their
ability to use evolutionary techniques to escape any given
therapy. There are now new technologies that will allow
us to turn therapeutic evolution on the evolution of the
tumor and thus beat the cancer at its own game.
Aptamers can be small peptide, DNA, or RNA mole-
cules that will bind in an antibody like fashion to any
given target. Large pools of randomized molecules can
be easily made and will provide the molecular diversity to
let the tumor cells select the best binding molecules to all
the different tumor cell clones. For example, by random-
izing the four bases of a 15-nucleotide RNA sequence it
is possible to create pools with more than 415 to 109 dif-
ferent molecules. A selection screen is set up in a way
allowing us to select the best RNA molecules out of the
random pool, that will bind with a high affinity and speci-
ficity to our tumor cells. Bound RNA species are then
recovered and amplified. This enriched RNA fraction is
then subjected to a new round of selection. After 10 to 20
rounds of selection, recovery, and amplification, the pool
will contain RNA molecules with high binding speci-
ficity. Figure 1-8 gives an overview of a typical selection
and amplification cycle that we have involved in in vitro
evolution to prostate cancer cells. Those aptamers can
then be analyzed and produced in large quantities. They
 Chapter 1 The Molecular and Cellular Biology of Urologic Cancers 17
Figure 1-8 Selection cycle for enriching the binding of a
random (109) RNA (aptamers) pool to tumor cells. PCR,
polymerase chain reaction for amplifying DNA; enriched RNA.
The final selected aptamer binds specifically to the tumor
cells.8
can be used as highly specific cancer probes, to improve
diagnosis or, when linked to a cytotoxic “warhead,” as a
new therapeutic approach to treat cancer.8
ACKNOWLEDGMENTS
We wish to acknowledge the outstanding effort of Vivian
Bailey in preparing this chapter and Don Vindivich in
constructing the figures.
REFERENCES
1. Levins M, Tjian R: Transcription regulation and animal
diversity. Nature 2003; 424:147.
2. Bray D: Molecular networks: the top-down view. Science
2003; 301:1864.
3. Stuart GR, Holcroft J, De Boer JG, Glickman BW:
Prostate mutations in rats induced by the suspected human
carcinogen 2-amino-1-methyl-6-phenylimidazol [4,5-6]
pyridine. Cancer; 60:266.
4. Nelson WG, De Marzo AM, Isaacs WB: Mechanisms of
disease prostate cancer. N Engl J Med 2003; 349:366.
5. Coffey DS: Similarities of prostate and breast cancer;
evolution, diet, and estrogens. Urology 2001; 57(Suppl
4A):31.
6. De Marzo AM, Nelson WG, Isaacs WB, Epstein JI:
Pathological and molecular aspects of prostate cancer. The
Lancet 2003; 361:955.
7. Easton DF, Schaid DJ, Whittemore AS, Isaacs WB: Where
are the prostate cancer Genes?—A summary of eight
genome wide searches. The Prostate 2003; 57:261.
8. Lupold SE, Hicks BJ, Lin Y, Coffey DS: Identification and
characterization of nuclease stabilized RNA molecules that
bind human prostate cancer cells via the prostate-specific
membrane antigen. Cancer Res 2002; 62:4029.
C H A P T E R
2 Gene Therapy for Urologic Cancer:
Basic Principles, Prospects, and
Limitations
Martin G. Sanda, MD, and Ronald Rodriguez, MD, PhD
Over 50 years of scientific research following the discovery
of DNA1 have led to recent insights that have set the stage
for preclinical development of gene therapy strategies and
their assessment in clinical trials. The enormous volume of
scientific research that comprises the foundation for ther-
apeutic use of molecular biology reflects the complexity of
linking the most fundamental unit of life, the human
genome, to direct clinical intervention. These profound
complexities were manifest as several unforeseen adverse
events in clinical gene therapy clinical trials observed con-
currently with observed effective treatment by gene ther-
apy.2,3 Consequently, the initial exuberant enthusiasm for
clinical gene therapy has been tempered by an emerging
respect for how the profound complexity of in vivo gene
transfer faces obstacles to therapeutic efficacy and carries
the potential for significant clinical toxicity.
Preclinical studies have identified several therapeutic
strategies based on gene replacement or gene transfer that,
in some cases, have moved to evaluation in clinical trials.
Gene therapy strategies under development include cor-
recting tumor-specific genetic abnormalities by either
inhibiting the function of oncogenes (abnormal tumor
genes that promote tumor cell longevity or proliferation)
or restoring functional tumor suppressor genes (such as
genes that can regulate DNA repair), which are commonly
functionally mutated or absent in cancer. Alternatively, the
immune response of patients with cancers harboring any
of these abnormalities can be stimulated by gene therapies
based on use of recombinant tumor vaccines. Pivotal to all
avenues of gene therapy is the gene transfer vector.
GENE TRANSFER VECTORS
As the vehicles for therapeutic gene delivery, gene
transfer vectors delegate clinical prospects and limita-
18
tions. Gene transfer vectors can be generally classified
as being of either viral or nonviral origin. Vector design
is guided by their desired functions: efficiency of gene
transfer, stability of gene expression, and safety of
clinical use.
Gene transfer efficiency indicates how well a vector
delivers a recombinant gene to a target cell and how
effectively the protein encoded by that gene is subse-
quently expressed. Highly efficient gene transfer is
desirable in almost all clinical strategies using gene
transfer. Two critical components determine gene
transfer efficiency: gene delivery by the vector and
activity of a vector’s expression cassette. The first deter-
minant of efficiency, gene delivery, refers to a vector’s
capacity for cellular attachment, entry, and delivery of
the therapeutic gene (within an expression cassette) to a
site such as the target cell nucleus at which gene expres-
sion can occur. Delivery mechanisms of each vector sys-
tem are distinct.4–6 Cell surface density of specific
receptors required for vector attachment, as well as sta-
bility of the vector itself in the micro-environment sur-
rounding the target cell, affects a vector’s capacity for
therapeutic gene delivery.7–9 The second principal
determinant of vector efficiency is the vector expression
cassette, which contains, in addition to the therapeutic
gene, a promoter sequence controlling therapeutic gene
transcription. Some vectors (such as poxviruses) encode
their own machinery for gene transcription,6 while oth-
ers rely entirely on preexisting polymerases in the target
cell10; however, all vectors carry a promoter region
flanking the therapeutic gene. The promoter pro-
foundly affects therapeutic gene expression and vector
efficiency.11
The stability of gene expression by a specific vector
system depends on the intracellular localization of the
 Chapter 2 Gene Therapy for Urologic Cancer: Basic Principles, Prospects, and Limitations 19

therapeutic gene by the vector. Typically, episomal local- Vector Production

ization (when the therapeutic gene is not integrated in
the target cell chromosome) leads to transient expression
of the gene because most mammalian cells have efficient
mechanisms for extruding episomal foreign DNA. In
contrast, vectors that allow integration of the transferred
gene into the host cell chromosomal DNA, such as retro-
viral vectors, provide longer duration of stable expres-
sion. Although stable, durable expression may be
desirable in treating hereditary disorders and chronic dis-
orders, it should be noted that transient gene expression
might be sufficient for the purposes of using gene trans-
fer for cancer treatment.10
RETROVIRUS VECTORS
Retroviral vectors were used in the first clinical trials of
gene therapy.12,13 Although retroviral vectors provide dis-
tinctly stable long-term expression of therapeutic genes,
use of these vectors is limited by complexity of retroviral
genetic engineering and vector purification as well as by
safety obstacles.3,8,9 These vectors are currently being
used predominantly in ex vivo gene transfer protocols,
although in vivo gene transfer applications are emerging.
Production of replication-deficient retroviral vectors is
accomplished with vector packaging cell lines (Figure 2-1).
Vector particles secreted into packaging cell supernatant
are purified and concentrated in preparation for use for
gene transfer.
Gene Delivery
Cells targeted for gene transfer using the purified retro-
viral vector incorporate the vector by endocytosis via a
specific receptor (Figure 2-2). Reverse transcriptase then
converts vector RNA into DNA, which is then integrated
into the target cell chromosomal DNA during target cell
proliferation. This requirement for target cell prolifera-
tion as a prerequisite to transferred gene expression is
unique to retroviral vectors; retroviral vectors thus do
not readily transfer genes to quiescent cells.8,9
Gene Expression
After integration of the retroviral vector expression cas-
sette (the therapeutic gene flanked by sequences that

Virus envelope
Vector genome with therapeutic or protein coat
gene expression casette
Viral genome containing
therapeutic gene
expression cassette

Factors for initiation of

expression in targety cell
Transfection Assembled
recombinant
viral vector
Viral vector particles
packaging
cell line

Transfection

Vector complementary
viral gene(s)

Figure 2-1 Production of recombinant viral vectors for gene therapy. A schematic
representation of retroviral vector production is shown; analogous systems are in use for the
production of adenoviral and poxvirus vectors. For retroviral vector production, packaging
cell lines in which the therapeutic gene has replaced retroviral gag, pol, and env genes
(these genes are normally required for retrovirus particle production and packaging by
infected cells). The packaging cell line has been co-transfected with these viral genes in
trans to complement the replication defective vector genome, allowing the packaging cell
line to produce and package replication-deficient viral vector particles. (Based on Danos O,
Mulligan RC: Proc Natl Acad Sci USA 1988; 85:6460; Ghosh-Choudhury G, Haj-Ahmad Y,
Brinkley P, et al: Gene 1986; 50:161; Mulligan RC: Science 1993; 260:926.)
20 Part I Principles of Urologic Oncology

Figure 2-2 Gene transfer by retrovirus vectors. Retroviral gene transfer is mediated by
integration of the therapeutic gene into the target cell chromosomal DNA, and therefore
requires target cell DNA replication. (Based on Danos O, Mulligan RC: Proc Natl Acad Sci
USA 1988; 85:6460; Mulligan RC: Science 1993; 260:926; Crystal RG: Science 1995;
270:404; Miller N, Vile R: FASEB J 1995; 9:190.)

Attributes and Applications

promote gene expression) into the chromosome of the
target cell, the therapeutic gene is expressed by the tar-
get cell’s own polymerases and other mediators of gene
expression. Because the therapeutic gene is integrated
into the target cell genome, it is stably expressed by the
cell long-term and is passed onto progeny should the
cell continue to proliferate. Further contributing to
long-term stability of retroviral transferred gene
expression is the immunologically inert phenotype of
these vector constructs: immune responses targeting the
vector itself have not been an obstacle to retroviral vec-
tor use. Although stable genomic integration, as can be
achieved with retroviral vectors, may be desirable for
some therapeutic strategies (such as tumor suppressor
gene replacement), stable and permanent alteration of
the target cell genome in vivo also poses potential safety
pitfalls such as potentially irreversible untoward genetic
effects in vivo. Reflecting the profound in vivo effects of
retrovirus vector integration into chromosomal integra-
tion, such vectors proved effective in treating severe
combined immunodeficiency disease in children; how-
ever, cancers developed in some of these children that
are believed to have been consequent to integration of
the retroviral vector.3
Due to limitations in the functional concentration (or
titer) of retroviral preparations, and rapid inactivation of
unbound retrovirus in vivo, direct in vivo gene transfer
using retroviral vectors has generally been inefficient,
with only a small fraction of target cells expressing the
transferred gene. Retrovirus vectors can, however, medi-
ate highly efficient gene transfer ex vivo (Table 2-1).4
Cancer therapy applications of retroviral vectors have
therefore predominantly involved ex vivo gene transfer,
for example, to augment the immunogenicity of patient-
derived tumor cells (by introducing into such tumor cells
an immunostimulatory gene) prior to use of such cells in
vivo as a gene-modified tumor cell vaccine or for marker
studies.12,14,15 Because retroviral gene transfer itself nei-
ther damages the host cell nor induces undesirable vec-
tor-specific immunity, these vectors are ideally suited for
gene-modified cancer cell vaccine therapies seeking to
elicit tumor-specific immunity. Despite early encourag-
ing results of clinical trials that used retroviral vectors to
create gene-modified tumor vaccine studies for renal
cancer and prostate cancer, the recent observation of vec-
tor-induced leukemias in children undergoing retroviral
gene replacement therapy3 will likely reduce enthusiasm
 Chapter 2 Gene Therapy for Urologic Cancer: Basic Principles, Prospects, and Limitations 21
Table 2-1 Attributes of Vectors for Therapeutic Gene Delivery
Duration of Therapeutic
Vector Gene Expression
Retrovirus Stable long-term
Adenovirus Transient
Poxvirus Transient
Nonviral plasmid or naked Transient
DNA
for clinical applications to only those wherein stable
chromosomal integration is required for the desired ther-
apeutic effect.
ADENOVIRUS VECTORS
Interest in adenoviral vectors was prompted by their
capacity for highly efficient gene transfer in vivo. The
propensity of adenovirus vectors to induce nonspecific
inflammation and a vector-specific immune response,
however, has limited efficacy of this vector system in clin-
ical trials evaluating adenovirus vectors for gene replace-
ment therapy for noncancerous diseases.9,16 Moreover, an
inflammatory response against the adenovirus vector has
been suspected as possibly contributing to the first inci-
dence of a fatal complication of gene therapy.2 Whether
the efficacy of antitumor therapies using this vector system
will be attenuated or augmented by inherent immuno-
genicity of adenoviral vectors remains to be elucidated.
Vector Production
Recombinant adenoviral vectors are rendered infectious
but replication defective (while retaining their capacity
to infect cells) by deletions in an early region DNA (E1)
required for viral replication.5 The deleted E1 region
and other regions of the adenovirus genome serve as
sites for therapeutic genes by using shuttle plasmids and
homologous recombination with complementary dele-
tion mutants (see Figure 2-1). A packaging cell line (293
cells, a transformed human embryonic kidney cell line
containing the adenovirus E1 DNA) transfected with
the E1 deleted adenoviral vector containing a gene of
interest is used to produce the replication-deficient ade-
noviral vectors.5 High concentrations of adenoviral vec-
tor (titer >1011 pfu/ml) can be readily purified.
Gene Delivery
Adenoviruses are taken up by the target cells via a two-
step process, involving binding and internalization.
Efficiency of Gene
Transfer Other
Variable Labile in vivo
Highly efficient Immunogenic
Highly efficient Immunogenic
Inefficient Fewer safety concerns
Binding occurs through the interaction of the knob of the
protruding viral capsid fiber protein to its cellular recep-
tor, referred to as Coxsackie and adenovirus receptor
(CAR). Internalization occurs as a result of the interac-
tion of the RGD motif of the viral penton base capsid
protein with the cellular integrins (αVβ5 or αVβ3,
Figure 2-3).9,17,18 After internalization, the vector is
transported from the endosome to the cytoplasm, where
the adenoviral protein coat is lost as the adenoviral DNA
migrates to the nucleus. In the target cell nucleus, the
vector remains epichromosomal and is not integrated
into the target cell chromosome. Replication of the tar-
get cell is not required for therapeutic gene delivery.
Gene Expression
Nuclear localization of the adenoviral vector allows the
target cell’s own polymerases and other mediators of
gene expression to participate in expression of the thera-
peutic gene. However, because they remain epichromo-
somal, expression of adenoviral vector genes is transient,
lasting only weeks.9
Attributes and Applications
Adenovirus vectors are characterized by transient
duration of gene expression in target cells, significant
induction (by the vector) of inflammation and immunity,
and capacity for highly efficient gene transfer in vivo
(see Table 2-1). The transient gene expression associated
with adenoviral vectors is less likely to constrain the util-
ity of these vectors for cancer therapy than for other
applications: gene-targeted immunotherapy, as well as
apoptosis-inducing therapies, does not require perma-
nent expression of therapeutic genes, and adenovirus
vectors have been effectively applied for such therapeu-
tic strategies in preclinical models.19,20 Indeed, the tran-
sient nature of adenovirus-mediated gene transfer
circumvents the safety issue of irreversible undesirable
genetic effects such as could be encountered with retro-
viral gene transfer.
22 Part I Principles of Urologic Oncology

Figure 2-3 Gene transfer by adenovirus vectors. Adenoviral vectors do not require target
cell DNA replication for efficient gene transfer. However, nuclear localization of the vector
DNA is required since target cell nuclear factors are used for gene expression. Because
these vectors are epichromosomal, therapeutic gene expression is typically less durable
than with retroviral vectors. (Based on Ghosh-Choudhury G, Haj-Ahmad Y, Brinkley P, et al:
Gene 1986; 50:161; Crystal RG: Science 1995; 270:404; Miller N, Vile R: FASEB J 1995;
9:190.)

Adenovirus vectors are potent immunogens.16
Although potentially desirable for gene-targeted
immunotherapies, the inherent immunogenicity of aden-
oviruses may also limit repeated administration of these
vectors due to sensitization-induced inflammatory toxic-
ity.9 Moreover, adenovirus-specific immunity may con-
strain in vivo gene transfer with adenoviral vectors by
inducing humoral and cellular responses capable of elim-
inating the vector and further reducing duration of target
gene expression.16 Despite these limitations, the recep-
tivity of many human cells to adenoviral transfection,
coupled with the relative stability and ease of production
of adenoviral vectors, led to significant tumor reduction
in several preclinical models of direct in vivo gene trans-
fer and broad clinical applications.19–22 The immuno-
genicity of adenoviral vectors was found to carry
potentially dire consequences; however, a systemic
inflammatory response, possibly manifested by unre-
stricted complement activation, was implicated in the
widely publicized death of Jesse Gelsinger, a patient who
received a dose of 38 trillion adenovirus particles on a
phase I trial of adenoviral gene therapy for an inherited
hepatic enzyme deficiency.2 Nevertheless, early phase
clinical studies using adenoviral vectors continue, and
utilizing adenoviral vectors for prostate cancer have
resulted in encouraging biologic activity and is an area of
active translational research.23–25
POXVIRUS VECTORS
Vaccinia and other poxvirus vectors are derived from
one of the greatest triumphs of post-classical medicine:
the smallpox vaccine.6 Jenner’s discovery in 1798 that a
bovine poxvirus was an effective human vaccine against
smallpox eventually led to implementation of a con-
certed worldwide vaccination program by WHO,
which was implemented in 1967, and Jenner’s predic-
tion of “the annihilation of the smallpox” was finally
realized in 1995, nearly 200 years after the introduction
of poxvirus vaccines for human use. Current use of
poxvirus vectors for experimental cancer therapy relate
to the ability of these vectors to induce potent immune
responses in vivo.
Vector Production
Because recombinant poxviruses are used as live, replica-
tion-competent viruses (albeit in attenuated or otherwise
 Chapter 2 Gene Therapy for Urologic Cancer: Basic Principles, Prospects, and Limitations 23

nonpathogenic forms when administered in vivo), pro-
duction can be achieved by simply infecting specific host
cells that allow productive infection.6 Genetically engi-
neered packaging cell lines, such as those used for retro-
virus or adenovirus vector production, are not required.
Immunostimulatory cytokine, accessory molecule, or
tumor antigen genes can be inserted into vaccinia or
other poxvirus vectors by flanking these genes with
poxvirus sequences in a “shuttle” plasmid and then intro-
ducing this plasmid into a cell that has been infected with
whole vaccinia virus. Homologous recombination (as
with adenoviral vector systems) in the vaccinia and shut-
tle plasmid co-transfected cells then leads to insertion of
the gene of interest in a small proportion of the viral
progeny (see Figure 2-1). Linking the therapeutic gene
with an adjacent selectable marker gene allows subse-
quent purification and production of exclusively recom-
binant poxvirus containing the gene of interest.6 Up to
25,000 base pairs of foreign DNA can be accommodated
by vaccinia vectors, representing the greatest size capac-
ity of currently available recombinant viral vectors for
transferred genes.6
cytoplasm and intracytoplasmic release of the virion
complex core (Figure 2-4).6 The virion complex core
contains the vector genome, as well as RNA polymerases
and other enzymes required for expression of the vector
genes; the vector remains in the cytoplasm, where gene
expression controlled by elements contained in the virion
complex core occurs.
Gene Expression
Poxvirus vectors are unique in their ability to express
therapeutic genes without requiring transport of the vec-
tor to the target cell nucleus. In contrast to other vector
systems, which require host cell nuclear factors and
enzymes for gene expression, poxviruses carry the appara-
tus for synthesis of translatable RNA (including virus-
encoded RNA polymerases, transcription factors, capping
enzymes, and poly(A)polymerases) either prepackaged
within the complex virus core or encoded within the viral
genome itself.4 Expression cassettes in poxvirus vectors
thus require unique poxvirus-specific promoter regions
that can be recognized by viral transcription factors.

Gene Delivery Attributes and Applications

Infectious poxvirus virions enter the target cell via fusion Poxvirus transfection is transient and eventually toxic to
of the virion lipoprotein envelope with the target cell the target cell (see Table 2-1). The successful history of

Figure 2-4 Gene transfer by poxvirus vectors. Poxvirus vector particles contain viral RNA
polymerases, obviating any need for nuclear localization or chromosomal integration.
Therapeutic gene expression occurs entirely in the target cell cytoplasm. (Based on Moss B:
Science 1991; 2252:1662.)
24 Part I Principles of Urologic Oncology

vaccinia use for smallpox eradication and the relative ease
of cloning genes into vaccinia vectors have uniquely
poised vaccinia and other poxvirus vectors for use as
recombinant tumor vaccines. As with adenovirus vectors,
use of poxviruses for immunogene therapy is tempered
by potentially competitive, antivector, immune response
induction.26
NONVIRAL VECTORS: LIPOSOMAL
GENE TRANSFER
Nonviral approaches to gene therapy avoid disadvantages
of viral vectors such as safety issues related to potential
replication-competent virus formation and limited target
cell diversity related to receptor requirements for viral
envelope adsorption.7,9,10,17,18 The most extensively
developed nonviral gene delivery systems are liposome-
mediated gene transfer and high-velocity particle-mediated
gene transfer, also known as the “gene gun.”
Vector Production
Plasmid–liposome complexes for gene delivery are
comprised of DNA formulated with cationic lipids.
Most of the cationic lipid–DNA complexes commonly
used for gene delivery in clinical trials are not true lipo-
somes containing plasmid DNA within a lipid envelope
but are rather particulate complexes in which plasmid
DNA is dispersed among the bound lipids.7,9,27
Gene Delivery
These complexes promote cellular gene delivery by
hydrophobic interaction and fusion of the lipid–DNA
complex with the target cell membrane. Unlike viral vec-
tors, however, no signal exists to facilitate transport of
the plasmid DNA containing the therapeutic gene to the
nucleus (Figure 2-5).7 Transfection efficiency is therefore
typically relatively inefficient (see Table 2-1). DNA com-
plexes with copolymers, in contrast, offer the added
advantage of incorporation of targeting ligands, such as
folate or transferrin. Early work in this regard has
demonstrated enhanced gene transfer with systemic
delivery of these targeted complexes.28,29
In contrast, high velocity particle-mediated gene
transfer, or gene gun, technology allows the delivery of
thousands of copies of DNA into targeted cells. This is
achieved by coating 1–3 μm gold particles with plasmid
DNA or mammalian chromosomal genomic DNA up to
44 kb in size; a gene gun is then used to deliver the par-
ticles in vivo by generating a high-pressure gas burst that
accelerates the particles to a velocity sufficiently high for

Figure 2-5 Nonviral gene transfer by liposomal vectors. Liposomal vectors in current use
are complexes of cationic lipids and plasmid DNA. Although relatively safe and
immunologically inert, liposomal vectors require nuclear localization for access to target cell
transcription factors. (Based on Ledley FD: Hum Gene Ther 1995; 6:1129; Crystal RG:
Science 1995; 270:404.)
 Chapter 2 Gene Therapy for Urologic Cancer: Basic Principles, Prospects, and Limitations 25
Figure 2-6 Nonviral gene transfer via particle bombardment
(gene gun). In the helium pulse gene gun, motive force is
generated by release of a high-pressure burst of helium gas
from a reservoir (A) at a preset pressure (150-700 psi). A
release valve (B) discharges helium through a cartridge
(C) containing DNA-coated gold particles. After being
dispersed by an exit nozzle (D), the DNA-coated gold
particles (E) penetrate target cells or tissue with sufficient
force to penetrate multiple cell layers and deliver plasmid
DNA intracellularly. (Reprinted from Yang NS, Sun WH: Nat
Med 1995; 1:481, with permission.)
penetration of multiple cell layers (Figure 2-6).8 As with
lipid–DNA complex gene transfer, translocation of
plasmid DNA to the nucleus after gene gun delivery is
not a specifically targeted event.
Gene Expression
Plasmid DNA that does manage to translocate to the
nucleus usually is not integrated into the target cell genome
and remains epichromosomal (see Figure 2-5).5 Similar to
adenoviral vectors, expression relies on target cell tran-
scription factors and is typically relatively transient.
Attributes and Applications
The principal advantage of nonviral gene delivery sys-
tems, including cationic lipid–DNA complexes, the gene
gun, and other nonviral delivery systems, is that these
systems circumvent three potentially problematic charac-
teristics of viral vectors: immune reactivity, reliance on
viral receptor expression by target cells, and safety issues
related to potential pathogenic recombinant contami-
nants in viral preparations. Enthusiasm and applicability
of nonviral vectors are tempered by relatively inefficient
gene delivery and transient therapeutic gene expression
(see Table 2-1). As transient expression systems, nonviral
and gene gun delivery systems have been useful for
induction of antitumor immunity. Induction of cytokine
secretion using the gene gun has been associated with
reduction of renal cell carcinoma progression in a mouse
model.30 Clinical studies using lipid–DNA complexes
have shown induction of antitumor immune mediators in
melanoma patients, and trials using these vectors for
renal cell cancer are underway.27,31
EMERGING VECTORS AND OTHER GENE
DELIVERY SYSTEMS
The preceding discussion has focused on gene transfer
vectors currently being used in clinical trials as investiga-
tive agents for urologic cancers. A variety of other novel
viral, as well as nonviral, vectors are currently under
development. Among emerging viral vectors are gene
delivery constructs derived from herpesvirus, parvovirus,
and adeno-associated viruses.32–34 Nonviral vectors
under development include eukaryote-derived vectors
such as Listeria monocytogenes and recombinant BCG, syn-
thetic constructs such as dendrimers, and others.35 The
ideal vector for most gene therapy applications will likely
evolve as a hybrid vector merging the desirable proper-
ties of viral vectors with advantageous attributes of non-
viral delivery systems.11
MOLECULAR TARGETS OF GENE THERAPY
Gene therapy for urologic malignancy can be catego-
rized into four distinct strategies based on the molecu-
lar target of gene transfer: immunogene therapy, direct
tumor cell death induction, antioncogene therapy, and
tumor suppressor gene restoration (Table 2-2).
Immunogene therapy affects tumor growth indirectly
by inducing a tumor-specific immune response either
via immunostimulatory gene transfer ex vivo (followed
by in vivo administration of genetically altered cells to
induce a tumor-specific immune response) or via direct
in vivo transfer of immunostimulatory or tumor anti-
gen genes. Direct tumor cell death induction relies on
delivery of genes encoding cellular toxins or apoptosis-
inducing proteins. Antioncogene therapy specifically
inhibits or eliminates oncogene activity. Tumor sup-
pressor gene restoration therapy inhibits tumor growth
by restoring genes that prevent transformation of the
normal cell but have been functionally disabled during
carcinogenesis. The preclinical rationale for these
gene therapy strategies, and consequent gene therapy
clinical trials treating urologic cancers are discussed
(Table 2-3).
Immunogene Therapy Via Ex Vivo Gene Transfer
Gene therapy via transfer of immunostimulatory genes to
induce a tumor-specific immune response is perhaps the
most extensively evaluated strategy of gene therapy to
date. This is partly because early gene transfer systems
limited gene therapy to strategies using ex vivo (rather
than in vivo) gene transfer, and this approach is widely
applicable as immunogene therapy using, for example,
patient-derived cultured tumor cells for a gene-modified
tumor cell vaccine.15,36–43 Generally, clinical applications
of these studies used retroviral vectors as the vehicles for
gene transfer.15,44 Strategies of immunogene therapy
26 Part I Principles of Urologic Oncology

Table 2-2 Characteristics of Gene Therapy Strategies in Current Clinical Trials

Therapeutic Gene Extent of Potential Efficacy In Vivo* Relative Obstacles

Immunogene: ex vivo transfer Systemic Tissue procurement and cell culture

required

Immunogene: in vivo transfer Systemic Vector-specific immunity may

interfere with induction of
tumor-specific immunity

Cyto-toxicity/apoptosis Local-regional Requirement for highly efficient

gene delivery in vivo; possibility of
cytotoxic injury to normal cells

Antioncogene/antisense Local-regional Requirement for highly efficient

gene delivery in vivo and durable
expression of therapeutic gene

Tumor suppressor Local-regional Requirement for highly efficient gene

delivery in vivo and durable expression
of therapeutic gene
*Based on current vector limitations.

Table 2-3 NIH-Approved Clinical Trials of Gene Therapy for Urologic Cancer
Principal Vector: Therapeutic
Strategy Investigator Gene Cancer Histology Status

Immunotherapy: gene Gansbacher Retrovirus: IL-2 Renal cell Open

transfer ex vivo Simons Retrovirus: GM-CSF Renal cell Completed
Simons Retrovirus: GM-CSF Prostate Open
Paulson Liposome: IL-2 Prostate Pending

Immunotherapy: gene Vogelzang Liposome: class I Renal cell Completed

transfer in vivo MHC
Figlin Liposome: class I Renal cell Open
MHC
Lattime Poxvirus-vaccinia: Transitional cell Open
GM-CSF
Chen Poxvirus-vaccinia: Prostate Open
PSA

Cytotoxic Scardino Adenovirus: HSV-tk Prostate Open

Anti-oncogene Steiner Retrovirus: myc Prostate Pending

antisense

Tumor suppressor Small Adenovirus: Rb gene Transitional cell Pending

gene restoration

have also been formulated that rely on gene transfer in
vivo.45–49 It is therefore useful to evaluate immunogene
therapy strategies in the context of whether the particu-
lar strategy requires ex vivo gene transfer or in vivo gene
transfer (see Table 2-2).
Therapies using genetically modified, patient-derived
cells for a genetically engineered tumor vaccine have
comprised the principal use of ex vivo immunogene ther-
apy for urologic malignancies in preclinical studies and
clinical trials as well. For these therapies, tumor cells iso-
lated from fresh surgical specimens are genetically trans-
duced during tissue culture with an immunostimulatory
gene. The resected genitourinary cancer cells serve prin-
cipally as vehicles for autologous tumor antigens and are
transduced for immunostimulatory gene expression. The
gene-modified tumor vaccine is typically irradiated ex
 Chapter 2 Gene Therapy for Urologic Cancer: Basic Principles, Prospects, and Limitations 27

vivo prior to being reinjected into the patient as a genet-
ically engineered tumor cell vaccine (Figure 2-7).
Initial preclinical studies evaluating this strategy of
gene therapy showed that a tumor-specific, T-cell
mediated immune response could be augmented by vac-
cination using tumor cells derived from the same tumor
but transduced to secrete IL-2; such vaccination pro-
tected animals from subsequent tumor challenge.36,37
Gamma-interferon gene transfer was shown to promote
a similar protective effect.38 Subsequently, transfer of

100 Treatment
GROUP A Hanks BSS (control)
GROUP B XRT-MLL
80 GROUP C XRT-MLL + SOLUBLE huGM-CSF 8500 ng
Percentage cancer free

GROUP D XRT-MLL-MFG-huGM-CSF 140 ng/10/24

6
CELL DOSE 5 X 10
60

40
(Wilcoxon P=0.001)

20

0
0 15 30 45 60 75 90 105 120 135 150
Vaccine Rx
(Day 3,13,23)
Days after prostate cancer implantation
A
Primary
culture

Immunostimulatory gene
transfer

Irradiation of
human gene modified
Surgery
prostate cancer vaccine

Vaccination

B
Figure 2-7 Immunogene therapy via ex vivo gene transfer. A, Preclinical models have
shown that vaccination of tumor bearing animals with tumor cells that have been retrovirally
transfected ex vivo to produce immunogene products (in this case GM-CSF) can induce
complete or partial tumor regression at a distant metastatic site (as shown in the illustrated
experiment using hormone-refractory Dunning rat prostate cancer). (Reprinted from Sanda
MG, Ayyagari SR, Jaffee EM, et al: J Urol 1994; 151:622, with permission.) B, Schema of an
analogous human gene therapy protocol being evaluated in an ongoing clinical trial based
on experiments such as that in part-figure A. (Reprinted from Sanda MG, Simons JW:
Urology 1994; 44:617, with permission.)
28 Part I Principles of Urologic Oncology
granulocyte-macrophage colony-stimulating factor
(GM-CSF) and other immunostimulatory genes into
tumor cells used for vaccination led to elimination of
preestablished microscopic tumor cell deposits in animal
models. Antitumor immune mediators (such as helper T
cells, cytolytic T cells, NK cells, and dendritic cells) are
activated by the expression of therapeutic immunostimu-
latory genes in close proximity to tumor-specific antigens
present in the genetically engineered tumor vaccine cells.
The immune mediators then circulate and, ideally, erad-
icate distant micrometastases. Preclinical in vivo efficacy
of such gene-modified tumor cell vaccines has also been
shown in several models of urologic malignancy, includ-
ing renal cancer, bladder cancer, and prostate cancer (see
Figure 2-7).14,40–43
Several clinical trials using immunogene therapy with
ex vivo gene transfer specifically for urologic cancers are
underway or forthcoming (see Table 2-3).15,44,50,51
Therapeutic genes encoding IL-2 and GM-CSF targeted
prostate cancer or renal cell carcinoma in these studies.
In one completed study, no dose limiting toxicities were
encountered, and a dose-dependent lymphocyte infiltrate
was noted at the vaccine site.15 The single patient who
exhibited a partial response in this phase I study also
showed the greatest DTH response in the study group,
suggesting that GM-CSF secreting vaccine cells can
induce tumor-specific immune responses with minimal
toxicity. Evaluation of potential clinical efficacy with this
strategy awaits a larger phase II study.
A significant limitation of these ex vivo gene transfer
therapies, however, is the need for cell culture of cancer
cells that serve as targets for gene transfer (see Table 2-2).
Problems associated with the need for cell culture
include: requisite surgery to procure adequate tumor vol-
umes for vaccine cell production; unreliable tumor cell
yield with regard to both tumor cell number and tumori-
genic genotype; and a requirement for cumbersome,
expensive cell culture for each treated subject, limiting
the widespread applicability of this therapy.15,41,52 To cir-
cumvent these limitations of ex vivo tumor cell culture
for gene transfer, the development of nonretroviral gene
transfer vectors has led to alternative immunogene ther-
apies using in vivo gene transfer techniques.
Immunogene Therapy Via In Vivo Gene Transfer
The advent of vectors capable of efficient and safe direct
gene transfer in vivo, such as poxvirus, adenovirus, and
liposome vectors, has provided an avenue for overcoming
problems unique to ex vivo gene transfer therapies such
as the need for tumor cell procurement and culture (see
Tables 2-1 and 2-2). Two general approaches using in vivo
gene transfer for immunogene therapy have been devel-
oped through preclinical studies to the arena of clinical
trials; one entails in vivo transfer of immunostimulatory
genes, and the other entails in vivo delivery of tumor
antigen genes by recombinant viral vectors vaccines.
In vivo gene transfer of immunostimulatory genes has
been evaluated using poxvirus and liposomal vectors
encoding GM-CSF, IL-2, IL-12, and other genes for
therapy of renal, bladder, and prostate cancer.30,31,48,53
Rather than removing tumor cells to achieve genetic
modification in vitro and then using the gene-modified
cells as a vaccine, the gene transfer vector is administered
directly into tumor in vivo, such as by intravesical instil-
lation or intratumoral injection. The transfected tumor
cells essentially function as an in situ vaccine to induce
activity both against the transfected primary tumor site
and distant metastases, without having undergone ex vivo
processing and culture. A potential advantage of this
approach is that genuine tumor antigen expression by the
in vivo-transfected tumor cells is conserved, while inter-
ference by in vitro artifact antigens is avoided (see Table
2-2). This approach has also been extensively evaluated
with other vector systems in nonurologic tumor models,
and clinical trials in urologic and other tumors based on
these studies have been undertaken.54–58
Some distinct advantages of bladder cancer and
prostate cancer, specifically, support a focus on these
malignancies with in vivo immunostimulatory gene
transfer. First, regional targeting of localized bladder and
prostate cancer is potentially readily achieved in these
sites by either intravesical administration or transrectal
prostatic injection. Second, prostate cancer immunogene
therapy poses the possibility of using not only tumor
antigens, but also potentially of normal prostate antigens
(such as prostate-specific antigen [PSA], expressed in
normal and malignant prostate cells alike) as targets of
immune effector cells.
Use of recombinant vectors encoding specific tumor
antigens as agents for recombinant vaccination differs
from other immunogene therapy strategies in that the
viral vector itself provides the antigen to stimulate a
tumor-specific immune response. In this setting, the
patient’s tumor cells are not relied on as an effective anti-
gen-presenting cell nor are they a required target of
direct immunogene transfer. Instead of targeting tumor
cells as the recipients of the therapeutic gene (as shown
in Figure 2-4), systemically administered recombinant
vector vaccines target professional antigen-presenting
cells as recipients for the therapeutic gene (which in this
strategy encodes a tumor antigen). By using antigen-
presenting cells, such as dendritic cells, to induce immune
mediators that then recognize and eliminate tumor cells,
this strategy avoids potential tumor cell mechanisms for
actively suppressing immune induction, such as secretion
of TGF-β.59–61 Initial studies using recombinant vectors
as tumor-specific vaccines focused on relatively simple
vector constructs encoding a specific tumor antigen alone
as the basis for induction of immunity. Along these lines,
 Chapter 2 Gene Therapy for Urologic Cancer: Basic Principles, Prospects, and Limitations 29
clinical trials have been conducted using a vaccinia vac-
cine encoding PSA for prostate cancer therapy.49,62 The
goal of vaccinia-PSA immune gene therapy is to induce
an immune response against any cells expressing PSA
under the hypothesis that activated PSA-specific T cells
will kill cancer cells that express PSA (as in the setting of
recurrence after radical prostatectomy). Innate immune
tolerance to PSA as a normal self-antigen, however, will
need to be overcome to achieve the desired therapeutic
effect.
The efficacy of preclinical immunogene therapy stud-
ies should be viewed in context. When evaluated in
highly lethal, nonimmunogenic tumor models, which
most closely mimic human malignancy, the antitumor
effect has been modest—in the range of 4-log kill. This
would indicate that clinical efficacy of a gene-modified
tumor cell vaccine approach may potentially be limited to
an adjuvant setting. In addition, characteristics common
among urologic cancers, including deficient class I MHC
expression, overproduction of immunosuppressive TGF-β,
and heterogeneous target tumor antigen expression, all
represent potential immune evasion mechanisms that
may impede efficacy of immunogene therapies. The
immunogene therapy patient conversely may harbor
generalized limitations to potential immune stimula-
tion.63 In addition, immune responses against the vector
backbone may interfere with tumor-specific immune
effectors. A new generation of recombinant vector vac-
cines seek to address these and other obstacles by com-
bining the advantages of immunostimulatory gene
transfer and vector-encoded tumor antigen gene transfer
in vectors designed to deliver two therapeutic genes in
one vector: an immunostimulatory gene in tandem with
a tumor antigen gene.46 Despite potential obstacles, ther-
apeutic efficacy in the setting of transient gene transfer
and durability of tumor-specific immunity comprise
advantages of immunogene therapy that fuel continued
clinical development.
Gene Transfer for Direct Induction of Target
Cell Death
Hypothetical barriers to tumor therapy by transfer of cell
death genes traditionally included the potential need for
nearly 100% efficient gene transfer in vivo to achieve
remission and lack of effective strategies for targeting
tumor cells specifically without concurrent death induc-
tion in normal tissues. The availability of vectors that
transfer genes efficiently in vivo, the discovery of
bystander effects which allow transmission of cell death
signals to nontransduced cells, the characterization of
organized cell death (apoptosis) pathway abnormalities in
cancer cells, and the development of dominant cell death-
inducing genes, however, have all prompted a reevalua-
tion of these hypothetical barriers (see Table 2-2).64–69
Three general approaches to targeting cell death (inde-
pendent of tumor-specific immunity) are in development.
First, gene transfer of a drug susceptibility gene (such as
herpesvirus thymidine kinase, HSV-tk) renders target
cells sensitive to subsequent gancyclovir-mediated cyto-
toxicity.70 Second, transfection of cellular toxin genes can
induce cell injury, disruption, and necrosis. Third, gene
transfer of dominant apoptosis-inducing genes can trigger
organized cellular death, or apoptosis.71,72
Gene transfer of HSV-tk, as a means of rendering
tumor cells susceptible to subsequent gancyclovir-
mediated cytotoxicity, was among the first approaches in
efforts to induce tumor cell death via gene transfer.70,73,74
In this system, gancyclovir acts as a prodrug that becomes
cytotoxic only after it is phosphorylated by HSV-tk.
Mammalian cells normally lack HSV-tk; hence the
requirement for gene transfer. Phosphorylation of gancy-
clovir by HSV-tk leads to the formation of gancyclovir
triphosphate, a potent nucleotide competitor that inter-
feres with DNA synthesis. A bystander effect, whereby
nontransduced adjacent malignant cells are killed in part
to the transfer of the toxic analog via gap junctions or
apoptotic vesicles, was initially described in HSV-tk gene
transfer studies.64 HSV-tk gene transfer can be accom-
plished by retroviral or adenoviral vectors in vivo. Due to
ease and efficiency of use, adenoviral vectors have been
used for HSV-tk gene transfer in animal models of
prostate cancer in which in vivo delivery was accom-
plished by intratumoral injection.75 Subsequent systemic
administration of gancyclovir led to significant reduction
of tumor growth. This effect was synergistic with andro-
gen withdrawal in a mouse model of androgen responsive
prostate cancer.68 Clinical trials based on these findings
and using intratumoral injection for delivery have been
completed with modest PSA responses.24,76
A limitation of HSV-tk gene transfer is the need to
coordinate and optimize administration of two agents:
the sensitizing gene transfer vector and the prodrug gan-
cyclovir. An alternative strategy for direct cytotoxicity is
gene transfer of cellular toxin genes, such as ricin and
diphtheria toxin, which disrupt protein synthesis result-
ing in lethal cellular injury.72 Although ricin gene trans-
fer itself has not been applied to urologic tumors, direct
administration of ricin gene products is cytotoxic to
human prostate cancer cells, providing rationale for fur-
ther development of this strategy.77 Adenoviruses encod-
ing diphtheria toxin have demonstrated remarkable
potency at eliminating established tumors;71,78 however,
the extreme potency of the toxin makes it capable of
killing nontarget cells, even when used with a tissue-
specific promoter. Hence, unless better transcriptional
control can be achieved, this approach will probably not
be readily translated into clinical utility.
Third and perhaps most promising of the gene ther-
apy strategies, which aim to directly induce cell death, is
30 Part I Principles of Urologic Oncology
gene transfer of apoptosis-inducing genes. Organized
cell death in the form of apoptosis differs from toxic or
necrotic cellular disruption (such as ricin-mediated toxi-
city) in that apoptosis occurs as a normal entity of the
eukaryotic life cycle in vivo, without concomitant inflam-
mation or other local toxicity. Prostate biology revealed
some of the earliest evidence for apoptosis as a normal
component of cellular homeostasis, and prostate cancer
was the first among several solid tumors whose growth
and progression has been shown to result from defective
apoptosis rather than augmented proliferation.79 Gene
products involved in a cascade of intracellular events
mediating apoptosis have been successfully targeted for
induction of apoptosis in tumor cells. An ideal apoptosis-
inducing gene would induce apoptosis in tumor cells
without altering homeostasis in normal cells. Candidate
genes that may exhibit such selective effects to some
degree include caspases and p53; the ability of adenoviral
vectors encoding these genes to induce apoptosis in
tumor cells in vitro and in vivo has been shown, and
effects on normal cells and stem cells are under intensive
study.20,22 Early findings indicate that gene transfer of
Bclx-s with adenovirus vectors, for example, has little
effect on normal cells while tumor growth was pro-
foundly affected in vivo.20
Oncolytic Virotherapy
During the late 1950s, a variety of viruses were evaluated
as cancer therapeutics; however, with the advent of
chemotherapy, improved radiotherapy, and the lack of
specificity of virotherapy, these strategies were largely
abandoned.80 In the early 1990s, however, a resurgence
in this concept occurred, when a herpesvirus was specifi-
cally engineered to replicate selectively in central nerv-
ous system tumors.81 Subsequently, it was found that
naturally occurring mutants of certain viruses were capa-
ble of selective replication in cancer cells defective in cer-
tain pathways. In the case of the E1B deleted Onyx-015
virus, replication occurred selectively in those cells that
were defective in some way in the p53 axis of apoptosis
regulation.82 Similarly, others discovered that the
reovirus was capable of enhanced replication in those
cells with activated ras.83 However, not all malignancies
share the same path to oncogenesis. Hence, efforts were
made to develop a conditionally replication-competent
oncolytic adenovirus (CRAd), which would only replicate
and passively lyse cells when it was in a particular cell
type. The first of these CRAds was CV706, which pref-
erentially replicated and lysed prostatic epithelial cells by
virtue of the PSA promoter and enhancer that were used
to activate the replicative genes, E1A and E1B.84 These
CRAds demonstrated excellent activity and specificity in
vitro and in vivo and hence were rapidly translated into
clinical trials.23–25 The results of these initial trials have
also been encouraging in that they have demonstrated a
clear dose response, with marked reductions of PSA
occurring in most of the men treated at the higher dose
levels. However, the response is limited, because the viral
infection lasts less than 2 weeks and not all of the cancer
cells are transduced by the replicating virus. Given
enough time, all the patients with clinical response
relapsed with a PSA progression. Of note, however, is the
fact that when these viruses are given directly into the
prostate, the presence of neutralizing antibodies had no
significant clinical impact on the efficacy of the vector.
Hence it appears that while such neutralizing antibodies
may present a serious obstacle to systemic oncolytic viral
therapy, it is of a lesser concern with local therapy.
Recent advances in the understanding of adenoviral
replication have discovered that the molecular pathways
necessary for promoting viral replication are also pivotal
in terms of sensitizing the cells to chemotherapy and
radiation therapy. The combination of radiation therapy
and CV706 results in a 6.7-fold enhancement of tumor
reduction over the predicted response from the addition
of the two treatments alone.85 This synergy of effect has
led to a robust enthusiasm for further clinical translation.
If oncolytic virotherapy can potentiate radiation therapy
significantly, then the acceptance of this combination is
likely to meet with less resistance. As urologists, this
combination would be particularly attractive if the com-
bined therapy could be administered contemporaneously
through a brachytherapy platform. Like other molecular
therapies, oncolytic adenoviral gene therapy is still highly
experimental and in its early developmental stages.
However, it is becoming increasingly clear that the earli-
est clinical utility of these methods will be in combina-
tion with conventional therapy and at least initially will
be limited to local-regional delivery.
Antioncogene Therapy: Approaches Using
Antisense and Ribozyme Constructs
Targeting oncogenes with gene transfer is theoretically
advantageous because this strategy can potentially selec-
tively affect tumor cell growth without affecting normal
cells, which may lack functionally expression of the target
oncogene. By exploiting the ability of complementary
RNA strands to bind to each other, delivery of genes con-
taining such complementary or “antisense” sequences to
specific oncogenes can revert the tumorigenic phenotype
by inhibiting expression of specific oncogenes in target
tumor cells. Interference with translational machinery due
to pairing of antisense RNA constructs with their oncogene-
encoding RNA targets is one mechanism of antioncogene
activity postulated as active in this strategy. By interfering
with translation of oncogene RNA, oncogenic proteins
are produced at much lower levels, if at all. In addition to
interfering with translation, moreover, antisense constructs
 Chapter 2 Gene Therapy for Urologic Cancer: Basic Principles, Prospects, and Limitations 31

may activate endogenous ribonucleases, which in turn
degrade the bound RNA. Regardless of the mechanism,
the net effect of antisense therapy is the reduction of
oncogenic protein expression due to binding of oncogene
RNA by the antisense gene product (see Table 2-2).
Although early antisense strategies focused on direct
administration of short antisense oligonucleotides (some-
times modified for improved solubility), more recently
the delivery of longer antisense constructs, as well as
dominant negative mutation constructs, via recombinant
vector systems has emerged.86–88 Retroviral transfer of a
myc antisense gene (delivered by direct injection of retro-
viral vector into small prostate cancer nodules in
rodents), for example, was found to impede in vivo
prostate cancer growth in a rodent model.89 Based on
these findings, a clinical trial of antioncogene therapy
using intraprostatic injection of retroviral vector encod-
ing antisense myc has been proposed.89
The discovery of ribozymes, or RNA sequences, that
catalyze RNA cleavage and splicing, opened a promising
extension of gene therapy strategies based on oncogene
targeting via antisense recognition of oncogene RNA
(Figure 2-8).90 Ribozymes can be designed to degrade
RNA containing a short segment of complementary
nucleotides. In theory, almost any RNA containing a
unique 15-base pair or longer sequence can be specifi-
cally degraded by designing a ribozyme containing a
complementary binding motif. Adenoviral vectors have
been used to deliver oncogene specific ribozymes (for
example, targeting H-ras in a bladder cancer cell line)
with consequent repression of in vivo tumorigenesis.91,92
The efficacy of this strategy in the setting of in vivo gene
delivery remains as yet untested. However, the direct tar-
get specificity of ribozyme-targeted antioncogene ther-
apy, in the setting of a well-characterized effector
mechanism, suggests that ribozyme-based strategies may
be the most promising antisense-based therapeutic strat-
egy under current development.
Tumor Suppressor Gene Restoration
The observation that renal cell cancer tumorigenicity can
be reversed by in vitro transfer of the von Hippel-Lindau
(VHL) gene prior to full biochemical and functional
characterization of the VHL gene product attests to the
potential utility of gene therapy targeting tumor suppres-
sor gene restoration.93,94 This observation indicates that
restoring tumor suppressor genes may reverse tumori-
genic potential of individual, in vitro transduced cells.
Tumor suppressor gene transfer in vivo, however, has had
less impressive effects than in vitro transfection.95 At least
two factors may contribute to the discrepancy between in
vitro and in vivo effects of tumor suppressor gene
restoration: first, intratumoral injection of vectors into
solid tumors is not a highly efficient approach for gene
delivery—most of the vector is likely cleared before it
accesses tumor cells, and the initial vector distribution in
injected tissue is unlikely to be uniform. Second, stable

Figure 2-8 Antioncogene ribozyme consensus sequence. The hammerhead ribozyme

contains three nonconserved helical regions (stems I, II, and III) along with the conserved
sequence of the central core. Stems I and III, which determine the specificity of the ribozyme
for its target, hybridize to target oncogene RNA. The target RNA is then cleaved at the site
indicated by the arrow, disabling oncogene expression. Nucleotides designated as N can be
any nucleotide. (Reprinted from Thompson JD, Macejak D, Couture L, Stinchcomb DT: Nat
Med 1995; 1:277, with permission.)
32 Part I Principles of Urologic Oncology

long-term integration (as with a retrovirus vector) of the
therapeutic suppressor gene, in the setting of 100% effi-
cient in vivo transduction, would be required to arrest
tumor growth (see Table 2-2).
This strategy could be optimized by using vectors
capable of stably integrating the transgene into the target
cell genome, such as retroviral vectors, and also capable
of highly efficient in vivo transduction, such as adenovi-
ral vectors. In that no vector currently has both of these
characteristics (see Table 2-1), using any vector system
will have limited efficacy at present. For example, one
potential tumor suppressor target, c-cam, is a cellular
attachment molecule, which is absent in some prostate
cancers, and thereby potentially contributes to the unin-
hibited and metastatic growth potential of these cells.
Intratumoral injection of an adenoviral vector encoding
c-cam, used to restore expression of this molecule in
preestablished prostate cancer xenografts, slowed but did
not reverse tumor progression (Figure 2-9).95 Similar
effects have been seen with adenovirus vector-based ther-
apy targeting restoration of other tumor suppressor genes.
Despite these limitations, survival of tumor-bearing ani-
mals can be extended with in vivo suppressor gene
restoration therapy, and a clinical trial that evaluates the
efficacy of Rb gene delivery via intravesical instillation of
adenovirus vector has been proposed (see Table 2-3).
The association of Rb gene abnormalities in bladder can-
cer and poor prognosis supports the rationale for intrav-
esical adenovirus-Rb gene therapy.96
For many tumor suppressor genes, restoration of sup-
pressor gene function alone may not suffice for cytore-
duction of established tumors even in the theoretical
setting of totally effective and durable in vivo tumor sup-
pressor gene transfer. Most tumor suppressor genes do
not encode signals for direct induction of cell death but
rather affect tumor growth more indirectly, such as by
regulating DNA repair, cellular attachment, or cell cycle
control.97 In this setting, restoration of normal suppres-
sor gene via gene transfer may require accompanying
cytoreductive systemic or regional therapies (chemotherapy,
radiation) to treat established tumors. The need for
accompanying cytoreductive therapy is further evidenced
by the transient expression associated with the most effi-
cient vector systems—once transgene expression fades,
the tumorigenic phenotype associated with absence of
the suppressor gene will reappear (efficient in vivo vec-
tors are required for this strategy as most, if not all, tar-
get cells must directly express, or confer expression via
bystander effect, of the transferred gene for effective
tumor reduction)

Figure 2-9 Tumor suppressor gene therapy inhibits tumor growth in animal models.
Injection of adenovirus encoding c-cam1 (filled circles) into human prostate cancer nodules
grown in nude mice reduced tumor growth compared to saline (filled triangle) and vector
(open circle) controls. Delay of tumor growth without complete tumor remission is typical of
strategies relying on local-regional injection of recombinant vectors encoding therapeutic
tumor suppressor, antioncogene, or cytotoxicity genes. (Reprinted from Kleinerman DI,
Zhang WW, Lin SH, et al: Cancer Res 1995; 55:2831, with permission.)
 Chapter 2 Gene Therapy for Urologic Cancer: Basic Principles, Prospects, and Limitations 33

Some tumor suppressor genes may also serve as gate-
keepers for intracellular apoptosis-inducing signals. In
addition to suppressing the tumorigenic growth potential
of individual cells, restoration of these tumor suppressor
genes should also be able to reduce established tumors
via apoptosis induction. The inability of an adenoviral
vector encoding p53 to eliminate preestablished malig-
nancy, however, indicates that near-complete transduc-
tion of all tumor cells may be required for optimal
therapeutic effect. This level of efficiency is clearly not
achieved by direct solid tumor injection with currently
available vectors. Improvements in vector and delivery
systems will be needed to optimize this, and other, gene
therapy strategies that rely on direct effects of gene trans-
fer in the tumor cell target.
FUTURE DIRECTIONS: TARGETING VECTOR
SPECIFICITY
Most vectors, which, at present, have shown functional
efficacy in vivo, lack significant specificity in target cell
attachment or restriction in transgene expression. The
vector envelopes or coats of retroviruses, adenoviruses,
and liposomal vectors enter cells via families of receptors
that, as a group, are virtually ubiquitous. The promoters
controlling transgene expression in these vectors are typ-
ically potent promoters susceptible to little or no regula-
tion by the host cell. Targeting of gene therapy to specific
cells or tissues has therefore been achieved principally via
the route of vector administration. The feasibility of con-
ferring specificity via the administration route, in the case
of urologic targets, has been demonstrated for renal cancer
after renal tubule vector infusion and for bladder epithe-
lium after intravesical instillation of viral vectors.98,99 This
approach may be applicable to local-regional therapy of
early stage, organ-confined malignancy (see Table 2-2).
Systemic applications of cytotoxic, antioncogene, or
tumor suppressor therapeutic gene transfer, however, will
require specific targeting based not only on vector
administration route but also on molecular rather than
mechanical targeting. Molecular vector targeting can be
achieved either by modifying tropism (altering the affin-
ity of the vector coat for attachment and entry to a lim-
ited range of human target cells) or by restricting
transcription (constructing expression cassettes contain-
ing promoters with selective activity in different tissues)
(Figure 2-10).
Modified Vector Tropism
Two approaches have been used for modifying vector
tropism. First, vectors can be derived from viruses with
inherent tropism for a specific tissue target. Due to the
relative paucity of molecular characterization of viruses
with natural and specific tropism for the genitourinary
tract, this approach has limited utility. Nevertheless, at

Figure 2-10 Restricting target cell specificity of recombinant viral vectors. The ability
to specifically target gene delivery can facilitate systemic gene therapy with cytotoxic
vectors. Approaches to confer specificity include: (A) engineering vector coat specificity;
(B) restricting promoter-regulated transcription; (C) chemically modifying vector-target affinity.
(Based on Miller N, Vile R: FASEB J 1995; 9:190.)
34 Part I Principles of Urologic Oncology
least one virus (BK virus, which has specific tropism for
transitional epithelium) has shown potentially useful
tropism specificity for transitional epithelium.100
Recombinant BK episomal vectors were constructed that
led to reporter gene expression specifically in human
transitional cell (TCC) lines that are relative to absent
expression in other tumor cells. Limited characterization
of the elements regulating BK specificity and lack of repli-
cation defective BK vectors, however, has limited further
development of this vector system thus far.
Second, molecular engineering and conjugate forma-
tion to alter the native vector coats has been used to con-
fer specific tropism. In regards to retroviral vectors,
engineering of envelope or vector coat sequences
(pseudotyping) has been limited, principally due to the
potential of functionally disrupting the ability of engi-
neered envelopes to mediate target cell attachment and
entry. Pseudotyping has thus succeeded in producing
vectors with extended or altered target cell tropism,
without more restricted target specificity per se.11 In
contrast, a detailed analysis of the fiber gene has allowed
the alteration of adenoviral tropism by either changing
the knob domains for different adenoviral serotypes, or
by specifically introducing targeting ligands into portions
of the knob that are unimportant for fiber folding and
viral assembly.101,102 Molecular conjugate formation has
successfully conferred altered and refined specificity to
adenoviral, liposomal, and retroviral vectors, alike. This
has been achieved via covalent linkage of vectors with lig-
ands such as growth factor receptors or antibody haptens,
which confer the desired tropism for cells expressing the
specific receptor and via noncovalent association of
hybrid vector components.103–106
Restricted Transgene Expression:
Transcriptional Targeting
An alternative to vector targeting at the target cell bind-
ing level is to limit expression of therapeutic genes by
regulating transcription with a promoter region having
either tissue restricted activity, or preferential activity in
malignant cells. Such promoter-regulated specificity has
been used to target retroviral and adenoviral vectors
alike.11,107 Tissue-specific promoters are potentially
useful for regulating expression of cytotoxic genes in
vectors targeting nonvital tissues, such as prostate, to
widen potential therapeutic windows.108 To this end,
vectors have been constructed with the promoter region
that normally regulates PSA expression used to control
expression of a reporter gene.109,110 Cloning of thera-
peutic cytotoxic genes, such as HSV-tk, into analogous
vectors using tyrosinase promoter has been shown to
inhibit tumor growth in melanoma animal models111;
analogous vectors to target prostate cancer are under
development.
In contrast to tissue-specific transcriptional targeting,
oncogene-associated regulatory sequences may promote
selective expression of therapeutic genes in tumor cells
that harbor transcriptional overexpression of the onco-
gene. This has been demonstrated with a vector using
ERBB2 promoter sequences to the cytotoxic gene cyto-
sine deaminase; this vector conferred selective sensitivity
on ERBB2-overproducing cells.112
SUMMARY
Based on a growing volume of preclinical data, clinical
trials of gene therapy for urologic cancer are underway.
Therapeutic genes that are under current or forthcoming
clinical study include immunogenes, cell death-inducing
genes, antioncogenes, and tumor suppressor genes.
Although systemic therapy with immunogenes is feasible,
other gene therapy strategies, which do not rely on an
intervening antitumor immune response, are at present
limited to local-regional targeting. This constraint is
largely due to limitations of gene transfer vectors, as well
as in vivo gene delivery systems. Refinement of gene
transfer vectors, such as hybrid vectors construction, is
actively being pursued to broaden the utility and applica-
bility of direct gene therapy strategies.
The early phase of cancer gene therapy clinical trials
should be viewed in context. Preclinical models predict
modest, if any, therapeutic effects with current forms of
human cancer gene therapy. Equally as important as clin-
ical outcome in gene therapy clinical trials, however, are
biologic surrogate endpoints to guide continued
improvement of gene therapy strategies. The earliest
clinical trials have indeed shown the ability of clinical
gene therapy to alter biology of human urologic can-
cer.15,23–25 However, groundbreaking clinical trials of
gene therapy have also been associated with significant
toxicity, including a fatality and induction of vector-
induced leukemia.2,3 To attain its full potential, gene
therapy must be approached with realistic expectations,
respect for its potential toxicity, and a recognition of the
need for its continued refinement.
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38 Part I Principles of Urologic Oncology
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C H A P T E R
3 Principles and Applications
of Radiation Oncology
Steven J. Chmura, MD, PhD, Wendla Silverberg, MD,
and Ralph R. Weichselbaum, MD
The treatment of both benign and malignant diseases
with ionizing radiation (IR) began shortly after the dis-
covery of x-rays by Wilhelm Roentgen in 1895.1 The
therapeutic applications of IR were quickly realized when
the first patient was treated by Emil Grubbe in 1896.2
Despite the initial enthusiasm in the clinical applications
of IR, subsequent experimental and clinical experience
demonstrated the adverse effects on normal tissues when
attempting to treat tumors located deep below the skin.
The development of implantable radioactive sources
(brachytherapy) permitted high doses of radiation to be
delivered directly to the tumor tissue while decreasing
the normal tissue toxicity with the first prostate patient
treated in 1909. The introduction of high-energy (mega-
voltage) external beam radiation therapy (EBRT) in the
1950s allowed treatment to a higher dose of tumors deep
within the body, while decreasing the surface dose to the
skin. Despite the advances in both the imaging of tumors
and the hardware and software employed to deliver radi-
ation therapy, normal tissue toxicity remains the limiting
factor in most human malignancies. The following sec-
tion reviews both the physical and biologic bases of radi-
ation therapy. Advances in both biologic modifiers and
new technologies to deliver radiation therapy that may
increase tumor cell killing while limiting normal tissue
complications are also discussed. Specific examples of
particular interest for urologic oncology are highlighted.
THE PHYSICS OF RADIATION THERAPY
AND DELIVERY
External Beam Radiation Therapy
EBRT is used to treat many tumor types, including head
and neck, gynecologic, thoracic, and genitourinary
malignancies. While earlier technologies utilized gamma
rays from radioactive sources, such as cobalt (Co60) to
deliver photon therapy, modern linear accelerators
(Figure 3-1) generate and deliver either high-energy
photons (x-rays) or charged particles (electrons). The
x-rays are produced through the deceleration of high-
kinetic energy electrons (bremsstrahlung) within the
head of the linear accelerator as they strike a tungsten
target.3 After striking the target, the electrons emit x-rays
with a spectrum ranging from zero energy to their maxi-
mum kinetic energy. The photons are emitted from a
point source, much like a flashlight, that diverges in a
cone shape. The energy of the photons decreases as the
inverse square of the distance (1/d2) from the source (the
inverse square law).3 Through advancements in technol-
ogy, the energy of radiation therapy has been greatly
increased since its clinical introduction, thus permitting
treatment of tumors deep within the body.
The beam quality or energy employed in a particular
patient refers to the highest energy photons generated.
Modern linear accelerator energies span from the kilo-
volt (kVp) to megavolt (MV) range. Outside of superfi-
cial treatment of such lesions, EBRT is almost exclusively
delivered in the 4 to 18 MV range. For example, most
prostate cancer patients are treated with energies ranging
from 6 to 18 MV in order to spare superficial tissues and
maximize the dose to the prostate.
The photons decelerate exponentially as they interact
with matter. The distance they travel through tissue is
proportional to their initial energy (see above). Thus,
higher energy beams are able to penetrate tissues deeper
and result in fewer interactions at the skin surface. As the
photons interact with matter, either superficially or deep
within tissues, charged particles, such as electrons, are
39
40 Part I Principles of Urologic Oncology
Figure 3-1 Example of a modern linear accelerator used to
deliver photons or electrons in the clinical setting.
set in motion that results in ionization and excitation of
other atoms. The energy absorbed in tissue by the sec-
ondary charged particles represents the dose delivered.
The accepted unit of dose is the gray (Gy), which is
defined as the absorption of 1 J/kg. In radiation therapy
clinical outcome papers, the terms centigray (cGy) or
radians (rad) are commonly used with 1 cGy (or rad)
representing 0.01 Gy. Prior to 3D treatment planning
techniques, dose was prescribed to a point, for example,
in the middle of a patient or in the middle of a tumor.
With modern 3D treatment planning techniques, dose
can also be prescribed to a volume of interest, for exam-
ple, the tumor and areas of tumor spread. Current 3D
planning terminology of dose refers to the minimum
dose absorbed by the volume of the target. The interac-
tion of the charged particles with tissue results in pro-
duction of free radicals along with direct damage to
DNA. The biologic effects of absorbed dose are dis-
cussed in detail later.
Linear accelerators can also be configured to produce
electrons by removing the tungsten target and guiding
them through the accelerator toward the patient. Unlike
the photons that comprise x-rays, an electron is a charged
particle that travels a known range in tissue. By selecting
the initial energy of the electrons, one can calculate the
depth of tissue that will be irradiated. Tissues beyond
that range receive little irradiation. Since electrons are
charged particles, they interact directly with matter in
tissue by depositing dose and causing damage to the
tumor cell.
Other types of particles have been employed as thera-
peutic modalities, including neutrons4 and protons.5
Neutron beams are similar to photon beams in that their
energy decreases exponentially in tissue. While neutron
beams have been employed to treat a variety of tumor
sites, including prostate and brain, they are seldom used
clinically, as multiple randomized studies have failed to
demonstrate a clear benefit when compared to photon
therapy in terms of tumor control and normal tissue tox-
icity. Proton beams are generated by a cyclotron. These
heavy charged particles are unique; they deposit their
dose near the end of their range. This phenomenon,
known as a Bragg peak, can be manipulated to deliver a
high dose to a small tumor deep within the body while
minimizing high doses to more superficial tissues.5
While there has been significant interest in expanding
the therapeutic applications of proton therapy, the sub-
stantial cost of a cyclotron (proton production machine)
along with limited clinical outcome data has resulted
in very few of them being constructed around the
world. As the technology to build cyclotrons becomes
cheaper to implement, more are expected to be con-
structed. Theoretic and preliminary data suggest that
proton therapy may be appropriate for prostate cancer
treatment.
Brachytherapy
In contrast to EBRT, brachytherapy delivers dose
through the placement of radioactive sources that remain
in place either temporarily (minutes to days) or perma-
nently. Initially, naturally occurring isotopes, such as
radium, were used in brachytherapy. Newer artificially
produced isotopes have replaced radium due to their
wider availability and improved safety profiles. The pre-
scribed dose in brachytherapy is normally defined based
on a limited number of 2D tissue points. Increasingly, 3D
dose prescriptions are becoming more common for
brachytherapy.
Intracavitary brachytherapy involves placement of the
sources within a body cavity. For example, most interme-
diate- to advanced-stage cervical cancers are treated, in
part, with a Fletcher-Suit applicator. A hollow tube (tan-
dem) is inserted into the uterus, and two other hollow
tubes (colpostats) are placed within the vagina against the
lateral fornices. Dose is delivered through insertion of
radioactive sources into the hollow tubes that are secured
in place. The sources (cesium 137) remain in place for 3
to 4 days (low-dose rate [LDR] brachytherapy) depend-
ing on the clinical scenario and choice of the physician.
Intracavitary brachytherapy has also been used to treat
tumors of the head and neck, biliary tree, and bronchi. By
placing the hollow cylinders or catheters before loading
the radioactive sources (after loading), radiation exposure
to the staff is minimized.
 Chapter 3 Principles and Applications of Radiation Oncology 41
Figure 3-2 Initial pelvic film immediately following
implantation of permanent iodine125 prostate brachytherapy
seeds. Due to subsequent swelling of the prostate, the seeds
will move and rotate during the next 60 days when they are
most radioactive.
Interstitial brachytherapy delivers dose directly
within a tumor or surgical bed. Hollow flexible
catheters are initially surgically inserted into the tumor
or site of tumor resection. After 5 to 7 days of healing,
radioactive needles are inserted into the catheters to
deliver dose. Prostate brachytherapy involves the
placement of permanent radioactive seeds (iodine 125)
within the prostate (Figure 3-2). These seeds deliver a
dose over the course of many months to the prostate
and surrounding tissue.
As discussed above, traditional LDR intracavitary
brachytherapy is delivered over 3 to 4 days as an inpatient
procedure or sources with a short half-life left in perma-
nently as is the case with prostate brachytherapy.
Recently, high-dose rate (HDR) techniques are increas-
ing in popularity. High-activity iridium sources deliver
dose rapidly, permitting patients to be treated as an out-
patient requiring only minimal anesthesia. Clinical stud-
ies employing HDR have demonstrated efficacy in head
and neck, cervix, and prostate.6–8
TREATMENT PLANNING AND DELIVERY
As previously described, the dose to be delivered during
EBRT is prescribed to a volume in 3D conformal radia-
tion therapy (3D-CRT). The aim of the prescription is to
uniformly irradiate the volume (target) while minimizing
the dose to surrounding normal tissues.9 The ability to
conform the dose to the target depends on many factors,
including target location, external contour of the patient,
tissue density, beam energies availability, and the EBRT
hardware availability.10–12 Current 3D treatment plan-
ning and 3D treatment (3D-CRT) rely almost exclusively
on computed tomography (CT)-based imaging to gener-
ate a customized plan for each patient. The following
sections outline treatment planning and plan generation
using a prostate patient as a model assuming that 3D
treatment planning is available.
Simulation and Patient Immobilization
Most prostate cancer patients are treated with fractionated
(administered in multiple daily treatments) EBRT for 6 to
8 weeks. Patients normally lie supine on the treatment
table as shown in Figure 3-1. In order to deliver dose to
the prostate each day and minimize dose to the surround-
ing normal tissue (such as the rectum), the patient’s posi-
tion on the table must be reproduced during each
treatment. In addition, patient motion must be minimized
during the treatment that normally lasts 5 to 15 minutes.
Prior to initial treatment, a simulation of the actual
treatment technique is performed to determine the ideal
patient positioning. In order to ensure the reproducibil-
ity of the patient’s position, immobilization devices are
constructed out of foam cradles that will be used on all
subsequent patient treatment days. Through the use of
these immobilization devices and newer imagining tech-
niques, such as video-assisted setup, radiation therapists
are able to reproduce patients’ positions to within mil-
limeters daily.
A CT simulator is a specialized scanner used to
directly acquire CT data while the patient is immobi-
lized in the desired treatment position. The CT data
acquired from imaging guides radiation therapy plan-
ning by providing geometric information on external
patient contour and tumor size, shape, and location rel-
ative to adjacent critical structures.13 Following the
acquisition of the CT data, the physician defines three
volumes to be used in the treatment planning process.
The gross tumor volume (GTV) represents the tumor
visible on the CT simulation data. The clinical target
volume (CTV) is defined as the GTV and the draining
lymphatic and other tissues that may contain micro-
scopic disease. The planning target volume (PTV) is
created based on expansion of the GTV and CTV in
order to compensate for patient setup uncertainty, such
as patient and organ motion. For a typical prostate
patient plan, the PTV expansion typically ranges from
0.6 to 1 cm.14 Normal tissues are also defined in order to
design a plan that will minimize the dose to those
organs, such as the rectum. The treatment planning is
based on the volumes entered by the physician following
the simulation.
42 Part I Principles of Urologic Oncology
Treatment Planning
Treatment planning software permits physicists and
physicians to generate a dose distribution superimposed
on the CT images and volumes that have been designed.
Although the specifics of the treatment planning software
may vary widely based on the technology available at
institutions, certain variables are universally required for
treatment planning. These variables include beam
energy, type of beam (photon or electron), number beam
angles, relative beam weights, and beam-modifying
devices. Superficial tumors can be treated with either
low-energy photon beams (100 to 250 kVp) or electron
beams. Tumors deep within the body, such as the
prostate, are treated with energies ranging from 6 to 18
MV and from 4 to 9 beam angles. For example, most
prostate plans employ 4 to 5 beam angles with 6 MV
photons. The beam modifying devices include cus-
tomized shielding blocks that alter the quality, intensity,
and shape of the beam. These are further discussed in the
section on intensity modulated radiation therapy
(IMRT).
Dose volume histograms (DVH) provide a quantita-
tive evaluation of treatment plans. The DVH represents
the volume of a particular organ irradiated as a function
of dose (Figure 3-3). These data coupled with known tox-
icity research aid the physician in selecting the proper
treatment plan. For example, based on both retrospective
and randomized data, most physicians planning a
prostate treatment attempt to limit the volume of rectum
receiving >70 Gy to <25% of the volume.
Figure 3-3 DVH from a head and neck cancer case planned
with IMRT. The PTV contains the primary tumor and draining
lymphatics plus a margin for microscopic disease and setup
uncertainty. The IMRT permits the brain stem and spinal cord
to receive a very low dose of RT compared to the PTV.
Treatment Delivery and Verification
Linear accelerators deliver the beam of photons or elec-
trons through a gantry that rotates 360 degrees around
the patient (Figure 3-1). The rotation of the gantry
around the table permits the beam to enter the patient’s
body from any angle. The beam is shaped at each gantry
angle by either a Cerrobend block cut by hand or a multi-
leaf collimator (MLC). Cerrobend attenuates (blocks)
nearly all of the beam energy.3 These custom blocks are
designed for each field during the treatment planning
stage, cut to the proper shape by a technician, and placed
manually in the head (Figure 3-1) of the gantry each day
of treatment. More recently, the MLC was developed to
permit dynamic block shaping under computer control.
A typical MLC consists of 80 to 120 leaves that are fixed
to the gantry head and powered by small electric motors.
The leaves are computer controlled and can be moved
either before (static) or during treatment (IMRT, dis-
cussed later). The leaves attenuate the beam similar to
the solid Cerrobend block permitting one to shape the
beam to virtually any shape.15
Quality assurance is usually performed at least on a
weekly basis through the use of verification (x-ray) films.
These films are checked by the physician to ensure that
the patient is positioned properly on the table and the
field shape (either through a Cerrobend block or MLC)
is correct. The treatment verification films are compared
against those taken during the initial simulation process
and the patients (or blocks) are moved to approximate the
original planning position.
Intensity Modulated Radiation Therapy
Recent advances in computer hardware and software
have dramatically changed the way in which 3D treat-
ment plans are constructed and EBRT is delivered to the
patient. With traditional 3D treatment planning, EBRT
is delivered with beams of uniform intensity and with a
static beam shape (though the use of a block or MLC).
(IMRT, as the name implies, permits nonuniform inten-
sity beams to be delivered to the patient. By allowing the
MLC to move during treatment, the shape of the beam
at each gantry angle can be altered. By modulating the
intensity and shape of the beam during treatment, high
doses of radiation can be delivered to the PTV while
minimizing dose to normal tissues.16 After the physician
defines the GTV, CTV, and PTV and determines the
normal tissue structures to avoid, the computer software
employs sophisticated algorithms to compute the inten-
sity and shape of the beam for each gantry angle. This
process is known as inverse planning.63,64 While no ran-
domized studies yet exist demonstrating the superiority
of this approach in terms of tumor control or normal tis-
sue complications compared to conventional treatment
 Chapter 3 Principles and Applications of Radiation Oncology 43
Figure 3-4 Comparison of a conventional plan (top) with an
IMRT plan in the pelvis used to treat an anal cancer patient.
The arrows demonstrate that the IMRT plan conforms to the
target delivering 100% of the prescribed dose, while the 2D
plan delivers 100% of the dose to a large volume of normal
tissue, including femoral heads and genitalia.
techniques, multiple prospective studies demonstrate at
least equal tumor control compared to historical controls
while greatly reducing normal tissue toxicity. For exam-
ple, prostate cancer IMRT minimizes the volume of the
bladder and rectum irradiated. This has permitted the
dose delivered to the prostate to be increased from 66 to
70 Gy to over 81 Gy at some institutions.17 An example
of a pelvic IMRT treatment plan from the University of
Chicago compared to a conventional 3D plan (Figure 3-4)
demonstrates that the patient treated with the IMRT
plan will receive less dose to the normal tissue that sur-
rounds the target.
IONIZING RADIATION AND ITS INTERACTION
WITH TUMOR CELLS AND NORMAL TISSUES
While the therapeutic applications of x-rays were quickly
realized since their introduction, the biologic basis by
which IR kills both normal tissues and tumor cells is a
subject of intense investigation. It is now clear that IR
kills both tumor and normal tissues through several
molecular mechanisms. The dose of IR absorbed in tis-
sues interacts with matter either directly or indirectly
through the hydrolysis of water and the formation of
reactive oxygen species (ROS). While both single- and
double-stranded DNA breaks occur following IR, it is
believed that accumulation of DNA double-stand breaks
(DSBs) are the main requirement for cell death to occur.
Following DNA damage, both tumor cells and normal
tissues respond by attempting to repair the damage, alter
the cell cycle, induce gene transcription, or promote cell
death.18,19 Cell death occurs through either a postmitotic
(necrotic) or apoptotic death that are discussed later. The
formation of ROS and the cellular response to DNA
damage are also influenced by cell membrane receptors
that initiate second messenger cascades that can mediate
cell death.20–23 The following sections describe cellular
response to IR and provide a brief overview of the bio-
logic events that determine whether a cell will live or die
following IR.
IONIZING RADIATION Interacts with Cellular
Targets and Generates Reactive Oxygen Species
IR interacts with matter either directly or indirectly
through production of ROS. IR causes ionization of cel-
lular H2O that produces free hydroxyl radicals. These
free radicals quickly interact with cellular targets. The
damage to the cellular targets, such as cell membranes,
proteins, and DNA, is deposited randomly and is a func-
tion of dose. Data demonstrate that damage by the short-
lived free radicals represents a majority of the clinically
relevant damage produced by conventional photon ther-
apy and electron therapy.24 Experimental evidence
demonstrates that double-strand breaks (DSBs) in the
sugar phosphate backbone of DNA result in most of the
cytotoxicity to both tumor cells and normal tissues.
While many factors contribute to the extent of DNA
damage following IR, cellular oxygen is critical as
hypoxic cells are up to 3-fold more resistant to killing by
IR compared to well-oxygenated cells.25 The presence of
cellular oxygen prolongs the lifetime of free radicals and
appears to fix free radical damage in the DNA. The dif-
ference between tumor cell killing in the presence and
absence of oxygen is termed the oxygen enhancement
ratio (OER). This is clinically relevant as tumor growth
may outpace its ability to generate new tumor vasculature
(angiogenesis). This growth results in areas of hypoxia
and necrosis within the tumor.26 The hypoxic regions,
while poorly vascularized, may remain resistant to IR
during fractionated radiation therapy. As the tumor
changes composition during fractionated RT, reoxygena-
tion of the once poorly hypoxic regions may occur dur-
ing some fractions of therapy, again providing a rationale
for fractionated treatment. In contrast to conventional
therapy, heavy charged particle radiation, such as proton
therapy, kills almost exclusively through direct interac-
tion with cellular targets and is thus not affected by oxy-
gen levels.27 Thus, through both direct and indirect
interactions with cellular structures, conventional EBRT
damages cellular targets resulting in eventual cell death.
44 Part I Principles of Urologic Oncology
The accumulated damage to DNA and other struc-
tures eventually results in the inability of cells to divide
(clonogenic death). The cell may undergo multiple cell
divisions before clonogenic death occurs. The activation
of programmed cell death (apoptosis) also plays a signifi-
cant role in certain normal and tumor tissues and may
occur within hours of exposure of cells to IR. These find-
ings demonstrate that tumor cells with a low mitotic index
(slow proliferation), such as some prostate cancers, may
take many months for complete histologic regression.28
Accumulation of DNA Damage Following IR
Induces A Cellular Repair Response
The accumulation of damage, if not repaired, will result
in the clonogenic or apoptotic death of cells. Cells that
acquire damage not beyond repair, termed sublethal
damage repair (SLDR), may repair the damage to the
DNA between fractions of radiation. It is believed that
many tumors have a poor repair response compared to
the surrounding normal tissues. This concept is crucial in
the attempt to permit recovery of normal tissues between
daily fractions while continuing to kill tumor cells. By
separating the doses of radiation, each day normal tissues
can induce a repair response prior to the second dose of
radiation. Tumor cells may be unable to repair their dam-
age thus it will accumulate until clonogenic or apoptotic
death occurs. This concept has been demonstrated in
both in vitro and in vivo models of cell killing.29,30
The local environment of the cell also plays a role in
its capacity to repair its damage or its decision to die fol-
lowing exposure to IR. Damage to cellular structures that
may be potentially lethal (PLDR) while a cell is exposed
to certain growth factors, such as oxygen concentration,
and cell–cell contact may be repaired if postirradiation
conditions are altered to enhance cell survival.31 Based on
both in vitro and in vivo studies, Weichselbaum and oth-
ers suggest that PLDR significantly contributes to radia-
tion therapy failure.32–34 The understanding of these
basic mechanisms has led to the development of agents
and techniques to enhance the tumoricidal effects of IR.
Therapeutic Ratio of Radiation Therapy
The probability of tumor cure is a function of many vari-
ables, including tumor type, size, radiation dose, and
fraction size. For example, microscopic (subclinical) dis-
ease from an epithelial-derived tumor is usually curable
with as little as 45 to 50 Gy. However, this dose would be
insufficient to cure microscopic disease derived from
high-grade astrocytomas, a large epithelial tumor, or T2
prostate cancer. Most doses used in clinical practice have
been empirically determined. The therapeutic ratio is
defined as the probability of obtaining a tumor cure
divided by the chance of a normal tissue complication.
Attempts to enhance the therapeutic ratio have come in
the form of altered fractionation schemes, addition of
radiation sensitizing agents, and use of radioprotectors.
These are discussed later.
Enhancement of the Tumoricidal Effects of IR with
Radiation Sensitizers
Clinical trials demonstrate that local control following
radiation therapy is significantly worse than in patents
with normal blood oxygen carrying capacity.35 Multiple
studies have demonstrated improvements in outcome of
patients treated with hyperbaric oxygen.36 In addition,
compounds that act as hypoxic cell sensitizers, such as
metronidazole and misonidazole, have been developed
and employed clinically. Despite promising studies in
vitro, few clinical studies have demonstrated improve-
ment in outcome at the expense of significantly increased
toxicity.37 While laboratory studies have demonstrated
significant enhancement of the antitumor effects of
hyperbaric oxygen or hypoxic cell sensitizers, the clinical
application of these techniques has not led to significant
therapeutic gain.
Clinically, the most commonly employed agents to
enhance radiation-mediated tumor cell killing are stan-
dard chemotherapeutics, such as 5-fluorouracil (5-FU),
cisplatin (CDDP), and paclitaxel. Combined treatment
with radiation therapy and chemotherapy has been
demonstrated in randomized trials of head and neck,
gynecologic, and lung cancers to be superior to treatment
with radiation alone. While the mechanisms of radiosen-
sitization vary, the combined use of these agents with IR
has led to improvements in local control of disease and
improved survival in many cancer sites.
Protection of Normal Tissue Through the Use
of Radioprotector Agents
While the addition of chemotherapeutic agents to radia-
tion therapy has enhanced the tumoricidal effects of IR,
this benefit is usually accompanied by an increase in nor-
mal tissue toxicity. The balance between tumor cell
killing and normal tissue toxicity defines the therapeutic
ratio and ultimately limits the probability of cure. In
order to increase the therapeutic ratio and limit toxicity
to normal tissues, agents that protect tissues from radia-
tion (radioprotectors) have been employed clinically.
Originally developed in the 1950s by the department of
defense, the radioprotector amifostine (Ethyol) acts as a
scavenger of free radicals. Following intravenous deliv-
ery, the compound amifostine penetrates into normal tis-
sues within minutes. However it is absorbed more slowly
in the tumor tissue providing a rationale for preferential
protection of normal tissues. Randomized studies in
head and neck and pelvic malignancies have shown some
 Chapter 3 Principles and Applications of Radiation Oncology 45
protection from expected radiation sequelae while not
decreasing local control of disease.38 The use of amifostine
use, however, remains fairly limited due to the expense
of the compound, limited randomized clinical data,
and often severe acute side effects including nausea and
hypotension.
Enhancement of the therapeutic ratio through
gene therapy
While attempts to employ gene therapy with cancer as a
single modality have met with limited clinical success,
laboratory and clinical data demonstrate that combining
gene therapy with IR may improve tumor curability.
Unlike combining IR with standard chemotherapy
agents that often have overlapping toxicity, gene therapy
can be tailored to target different and partially nonover-
lapping mechanisms of tumor cell killing. Current
research in gene therapy aims to: (1) replace mutated
genes (p53) that may sensitize cells to IR; (2) deliver
genes encoding pro-drug converting enzymes into
tumor cells, allowing toxic agents to be generated in the
tumor bed, thereby decreasing the risks of systemic tox-
icity; (3) construct genetically engineered viruses with
therapeutic genes under the control of radiation
inducible promoters; and (4) enhance replication com-
petent viruses that proliferate preferentially in tumor
cells following IR. While current technology limits the
efficiency of gene transfer to tumor cells, radiation may
enhance the “bystander effect” of specific gene therapy
designs that employ a diffusible product.39–42 Clinical
studies are currently underway employing a wide variety
of these techniques.
DNA Damage, the Cell Cycle, and Repair
Tumors represent a heterogeneous population of grow-
ing cancer cells that are distributed unevenly throughout
the cell cycle with most in the resting or G1 phase. As
previously discussed, damage to the DNA represents the
critical target for IR-induced cell death. In vitro and in
vivo data demonstrate that the extent of DNA damage
and tumor cell death is, in part, dependent on the phase
of the cell cycle. While exceptions exist, the most
sensitive phases of the cell cycle are G2/M. Cells are least
sensitive to IR in late S-phases.43 Identification of differ-
ential sensitivity based on cell cycle provides further
rationale for fractionated treatment regimens. Since
tumor cells are an asynchronous population, after each
fraction those in the most sensitive phases will be killed
while the resistant phases will progress to other phases of
the cycle. This process is termed reassortment. Thus,
with standard EBRT with photons, fractionation permits
cells to be exposed to radiation while the cells are in their
most sensitive phases.
DNA damage induces cell cycle arrest. The cell sig-
naling pathways that monitor DNA damage and initiate
cell cycle arrest are referred to as checkpoint controls.
For example, the commonly mutated tumor suppressor
gene and transcription factor p53 promotes cell cycle
arrest at the G1 checkpoint following DNA damage
through transcription of p21 that inhibits progression to
S-phase. The exact phase of the arrest is dependent on
the genetic mutations present in the tumor cell. Arrest of
the cell cycle in damaged cells represents an evolutionar-
ily conserved survival mechanism to ensure the fidelity
and transmission of genetic information. By preventing
progression through the cycle, the damage induced by IR
can be repaired before the cell continues to grow and
divide. Failure to repair the damage leads to genetic
instability and cell death.44
As previously noted, while IR induces both single-
and double-strand DNA breaks, DSBs are responsible
for most tumoricidal effects of IR. DNA damage is
repaired in mammalian cells through two distinct
molecular pathways: homologous recombination and
nonhomologous recombination. Homologous recombi-
nation involves various repair proteins, such as rad51,
that identify homologous DNA to be used as a template
to direct error-free repair of the genetic information.45
However, the predominant mechanism of repair in
human cells is nonhomologous recombination. During
this process, DSBs are identified by protein complexes
and the ends joined by ligases (xrcc4).46 Due to the sim-
ple end-joining and lack of a template for repair, non-
homologous recombination results in mutant
chromosomes. The protein sensors of DSBs that initi-
ate the repair cascade are a focus of intense investiga-
tion since inhibition of those sensors would sensitize
tumor cells to IR.
Ionization Radiation-Induced Cell Death:
Apoptosis and Necrosis
One major biologic determinant of radiation therapy fail-
ures is tumor radioresistance.47–49 As previously dis-
cussed, exposure of mammalian cells to IR results in a
loss of cellular reproductive capability (mitotic death) by
inducing DNA DSBs and lethal chromosomal aberra-
tions.50 Morphologic characteristics of IR-induced
mitotic death include multinucleated giant cells, cell–cell
fusions, and loss of membrane integrity that is also a
characteristic of necrotic cell death. Daughter cells with
limited divisional potential can arise from lethally irradi-
ated mother cells to form abortive colonies. Death dur-
ing cell division due to lethal mutations or damaged
chromosomes following IR is a well-studied mechanism
of tumor cell killing.51
In contrast to necrotic death, apoptosis induced by IR
results in activation of a genetic program initiated by
46 Part I Principles of Urologic Oncology
cytoplasmic or nuclear events culminating in cytoplasmic
blebbing, chromatin condensation, and DNA fragmenta-
tion.52–54 The induction of apoptosis may occur immedi-
ately after irradiation (interphase death), after arrest in
the G2 phase,55 or following one or more cell divi-
sions.56,57 Apoptosis may represent an important mecha-
nism of death in some cell types following IR, such as
lymphomas.56 It has been proposed that the direct effects
of x-rays on the nucleus and DSBs initiate a cascade of
signaling events, such as p53 induction, that culminates
in the activation of proteases (caspases) that execute the
cell death program.55,56 While the signal to undergo
apoptosis following IR is generally considered to origi-
nate in the nucleus,55,56,58,59 studies demonstrated that
the production of the lipid second messenger ceramide
from sphingomyelin hydrolysis immediately following IR
contributes to the apoptotic response.60–62 Current
research efforts aim to enhance the cytotoxicity of IR
through development of small molecules that exploit the
apoptotic program.
THE CLINICAL PRACTICE OF RADIATION
ONCOLOGY
Definitive and Adjuvant Radiation Therapy
Therapeutic radiation (RT), delivered via external beam
or brachytherapy, by itself can cure many human malig-
nancies, including head and neck, cervix, lymphoma,
prostate, and pure seminomas. RT alone demonstrates
equivalent local control compared with surgery in head
and neck malignancies while better preserving normal
organ function.63,64 Similar results have also been seen in
early cervical cancer trials.65 To date, no completed ran-
domized study employing modern surgical and radiation
techniques for prostate cancer exists.
RT is commonly employed as part of a combined
modality approach in cancer therapy. It is routinely
used as an adjuvant to surgical excision to sterilize
potential microscopic disease in lymph nodes or from
surgical margins. Preoperative RT is used for large
unresectable tumors, such as sarcomas or rectal cancer,
in an attempt to permit eventual surgical excision or
organ conservation.66 More commonly, postoperative
RT is employed following definitive surgical findings
of margin status, tumor pathology, and stage of disease.
The decision to employ postoperative RT can then be
made and treatment type and dose tailored to the spe-
cific case. Common postoperative RT applications
include tumors of the head and neck, lung, breast, gen-
itourinary, gastrointestinal tract, and central nervous
system.
As previously discussed, chemotherapy may be com-
bined with RT in order to increase tumor cell killing.
Commonly, chemotherapy is given prior to RT (neoad-
juvant) or simultaneously (concomitant) with RT. Recent
randomized studies demonstrate improvements in local
control of disease, organ preservation, and overall sur-
vival when comparing RT alone with combined modality
treatment in diseases that include the head and neck,
bladder, cervix, esophagus, and lung. Postoperative
chemoradiotherapy is also employed for gastric, rectal,
and head and neck tumors. Concomitant RT appears to
produce better local control in some disease sites while
producing significant more acute toxicity. Thus, current
clinical trials seek to identify more active chemother-
apy agents with fewer overlapping toxicities and to deter-
mine the optimal timing and delivery of chemotherapy
with RT.
Palliative Radiation Therapy
for Metastatic Disease
Painful metastatic disease is effectively treated with a
combination of pain medication and RT. Osseous metas-
tases are commonly observed in advanced breast, lung,
and prostate patients. Pain relief from an abbreviated
course of RT can reduce or eliminate pain in 70% to
80% of cases.67 A recently completed randomized study
by the Radiation Therapy Oncology Group (RTOG)
compared a large single fraction of 8 Gy to the more con-
ventionally used 10 fractions (3 Gy) to 30 Gy in breast
and prostate patients.68 Equivalent outcome in terms of
pain relief and complications were found suggesting that
shorter courses of palliative RT may be as effective in the
patient with metastatic disease. Longer follow-up is
needed, however, to determine if long-term complica-
tions and duration of pain relief will remain equivalent.
Patients who develop multiple cerebral metastases
from lung, bladder, breast, and other tumors suffer neu-
rologic sequelae from both the expanding tumor mass
itself and subsequent edema formation. Combining ini-
tial steroid treatment with fractionated RT to the entire
brain (typically 30 and 3 Gy fractions) improves neuro-
logic function in over 50% of patients. Patients with a
single brain metastasis benefit from combined surgical
resection and postoperative RT.
Spinal cord compression is also effectively treated
with palliative RT. Again, the neurologic compromise is
often treated with a combined modality approach. High-
dose steroids reduce the surrounding edema and provide
often rapid neurologic improvement. A recent random-
ized study demonstrates that surgical excision and stabi-
lization of the vertebral bodies involved with tumor
followed by RT provide superior pain relief and improve-
ment of neurologic function compared with RT alone.69
In patients deemed surgically inoperable, RT is normally
delivered in 3 Gy fractions to a total dose of 30 Gy.
The dose of 30 Gy provides good tumor control while
offering almost no additional risk that the radiation itself
will damage the spinal cord.
 Chapter 3 Principles and Applications of Radiation Oncology 47

tum or lung, as the volume of tissue irradiated increases

Acute and Chronic Radiation Sequelae
As previously stated, the therapeutic index of radiation
therapy is defined as the probability of tumor cure
divided by the probability of severe toxicity. The nor-
mal toxicity of radiation therapy is a function of the vol-
ume and type of tissue exposed to IR, dose fraction, and
total dose. The currently employed radiation sensitiz-
ers, standard chemotherapy, also increase acute and
chronic toxicity of RT. Acute radiation sequelae occur
through damage to actively dividing normal tissues.70
Commonly seen acute toxicities during or shortly fol-
lowing fractionated radiation therapy include skin
desquamation, diarrhea, and mucositis. Chronic seque-
lae normally develop months to years after radiation
therapy and result from fibrosis and subsequent scarring
of normal tissues.
While acute toxicity can normally be managed dur-
ing the course of treatment, chronic toxicity remains
the limiting factor when determining the maximum
dose to deliver in the effort to cure the tumor. The
probability of causing a chronic toxicity in 5% of the
treated population at 5 years is termed the TD5/5.
Injury to a portion of certain organs (i.e., spinal cord)
markedly impairs the function of the entire organ. For
these organs radiation oncologists have developed
empiric dose constraints to limit observed toxicity to
almost 0%. For example, a dose of 45 to 50 Gy maxi-
mum to any point on the spinal cord is accepted as the
standard of care. For other structures, such as the rec-
so does the probability of complications. An example of
this volume and complication relationship is seen in the
recently completed randomized 3D conformal dose-
escalation study for prostate cancer. In order to achieve
better local control of low and intermediate risk
prostate cancer with EBRT, Pollack et al. randomized
patients to 78 Gy versus 70 Gy in 2 Gy fractions.69
With 100 months of follow-up, the 78-Gy group
showed significantly better PSA-free survival in the
intermediate risk group demonstrating that increased
dose leads to more prostate cancer cures in this popu-
lation. However, grade 2 (TABLE 3-1) or greater rec-
tal complications were also increased. Upon further
analysis a dose/volume relationship can be seen in
terms of complications. If the percentage of rectum
treated to >70 Gy was <25%, grade 2 or higher com-
plications were <15%. However, if the volume
exceeded 25%, the probability of complication rose to
45%. These data from randomized dose escalation
series for prostate, as well as other disease sites, guide
the radiation oncologist when balancing the desire to
deliver higher dose for increased probability of cure
with the chance of chronic complications.
SUMMARY
Radiation therapy has been used to treat cancer patients
since 1896. The development of modern linear accelera-
tors, sophisticated computer planning software, and an

Table 3-1 RTOG Toxicity Scoring System

Organ 0 Grade 1 Grade 2 Grade 3 Grade 4

Large None Mild diarrhea Moderate diarrhea Surgery is required Fistula or perforation
intestine/ and cramping (bowel movement due to bleeding or develops
rectum with bowel > 5 times/day) or obstruction of
movement < 5 excessive rectal bowel
times/day mucus or mild
but intermediate
bleeding

Spinal cord None Mild Lhermitte’s Severe Lhermitte’s Neurologic findings Paraplegia
syndrome syndrome on examination
that can be
accounted for by
damage at the level
of spinal cord in
the radiation field

Bladder None Microscopic Increased frequency Severe frequency Bladder capacity

hematuria of urination with or dysuria < 100 cc, hemorrhagic
occasional Macroscopic cystitis, or necrosis
macroscopic hematuria
hematuria Bladder capacity
reduced to < 150 cc
48 Part I Principles of Urologic Oncology
increased understanding of the basic biology that under-
lies the cytotoxicity of IR has allowed the field to cure
more human tumors, decrease the need for large and
debilitating surgical procedures, and decrease the proba-
bility of complications. Current clinical trials in most dis-
ease sites demonstrate that combined modality therapy
with chemotherapy and radiation remains superior to
radiation alone despite the increase in toxicity. Future tri-
als with more novel chemotherapeutic agents aim to pro-
vide similar radiation sensitization while decreasing the
overlapping toxicities. More advanced molecular biology
techniques have enabled gene therapy to be combined
with radiation in order to achieve a similar goal. We
expect the advancements in both hardware, software, and
biology will lead to further increases in the therapeutic
ratio in the future.
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41. Belyakov OV, et al: Direct evidence for a bystander effect
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43. Terasima T, Tolmach LJ: Variations in several responses of
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C H A P T E R
4 Principles of Chemotherapy
for Genitourinary Cancer
David I. Quinn, MBBS, PhD, FRACP,
Patrick J. Creaven, MD, PhD,
and Derek Raghavan, MD, PhD
Cytotoxic chemotherapy has been in use for the manage-
ment of advanced cancer for more than a century,1 aris-
ing from concepts developed by Lissauer, Ehrlich, and
many others. The initial attempts at such treatment were
characterized by a lack of specificity, with a fine balance
between the toxicity to the tumor and that experienced
by the host. As reviewed in detail elsewhere,1 during the
past century, there has been some refinement in our
application of chemotherapy to the treatment of cancer,
predicated on an improved understanding of the bio-
chemical basis of its action and a clearer insight into the
cellular and molecular mechanisms underlying normal
and malignant growth.
TUMOR CELL BIOLOGY IN RELATION
TO CHEMOTHERAPY
The anticancer agents are a varied collection of drugs
that act through a range of mechanisms predominantly
focused on interference with cell reproduction. The dif-
ferences between the growth characteristics of normal
and malignant tissues form the major basis of the effec-
tive use of cytotoxic chemotherapy.2 Differences between
the cellular transport characteristics of these agents may
also contribute to the difference in response to some
cytotoxics. It is also apparent that there are important
differences between intracellular metabolic functions,
such as the expression of glutathione, an intracellular
scavenger that interacts with some alkylating agents and
the platinum complexes to inactivate them. More recent
data suggest that there may be subtle interactions
between the expression of growth controlling factors
(such as the receptor for the epidermal growth factor
[EGF]) and the impact of cytotoxic agents, with potential
for resulting synergistic or antagonistic effects.
Normal tissues are composed predominantly of a
static population of cells (which rarely undergo cell divi-
sion), an expanding population (which retain the ability
to grow, under stringent physiologic control mecha-
nisms) and a self-renewing population (for tissues that
turn over rapidly, such as bone marrow and gastrointesti-
nal mucosa). In this situation, balance is maintained
between natural attrition and replacement.
The static, or terminally differentiated, population
usually includes cells that do not undergo cell division
after fetal life, such as skeletal muscle and neuronal tis-
sue. The cells of an expanding population do not nor-
mally undergo continuous growth and division but may
respond to stress (such as injury) with a period of replace-
ment growth. For example, hepatocytes can respond to
surgical resection of liver tissue by re-entering the cell
cycle and replacing the lost tissue. Another example of
the expanding population is the stem cells found in the
bone marrow; these normally rest in the G0 phase but can
re-enter the cell cycle. The fact that they are predomi-
nantly in G0 may protect them, in part, from the effects
of cytotoxic agents.
By contrast, the self-renewing cell populations (e.g.,
gastrointestinal tract, hair follicles, bone marrow) are in
a continuous proliferative state, with constant cell
turnover, and are thus most commonly injured by cyto-
toxic chemotherapy; the static cell populations are the
least vulnerable to the effects of chemotherapy.
Malignant growth is essentially uncontrolled, occur-
ring as a result of a breakdown in the mechanism(s) that
turn off growth. The patterns that contribute to tumor
51
52 Part I Principles of Urologic Oncology
growth may include reduction in the duration of the cell
cycle, a decrease in the rate of cell death, or an increase
in recruitment of cells into the active cell cycle. In gen-
eral, it appears that malignant growth follows a
Gompertzian pattern,2 in which a period of exponential
growth is followed by a slowing of the growth rate.3,4
This may occur through the tumor outgrowing its vascu-
lar supply,5 due to the development of toxic breakdown
products associated with cellular turnover, or through
other subtle cell–cell interactions. In addition to unregu-
lated cell growth, malignancy is characterized by tissue
invasion and metastasis, sustained angiogenesis, and eva-
sion of apoptosis or programmed cell death.6
Cellular Kinetics and Cell Cycle Control
The kinetics of tumor cell growth, both in vitro and in
vivo, has been the subject of considerable study,2
although our concepts regarding this topic remain quite
fluid. Surprisingly little information is available regard-
ing the kinetics of human tumor growth,7 although a
greater body of information is available regarding the
growth of animal tumors.2 It is generally agreed that
tumor cells grow through an orderly sequence of steps:
1. The initial growth phase (G1) is characterized by
synthesis of RNA and protein, as well as DNA repair;
this is a period of variable length, and its duration will
determine the length of the total cell cycle of the
individual cell.
2. This is followed by the synthetic (S) phase, in which
new DNA is synthesized.
3. The cells progress through the G2 phase, in which
the total DNA content is double that of the normal
cell.
4. The mitotic (M) phase sees the division of the
chromosomes and separation into two offspring cells.
5. After mitosis, the cells may spend a variable period of
time in a resting state known as G0—the cells are out
of active cycle and appear not to be affected by
chemotherapy to any major extent.
A detailed description of the molecular biology of cell
cycle control is beyond the scope of this chapter, but the
principles have been reviewed elsewhere.6,8,9 In brief,
several candidate genes and growth factors appear to reg-
ulate the various steps of the cell cycle. Entry into G1
from S phase is regulated by a range of growth factors
and interrelated molecular mechanisms culminating in
retinoblastoma protein (pRb) phosphorylation. When
hypophosphorylated, pRb blocks proliferation by seques-
tering and altering the function of E2F transcription fac-
tors that control the expression of banks of genes
essential for the progression from G1 to S phase.10–13
Disruption of the pRb pathway liberates E2Fs and allows
unregulated cell proliferation. The classic negative regu-
lator of cellular proliferation is transforming growth fac-
tor beta (TGFβ). TGFβ acts through a number of
mechanisms to inhibit cell cycle progression.14 It directly
induces increased production of cyclin-dependent kinase
(CDK) inhibitors such as p15INK4B, p27Kip1, and
p21Cip1.15–17 These proteins, in turn, act to block the
activity of cyclin: CDK complexes responsible for pRb
phosphorylation.18,19 TGFβ also suppresses the expres-
sion of the c-myc gene, which has a physiologic role in
increasing the rate of G1 to S phase transition through
mechanisms that are still being elucidated.20,21 EGF,
which binds to a cell membrane associated receptor to
initiate a chain of signal transduction, acts to increase the
rate of cell cycle proliferation in part by decreasing the
quantity of p27Kip1 present.22 In cell line experiments,
blockade of the epidermal growth factor receptor
(EGFR) results in increased p27Kip1 and arrest of the can-
cer cell in G1 phase as it is unable to transit into S
phase.23 Furthermore, p53 regulates cell cycle progres-
sion through synthesis of the CDK inhibitor, p21Cip1.16
Hence, cellular transit through the G1/S transition may
be influenced by a number of factors, including growth
factor concentration and effect, receptor expression and
activity, cell cycle regulatory molecule expression, and pRb
action. For example, a more rapid cell cycle could arise
from any or a combination of increased EGF concentra-
tion, EGFR receptor overexpression, loss of CDK
inhibitor expression, cyclin overexpression, or retinoblas-
toma gene mutation. The net rate of cell proliferation is
a synthesis of a multitude of potential effectors on the
pRb pathway.
Several oncogenes, such as ras, c-myc, and src have
activity in the M phase of the cell cycle; in fact, they may
actually interact in the process leading to activation of
the M-phase promoting factor, which in turn controls
entry into mitosis (the second major cell cycle control
point at the G2/M phase transition).24 Variation in the
activity of these oncogenes, whether induced by amplifi-
cation, mutation, or exogenous regulators, can result in
altered transition through mitosis.24–26 Tumor progres-
sion may be a function of a series of events that involve
progressive loss of control over entry into the S phase
and loss of regulation of M phase; such progression is due
to genetic instability and is central to the evolution of
malignancy.24 These changes may, in part, be contingent
on the loss of M phase checkpoint function, a mechanism
by which the cell cycle pauses transiently and allows
checking of the accuracy of replication.27,28
The concept of the cell cycle is of great importance to
our understanding of cytotoxic action. Most agents affect
some aspect of the synthesis of DNA, RNA, or protein,
acting at different points within the cell cycle. This may
be very important when adding agents in a combination
regimen, for example, the use of a spindle poison (such as
 Chapter 4 Principles of Chemotherapy for Genitourinary Cancer 53
a vinca alkaloid) may hold up cells from entry into the G1
phase and thus reduce the impact of an agent that acts
predominantly at that point of the cell cycle. In turn, inhi-
bition of G1/S phase transition may invalidate the effect of
agents that act at or subsequent to this point, such as
topoisomerase inhibitors.29 These potential effects are
limited by the fact that many agents act at multiple points
in the cell cycle. Inhibition of checkpoint function may
explain how tumor cells can be more vulnerable to the
effects of cytotoxic agents than are normal cells—thus the
vulnerability of cancer cells to agents that target the S
phase or M phase may occur because the malignant cells
proceed unchecked through the cell cycle despite a series
of errors, whereas the normal cells stop at finite check-
points while needed repairs occur. In addition, there is an
increasing trend toward designing drugs that target spe-
cific parts of the cell cycle machinery. Examples of mitotic
phase regulators include vinca alkaloids, taxanes, and
epothilones30,31 whereas flavopiridol and UCN-01, which
are currently under development, inhibit cyclin-dependent
kinases active in G1/S phase transition.32–35
Cell cycle characteristics can be measured in several
ways, including the use of labeling of mitoses,2 flow
cytometry,36 and surrogate markers of cell cycle transit or
proliferation such as Ki67 immunohistochemical index.37
When considering the biology of tumor growth as
assessed by flow cytometry, the proportion of cells in
G1 + S phases is thought to be most important, although
the level of aneuploidy (proportion of cells that do not
have a normal or diploid DNA content) appears to be
important as a prognostic determinant in some tumors.
Another more direct parameter of the cell cycle is meas-
urement of tumor doubling time.2
Also of importance is the growth fraction (proportion
of cells within a tumor that are in active proliferative
phase), which can range from 25% to more than 90% in
human tumors, often with areas of variation within indi-
vidual tumor deposits. The rate of cell loss is also impor-
tant—in most tumors, it is high, ranging from 70% to
greater than 90%.2 In general, the length of the G1 phase
is one of the primary determinants of proliferative
behavior—thus, if G1 is short, the duration of the cell cycle
is usually rapid, whereas cells with a long G1 or those that
spend considerable time in G0 have a much longer cell
cycle and are less sensitive to the impact of chemotherapy.
The Balance between Cell Proliferation
and Apoptosis
Apoptosis or programmed cell death occurs in normal as
well as neoplastic cells. The process is complex and reg-
ulated by a variety of molecular pathways. The best
understood of these pathways center on the tumor sup-
pressor gene, p53,38,39 and the oncogene, Bcl2.40 A
detailed review of apoptosis is beyond the scope of this
chapter but has recently been reviewed.41–43 The interac-
tion between cell proliferation and apoptosis determines
the net growth of a tumor mass. These factors have been
evaluated in relation to cancer development and progres-
sion in a number of human cancers, including prostate
cancer (PC). Normal prostate epithelial cells have a very
low replicative rate that results from replacement of the
cell every 500 days and no net increase in cell number.44
In “low grade” prostatic intraepithelial neoplasia (PIN),
epithelial cells undergo proliferation in excess of dying so
that they have a doubling time of around 150 days. Upon
development of “high grade” PIN, there is an increase in
both replication and cell death so that there is no net
increase in cells but the turnover time is around 56 days.
Subsequent transition to invasive PC involves little
change in proliferation but rather a reduction in cell
death and a mean doubling time of around 500 days.
Metastatic PC cells have both increased proliferation and
cell death rates with a mean doubling time of around 33
days for lymph node and 54 days for bone metastases in
hormone sensitive cases.44 In metastatic androgen-
independent PC, there is no further increase in cellular
proliferation and an increase in cell death. The reasons
for this increase in cell death are unclear but may relate
to local or general nutrient delivery. Hence, PC has a
very long doubling time even in metastatic disease with
relatively subtle changes in proliferation and cell death
that mark transition between stages of the progression
of the disease.44 The relative balance between prolifer-
ation as determined by cell cycle transit and pro-
grammed cell death varies between cancer types and
may influence sensitivity to a variety of anticancer ther-
apies. When PC is treated with androgen ablation, the
result is increased apoptosis in a minority of cells with
decreased proliferation in the majority of cells, demon-
strating the importance of this balance in response to
therapeutic interventions.45
In other tumors, varying amounts of reduction in cell
proliferation and increase in apoptosis are seen among
tumors exposed to hormonal and cytotoxic therapy.46 In
urologic oncology, the balance between reduced cellular
proliferation and increased cell death is best illustrated in
the response of metastatic nonseminomatous germ cell
tumors to chemotherapy. More than 90% of patients
with this condition are cured. In responding to
chemotherapy a major proportion of cancer cells
undergo apoptosis. However, certain cells within the
tumor, particularly within teratomatous elements, are
resistant to apoptosis and undergo reduction in prolifer-
ative rate and may differentiate into “mature” ter-
atoma.47–50 These areas may remain as quiescent masses
for protracted periods of time but have the potential to
de-differentiate and manifest cancer recurrence, which
typically is resistant to further chemotherapy.51,52 Based
on this, the therapeutic approach to these masses involves
54 Part I Principles of Urologic Oncology
surgical excision, particularly where teratoma has been
identified in the primary tumor.53–55 Recent work sug-
gests that mature teratoma may have a molecular signa-
ture that distinguishes it from cancer cells undergoing
apoptosis and those that appear morphologically unal-
tered after chemotherapy.56 Whether this molecular
approach will be of therapeutic utility remains to be seen.
Clonality of Tumor Cell Populations
In animal tumors, which tend to be clonal in nature, first
order kinetics appear to apply in response to chemother-
apy—that is, a dose of single-agent chemotherapy will
kill a fixed proportion of tumor cells. For example, if a
tumor mass containing 107 cells is treated with an agent
that kills 90% of the cells, 9 × 106 cells will be killed by a
single dose, leaving behind 106 viable cells (or 10% of the
original tumor mass). A second dose will kill 9 × 105 cells,
leaving 105 cells still alive. If treatment is not repeated,
these cells will regrow, and the mass will rapidly return to
its former size. This is also influenced by the proportion
of cells that undergo spontaneous cell death, as well as
the proliferative rate of any remaining viable cells.
In the human setting, the situation is much more com-
plex, as many human tumors appear not to be purely uni-
clonal in nature but rather are composed of multiple
subpopulations of cells with different characteris-
tics.52,57–61 It is not clear whether this is due to the evolu-
tion from single clonal populations (stem cells) or is due to
initial evolution of multiple clones in response to an initial
carcinogenic stimulus. Heterotypic signaling mechanisms
between the diverse cell types that comprise a human
tumor are likely important regulators of primary tumor
cell proliferation and other malignant characteristics.62,63
PHARMACOLOGY OF ANTICANCER AGENTS
The time course of drugs in the body is determined by
the rates of drug absorption, distribution, metabolism,
and excretion. The mathematical description of these
rate processes is referred to as pharmacokinetics. Often
the data can be fitted to mathematical models, which are
simplified descriptions of the complex physiologic reali-
ties. Many of the processes involved are so-called “first
order”; that is, the rate at which the process occurs is pro-
portional to the drug concentration, although some
processes that are enzyme or carrier-dependent follow
Michaelis Menten kinetics in which the process is first
order at low concentrations and zero order (i.e., occur-
ring at a fixed rate) at high concentrations of the drug.
Absorption
Cytotoxic agents may be administered directly into the
circulation (intravenous or arterial administration) or
by the extravascular approach, which includes oral,
intramuscular, intrathecal, intravesical, and intraperi-
toneal routes. The route of extravascular delivery will
influence absorption. Factors that determine the
uptake characteristics of a drug include the structure
and size of the molecule and its pKa and, thus, its solu-
bility characteristics.
The clinical activity of specific agents may vary sub-
stantially with the nature of the route and schedule of
administration and consequent absorption. For example,
cyclophosphamide can be administered orally in a dose of
100 mg/m2/day for 14 days to patients with advanced PC,
and is well tolerated, causing only modest myelosuppres-
sion and gastrointestinal toxicity.64 When administered
to similar populations of patients by intravenous bolus
injection (e.g., 750 to 1000 mg/m2 every 3 weeks), the
side effects may be more substantial65 with no apparent
improvement in therapeutic outcome.
Successful intravesical chemotherapy is predicated
on the desire for cytotoxics to be active locally without
systemic absorption, thus protecting the patient from
systemic side effects while maximizing the concentra-
tion at the tumor surface. Thus, thiotepa, a small,
readily absorbed molecule is potentially less useful in
this context than larger molecules, such as doxoru-
bicin or mitomycin C.66–68 Furthermore, the level of
systemic absorption of thiotepa can be increased if it
is administered soon after transurethral tumor resec-
tion in the presence of a residual denuded bladder
epithelium.69
Ultimately the key to therapeutic effectiveness of any
cytotoxic agent is a function of the product of its concen-
tration and the time available at the tumor site (C × T).
Most cytotoxics are administered by intravenous or
intraarterial routes, and the calculation of the actual
plasma C × T equation is made accordingly.
Distribution and Transport
The amount of cytotoxic agent available at the tumor
target and the length of time during which it is present
determines its level of efficacy. Several factors will influ-
ence this, including the lipid solubility of the drug, its
binding to protein and other carriers (with consequent
variation on free drug concentrations), and the mecha-
nisms available to allow entry into the tumor (such as
passive diffusion or active transport). A major factor will
be the plasma levels of the drug, a major determinant of
which is its distribution characteristics. Following rapid
intravenous injection, the plasma concentration (Cp ) of
the drug will initially fall rapidly. With the elapse of
time after the dose, the rate of decline will decrease. A
plot of the natural logarithm (ln) Cp against time (semi-
log plot) will generally show two components of the
plasma decay: an initial rapid component and a subse-
 Chapter 4 Principles of Chemotherapy for Genitourinary Cancer 55
quent slower component, both of which have the char-
acteristics of log-linear, that is, first order, processes.
Mathematically, such plasma decay can be fitted to a
two-compartment model in which the body is conceptu-
alized as consisting of two compartments, a central com-
partment into which the drug is introduced and a
peripheral or tissue compartment into which it diffuses,
ultimately to equilibrium. The second component of the
plasma decay consists of elimination processes consist-
ing of metabolism or excretion. The rate of this second
process will give the half-life of the drug in the body and
is an important pharmacokinetic characteristic of all
drugs (t1/2β). For some drugs, such as the anthracyclines,
a third component of the plasma decay is seen indicat-
ing a so-called deep tissue compartment, usually corre-
sponding to the binding of the drug to some tissue
component, such as nucleic acid, from which the drug is
slowly released. An even simpler model in which the
body is regarded as a single compartment can sometimes
be used; however, for many drugs it can lead to major
errors in computing the important pharmacokinetic
parameters. It is important to recognize that these
“compartments” are mathematical constructs, which
usually have little or no correspondence with actual
physiologic compartments. The total area under the
plasma concentration-times-time curve (AUC or C × T)
is an important measure of the total exposure of the tis-
sues to the drug. Other important pharmacokinetic
parameters, which can be calculated from the indices of
plasma decay, are the total body clearance (ClB) and the
apparent volume of distribution (VD), the theoretical
volume required to dissolve the total body content of
the drug if it were uniformly distributed in the concen-
tration found in plasma.
In general, the drug is distributed between the
intravascular, extracellular and intracellular water but has
to cross a membrane to pass from one of these to another.
In addition, certain sites are protected from easy drug
access. Such sanctuaries are usually characterized by
lower drug concentration than other tissues. Conversely,
some drugs are disproportionately concentrated in par-
ticular tissues as exemplified by the accumulation of
estramustine in prostatic tissue.70
The presence of sanctuary sites may be of real impor-
tance; for example, the blood-brain barrier appears to
protect the brain against the local uptake of cytotoxic
agents, and thus the brain may be the site of first relapse
in tumors that are otherwise quite responsive to
chemotherapy.71 Similarly, it appears that the testis may
functionally constitute a sanctuary site against the effect
of chemotherapy—up to a third of patients treated for
metastatic testis cancer before surgical removal of the
affected testis will have residual cancer within the testis at
subsequent orchiectomy, despite the attainment of extra-
testicular complete response.72
Metabolism
Drug metabolism may occur both outside and within
tumor cells. There are two important types of metabolism
of antitumor agents. Antitumor agents, which resemble
normal metabolites, are often metabolized by the same
mechanisms as the normal metabolites that they resemble.
Most purine and pyrimidine antimetabolites require activa-
tion to a nucleotide (usually the triphosphate) in order to be
active, and these reactions are carried out by the mecha-
nisms in the cell used to metabolize the corresponding nor-
mal preformed purines and pyrimidines (the so-called
salvage pathways). Some of the antifolates undergo polyg-
lutamation by the mechanisms used for folates.
Degradative pathways such as those responsible for reduc-
ing 5-fluorouracil (5-FU) to dihydro-5-fluorouracil and
converting cytosine arabinoside to the corresponding uracil
arabinoside by deamination,73–75 are also active in the cell.
These reactions occur in the cells of the tumor and in the
cells of normal tissues. In the case of capecitabine, a novel
oral fluoropyrimidine carbamate, intracellular conversion
of parent drug to 5-FU occurs preferentially so that there
is more active drug in cancer tissue than adjacent normal
cells.76,77 This occurs under the enzymatic effects of cyti-
dine deaminase and thymidine phosphorylase, which
metabolize capecitabine to 5′-deoxy-5-fluorocytidine, 5′-
deoxy-5-fluorouridine, and fluorouracil.76,78 In addition to
these specific metabolic reactions, compounds that do not
show resemblance to physiologic substrates are metabo-
lized primarily in the liver by the pathways used for detox-
ification of xenobiotics. The most important of these is
oxidation, often followed by conjugation. Oxidation is car-
ried out by cytochrome P450, a family of enzymes located
primarily in the microsomal or smooth endoplasmic retic-
ulum fraction of the liver.79,80 This pathway is very non-
specific in terms of structural requirements and oxidizes
most lipid soluble compounds. It is this pathway that is
responsible for the initial oxidation of the oxazaphospho-
rine ring of the oxazaphosphorines cyclophosphamide and
ifosfamide, a reaction leading to the conversion of these
compounds to their active metabolites.81–84
Knowledge of the metabolism of cytotoxic agents is
important in designing treatment strategies, for example,
intravesical delivery of cyclophosphamide would make
no sense, as the drug requires hepatic metabolism to its
active form to be effective (see later). In the patient with
hepatic dysfunction or failure, impaired hepatic conjuga-
tion and/or oxidation will alter the metabolism of dox-
orubicin, the taxanes, irinotecan, and the vinca alkaloids,
whereas the microsomal activation of cyclophosphamide
may be impaired in this clinical setting.85–91
Excretion
Excretion of cytotoxic agents occurs predominantly in
the kidneys and liver, and abnormalities in the function of
56 Part I Principles of Urologic Oncology
either or both organs may substantially influence the pat-
tern of toxicity.85 Renal dysfunction will particularly
affect the disposition of the platinum complexes,
methotrexate, and bleomycin,92–95 and this may be an
important issue in a patient with renal tract outflow
obstruction due to a large primary tumor of bladder,
prostate, or urethra or with obstruction from enlarged
retroperitoneal nodes.
Factors Modifying Pharmacokinetics
Absorption of drugs may be affected by diseases of the GI
tract, previous surgery, compounds that change the pH
of the gut, coadministration of other drugs, and a variety
of other factors.96–98 Distribution can be influenced by
disease states, such as cardiac failure, ascites, pleural effu-
sion, and edema.99 Age and amount of adipose tissue may
have an impact on the clearance and toxic effects of cyto-
toxic agents. For example, obesity appears to reduce the
clearance of both doxorubicin and ifosfamide,100,101
although it is not clear that this has an impact on toxicity
of the individual drugs. Age may alter disposition of dox-
orubicin; for example, Robert and Hoerni102 demon-
strated reduced clearance in older patients, compared
with younger cohorts. Numerous factors have been
shown to affect the rate at which drugs are metabolized
by cytochrome P450 microsomal enzymes in the gut and
liver.79,98,103A large number of compounds can induce
P450, including phenobarbital, carbamazepine, rifampin,
and phenytoin, chlorinated hydrocarbon insecticides,
food additives, and tobacco consumption. Some antineo-
plastic agents may inhibit drug metabolism, as may the
occurrence of hepatic disease.104,105 Excretion of com-
pounds by the kidneys depends heavily on renal function.
Coincidental administration of compounds that can com-
pete for tubular reabsorption may have an effect on renal
clearance of certain compounds,106 as may urinary pH if
the compound is able to become ionized.94,107,108
MECHANISMS OF DRUG RESISTANCE
There are several mechanisms of resistance to cytotoxic
chemotherapy (Table 4-1). In general, these can be clas-
sified on the basis of cellular distribution. Intracellular
factors include those that act at the cell surface, others
within the cytoplasm, and those that function at the level
of the nucleus. In addition, there are extracellular factors,
such as those that affect the distribution and metabolism
of the drugs, including competitors for cellular transport
mechanisms.
Some cytotoxic agents can be exported from tumor
cells through a mechanism based on the cellular surface,
the so-called multidrug efflux pump, which was origi-
nally characterized by the expression of a specific 170 kD
protein complex, P-glycoprotein.109–111 It was initially
demonstrated that response to the cellular effects of
agents as diverse as the vinca alkaloids, actinomycin D,
estramustine, mitoxantrone, and doxorubicin is reduced
in normal and malignant cells that express a protein
complex on the cell surface, coded by a series of mul-
tidrug resistance (mdr) genes.112–114 This occurs as a
result of reduced intracellular concentrations of the
agents due to increased cellular efflux.115 Expression of
the mdr phenotype may be present before therapy or
appear as a result of induced resistance during treat-
ment.116 More recent research has elucidated a diverse
family of P-glycoproteins that acts physiologically to
facilitate influx and efflux of xenobiotics from a variety of
cells.117,118 Alteration in the expression and activity of
these molecules can have a significant effect of drug
pharmacokinetics both at a whole body and cellular
level.119
Expression of mdr phenotype has been identified in
renal carcinoma,120 although its significance has been dif-
ficult to define as most renal carcinomas are resistant to
the available cytotoxic agents, and the presence/absence
of this phenotype does not correlate with outcome. The
study of the multidrug phenotype in bladder cancer cells
has also proved to be a difficult problem, as the expres-
sion of P-glycoprotein in bladder cancer has been highly
variable and inconstant.121–124 It has now been shown
that expression of P-glycoprotein may be upregulated in
resistant populations of bladder cancer cells after treat-
ment with the MVAC regimen.125 In other tumor types,
multidrug resistance can occur in the absence of expres-
sion of the 170 kD P-glycoprotein, whereas other pro-
teins may be associated with very similar patterns of
resistance,126 perhaps explaining this phenomenon in the
absence of expression of this P-glycoprotein.
Ultimately, apart from its predictive function, this
work is unlikely to be of great importance unless the mdr
phenotype can be overcome at a functional level.127 For
example, the calcium channel blockers, such as vera-
pamil, have been shown to reverse multidrug resist-
ance,128 although the toxic side effects of this approach
have precluded routine use while some data suggest that
compensatory effects such as altered blood flow may
diminish tumor sensitization at clinically attainable con-
centrations.129 Although clinical trials have not yet been
published in bladder cancer, work initiated in our labora-
tories suggests that verapamil can overcome the impact
of the mdr phenotype, at least in bladder cancer cell lines
in vitro.130
Furthermore, Brandes et al.131,132 have shown that
N,N-diethyl-2-[4-(phenylmethyl)phenoxy]-ethanamine
(DPPE, Tesmilifene), an intracellular histamine antago-
nist, enhances the anticancer effect of cytotoxic agents
and that DPPE may modulate the function of the P450
hepatic enzyme system and may alter the expression of
multidrug resistance phenotype. They have shown that
 Chapter 4 Principles of Chemotherapy for Genitourinary Cancer 57

Table 4-1 Mechanisms of Tumor Drug Resistance

Example or Potential Cause

Macro-pharmacokinetic mechanisms: ineffective dose of drug in the body

Inadequate dose Miscalculation or decreased dose due to prior excessive toxicity

Inadequate absorption Short bowel syndrome after surgical resection or coingestion

of drug binder such as cholestyramine

Induced metabolism P450 microsomal enzyme-inducing drug for liver metabolized agent such as
paclitaxel or docetaxel

Failure to metabolize to active drug Ifosfamide or cyclophosphamide

Induced excretion

Micro-pharmacokinetic mechanisms: ineffective intracellular concentration of drug

Impaired tumor blood flow Local radiotherapy or scarring after surgery, sanctuary site such as central nerves
system or testis

Impaired tumor uptake Methotrexate

Induced intracellular metabolism 5-FU metabolism, methotrexate

of drug to inactive or exportable
metabolite

Drug efflux P-glycoprotein and doxorubicin

Pharmacodynamic intracellular mechanisms

Mutated target that does Tubulin mutations and taxane or vinca alkaloid therapy. Androgen receptor
not respond to drug mutation for androgen deprivation

Overexpressed target that Thymidylate synthetase and fluoropyrimidines

overcomes drug effect

Compensation by cellular mechanisms DNA repair enzyme over expression and platinum drugs. Apoptosis resistance due
to mutated p53 or overexpressed Bcl2. Lack of cell cycle response due to pRB
mutation, cyclin overexpression, or loss of CDK inhibition

DPPE appears to enhance the anticancer efficacy of
cyclophosphamide against hormone-refractory PC
(HRPC), an observation that we have confirmed for
mitoxantrone.133
The mechanisms of resistance to the platinum coordi-
nation complexes have been studied in detail, particularly
in relation to ovarian cancer and malignant melanoma.
Although several mechanisms have been identified,
including factors that influence cellular accumulation, sig-
nal transduction, ionic fluxes, and intracellular enzyme
function,134,135 the function of the intracellular scavenger,
glutathione (GSH), has increasingly been the focus of
particular attention in the context of the resistance of
bladder cancer to the effects of cisplatin. GSH is found in
most mammalian cells and has many functions, including
regulation of protein and DNA synthesis and detoxifica-
tion. It appears to react with cisplatin, reducing its intra-
cellular availability. Inhibitors of GSH synthesis, such as
buthionine sulfoximine, have been shown to cause a
decrease in intracellular levels of GSH with a concomi-
tant increase in the cytotoxicity of some anticancer agents,
such as the alkylating agents, cisplatin136 and paclitaxel.137
Although much of the experimental data regarding the
significance of glutathione in cisplatin resistance has been
derived from models of ovarian cancer, very high levels of
glutathione are present in cell lines derived from bladder
cancer, and this may correlate with cisplatin resistance.138
It should be emphasized that our understanding of
these mechanisms is relatively crude, and there appear to
be other factors that influence the responsiveness of
bladder cancer to cytotoxic chemotherapy. It appears that
the expression of several oncogene products may influ-
ence resistance to cytotoxic agents. The exact nature of
this interaction is not yet clear and is particularly difficult
58 Part I Principles of Urologic Oncology
to define as several of these products code for specific
aspects of cellular growth control irrespective of expo-
sure to cytotoxic agents. For example, it has been shown
that the interaction of EGF and its specific receptor
(EGFR) are involved in the regulation of growth of blad-
der cancer. However, in vitro treatment with EGF can
increase cellular sensitivity of epithelial tumors to cis-
platin.139,140 Conversely, it has also been shown that spe-
cific monoclonal antibodies and small molecules block
EGFR function,141 and treatment with these agents plus
cisplatin can cause a synergistic antitumor effect.142
These data are particularly difficult to interpret in view
of the previously documented impact of expression of
EGFR on the natural history of bladder cancer, and the
demonstration that erbB-2 gene amplification and over-
expression is an adverse prognostic determinant in blad-
der cancer.143–145 Recent clinical trials have not
delineated a clear additive or synergistic effect of anti-
EGFR therapies with cytotoxic chemotherapy but this is
not surprising given the conflicting preclinical model
data available.
Another complex relationship has been demonstrated
between the expression of p53 (a suppressor gene prod-
uct), growth regulation, and cytotoxic response in blad-
der cancer. Alterations of the p53 gene are among the
most frequent genetic abnormalities found in human
cancer146 and appear to have a broad range of postulated
roles in cell growth control, including involvement in
cellular repair and apoptosis.38 Apoptosis is regarded as
one of the forms of physiologic cell death as it represents
a genetically determined cellular sequence that is part of
the normal tissue homeostatic mechanism. It has been
shown that p53, which is normally present only tran-
siently, can be induced to accumulate within the cell by
exposure to cytotoxic agents, such as cisplatin and mito-
mycin C, and conversely that p53-dependent apoptosis
modulates the cytotoxicity of radiotherapy, 5-FU, and
doxorubicin.147–151 These issues may be of particular
importance as it has already been postulated that p53
expression may constitute an independent prognosticator
of response to the MVAC regimen.152,153 As p53 may be
induced by cytotoxic exposure, it is possible that the tim-
ing of tissue sampling may be critical in determining the
expression of this potential prognostic factor, especially if
intravesical or systemic chemotherapy has been used
previously.
Models for Overcoming Drug Resistance of Tumor
Populations: Clinical Implications
Several models have been proposed to explain the vary-
ing levels of resistance to the impact of chemotherapy
seen in human tumors. For example, Goldie and
Coldman154 proposed that tumors have a spontaneous
mutation rate and that the larger the number of tumor
cells, the greater the chance of spontaneous mutation.
As a consequence, they proposed that the most effective
mechanism for cancer killing would be to initiate
chemotherapy early (with a small cellular burden) and
to introduce multiple agents in an attempt to overcome
the various mechanisms of resistance. To date, this
hypothesis has not been validated in clinical trials,
although most of the studies reported have been flawed
and have not truly evaluated the principles of this
hypothesis.
Another model of resistance, proposed after a
reassessment of the model presented by Goldie and
Coldman,155 leads to the conclusion that cytotoxic
agents can be used most effectively in sequence rather
than as combination schedules. Thus an initial series of
treatments with the less effective of two drugs would
eliminate a proportion of the tumor cells present, leav-
ing behind a resistant population that may respond to
several courses of treatment with the more effective
drug; in this way, it is postulated that the impact of the
less effective therapy can be maximized.155
ASSESSMENT OF THE EFFICACY
OF ANTICANCER TREATMENT
The efficacy of anticancer treatment can be assessed in a
variety of ways, depending on the endpoints under con-
sideration. In most current studies, a reduction in
tumor-related symptoms (subjective response), the
development of tumor shrinkage (objective response),
length of disease-free or overall survival or improvement
in quality of life are regarded as significant indices of
patient benefit in response to treatment. In order to
assess these outcomes objectively and accurately, we use
the process of the clinical trial wherein a defined popu-
lation of patients, who fit specified criteria, are managed
according to a defined protocol with specified measure-
ment of outcome. A clinical trial may be one of two
types66,156: (i) An “explanatory” trial has the primary aim
of acquisition of information. Thus it usually only
requires small numbers of patients and often has a bio-
logic endpoint (e.g., tumor response). A typical example
is the assessment of the new anticancer agent, gem-
citabine, in the treatment of advanced bladder cancer,
which provides the documentation of response and tox-
icity but does not give comparative information versus a
standard type of treatment. It is often appropriate to
report only the patients who are fully treated (complete
the minimum requirements of the protocol of assess-
ment) in order to minimize the chance of rejecting an
active new approach. However, this may overestimate
the potential benefit of the drug in the general patient
population. (ii) A “pragmatic” trial is concerned with the
assessment of comparative patient benefit, which can
then be used as a guide to decision-making in treatment.
 Chapter 4 Principles of Chemotherapy for Genitourinary Cancer 59
For example, the recent intergroup randomized trials
that compare neoadjuvant intravenous chemotherapy
plus locoregional treatment versus locoregional treat-
ment alone for invasive bladder cancer are pragmatic tri-
als and require large numbers of patients.157–159 As the
goal of a pragmatic trial is to determine overall benefit
to all eligible patients, endpoints should include both
quality and quantity of survival, and it is important to
report the outcome for all entered patients, irrespective
of treatment received.
Another classification of clinical trials is according to
the descriptors, “phase I,” “phase II,” “phase III,” and
“phase IV”. A phase I trial is designed to determine the
appropriate clinical dosage of a new treatment (often
being translated from preclinical studies) and to assess
the side effects of this treatment. Such trials will often
incorporate pharmacologic studies that will allow a
clearer understanding of the distribution and metabolism
of the novel agent in humans. Although anticancer
response is recorded, this is not a primary endpoint of a
phase I trial, and the process of consent must make
patients understand that the chance of a significant
tumor shrinkage is only small. Patients will often partic-
ipate in such trials in the hope that they may secure the
small percentage chance of success, or occasionally for
reasons of altruism.160 Regrettably, it has become
increasingly clear that patients often have a very poor
understanding of the true purpose of phase I trials and of
the small likelihood of individual patient benefit.161
Phase I trials are explanatory in nature and should be
designed to minimize the expenditure of patient
resources, usually with only 3 to 4 patients being entered
at each dose level.162 These numbers allow relatively
accurate identification and description of toxicity at each
dose level, without the necessity to treat unreasonably
large numbers of patients at potentially subtherapeutic
doses.
Unless the toxicity from a phase I trial is prohibitive or
truly unpredictable and dangerous, the new agent will
usually proceed to phase II testing. In most cases, an
absence of antitumor activity in phase I testing will not
necessarily preclude initial phase II assessment, although
demonstration of activity in phase I testing tends to raise
the priority of a novel agent for further investigation.
Phase II trials are also explanatory and attempt to define
the extent to which a new approach has antitumor activ-
ity. These studies usually involve treatment of defined
groups of patients with a particular disease with a prede-
termined dosage of a novel agent, with assessment of
tumor shrinkage and toxicity as primary endpoints. The
demonstration of tumor shrinkage does not equate with
long-term patient benefit, which is assessed subsequently
in a phase III trial. Detailed mathematical assessments of
patient numbers required to document true anticancer
efficacy, minimizing false positive and false negative out-
comes, have been published elsewhere.163–165 In general,
phase II studies require relatively small numbers of
patients (usually less than 50, depending on the number
of responses seen).
Phase III trials are designed to define the role of a
new treatment compared to a standard approach. These
studies are pragmatic in concept and usually require ran-
domization and relatively large numbers of patients. The
number of required patients is predicated on the level of
statistical confidence (power) that is required for the
outcome.
A more recent term, the “phase IV” trial, is used to
describe a post-marketing study—that is, one in which a
pharmaceutical company attempts to develop additional
information regarding the indications for a newly
approved agent (which is now being marketed); sometimes
such studies are actually marketing (or “seeding”) studies,
in which the primary purpose of the trial is to increase the
level of interest or familiarity among physicians.
The requirements of these clinical trials and a detailed
discussion of the potential sources of error (Table 4-2)
are beyond the scope of this chapter but have been
reviewed elsewhere.66,166
SPECIFIC AGENTS COMMONLY USED AGAINST
GENITOURINARY CANCERS
Platinum Complexes
Cisplatin (cis-diamminedichloroplatinum II) was intro-
duced into the clinic in 1972 when observations by
Rosenberg167 of its activity in interfering with the growth
of Escherichia coli led to the demonstration of broad-
spectrum antitumor activity in experimental tumors. The
lead compound of the platinum antitumor drugs, cis-
platin (Figure 4-1), has contributed in a major way to the
development of cure in testicular germ cell tumors and is
highly active in combination in bladder cancer.
The mode of action of the platinum complexes
involves the formation of positively charged (electron-
deficient) moieties that form adducts with DNA. These
Table 4-2 Potential Sources of Error in Clinical Trials
Failure to establish uniform reporting criteria of efficacy
and toxicity
Measurement error
Bias in patient sampling: selection, exclusion
Insufficient patient numbers
Use of historical controls
Stage migration
Inadequate follow-up
60 Part I Principles of Urologic Oncology
O O
H3N Cl H3N O NH2
Pt Pt
H3N Cl H3N O NH2
O O
1 2
Figure 4-1 Structures of cisplatin (1), carboplatin (2), oxaliplatin (3).
adducts are primarily intrastrand cross-links. Interstrand
cross-links also form but in much smaller amounts. They
are, however, much more lethal than the intrastrand
cross-links. The contribution of the two types of adducts
to the overall cytotoxicity of platinum complexes is a
matter of dispute. Based on the sites of action of cisplatin,
its major focus of activity is in the G1 and S phases of the
cell cycle. Resistance to the platinum complexes may be
due to impaired cell uptake of the drug,168 inactivation of
the active species by intracellular thiols (primarily glu-
tathione),138,69,170 and enhanced capacity of the cell to
repair the damage to DNA.171–174
Cisplatin is usually administered intravenously or
intraarterially, and in both instances it has been shown
that its most dangerous toxic side effect, nephrotoxicity,
is markedly reduced or eliminated if a high urine output
is maintained (via enforced parenteral hydration before,
during and after cisplatin administration, augmented by
the use of mannitol, and in some instances small doses of
furosemide). In early studies, cisplatin was administered
for intravesical use by instillation through a urinary
catheter, but unpredictable allergic reactions with occa-
sional anaphylaxis were documented, and this indication
is no longer under investigation.
Measurement of total plasma platinum after adminis-
tration of cisplatin shows a triphasic disappearance curve
with half-life values of 20 minutes, 1 hour, and 24
hours92,175; the terminal phase probably reflects the slow
release of platinum from plasma proteins. More than
90% of excretion is via renal mechanisms (a combination
of glomerular filtration and tubular secretion), with less
than 10% due to biliary excretion. The plasma decay of
unchanged cisplatin generally has a monophasic pattern
with a t1/2 of less than 1 hour.176
Renal failure, with acute tubular necrosis, degenera-
tion, and interstitial edema, is the dose-limiting toxic
effect, as noted above.177,178 Additional side effects of
parenteral administration include severe nausea and
vomiting, diarrhea, and occasional anaphylaxis.
Ototoxicity, manifested by high frequency hearing loss,
has been well documented, with a greater level of dam-
age demonstrated by audiometry than on clinical
grounds. With higher doses of cisplatin, and especially in
O C
Pt
O C
3
combination regimens that include the vinca alkaloids,
neurotoxicity is an important side effect. This may pres-
ent clinically as peripheral or autonomic neuropathy and
may be seen more commonly on nerve conduction test-
ing.179 A range of cardiovascular side effects has been
reported, including hypertension, myocardial infarctions,
EKG abnormalities, and an increased risk of peripheral
thromboembolic phenomena and Raynaud’s phenome-
non.180 However, in some cases, the relationship between
cisplatin and these side effects is obscured by the impact
of antecedent cigarette smoking by the population of
patients under treatment. Myelosuppression may occur
with standard doses of cisplatin, with anemia occurring in
particular. Occasionally a Coombs’ positive hemolytic
anemia has been documented. Leukopenia and thrombo-
cytopenia occur sometimes but are usually not dose lim-
iting. In an attempt to overcome the substantial toxic
effects of this useful agent, a range of analogs has been
developed in an effort to reduce toxicity without loss of
activity (see later).
Cisplatin is still among the most widely used cytotoxic
agents in the management of genitourinary cancer. In
addition to being one of the drugs of choice in the man-
agement of germ cell tumors and bladder cancer, cisplatin
has activity against adenocarcinoma and small cell carci-
noma of the prostate, adrenal cancer, and penile cancer.
Carboplatin
As noted earlier, cisplatin is one of the most active and
useful agents in the management of genitourinary malig-
nancy. However, its substantial toxicity has led to the
search for analogs with equivalent anticancer activity but
a reduced pattern of side effects, culminating in the intro-
duction of several second-generation compounds into
clinical trials. One of these, carboplatin, was developed
largely at the Institute for Cancer Research in the United
Kingdom and is now commercially available in the
United States. While considerably less toxic than cisplatin
(it has very little nephrotoxicity, considerably less neuro-
toxicity and ototoxicity, and produces much less nausea
and vomiting), it is highly cross-resistant with the older
compound. This may be related to the fact that once the
 Chapter 4 Principles of Chemotherapy for Genitourinary Cancer 61
cyclobutanedicarboxylato-leaving group has separated
from the molecule, the structure of the active hydrated
species is identical to that of cisplatin (see Figure 4-1).
Thus the major difference is in the kinetics of the forma-
tion of the active species.181 Carboplatin is much more
stable in serum than cisplatin and diffuses into tissues rap-
idly so that only 24% of a dose is bound by plasma pro-
tein 4 hours after a dose.182 The terminal serum half-life
of platinum is similar in patients given either carboplatin
or cisplatin.93 The elimination of carboplatin occurs pre-
dominantly through the kidneys, where renal clearance
closely parallels glomerular filtration rate.183,184On this
basis, Calvert has developed a formula, based on creati-
nine clearance, that predicts safe carboplatin doses for
individual patients relative to the chance of myelotoxicity,
specifically thrombocytopenia.184
Carboplatin has activity in testicular, urothelial, and
prostate185–187cancers but not renal cell cancer. Despite
this it has failed to establish itself as first-line therapy in
any urologic malignancy. Its equivalence with cisplatin
has been demonstrated against lung cancer188,189 and in
ovarian cancer,190,191 but this has not been the case in
genitourinary cancer.192,193 Of particular importance, it
appears that carboplatin is inferior to cisplatin for man-
agement of cancers of the testis and bladder. However, in
combination carboplatin may be incorporated into regi-
mens that will eventually prove to have favorable efficacy
toxicity profiles compared to those incorporating cis-
platin. The results of trials directed at proving this in
urologic cancer have been inconclusive or disappointing
to date.194–197 Carboplatin remains a well-tolerated,
largely second-line therapy in a range of genitourinary
malignancies.
Oxaliplatin
Oxaliplatin was synthesized by Kidani et al.,198 and there
is evidence that in solutions containing high chloride
content the oxalato group is replaced by chloride.199 The
drug produces a characteristic peripheral neuropathy that
is characterized by a cold-induced dysesthesia, which
tends to be cumulative.200,201 Oxaliplatin has undergone
extensive phase II and phase III clinical trials predomi-
nantly in gastrointestinal malignancies, while demon-
strating some activity in a range of cancers including
urothelial tumors in phase I testing.202 A group of
German investigators has shown significant anticancer
effect in patients with previously treated germ cell
tumors. As a result of these trials, oxaliplatin has recently
been licensed internationally for the treatment of col-
orectal cancer.203 It will be further evaluated in other pri-
mary tumor sites, including bladder cancer and germ cell
tumors, for increased activity compared to cisplatin and
carboplatin204,205 or for activity in platinum-resistant
tumors.
Anticancer Antibiotics
Bleomycin
Bleomycin is isolated from the fungus Streptomyces vertic-
ullus and consists of a complex molecule of high molecu-
lar weight. It is composed predominantly of so-called A2
peptides, which contain a DNA-binding portion and an
iron-binding component at the opposite end (Figure
4-2). Its primary action is to produce single-strand and
double-strand breaks in DNA through the action of oxy-
gen radicals formed in association with activation of the
Fe++–bleomycin complex that binds to nitrogen-containing
groups in the bleomycin molecule. The entire complex,
consisting of Fe++–bleomycin–oxygen binds to DNA,
through intercalation by the bithiazole groups of
bleomycin, and DNA damage is created through the for-
mation of superoxide or hydroxyl radicals. Tumor cells
are most sensitive to the effects of bleomycin in late G2
or the M phase,206 although cells may also be killed in G1
phase.207 The mechanism of resistance to bleomycin has
not been delineated with certainty, although it does
appear that a cytosolic hydrolase may function to inacti-
vate the drug.208
Bleomycin is administered either by subcutaneous
bolus dosing, intravenously (bolus or continuous infu-
sion) or by intramuscular injection. The optimal route
has not been defined, although it is most commonly used
(in combination with cisplatin and etoposide) as a weekly
bolus dose. Bleomycin has a biphasic clearance, with t1/2α
of about 20 minutes and a t1/2β of about 3 hours.
Bleomycin is excreted predominantly via the kidneys,
with more than 50% being excreted in the first 24
hours.95 Of importance, the dosage should be modified in
a patient with impaired renal function, and caution
should be used when the drug is administered after cis-
platin, which can cause transient renal dysfunction.
The major toxic effect of bleomycin is interstitial
pneumonitis, the pathogenesis of which is poorly under-
stood. The syndrome may be characterized by the evolu-
tion of subtle pulmonary symptoms, including cough,
dyspnea on exertion, chest pain, and fever, or occasion-
ally may be revealed only by changes in lung function
tests. Pulmonary toxicity occurs especially in older
patients, those who have previously received pulmonary
or mediastinal irradiation, those with underlying lung
disease, and in particular in cigarette smokers. In a study
of the chronic toxic effects of bleomycin, we were unable
to demonstrate major pulmonary toxicity in patients who
did not smoke.179 In our experience, the acute toxicity of
bleomycin can usually be ameliorated by corticosteroids,
although care should be taken to avoid tapering the dose
too quickly. Other side effects include mild myelosup-
pression, allergic reactions, fever, Raynaud’s phenome-
non, and cutaneous pigmentation.
The major indication for the use of bleomycin is in the
management of germ cell tumors, and most attempts to
62 Part I Principles of Urologic Oncology

NH2

H2N O NH2

N
O O
H
R1

N
O
H
O HO N
H2N 6
O NH N
N N O
H H HO 6

N
O CH3
HO N BLEOMYCIN A2 –NH(CH2)3 S+
OH OH
O H CH3

O NH2
1 OH
OH BLEOMYCIN B2 –NH(CH2)4 N +
O H
OH NH2

O NH2

O OH
O OH
O
O CH2O C NH2 OH

H2N OCH3
O
CH3 CH3O O OH
N N
3
CH3 O
O NH2
2
HO

H
N
OH O HN OH

OH O HN OH
N
H
4

Figure 4-2 Structures of bleomycin (1), mitomycin C (2), doxorubicin (3), mitoxantrone (4).
 Chapter 4 Principles of Chemotherapy for Genitourinary Cancer 63
delete it from standard protocols have resulted in
reduced pulmonary toxicity but at the expense of a
reduced cure rate.209,210 In addition, it has also been
applied in some series to the management of advanced
cancer of the penis. There appear to be no current indi-
cations for its use in the treatment of bladder cancer,
renal carcinoma, or PC.
Mitomycin C
Mitomycin C is an anticancer and antibacterial antibiotic
isolated from Streptomyces caespitosus.211 It is unusual in
that it undergoes activation in a hypoxic environment, a
characteristic of solid tumors. It is activated by visible
(but not ultraviolet light) and is unstable in acidic and
extreme basic conditions. Mitomycin is activated by
reduction of a quinone moiety, mediated by microsomal
enzymes, such as cytochrome reductase, DT-diaphorase,
xanthine oxidase or cytochrome P450 reductase, or even
by exposure to acidic pH. This releases a methanol side
chain from the molecule and allowing an aziridine ring to
open (see Figure 4-2). This exposes the alkylating site.
The alkylating agent cross-links complementary DNA
strands. Oxygen-free radicals may also participate in the
cytotoxic function of mitomycin C through the produc-
tion of DNA strand breaks.212,213
Mitomycin is usually administered by intravenous
injection or through a urinary catheter for intravesical
use. Its large molecular weight allows it to be retained
within the luminal surface of the bladder, without signif-
icant systemic absorption. Because the drug is degraded
at acid pH, the urinary pH must be maintained at alka-
line levels for intravesical use.
Because of its ubiquitous metabolism, mitomycin is
cleared rapidly after intravenous or intraarterial injec-
tion. Renal excretion is minor (10% of administered
dosage), and hepatic excretion seems to play only a minor
role despite the importance of hepatic inactivation.
Hepatic dysfunction does not appear to alter the phar-
macokinetics of this drug to any great extent.214,215
The major toxic effect of mitomycin is myelosuppres-
sion, which involves platelet, leukocyte, and erythrocyte
precursors.62 Of importance, this myelosuppression may
be delayed and can occur 6 to 7 weeks after treatment.
The level of myelosuppression correlates with dosage,
and there appears to be a cumulative effect as well. Other
side effects include gastrointestinal disturbances, occa-
sional stomatitis, and renal toxicity.216,217 Mitomycin C
can occasionally induce microangiopathic hemolytic ane-
mia with associated renal failure (the hemolytic-uremic
syndrome); this syndrome can be delayed in onset.216,217
Not infrequently, mitomycin C will cause interstitial
pneumonitis, especially in high cumulative doses and in
patients who have had prior chest irradiation; the syn-
drome is characterized by progressive cough and dysp-
nea, accompanied by changes in pulmonary function
tests, and responds dramatically to high dose corticos-
teroids.218 Mitomycin C is a vesicant and causes extensive
soft tissue reaction if extravasated; sometimes the ulcera-
tion will occur as a delayed phenomenon.
The major indications for the use of mitomycin C
include intravesical administration for superficial bladder
cancer and intravenous administration for advanced blad-
der cancer; activity of mitomycin has also been demon-
strated in the management of adenocarcinoma of the
prostate and in advanced penile carcinoma. There is no
routine role for this agent in the management of renal
carcinoma, germ cell tumors, or adrenal carcinoma.
Doxorubicin and Other Anthracyline Antibiotics
Doxorubicin (Adriamycin) is a high molecular weight
anthracycline antibiotic isolated from Streptomyces
peucetius var. caesius. Its structure includes a water-soluble
basic reducing amino sugar linked by a glycosidic bond to
carbon atom 7 on the D ring of the chromophore agly-
cone, adriamycinone. This four-ring planar structure
constitutes the anthraquinone nucleus (see Figure 4-2).
Several analogs are in clinical use, including epirubicin
(which differs in the steric configuration of the −OH
group on the 4′ position of the daunosamine sugar) and
idarubicin (which lacks an A ring −OCH3 substitution).
A detailed discussion of each of these agents is beyond
the scope of this review but has been covered elsewhere
in detail.219
There appear to be several possible mechanisms of
cytotoxic action of the anthracycline antibiotics, includ-
ing the formation of free radicals, intercalation between
nucleotide pairs in the DNA molecule, and the initiation
of topoisomerase type II-dependent DNA fragmenta-
tion.220 Doxorubicin appears to be active in all phases of
the cell cycle, with its maximal effect in S phase; however,
it is not phase specific. For example, its topoisomerase
type II function is concentrated in G2.
Doxorubicin and epirubicin can be administered by
bolus or continuous intravenous or intra-arterial injec-
tion or via urinary catheter for intravesical use. These
drugs have a characteristic red color. Doxorubicin is
extremely vesicant, and great caution should be used in
its administration. After intravascular administration,
the pharmacokinetics of doxorubicin and analogs are
best represented by two- or three-compartment model-
ing.221 The plasma half-lives are 11 minutes, 3 hours,
and 25 to 30 hours; it is likely that the long terminal
phase is due to slow dissociation from DNA. These
agents are rapidly distributed (into liver, lymph nodes,
muscle, bone marrow, fat and skin but not central nerv-
ous tissue), and more than 70% is bound to plasma pro-
teins. These drugs are extensively metabolized and are
excreted predominantly in the bile and feces. Biliary
64 Part I Principles of Urologic Oncology
excretion accounts for more than 40% of each dose,87
whereas less than 10% is excreted in the urine.
Obstructive hepatic dysfunction interferes with the dis-
position of these agents and mandates dose modifica-
tion, whereas hepatocellular dysfunction without
impaired conjugation does not seem to require these
changes in dosing.222 One potentially attractive feature
of idarubicin is its retention of antitumor activity when
administered orally. Although apparently useful in the
treatment of leukemia and lymphoma, its utility against
the solid tumors appears more limited.
The most common dose-limiting acute toxic effect is
myelosuppression, with leukopenia at 10 to 14 days after
treatment. Thrombocytopenia and anemia occur but are
less clinically important. As noted above, doxorubicin is a
significant vesicant and can produce extensive ulceration
and soft tissue necrosis after extravasation. The other
dose-limiting toxic effects are found in the heart. Dose-
related cardiomyopathy has been extensively described223
and usually occurs with cumulative doses greater than
500 to 550 mg/m2 in previously untreated patients.
These effects are more pronounced with conventional 3
weekly bolus dosing than if weekly low dose bolus dosing
or 96-hour continuous low dose infusion is implemented.
Other factors that predispose to cardiac toxicity include
known cardiac disease, prior mediastinal or cardiac irra-
diation, age greater than 70 years, and chronic hyperten-
sion. In addition to cardiomyopathy, other cardiac
effects have been recorded, including nonspecific EKG
changes, occasional rhythm disturbances, an uncommon
myocarditis-pericarditis syndrome, and rarely sudden
death. It has been suggested that epirubicin may be less
cardiotoxic than doxorubicin, although the contrary view
has been expressed that equiactive doses of the two
agents are equitoxic.224
Of importance, doxorubicin is a radiosensitizer and
has a radiomimetic function—thus it will cause recall
reactions in areas previously treated with radiotherapy.225
Other toxic effects include nausea, vomiting, stomatitis,
and alopecia.
The clinical indications for the use of this group of
agents against the genitourinary cancers have been
defined on the basis of the activity of doxorubicin. At
present, it is still not clear whether the analogs, epiru-
bicin and idarubicin, offer any clear advantage in this
context. Doxorubicin has been identified as one of the
agents of choice for use against superficial and advanced
bladder cancer and has significant activity against adeno-
carcinoma and small cell carcinoma of prostate. In previ-
ous experience, in particular at the University of Indiana
and at the Memorial Sloan Kettering Cancer Center in
New York, doxorubicin was built into combination
chemotherapy regimens for germ cell tumors but has
been deleted in more recent trials, based on randomized
trials in Indiana in which it appeared not to add to the
anticancer effect of standard cisplatin-based combination
regimens. Limited activity against adrenal carcinoma has
been recorded,226,227 but the drug appears to be inactive
against renal carcinoma.228
Mitoxantrone
Mitoxantrone is an anthracenedione, structurally related
to the anthracyclines.229,230 In comparison with anthracy-
clines the structure of mitoxantrone maintains the planar
polycyclic aromatic ring associated with intercalation but
is without their characteristic sugar moiety associated
with production of intracellular free radicals implicated
in anthracycline cardiotoxicity (see Figure 4-2). It has
characteristic blue color and is administered as an intra-
venous infusion.230
Mitoxantrone is highly protein bound in serum
(>95%) and has a very large volume of distribution (450
to 5200 l/m2).231–235 It undergoes hepatic metabolism and
biliary excretion with only around 7% of drug found
unchanged in the urine.231 This suggests that dose reduc-
tion in liver disease may be warranted while adjust-
ment for renal impairment may not be of value.236 The
terminal half-life is long ranging from 8.9 to 189
hours.235,237,238 Mitoxantrone acts through DNA interca-
lation, DNA–protein cross-linkage and DNA–DNA
linkage, and topoisomerase II inhibition.236
The major acute toxicity of mitoxantrone is myelo-
suppression, especially neutropenia, while nausea and
vomiting tends to be mild. Cardiac toxicity occurs with
mitoxantrone but is less common than with the anthra-
cyclines. Alopecia secondary to mitoxantrone administra-
tion is normally mild.239 Mitoxantrone has significant
activity in PC but not other genitourinary cancers.240,241
It has been licensed by the FDA for use in symptomatic
HRPC based on the results of a randomized trial con-
ducted by National Cancer Institute of Canada showing
major improvement in quality of life.242–244 The potential
role of mitoxantrone in earlier stage disease is under
intense investigation245,246 and is the subject of a ran-
domized trial being carried out by the Southwest
Oncology Group.
Drugs That Act Through Tubulin Modulation
Vinca Alkaloids
The vinca alkaloids, which occur naturally in the peri-
winkle (Catharanthus roseus), are formed from two multiple-
ring planar units, an indole nucleus and a dihydroindole
nucleus. The two most commonly used drugs, vincristine
and vinblastine, are almost identical, differing only in a
single substitution on the dihydroindole nucleus.247
They both act by binding to tubulin and inhibit micro-
tubule assembly, which in turn inhibits mitotic spindle
formation. This causes an accumulation of cells in
 Chapter 4 Principles of Chemotherapy for Genitourinary Cancer 65
metaphase. Although the vinca alkaloids are thought to
be cell cycle phase specific for mitosis, the cytotoxic
effect probably occurs in S phase and its effect seen in the
M phase. After intravenous administration, the vinca
alkaloids are extensively bound by serum proteins and
blood components and are rapidly cleared from the
plasma and concentrated in various tissues. The disposi-
tion is triphasic,90,248 with a rapid initial half-life (t1/2α
less than 5 minutes), t1/2β of 1 to 2 hours, and t1/2γ of 1 to
3 days. They approximate total body water in their dis-
tribution. The major route of excretion is hepatic,249 with
appreciable amounts appearing in the stool, and liver dis-
ease may necessitate a change in dosage. A small compo-
nent of excretion is urinary.
Although similar in structure, the vinca alkaloids have
substantially different profiles of toxicity. Vincristine is
predominantly associated with neurologic side effects,
including a range of peripheral sensorimotor neuropathic
changes, autonomic neuropathy, jaw pain, and central
nervous system effects. Less commonly vincristine causes
myelosuppression, gastrointestinal effects, alopecia, and
the syndrome of inappropriate ADH production. By con-
trast, vinblastine is associated with predominant myelo-
suppression (in particular granulocytopenia), more
marked gastrointestinal toxicity (especially paralytic
ileus), and alopecia; the neurologic toxicities, while quite
prominent, occur less frequently and less severely than
for vincristine. Both agents are significant vesicants.
The vinca alkaloids have had particular application in
the treatment of advanced germ cell tumors,250,251 small
cell cancer of the prostate, and in bladder cancer (vin-
blastine, in particular)252 but appear to have less single
agent activity in the treatment of prostate adenocarci-
noma, adrenal carcinoma, and renal carcinoma.
As noted earlier, the vinca alkaloids have substantial
clinical activity against the urologic malignancies, in par-
ticular germ cell tumors and urothelial malignancy. For
this reason, the development of new vinca alkaloids with
a higher degree of experimental antitumor activity is of
interest. A potentially promising new agent in this class is
vinorelbine (Navelbine), which has been under investiga-
tion in Europe and has recently been introduced into the
United States. The compound is 5′-noranhydrovinblas-
tine. Although it shares the mode of action of the other
vinca alkaloids, discussed earlier, in experimental systems
it has less affinity for axonal microtubules compared with
its affinity for the microtubules of the mitotic spindle.
This indicates the possibility that it might produce inter-
ruption of mitosis at concentrations that would not give
rise to neurotoxicity.253 It has also shown a higher degree
of activity than vincristine or vinblastine against some
experimental tumors.254,255 In phase I testing, neutrope-
nia was the dose-limiting toxicity, and the maximam tol-
erated dose (MTD) was 35 mg/m2/week. It did give rise
to peripheral neuropathy at higher doses, but this was
relatively mild.256 An initial study of the pharmacokinet-
ics by Bore et al.,257using tritiated vinorelbine and also a
radioimmunoassay, showed a low urinary excretion based
on elimination. The primary excretion route was the
feces, with 34% to 58.4% of the total dose being excreted
by this route over a period of 21 days.257More recently,
Rowinsky et al.258 published the results of a bioavailabil-
ity study in which the drug was given intravenously and
orally to the same patients. Bioavailability was 27% ± 14%.
The volume of distribution was large, 20.02 ± 8.55 l/kg,
and the terminal phase half-life was 18 hours. Plasma
decay was triphasic.258
Vinorelbine has activity in HRPC259 but has not pro-
duced impressive results in limited trials in patients with
testicular germ cell tumors, renal cell carcinoma, or
urothelial cancer.204,260 The activity of vinorelbine in PC
is apparently increased by the concurrent administration
of estramustine but with the consequent side effects
attributable to the estrogenic effects of that drug.261–263
The potential of this combination relative to other
chemotherapeutic approaches in this setting remains to
be determined.
Taxanes
A very important new class of drugs that is being exten-
sively evaluated in a broad spectrum of tumor types is the
taxanes. The two FDA-licensed drugs in this class are
paclitaxel and docetaxel; the structures are shown in
Figure 4-3. Paclitaxel is extracted from the bark of the
western yew tree264; and, initially, this severely limited
the supply of the drug for investigation. Compounded by
the low water solubility of the drug, this slowed the
development of the drug. However, these difficulties
were overcome because of the interest generated by the
high degree of activity of the drug in experimental sys-
tems and because the drug was shown to have a unique
mode of action.265–270 The drug acts on the microtubules,
but unlike the vinca alkaloids, which also interact with
microtubules, the taxanes stabilize the microtubule. It
has been shown that a microtubule is in dynamic equilib-
rium with the tubulin heterodimers, which make up its
structure. These associate at one end and dissociate at the
other. The action of the vinca alkaloids is to prevent the
tubulin from binding and thus the microtubules undergo
spontaneous disassembly. The action of the taxanes is the
opposite. The microtubule is stabilized, so that growth
continues by association of tubulin but disassembly does
not occur. Thus the cell becomes filled with a tangle of
elongated but functionally useless microtubules, leading
to cell death.
Paclitaxel has undergone very extensive testing and is
approved for use in ovarian carcinoma271 and lung can-
cer. In phase I studies, it was initially given by short infu-
sion.272,273 However, acute allergic reactions and
66 Part I Principles of Urologic Oncology

R C O
O
O O R
R OH
R
C NH C CH C O
R
H OH
HO
O
O
R=CH3 O
C
C R
1 O
O
HO H O OH
H
CH3
H OH H3C
O CH3
H
CH3
CH3 NH H O H
H3C HO H O

H3C O O O O H O
O

CH3

Figure 4-3 Structures of paclitaxel (1), docetaxel (2).

disturbances of cardiac rhythm led to progressive length-
ening of the infusion time to 24 hours, which became the
standard for administration of the drug. When given by
24-hour infusion, the MTD was 200 to 275 mg/m2 given
every 3 weeks. The dose-limiting toxicity was neutrope-
nia, which was often profound but short lived and which
relatively uncommonly led to toxic death.274 Other toxi-
cities, as noted above, included acute cardiac effects
(mainly arrhythmias), hypersensitivity reactions, peripheral
neuropathy, and gastrointestinal toxicity. In a phase I
study in leukemia,275 in which grade IV myelosuppres-
sion was accepted as routine, mucositis was the dose-lim-
iting toxicity at a dose of 390 mg/m2. Total alopecia was
another feature, and it involved the hair on the head,
body hair, and eyelashes. It was subsequently recognized
that paclitaxel-related cardiac arrhythmias276 (and in par-
ticular bradycardia, the most common of the paclitaxel-
related arrhythmias) are clinically less dangerous than
initially feared. With suitable premedication with
steroids, H1 and H2 histamine antagonists, the drug can
be safely given by a 3-hour infusion.277 This markedly
reduces the myelosuppression without apparently reduc-
ing the antitumor effect.278,279 One-hour infusion of the
drug is currently under evaluation. These developments
are important in enabling the drug to be given on an out-
patient basis. The pharmacokinetics of paclitaxel were
evaluated during the early clinical studies using high per-
formance liquid chromatography (HPLC) assay for the
drug. Both a biphasic and a triphasic plasma decay have
been described, with the terminal phase half-life being in
the range of approximately 4 to 7 hours for the biphasic
plasma decay and in the range of approximately 10 to 50
hours where a gamma phase was described.280 The earlier
studies reported linear pharmacokinetics, but recent
reports have indicated nonlinear pharmacokinetics with
shorter infusions. Volumes of distribution have been
variable in the reported studies and have been generally
in the range of 50 to 100 l/m2; however, very large vol-
umes of distribution have been described in the study
reported by Huizing et al.281 Very little of the drug is
eliminated unchanged through the kidneys and systemic
clearance appears to result from metabolism, biliary
excretion, and binding to tissue components. The main
route of metabolism is by cytochrome P450-dependent
hydroxylation, the principal hydroxylated metabolite in
bile being 6-hydroxy paclitaxel.282 Of interest, cisplatin
 Chapter 4 Principles of Chemotherapy for Genitourinary Cancer 67
given first in combination with paclitaxel is more toxic
than the reverse sequence. This appears to be related to
the fact that cisplatin inhibits the metabolism of paclitaxel,
causing an increase in the area under concentration ×
time curve (AUC) of the latter drug.283 For the same
schedule of administration, the degree of myelosuppres-
sion is related to the total drug exposure as measured by
the AUC. A shorter infusion gives less toxicity for the
same AUC than a longer infusion, suggesting that dura-
tion of exposure to a minimum cytotoxic concentration
may be an important factor in the toxicity of the drug.284
Paclitaxel has shown antitumor activity in early studies of
germ cell tumors and transitional cell carcinoma of the
urothelium. Patients with germ cell tumors, with prior
therapy, showed a 24% response rate to paclitaxel
250 mg/m2 24-hour infusion with 2 CR and 4 PR in 25
patients.285 Previously untreated patients with transi-
tional cell carcinoma of the urothelium received the same
dose and schedule of paclitaxel and showed a 42%
response rate.286 Studies in renal cell carcinoma have
been negative.287 Early studies with paclitaxel in HRPC
show modest single agent activity,288 and subsequent tri-
als have examined the potential of adding other agents to
the taxanes including estramustine and carboplatin (see
later).185,289
Docetaxel (taxotere, Figure 4-2) is a synthetic analog
of paclitaxel that is prepared from 10 diacetyl baccatin
III, a compound extracted from the needles of the
European yew tree, Taxus baccata. It is thus derived from
a biologically renewable source. It is more potent in vitro
than paclitaxel.290 Although its mode of action is similar,
it is reportedly active against cells, which are resistant to
paclitaxel.290 It has undergone phase I testing in 1-hour,
2-hour, 6-hour, and 24-hour infusions291–293 and as a 1-
hour infusion daily for 5 days.294 The MTD ranged from
70 to 115 mg/m2, and neutropenia was dose limiting in
all of the studies, although mucositis was also a major
toxicity in the study of the 24-hour infusion.293 It has
been suggested that anaphylactic reactions are less com-
mon with docetaxel than with paclitaxel but that skin tox-
icity may be more marked. Plasma decay is triphasic with
a gamma phase t1/2γ of 11.8 ± 6.7 hours.292 Docetaxel has
activity in HRPC,295 where it is currently most com-
monly combined with estramustine,296–298 urothelial can-
cer,299 penile cancer, and testis cancer. It has limited
activity in renal cell carcinoma.300 At present, it is diffi-
cult to be dogmatic regarding the respective merits of
paclitaxel and docetaxel with respect to antitumor effi-
cacy, but it is quite clear that they have different spectra
of toxicity.
Estramustine
Estramustine is constituted by the carbamate linkage of
estradiol and nor-nitrogen mustard molecules and is
therefore best considered a combination hormonal-
cytotoxic therapy. However, the mechanism by which
estramustine exerts its antineoplastic effect is unclear.
Following oral ingestion estramustine phosphate is rap-
idly dephosphorylated and absorbed with a bioavailabil-
ity of 37% to 75%.301 Concurrent ingestion of calcium
rich foods, such as dairy products, can interfere with
estramustine absorption.302 After absorption estramus-
tine is metabolized to estromustine, which is preferen-
tially taken up by and retained in prostate tissue and PC
cells by estramustine-binding protein.303 Estramustine is
metabolized in the liver and excreted in the bile with very
minimal renal excretion.301 The terminal half-life of
estromustine is 10 to 20 hours.301
As a single agent, estramustine has not demonstrated
benefit over continued or alternate hormonal therapy in
PC.304 However, in combination with selected cytotoxic
agents, the current clinical wisdom is that estramustine
appears to contribute to increased response,259,305–307
although this has not been proven in well-structured tri-
als. While the mechanism for this is unclear, the effect of
estramustine may occur through a phase activation of PC
cells so that they are more sensitive to subsequent or con-
current cytotoxic effect. Estramustine alters cellular
microtubular configuration and may have synergy with
other drugs that act on microtubules such as taxanes
(paclitaxel, docetaxel) and vinca alkaloids (vincristine,
vinblastine, and possibly vinorelbine).305,308–310 Recent
reports from phase I and phase II trials suggest that the
combination of estramustine and docetaxel is well toler-
ated and produces a decrease of >50% in serum PSA in
around 50% of HRPC cases treated.296,297,311–315 Given
significant estrogenic side effects related to estramustine
therapy, particularly thromboembolic phenomena, its
place in combination therapy with cytotoxic agents for
HRPC still requires proof of efficacy over the cytotoxic
agents alone, as well as the optimization of dose and
scheduling to minimize toxicity.
Alkylating Agents
The alkylating agents are a group of chemical com-
pounds of diverse structure, which share the common
property of labile, electrophilic alkyl groups that can
react with most biologic molecules to form adducts. The
alkyl groups can be added to oxygen, nitrogen, phospho-
rus, or sulfur atoms, and thus can function at extremely
diverse sites. However their most important reactions are
with the nitrogen atoms of DNA, particularly the N7
position of guanine residues, altering the structure or
function of the DNA. These drugs are all cell cycle
dependent, but not cell cycle specific; that is, they exert
their effects on cells throughout the cell cycle (analogous
to radiation). They appear most active against rapidly
proliferating cells. Agents included in this group include
68 Part I Principles of Urologic Oncology
cyclophosphamide, ifosfamide, thiotepa, melphalan,
nitrogen mustard, busulfan, chlorambucil, and the
nitrosoureas.
The alkylating agents, through their common mecha-
nism of action, are potentially cytotoxic and carcino-
genic. Although sharing common functional traits,
differences in their chemical structures account for the
variation in their pharmacologic characteristics. This is
of particular importance as an explanation for why cross-
resistance may not occur in all situations.
Cyclophosphamide
Cyclophosphamide is 2-bis-(2-chloroethyl)amino-
tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide mono-
hydrate, a cyclic phosphamide ester of nor-nitrogen
mustard. The monohydrate is not ionized and is lipid sol-
uble. This agent is a bifunctional substituted nitrogen
mustard, which must be activated in the liver before it is
active. Its activation is a multistep process that occurs in
the hepatic microsomal P450 enzyme system.83,316 There
is thus no rationale to using the drug for intraarterial
chemotherapy nor as an intravesically administered
agent. It can be usefully administered as an oral agent
(90% bioavailability) or intravenously. Hepatic inactiva-
tion is the major mechanism of active drug elimination,
whereas after intravenous administration about 15% of
the drug is excreted unchanged in the urine and the rest
as metabolites. The plasma half-life is approximately 5 to
6 hours.316
As cyclophosphamide is bifunctional, it can cross-link
the two strands of DNA, yielding an interstrand cross-
link, or can produced intrastrand cross-links, or even can
bind DNA to protein. The binding of the active metabo-
lite of cyclophosphamide to DNA does not cause cell
death per se; rather the cells progress slowly through the
S phase and arrest and subsequently die in the G2 phase.
Information regarding potential drug interactions
with cyclophosphamide is relatively scant. As it must be
metabolized by hepatic microsomes to be active, drugs,
which induce this system (such as the barbiturates,
phenytoin, and carbamazepine) may increase the conver-
sion of cyclophosphamide to its metabolites; similarly
cyclophosphamide may have an impact on the activity of
the barbiturates. It has also been reported that cimetidine
increases the toxicity of cyclophosphamide via a change
in the concentration × time relationship of its active
metabolites.317,318
Cyclophosphamide produces significant leukopenia
and immunosuppression but is not usually associated
with thrombocytopenia.83,89 Nausea and vomiting may
occur, although usually in association with high dose
intravenous usage. Similarly alopecia is more commonly
associated with high dose administration. Of particular
importance, excretion of acrolein, one of the metabolites,
which is particularly irritating to the bladder mucosa, can
cause hemorrhagic cystitis, and this can lead to bladder
fibrosis or even transitional cell carcinoma of the bladder.
In the context of intravenous administration, this toxic
effect can be avoided by the use of sodium-2-mercap-
toethane sulfonate (MESNA), which is excreted in the
urine, providing reactive thiols that bind to the acrolein,
protecting the bladder mucosa. Occasionally, cyclophos-
phamide may cause interstitial pneumonitis, gonadal
atrophy, anaphylaxis, and in higher doses, the syndrome
of inappropriate ADH production and cardiotoxicity
(including acute cardiac necrosis when given in trans-
plant-intense dosage).
The most common application of cyclophosphamide
for genitourinary cancer is in the treatment of adenocar-
cinoma of the prostate,64,65 and it has also been used
in the past in the treatment of advanced germ
cell tumors.250,319 It is less frequently used for germ cell
tumors in current practice because of the risks of car-
cinogenicity and infertility. The drug is inactive in the
treatment of renal and adrenal carcinomas and has only
limited activity in the treatment of bladder cancer.
Ifosfamide
Ifosfamide is a structural analog of cyclophosphamide,
differing only in the position of one of the two
chloroethyl groups. It is also a metabolically activated
alkylating agent and must first undergo hydroxylation by
hepatic microsomes.316 However, the change in its struc-
ture has resulted in changed pharmacology, and its acti-
vation within the liver occurs more slowly than for
cyclophosphamide.
Ifosfamide is well absorbed orally and can also be
administered intravenously. Its pharmacology is similar
to that of cyclophosphamide. Its plasma half-life has been
reported to be as short as 5 to 6 hours, either after oral or
intravenous administration,82,320 although Creaven et
al.81 documented a plasma half-life of radioactively
labeled ifosfamide of nearly 14 hours. In current clinical
practice, it is most commonly administered intra-
venously, with schedules varying from a single infusion,
to multiple-day schedules, with MESNA coverage to
prevent hemorrhagic cystitis. Creaven et al.81 have sug-
gested that the alkylating activity ratio of ifosfamide is
1:5, when compared to cyclophosphamide. The pattern
of toxicity is similar to that of cyclophosphamide,81 but
with less myelosuppression and a greater tendency to
cause cystitis. In addition, ifosfamide has a greater preva-
lence of central nervous system toxicity, including altered
mental status, cerebellar dysfunction, seizures, and
extrapyramidal effects.81,321,322 It is not really clear
whether there is a definite dose-response relationship for
ifosfamide, and thus an optimal dose has not been
defined.
 Chapter 4 Principles of Chemotherapy for Genitourinary Cancer 69
Ifosfamide is currently used in salvage and high-risk
regimens for advanced germ cell tumors323–235 and for
metastatic urothelial cancer.326–328 In broad-based phase
I and phase II trials, little activity has been reported in
PC, although the drug has not been assessed since PSA
has been introduced as a surrogate marker of response.
Ifosfamide is inactive in renal carcinoma, but single agent
activity has been identified in squamous cell carcinoma,
including cancer of the penis.
Thiotepa
N,N′,N′′-triethylenethiophosphoramide (thiotepa) is an
aziridine drug, a polyfunctional alkylating agent, which
can produce interstrand cross-links, DNA adducts and
strand breaks, and a range of other DNA lesions.329 After
IV injection the t1/2α was 7.7 minutes and the t1/2β 25
minutes in the study by Cohen et al.330
Thiotepa is administered by intravenous or intracavi-
tary routes, the latter including intraperitoneal, intrathe-
cal, and intravesical delivery. It is not a vesicant and does
not cause local soft tissue reactions.
In the standard dose range, thiotepa is associated with
myelosuppression, both granulocytopenia and thrombo-
cytopenia, as well as nausea, vomiting, headache, and
occasionally alopecia. In transplant-intense doses,
thiotepa may cause mucositis, cutaneous changes, and
occasional organic brain syndrome.331 When adminis-
tered intravesically, thiotepa causes little systemic toxicity
unless used within a few days of extensive transurethral
resection; thiotepa, a relatively small molecule, is
absorbed significantly through an extensively denuded
bladder surface.
The major clinical application for thiotepa has been in
the intravesical chemotherapy of superficial bladder can-
cer,67 although this agent is now used less frequently
because of its risk of carcinogenicity and the develop-
ment of more effective treatment options.
Epipodophyllotoxins
Podophyllotoxin, a derivative of the mandrake root, has
been known to have antimitotic properties for more than
half a century, and extracts of the mandrake root have been
used for medicinal purposes for centuries.332 Although the
early podophyllotoxin derivatives were excessively toxic,
two derivatives (etoposide and teniposide) have shown
substantial clinical activity with a tolerable profile of side
effects.332–334 Although initially believed to act by binding
to tubulin and inhibiting microtubule assembly, additional
studies have suggested that the epipodophyllotoxins arrest
cells in late S phase or early G2 phase,335 rather than at G2-
M. More recently, these agents have been shown to exert
their anticancer effects by impeding the function of the
topoisomerase II enzyme.336
O O
O
O
O
O
H
O
O
O
O
H
O O
O
Figure 4-4 Structure of etoposide.
Each compound has a complex structure composed of
a multiringed structure linked to a glucopyranoside sugar
(see etoposide structure in Figure 4-4). Both drugs are
routinely administered intravenously, although etoposide
is now formulated for oral administration. The optimal
schedule of administration has not been defined,
although prolonged schedules (multiple daily short infu-
sions or continuous infusion) are most commonly
employed because of the phase-specific mode of action.
The pharmacokinetics is biphasic, with half-life values of
90 minutes and 3 to 11 hours.334 After administration
of radiolabeled etoposide to humans, 40% to 90% of
radioactivity is recovered in the urine within 48 hours,
fecal recovery is less than 20%, and biliary excretion is
only minimal.332.
The major toxicity of the epipodophyllotoxins is dose-
related myelosuppression, with predominant leukope-
nia.333 Gastrointestinal complications, such as nausea,
vomiting, and anorexia are usually mild. Other side
effects include alopecia, headache, fever, and hypoten-
sion. Severe hypotension may occur if the drug is infused
too rapidly, and this can occasionally be accompanied by
bronchospasm or rarely by anaphylaxis. It is believed that
these allergic phenomena may be due to the use of the
diluent, cremophor. Etoposide phosphate, a water-
soluble derivative that is rapidly hydrolyzed to etoposide
in the plasma, is currently undergoing clinical trial.
Recently there has been emerging information that
etoposide is occasionally associated with iatrogenic acute
myeloid leukemia, and such cases have now been
recorded among patients cured of germ cell tumors.180
The indications for the use of the epipodophyllotoxins
for genitourinary cancer are relatively limited, with the
most common application being in the management of
advanced germ cell tumors.250,251 Most studies have sug-
70 Part I Principles of Urologic Oncology
gested that there is only very limited activity against
bladder cancer and prostatic adenocarcinoma, although
there is a clear role for this drug in the treatment of small
cell anaplastic PC. Etoposide is inactive in the treatment
of renal carcinoma, and only scant data are available with
respect to penile and adrenal cancers.
Antimetabolites
Antifolates
The role of the antimetabolites in cancer treatment was
first explored 50 years ago with the investigation of
aminopterin, an analog of folic acid. This early work gave
rise to the development of methotrexate, the 4-amino,
10-methyl analog of the parent compound, which has
come to be one of the most widely used agents for the
genitourinary cancers.
Methotrexate inhibits dihydrofolate reductase
(DHFR), an important enzyme in folic acid metabolism,
which catalyzes the reduction of dihyrofolate to
tetrahydrofolate. DHFR maintains the intracellular
reduced folate pool, which in turn is required for the
synthesis of thymidine and purines and thus for the pro-
duction of DNA, RNA, and protein. Methotrexate
undergoes polyglutamation intracellularly to varying
extents; the polyglutamated forms do not traverse cellu-
lar membranes. Polyglutamation occurs to a greater
extent in tumor cells than in normal cells, and this may
explain the selective action of the drug. The polygluta-
mated form is retained preferentially within cells, some-
times for very lengthy periods337 and can directly
inhibit other folate-dependent enzymes, including
thymidylate synthase.338
Methotrexate may also cause single- and double-
stranded breaks in DNA.339 It is most active against rap-
idly proliferating cells and appears to exert its major
effect during S phase; and is thus classified as a cell cycle
phase-specific antimetabolite.
Methotrexate uses the same active transport mecha-
nisms to enter cells as does folic acid. At least two such
mechanisms have been identified, including a low-affinity
carrier that transports methotrexate and reduced folates
and a high-affinity system, which is more avid for
reduced folates than for methotrexate. The metabolic
block induced by methotrexate can be circumvented by
the use of calcium leucovorin, which feeds into the folic
acid cycle beyond the block of DHFR. Calcium leucov-
orin and its metabolite, 5-methyltetrahydrofolate, share
the latter common transport mechanism with methotrex-
ate. It appears that normal cells can be selectively rescued
by calcium leucovorin, either because of differences in
transport or because of differences in the rate of DNA
synthesis between normal and cancer cells. The complex
biochemistry of methotrexate, its reversal and mecha-
nisms of resistance, is beyond the scope of this chapter
but has been detailed elsewhere.340
Methotrexate may be given by oral, intramuscular,
intravenous, intraarterial or intrathecal routes. An optimal
dosing route and schedule has not been defined. A broad
range of parenteral dosing has been reported, with doses as
varied as in the range between 50 and 15,000 mg/m2,
predicated on the ability to rescue normal tissues with
calcium leucovorin. Caution must be exercised as the
higher dose range is potentially lethal if sufficient leu-
covorin is not administered. Alkalinization (as measured
by assessment of the urine pH), by increasing the solu-
bility of the drug and of the 7-hydroxy metabolite will
also reduce toxicity. Methotrexate levels must be moni-
tored after high dose treatment to determine the length
of leucovorin rescue.
More than 50% of the drug is bound to plasma pro-
teins. Methotrexate is widely distributed in the body. In
standard doses, methotrexate is excreted unchanged in
urine, whereas in high doses some metabolism of the
drug occurs. Plasma decay of methotrexate is either
biphasic or triphasic,341–343 with the terminal phase of
excretion having been reported to be in the range of 10
to 26 hours. Methotrexate is highly schedule dependent;
its toxicity is more a function of the time during which
plasma levels are maintained above a minimum cytotoxic
concentration than of the total AUC. Thus any factor
that can lead to a prolonged low level of drug will greatly
increase its toxicity. Principal among such factors are
impaired renal function and localization in “third space”
compartments such as pleural effusion or ascites with a
slow release into the circulation. In these situations,
methotrexate must be used with caution; rescue with leu-
covorin employed as necessary.
The spectrum of toxicity of methotrexate is a function
of age, dose, the use of calcium leucovorin, drug metabo-
lism, drug interactions, and renal function.340,344 Patients
may experience no toxic effects at all. Hematologic
side effects include leukopenia, thrombocytopenia, and
anemia. Gastrointestinal toxicity includes nausea, vomit-
ing, diarrhea, and stomatitis. Hepatotoxicity has been
reported in patients receiving chronic low dose oral ther-
apy and in high dose parenteral administration.
Occasionally, methotrexate can cause self-limited pneu-
monitis. One of the most dangerous toxic effects is the
induction of renal failure, as adequate renal function is
necessary to ensure satisfactory excretion of the drug.
Methotrexate can cause skin rash, pruritus, urticaria,
alopecia, and a range of other cutaneous side effects. Less
commonly, central nervous toxicity can occur, especially
after intrathecal administration.
Fluoropyrimidines
5-Fluorouracil (5-FU) was synthesized to act as a false
pyrimidine and thus to inhibit the formation of thymi-
dine.345 There are several proposed mechanisms of
action, including inhibition of thymidylate synthase by an
 Chapter 4 Principles of Chemotherapy for Genitourinary Cancer 71
active metabolite (FdUMP), incorporation of the triphos-
phate 5-FUTP into RNA, and incorporation of the 2′
deoxy triphosphate 5-FdUTP into DNA.346 The pres-
ence of reduced folate is critical to the function of 5-FU
in inhibiting thymidylate synthase. Gastrointestinal
tumors with increased expression of thymidylate synthase,
with or without increased levels of the metabolizing
enzymes, thymidine phosphorylase, and dihydropyrimi-
dine dehydrogenase, tend to be resistant to fluoropyrim-
idines.347 Testing for expression levels in individual
tumors may identify genitourinary cancers with suscepti-
bility to this group of drugs, but further testing of this
hypothesis is required.348
5-FU can be administered by oral, intravenous,
intraarterial, or intraperitoneal routes. Bioavailability is
poor and erratic when the drug is given by mouth,349 and
this route of administration is no longer used (however,
see following discussion on modulation and capecitabine).
When given intravenously the drug has an extremely
short terminal phase half-life measured in minutes.73,350
This is due to its rapid degradation by dihydrouracil
dehydrogenase (DHD) to 5,6-dihydro 5-FU that then
undergoes ring rupture and is degraded to small mole-
cules.346 A rare deficiency of this enzyme can lead to
severe toxicity following administration of 5-FU.346
Because of its mode of action, 5-FU is an S-phase spe-
cific drug and this combined with its extremely short half-
life would lead one to anticipate that it would be highly
schedule dependent. However, paradoxically, rapid infu-
sions of 5-FU are more toxic than the same dose given over
a period of several hours. This is probably due to the fact,
although that the drug itself has an extremely short plasma
half-life, the persistence of the active metabolite FdUMP
intracellularly is measured in days.351 The bolus injection of
the drug probably temporarily exceeds the capacity of
DHD, thus making drug available for conversion to active
metabolites. The nucleoside derivative of 5-FU, 5-fluoro-
2′-deoxyuridine (FUdR, floxuridine) is extremely schedule
dependent. The dose that can be given by short-term infu-
sion is approximately three orders of magnitude greater
than the dose that can be given when the drug is given by a
long-term continuous infusion.352
A number of compounds have been used in conjunction
with fluoropyrimidines to enhance their activity through
biochemical modulation. These include interferon, PALA
(N-phosphonoacetyl-L-aspartate), and leucovorin.353 Of
these, leucovorin has been the most extensively investi-
gated and has proven to be the most clinically useful by
raising the response rate to 5-FU in colorectal cancer by a
factor of about three.354 It acts by leading to stabilization
of the ternary complex formed between the active metabo-
lite FdUMP, the active site of the enzyme thymidylate syn-
thase, and a reduced folate cofactor (5, 10 methylene
tetrahydrofolate), which is derived from leucovorin.355 An
investigational modulator eniluracil has been evaluated in
a clinical trial setting.356–358 This compound, which
inhibits DHD, decreases the first-pass effect and enables
5-FU to be given orally.
Capecitabine is an orally bioavailable prodrug of
5-FU.359 It is generally administered on a twice-daily basis
either continuously or with a week-off therapy every 3 or
4 weeks. After absorption capecitabine is metabolized by
hepatic carboxylesterase to 5′-deoxy-5-fluorocytidine
and then converted to 5′-deoxy-5-fluorouridine by cyti-
dine deaminase, which is also present in the liver.76
5′-Deoxy-5-fluorouridine then enters cells and is metab-
olized by thymidine phosphorylase to 5-FU. The result is
a cellular 5-FU concentration that exceeds that achieved
in the serum and surrounding normal tissue.76
Capecitabine has been evaluated as a potential alternative
to 5-FU infusion in a number of cancer types.360.361 It has
modest activity in renal cell carcinoma,362,363 but is yet to
be fully evaluated in other genitourinary cancers.
The primary toxicities of the fluoropyrimidines are
gastrointestinal toxicity, stomatitis and diarrhea, and
myelosuppression. The pattern of toxicity varies with the
schedule of administration and is also influenced by the
presence of modulators. Weekly bolus 5-FU produces
mainly myelosuppression (primarily leukopenia). Loading
dose 5-FU, prolonged infusions, and 5-FU used with leu-
covorin produce primarily gastrointestinal toxicity; cere-
bellar toxicity and cardiotoxicity have been described364
but are uncommon at standard doses. Capecitabine may
produce tenderness and desquamation of the hands and
feet (the so-called hand-foot syndrome), in addition to the
side effects seen with other fluoropyrimidines.
Gemcitabine
A new pyrimidine antimetabolite, 2′deoxy-2′difluoro-
cytidine (gemcitabine), has recently been introduced into
clinical practice for urothelial and a range of other
tumors. In preclinical systems gemcitabine showed very
significant activity against experimental solid tumors365
and human tumor xenografts.75 Its structure is shown in
Figure 4-5. Like cytosine arabinoside, an antimetabolite
which it resembles structurally, it is activated intracellu-
larly to the triphosphate, 2′deoxy-2′difluoro-cytidine
5′-triphosphate (dFdCTP), and in this form is incorpo-
rated into DNA.366–368 Gemcitabine entry to cells
requires the presence of the nucleoside transporter sys-
tem, with cells deficient in this transporter being gemc-
itabine resistant.366 The presence of dFdCTP within the
cells inhibits its own degradation via deamination by
deoxycytidine deaminase and promotes 2′deoxy-2′diflu-
oro-cytidine phosphorylation by deoxycytidine kinase
(dCK), at least in part by ribonucleotide reductase (RR)
inhibition. Forced overexpression of cytidine deami-
nase,369 increased expression of RR370 and decreased
expression of dCK371,372 are associated with decreased
sensitivity to gemcitabine in cell line systems. The anti-
neoplastic effect of gemcitabine derives, in part, from
72 Part I Principles of Urologic Oncology
NH2
N tional amount of drug wasted therapeutically but
N given that fixed dose rate infusion at 10 mg/m2/minute
HOCH2
O practice.
F cancer was noted in the phase I study by Pollera et al.382
OH F
Figure 4-5 Structure of gemcitabine.
dFdCTP incorporation into DNA instead of dCTP
by polymerases involved in repair.373 However, RR is an
S-phase specific, potentially rate-limiting enzyme for
DNA synthesis. The activity of gemcitabine is cell cycle
specific with blockade at the G1/S phase transition, per-
haps suggesting that RR inhibition is an important con-
tributor to gemcitabine antineoplastic effect.
In the initial phase I clinical trial, the drug was given
over a 30-minute infusion weekly for 3 weeks every 4
weeks. The maximum tolerated dose was 790 mg/m2
with myelosuppression, predominantly thrombocytope-
nia and anemia, being the dose-limiting toxicity.374,375
Other toxicities have been relatively mild. However, sub-
sequent studies have shown that considerably higher
doses can be given safely, particularly to patients with lit-
tle or no prior therapy. In patients with nonsmall cell
lung cancer and no prior therapy, O’Rourke et al.376
found that 2500 mg/m2 given over 4 hours every 2 weeks
was below the MTD. Initial pharmacokinetic studies
showed a rapid elimination of the drug with a median
half-life of 8 minutes. The drug was rapidly converted to
the corresponding uracil metabolite 2′,2′-difluo-
rodeoxyuridine, which had a longer half-life, with a
median of 14 hours. The active metabolite 2′,2′-difluo-
rodeoxycytidine triphosphate was analyzed in circulating
mononuclear cells. A peak was observed within 30 min-
utes of the end of the infusion and increased with dose up
to a dose of 350 mg/m2. Beyond this dose, there was no
increase in the active metabolite indicating saturation of
the activation to the triphosphate.366 Subsequent study
suggests that infusion of gemcitabine at a fixed dose rate
of 10 mg/m2/minute produces an optimal cellular level of
active metabolite.377,378 Infusion rates faster than this
may result in a lower cellular exposure (area under the
concentration curve concentration) of 2′,2′-difluo-
rodeoxycytidine triphosphate by exceeding the rate at
which the nucleoside transporter system and/or which
the enzymes involved in producing this active metabolite
can act.378–381 The net result of faster infusions is that the
maximal 2′,2′-difluorodeoxycytidine triphosphate con-
centration is achieved for a shorter time with the addi-
potentially contributory to side effects. On this basis and
does not produce more toxicity than more rapid infusion,
administration of gemcitabine in this manner is standard
Antitumor activity for gemcitabine against bladder
in 14 patients receiving gemcitabine at doses greater than
875 mg/m2, they observed 1 CR and 2 PR. A response
rate of 28% was observed in a phase II trial in previously
untreated patients with bladder cancer.383 Subsequently,
the combination of gemcitabine and cisplatin was
assessed in a phase II trial with a response rate of 41%.384
This combination was then compared to MVAC in a ran-
domized phase III trial and found to produce equivalent
response and survival with better quality of life.375 De
Mulder et al.385 noted response rate of 8.1% or 3 of 39
patients who could be evaluated in a phase II study of
gemcitabine in renal cell carcinoma, with durable
responses exceeding 12 months in 2 patients.
Subsequently, researchers at the University of Chicago
have reported on combination of gemcitabine with 5-FU
in RCC with possible improved survival over historical
controls and response rate of 17%.386 This study is cur-
rently being replicated with dose-scheduling variation
and the incorporation of capecitabine instead of 5-FU.
Phase II studies in PC are ongoing, but highly prelimi-
nary data suggest that gemcitabine may have some pallia-
tive benefit in the absence of major falls in serum PSA
concentration,387 Gemcitabine has some activity in
chemo-refractory testicular cancer388,389 and this is being
pursued in further clinical trials.
CAMPTOTHECINS
An important group of drugs under active clinical devel-
opment are analogs of camptothecin. Camptothecin was
isolated from extracts of the Japanese tree Camptotheca
acuminata by Wall et al.390 and shown to be active in
experimental leukemia and some solid tumors. The
structure of the camptothecins incorporates five rings
(Figure 4-6). The fifth, or E, ring can exist in a closed
ring lactone or an open ring hydroxy acid form. The
closed ring form of camptothecin is highly water insolu-
ble; however, the sodium salt of the open ring hydroxy
acid form is water soluble. It was in this form that
the compound was introduced into early clinical trials in
the late 1960s. Phase I trials showed that the compound
gave rise to substantial gastrointestinal toxicity and
myelosuppression and also had a tendency to produce
hemorrhagic cystitis.391,392 It showed antitumor activity
 Chapter 4 Principles of Chemotherapy for Genitourinary Cancer 73
R2 R3
R1
N
CH3CH2
R1
Irinotecan N N
Topotecan OH
Figure 4-6 Structures of irinotecan (CPT-11), topotecan.
in the phase I studies, but a subsequent phase II study in
gastrointestinal malignancies proved to be negative,393
and development of the compound was halted. Work
continued in the laboratory on the mode of action of this
compound, which proved to be unique.394–398 The com-
pound combines with a cleavable complex formed
between DNA and the enzyme topoisomerase I, an
enzyme important in relieving the torsion that develops
as the strands of DNA unwind for replication and tran-
scription. The role of topoisomerase I is to cleave one of
the strands of the DNA, thus allowing the supercoiled
DNA to unwind. The combination of camptothecin with
the cleavable complex prevents the resealing of the DNA
and thus causes single-strand DNA breaks.397,399
Mutations in topoisomerase I mutations alter both DNA
cleavage and unwinding, as well as the interaction with
camptothecin.400 The identification of this unique mode
of antitumor action stimulated the development of
analogs of camptothecin that would be more soluble and
more active. It was shown that the closed ring form of the
E ring is essential for activity, being several orders of
magnitude more active than the hydroxy acid form.401
This may account for the variable activity of camp-
tothecin, which as noted above, was given as a sodium
salt of the open ring hydroxy acid form. Several com-
pounds were developed as analogs of camptothecin; to
date, the two most important are irinotecan (CPT-11)
and topotecan. The structures of these are shown in
Figure 4-6.
O
OH O
R2 R3
O
C O H CH3CH2
(CH3)2NCH2 H
Irinotecan
Irinotecan is 7 ethyl 10[4-(1 pyridino)-1-pyridino] car-
bonoxy camptothecin. It is the most extensively evaluated
of the newer camptothecins. In phase I studies, the drug
showed major toxicities of leukopenia, nausea, and vom-
iting and diarrhea.402 On a weekly schedule the recom-
mended dose for phase II studies was 100 mg/m2/week,403
and when intermittent doses were administered every
3 weeks,404 the recommended dose was 240 mg/m2. With
intensive treatment of diarrhea with loperamide, dosing
up to 750 mg/m2 every 3 weeks has been reported.405,406
A variety of other schedules have been reported, includ-
ing a single dose every 4 weeks, 5-day continuous infu-
sion every 3 to 4 weeks, and daily 3× every 3 weeks.402
CPT-11 is virtually inactive in vitro. To be activated, it
must be hydrolyzed to 7-ethyl-10-hydroxy camptothecin
(SN38), which is 3 orders of magnitude more active than
the parent drug.407 Consequently, pharmacokinetic stud-
ies of the drug require the measurement of the total and
the lactone forms of both CPT-11 and SN38. No rela-
tionship between nonmyeloid toxicity and any pharma-
cokinetic parameter was found in the study of Rowinsky
et al.404 A relationship between AUC of total SN38 and
percent decrease in absolute neutrophil count (ANC) was
found using a sigmoidal Emax model.
Irinotecan is still undergoing early phase trials in the
genitourinary malignancies. The Southwest Oncology
Group is conducting a phase II trial for patients with
74 Part I Principles of Urologic Oncology
advanced bladder cancer, and other studies in PC are
ongoing. We are not aware of published data with respect
to the utility of this agent in renal and other genitouri-
nary cancers.
Topotecan
Topotecan is a semisynthetic water soluble camptothecin
analog, which in preclinical systems is active against
experimental tumors and against human xenografts. In
early phase I trials, the drug was given daily for 5 days
every 3 or 4 weeks.408,409 On this schedule, the dose-
limiting toxicity was neutropenia, and the recommended
dose for phase II studies was 1.25 to 1.5 mg/m2.
Subsequent studies have evaluated infusions of from 24
hours up to 21 days.410–412 With the 24-hour infusion, a
dose of 1.5 mg/m2/week was recommended for phase II
evaluation. Thrombocytopenia was more marked than
neutropenia in the 21-day infusion study (MTD of
0.53–0.6 mg/m2/day in patients previously treated with
cytotoxic therapy and 0.8 mg/m2/day in chemotherapy
naïve patients). Of interest, granulocyte-colony stimulat-
ing factor (G-CSF) did not permit dose intensification in
one study because dosing was limited by fatigue and
thrombocytopenia.409 In pharmacodynamic studies, dose
but not the AUC of the topotecan lactone could be
related to mean percentage change in ANC by a sig-
moidal Emax model. The dose required to produce a 50%
decrease in ANC was 0.86 mg/m2/day, given daily for 5
days.408
Data on the activity of topotecan against genitouri-
nary tumors is scant, but evaluation is ongoing.
SUMMARY
There is no current consensus on the optimal strategy for
the clinical use of chemotherapy against cancers of the
genitourinary tract. The most common approach has
been to use combination regimens in preference to single
agents, predicated largely on the success of combination
chemotherapy for a variety of other solid tumors. There
is no doubt that the introduction of the combination of
cisplatin, etoposide, and bleomycin revolutionized the
management of advanced germ cell tumors, providing a
cure rate of up to 90%, compared to a cure rate of less
than 40% with single agent treatment. Similarly, after
several years of clinical development of combination reg-
imens for bladder cancer, a seminal randomized trial
revealed a survival benefit from the combination of
MVAC compared to cisplatin alone in this context. A fur-
ther landmark trial demonstrated that the combination of
gemcitabine and cisplatin was equivalent in efficacy to
MVAC but less toxic. Mitoxantrone has an established
role in improving symptoms and quality of life in HRPC,
while taxane-based combinations may provide a further
advance or at worst a further option in patients with this
stage of disease.
By contrast, randomized trials have not proved a role
for combination chemotherapy in renal carcinoma and
clinical practice in this areas is still in an early stage of
evolution. At present, one of the major investigational
emphases is the combination of conventional and novel
cytotoxic agents with biochemical and biologic modula-
tors that target the effectors of multidrug resistance, cel-
lular regulation, and immunologic function. However,
these studies are beyond the scope of this chapter on
principles and applications of conventional chemother-
apy. Further clinical trials to evaluate new approaches are
required in the genitourinary cancers, and in particular
those tumors that fail to respond to conventional first-
line therapy. In addition to the need for new treatment
strategies, careful definition of endpoints and appropriate
design of clinical trials is essential if outcomes are to
improve.
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C H A P T E R
5 Immunotherapy: Basic Guidelines
Jason B. Wynberg, MD, FRCSC, W. Marston Linehan, MD,
and Richard Childs, MD
Harnessing the power of the immune system against
malignant cells is often thought of as a relatively modern
treatment modality for patients with advanced cancer.
However, more than 100 years have passed since the first
report was published by Dr. W. Coley documenting
immune-mediated disease regression against cancer fol-
lowing injections of bacterial toxins directly into tumor
lesions.1 Since then, investigators have gained tremen-
dous insight into the mechanisms by which tumors are
able to evade the innate immune system2–4 (Table 5-1)
and remain resistant to “conventional” cancer
immunotherapies. The steady expansion in our knowl-
edge of tumor biology over the past few decades is grad-
ually being translated into improvements in the efficacy
and safety of cancer immunotherapeutics.
CYTOKINE THERAPY
Cytokines are protein molecules produced and secreted
by immune and inflammatory cells that bind to comple-
mentary cytokine receptors resulting in either the stimu-
lation or inhibition of immune cells. Cytokines usually
act in an autocrine or paracrine fashion, in contrast to
hormones, which typically act at a distance from their
cells of origin. Following the binding of the cytokine to
its receptor target, cell signaling is initiated through
intracellular pathways, such as the Jak-STAT tyrosine
kinase, Src, Zap70 and related proteins, phosphatidyli-
nositol 3-kinase, IRS-1, IRIS-2, and phosphatases.5
Cytokines that typically up-regulate immune responses
include interleukin-2 (IL-2) and interferon (IFN), whereas
cytokines that typically down-regulate immune responses
include transforming growth factor β, interleukin-6, and
interleukin-10. Through their secretion of immunosup-
pressive cytokines (e.g., transforming growth factor β),
certain tumors are able to directly impair the hosts’
immune defenses. Interestingly, some tumors can stimu-
late their own proliferation by secreting IL-2, which
88
binds to IL-2 receptors expressed on their cell surfaces.
Administration of IL-2 at pharmacologic doses, as is
done in the treatment of metastatic renal cell carcinoma
(RCC), appears to directly interrupt this autocrine
pathway.6,7
The field of cytokine therapeutics has grown dramat-
ically since the development of recombinant DNA tech-
nology in the 1980s, which enabled cytokines to be
produced in large quantities.8–10 A discussion of the
cytokines commonly administered in the setting of
advanced urologic malignancy is presented below.
Interleukin-2 and Interferon-a
Background
In 1992, the Food and Drug Administration (FDA)
approved high-dose IL-2 for the treatment of metastatic
RCC.11 Although the precise mechanism accounting for
tumor regression in RCC patients treated with IL-2 is
not known,12 many in vitro effects of IL-2 on immune
effector populations have been characterized (Table
5-2).13,14 Whereas IL-2 and resting lymphocytes sepa-
rately fail to kill RCC tumor cells, prior incubation of the
same lymphocytes with IL-2 significantly augments their
in vitro tumor cytotoxicity. These observations provided
some of the first preclinical evidence that the immune
system could mediate antitumor effects, providing theo-
retical grounds for the pursuit of immune-based cancer
therapy in humans. Unlike the interleukins, IFNs are a
family of proteins secreted by leukocytes in response to
viral infection and other antigenic stimuli. IFNs have
powerful antiproliferative and immunoregulatory activity
(Table 5-3),13 such as up-regulation of class I and class II
major histocompatibility complex (MHC) molecules.15
When administered in a therapeutic setting, IFN-α
is typically given as a subcutaneous injection. Due to its
relatively short half-life, IFN-α is most commonly
administered at least three times per week. Recently,
 Chapter 5 Immunotherapy: Basic Guidelines 89

Table 5-1 Mechanisms of Tumor Escape from Immune System

Tumor-related Host-related

Decreased tumor Ag expression Antigen-specific suppressor T cells

Decreased MHC class I expression Deficient presentation of tumor antigens by host antigen-presenting cells
Failure to express immune costimulatory Failure of host effectors to reach the tumor (e.g., stromal barrier)
molecules (e.g., B7.1)
Production of immune inhibitors (e.g., TGFβ, Immune dysfunction due to carcinogen, infections, age
IL-6, IL-10, free tumor Ag)
Tumor antigens weakly immunogenic
Induction of T cell apoptosis by tumor Development of T cell anergy or tolerance to tumor antigens
expression of Fas ligand (FasL)

MHC, major histocompatibility complex; TGFβ, transforming growth factor β; Ag, antigen.

Table 5-2 Effects of Interleukin-2 Cytokine Therapy as Treatment of Metastatic

Proliferation of T cells, B cells, NK cells, and monocytes
Potentiation of Fas-mediated apoptosis of T cells to
prevent clonal persistence
Induction of antibody synthesis by B cells
No direct anti-tumor activity
Table 5-3 Effects of Interferon-alfa
Direct antiproliferative effects on tumor and other tissues
Antiviral activity
Occasionally promotes partial reversal of the malignant
phenotype
Increases expression of MHC molecules and tumor-
associated Ags
Activates T cells, augments NK cell function
Upregulates macrophage antigen presentation
Increases macrophage production of angiogenesis-inhibitor
MHC, major histocompatibility complex; NK, natural killer; Ag,
antigen.
investigators have shown that the serum half-life of IFN-
α-2b can be extended dramatically by covalently linking
polyethylene glycol (PEG) to its histidine-34 moiety,
thus making dosing schedules more convenient16. IFNs
may have direct antitumor effects against a variety of
malignancies, including hairy cell leukemia, cervical
intraepithelial neoplasia, basal cell cancer, Kaposi’s sar-
coma, melanoma, renal cell carcinoma, multiple
myeloma, and chronic myelogenous leukemia.13
Renal Cell Carcinoma
Despite early enthusiasm based on favorable outcome of
pilot clinical trials, neither IL-2 nor IFN-α has proven to
be a panacea for the treatment of metastatic RCC (Table
5-4).17–30 Unfortunately, the great majority of patients
treated with either cytokine fail to respond, with median
survival typically being 2 years or less.
Despite their overall low response rate, however, some
patients clearly benefit from treatment with IL-2 and
IFN-α. Partial responses, defined as a ≥50% reduction in
the sum of the products of maximal perpendicular diam-
eters of all measurable metastatic lesions, occur in
approximately 15% of patients treated with either IL-2
or IFN-α (see Table 5-4). Although partial responses can
be associated with significant disease palliation, long-
term survival in partial responders is a rare event.
Among patients who achieve a complete response
(defined as the complete disappearance of all evidence of
metastatic disease for at least 1 month) to high-dose IL-
2 therapy, 60% to 90% remain alive and free of disease
for 8–10 years after treatment. In contrast, virtually no
evidence exists of long-term survival following IFN-
based therapy (see Table 5-4). It is, therefore, not sur-
prising that many urologists and oncologists consider
high-dose IL-2 to be superior to IFN-α in the treatment
of metastatic RCC.
Nonetheless, many oncologists continue to treat
metastatic RCC patients with IFN-α, largely due to con-
cerns regarding the substantial toxicities associated with
high-dose IL-2. Toxicities associated with high-dose
IL-2 therapy are primarily the consequence of a cascade
of cytokines being released from circulating leukocytes
following drug exposure. This cytokine shower can sig-
nificantly increase capillary permeability, leading to dra-
matic fluid shifts, reduced peripheral vascular resistance,
and sometimes profound hypotension, renal failure, and
pulmonary edema. The severity of these symptoms is
dose dependent. Toxicities related to IFN therapy are
also dose and schedule dependent, and include primarily
 90

Table 5-4 Treatment with Il-2 or IFN-α in Metastatic Clear Cell RCC
Prior Median
Nephrectomy Survival
References (%) N (Months) PR (%) CR (%) Long-Term Survival of CRs

High-dose IV IL-2 Fisher et al.17 85 255 16.3 8 7 >60% of CRs alive, NED at 10 years

Yang et al.18 93 156 18 14 7 73% of CRs alive, NED at median 9.3 years

Dutcher et al.19 86 71 15.5 11 7 90% of CRs alive, NED at >8 years20

Part I Principles of Urologic Oncology

Subcutaneous IL-2 Yang et al.18 93 150 18 9 4 50% of CRs alive, NED at median 10.1 years

Subcutaneous IL-2/IFN-α McDermott et al.21 75 94 NA 10 2 No long-term data available

Dutcher et al.22 87 47 20 13 4 One CR alive at 49 (+) months

Rogers et al.23 82 33 10 9 0 No long-term data available

Negrier et al.24 79 70 13 2 0 Not applicable—no CRs

Subcutaneous IFN Mickisch et al.25 100 42 17 7 12 No long-term data available

Flanigan et al.26 100 92 11.1 3 0 Not applicable—no CRs

Negrier et al.27 92 147 13 5 1 One CR alive, NED at 10 years28

Motzer et al.29 52 145 15 6 1 No long term data available

Gleave et al.30* 86 91 12 1 3 No long-term data available

IL-2, interleukin-2; IFN-α, interferon-alpha; RCC, renal cell carcinoma; N, number of patients; CR, complete response; PR, partial response; IV, intravenous; mos., months; NED, no evidence
of disease; NA, not available.
Note: No treatment-related mortalities were experienced in any of the above studies, except for Fisher et al.17, in which 4% of patients receiving high-dose IL-2 died of treatment-related
complications.
*IFN-γ rather than IFN-α was used in this study.

hematologic effects (i.e., bone marrow suppression and
cytopenias) and flu-like symptoms.13,15,25 A large prelim-
inary series of patients given high-dose IL-2 at the
National Cancer Institute reported a 4% treatment-
related mortality rate.17 Because this mortality rate
approached the complete response rate with high-dose
IL-2, many oncologists still consider it unacceptable to
have one regimen-related death for every patient cured
with this therapy.
Since its initial use, the mortality rate related to high-
dose IL-2 therapy has dropped dramatically at the
National Cancer Institute, with no deaths among the last
800+ patients treated. This improvement in outcome is
likely multi-factorial, owing to alterations in eligibility
criteria, the treatment regimen, and improvements in
supportive care.31 Other groups similarly contend that
high-dose IL-2 can be given safely when patients are
carefully selected and treatment is given in a well-
monitored setting.32,33
Despite improvements in morbidity related to high-
dose IL-2 therapy, there has been considerable interest in
the development of low-dose IL-2 regimens in the hope
of reducing drug-related complications. A randomized
study comparing high-dose versus low-dose IL-2 in the
setting of metastatic RCC has recently been completed.18
The vast majority of patients enrolled on this trial (93%)
had previously undergone cytoreductive nephrectomy.
Although no regimen-related mortalities occurred in this
study, toxicities were greater in the high-dose IL-2 arm
compared to the low-dose IL-2 arm, especially in terms
of clinically significant hypotensive episodes (36.4% ver-
sus 2.9%, respectively). The overall response rate (CR +
PR) was higher in the high-dose versus the low-dose arm
(21% versus 13%, p = 0.048). Importantly, the durability
of responses among complete responders was superior in
the high-dose arm (73% disease-free + an additional 18%
1.0
0.9
0.8
Proportion surviving
0.7
0.6
0.5
0.4
0.3 p2 = 0.04
0.2
0.1
0.0
0 12 24 36 48 60 72 84
A Survival time in months
Figure 5-1 A, Disease-free survival in patients achieving a complete response with high-dose
or low-dose IL-2. B, Survival by treatment received—high-dose or low-dose IL-2. (From Yang
JC, Sherry RM, Steinberg SM, et al: J Clin Oncol 2003; 21(16): 3127-3132, with permission.)
Chapter 5 Immunotherapy: Basic Guidelines 91
disease-free following a resection of limited recurrent
disease = total 91% alive and disease-free at a median of
9.3 years) compared to the low-dose arm (50% alive and
disease-free at a median of 10.1 years) (Figure 5-1A).
However, no difference in overall survival was observed
between the high-dose and low-dose cohorts (Figure
5-1B), again reflecting the unfortunate fact that complete
responders to any form of IL-2 therapy are in the signif-
icant minority.
Another prospective randomized study compared low-
dose intravenous IL-2 (group 1) versus subcutaneous
IFN-α-2a (group 2) versus both drugs combined
(group 3) in patients with metastatic RCC.27 A total of
425 patients were randomized between 1992 and 1995
into one of three treatment groups. As with the previous
trial, the majority of patients (>90%) enrolled in the
study had undergone a prior nephrectomy. Toxicities
were most evident among those receiving IL-2 (groups 1
and 3), including 67% who became hypotensive and 50%
who experienced high fevers. Importantly, all patients
ultimately recovered from these adverse events and
returned to their pretreatment status. Response rates
were 6.5%, 7.5%, and 18.6% (p < 0.01) for patients
receiving IL-2, IFN-α-2a, and IL-2 plus IFN-α-2a,
respectively. Although the response rate was higher
among those receiving both IL-2 and IFN-α, no long-
term survival benefit was observed in this group
(Figure 5-2).
Biochemotherapy is another field of research wherein
chemotherapeutic drugs are administered concomitant
with biologic agents, such as IL-2, in hopes of improving
therapeutic indices. 5-Flurouracil (5-FU) has been the
most widely used chemotherapeutic agent that has been
combined with cytokines in the setting of advanced
RCC, with response rates up to 30% in several small
studies. However, the vast majority of responses are par-
1.0
0.9
High dose
0.8
Proportion surviving
0.7 High-dose versus low-dose
0.6 (p = 0.41)
0.5
Low dose
0.4
0.3
High dose (fail/total = 117/155)
0.2
0.1
Low dose (fail/total = 121/150)
0.0
96 108 120 132 0 12 24 36 48 60 72 84 96 108 120 132
B Survival time in months
92 Part I Principles of Urologic Oncology

100 Interferon alfa-2a

90 Interleukin-2 + interferon alfa-2a
80 Interleukin-2

Overall survival (%)

70
60
50
40
30
20
10
0
0 6 12 18 24 30 36
Months after randomization
Kaplan-Meier curves for overall survival among patients in the three treatment groups.
Tick marks represent censored data on patiients who were alive or lost to follow-up. The results
shown are from an intention-to-treat analysis. p = 0.55 for the comparison among the groups.

Figure 5-2 Overall survival in patients treated with IFN-α-2a with or without IL-2. (Based on
Negrier S, Escudier B, Lasset C, et al: N Engl J Med 1998; 338(18):1272–1278, with
permission.)

tial only, with no data supporting long-term disease-free
survival using this approach.34
Reactive oxygen species (ROS) are released by tumor
infiltrating monocytes and macrophages and inhibit
cytokine-stimulated lymphocytes. Histamine dihy-
drochloride is a biogenic amine that inhibits the formation
of ROS and has been used in clinical trials as an adjuvant
to IL-2 and IFN-α with a view to reducing oxidative inhi-
bition of lymphocytes.35 Although clinical efficacy has
been observed in melanoma patients,36 no benefit has yet
been observed in the setting of advanced RCC.37
Tumor necrosis factor–related apoptosis-inducing lig-
and (TRAIL) is a trans-membrane protein expressed on
immune cells that plays a primary role in natural killer
cell-mediated tumor surveillance. Based on its high
specificity and cytotoxicity against tumor cells in vitro,
TRAIL remains as an active area of research.38–40
Intravesical Interferon Therapy for the Treatment
of Superficial Bladder Cancer
Intravesical IFN-α is currently being evaluated as an
immunotherapeutic agent in patients with superficial
bladder cancer. Interim results from a national multicen-
ter phase II trial of combination Bacille Calmette-Guerin
(BCG) plus IFN-α-2b suggest that this agent has bio-
logic activity in this setting.41 A total of 337 patients who
could be evaluated with moderate to high-risk superficial
tumors (BCG naïve = 206 patients, BCG failures = 131
patients) received induction, followed by maintenance
courses of BCG + IFN-α. At a median follow-up of 24
months, the simple tumor recurrence rates were 35% for
BCG-naïve patients and 53% for BCG-failure patients.
Kaplan– Meier estimates for freedom-from-disease were
71% and 61% for BCG-naïve patients and 53% and 40%
for BCG-failure patients at 1 and 2 years, respectively.
The toxicity-related premature dropout rate among
BCG-naïve patients was 3.7% and among BCG-failure
patients was 7.3%. This multicenter trial substantiates
the earlier encouraging reports of the efficacy of combi-
nation BCG + IFN as upfront and salvage therapy for
patients with moderate to high-risk superficial bladder
cancer.41–43 Longer follow-up will be needed to define
the ultimate role this cytokine will play in the treatment
of superficial bladder cancer.
Colony-Stimulating Factors
Both granulocyte colony-stimulating factor (G-CSF) and
granulocyte-macrophage CSF (GM-CSF) are recombi-
nant cytokines that stimulate the bone marrow to
increase production of neutrophils, monocytes,
eosinophils, and dendritic cells. Both cytokines are used
clinically to speed recovery from chemotherapy-induced
neutropenia. Because GM-CSF also has immunomodu-
latory effects (Table 5-5),13,44 investigators have explored
whether this agent has immunotherapeutic activity in
RCC patients. Unfortunately, to date no significant clin-
ical benefits have been attributable to this cytokine.45–48
BACILLE CALMETTE-GUERIN
Intravesical BCG for bladder cancer represents one of
the most clinically successful applications of nonspecific

Table 5-5 Effects of GM-CSF
Activates macrophages, monocytes, and dendritic cells
Enhances tumoricidal activity of macrophages and
monocytes against tumor
Upregulates macrophage antigen presentation
Increases macrophage production of angiogenesis-inhibitor
Enhances antibody-dependent cellular toxicity
Chemotactic for monocytes and polymorphonuclear cells
GM-CSF, granulocyte-macrophage colony-stimulating factor.
immunotherapy. The immunologic events associated
with the BCG-induced antitumor responses are not well
understood, however, it is clear that stimulation of T
lymphocytes with subsequent T-cell cytokine secretion
are downstream effects of BCG that are critical to its
antitumor activity.49–51 The clinical results of intravesical
BCG as treatment for patients with superficial bladder
cancer are discussed in detail in Chapter 18.
ADOPTIVE CELLULAR THERAPY
Lymphokine-Activated Killer Cells
Lymphokine-activated killer (LAK) cells are generated ex
vivo by collecting circulating lymphocytes by large vol-
ume of lymphocytapheresis and incubating them in IL-2-
rich media for several days (Figure 5-3A). Although LAK
cells have shown dramatic MHC class I nonrestricted
cytotoxicity against RCC and other tumor cells in vitro,
their clinical value in humans is questionable, as two
phase III randomized trials failed to demonstrate a sur-
vival advantage in metastatic RCC patients treated with
LAK cells + high-dose IL-2 compared to those who
received high-dose IL-2 alone.52,53
Tumor-Infiltrating Lymphocytes
Tumor-infiltrating lymphocytes (TILs) are lymphocytes
(T cells + NK cells) that are extracted from fresh tumor
specimens (e.g., nephrectomies) and expanded in vitro in
IL-2-rich media (see Figure 5-3B). By virtue of their hav-
ing infiltrated into tumor tissue and their previously
demonstrated antitumor activity in vitro (class I MHC
restricted), TILs are thought to contain a population of
T cells that recognize antigens specific to the tumor.
Following in vitro expansion, TILs are reinfused into the
patient along with other immunomodulators, such as
IL-2. A trial evaluating TIL + IL-2 in patients who failed
in previous IL-2-based therapy for metastatic melanoma
or RCC demonstrated a 14% response rate.54 Given the
historical data showing the ineffectiveness of IL-2
Chapter 5 Immunotherapy: Basic Guidelines 93
retreatment in patients who had previously failed IL-2,
these data provided indirect evidence suggesting in vivo
activity of TIL in humans. However, in a follow-up mul-
ticenter, randomized phase III trial of TILs with IL-2 in
the setting of metastatic RCC, patients who received
TILs + IL-2 failed to have a survival advantage or
improved response rate compared to those receiving
IL-2 alone (see Figure 5-3B).55
Although unselected TILs appear to be of limited
benefit in patients with metastatic RCC, a recent study
demonstrated significant clinical benefits when TILs,
prescreened in vitro for cytotoxicity against melanoma
cells, were expanded and then given back to melanoma
patients following nonmyeloablative immunosuppression
(see Figure 5-3C).56 It has been hypothesized that
immunodepleting chemotherapy given with this regimen
may have created “immunologic space” or perhaps oblit-
erated T-suppressor cell populations, allowing for an
increased in vivo expansion of melanoma-toxic TIL.
HEMATOPOIETIC CELL TRANSPLANTATION
Approximately 35 years ago, allogeneic hematopoietic
stem cell transplantation (HCT) was devised as a method
to maximize the dose of chemotherapy that could be
given to patients with advanced malignancies. It was
hypothesized that patients with chemotherapy-resistant
tumors might benefit from “dose-intensification,” largely
based on evidence showing a dose–response relationship
of some neoplasms to chemotherapy. The transplanta-
tion of HLA-matched hematopoietic stem cells (the allo-
graft) is used as a means of regenerating hematopoiesis
rendered defunct as a consequence of intensive
chemotherapy (the conditioning regimen). The tradi-
tional method of harvesting hematopoietic stem cells is
via multiple bone marrow aspirations from the posterior
iliac crest under general anesthetic. Alternatively, G-CSF,
GM-CSF, or even low-dose chemotherapy, can be used
to mobilize bone marrow stem cells, which are then col-
lected from the peripheral circulation by leukapheresis.
The actual bone marrow transplant involves simply
infusing the allograft into one of the patient’s peripheral
or central veins. The infusion of the donor allograft
(referred to as “day 0”) is usually performed 1–2 days fol-
lowing the completion of the conditioning regimen.57
The allograft consists of not only donor hematopoietic
stem cells but also immune cells (including NK, B, and
T-cells) that were eradicated in the patient by the condi-
tioning regimen. Patients typically receive immuno-
suppressive drugs, such as cyclosporine (CSA), or
tacrolimus, for the first 3–6 months following the proce-
dure to prevent the donor immune cells from attacking
normal host tissues, such as the liver, GI tract, or skin, a
complication known as graft-versus-host disease
(GVHD).
 94

Collection of lymphocytes Preparation of lymphocytes Single treatment cycle (days) Results

Lymphokine
A activated
killer cells Lymphocytes + IL-2
Lymphocytes isolated from circulating ⫻ 5 days
(LAK cells) 1 4 7 10 13 16 19 22 25 28 31
blood on days 8–10 ( ) (following IL-2) No improvement in objective
response rate over IL-2-alone
Part I Principles of Urologic Oncology

regimen in metastatic RCC

Tumor
patients52,53,55
infiltrating
B
lymphocytes Unselected TILs + IL-2
(TILs) Tumor infiltrating lymphocytes (TILs)
⫻ 5 days
extracted from renal cell carcinoma 1 4 7 10 13 16 19 22 25 28 31

Immunodepleting
C chemotherapy Partial response in 6/13
+ melanoma patients;
Tumoricidal TILs + IL-2
Tumoricidal Tumor infiltrating lymphocytes (TILs) no complete responses56
In vitro screening 14 days
extracted from melanoma tumor 1 4 7 10 13 16 19 22 25 28 31
TILs of TILs against
melanoma cells

Intravenous IL-2.
Leukapheresis (collection of lymphocytes from peripheral blood).
Lymphocyte infusion.
Tumor with infiltrating lymphocytes (TILs).
Immunodepleting chemotherapy.
RCC, Renal cell carcinoma.

Figure 5-3 Newer methods of adoptive immunotherapy. A, LAK cells. (Based on Law TM,
Motzer RJ, Mazumdar M, et al: Cancer 1995; 76(5):824–832, with permission.) B, TIL cell.
(Based on Figlin RA, Thompson JA, Bukowski RM, et al: J Clin Oncol 1999;
17(8):2521–2529, with permission.) C, Tumoricidal TILs. (Based on Dudley ME, Wunderlich
JR, Robbins PF, et al: Science 2002; 298(5594):850–854, with permission.)

In conventional myeloablative HCT, the primary anti-
tumor effect comes from the high-dose chemotherapy
and/or total body irradiation (conditioning regimen)
(Table 5-6). The term “myeloablative” indicates that the
patient’s bone marrow is totally obliterated as a result of
these highly cytotoxic interventions. It is now known that
powerful antitumor effects against those malignant cells
surviving high-dose conditioning are generated by donor
lymphocytes transplanted with the allograft. This allo-
geneic immune-mediated antineoplastic effect, called
graft-versus-leukemia (GVL) or graft-versus-tumor
(GVT), is capable of curing patients with a variety of
treatment-refractory hematologic malignancies.
Knowledge of RCCs susceptibility to immune effec-
tors has recently led investigators to test allogeneic trans-
plantation as a form of immunotherapy in patients with
metastatic RCC. Pilot trials were based on the hypothe-
sis that GVT effects, analogous to the GVL effect seen in
leukemias and lymphomas, might be generated following
the transplantation of allogeneic donor T cells.58
Nonmyeloablative Hematopoietic Cell
Transplantation
“Mega-dose” conditioning is largely responsible for the
25% to 35% regimen-related mortality associated with
traditional myeloablative HCT. The powerful and cura-
tive capacity of the GVT effect has recently brought into
question the need for toxic myeloablative conditioning
regimens. Reduced intensity conditioning regimens or
nonmyeloablative transplants were proposed as a poten-
tially less toxic alternative to conventional HCT. In con-
trast to a myeloablative HCT, the primary antitumor
effect in a nonmyeloablative HCT results from the immune
cells that are transferred to the patient from the immuno-
competent HLA-matched donor. In this setting, the con-
ditioning regimen serves primarily to suppress the
patient’s immune system just enough to prevent host
rejection of the donor allograft (see Table 5-6).
Accordingly, the dose of chemotherapy and toxicities
related to the conditioning regimen are less following
nonmyeloablative compared to myeloablative HCT.
After donor cell engraftment, the patient’s hematopoietic
Table 5-6 Allogeneic Hematopoietic Cell Transplantation (HCT)
Conditioning
Regimen
Myeloablative allogeneic HCT High-dose chemotherapy +/−
(Conventional HCT) Total Body XRT
Non-myeloablative HCT Low-dose chemotherapy +/−
(“Mini-transplant”) Low-dose total body XRT
HCT, Hematopoietic cell transplantation; HLA, Human leukocyte antigen; XRT, External beam radiation therapy.
Chapter 5 Immunotherapy: Basic Guidelines 95
cells typically contain cells from both the patient and the
donor, a condition referred to as mixed chimerism (in
Greek mythology, a Chimaira was a fire-spouting mon-
ster with a lion’s head, goat’s body, and serpent’s tail).59
Mixed chimerism results in a “tolerogenic state,” mean-
ing that the immune cells that develop from the donor’s
engrafted cells are unable to kill the patient’s tumor. In
order for these cells to acquire antitumor activity, the
hematopoietic environment needs to transition to “full
donor chimerism,” in which patient’s immune system is
completely replaced by donor cells. This transformation
is facilitated by the withdrawal of posttransplant
immunosuppression (e.g., tacrolimus or cyclosporine)
and the administration of donor lymphocyte infusions.60
Nonmyeloablative HCT is capable of inducing curative
GVT effects against a number of hematologic malignan-
cies. Equally important, preliminary data show the
approach is associated with a lower risk of regimen-related
mortality (7.5% to 18%) compared to conventional mye-
loablative procedures (25% to 35%). The improved toxic-
ity profile observed with nonmyeloablative HCT has
provided the basis for exploring allogeneic immunother-
apy’s potential to induce GVT effects in patients with
treatment-refractory solid tumors. Recently, a few groups
have published the results of pilot trials investigating
nonmyeloablative HCT for the treatment of cytokine-
refractory metastatic RCC. The strategy used at the
National Institutes of Health involves nonmyeloablative
conditioning with a cyclophosphamide and fludarabine-
based regimen, intended to induce host immunosuppres-
sion, followed by infusion of a G-CSF mobilized
peripheral blood stem cell graft from an HLA-identical
sibling donor (Figure 5-4). Ten of the first nineteen61 and
subsequently 22 of the first 55 patients undergoing this
approach had evidence for a GVT effect, including 6 patients
who had a complete response and 15 with a partial response.
Many of the responses were durable, including the first
patient treated who remains in complete remission 512 years
after transplantation. GVHD was the most common com-
plication, with approximately two-thirds of the patients
experiencing acute grade II–IV GVHD. However,
patients developing this complication were more likely to
have a disease response than those who never developed
Source of Mechanism of Tumor
Transplanted Cells Regression
HLA-compatible donor Conditioning regimen and
graft-versus-tumor effects
HLA-compatible donor Immune mediated via
graft-versus-tumor effects
96 Part I Principles of Urologic Oncology

Transfuse donor
Nonmyeloablative T-cells (DLI)
chemotherapy
Transplant day

–7 –6 –5 –4 –3 –2 –1 30 45 60 100

GVT effect
Transfuse the
allograft
Taper dose of cyclosporine
Cyclosporine

DLI, Donor lymphocyte infusion; GVT, Graft-versus-tumor.

Figure 5-4 Nonmyeloablative hematopoietic cell transplantation.

GVHD.61 Disease regression was typically delayed by 4–6
months following the procedure, and occurred after
cyclosporine had been tapered and after T-cell chimerism
had converted to predominantly donor in origin. Despite
the advanced disease status of patients enrolled on this
pilot trial, transplant-related mortality was relatively low,
with 6 patients succumbing to nonrelapse-related mortal-
ity. Figure 5-5 shows a clinical response following non-
myeloablative HCT in a patient with metastatic RCC that
was refractory to high-dose IL-2. Preliminary experience
would suggest that certain patient and tumor characteris-
tics herald a better outcome, such as small tumor burden,
lung-only disease, slow rate of tumor growth, and good
patient performance status. Several other groups have
recently reported graft-versus-RCC effects following non-
myeloablative HCT. Using cyclophosphamide and flu-
darabine for pretransplant conditioning, investigators at
the University of Chicago achieved complete donor

Prior to graft-versus-tumor effect

Day 100 Posttransplant Day 100 Posttransplant

A-1 B-1
Following graft-versus-tumor effect
Day 189 Posttransplant Day 189 Posttransplant

A-2 B-2
Figure 5-5 Clinical response following nonmyeloablative hematopoietic cell transplantation
in a patient with metastatic refractory RCC.
 Chapter 5 Immunotherapy: Basic Guidelines 97

engraftment in 12 of 15 metastatic RCC patients undergo-
ing an HLA-matched sibling transplant, four of whom had
a partial response. None of the patients who rejected the
allograft demonstrated a disease response.62 Investigators
from Milan, Italy, reported 4 of 7 patients having a disease
response following a nonmyeloablative transplant that used
Thiotepa and fludarabine-based conditioning regimen.63
Although these pilot results are encouraging, this
approach remains experimental and should be reserved
for patients with metastatic RCC who have previously
failed cytokine therapy, especially considering the risk of
fatal complications (mostly severe GVHD) associated
with the procedure. The primary outcome of these trials
has been to establish evidence of GVT effects against this
malignancy. Larger trials and refinements in the trans-
plant technique to decrease the risk of GVHD are
needed to define the role transplantation will ultimately
play in their management of these patients.
MONOCLONAL ANTIBODIES
The potential of antibodies to function as “magic bullets”
for the treatment of cancer has great appeal due to their
tremendous target specificity. Based on the preliminary
success of antiCD20 (Rituximab) for low-grade lym-
phomas and antiHER-2 (Herceptin) for breast carci-
noma, monoclonal antibodies (mAbs) for treating cancer
remain a very active area of research.
Therapeutic monoclonal antibodies were originally
derived from rodents. One of the major problems with
murine antibodies is their immunogenicity; the patient’s
immune system recognizes them as being foreign (Figure
5-6A), leading to an antibody attack against the mouse
antibody (human antimouse antibody, HAMA). This
host immune response not only neutralized the thera-
peutic potential of foreign antibody but also occasionally
caused life-threatening anaphylactoid reactions.64 Two
antibody design strategies were subsequently developed
to overcome this problem.64,65 Chimeric antibodies are
rodent–human antibody constructs, wherein the variable
(antigen binding) region is of rodent origin and the con-
stant (effector) region is of human origin (Figure 5-6B).
Humanized antibodies are antibody constructs in which
rodent gene segments coding for the antigen binding
loops are grafted onto human antibodies (Figure 5-6C).
More recently, phage display technology and transgenic
approaches have enabled the production of entirely
human recombinant antibodies.64,65

“Naked” antibody Chimeric antibody

Rodent constant regions (heavy, light chains) Human constant regions (heavy, light chains)
Rodent variable region (heavy, light-chain) Rodent variable region (heavy, light-chain)
Rodent CDR (complementarity-determining Rodent CDR (complementarity-determining
region) region)
A B
Humanized antibody

Human constant regions (heavy, light chains)

Rodent variable region (heavy, light-chain)
Rodent CDR (complementarity-determining
region)
C
Figure 5-6 Therapeutic rodent monoclonal antibodies (mAbs). A, Naked rodent mAb.
B, Chimeric rodent-human mAb. C, Humanized mAb.
98 Part I Principles of Urologic Oncology

The first two antibodies to be approved by the FDA
were Rituximab, a chimeric antiCD20 monoclonal
antibody for treatment of low-grade non-Hodgkin’s lym-
phoma, as well as Herceptin, a humanized monoclonal
antibody against HER-2 for the treatment of metastatic
breast cancer. Both drugs have shown individual activity in
cancer patients with chemotherapy refractory tumors.
Research efforts are underway to develop effective anti-
bodies against prostate-specific membrane antigen (PSMA)
in prostate cancer and G250, a cell surface antigen in RCC
(clear cell type). However, besides HAMA, a number of
other factors limit the efficacy of antibody therapy includ-
ing their ability to mediate cell death once they have bound
to their tumor target (Table 5-7).64,65 Strategies are cur-
rently being developed to overcome these barriers in hopes
of enhancing antibody efficacy. One such approach
Table 5-7 Barriers to Effective Antibody Cancer Therapy
Mouse antibodies are immunogenic, provoking human
anti-mouse antibody (HAMA) response
Difficulty in identifying antigens that are expressed on
tumor cells and not on normal cells
Antigen-loss on tumor cell surface
Adequate delivery of antibody to tumor depends on good
vascularity of tumor
Short half-life of some antibodies requires repeated
administrations
Antibodies are usually species-specific, limiting preclinical
animal toxicology studies
involves the conjugation of effector moieties to the anti-
body to improve tumor killing (Table 5-8).64,65
Vascular endothelial growth factor (VEGF) promotes
endothelial cell proliferation and is often secreted by
tumors in order to establish and/or increase their blood
supply. Clear-cell RCCs often produce and secrete high
levels of VEGF due to mutations in the von Hippel-
Lindau tumor suppressor gene.66–68 A recent randomized,
phase II trial was conducted to assess the efficacy of
Bevacizumab, an anti-VEGF humanized monoclonal
antibody, in the setting of advanced clear-cell RCC.69
One-hundred and sixteen patients were randomized to
receive either placebo, low-dose Bevacizumab (3 mg/kg
every 2 weeks), or high-dose Bevacizumab (10 mg/kg every
2 weeks). The vast majority (>89%) had previously under-
gone nephrectomy and received (and failed) IL-2 therapy.
At a second interim evaluation (at a median follow-up
time of 27 months from study entry), the National Cancer
Institute data safety and monitoring board recommended
closure of accrual on the basis of the difference between
the placebo and high-dose Bevacizumab in the time to
progression of disease (2.5 months and 4.8 months,
respectively, p < 0.001 by log-rank test). Only 4 of 116
patients had objective responses (all of which were partial
responses), and all of these had received high-dose
Bevacizumab. In the high-dose cohort, the response rate
was 10% (4 of 39 patients). At the last analysis, there were
no significant differences in overall survival between
groups ( p > 0.20 for all comparisons).
Bevacizumab has further demonstrated antitumor
activity in preclinical studies against hormone-refractory
prostate cancer70 and in a phase II randomized trial
(Bevacizumab + Fluorouracil/Leucovorin versus
Fluorouracil/Leucovorin) in the setting of metastatic col-
orectal carcinoma.71

Table 5-8 Antibody Strategies in Cancer Therapy

Ab-Conjugate Mechanism of Tumor Cell Killing

“Naked” Ab (unconjugated) CDC, ADCC, direct antiproliferative effects, idiotype/anti-idiotype network

Ab-radioisotope Direct radiation-induced cytotoxicity

Ab-immunotoxin Once inside the cell, toxin irreversibly blocks an essential metabolic process

Ab-drug Tumoricidal drug internalized by tumor cell

Ab-photosensitizer Photosensitizer-moiety produces oxygen free radical when exposed to light

Ab-Ab (bispecific Ab’s) Unlike direct conjugations of effector agents to a single antibody, the effector and
antigen-binding domains are bound to separate, covalently-linked antibodies

Ab-enzyme, then prodrug (ADEPT) Enzyme-Ab conjugate administered first, followed by prodrug. Enzyme converts
prodrug into active cytotoxic agent at tumor site only

Ab, antibody; CDC, complement-dependent cytotoxicity; ADCC, antibody-dependent cell-mediated cytotoxicity; ADEPT, antibody-dependent
enzyme-mediated cytotoxicity

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C H A P T E R
6 Health-Related Quality of Life Issues
in Urologic Oncology
David F. Penson, M.D., M.P.H., and Mark S. Litwin, M.D., M.P.H.
The primary goal of health care providers when treating
patients with urologic malignancies has traditionally been
to prolong patient survival. However, as the past decade
has brought new screening modalities and improvements
in treatment, clinicians and researchers have begun to
focus on other outcomes as well. In particular, as we have
recognized that cancer and its treatment affects both
quantity and quality of life in our patients, it has become
clear that various components of well-being must also be
addressed when treating individual patients with cancer or
when conducting cancer clinical trials.1 While clinicians
must still focus on “traditional” outcomes, such as 5- or
10-year survival rates, complete and partial responses, or
serum tumor marker levels, the increased attention to
patients’ overall well-being has generated interest in more
“refined” endpoints in urologic oncology. One such end-
point is health-related quality of life (HRQOL).
HRQOL encompasses a wide range of human experi-
ence, including the daily necessities of life, intrapersonal
and interpersonal responses to illness, and activities
associated with professional fulfillment and personal hap-
piness.2 Importantly, HRQOL involves patients’ percep-
tions of their own health and ability to function in life.
HRQOL is often confused with functional status. While
functional status is an important dimension of HRQOL,
there are numerous other aspects of HRQOL, including
role function, vitality, mental health, pain, and psychoso-
cial interactions, which are equally important. Despite
the commonly held belief that this type of data cannot be
easily collected, patients’ compliance with HRQOL
questionnaires is usually high.3 The impact of HRQOL
in clinical oncology is now considered so important that
a cancer trial is considered incomplete without the inclu-
sion of HRQOL outcomes.1,4
In this chapter, we review quality of life issues in uro-
logic oncology. We initially review the methodology of
102
HRQOL research and discuss various instruments avail-
able to assess HRQOL in genitourinary cancers. We
then briefly examine the current literature regarding the
effect of urologic malignancies on quality of life.
Necessarily, we focus primarily on prostate cancer, as this
has the largest body of literature. However, we touch on
quality of life issues in bladder, kidney, and testicular can-
cers as well.
THE METHODOLOGY OF HEALTH-RELATED
QUALITY OF LIFE RESEARCH
HRQOL Instruments
It is difficult for the novice to understand the task of
objectively quantifying quality of life, which is an inher-
ently qualitative phenomenon.5 However, the principles
of psychometric test theory 6 may be applied to produce
accurate assessments of HRQOL. HRQOL data are col-
lected using patient-centered surveys, called instruments.
Instruments can be self-administered by the patient or
can be administered with the assistance of a neutral third-
party interviewer in a standardized fashion. Instruments
typically contain multiple questions, or items, that are
organized into scales. Each scale measures a different
aspect, or domain, of HRQOL. Domains can be general
or disease-specific. General HRQOL domains address
the components of overall well-being, while disease-
specific domains focus on the impact of particular
organic dysfunctions that affect HRQOL.7 General
HRQOL domains typically address general health per-
ceptions, sense of overall well-being, and function in the
physical, emotional, and social domains. Cancer-specific
HRQOL domains focus on more directly relevant
domains, such as anxiety about cancer recurrence, nausea
from chemotherapy, or urinary incontinence from
sphincter damage.
 Chapter 6 Health-Related Quality of Life Issues in Urologic Oncology 103
Creation and Testing of New Instruments
It is ill-advised to use casually constructed instruments
in HRQOL research, as this can result in inaccurate
data and flawed conclusions. Therefore, before an
instrument is used in a clinical setting, statistical and
psychometric testing must be performed to measure the
survey’s reliability and validity. Because psychometric
testing is so rigorous and time-intensive, it is always
preferable to use an established, validated instrument
when available. Another advantage of using published
instruments in the collection of HRQOL data is that
they allow researchers to compare new results to previ-
ously studied populations.
If an appropriate, established HRQOL instrument is
not available for the disease process one is interested in
studying, it may be reasonable to design a new instru-
ment. The first step in this difficult process is to pilot test
the questionnaire to ensure that the patient population
can easily understand and complete the survey. Pilot test-
ing often reveals problems that the researchers may not
notice, such as the inadvertent use of medical jargon that
patients do not understand (leading to unanswered ques-
tions or inaccurate responses), use of diminutive print
size (causing difficulty reading the question), or unclear
wording (leading patients to misunderstand the ques-
tion). After pilot testing, new instruments are evaluated
for the two fundamental psychometric statistical proper-
ties of reliability and validity.
Table 6-1 Types of Reliability
Type of Reliability Characteristics
Test–Retest Measures the stability of
responses over time, typically in
the same group of respondents
Intraobserver Measures the stability of responses
over time in the same individual
respondent
Alternate-form Uses differently worded stems or
response sets to obtain the same
information about a specific topic
Internal consistency Measures how well several items
in a scale vary together in a sample
Interobserver Measures how well two or more
respondents rate the same
phenomenon
Reliability
Reliability refers to how reproducible the scale is. In other
words, what proportion of a patient’s test score is true and
what proportion is due to random variation. Several types
of reliability are typically assessed. Test–retest reliability is a
measure of response stability over time. It is assessed by
administering scales to patients at two distinct time
points, typically 1 month apart. The correlation coeffi-
cients between the two scores reflect the stability of
responses. Test–retest reliability is most easily assessed
when the domain of interest is unlikely to change over
short periods of time. When assessing test–retest reliabil-
ity, one needs to ensure that the interval between admin-
istrations is not too long, as real change can occur in the
variable, artificially deflating test–retest reliability coeffi-
cients. Internal consistency reliability is a measure of the
similarity of an individual’s responses across several items,
indicating the homogeneity of a scale.6 The statistic used
to quantify the internal consistency of a scale is called
Cronbach’s coefficient alpha.8 Generally accepted stan-
dards dictate that reliability statistics measured by these
two methods should exceed 0.70.9 These and various
other forms of reliability are reviewed in Table 6-1.
Validity
Validity refers to how well the scale or instrument measures
the attribute it is intended to measure. Content validity,
Comments
Requires the administration of survey to a sample
at two different and appropriate points in time.
Time points that are too far apart may produce
diminished reliability estimates that reflect actual
change over time in the variable of interest
Requires completion of a survey by an individual
at two different and appropriate points in time.
Time points that are too far apart may produce
diminished reliability estimates that reflect
actual change over time in the variable of interest
Requires two items in which the wording is different
but aimed at the same specific variable and at
the same vocabulary level
Usually requires a computer to carry out calculations
May be used to demonstrate reliability of a survey
or may itself be the variable of interest in a study
104 Part I Principles of Urologic Oncology
sometimes incorrectly referred to as face validity, is the non-
quantitative assessment by experts of the scope and com-
pleteness of a proposed items and scales. It is more
superficial than other types of validity, and considered by
some not to be a true measure of validity at all.10
Nevertheless, it is almost always included in the early stages
of instrument development, even if only as a general review
of items by physicians or patients. Criterion validity requires
the correlation of scale scores with other measurable health
outcomes (predictive validity) and with results from other
established tests (concurrent validity). For example, the pre-
dictive validity of a new HRQOL scale for bony pain in
prostate cancer might be correlated with narcotic usage.
Likewise, the concurrent validity of a new urinary inconti-
nence scale in prostate or bladder cancer could be correlated
with objective results on urodynamic testing. Construct
validity is a measure of how meaningful the scale or survey
instrument is when in practical use. It is often requires years
of experience with a survey instrument to assess correctly.
Often it is not calculated as a quantifiable statistic but as a
gestalt of how well a survey instrument performs in a mul-
titude of settings and populations over time. An overview of
the various types of validity is presented in Table 6-2.
Collection of HRQOL Data
In addition to using validated and reliable HRQOL instru-
ments, clinicians and researchers must collect data in a
manner that minimizes bias. For example, data regarding
sexual dysfunction following radical prostatectomy should
not be collected directly by the operating surgeon, as
patients have an unconscious desire to produce responses
that they think their physicians want to hear.11 This intro-
duces measurement error. Therefore, it is always preferable
that data be gathered by disinterested third parties or that
instruments be self-administered by patients to avoid bias.
Table 6-2 Types of Validity
Type of Validity Characteristics
Face Casual review of how good an item
or group of items appear
Content Formal expert review of how good
an item or series of items appear
Criteron: Concurrent Measures how well the item or scale
correlates with “gold standard”
measures of the same variable
Criterion: Predictive Measures how well the item or scale
predicts expected future
observations
Construct Theoretical measure or how
meaningful a survey instrument is
Many clinicians and researchers find the process and
patient-centered data collection daunting and mistakenly
believe that they can accurately estimate a patient’s qual-
ity of life. Numerous studies have documented that
physicians tend to underestimate both the degree of
symptoms and their negative effect on HRQOL.12–14
Therefore, it is usually preferable to obtain HRQOL
data directly from patients; the treating physician should
not attempt to estimate the patient’s HRQOL.
ESTABLISHED HRQOL INSTRUMENTS FOR USE
WITH UROLOGIC MALIGNANCIES
HRQOL instruments tend to be general or disease-
specific, depending on the domains addressed with the
survey. When studying urologic cancers, it is preferable
to use both general and disease-specific instruments, as
disease-specific symptoms can have profound effects on
both disease-specific HRQOL and patients’ general well-
being and overall functional status. The broad effect of
certain symptoms associated with urologic cancer may be
overlooked if researchers do not use both general and
disease-specific measures.15
Established General HRQOL Instruments
General HRQOL instruments focus on general domains
of HRQOL and have been extensively researched and
validated in many types of patients, including sick and
well. Examples include the RAND Medical Outcomes
Study 36-Item Health Survey (also known as the
SF-36),16–20 the quality of well-being scale (QWB),21–25
the sickness impact profile (SIP),21,26,27 and the
Nottingham health profile (NHP).21,28–31 All of these
instruments assess the various general components of
HRQOL, including physical and emotional functioning,
Comments
Assessed by individuals with no formal training in the
subject under study
Usually assessed by individuals with expertise in some
aspect of the subject under study
Requires the identification of an established, generally
accepted gold standard
Used to predict outcomes or events of significance
that the item or scale might subsequently be used to
predict
Determined usually after years of experience by numerous
investigators
 Chapter 6 Health-Related Quality of Life Issues in Urologic Oncology 105
social functioning, and symptoms and have been thor-
oughly validated and tested.
Cancer-Specific HRQOL Instruments for Use
in Urology
A number of cancer-specific instruments have long been
available. However, recently, many have had modules
developed that are specific for urologic disease. For
example, the European Organization for Research and
Treatment of Cancer (EORTC) Core Quality of Life
Questionnaire (QLQ-C30)32 is a 30-item questionnaire
that includes five scales (physical, role, emotional, cogni-
tive, and social functioning), a global health scale, three
symptom scales (fatigue, nausea/vomiting, and pain), and
six single items concerning dyspnea, insomnia, appetite
loss, constipation, diarrhea, and financial difficulties due
to disease. The EORTC QLQ-C30 can be used in
patients with any type of cancer. However, a 20-item
prostate cancer module has recently been developed that
specifically includes a bowel symptom scale, urinary
symptom scale and sexuality scale. This module has
been validated and shown to be reliable in men with
both localized33,34 and metastatic35 prostate cancer.
Unfortunately, this instrument does not distinguish
between function and bother in these domains.
Another example of a cancer-specific HRQOL instru-
ment that now has modules for various urologic malig-
nancies is the Functional Assessment of Cancer Therapy
(FACT).36–39 The main FACT instrument includes a set
of 28 general items that pertain to all cancer patients
(FACT-G). Each item contains a statement that a patient
may agree or disagree with across a five-point Likert
range. The FACT-G domains include well-being in four
areas: physical, social-family, emotional, and functional.
The FACT-P, a new module to measure HRQOL in men
with prostate cancer, was recently validated and may
prove useful in the future.40 There is also a FACT mod-
ule for bladder cancer, although this has not been widely
used or validated. The FACT may be accessed at
http://www.facit.org/facit_questionnair.htm.
HRQOL Instruments Designed Specifically for Use
in Urologic Malignancies
A number of instruments developed for use specifically in
urologic cancers. In the past, most of the research focus
has been in prostate cancer, and, therefore, there are more
established instruments available for use in this malig-
nancy. Recently, new HRQOL instruments have been
developed for use in bladder and kidney cancer as well.
In prostate cancer, the University of California, Los
Angeles Prostate Cancer Index (UCLA PCI) was the first
validated instrument specifically designed for use in this
condition and has been the gold standard for measuring
prostate cancer-specific HRQOL.41,42 It is a 20-item,
self-administered tool that takes about 10 minutes to
complete. It is typically administered alongside the
SF-36, a general HRQOL instrument.19 The 20 items of
the UCLA PCI are specific for prostate cancer and com-
prise six scales (urinary function and bother, sexual func-
tion and bother, and bowel function and bother) from 0
to 100, with higher scores representing better outcomes.
The UCLA PCI has now been used in several national
and international studies and has recently been validated
in Spanish.43 The UCLA PCI makes the important dis-
tinction between function and bother in the prostate-
specific domains. This feature is significant because the
bother experienced by patients does not necessarily cor-
relate with the level of dysfunction.44
Although the UCLA PCI has been validated and is
widely used, its focus on urinary incontinence does not
attend to irritative voiding complaints. Hence,
researchers at the University of Michigan developed the
Expanded Prostate Cancer Index-Composite (EPIC).
Building on the UCLA PCI, Wei et al.45 added 30 items
to the existing disease-specific domains, for a total of 50
items. The EPIC added additional items to the three
existing bother domains (urinary, sexual, and bowel),
developed hormonal function and bother domains, and
most importantly, expanded the urinary domain by
adding items that capture irritative voiding symptoms.
Therefore, the EPIC contains eight disease-specific
domains: sexual function and bother, urinary function
and bother, bowel function and bother, and hormonal
function and bother. The urinary function domain con-
tains two distinct subscales, urinary incontinence and uri-
nary irritation/obstruction, each with a separate
summary score. Because the disease-specific domains of
the EPIC instrument include significantly more items
than the original UCLA PCI, general HRQOL is typi-
cally measured using the 12-item RAND SF-1246 rather
than the SF-36.
HEALTH-RELATED QUALITY OF LIFE IN SPECIFIC
UROLOGIC MALIGNANCIES
Prostate Cancer
Of all genitourinary tumors, prostate cancer is the malig-
nancy with the largest body of HRQOL research. There
are considerable data in both metastatic and localized dis-
ease because both prostate cancer and its treatment affect
quality of life.
In the case of metastatic prostate cancer, patients
experience decrements in quality of life due to both
painful bony lesions and hormone ablation therapy.
Investigators have shown that as metastatic prostate can-
cer progresses from hormone-sensitive to hormone
resistant disease, general HRQOL worsens accord-
ingly.47 Kim et al.48 also noted that among patients
106 Part I Principles of Urologic Oncology
treated for metastases, those with progressive disease
appeared to have worse quality of life than those with sta-
ble disease, particularly for pain, fatigue, sleep, and phys-
ical and role functioning. Studies have shown that
treatment of advanced prostate cancer improves
HRQOL. Albertsen et al.35 studied metastatic prostate
cancer patients in remission on LHRH agonists and flu-
tamide and found that their general HRQOL was indis-
tinguishable from an age-matched control population of
men without prostate cancer. While treatment of
advanced prostate cancer appears to improve HRQOL,
at least initially, the therapy itself can negatively affect
HRQOL. This is of particular concern in men who pres-
ent with advanced but asymptomatic prostate cancer, as,
in these patients, the tumor itself probably has little
impact on HRQOL. For example, Herr and O’Sullivan49
compared patients receiving hormonal therapy to those
being observed for asymptomatic advanced disease.
Patients who elected to observation until the develop-
ment of symptoms had better HRQOL than those who
opted for early intervention. In particular, men who
received early therapy experienced significantly more
fatigue and hot flashes that impacted quality of life than
those who delayed treatment. Other studies note similar
findings. For example, Green et al.50 demonstrated that
early hormone ablation therapy was associated with
worse sexual function and decreased role and social func-
tioning. However, the patients who received early hor-
monal therapy did report better physical function than
those who received deferred management. Although not
a study of metastatic prostate cancer, researchers from
the Prostate Cancer Outcomes Study (PCOS)51 com-
pared men with localized disease who received hormone
ablation therapy to men with localized disease who were
observed. Those who elected hormone ablation therapy
reported worse sexual function and more physical dis-
comfort. Although all of these studies were observational
in nature and therefore may have been influenced by
selection bias, they all underscore the potential deleteri-
ous effects of hormone therapy on HRQOL.
Once patients elect to receive treatment for metastatic
prostate cancer, studies demonstrate that there is little
difference in HRQOL outcomes between men undergo-
ing medical versus surgical castration. Litwin et al.52
identified no differences in any of the general or disease-
specific domains of the RAND 36 Item Health Survey
(SF-36) or the UCLA Prostate Cancer Index when com-
paring men who underwent orchiectomy to those receiv-
ing combined androgen blockade. Although the method
of castration does not appear to have a significant impact
on HRQOL, the presence or absence of additional
androgen blocker therapy does influence HRQOL. In a
clinical trial of 739 men with stage M1 prostate cancer,
patients randomized to orchiectomy plus flutamide
reported significantly more diarrhea than those who were
randomized to orchiectomy plus placebo.53 However, the
negative impact of androgen receptor blockade on
HRQOL due to gastrointestinal side effects may be less
in patients receiving bicalutamide.54
Quality of life is of particular importance to men with
hormone resistant disease where the goal of therapy is
often palliative in nature. A number of studies have doc-
umented that various chemotherapeutic agents improve
HRQOL in men with hormone-resistant disease. For
example, Osoba et al.55 assessed HRQOL in 161 men
randomized to receive prednisone alone versus pred-
nisone and mitoxantrone over a 26-week follow-up
period. At 6 weeks, patients taking prednisone alone
showed no improvement in HRQOL scores, whereas
those taking mitoxantrone plus prednisone showed sig-
nificant improvements in global quality of life ( p = 0.009)
and four functional domains ( p < 0.01). In the cross-over
arm of the study, the addition of mitoxantrone to pred-
nisone after failure of prednisone alone was associated
with improvements in pain, pain impact, pain relief,
insomnia, and global quality of life ( p < 0.003). After 18
weeks of therapy, those receiving mitoxantrone plus
prednisone continued to improve in 11 of the 14 function
and symptom scales of the HRQOL measures used. This
study and others56,57 demonstrate that palliative
chemotherapy can lessen the physical burden of prostate
cancer in men with advanced hormone-resistant disease.
Although these treatments may not prolong life
expectancy, a documented quality of life advantage for a
given treatment will result in benefit to the patient and
should be strongly considered when choosing therapies.
In the case of localized prostate cancer, most of the
research examining HRQOL has focused on the effect of
treatment on quality of life. However, even in the case of
localized disease, prostate cancer itself appears to have an
effect on HRQOL. Bacon et al.58 compared general
HRQOL in 783 men from the Health Professionals
Follow-up Study cohort with incidental prostate cancer
to 1928 age-matched controls. They found that the men
with localized prostate cancer had worse general health,
vitality, social function, and role limitations due to phys-
ical and emotional problems (all p values <0.004) than the
control subjects. Although the differences were small,
this study demonstrates that localized prostate cancer
itself may affect quality of life.
All of the treatments for localized prostate cancer are
associated with side effects, such as sexual, urinary or
bowel dysfunction, which can impact quality of life.
Although there are differences in disease-specific
HRQOL outcomes between treatment, it appears there
is no difference in general HRQOL outcomes between
therapies, at least once the patient gets beyond the imme-
diate posttreatment period. Penson et al.59 analyzed data
from PCOS, a population-based cohort of 5672 men
with prostate cancer followed for 2 years after diagnosis
 Chapter 6 Health-Related Quality of Life Issues in Urologic Oncology 107
of localized disease. Of the 2693 analyzed, no differences
were seen comparing various treatments for localized
prostate cancer. Interestingly, men with sexual and uri-
nary dysfunction had significantly worse outcomes in the
bodily pain, mental health, role limitation, vitality, and
overall health status domains of general HRQOL, when
controlling for baseline function, treatment, and 27 other
co-variates. This underscores the importance of under-
standing the effect of the various therapies for localized
prostate cancer on disease-specific HRQOL.
There is a significant body of literature examining
disease-specific HRQOL outcomes after treatment for
localized prostate cancer. A recent randomized, clinical
trial comparing radical prostatectomy (RP) to watchful
waiting (WW), quality of life data were available in 189
men who had RP and 187 who had WW (mean follow-
up, 68 months). In the sexual domains, 55% of RP
patients reported insufficient erections and 30%
reported great distress due to their erectile dysfunction
(as opposed to 30% and 17%, respectively, in the WW
group). In urinary domains, 18% reported moderate-
to-severe urinary leakage and 9% reported great dis-
tress from this leakage (as opposed to 2% and 3%,
respectively in the WW group). However, there were
no differences between the two groups in overall dis-
tress from urinary symptoms, presumably due to a higher
incidence of obstructive symptoms in the WW patients.60
Stanford et al.61 studied the 1291 men in PCOS who
underwent RP for localized prostate cancer, noting that
8.4% of men were incontinent and 59.9% of men were
impotent 2 years after surgery. Other studies have
reported impotence rates ranging from 29%62 to 88.4%63
and incontinence rates from 4%64 to 33%63 after surgery.
In contrast to radical prostatectomy, patients undergo-
ing external beam radiotherapy (EBRT) tend to experi-
ence less urinary incontinence and sexual dysfunction but
more bowel dysfunction and irritative voiding symptoms.
For example, researchers compared long-term HRQOL
outcomes in 120 men who underwent EBRT to 125
age-matched controls.65 At 8 years after treatment, 54%
of patients and 31% of controls reported urinary prob-
lems, most of which were irritative in nature. In another
study of 129 men undergoing EBRT, 15% reported uri-
nary dysfunction to the extent that they had to modify
their activities of daily living and 2% felt virtually house-
bound by their irritative voiding symptoms.66 Crook et
al.67 studied bowel dysfunction in 192 men undergoing
EBRT and noted that 25% reported moderate and 11%
reported severe bowel changes. In another study of 200
EBRT patients, 59% reported gastrointestinal problems,
although 90% of these problems were classified as
minor.68 Finally, it is worth noting that, while the inci-
dence of sexual dysfunction following EBRT appears to
be initially less than that following surgery, it is not
insignificant. In the study of long-term HRQOL follow-
ing EBRT mentioned above, 65% reported sexual dys-
function 8 years after EBRT.65 Similarly, another study
that noted actuarial potency rates of 96, 75, 59, and 53%
at 1, 20, 40, and 60 months after EBRT.69 In summary,
EBRT also affects disease-specific HRQOL although
somewhat differently than surgery.
While interstitial brachytherapy (IB) is similar to
EBRT in that radiation is delivered to the prostate in
hopes of killing cancer cells, the effect of this treatment
on disease-specific HRQOL is different, given the fact
that higher doses of radiation can be targeted to the
prostate with IB. In particular, men undergoing IB are at
increased risk for experiencing irritative voiding symp-
toms. Lee et al.70,71 prospectively measured HRQOL in
31 men prior to IB and at 1, 3, 6, and 12 months
posttreatment. At 3 months, patients were noted to have
significant irritative voiding symptoms when compared
to baseline (15 versus 8, respectively), as measured by the
International Prostate Symptom Score (IPSS). By one
year, however, mean irritative voiding scores had
returned close to baseline (10 versus 8). Sexual and bowel
dysfunction can also occur after IB, although not to the
same degree as is seen after EBRT. In one cross-sectional
study, 35 patients who were potent pretreatment were
evaluated 6 months following IB. Eighty-seven percent
retained their potency, while 3% reported rectal bleed-
ing.72 With longer follow-up, Talcott et al.73 reported a
44% incidence of complete impotence, a 14% incidence
in rectal urgency and a 6% incidence of rectal bleeding.
Brandeis et al.74 compared 74 men who underwent radi-
cal prostatectomy to 48 men who received brachytherapy
and 134 age-matched controls. They found that men
who underwent radical prostatectomy had significantly
worse outcomes in terms of urinary incontinence when
compared to the brachytherapy patients. However,
patients who underwent brachytherapy had significantly
more irritative voiding symptoms than those who under-
went prostatectomy. Interestingly, when asked about how
much bother either type of urinary problem caused in the
patient’s life, there was no differences between the groups.
This study clearly demonstrates that men undergoing rad-
ical prostatectomy have more urinary incontinence than
men undergoing brachytherapy, while those receiving
brachytherapy report greater irritative voiding symptoms,
although both groups experience similar levels of bother.
Recently, a number of cross-sectional studies have
been published comparing disease-specific HRQOL
outcomes after surgery, external beam radiotherapy and
interstitial brachytherapy. Although all three stud-
ies75–77 indicate that sexual dysfunction is common after
all treatments for localized prostate cancer, the results
in the urinary and bowel domains are somewhat contra-
dictory. Wei et al.75 found no difference between IB and
RP in mean urinary function scores, while both Davis et
al.76 and Bacon et al.77 note significantly better urinary
108 Part I Principles of Urologic Oncology

function following IB when compared to surgery. This
may be related to differences in patient selection or
brachytherapy technique. Perhaps more interesting,
however, are the results in the urinary bother domain,
where both Wei et al.75 and Bacon et al.77report less
bother in the surgery group than in the IB group. This
may be related to irritative voiding symptoms often
seen after brachytherapy. Wei et al. compared HRQOL
outcomes in the urinary function:irritative domain and
found men undergoing IB had significantly lower mean
scores (72 out of 100) when compared to men undergo-
ing EBRT (84 out of 100) or surgery (90 out of 100).
Although these findings are useful when counseling
patients who are choosing therapy for localized prostate
cancer, one must remember that all of these studies were
observational in nature, which can introduce selection
bias and may influence patient-centered outcomes, such
as HRQOL. Ultimately, a well-designed randomized
clinical trial is needed. (Table 6-3).
Bladder Cancer
There are considerably fewer reports studying HRQOL
in bladder cancer patients. This is due, at least in part, to
the lack of a validated HRQOL specific for bladder can-
cer patients. Despite this, there are still a number of
reports examining HRQOL following treatment for
muscle-invasive bladder cancer. As part of the rationale
for performing orthotopic neobladder urinary diversion
in these patients is to maintain normal body image and
quality of life, the majority of studies have compared
HRQOL following differing types of urinary diversion.
For example, Bjerre and colleagues78 compared men
undergoing cystectomy followed by either ileal conduit
or orthotopic urethral Kock bladder substitution. They
showed that urine leakage caused much less distress in
those who underwent bladder substitution, while body
image was surprisingly similar in both groups. Global
satisfaction with life was high and similar in both groups.
Hunt Raleigh et al.79 compared HRQOL among bladder
cancer patients treated with ileal loop or neobladder and
found no significant differences noted in general
HRQOL between the two groups, although patients
with ileal loop diversion were more likely to report a neg-
ative impact on their social activity. Hara et al. also com-
pared HRQOL following orthotopic neobladder or ileal
loop diversion and noted minimal differences in
HRQOL outcomes.80 These studies, and others,81 imply
that the type of urinary diversion has little impact on
HRQOL outcomes in these patients.

Table 6-3 Results of Three Cross-sectional Studies Comparing Disease-specific Hrqol

after Treatment for Localized Prostate Cancer
Wei et al. study75 Bacon et al. study77 Davis et al. study76

Number of subjects

Surgery 570 421 220

EBRT 127 221 188

IB 61 69 103

Domains

Urinary function EBRT(93)*>IB(82)>RP(78) EBRT(89)*>IB(87)*>RP(76) IB(88)*>EBRT(87)*>RP(68)

Urinary bother RP(8%)>EBRT(10%)>IB(28%) EBRT(83)>RP(82)>IB(75)* EBRT(83)*>IB(77)>RP(74)

Bowel function RP(93)>EBRT(85)*>IB(76)*,† RP(86)>EBRT(81)*>IB(80)* RP(86)>IB(83)†>EBRT(77)*

Bowel bother RP(3%)>EBRT(7%)>IB(17%) RP(86)>EBRT(78)*>IB(72)* RP(83)>IB(79)>EBRT(72)*

Sexual function EBRT(39)>RP(34)>IB(27)† IB(36)*>EBRT(34)*>RP(26) IB(32)*>EBRT(26)*>RP(18)

Sexual bother EBRT(46%)>RP(50%)>IB(60%) IB(54)*>EBRT(51)*>RP(43) IB(40)*=EBRT(40)*>RP(25)

Note: Treatments are ranked by mean scores from best to worst, which are presented in the parenthesis. All HRQOL scores are 0 to 100 with
higher scores being better quality of life. The one exception to this is the results from the bother domains in the Wei et al. study. As these results
were not presented as summary scores, the numbers in parenthesis represent the percentage of patients who reported that symptoms in the
particular domain were a moderate or big problem. No statistical testing was performed on the bother domains from the Wei et al. study. External
beam radiotherapy and interstitial brachytherapy were not compared statistically in the Bacon et al. study.
IB, interstitial brachytherapy; EBRT, external beam radiotherapy; RP, radical prostatectomy.
*Statistically significantly different from radical prostatectomy at a p-value less than 0.05.
†Statistically significantly different from EBRT at a p-value less than 0.05.
 Chapter 6 Health-Related Quality of Life Issues in Urologic Oncology 109
In contrast, others have noted better HRQOL follow-
ing continent urinary diversions, such as orthotopic
neobladders. For example, Boyd et al.82 noted that self-
image was worse among patients with ileal conduits than
in those with continent cutaneous Kock reservoirs,
although no differences were seen in mental or emotional
health indices. Dutta et al.83 compared patients undergo-
ing orthotopic neobladder to those undergoing ileal loop
following cystectomy for bladder cancer. Although the
study was confounded by age and co-morbidity, the
patients undergoing neobladder were found to have mar-
ginally better general HRQOL outcomes. Hardt et al.84
reported results from a prospective study of 44 patients
undergoing radical cystectomy and either ileal loop
(incontinent) diversion or continent diversion for bladder
cancer. At 1 year after surgery, general HRQOL had
returned to baseline in both groups, but general life sat-
isfaction and social functioning were better in the conti-
nent diversion group while they were decreased
following incontinent diversion. Finally, McGuire et al.85
compared HRQOL outcomes following incontinent or
continent diversion and demonstrated that patients
undergoing incontinent diversion had significantly
decreased mental health. While these studies must all be
considered preliminary, they do provide some support
for the commonly held belief that continent diversions,
such as orthotopic neobladders, result in better quality of
life. More prospective data are needed to confirm this
hypothesis.
Kidney Cancer
There are surprisingly few reports on HRQOL in kidney
cancer patients. While a few of the reports of focused on
HRQOL in patients with metastatic disease,86–89 recently
a number of reports have focused on HRQOL following
various surgical techniques for removal of the primary
tumor. For example, Shinohara et al.90 compared
HRQOL outcomes following either radical or partial
nephrectomy for renal cell carcinoma. They noted that,
while there were no differences in long-term survival or
HRQOL, patients undergoing partial nephrectomy had
better physical function in the immediate postoperative
period than those undergoing radical nephrectomy. Clark
et al.91 performed a similar study. While they noted no
difference in overall HRQOL between partial and radical
nephrectomy patients, they did find that patients with
more intact renal parenchyma reported better physical
health. Finally, Pace et al.92 compared HRQOL following
laparoscopic or open radical nephrectomy. Again, while
there were no differences in long-term general HRQOL
outcomes, patients undergoing laparoscopic nephrectomy
reported better HRQOL immediately postoperatively
and returned to their baseline HRQOL state quicker.
These studies indicate that the type of operation and the
surgical technique used appear to influence short-term
HRQOL outcomes in kidney cancer.
Testicular Cancer
There has been minimal HRQOL research in patients
treated for testis cancer. Joly et al.93 compared long-term
HRQOL outcomes in testicular cancer survivors to age-
matched controls and found no differences. In another
study, Fossa et al.94 studied HRQOL outcomes in men
with good prognosis metastatic germ cell tumors. They
noted that two years after treatment, 36% of patients had
improved general HRQOL, while general HRQOL had
deteriorated in 13% of patients. The remaining patients
were effectively unchanged. Arai et al.95 used a Japanese
translation of a questionnaire that had been validated in
English to assess HRQOL in men treated for testicular
cancer. Patients treated with chemotherapy (with or
without retroperitoneal lymph node dissection), radio-
therapy, and surveillance were compared. Working abil-
ity was better in the radiotherapy and chemotherapy
groups. These patients also reported a greater overall sat-
isfaction with life than those in the surveillance group.
Weissbach et al.96 compared HRQOL outcomes in men
undergoing retroperitoneal lymph node dissection
(RPLND) or upfront chemotherapy for stage II non-
seminomatous germ cell tumors as part of a prospective,
multicenter clinical trial. HRQOL outcomes were simi-
lar between the two groups, leading the authors to rec-
ommend surgery for these patients, as chemotherapy
could then be avoided in a considerable number of
patients with little effect on quality of life.
SUMMARY
HRQOL is an essential outcome for patients with geni-
tourinary malignancies. While patients are concerned
with maximizing their life expectancy following a diag-
nosis of cancer, they are often just as concerned, if not
more so, with maintaining their quality of life after treat-
ment. Clinicians and researchers must be sensitive to this
and focus more attention of the effects of therapy on can-
cer survivors’ quality of life.
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112 Part I Principles of Urologic Oncology
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C H A P T E R
7 Image-Guided Minimally
Invasive Therapy
Agnieszka Szot Barnes, M.D., M.S.,
and Clare M.C. Tempany, M.B., B.A.O., B.Ch.
The field of image-guided minimally invasive procedures
has undergone a revolutionary change in the past decade.
We have seen the development of advanced image-
guided therapies for treatment of many different diseases,
ranging from brain tumor resection and treatment to
magnetic resonance (MR)-guided prostate brachytherapy
and MR-monitored thermal therapies, such as cryother-
apy. In the field of urologic oncology, today there are
many image-guided procedures for obtaining diagnoses
and guiding and delivering treatment. These range from
simple biopsies to image-guided tumor ablations.
Minimally invasive therapy is used to treat the disease
by operating through natural body openings or small
incisions, thereby reducing the cosmetic or loco-regional
tissue damage and the potential complications of open
surgery. By reducing the need for invasive surgery, hospi-
talization is shortened, with fewer complications and
faster recovery. These procedures have been allowed by
the development of improved surgical techniques and,
perhaps more importantly, improved imaging tech-
niques. Because direct visualization without surgical
intervention is not possible, the ability to combine mul-
tiple imaging modalities to plan and execute the surgery
has permitted the full use of the new surgical techniques.
This combination of imaging and therapy is known as
image-guided therapy (IGT).
The purpose of IGT is to integrate the anatomic and
physiologic information acquired before treatment with
the therapy methods and allow the control and guidance
of the treatment while it is being performed to improve
the accuracy of treatment delivery. Not only can image-
guidance improve targeting of cancer tissue during ther-
apy but it can also spare adjacent tissues and organs from
being damaged during treatment. IGT is a multidiscipli-
nary field in which surgeons, radiologists, oncologists,
and computer experts combine efforts to integrate imag-
ing systems with therapy systems.
Image-guided minimally invasive therapy is experi-
encing rapid growth driven by the introduction of new
imaging modalities and significant improvement of exist-
ing ones as well as improving computer performance.
The most important advancements of this field include
integrating preprocedure and intraprocedure imaging,
further improving image quality, and testing the usability
of the techniques in clinical settings.
HISTORY
IGT evolved over the years with major advances in image-
guided neurosurgery spreading to other disciplines,
including urologic oncology. In many cases, brain tumors
may visually resemble healthy tissue to the naked eye or
the extent of tumor invasion may be obscured by overlying
healthy tissue. Before image guidance the procedures were
performed without proper visualization of the extent of
the tumor or its specific geometry.
In the past decade or so, MR imaging (MRI) and com-
puted tomography (CT) techniques have improved enor-
mously. We have seen rapid MR scanners with high field
strengths become standard clinical tools in many radiol-
ogy departments around the world. New multidetector
CT scanners allow rapid acquisition of high-resolution
CT data sets that can now be reconstructed in coronal or
sagittal planes. As the technology has advanced, the impact
of the image data has expanded. Now imaging alone diag-
noses nearly all renal cell carcinomas. Imaging alone stages
the extent of vascular invasion by a renal cell tumor and
plans the surgical approach. Three-dimensional (3D)
reconstructions allow the surgeon to determine the feasi-
bility of a partial nephrectomy.
113
114 Part I Principles of Urologic Oncology
The imaging of solid organs, both to identify pathology
and to accurately locate critical structures, has become the
province of x-ray CT and MRI. CT has been used prima-
rily for guiding biopsies, although the advent of “CT flu-
oroscopy” has stimulated use in guiding interventional
procedures, such as radiofrequency (RF) ablation.
Intraoperative ultrasound (US) has been used with
increasing success for many decades, particularly in the
imaging of solid organs, which can be directly con-
tacted by the probe, giving both excellent imagery and
explicit orientation of the image. US is particularly
useful in observing vascular structures, which are both
important landmarks and vital structures to be avoided
during the resection of solid organs. Laparoscopic US
shares the imaging advantages of intraoperative use,
but due to the small size of the imaging head and the
offset required for endoscopic insertion, it could be
more difficult to interpret the content and orientation
of the images.
The penetration of real-time CT and MRI into the
broad range of surgical procedures has been slow, due to
the complexity and cost of their implementation and dif-
ficult access to the patient. In the case of MRI, additional
obstacles have been the incompatibility of surgical tools,
devices and operating room equipment with the magnetic
field environment and the challenge of interpreting the
MR image, which may require extensive training and/or
expert consultation.
The attractiveness of MRI for guiding simple proce-
dures, such as biopsies, was recognized as early as the
mid-1980s. Many of the initial obstacles of real-time
MRI guidance were overcome when an open MR scanner
was introduced to guide neurosurgical procedures in
Brigham and Women’s Hospital in Boston in December
1993. This new revolutionary method was envisioned by
Dr. Ferenc Jolesz—radiologist and neurosurgeon—in
1987 when he began to put together a team of collabora-
tors to create the “operating room of the future.”1 The
0.5 T intraoperative MR scanner was designed by GE
Medical Systems (Signa SP) and installed in a designated
MR therapy (MRT) suite.2 The scanner has a vertical gap
that allows the physician to enter between the two mag-
nets and makes it easy to access the patient to perform
treatment (Figure 7-1). Images are generated using fast
sequences resulting in near real-time imaging without
disruption of the procedure. Initially, the scanner was
used to guide percutaneous or transcranial biopsies but
currently it is utilized in a variety of procedures from
neurosurgery to prostate brachytherapy and biopsy.
Since then, many other open configuration magnets
have been introduced, including 0.2 T vertical-type mag-
nets (Picker, Siemens) and shorter-bore magnets (Philips,
Picker). Conventional 1.5 T magnets are also used to
guide various procedures. The main disadvantage of
Figure 7-1 Open 0.5 T MR system for performing image-
guided procedures.
these scanners is the difficulty they pose to accessing
the patient during the procedure, while their main
advantage is higher field strength and therefore better
image quality.
In the field of urology, IGT has advanced significantly
from lithotripsy—shockwave removal of kidney stones
under US or fluoroscopy guidance—to MR-guided pro-
cedures. While fluoroscopy remains a very popular
method of image guidance in urology, it can expose
both the patient and the physician to radiation. The
advances in CT imaging made it possible to perform
CT fluoroscopy in real time. These advances, including
3D reconstruction, play a large role in the guidance of
urologic procedures, including CT-guided tumor abla-
tions and CT-guided prostate brachytherapy and
biopsy. Ultrasound guidance still remains very popular
in clinical urology mainly because of its lower cost and
portability, the possibility of real-time imaging, and the
safety for both patient and urologist. Currently, many
centers successfully use transrectal US (TRUS) to guide
prostate biopsies and brachytherapy. MR has unique
assets as a guidance modality, allowing not only target
identification but also therapy monitoring. This is best
illustrated by MR-guided focused ultrasound (MRgFUS).
Finally, advances in MR imaging include image recon-
struction in multiple planes, a higher signal-to-noise
ratio that allows excellent differentiation between tis-
sues, and new contrast agents to make feasible MR-
guided diagnostic techniques, such as MR angiography
and MR spectroscopy. The creation of open interven-
tional MR also made MR guidance possible for several
urologic procedures, including prostate brachytherapy
and biopsy.3

OVERVIEW OF CURRENT MR-GUIDED
IMAGE-GUIDED THERAPY APPLICATIONS
The field of MR imaging for guiding interventions and
therapy is attracting considerable research attention. MRI
is superior to any other method in brain tumor localization
and assessment and therefore is an excellent method for
surgical guidance. Tumor margins and extent can be well
defined, which in turn provides the possibility of complete
tumor eradication with minimal damage to healthy brain
tissue. MR-guidance for neurosurgery provides substantial
help in performing brain tumor surgery.3 The use of com-
puterized navigation and 3D modeling further enhances
precise tumor resection.
These improvements in MR-guided neurosurgery
techniques, including 3D modeling, have provided a
framework for an MR-guided prostate intervention pro-
gram guiding prostate cancer therapy with interstitial
brachytherapy—the permanent placement of radioactive
sources (commonly I-125) directly into the prostate.
Prostate MRI, especially with combined endorectal and
phase-array coils, provides images of even higher resolu-
tion and is used in prostate cancer staging, as well as in
determination of extraprostatic disease with up to 82%
accuracy.5,6 The T1- and T2-weighted images are helpful
in differentiating between postbiopsy hemorrhage, which
presents as a high T1 and a low T2 lesion, and prostate
cancer, which presents as a low T1 and a low T2 lesion.
Contrast-enhanced images and prostate spectroscopy are
of great importance in distinguishing between normal and
cancerous tissues. Bladder and prostate cancers may expe-
rience higher perfusion than does normal tissue, which is
detected as signal enhancement following intravenous
Figure 7-2 Prostate gland segmentation and registration. Segmentation identifies PZ
(solid arrow) and central gland (hollow arrow) in pre-therapy endorectal coil MR (1.5 T, left)
and MR-guided therapy images 0.5 T, right). Registration matches the segmented areas
in the different images.
Chapter 7 Image-Guided Minimally Invasive Therapy 115
injection of MR contrast agents (such as Gadolinium-
DTPA); relative peak enhancement, time to peak, and
washout are of great importance in distinguishing and char-
acterizing cancer.7–9 Added value comes from spec-
troscopy, where metabolic differences can distinguish
between cancer and healthy tissues. Normal prostate
metabolism is characterized by high citrate and low
choline/creatinine levels, whereas in cancerous tissue these
ratios are reversed.10 Prostate multivoxel spectra convey-
ing metabolic information are superimposed on endorec-
tal and multiphase-array MR anatomic images, allowing
for precise localization of the tumor. Prostate imaging is
now moving towards use of higher-field 3 T scanners,
which provide images with higher signal-to-noise ratio,
which in turn allow for better visualization of prostatic
substructures and increased MR-spectroscopy resolution.
The development of an interventional MR therapy
(MRT) system has made it possible to perform prostate
brachytherapy under MR guidance. Even at lower field
strength than is routinely used for prostate cancer imag-
ing (0.5 T versus 1.5 T), MRI provides images of good
quality for target visualization, as well as identification of
the urethra and rectum (see Figure 7-2 for comparison of
1.5 T and 0.5 T images). Computer software has been
developed to provide dosimetry analysis, used for both
treatment planning and monitoring based on intraopera-
tive MR images.11 Image-processing methods adapted
from brain surgery are available to further facilitate pre-
cise radiation delivery to the prostate gland while sparing
surrounding tissues. Currently, treatment delivery with a
robot assistance system is being developed and tested to
improve radioactive seed placement.
116 Part I Principles of Urologic Oncology
After installation of the first interventional magnet at
Brigham and Women’s hospital in 1993, several other cen-
ters were created at teaching hospitals around the country,
including Stanford University and the University of
Mississippi. Since then the number of centers has grown
and now includes many more sites in the U.S. and overseas.
A great strength of MRI lies in its sensitivity to tem-
perature changes.12–14 This sensitivity allows specialists
to monitor in real-time the delivery of several thermal
energy treatments, including RF and laser therapy for
brain tumors, and cryotherapy and high-intensity FUS
for breast, prostate, liver, and uterine lesions. Currently,
MRI is a very useful guidance method for cryotherapy—
tumor ablation by use of freezing—because it allows for
monitoring of the location and size of the ice ball in mul-
tiple dimensions.4 Intraoperative MR images are used to
depict the slow expansion of the ice ball, as well as tissue
damage caused by the freezing process.
MR-guided FUS is a very promising method for non-
invasive cancer treatment. While other minimally inva-
sive therapies require direct insertion of special probes to
reach the tumor, this method uses a high-intensity US
beam focused on the target lesion (as seen on the MR
image) without disruption of skin and other tissues. FUS
is based on the use of acoustic energy and its secondary
thermal effect, which cause thermal coagulation of the
target tissue. As early as 1955, it was clinically shown that
FUS was capable of destroying mammalian tissues.15
Broad use of this treatment method has been hindered by
a lack of appropriate image-guidance techniques for the
tumor-targeting, and most importantly for the real-time
monitoring of temperature changes. The introduction of
MR guidance provided an excellent method for monitor-
ing treatment planning and delivery with direct temper-
ature mapping (using MR phase-contrast techniques), as
well as posttreatment confirmation of necrotic tissue
changes.6 Using the MR images, the physician can iden-
tify the target lesions; temperature change during treat-
ment delivery is monitored using MR temperature maps.
A special transducer moves from one spot to another, fol-
lowing a pretreatment plan, until the entire volume is
treated. To date, this method has been successfully used
in the treatment of breast fibroadenomas, breast cancers,
and uterine leiomyomas.16–18 Application of this treat-
ment to prostate cancer, liver lesions, and brain tumors is
currently under investigation.
IMAGE-GUIDED THERAPY: ROLE OF IMAGE
PROCESSING
The key to IGT is the integration of a coordinated image
process with the therapy process. Early problems with
IGT included lack of integration of the imaging with
therapy instruments, as well as difficulties with image
display and processing, especially when using MR pro-
cessing. As the image processing technology improved,
feedback from imaging to the therapy became possible
and the role of imaging became more prominent, using
MRI for intraoperative guidance as well as diagnosis. As
the processing improved, imaging became almost instan-
taneous or “real-time,” allowing for tight integration of
imaging and therapy.
There are several components critical to all image-
guided therapies; these are: planning, targeting, naviga-
tion, control, and monitoring. Pretreatment planning
allows for the assessment of the approach that will pro-
vide the most effective eradication of the tumor and at
the same time the least damage to the surrounding vital
organs. For example, when delivering radiation therapy,
pretreatment dosimetry planning determines the volume
of the target and the placement of radiation sources.
Targeting during IGT refers to precise pretreatment
localization of all tumor targets that need to be treated
and is essential for precise navigation of equipment dur-
ing treatment delivery. Navigation refers to the guidance
of surgical equipment during procedures to target the
tumors precisely and spare healthy tissue. Current
research efforts in the field of navigation are directed
towards automatization of the procedure and increasing
the use of surgical robots.19,20 Real-time controlling and
monitoring of the treatment delivery by means of intra-
operative imaging allows for necessary adjustments of the
therapy to reflect movement of the tissues and permits
alterations of he plan in response to initial therapy.
Many different image postprocessing techniques have
been developed to allow use of anatomic and functional
information to improve tumor detection and treatment
planning. These techniques include image segmentation,
fusion, and registration. The purpose of image segmenta-
tion is to distinguish organs or structures of interest (e.g.,
prostate or its peripheral zone [PZ]) from the surround-
ing organs and tissue in order to perform volumetric and
shape analyses, as well as treatment planning (see Figure
7-2). This is currently done by either manual outlining of
the structure of interest or by semiautomated methods.21
The future of medical image segmentation is to automate
the process and replace manual segmentation.22,23
Registration is a technique used to match images taken using
different modalities, the same modality at different time
points, or different imaging sequences (see Figure 7-2).
The process involves mapping one image into the coordi-
nate system of another image. Fusion is the merging of
the anatomic and functional information provided by dif-
ferent imaging modalities into a single volume in order to
provide better information about the underlying anatomy
and tissue characteristics (Figure 7-3). Applications for
fused images include not only IGT but also minimally
invasive diagnosis and treatment planning.

Figure 7-3 MR-CT image fusion of prostate gland. Registration allows fusion of MR image
(left) with CT image to yield fused image (right). Black arrows indicate radioactive seeds.
IMAGE-GUIDED MINIMALLY INVASIVE THERAPY
IN UROLOGY
Many of the image-guided minimally invasive therapies
in urologic oncology are directed toward diagnosis and
treatment of prostate cancer.
In prostate procedures, IGT and diagnosis can be
guided by different image modalities; transrectal TRUS
(TRUS) is the most widely used method. TRUS provides
good delineation of the prostate margin, simplicity of
imaging, relatively low cost compared to other modali-
ties, and availability. TRUS is a widely used technique for
guidance of both prostate biopsies and brachytherapy.
However, for prostate cancer diagnosis, the positive pre-
dictive value of this method remains quite low (17% to
57% for hypoechoic lesions, as summarized by Boges et
al.24). Currently, research focuses on improving the accu-
racy of TRUS in the detection and staging of prostate
cancer, including features such as power and color
Doppler, 3D imaging, and elastography.
CT guidance was used primarily for prostate biopsies
but has also been introduced in prostate cancer therapy
guidance.25 CT provides visualization of prostate bound-
aries and with the placement of a Foley catheter in the
bladder allows for good visualization of the urethra that
helps avoid urethral damage during treatment delivery.
MR guidance of prostate procedures grew in impor-
tance after the development of the interventional MR
scanner described earlier. Compared to US and CT
imaging, MR imaging provides superior visualization of
the prostate and its zonal anatomy, tumor location, and
surrounding vital organs like the rectum, neurovascular
bundles (NVBs), and urethra.
Chapter 7 Image-Guided Minimally Invasive Therapy 117
Minimally invasive image-guided procedures for early
stage organ-confined prostate cancer include diagnosis
using US-, CT- and MR-guided biopsy; and therapy
using cryotherapy, CT-guided brachytherapy (CTBT),
2D transrectal US-guided brachytherapy (USBT)—both
with and without external beam radiation therapy, with
and without neo-adjuvant hormonal therapy; MR-guided
brachytherapy (MRBT), with and without external beam
radiation therapy; and FUS.
In general, the group of patients that may benefit
from IGT as monotherapy for prostate cancer is com-
prised of men with organ-confined disease. Lieberfarb
et al.26 showed that in low-risk patients with clinical stage
≤ T2a (according to the American Joint Commission on
Cancer Staging—AJCC system), PSA ≤10 ng/ml, and
≤ 50% positive biopsies, the likelihood of extracapsular
extension (ECE) with or without positive margins was
18%, and seminal vesicle involvement was 2%. These
patients may be “ideal” candidates for IGTs. For an
overview of prostate therapy outcomes see Jani and
Hellman (2003)27 and Peschel and Colberg (2003).28
Cryotherapy
Cryotherapy refers to the application of low tempera-
tures to necrotize the tumor. In addition to its use as a
primary treatment for prostate cancer it has also been
used as a salvage therapy after failure of radiation ther-
apy.29–31 Cryosurgery was first proposed as a treatment
for prostate disease in 1966.30 In the following years,
several open transperineal procedures were performed
under visual control. Because of many serious posttherapy
118 Part I Principles of Urologic Oncology
complications, including urethro-cutaneous and urethro-
rectal fistulas, cryosurgery was not commonly used until
its revival with US guidance in 1993.33
Procedure Cryotherapy is usually performed with the
patient placed in the lithotomy position and placed under
general anesthesia. The specific technique and the num-
ber of freezing cycles vary slightly between centers, with
2 cycles used most commonly. After positioning of the
TRUS probe, multiple suprapubic cryoprobes are placed
using US guidance. To prevent damage to the urethra, a
warming urethral catheter is placed. Thermal sensors are
placed around the periphery of the gland to allow good
temperature control in critical locations. At the end of
the procedure, the cryoprobes are thawed and removed.
A newer approach to the use of cryotherapy in image-
guided interventions is MR-guided cryotherapy, which
has the major advantage of allowing clear visualization of
the “ice-ball” induced in the tissue, as it occurs. This
allows for direct thermal monitoring of the treatment
effect (Figure 7-4).
Outcomes Because of the fairly recent revival of
cryotherapy due to image guidance improvements, the
long-term treatment results are still being investigated.
Several groups reported their preliminary results follow-
ing TRUS-guided cryotherapy. At 5 years, the progres-
sion-free rate defined as undetectable PSA (< 0.3 ng/ml)
ranged from 48% to 77%, depending on patients’ risk
factors.34,35
Figure 7-4 Axial MR image showing a percutaneous
cryotherapy probe in the lateral aspect of the left kidney
during an MR-guided cryoablation of a small renal cell
carcinoma. The “black” ice-ball is clearly seen (solid arrow);
note the close proximity of the left colon (hollow arrow).
Complications of the treatment included incontinence,
urethral sloughing, rectal fistula, and perirectal abscess.34–36
Patients self-reporting erectile dysfunction (ED) follow-
ing cryosurgery were many compared to other minimally
invasive prostate cancer treatments, ranging from 53% to
87%.34–37 A recent study showed pilot results on a new
“nerve sparing” cryosurgery with the preservation of
potency in 7 of 9 treated men at a median follow-up of 36
months (range from 6 to 72 months).38
Brachytherapy
Interstitial brachytherapy refers to the permanent
placement of small radioactive sources directly into the
prostate. These are typically iodine (I-125) or palla-
dium sources contained within a titanium-jacket and
measure about 4 mm in length. Similar to cryosurgery,
interstitial brachytherapy can be used as a primary
treatment or as a salvage therapy after external beam
radiation or initial implant failure.39–41 Interstitial
brachytherapy for prostate cancer was introduced in the
1960s by Scardino and Carlton.42 The placement of
radioactive seeds was performed using a freehand tech-
nique that did not provide homogenous seed distribu-
tion and resulted in both underdosing of tumors and
overdosing of vital structures (rectum, urethra, NVBs).
This resulted in many posttreatment complications,
and the procedure was discontinued until its revival
with US image guidance in 1983 by Holm and col-
leagues.43 Further improvements in imaging techniques
and technology resulted in the first MR-guided implant
being performed at 1997 at Brigham and Women’s
Hospital in Boston.44
Ultrasound-Guided Brachytherapy
Procedure A patient is placed in the lithotomy position,
a Foley catheter is inserted, and general or spinal anes-
thesia is administered. The TRUS probe and probe stabi-
lizer are positioned and the probe stepper is attached to
the stabilizer. US images are obtained every 5 mm from
the apex to the base. Some centers use designated treat-
ment planning software for preplanning of the proce-
dure.45 The images are transferred to a laptop computer
connected to the US equipment. A 3D reconstruction of
the prostate, urethra, and rectum is produced, and the
dose of radiation to those structures is visualized. Dose-
volume histograms and the number of radioactive seeds
per needle are then calculated. The template for needle
guidance is placed against the patient’s perineum. After
insertion of each needle a sagittal mode of the US acqui-
sition is also used to determine the depth of the needle
insertion. Some centers use fluoroscopy to visualize seed
placement.45

Outcomes Although investigators used slightly differ-
ent definitions of biochemical failure, the overall results
of similar studies are quite consistent. At present, there
are only a few studies presenting 10-years outcome data
for prostate USBT. Biochemical disease-free survival rates
after 10 years following treatment ranged from 70% to
87%.46–48 At 5 years, relapse-free survival rates reached
85% to 94% for the low-risk group, 77% to 82% for the
intermediate-risk group, and 62% to 65% for the high-
risk group.49–51
Reported complications following USBT included
urinary incontinence, urethral strictures, cystitis, uri-
nary retention, prostatitis, proctitis, rectal ulceration,
and rectal fistulas. Transient irritation and obstruction
of the urinary tract 2 to 6 months after treatment were
common and about 10% of patients showed symptoms
of acute urinary retention (AUR).52 Preservation of
potency ranged from 64% to 79% at 3 years to 39% at
6 years. Pretreatment ED and a higher implant dose
caused greater impotence.53–55
CT-Guided Brachytherapy
Procedure The prostate gland immobilization before
the procedure is similar to US-guided therapy. A Foley
catheter, with radio-opaque wire to fluoroscopically
localize the urethra, is placed, and general anesthesia is
administered. Preoperative CT images collected using
5 mm slices are used to outline the prostate gland for
treatment planning. Posteroanterior and lateral fluoro-
scopic images are used to determine needle position
before seeds are deposited. The seeds are placed under
fluoroscopic control.
Recently, CT-guided transischiorectal stereotactic
brachytherapy has been introduced and tested.56–58 This
approach can be used in patients with larger prostates.
Transischiorectal CT images acquired every 5 mm are
used for pretreatment planning. The patient is placed in
the prone position, a Foley catheter is inserted and
spinal or epidural anesthesia is administered. A 3D
stereotactic template used to guide needle placement is
attached to the CT table and tilted at the same angle as
the gantry. Electronic grids are superimposed on every
second CT image to determine needle depth. CT
images are used for needle visualization, placement cor-
rections are introduced if necessary, and radioactive
seeds are deposited.
Outcomes Biochemical disease-free survival rates
reached 99% for low, 96% for intermediate, and 90%
for the high-risk group at a median follow-up of
4.5 years (2 to 8 years).59 Treatment complications
included urinary retention, incontinence, and rectal
symptoms.
Chapter 7 Image-Guided Minimally Invasive Therapy 119
MR-Guided Brachytherapy
Patient Selection The patient selection criteria for this
program in our institution are clinical stage T1cNXM0
(according to AJCC), PSA less than 10 ng/ml, biopsy
Gleason score not more than 3 + 4, low cancer volume,
and endorectal MRI demonstrating organ-confined dis-
ease. Patients with prior transurethral resection of the
prostate (TURP) are excluded. We do not exclude men
with larger-volume prostates, as pubic arch interference
can be avoided in this approach. All patients undergo
endorectal coil MRI for prostate cancer staging prior to
the treatment visit (Figures 7-5 and 7-6). An MR radiolo-
gist assesses prostate gland volume, tumor location and
volume, the presence or absence of extraglandular disease,
seminal vesicle invasion (SVI), and possible spread to
pelvic lymph nodes or bones.
Procedure This multidisciplinary procedure uses
many different computer, imaging and technical skills
and therefore requires the cooperation of specialists from
various medical and nonmedical fields, including radia-
tion oncologists, medical physicists, radiologists, anes-
thesiologists, urologists, nurses, radiology technologists,
and computer scientists.
For the procedure the patient is placed in an open
configuration 0.5 T Signa SP MR scanner in the litho-
tomy position. The patient is positioned on the table
between two magnets with vertically oriented open space
for easier access to the patient during the treatment (see
Figure 7-1). A Foley catheter is inserted, skin prepared,
the template for needle guidance placed against the
patient’s perineum and secured, and a rectal obturator is
inserted (Figure 7-7). T2-weighted MRI images are
acquired in the axial, coronal, and sagittal planes. The
radiologist uses the T2-weighted images (see Figure 7-2,
right) to identify the peripheral zone (PZ), urethra, and
anterior rectal wall on each axial MR slice. These are
then outlined using the 3D Slicer surgical simulation
software designed and operated by members of the
Surgical Planning Laboratory (SPL) at Brigham and
Women’s Hospital in Boston (Figure 7-8). The 3D Slicer
is free, open-source software for two- and three-dimen-
sional display, registration, and segmentation of medical
images (see www.slicer.org for more information on 3D
Slicer). Pretreatment planning, as well as calculation of
the MRI-based peripheral zone as a clinical target vol-
ume (CTV), is then performed by the medical physicists
using designated planning software.11 The number of
I-125 seeds per catheter and the depth of catheter inser-
tion are calculated. The physicians then insert each pre-
loaded catheter into the prostate gland. After every
catheter insertion, axial gradient-echo MR images are
obtained in real-time and compared to the catheter’s
expected location according to the plan. Dose volume
120 Part I Principles of Urologic Oncology

Figure 7-5 Endorectal coil MRI of prostate. Axial (left) and coronal (right) T2-weighted
images provide superior visualization of the prostate and its zonal anatomy. White solid
arrows indicate PZ, hollow arrows indicate central gland, and striped arrows indicate
endorectal coil.

Figure 7-6 Prostate cancer. Axial T2-weighted erMRI image Figure 7-7 Close up view of a patient in the open 0.5T Signa
shows low signal lesion located in PZ (white arrow). SP magnet, during MR-guided prostate brachytherapy. The
patient is in the lithotomy position and the perineal template
used for catheter guidance is seen in the center.

histograms (DVH) for the CTV, anterior rectal wall, and
urethra are recalculated, adjustment of the catheter place-
ment is performed when necessary, and seeds are
deposited.
Approximately 6 weeks after the procedure, MRI and
CT imaging of the prostate is performed to identify the
location of radioactive seeds and calculate final DVHs.
Since seeds can be well visualized on CT images, and the
underlying anatomy is better depicted on MR images,
MR-CT fused images are used to calculate dose distribu-
tion to the surrounding tissues (Figure 7-9).
Outcomes Long-term biochemical outcomes were
compared for similar patients over similar time frames
between MR-guided brachytherapy and radical prostate-
ctomy by D’Amico et al.60 At 5 years, PSA control was
95% for brachytherapy and 93% for RP patients (median
follow-ups were 3.95 and 4.2 years for brachytherapy and
RP patients, respectively). The percentage of positive
prostate biopsies was found to be a significant predictor
of the time to postbrachytherapy PSA failure.
Short-term toxicity following MR-guided brachyther-
apy was rare, and no patient reported gastrointestinal or
 Chapter 7 Image-Guided Minimally Invasive Therapy 121

Figure 7-8 Image segmentation using 3D Slicer surgical navigation software. PZ (solid
arrow), rectal wall (hollow arrow), and urethra (striped arrow) are identified on T2-weighted
image acquired in a 0.5 T scanner for MRBT planning.

Figure 7-9 MR-CT fusion of post-MRBT images. Post-therapy MR image (left) and CT image
(middle) are fused resulting in MR-CT image (right) to allow better visualization of individual
seeds and facilitate dose distribution calculation. Black arrows indicate radioactive seeds.
122 Part I Principles of Urologic Oncology
sexual dysfunction during the first month after treat-
ment.61 Acute urinary retention (AUR) was observed in
12% of men within 24 hours of removal of the Foley
catheter and was self-limiting within 1 to 3 weeks. MR-
determined prostate volume, transitional zone (TZ) vol-
ume, and total number of seeds were found to be
significant predictors of AUR on univariate analysis. The
TZ volume was the only significant predictor of AUR on
multivariate logistic regression analysis. The authors
concluded that benign prostatic hyperplasia (BPH) that
results in larger TZ volume is the most important pre-
dictor of AUR. No urinary incontinence was seen at a
median follow-up of 14 months (from 9 months to 2
years).62
MR-guided brachytherapy is a very new approach;
thus, there is only one report to date summarizing
long-term toxicity.63 Albert et al.63 found low inci-
dence of rectal bleeding (8%) and no urethral stric-
tures at a median follow-up of 2.8 years (0.5 to 5
years). While ED reached 82%, two-thirds of the
patients reported good erectile function after sildenafil
(Viagra). No radiation cystitis was estimated at 4 years
after MRBT.
Quality of life (QoL) outcomes collected using a pre-
viously validated questionnaire64 are currently being
assessed, and early reports indicate that MR-guided
prostate brachytherapy has better symptomatic outcomes
than the conventional US-guided approach (J. Talcott,
personal communication).
Current research projects will continue to study the
radiation dose distribution to vital organs and its
impact on the side effects. Image-segmentation tech-
niques are used to identify those important organs on
endorectal coil MR images. Radiation dose to the
organs can then be correlated with changes in patient-
reported QoL.
Focused Ultrasound Surgery
US-Guided High-Intensity Focused Ultrasound
for Prostate Cancer
This approach uses a high-intensity US beam that is
focused on the target lesion, which then undergoes ther-
mal coagulation. In 1996, Galet et al.65 were the first to
evaluate clinical application of FUS for treatment of
organ-confined prostate cancer.
Procedure For the treatment the patient is placed in
the lateral position and anesthetized. A suprapubic
catheter is placed to assure urinary drainage, and an
imaging and treatment probe is inserted into the rectum.
The probe is surrounded with a balloon filled with cool-
ing fluid to avoid overheating of the rectal wall. Target
areas are identified using biplanar US imaging and the
treatment is planned. Therapy is performed using a 2.25
to 3-MHz transducer.
Outcomes Early results showed 56% to 100% therapy
response rates when using Ablatherm probes; however,
the criteria of PSA failure after FUS are still under
debate.66–72 Blana et al.73 reported outcomes following
FUS for localized prostate cancer at a median follow-up
of 22.5 months (4 to 62 months). After a follow-up for 22
months, 87% of patients had a PSA level below 1ng/ml,
and 93.4% had negative control biopsies. Reported treat-
ment adverse effects included urinary tract infection,
stress incontinence, rectal burn, rectourethral fistulas,
urethral stricture, and impotence.
MR-guided FUS for treatment of prostate disease is
currently under investigation; initial animal tests appear
very promising. FUS treatment can be monitored by
thermal maps and contrast-enhanced MRI (Figure 7-10).
Diagnosis
US-Guided Prostate Biopsy
Currently, diagnosis of prostate cancer is aided using
TRUS to guide the biopsy and is a widely used and
accepted procedure.74–76 However, the sensitivity and
positive predictive value of sextant biopsy remain quite
low, 60% and 25%, respectively.77–79 The first transper-
ineal prostate biopsies under US control were performed
in the mid-1980s, and a few years later TRUS become
the primary modality for biopsy guidance.80 Initially, the
sextant biopsy technique recommended the collection of
six samples from the base, mid-gland, and apex on both
sides. Subsequent literature, however, showed the advan-
tages of increasing the number of samples to 10, 11, or
even 12 to detect cancer with up to a 96% success rate. It
was also recommended that the number of core biopsies
increase with the prostate volume, since bigger gland
sizes introduced high sampling error and therefore
required more sampling.81–85 However, the ideal number
of cores is still not clear.
Procedure Prior to the insertion of the endorectal
probe, the patient undergoes a digital rectal exam
(DRE). The patient is positioned on the table in either
litothomy or lateral decubitus position. The ultrasound
probe is inserted and stabilized and the prostate volume
is calculated using transverse and sagittal imaging. If the
procedure is performed in lithothomy position, the tem-
plate for needle guidance is placed against the patient’s
perineum. The positions of needles are identified by grid
coordinates on the template and the depth by the probe
stepper attached to the probe stabilizer. These coordi-
nates are used to guide biopsy under real-time US imag-
ing. Biopsy is performed using an 18-gauge biopsy gun.

Figure 7-10 MR-focused US surgery of uterine fibroid. A,
Coronal T2-weighted FSE image (4000/90) used for
treatment planning. The sonication locations and sizes
(circles and grid) were determined by the planning software
from this prescription (and the tissue depth) and displayed on
top of the treatment plan. During the treatment, the
accumulated thermal dose (hollow arrow) was displayed on
top of the treatment planning images. A dose threshold of
240 equivalent minimum at 43 ˚ C is displayed. B, Sagittal T2-
weighted image (2500/98) showing the treatment plan and
the area that achieved the threshold thermal dose. C–D,
Temperature sensitive phase-difference FSPGR images
(39.9/19.7) acquired at peak temperature rise during two
sonications, one imaged perpendicular to the direction of the
US beam (Coronal, C), and one imaged parallel to the
direction of the beam (sagittal, D). These images were used
to estimate the thermal dose (white line) for each sonication.
E–F, Result of the treatment. E, Sagittal contrast-enhanced
gradient-echo image (245/1.8) acquired 2 days after US
therapy. The nonenhancing area (white arrow) is clearly seen.
F, Gross pathologic cut specimen showing the central area
of hemorrhagic necrosis. (From Tempany MC et al: Radiology
2003; 226(3):902.)
Chapter 7 Image-Guided Minimally Invasive Therapy 123
MR-Guided Prostate Biopsy
In addition to being an excellent method for guiding
prostate cancer therapy, MR imaging also appears to
be useful for guiding diagnostic biopsy.86 Similar to its
use in therapy, metabolic information from spec-
troscopy and dynamic contrast MR data can be com-
bined with routine MR images to allow precise tumor
targeting.
Our group has adapted the interventional MR system
to perform MR-guided prostate biopsy.86,87 This
transperineal technique eschews endorectal devices and
provides an excellent diagnostic alternative for patients
who have undergone rectal surgeries and in whom
US-guided procedure is impossible to perform. An addi-
tional group of men who can be benefited from
MR-guided procedure are those with persistently rising
PSA values and have had prior negative US-guided
biopsies. Preliminary feasibility results of this method
for facilitating prostate cancer diagnosis are promising.73
One of the unique aspects of this approach is the inter-
active imaging provided by using the 3D Slicer, as
reported by Hata et al.86, which facilitates T2 imaging in
“near-real time.” D’Amico et al.88 reported results of the
procedure from two MRI-targeted lesions in a patient
who could not undergo US-guided procedure because of
previous rectal surgery. Several transurethral biopsies
yielded negative results in this patient. Following MR-
guided biopsy, cancer was confirmed in 15% and 25% of
the 2 cores.
Procedure Prior to the procedure, each patient under-
goes endorectal coil MRI using a 1.5 T imaging system.
The T1- and T2-weighted and contrast-enhanced images
are collected, and multivoxel spectroscopy is performed.
Using this information, the radiologist identifies biopsy
targets. Patient positioning for the procedure and initial
preparation is similar to MRBT except that an endorectal
obturator may not be used in some cases with previous rec-
tal surgery. Subsequently, T2-weighted images are col-
lected at 3.5 mm intervals in a 0.5 T interventional system.
The information from preprocedure and intraprocedure
images are correlated and target lesions are identified.
Computer software is used to calculate appropriate coordi-
nates on the perineal template for the needle insertion, as
well as needle insertion depth. Additionally, 0.5 T T2-
weighted images and intraprocedure fast gradient-echo
images are loaded into the 3D Slicer software and displayed
in an alternating fashion to provide real-time image guid-
ance during biopsy. All target locations along with sextant
biopsies of the PZ from the right and left apex, mid-gland,
and base are sampled using MR-compatible 18 gauge
biopsy guns. Figure 7-11 shows an axial view of the needle
tip artifact in PZ after needle insertion and just before
124 Part I Principles of Urologic Oncology

B
Figure 7-11 Biopsy needle artifact. Axial (A) and coronal (B) view of prostate gland on pre-
(left) and intra-MR-guided biopsy images (middle and right). The black arrow indicates the
tip of the biopsy needle. (From D’Amico Av, Loeffter JS, Harris JR. Image guided diagnosis
and treatment of cancer. Totowa, NJ, Humana Press, 2003.)

biopsy. This procedure is currently done under anesthe-

sia as a day surgical procedure. It is well tolerated and
offers a second-line biopsy approach in selected patients.

Figure 7-12 Biopsy needle antifact. Real-time 3D view of
prostate gland on intra-MR-guided biopsy images.
SUMMARY
The areas covered in this chapter serve to illustrate the
significant advances that have occurred in image-guided
procedures and therapy for both diagnosis and treatment
of prostate cancer. These are only some of the many new
IGT applications available today. As the imaging tech-
niques continue to improve and as surgical approaches
become even less invasive or completely noninvasive (as
with FUS), the future looks very exciting for both urol-
ogy patients and their doctors.

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68. Gelet A, Chapelon JY, Bouvier R, et al: Transrectal high-
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71. Beerlage HP, Thuroff S, Debruyne FM, Chaussy C, de la
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Chapter 7 Image-Guided Minimally Invasive Therapy 127
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81. Eskew LA, Bare RL, McCullough DL. Systematic 5
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83. Chen ME, Troncoso P, Johnston DA, Tang K, Babaian
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C H A P T E R
8 Adrenal Tumors
E. Darracott Vaughan, Jr, MD
The major adrenal tumors that will be discussed in this
chapter include adrenal cortical adenomas producing pri-
mary hyperaldosteronism and Cushing’s syndrome, adre-
nal cortical carcinoma, the incidentally identified adrenal
mass, and pheochromocytoma. Actually, the most com-
mon tumors involved in the adrenal gland are metastatic
tumors to the adrenal, and the management of such
lesions generally is dependent on the treatment of the
primary disease entity. It is fortunate that the diagnosis of
adrenal disorders is extremely accurate using the combi-
nation of precise analytical methods for the measurement
of the abnormal secretion of adrenal hormones and
sophisticated radiographic techniques for the localization
and characterization of specific adrenal lesions.1,2
The management of patients with adrenal tumors
requires a clear understanding of the normal physiology
of the adrenal medulla and cortex; a three-dimensional
concept of the adrenal anatomy, as well as adjacent struc-
tures; and the knowledge of the various pathologic enti-
ties that may involve the adrenal. Moreover, the
operating surgeon must be well aware of the nuances
involved in the diagnosis of the different adrenal entities,
be aware of potential intraoperative phenomena that are
unique to these patients, and be alert to specific postop-
erative complications that may occur.3 This chapter will
review the preoperative, intraoperative, and postopera-
tive aspects of each of these specific entities and will out-
line surgical approaches with operative hints to guide
those interested in adrenal surgery.
The adrenal glands are paired retroperitoneal organs
that lie within the perinephric fat, at the anterior, supe-
rior, and medial aspects of the kidneys. Their location in
juxtaposition with other organs, as well as the periadrenal
fat, renders them ideal for sectional imaging by com-
puted tomography (CT). Thin-cut CT scanning allows
precise identification of lesions as small as 0.5 cm. The
CT scan remains the best imaging device for the identi-
fication of small adrenal lesions, whereas magnetic reso-
nance imaging (MRI) gives information concerning cell
type and aids in the differentiation of adenomas from
medullary tumors or metastatic carcinoma.4 Other
advantages of MRI scanning will be discussed later. The
right adrenal lies above the kidney posterior and lateral
to the inferior vena cava (IVC) and its solitary venous
drainage is via a short sturdy vein that enters the IVC in
a posterior fashion. Hence, the right adrenal gland is best
approached through a posterior or modified posterior
incision.5 The left adrenal is in more intimate contact with
the kidney, overlying the upper pole of the kidney with its
anterior and medial surfaces behind the pancreas and
splenic artery. It is best exposed through a flank approach
or a thoracoabdominal approach if the lesion is large.
The adrenals have a delicate, rich blood supply esti-
mated to be 6 to 7 ml/g/min without a dominant adrenal
artery. The inferior phrenic artery is the main blood sup-
ply with additional branches from the aorta and renal
arteries. The small arteries penetrate the gland in a cir-
cumferential stellate fashion leaving both the anterior
and posterior surfaces avascular (Figure 8-1). During
adrenalectomy, an important technical goal is to divide
the superior and lateral blood supplies to the adrenal
first, allowing the adrenal to remain attached to the kid-
ney, which can be used to draw the adrenal gland inferi-
orly and anteriorly during the resection. On the left side,
the adrenal vein drains into the left renal vein; however,
there is also a medially located phrenic drainage branch,
which, if not appropriately ligated, can cause trouble-
some bleeding (Figure 8-2). The left adrenal vein is also
a guide to the left renal artery, which often lies dorsal to
the vein. One potential complication of left adrenalec-
tomy is the inadvertent ligation of the apical renal arte-
rial branch to the upper pole, which lies in close contact
to the inferior border of an adrenal tumor.
The basic physiology of the adrenal cortex and
medulla, as well as the various pathologic entities, will be
discussed under specific disorders.
131
132 Part II Adrenal Gland
Figure 8-1 Arterial supply of left and right adrenal glands.
CUSHING’S SYNDROME
Cushing’s syndrome is the term utilized to describe the
symptom complex caused by excessive circulating gluco-
corticoids. We must remember that the term is all-
encompassing and includes: patients with pituitary
hypersecretion of adrenocorticotrophic hormone
(ACTH) (corticotropin); Cushing’s disease, which
accounts for 75% to 80% of patients with endogenous
Cushing’s; adrenal adenomas or carcinomas; ectopic
secretion of ACTH, or corticotropin-releasing hormone
(CRH) syndrome.6 Before assuming that a patient has
one of these pathologic entities, there should be a thor-
ough questioning of the patient about the use of steroid-
containing preparations. At times patients are unaware
that a substance they use, particularly creams or lotions,
contains steroids, and if the patient is on any type of
medication at all, it should be carefully reviewed for
steroid content. There are few diseases in which the clin-
ical appearance of the patient can be as useful in suspect-
ing the diagnosis. Old photographs are helpful in
documenting recent changes in appearance that
occurred. The more common clinical manifestations of
Cushing’s syndrome found in different series of patients
are shown in Table 8-1. The clinical findings do not dis-
tinguish patients with Cushing’s disease from those with
adrenal adenoma; however, patients with adrenal carci-
noma are more likely to show virilization in the female or
feminization in the male. Patients with ectopic ACTH
may present with manifestations of the primary tumor. It
is also important to remember that some nonendocrine
Figure 8-2 Venous drainage of left and right adrenal glands
with particular attention to the intercommunicating vein on
the left.
disorders mimic the clinical and even the biochemical
manifestations of Cushing’s syndrome. These patients
have been termed to have “pseudo”-Cushing’s syndrome;
this may exist in patients with major depression or in
patients with chronic alcoholism.6
There are a myriad of tests both to diagnose the pres-
ence of Cushing’s syndrome and then to identify which
subentity is present. Fortunately, due to recent develop-
ment of extremely accurate assays for urinary and plasma
cortisol, as well as plasma corticotropin, this task has
become much easier. The approach that has recently
been reported by Orth6 is shown in Figure 8-3.
The clinical diagnosis of Cushing’s syndrome is con-
firmed by the demonstration of cortisol hypersecretion.
At the present time the determination of 24-hour urinary
excretion of cortisol in the urine is the most direct and
reliable index of cortical secretion. Orth recommends
that urinary cortisol should be measured in two and
preferably three consecutive 24-hour urine specimens,
collected on an outpatient basis.
Once the diagnosis has been established, the next
chore is to determine whether there is Cushing’s disease
due to hypersecretion of plasma corticotropin (ACTH)
from the pituitary or primary adrenal disease. Herein is
the major change in our approach to patients with
Cushing’s disease. In the past, high- and low-dose dex-
amethasone suppression tests have been used to accom-
plish this task. At present, the low-dose dexamethasone is
generally used to rule out pseudo-Cushing’s syndrome.
The differentiation of corticotropin-dependent Cushing’s
 Chapter 8 Adrenal Tumors 133

Table 8-1 Clinical Manifestations of Cushing’s entiate between pituitary and adrenal Cushing’s syn-
Syndrome drome. Patients are given high-dose dexamethasone
All* Disease† Adenoma/
(2 mg every 6 hours for 2 days), and plasma cortisol and
(%) (%) Carcinoma‡ (%) urinary free cortisol levels are measured. In patients with
pituitary disease, there should be a 50% or greater sup-
Obesity 90 91 93 pression in cortisol. Patients with adrenal adenomas or
carcinomas fail to suppress cortisol secretion. The high-
Hypertension 80 63 93 dose dexamethasone suppression test may also be useful
Diabetes 80 32 79
to identify ectopic ACTH syndrome, where there is usu-
ally complete resistance to high-dose dexamethasone
Centripetal obesity 80 — — suppression.
Treatment is obviously dependent on the underlying
Weakness 80 25 82 lesion. Patients with adrenal adenomas or carcinomas are
Muscle atrophy 70 34 —
generally treated with surgical extirpation of the lesions.
Patients with Cushing’s disease have confirmation with
Hirsutism 70 59 79 pituitary CT or MRI and usually are treated with transsphe-
noidal pituitary tumor removal, and patients with ectopic
Menstrual abnormal/ 70 46 75 ACTH have treatment directed towards the primary tumor.
sexual dysfunction The surgical approach and preparation of patients with
Purple striae 70 46 36 adrenal Cushing’s disease will be discussed later.
If the patient is identified as having adrenal Cushing’s,
Moon facies 60 — — the next step is radiographic localization with CT scan-
ning.7 Adrenal adenomas are usually larger than 2 cm,
Osteoporosis 50 29 54 solitary, and associated with atrophy of the opposite
Early bruising 50 54 57 gland. The density is low because of the high concentra-
tion of lipid (Figure 8-4). Adrenal carcinomas are often
Acne/pigmentation 50 32 — indistinguishable from adenomas except for the larger
size, carcinomas usually being greater than 6 cm.8
Mental changes 50 47 57 Necrosis and calcification are also more common in asso-
Edema 50 15 — ciation with adrenal carcinomas but are not specific.
Clearly, large irregular adrenal lesions with invasion rep-
Headache 40 21 46 resent carcinoma; however, metastatic carcinoma to the
adrenal has the same appearance.
Poor healing 40 — — MRI is not usually necessary in patients with
From Scott HW Jr: In Scott HW (ed): Surgery of the Adrenal Cushing’s syndrome unless the lesion is large; the ration-
Glands. Philadelphia, JB Lippincott Co, 1990, with permission. ale for MRI is to obtain anatomic information concern-
*Hunt and Tyrell, 1978. ing surrounding structures or invasion of the IVC, a rare
†Wilson, 1984.
‡Scott, 1973.
but well-recognized entity.9
Adrenal cortical scanning with iodinated cholesterol
agents is no longer routinely utilized but can be helpful
syndrome versus corticotropin-independent Cushing’s in differentiating functional adrenal tissue from other
syndrome is determined by the concurrent late afternoon retroperitoneal lesions.10
or midnight measurement of collection of blood for the
simultaneous measurement of plasma corticotropin and
INCIDENTALLY DISCOVERED ADRENAL MASSES
cortisol. Thus, if the patient’s cortisol concentration is
above 50 μg/dl and the corticotropin concentration The increased utilization of abdominal ultrasound and
is below 5 pg/ml, then the cortisol secretion is ACTH CT scanning has led to a new classification of adrenal
independent and the patient has a primary adrenal prob- lesions termed the “incidentally identified unsuspected
lem. In contrast, if the plasma corticotropin concentra- adrenal mass” or “incidentaloma.”8 Our approach to the
tion is greater than 50 pg/ml, then the cortisol secretion incidentally identified adrenal mass is shown in Figure 8-5.
is ACTH dependent and the patient has Cushing’s syn- Several points do not warrant controversy. First, there is
drome or ectopic ACTH or CRH syndrome.5 In situa- an agreement that all patients with solid adrenal masses
tions where the two-site immunoradiometric assay test is should undergo biochemical assessment. If biochemical
not available, the high-dose dexamethasone suppression abnormalities are identified, the lesions should be treated
test has always been used as the standard test to differ- as described elsewhere in the chapter, usually by removal
134 Part II Adrenal Gland
Figure 8-3 Identifying Cushing’s syndrome and its causes.
of the offending lesion. However, the extent of biochem-
ical assessment has been reviewed, and a selective
approach has been outlined that markedly limits cost
without sacrificing diagnostic accuracy.11 A very limited
evaluation is recommended, including tests only to rule
out pheochromocytoma, potassium levels in hypertensive
cases, and glucocorticoid evaluation only in the presence
of clinical stigmata of Cushing’s syndrome or virilization.
The second point that is not controversial is that non-
functioning solid lesions larger than 5 cm should be
removed. This is based on the finding that adrenal malig-
nancies are almost always larger than 6 cm. However, we
feel that CT scanning may underestimate the size of an
adrenal, and we suggest that exploration be performed
when lesions are more than 5 cm on CT or MRI.12
Furthermore, if lesions are purely cystic by CT or MRI,
cyst puncture is often not necessary and these lesions can
be followed (Figure 8-6). The controversy arises in the
management strategy for the solid adrenal lesions smaller
than 5 cm in size. The current approach has been to use
MRI imaging in this situation. Most adenomas appear
slightly hypointense or isointense relative to the liver or
spleen on T1-weighted images and slightly hyperintense
or isointense relative to hepatic or splenic parenchyma
 Chapter 8 Adrenal Tumors 135

Figure 8-4 CT scan of a patient with right adrenal adenoma.

Figure 8-5 Evaluation of incidentally found adrenal mass.

Figure 8-6 Multilocular benign renal cyst in an asymptomatic patient that was incidentally
identified. A, CT scan showing left adrenal cyst. B, Coronal MRI showing the lobular
suprarenal adrenal cyst. In this case, exploration was carried out because of multilocular
nature. The cyst was benign.
136 Part II Adrenal Gland
on T2-weighted images. There is little change in the
intensity from T1- to T2-weighted studies. In contrast,
the general notion is that adrenal cortical carcinoma is
hypointense relative to liver or spleen on T1-weighted
images and hyperintense to the liver or spleen on T2-
weighted images. Thus, if the mean signal intensity ratio
between the lesion and the spleen is over 0.8, it is
unlikely that the lesion is a benign adenoma. However, it
should be remembered that there are a number of enti-
ties other than adrenal carcinoma that can cause high
intensity, including neural tumors, metastatic tumors to
the adrenal, adrenal hemorrhage, and other retroperi-
toneal lesions.4,13,14 An additional study that has shown
accuracy is the fine-needle adrenal biopsy guided by
ultrasound or CT. In a large series from Finland, signifi-
cant cytologic material was obtained in 96.4% and the
accuracy to differentiate benign from malignant disease
was 85.7%.15 However, the utilization of aspiration
cytology requires an extremely experienced cytologist,
and in fact there is often inability to distinguish an adre-
nal adenoma from a carcinoma even on pathologic review
of the entire specimen.
It is our general approach that if there is either any
radiographic evidence that argues against a characteristic
benign adenoma or any change in size of an adrenal
lesion with repeated studies, then we feel that adrenalec-
tomy is indicated. This fairly aggressive approach is jus-
tified in view of the extremely poor prognosis of patients
when adrenal carcinoma is diagnosed, even when the
lesion is localized.
ADRENAL CARCINOMA
Adrenal carcinoma is a rare disease with a poor progno-
sis. The incidence is estimated as 1 case per 1.7 million,
accounting for only 0.02% of cancers. A practical sub-
classification for adrenal carcinomas is according to their
ability to produce adrenal hormones. In a series by Luton
et al.,16 79% of adrenal tumors were functional, a higher
percentage than previously reported due to more sensi-
tive assays. The varieties of functioning tumors are
shown in Table 8-2. However, this classification is some-
Table 8-2 Classification of Adrenal Carcinoma
Functional
Cushing’s syndrome
Virilization in females
Increased DHEA, 17-ketosteroids
Increased testosterone
Feminizing syndrome in males
Hyperaldosteronism
Mixed combination of above
Nonfunctional
DHEA, dehydroepiandrosterone.
what contrived, since many of these tumors will produce
multiple adrenal hormones and also because of the clear
evidence that a tumor may secrete one hormone at
one point in its natural history and additional hormones
at a later phase when there is increased tumor mass.
The most commonly identified functional tumor is
one causing Cushing’s syndrome. The most common
characteristic to delineate Cushing’s syndrome due to
carcinoma rather than adenoma has been the presence of
virilization with elevated 17-ketosteroid levels. More
recently, the measurement of DHEA has been useful in
identifying these patients.
Other rare functional tumors include both testos-
terone- and estrogen-secreting adrenal cortical tumors.
Rarely, virilization can occur in the absence of elevated
urinary 17-ketosteroids and raises the possibility of pure
testosterone-secreting ovarian or adrenal lesions.17 Of
the two sites of origin, adrenal cortical tumors secreting
testosterone are exceedingly rare. In contrast to other
tumors described in this section, these tumors are usually
small, less than 6 cm, and many behave in a benign fash-
ion. In contrast, most feminizing tumors occur in males
25 to 50 years of age, and they are usually larger, often
palpable, and highly malignant.18 Characteristically, the
patients present with gynecomastia; in addition they may
exhibit testicular atrophy, impotence, or decreased libido.
We have also seen a presentation with infertility and
oligospermia. These tumors secrete androstenedione,
which is converted peripherally to estrogen. Other
steroids may also be secreted, and the clinical picture may
be mixed with associated cushingoid features.
The management of adrenal cortical carcinoma is sur-
gical removal of the primary tumor. The most common
sites of metastasis include lung, liver, and lymph nodes.19
Often these tumors extend directly into adjacent struc-
tures, especially the kidney, and surgical removal may
require removal of the primary tumor and adjacent
organs, including the kidney, spleen, as well as local
lymph nodes. Unfortunately, despite en bloc resection
even in patients without evidence of metastatic disease,
the 5-year survival rate is only approximately 50% with
complete resection and 25% overall.20 Because of the
poor prognosis there has been an intense search for effec-
tive adjunctive chemotherapy, but this search has been
frustrating and it is generally believed that conventional
chemotherapy is not effective, probably because of
P-glycoprotein expression.21 The most success has
been reported with the adrenolytic 1,1-dichloro-
2-(o-chlorophenyl)-2-(p-chlorophenyl)-ethane(o,p¢-DDD)
or Mitotane. This DDT derivative has been shown to
induce tumor response in 35% in a review of 551 cases
reported in the literature.22 However, despite these
response rates, survival time has not been prolonged and
there is intense toxicity. Recently, it has been suggested
that patients even without the presence of metastatic
 Chapter 8 Adrenal Tumors 137

disease be given adjunctive o,p¢-DDD, and trials are
currently in progress to determine if this approach is
efficacious.
In general, there is an extremely poor prognosis in
patients with adrenal cortical carcinoma and an obvious
need for the development of new treatment strategies.
HYPERALDOSTERONISM
The term hyperaldosteronism originally was coined by Dr.
Jerome Conn to describe the clinical syndrome charac-
terized by hypertension, hypokalemia, hypernatremia,
alkalosis, and periodic paralysis due to an aldosterone-
secreting adenoma.23 We now realize that this metabolic
syndrome can be caused by either a solitary adrenal ade-
noma or by bilateral adrenal zona glomerulosa hyperpla-
sia. One of the clinical chores is to delineate patients with
hyperplasia from those with adenoma.24 The syndrome
of primary hyperaldosteronism is now identified by the
combined findings of hypokalemia, suppressed plasma
renin activity (PRA) despite sodium restriction, and a
high urinary and plasma aldosterone level after sodium
repletion in hypertensive patients. The current evalua-
tion of patients suspected of having hyperaldosteronism
is shown in Figure 8-7. The primary physiologic control
of aldosterone secretion is angiotensin II (Figure 8-8).
Other control mechanisms are ACTH and potassium. A
clear knowledge of the physiology of the renin–
angiotensin–aldosterone system (RAAS) is mandatory in
order to understand the pathophysiology and evaluate
patients with primary hyperaldosteronism.25,26 The criti-
cal sensor in the RAAS resides in the juxtaglomerular
apparatus within the kidney. Thus, in response to a vari-
ety of stimuli, but primarily decreased renal perfusion, or
a decreased intake of sodium, there is an increased renin
release, formation of angiotensin II, and subsequent

Hypertension

>3.6 Serum K ⱕ3.6

ⱕ1.0 PRA >1.0

Replete
K and Na

1⬚ aldosteronism 1⬚ aldosteronism
is unlikely is unlikely
24-hour urine:
K > 40 mEq and
Aldosterone > 15 mcg
No Check urine:
Cortisol
DOC
Adrenal CT scan

Hyperplasia or normal Equivocal Unilateral adenoma

Postural stimulation test (+) (or)

Plasma 18 OHB > 100 ng% (or)
Elevated urinary 18 OH-F, 18 oxo-F

No
Yes

Adrenal sampling

Not
Lateralized Lateralized

Medication Adrenalectomy
Figure 8-7 Identifying primary hyperaldosteronism.
138 Part II Adrenal Gland
Effective
RENAL
circulating
blood
potassium volume
excretion
Renal sodium Renal perfusion
retention
Aldosterone Juxtaglomerular
secretion
Angiotensinogen
Angiotensin II Renin release
Potassium
balance
Converting Angiotensin I
enzyme
Figure 8-8 Control of aldosterone secretion by means of
interrelationships between the potassium and renin-
angiotensin feedback loops.
aldosterone secretion. Therefore, the term secondary
hyperaldosteronism is utilized when there is increased renin
secretion and secondary aldosterone production.27,28 The
most common examples of secondary hyperaldostero-
nism would be renovascular hypertension and malignant
hypertension. In contrast, with an adrenal adenoma or
adrenal hyperplasia there is primary secretion of aldos-
terone and subsequently the sodium retention that
occurs leads to a suppression of plasma renin activity.
Therefore, returning to Figure 8-7, the hallmark of
the entity is hypokalemia. However, some patients real-
ize that weakness occurs with increased sodium intake
and therefore restrict their sodium, and may have a
more normal potassium than that first observed.
Therefore, the entity should not be ruled out until the
patient has sodium loading with 10 g of sodium a day
for several weeks and repeat potassium measurements.
A small subset of patients exhibits normokalemic
hyperaldosteronism, and if there is a high index of sus-
picion for the disease, these patients should be studied
further. If there is hypokalemia, a 24-hour urine should
be collected demonstrating that there is urinary loss of
potassium. The critical test is the measurement of
plasma renin activity at a time when the patient is
either on a low-sodium diet or is challenged with a
diuretic. If the patient has hyperaldosteronism, the
plasma renin activity remains inappropriately low
despite sodium depletion. Because potassium is also a
stimulus of aldosterone, the patient should be potas-
sium repleted before measuring 24-hour urine and
plasma aldosterone levels. Both of these values should
be elevated in hyperaldosteronism.
At this point the question is whether the patient has a
unilateral adenoma or bilateral adrenal hyperplasia, and
the imaging study of choice is an adrenal CT scan with 3
to 5-mm cuts through both adrenal glands. The next step
that is traditionally performed would be adrenal vein
sampling. The difficulty with adrenal vein sampling is
obtaining adequate collections from the short, stubby,
right adrenal vein, and when samples are collected, corti-
sol levels should also always be collected to ensure proper
History Suspect
physical exam
BP x 3 > 140/90 pheochromocytoma
pressure Basic lab tests
apparatus
Plasma norepinephrine
Epinephrine
Diagnosis Elevated
Dopamine
pheochromocytoma
Urinary catechols
Normal
Localize
− Evaluate for
CTT − Venous sampling other causes
MIBG
+
MRI
+
α- blockade, then remove
Figure 8-9 Identifying pheochromocytoma.
catheter placement. An appropriate way of analyzing
aldosterone levels is with comparative aldosterone/corti-
sol ratios from each side. It is our general policy to have
positive lateralizing information, as well as a positive CT
scan, before recommending exploration and unilateral
adrenalectomy. However, more recently, in patients who
have elevated plasma 18-hydroxy-B levels and elevated
urinary 18-hydroxy-F levels, at times we have not
required sampling when a clear adenoma was demon-
strated on CT scan. In contrast, we have demonstrated a
subset of patients with radiographic bilateral hyperplasia
who will lateralize adrenal vein sampling for aldosterone.
In this setting, we have performed unilateral adrenalec-
tomy and a significant number of those patients have
favorable biochemical and blood pressure responses,
although most have required the continuation of some
antihypertensive medication.24
Finally, in patients who have normal CT scans yet lat-
eralize on sampling, if they show elevated 18-hydroxy
products, we will operate; if not, we will follow those
patients. The majority of patients with bilateral hyper-
plasia will not lateralize with adrenal vein sampling for
aldosterone. Those patients are treated with spironolac-
tone at an appropriate dose to control blood pressure.
Often, they will need other medications, such as calcium
channel blockers.
PHEOCHROMOCYTOMA
Pheochromocytoma is an uncommon entity, but one that
has potentially lethal sequelae for the patient if not diag-
nosed. Therefore, it is generally felt that all patients with
sustained hypertension should have the appropriate
studies performed to rule out pheochromocytoma
(Figure 8-9).29,30

The clinical manifestations exhibited by patients with
pheochromocytoma are due to the physiologic effects of
the catecholamines, dopamine, epinephrine, and norep-
inephrine. However, other signs and symptom com-
plexes exhibited may be extremely variable, including
the asymptomatic patient in whom a lesion is picked up
simply on CT scan. In all reported series, hypertension
is by far the most common sign (Table 8-3). As far as the
type of hypertension, the patients may have either sus-
tained hypertension, paroxysmal or dramatic attacks of
hypertension, or sustained hypertension with superim-
posed paroxysms. Most series have shown this latter
constellation of findings to be the most common in
patients with pheochromocytoma. In addition, the fre-
quency of attacks among patients is quite variable, rang-
ing from a few times a year to multiple daily episodes. In
addition, the duration may be minutes or hours and the
nature of the attacks can vary dramatically. Most patients
will exhibit a paroxysm or an episode once a week, and
most of the attacks will last less than an hour. Usually, the
attacks occur in the absence of recognizable stimuli, but a
number of factors—particularly exercise, posture, trauma,
or a variety of other situations—may precipitate an attack.
One specific entity is noteworthy: catecholamine-
induced cardiomyopathy. 31 Patients with cate-
cholamine-induced cardiomyopathy will present with
decreased cardiac function and congestive heart failure,
and it is mandatory that their cardiac status be stabilized
with the use of appropriate a- and b-adrenergic block-
ing agents as well as a-methylparatyrosine (a tyrosine
hydroxylase inhibitor) (Figure 8-10) to cut down on cat-
echolamine production before surgery is contemplated.
Generally, the cardiomyopathy is reversible, and the
patients can be operated on within weeks or months
after the initial diagnosis and treatment is instituted.
An appreciable number of pheochromocytomas have
been found in association with other disease entities and
hereditary syndromes. These entities include the associ-
ation of tumors of the glomus jugulare region, neurofi-
bromatosis, Sturge-Weber syndrome, and the von
Hippel-Landau and familial multiendocrine adenopathy
(MEA) syndromes. Pheochromocytomas occur in MEA-
2, a triad including pheochromocytoma, medullary carci-
noma of the thyroid, and parathyroid adenomas (Sipple’s
syndrome). Pheochromocytomas may also be a part of
MEA-3, which also includes medullary carcinoma of the
thyroid, mucosal neuromas, thickened corneal nerves,
ganglioneuromatosis, and frequently marfanoid habitus.
It is now believed that the relatives of patients with all of
these syndromes should be evaluated for the presence of
occult pheochromocytoma. In addition, there is a well-
known entity of familial pheochromocytoma in which
multiple members of the kindred will be found to have
multiple lesions and all members of such families should
be both screened and then followed for the appearance of
Chapter 8 Adrenal Tumors 139
these tumors. The mechanism of the increased incidence of
pheochromocytomas in association with neuroendocrine
dysplasias and medullary carcinoma of the thyroid may be
explained by the amine precursor uptake and decarboxyla-
tion (APUD) cell system of Pierce. The APUD cells
derived from the neural crest of the embryo share common
ultrastructural and cytochemical features and elaborate
amines by precursor uptake and decarboxylation.32,33
The laboratory diagnosis of pheochromocytoma is
now extremely accurate, utilizing the urinary plasma
measurements of catecholamines and their by-products
(see Figure 8-9). Extremely accurate assays exist for these
amines.34 At the present time it is felt that urinary cate-
cholamines remain the measurement of choice with the
measurement of total urinary catecholamines and
metanephrines. Approximately 95% of patients will have
elevated levels of these substances. In the patient with a
severe paroxysmal hypertension who presents in the
midst of hypertensive crisis, the plasma catecholamines
are almost always elevated and can be utilized.
Stimulation or suppression tests are generally not uti-
lized at the present time. The one situation where they
may be useful is in the patient who appears to have essen-
tial hypertension but borderline elevated catecholamines,
and in this setting a clonidine suppression test may be
useful. Following a single 0.3-mg oral dose of clonidine
the patients with neurogenic hypertension at rest show a
fall in norepinephrine, whereas patients with pheochro-
mocytomas do not.34
The radiographic test that is most useful in both iden-
tifying and characterizing neuroendocrine adrenal
tumors, and in identifying surrounding structures, is the
MRI scan. We have been impressed with the multiple
uses of MRI scans in patients with pheochromocytoma.
Therefore, the test is as accurate as a CT scan in identi-
fying lesions and also has a characteristic bright light
bulb appearance on the T2-weighted study (see Figure
8-10).3 In addition, sagittal and coronal imaging can pro-
vide excellent anatomic information concerning the rela-
tionship between the tumor and the surrounding
vasculature. Therefore, we feel that the MRI should be
the initial scanning procedure in patients with the bio-
chemical findings of pheochromocytoma.
An alternative approach that also is useful at times,
particularly for residual or multiple pheochromocy-
tomas, is the metaiodobenzylguanidine (MIBG) scan that
images medullary tissue.35,36 This test may be more sen-
sitive than CT or MRI picking up small extra-adrenal
lesions and has major use in patients where multiple
lesions are suspected.
ADRENAL SURGERY
Adrenalectomy is the treatment of choice in most patients
who have undergone appropriate metabolic evaluation
140 Part II Adrenal Gland

Table 8-3 Symptoms Reported by 76 Patients (Almost all Adults) with

Pheochromocytoma Associated with Paroxysmal or Persistent Hypertension
Paroxysmal P e r s i s t e n t
Symptoms (37 Patients) (%) (39 Patients) (%)

Symptoms Presumably Due to Excessive Catecholamines or Hypertension

Headache (severe) 92 72
Excessive sweating (generalized) 65 69
Palpitations ± tachycardia 73 51
Anxiety or nervousness (± fear of impending death, panic) 60 28
Tremulousness 51 26
Pain in chest, abdomen (usually epigastric), lumbar regions,
lower abdomen, or groin 48 28
Nausea ± vomiting 43 26
Weakness, fatigue, prostration 38 15
Weight loss (severe) 14 15
Dyspnea 11 18
Warmth ± heat intolerance 13 15
Visual disturbances 3 21
Dizziness or faintness 11 3
Constipation 0 13
Paresthesia or pain in arms 11 0
Bradycardia (noted by patient) 8 3
Grand mal 5 3

Manifestations Due to Complications

Congestive heart failure ± cardiomyopathy
Myocardial infarction
Cerebrovascular accident
Ischemic enterocolitis ± megacolon
Azotemia
Dissecting aneurysm
Encephalopathy
Shock
Hemorrhagic necrosis in a pheochromocytoma

Manifestations Due to Coexisting Diseases or Syndromes

Cholelithiasis
Medullary thyroid carcinoma ± effects of secretions of serotonin,
calcitonin, prostaglandin, or ACTH-like substance
Hyperparathyroidism
Mucocutaneous neuromas with characteristic facies
Thickened corneal nerves (seen only with slit lamp)
Marfanoid habitus
Alimentary tract ganglioneuromatosis
Neurofibromatosis and its complications
Cushing’s syndrome (rare)
Von Hippel-Lindau disease (rare)
Virilism, Addison’s disease, acromegaly (extremely rare)

Symptoms Caused by Encroachment on Adjacent Structures or by Invasion and Pressure Effects

of Metastases

From Manger WM, Gifford RW Jr: Pheochromocytoma. In Laragh JH, Brenner BM (eds): Hypertension Pathophysiology Diagnosis and
Management. New York, Raven Press, 1990, with permission.

Figure 8-10 MRI of pheochromocytoma.
and have been found to have a surgical lesion. Although
most adrenal tumors are removed with a laparoscopic
approach, the principles of open adrenal surgery apply
and warrant review. However, the surgeon must be aware
that there are unique aspects to the care in these patients,
including specific preoperative management as outlined
in Table 8-4. Accordingly, patients with hyperaldostero-
nism who are generally healthy require spironolactone
100 to 400 mg/day to restore their potassium supply.
Patients with Cushing’s syndrome have severe systemic
effects from the hyperglucocorticoidism. They are often
obese, have diabetic tendencies, are poor wound healers,
easily sustain bony fractures, and are susceptible to infec-
tion. Thus, they are at high risk for complications. In
selected patients with markedly elevated cortisol levels
the preoperative use of metabolic blockers, such as
metyrapone, is required to reverse some of the clinical
findings prior to adrenalectomy. Certainly, glucocorti-
coid replacement is required throughout the surgical
procedure and postoperatively until the function of the
contralateral adrenal gland occurs. Finally, in patients
with a pheochromocytoma, adrenergic blockade gener-
ally with Dibenzyline is required, and at times the block-
ade of catecholamine production with metyrosine is also
useful as previously discussed. The additional preopera-
tive evaluation that is mandatory in patients with
Chapter 8 Adrenal Tumors 141
pheochromocytoma is consultation with the anesthesiol-
ogist, who can be well aware of the patient and can plan
strategy for management.37
Thus, the management of patients with an adrenal dis-
order is approached on a team basis, including experi-
enced endocrinologists, radiologists, anesthesiologists,
and urologists or general surgeons.
Numerous approaches can be made to the adrenal
gland (Table 8-5). The proper approach depends on the
underlying cause of adrenal pathology, the size of the adre-
nal, the side of the lesion, the habitus of the patient, and
the experience and preference of the surgeon. In most
cases, there are a number of different options available,
and a careful review of all the variables is required before
a choice is made. Thus, each case should be considered
individually, although some approaches are preferable for
a given disease. For example, in patients with large adrenal
tumors, a thoracoabdominal approach is often utilized. In
contrast, a posterior or modified posterior approach is pre-
ferred for small localized lesions. Finally, in patients with
multiple lesions, either extra-adrenal or bilateral will be
explored using a transabdominal chevron incision.
Before describing the specific techniques, a number of
unifying concepts warrant attention. First, adequate visu-
alization is imperative, as the adrenal glands lie high in
the retroperitoneum and quite posterior. Therefore, the
142 Part II Adrenal Gland

Table 8-4 Preoperative Management Table 8-5 Surgical Approaches in Adrenal Disorder
Treatment Approach

Primary hyperaldosteronism Spironolactone, 100–400 mg/ Primary hyperaldosteronism Posterior (left or right)
day, 2–3 weeks Modified posterior (right)
Follow K+ until normal Eleventh rib (left > right)
Blood pressure should fall Posterior transthoracic

Cushing’s syndrome
Pheochromocytoma
Control of glucose
abnormalities
Documentation of
osteoporosis
Glucocorticoid replacement
(before, during, and after
surgery)
Perioperative antibiotics
Adrenergic blockade
Phenoxybenzamine
(Dibenzyline),
20–160 mg/day
Metyrosine (if needed)
Volume expansion
Crystalloid
β-Blockade if cardiac
arrhythmias (only after
α-blockade established)
Anesthesia consultation
Cushing’s adenoma
Cushing’s disease
Bilateral hyperplasia
Adrenal carcinoma
Bilateral adrenal ablation
Pheochromocytoma
Neuroblastoma
Eleventh rib (left or right)
Thoracoabdominal (large)
Posterior (small)
Bilateral posterior
Bilateral eleventh rib
(alternating)
Thoracoabdominal
Eleventh rib
Transabdominal
Bilateral posterior
Transabdominal (chevron)
Thoracoabdominal (large,
usually right)
Eleventh rib
Transabdominal
Eleventh rib

From Vaughan ED Jr: Adrenal surgery. In Marshall FF (ed): Textbook From Vaughan ED Jr: Adrenal surgery. In Marshall FF (ed): Textbook
of Operative Urology. Philadelphia, WB Saunders Co, 1996, with of Operative Urology. Philadelphia, WB Saunders Co, 1996, with
permission. permission.

use of a headlight by both the surgeon and first assistant
is critical, and hemostasis should be rigorously maintained.
The operator should bring the adrenal down by initially
exposing the cranial attachments and dividing the rich
blood supply between either right-angled clips or utiliz-
ing a forceps cautery or the harmonic scalpel. Thus, it is
often simplest to begin the dissection laterally, identify-
ing the vascular supply and working around the cranial
edge of the gland. The posterior surface is generally
devoid of vasculature and after the gland is freed superi-
orly with gentle traction on the kidney, the gland can be
brought inferiorly for control of the adrenal vein. The
only tumor handled in a different fashion would be a
pheochromocytoma where intent should be made to
obtain control of the adrenal vein early so as to stabilize
the patient from a burst of catecholamine release during
manipulation. The adrenal gland is extremely friable and
fractures easily, which can cause troublesome bleeding.
Therefore, tension or traction should be maintained on
the kidney or surrounding structures and not on the
adrenal itself. The concept has been stated that the
“patient should be dissected from the tumor,” a view that
is particularly true for pheochromocytomas, in which the
glands should not be manipulated (Figure 8-11).
Posterior Approach
The posterior approach can be used for either bilateral
adrenal exploration or unilateral removal of small tumors
(Figure 8-12).
The bilateral approach is rarely utilized today because
of our excellent localization techniques. It is now utilized
primarily for ablative total adrenalectomy. The options
for incisions are shown in Figure 8-12; generally rib
resection is preferable to gain high exposure. After stan-
dard subperiosteal rib resection, care should be taken
with the diaphragmatic release, and the pleura should be
avoided, and the diaphragm swept cranially.
The fibrofatty tissues within Gerota’s fascia are swept
away from the paraspinal musculature, exposing a subdi-
aphragmatic “open space” that is at the posterior apex of
the resection. The liver within the peritoneum is dis-
sected off the anterior surface of the adrenal and the cra-
nial blood supply is divided. Medially on the right, the
IVC is visualized. The short, high adrenal vein entering
the cava in a dorsolateral position is identified and can be
clipped or ligated. The adrenal can then be drawn cau-
dally by traction on the kidney. The adrenal arteries will
issue from behind the IVC and these must be carefully
clipped; otherwise, troublesome bleeding can occur.

Figure 8-11 MRI of recurrent pheochromocytoma with an excellent demonstration of anterior
crossing right renal vein, feeding lumbar vein, and involvement of right renal artery.
Figure 8-12 Posterior approach to the adrenals.
Chapter 8 Adrenal Tumors 143
Finally, the adrenal is removed from the superior
aspect of the kidney and care must be taken to avoid api-
cal branches of the renal artery. On the left, the approach
is similar with division of the splenorenal ligament given
initial lateral exposure.
The posterior approach can be modified for a
transthoracic adrenal exposure to the diaphragm38; how-
ever, this more extensive approach is rarely necessary for
small adrenal tumors.
Modified Posterior Approach
Although the posterior approach has the advantage of
rapid adrenal exposure and low morbidity, there are def-
inite disadvantages. This approach may impair respira-
tion, the abdominal contents are compressed posteriorly,
and the visual field is limited. In addition, if bleeding
occurs, it is difficult to extend the incision to gain a bet-
ter exposure. Therefore, we have developed a modified
posterior approach for right adrenalectomy utilizing the
Gil-Vernet position.39
The approach is based on the anatomic relationship
with the right adrenal, which lies deep posterior and high
in the retroperitoneum behind the liver (Figure 8-13A).
In addition, the short, stubby right adrenal vein enters
the IVC posteriorly at the apex of the adrenal. Hence, we
utilize an approach that is posterior, but the patient is in
a modified position, similar to that used for a Gil-Vernet
dorsal lumbotomy incision.40 The patient is first placed
in a formal lateral flank position and then allowed to fall
forward into the modified posterior position (see Figure
8-13B). Subsequently, the 11th or 12th rib is resected
144 Part II Adrenal Gland
Figure 8-13 Modified posterior approach to the right adrenal.
with care to avoid the pleura. The diaphragm then is dis-
sected off the underlying peritoneum and liver in order
to gain mobility. Similarly, the inferior surface of the
peritoneum, closely associated with the liver, is sharply
dissected from Gerota’s fascia, which is gently retracted
inferiorly. It is of note that the adrenal gland is not iden-
tified during the early portion of the dissection, and
because of the modified posterior approach, the surgeon
can become disoriented if not thoroughly familiar with
anatomic relationships.
The adrenal will become visible in the depth of the
incision as the final hepatic attachments are divided. The
lateral, empty space can be found exposing the posterior
abdominal musculature and often the IVC. Multiple
small arteries course behind the IVC and emerge over
the paraspinal muscles, and these are clipped and divided.
At this point the adrenal can usually be moved poste-
riorly against the paraspinal muscles exposing the ante-
rior surface of the IVC below the adrenal gland.
The major advantage of this approach is that the adre-
nal vein is easily identified because it emerges from the
segment of the IVC exposed and courses up to the adre-
nal, which now rises toward the surgeon. In other flank
or anterior positions the adrenal vein resides in its poste-

rior relationship, requiring caval rotation and the chance
of adrenal vein avulsion. After adrenal vein exposure, it is
doubly tied and divided or clipped with right-angle clip-
pers and divided (see Figure 8-13D).
The remaining removal of the adrenal is as we previ-
ously described for the posterior approach.
On the left side we do not use this modified approach
and use a standard flank approach with a fairly small
incision.
We have used the modified posterior approach for all
patients with right adrenal aldosterone-secreting tumors
and for other patients with benign adenomas of less than
6 cm. We do not recommend the approach for patients
with large lesions or malignant adrenal neoplasms. The
approach has been used for patients with relatively small
pheochromocytomas.
Flank Approach
The standard extrapleural, extraperitoneal 11th rib resec-
tion is excellent for either left or right adrenalectomy.
After completion of the incision, the lumbocostal arch is
utilized as a landmark showing the point of attachment of
the posterior diaphragm to the posterior abdominal mus-
culature. Gerota’s fascia, containing the adrenal and kid-
ney, can be swept medially and inferiorly, giving exposure
to the splenorenal ligament on the left, which should be
divided to avoid splenic injury (Figure 8-14). Working
anteriorly on the left, the spleen and pancreas within the
peritoneum can be lifted cranially, exposing the anterior
surface of the adrenal gland.
On the right side, a similar maneuver is used to lift the
liver within the peritoneum off the anterior surface of the
adrenal. Quite often the adrenal gland cannot be identi-
fied precisely until these maneuvers are performed. One
should not attempt to dissect into the body of the adre-
nal or to dissect the inferior surface of the adrenal off the
Figure 8-14 Release of splenorenal ligament early in
exposure of left adrenal.
Chapter 8 Adrenal Tumors 145
kidney. The kidney is useful for retraction. The dissec-
tion should continue from lateral to medial along the
posterior abdominal and diaphragmatic musculature,
with precise ligation or clipping of the small but multiple
adrenal arteries. While the operator clips these arteries
with one hand, the opposite hand is employed to retract
both adrenal and kidney inferiorly. With release of the
superior vasculature, the adrenal becomes easily visual-
ized. On the left medially, the phrenic branch of the
venous drainage must be carefully clipped or ligated
(Figure 8-15). This vessel is not noted in most atlases but
can cause troublesome bleeding if divided. The medial
dissection along the crus of the diaphragm and aorta will
lead to the renal vein; finally, the adrenal vein is con-
trolled, doubly tied, and divided. The adrenal is then
removed from the kidney with care to avoid the apical
branches of the renal artery (see Figure 8-15).
On the right side, the dissection is similar. However,
after release of the adrenal from the superior vasculature,
it is helpful to expose the IVC and divide the medial arte-
rial supply. This maneuver allows mobilization of the cava
for better exposure of the high posterior adrenal vein,
which is doubly tied or clipped and divided (Figure 8-16).
Figure 8-15 Further exposure of left adrenal including
phrenic vein.
146 Part II Adrenal Gland
Figure 8-16 Exposure of right adrenal with and without nephrectomy.
Patients with large adrenal carcinomas may require an en
bloc resection of the adrenal and kidney following the
principles of radical nephrectomy (see Figure 8-16).
A major deviation from this technique is used for the
patient with pheochromocytoma, in whom the initial dis-
section should be aimed toward early control and divi-
sion of the main adrenal vein on either side. Obviously, in
this setting, the anesthesiologist should be notified when
the adrenal vein is divided because a marked drop in
blood pressure often occurs, even when the patient is
adequately hydrated.
After removal of the adrenal, inspection should be
made for any bleeding and for pleural tears of the
diaphragm. The kidney should also be inspected. The
incision is closed without drains with interrupted 0 poly-
dioxanone sutures.
 Chapter 8 Adrenal Tumors 147

Thoracoabdominal Approach
The thoracoabdominal 9th or 10th rib approach is uti-
lized for large adenomas; for some large adrenal carcino-
mas, and for well-localized pheochromocytomas. The
incision and exposure are standard, with a radial incision
through the diaphragm and a generous intraperitoneal
extension. The techniques described for adrenalectomy
with the 11th rib approach are used.

Transabdominal Approach
The transabdominal approach is commonly selected for
patients with pheochromocytomas, for children, and for
some patients with adrenal carcinomas. The concept is to
have the ability for complete abdominal exploration to
identify either multiple pheochromocytomas or adrenal
metastases.
I use the transverse or chevron incision, which I
believe gives better exposure of both adrenal glands than
a midline incision. The rectus muscles and lateral
abdominal muscles are divided, exposing the peritoneum.
Upon entering the peritoneal cavity, the surgeon should
gently palpate the para-aortic areas and the adrenal areas.
Close attention is given to blood pressure changes in an
attempt to identify any unsuspected lesions if the patient Figure 8-17 Exposure of right adrenal and left adrenal
utilizing a transabdominal approach.
has a pheochromocytoma. This maneuver is less impor-
tant today because of the excellent localization tech-
niques previously discussed. In fact, with precise
preoperative localization of the offending tumor, the
chevron incision does not need to be completely sym-
metric and may be limited on the contralateral side.
If the patient has a lesion on the right adrenal, the
hepatic flexure of the colon is reflected inferiorly. The
incision is made in the posterior peritoneum lateral to the
kidney and carried superiorly, allowing the liver to be
reflected cranially (Figure 8-17). Incision in the peri-
toneum is carried downward, exposing the anterior sur-
face of the IVC to the entrance of the right renal vein.
Once the cava is cleared, one or two accessory hepatic
veins are often encountered, which should be secured
(Figure 8-18B). These veins are easily avulsed from the
cava and may cause troublesome bleeding. Ligation of
these veins gives 1 to 2 cm of additional caval exposure of
the short posterior right adrenal vein. Small accessory
adrenal veins may also be encountered. The cava is then
rolled medially, exposing the adrenal vein, which should
be doubly tied or clipped and divided (Figure 8-18C).
After control of the adrenal vein, it is simplest to pro-
ceed with the superior dissection, lifting the liver off the
adrenal and securing the multiple small adrenal arteries
arising from the inferior phrenic artery, which is rarely
seen. The adrenal can be drawn inferiorly with retraction
on the kidney, and the adrenal arteries traversing to the
adrenal from under the cava can be secured with right-
angled clips. The final step is removing the adrenal from Figure 8-18 Further transabdominal exposure of the right
the kidney. adrenal with ligation of an accessory right hepatic vein.
148 Part II Adrenal Gland
The left adrenal vein is not as difficult to approach
because it lies lower, partially anterior to the upper pole
of the kidney, and the adrenal vein empties into the left
renal vein. Accordingly, on the left side, the colon is
reflected medially, exposing the anterior surface of
Gerota’s capsule; the initial dissection should involve
identification of the renal vein (see Figure 8-17B). In
essence, the dissection is the same as for a radical
nephrectomy for renal carcinoma. Once the renal vein is
exposed, the adrenal vein is identified, doubly ligated,
and divided. After this maneuver the pancreas and splenic
vasculature are lifted off the anterior surface of the adre-
nal gland. Because of additional drainage from the adre-
nal into the phrenic system, I generally continue the
medial dissection early to control the phrenic vein. I then
work cephalad and lateral to release the splenorenal liga-
ment and the superior attachments of the adrenal. The
remainder of the dissection is carried out as previously
described.
After removal of the tumor, regardless of size, careful
inspection is made to ensure hemostasis and the absence
of injury to adjacent organs. Careful abdominal explo-
ration is carried out, after which the wound is closed with
the suture material of choice. No drains are used.
Patients with multiple endocrine adenopathy of family
histories of pheochromocytoma, as well as pediatric
patients, should be considered at high risk for multiple
Figure 8-19 MRI showing bilateral adrenal pheochromocytoma in a patient with bilateral
glomus jugulare tumors. A, Small right adenoma that was enucleated and which was
partially resected. B, Large left bright pheochromocytoma that was totally removed.
lesions. Preoperative evaluation should identify these
lesions, but, regardless, a careful abdominal exploration
should be carried out.
In patients with suspected malignant pheochromocy-
tomas, en bloc dissections may be necessary to obtain
adequate margins, a concept that also applies in patients
with adrenal carcinomas. Evaluation with MRI to obtain
transverse, coronal, and sagittal images is extremely use-
ful to define clearly the adrenal relationships to the IVC
and renal vessels as well as to localize the adrenal vein.
In patients with pheochromocytomas, postoperative
management includes maintenance of arterial and venous
lines in an intensive care setting until they are stable. Often,
24 to 48 hours are required for the full effect of phenoxy-
benzamine, the α-blocking agent commonly given, to wear
off and for normal α-receptor activity to be restored.
PARTIAL ADRENALECTOMY
The standard treatment for patients with the adrenal
lesions described has been total adrenalectomy.
However, there recently has been reported an excellent
paper showing the utility of partial adrenalectomy in
patients with primary hyperaldosteronism.41 I have not
used partial adrenalectomy in a patient for normal con-
tralateral adrenal, but certainly have used the technique
in patients with bilateral disease (Figure 8-19). Thus, in

one patient with a pheochromocytoma on one side and
a nonfunctioning adenoma on the other, the adenoma
was simply enucleated from the adrenal. In a second
patient with bilateral pheochromocytomas, the larger
lesion was totally excised with partial adrenalectomy
was utilized to remove the contralateral tumor. Care has
to be taken to obtain thorough hemostasis when per-
forming a partial adrenalectomy because of the vascular
nature of the adrenal. Partial adrenalectomy or adrenal
sparing surgery is most useful in patients at risk for
multiple adrenal tumors, such as von Hippel-Landau
kindreds.42,43,44
CRYOSURGERY
Cryoablation is currently used as a surgical alternative for
the treatment of prostatic, lung, brain, pharyngeal, and
liver tumors. We have demonstrated in a canine model45
that adrenal cryoablation is effective in destroying adre-
nal tissue and is safe. We have successfully used the tech-
nique in one patient with primary hyperaldosteronism.
Adrenal laparoscopic cryoablation may shorten operative
time and be as effective as total adrenalectomy in patients
with small lesions.
ABLATION
Successful adrenal ablation using transcatheter arterial
infusion of ethanol has been described in 33 cases of pri-
mary hyperaldosteronism; the approach was successful in
27 cases (82%). Five patients required surgical adrenalec-
tomy. This technique may be useful in the patient who is
at high risk with use of general anesthesia.46 More
recently, direct percutaneous tumor injection with
ethanol has given excellent results in 41 patients with
pheochromocytoma with reversal of hormonal abnor-
malities.47
LAPAROSCOPIC ADRENALECTOMY
Laparoscopic adrenalectomy, first reported in 1991,48 is
now the surgical approach of choice for adrenal removal
in the majority of patients.49 The exceptions are patients
with large irregular adrenal carcinoma where adjacent
organs may be involved, large pheochromocytomas,
patients with large adrenal hemorrhage, and in some
cases of metastatic disease.
Chapter 8 Adrenal Tumors 149
A variety of laparoscopic approaches to the adrenal
exist.50,51 The lateral transperitoneal, anterior transperi-
toneal, lateral retroperitoneal, and posterior retroperi-
toneal techniques have been described similar to the
rationale for an open approach. The laparoscopic
approach depends on the patient’s habitus, the underly-
ing pathology and the skill and experience of the operat-
ing surgeon.1 The results of these approaches mirror the
results of open adrenalectomy with less morbidity and
hospitalization time for the patient.52
The lateral transperitoneal approach is the technique
most often reported in the literature. Most laparoscopic
surgeons have extensive experience identifying, dissect-
ing, and mobilizing the adjacent organs required in order
to obtain adrenal exposure and removal. For this
approach the patient is placed in a full lateral position
(Figure 8-20A and B). Bilateral adrenalectomy requires
repositioning and redraping.
In contrast, the retroperitoneal approaches avoid dis-
section and mobilization of intra-abdominal viscera
(Figure 8-21A and B). The major limitation is the small
working space that compromises instrument placement
and crossing of instruments can occur. The approach is
best for patients with small adrenal tumors. Balloon infla-
tion is used to dissect the retroperitoneal space. During
this procedure, close blood pressure monitoring is neces-
sary in patients with pheochromocytoma since the
expanding balloon may compress the tumor with catec-
hol release.
Regardless of the approach utilized the principles of
adrenal surgery previously described are the same.
SUMMARY
We are fortunate that our ability to diagnose the specific
adrenal entities that mandate a surgical approach is
extremely accurate. The combination of analytic
methodology to measure the appropriate adrenocortical
and medullary hormonal production and the radiologic
techniques for localization are superb. The management
of these adrenal disorders usually employing a laparo-
scopic approach following localization is highly success-
ful, resulting in a reversal of both metabolic
abnormalities and the hypertension that often accompa-
nies these diseases. Indeed, this is a true success story
with the evolution of these different techniques over the
past 50 years.
150 Part II Adrenal Gland

Figure 8-20 A, Trocar placement for left transperitoneal adrenalectomy. The distribution is a
mirror image of that used for the left side. Dissection of the left adrenal gland: the spleen (3),
pancreas (4), left lobe of the liver (2), renal vein (5), and kidney are shown. The left adrenal
vein (1) has been isolated. A clip is applied to the adrenal vein before dividing it (inset, right).
The inset (left) shows the patient’s position on the operating table. B, Trocar placement for a
right transperitoneal adrenalectomy: supra-umbilical trocar for camera (if only three trocars
are used) or splenic retractor (if four trocars are used). Trocars at anterior axillary line and
midaxillary line for instruments for dissection. Fourth trocar halfway between midline and
anterior is shown. A clip is applied to the adrenal vein before dividing it (inset, right). The
inset (left) shows the patient’s position on the operating table.

Figure 8-21 A, The retroperitoneal approach for the left adrenal gland (1): the adrenal vein
(2) is seen anterior to the renal artery (4); the renal artery (4) and vein (6) are identified early
in the dissection. The kidney (7) and ureter (8) are also depicted. The inset (left) shows the
patient’s position on the operating table.
Continued

Figure 8-21 cont’d B, The retroperitoneal approach for the right adrenal gland (1): the
adrenal vein (2) is seen at its takeoff from the vena cava (5); the renal artery (4) and vein (6)
are identified early in the dissection. The kidney (7) and ureter (8) are also depicted. The
inset (left) shows the patient’s position on the operating table.
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20. Schulick RD, Brennan MF: Adrenocortical carcinoma. In
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manifestation, treatment and prognosis of adrenocortical
cancer. Eur J Cancer 1993; 29A:1036–1038.
22. Wooten MD, King DK: Adrenal cortical carcinoma.
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24. Blumenfeld JD, Vaughan ED Jr.: Diagnosis and treatment
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25. Laragh JH, Angers M, Kelly WG, et al: The effect of
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27. Vaughan ED Jr, Sosa RE: Renovascular hypertension and
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28. Mann SJ, Atlas SA: Hypertensive emergencies. In Laragh
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29. Manger WM, Gifford RW Jr: Pheochromocytoma:
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31. Imperato-McGinley J, Gautier T, Ehlers K, et al:
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32. Bolande RP: The neurocrestopathias: a unifying concept
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33. Pearse AG, Polak JM: Cytochemical evidence for the
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34. Liu Z, Siragy HM, Carey RM: Diagnostic tests of adrenal
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35. Shapiro B, Copp JE, Sisson JC, et al: Iodine-131
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36. Campeau RJ, Garcia OM, Correa OA, Rege AB:
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38. Novick AC, Straffon RA, Kaylor W: Posterior
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39. Vaughan ED Jr, Phillips H: Modified posterior approach
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40. Gil-Vernet J: New surgical concepts in removing renal
calculi. Urol Int 1965; 20:255–262.
41. Nakada T, Kubota Y, Sasagawa I, et al: Therapeutic
outcome of primary aldosteronism: adrenalectomy versus
enucleation of aldosterone-producing adenoma. J Urol
1995; 153:1775–1780.
42. Walther MM, Keiser HR, Choyke PL, et al: Management
of hereditary pheochromocytoma in von Hippel-Lindau
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43. Walther MM, Herring J, Choye PL, Linehan WM:
Laparoscopic partial adrenalectomy in patients with
hereditary forms of pheochromocytoma. J Urol 2000;
164:14–17.
44. Pavlovich CP, Walther MM: Partial adrenalectomy:
indications and technique. In Belldegrun A, Ritchie A,
Figlin R, Oliver R, Vaughan ED Jr (eds): Renal and
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45. Schulsinger DA, Sosa RE, Perlmutter AP, Vaughan ED
Jr.: Acute and chronic interstitial cryotherapy of the
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Vaughan ED Jr (eds): Renal and Adrenal Tumors. Oxford,
Oxford University Press, 2003.
46. Ueno K, Nakajo M, Miayazono, N, et al: Transcatheter
adrenal arterial embolization of cortisol-producing
tumors: two cases of Cushing’s Syndrome. J Vascular
Interventional Radiol 2000; 11:141.
47. Wang P, Zuo C, Qian Z, et al: CT-Guided percutaneous
ethanol injection in the treatment of hyperfunctioning
pheochromocytoma. J Urol 2003; 170:1132–1134.
48. Gagner M, Lacroix A, Bolte E: Laparoscopic
adrenalectomy and Cushing’s syndrome and
pheochromocytoma. N Engl J Med 1992; 327, 1003–1006.
49. Del Pizzo JJ, Shichman SJ, Sosa RE: Laparoscopic
adrenalectomy: the New York-Prebyterian Hospital
experience. J Endosc 2002; 16:591.
50. Meraney AM, Gill IS: Laparoscopic versus open
adrenalectomy. In Belldegrun A, Ritchie A, Figlin R,
Oliver R, Vaughan ED Jr (eds): Renal and Adrenal
Tumors. Oxford, Oxford University Press, 2003.
51. Shichman S, Sosa RE, Vaughan ED Jr.: Lateral
transperitoneal laparoscopic adrenalectomy. In Belldegrun
A, Ritchie A, Figlin R, Oliver R, Vaughan ED Jr (eds):
Renal and Adrenal Tumors. Oxford, Oxford University
Press, 2003.
52. Baba S, Iwamura M: Laparoscopic adrenalectomy
by the posterior lumbar approach. In Belldegrun A,
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Oxford, Oxford University Press, 2003.
C H A P T E R
9 Open and Laparoscopic Surgery
of Adrenal Tumors
David S. Wang, MD, and Howard N. Winfield, MD
The adrenal glands are known to harbor a variety of
benign and malignant tumors. Due to the size and loca-
tion of the adrenals, lesions of the adrenal gland are
rarely detected because of local symptomatic growth.
Instead, most adrenal tumors are diagnosed either inci-
dentally or because of hormonal activity. In general,
lesions that should be surgically removed include lesions
that are hormonally active, tumors suspicious for adreno-
cortical carcinoma, or nonfunctioning adrenal lesions
5 cm or greater in size.
Traditionally, surgical procedures involving the adre-
nal gland were performed through an open incision with
a variety of approaches. In 1992, the laparoscopic
approach to adrenalectomy was introduced,1 offering a
less invasive alternative to open adrenalectomy. As expe-
rience with laparoscopic adrenalectomy is increasing, the
indications for laparoscopic adrenalectomy have
expanded while the absolute contraindications have
diminished. Indeed, laparoscopic adrenalectomy has
become the standard of care and the technique of choice
for most benign adrenal lesions.
This chapter reviews the basic diagnosis and hormonal
evaluation, indications, preoperative considerations, and
techniques of open and laparoscopic adrenalectomy for
benign and malignant tumors of the adrenal gland. The
full evaluation of the patient with an adrenal lesion is dis-
cussed in the previous chapter.
DIAGNOSIS
Adrenal lesions historically were diagnosed secondary to
clinical manifestations of endocrinopathies. However,
widespread use of abdominal ultrasound, computed
tomography (CT) scanning, and magnetic resonance
imaging (MRI) has led to the not-infrequent finding of
the incidental adrenal mass. Figures 9-1 and 9-2 show
typical examples of adrenal lesions diagnosed on CT and
MRI. The differential diagnosis of the incidental adrenal
mass is extensive and includes the benign nonfunctioning
adenoma, hormonally active cortical tumor, myelolipoma,
pheochromocytoma, adrenocortical carcinoma, and
metastatic lesion.
Tumors diagnosed incidentally on CT scan or MRI are
managed according to size and hormone functional status.
Patients with hormonally active adrenal tumors, such as
aldosteronoma, Cushing’s syndrome, or pheochromocy-
toma, should generally undergo surgical removal.
Hormonal evaluation of these patients is critical because
preoperative and postoperative considerations regarding
hypertensive control, electrolyte imbalances, and fluid
shifts are paramount to ensure good surgical outcomes and
minimize complications. A summary of standard labora-
tory tests in the evaluation of an adrenal lesion is listed in
Table 9-1. Most hormonally active tumors should be
removed, particularly in the case of pheochromocytoma
and cortisol-secreting tumors.2,3 Occasionally, medical
management of aldosteronomas may be satisfactory to cir-
cumvent the need for surgical management, particularly in
patients who are poor surgical candidates.4 However, side
effects of pharmacotherapy may become intolerable.
Hormonally inactive tumors have traditionally been
managed according to size. Tumors less than 3 cm are
almost always benign adenomas and generally require no
further treatment unless clinical signs of hormonal activ-
ity develop. Tumors greater than 6 cm are worrisome for
adrenocortical carcinomas, and thus surgical excision is
recommended given the aggressive nature of adrenal can-
cer.5 Nonfunctional lesions between 3 and 5 cm generally
require close follow-up with serial imaging studies every
6 months. These lesions should be removed if tumors
demonstrate interval change in appearance or develop
endocrine activity.
153
154 Part II Adrenal Gland

Table 9-1 Routine Laboratory Tests Useful in the

Evaluation of Adrenal Lesions
Frequency
of Usage

Cushing’s Syndrome

24-hour urine cortisol Common

Plasma ACTH and plasma cortisol Common

Low-dose dexamethasone suppression test Occasional

High-dose dexamethasone suppression Occasional

test

Metapyrone stimulation test Rare

Figure 9-1 CT scan of the abdomen demonstrating left Petrosal sinus ACTH measurement Extremely rare
adrenal lesion (arrow).
Hyperaldosteronism

Unprovoked hypokalemia Common

Plasma aldosterone level Common

Urinary aldosterone level Common

Aldosterone-to-renin ratio Common

Postural stimulation test Rare

Adrenal vein sampling of aldosterone Extremely rare

Pheochromocytoma

Plasma catecholamines Common

Urine catecholamines Common

Clonidine suppression test Occasional

Figure 9-2 MRI of the abdomen demonstrating left adrenal
lesion (arrow). Adrenal vein sampling of catecholamines Extremely rare

As mentioned previously, lesions of the adrenal gland

greater than 6 cm are worrisome for adrenal cancer. In
one meta analysis, 105 of 114 adrenocortical carcinomas
measured 6 cm or greater in diameter.6 Because CT scan
can underestimate the size of lesions by as much as 1 cm,7
it is suggested that all lesions on CT scans that are 5 cm
or greater be removed. In cases when there is concern for
adrenal carcinoma with local extension into adjacent
organs, such as the kidney, colon, or spleen, then open
radical adrenalectomy with possible en bloc resection of
adjacent organs is the preferred approach.8,9 More
recently, improvements in radiologic imaging tech-
niques, such as unenhanced and delayed enhanced CT
with densitometry, chemical-shift MRI, and NP-59
scintigraphy, have further assisted in differentiating
benign from malignant neoplasms.10
ALDOSTERONOMAS
Primary hyperaldosteronism (Conn’s syndrome) is a rare
etiology of hypertension (less than 1%). Other clinical
manifestations of Conn’s syndrome arise from increased
total body sodium content and a deficit in total body
potassium. Symptoms include urgency, frequency, noc-
turia, muscle weakness, paresthesias, or visual distur-
bances.4,11 CT scan or MRI can detect adrenal adenomas
as small as 1 cm. Laboratory manifestations include
hypokalemia, elevated plasma and urinary aldosterone
level, elevated serum aldosterone-to-renin ratio, and sup-
pressed plasma renin activity.4,11 Once an important part
of the evaluation, adrenal vein sampling is rarely used to
confirm and localize the lesion.
 Chapter 9 Open and Laparoscopic Surgery of Adrenal Tumors 155
Once the diagnosis is confirmed, medical control of
hypertension and correction of hypokalemia should be
instituted at least several weeks prior to adrenalectomy.
The most effective medication for management of
hyperaldosteronism is spironolactone, a competitive
antagonist of the aldosterone receptor.4 Side effects of
aldosterone include hyperkalemia, sexual dysfunction,
gynecomastia, gastrointestinal disturbances, and meta-
bolic acidosis.12 Alternative medications include potas-
sium-sparing diuretics, calcium channel blockers, and
converting-enzyme inhibitors. 11 Hypertension is
improved or cured in more than 90% of patients fol-
lowing adrenalectomy.13
CUSHING’S SYNDROME
Cushing’s syndrome is used to describe the symptom
complex that results from excess circulating glucocorti-
coids, regardless of etiology.3 Nonadrenal causes of
hypercortisolism include pituitary adenomas, ectopic
corticotrophin production, and exogenous steroid use.
The urologist is most often confronted with an adrenal
lesion as the etiology of Cushing’s syndrome.
Cushing’s syndrome manifests with a variety of well-
recognized clinical features, including hypertension,
truncal obesity, moon facies, easy bruising, and mood dis-
orders. Diagnosis is confirmed by laboratory testing.3
Hypercortisolism is best diagnosed by 24-hour urinary
cortisol measurement. The low-dose dexamethasone
suppression test can be used to further diagnose
Cushing’s syndrome if urinary cortisol measurement is
equivocal. Abdominal CT scan and MRI can identify
adrenal adenomas or bilateral adrenal hyperplasia.
PHEOCHROMOCYTOMA
Pheochromocytomas can be challenging tumors to treat
because of the unique manifestations of chronic and
acute catecholamine excess. Successful surgical manage-
ment of pheochromocytoma requires close collaboration
among the surgeon, endocrinologist, and anesthesiolo-
gist. It is essential to have an anesthesiologist familiar
with pheochromocytoma that is able to adequately man-
age blood pressure intraoperatively and who is familiar
with which anesthetic agents to avoid. In general, cate-
cholamine excess results in hypertension, tachycardia, and
a host of clinical manifestations. Laboratory diagnosis is
made by elevated levels of catecholamines in the blood and
urine. Radiographic diagnosis is achieved with either CT
scan or MRI. MRI imaging classically demonstrates a
bright image on a T2-weighted study. Additionally,
metaiodobenzylguanidine (MIBG) nuclear medicine scan-
ning can help confirm and localize pheochromocytomas.
The treatment of choice for most pheochromocy-
tomas is surgical excision. In the past, all pheochromo-
cytomas were treated through an open approach, with
early control of the adrenal vein. However, with increas-
ing experience worldwide with laparoscopic adrenalec-
tomy, pheochromocytoma is no longer considered a
contraindication to laparoscopic surgery. In fact, laparo-
scopic adrenalectomy for pheochromocytomas has now
been performed successfully at many centers of laparo-
scopic excellence and reported in several series.14–16
Regardless of the surgical approach chosen, preopera-
tive medical preparation is essential, and includes optimal
control of blood pressure with alpha blockade or calcium
channel antagonists.2 Beta-blockers may be used to con-
trol reflex tachycardia after initiation of alpha blockade.
In addition, aggressive fluid expansion is necessary to
increase circulating plasma volume and prevent postop-
erative hypotension. Close monitoring intraoperatively
includes careful attention to blood pressure, central
venous pressure, and urinary output. An arterial line and
central venous line are routinely used, and occasionally a
Swan-Ganz catheter is employed. Severe hypertension
can be controlled with sodium nitroprusside or phento-
lamine, and hypotension can be controlled with fluid
resuscitation and norepinephrine.
ADRENOCORTICAL CARCINOMA
Adrenocortical carcinoma is a rare malignancy with an
estimated incidence of 0.5 to 2.0 cases per million annu-
ally.17,18 Although adrenal cancer is known to occur at all
ages from early infancy to the 8th decade of life, there
appears to be a bimodal distribution during the first
decade of life in children and in the fourth or fifth decade
of life in adults.19,20 The prognosis is uniformly poor,
although pediatric patients generally have a better prog-
nosis because they more commonly present earlier with a
hormonal syndrome.
The majority of adrenocortical carcinomas are func-
tional, with 62% of adrenal cancers being functional in
one study.17 The most common syndrome associated with
adrenocortical carcinoma is Cushing’s syndrome. Typical
clinical symptoms of adrenocortical carcinoma include
abdominal pain, weight loss, fever, weakness, anorexia,
nausea, and myalgia. Unfortunately, many of these symp-
toms are often associated with advanced disease.
The primary treatment modality for suspected adreno-
cortical carcinomas is complete surgical excision of the
tumor. Complete surgical excision appears to offer the
patient the best chance of cure. In one series, the 5-year
survival of adrenocortical carcinoma after surgery was
55% following complete removal with negative margins
versus 5% for incomplete removal.21 When surrounding
organs, such as kidney, colon, or spleen, are infiltrated by
adrenocortical carcinoma, then en bloc excision of sur-
rounding organs offers the patient the best chance of long-
term survival. It is unclear whether the debulking of
156 Part II Adrenal Gland
tumors that cannot be excised completely offers a survival
advantage. Radiation therapy and chemotherapy are
largely ineffective for metastatic disease.18
The suspected adrenocortical carcinoma should be sur-
gically approached in an open fashion rather than laparo-
scopic fashion. Because complete surgical excision of the
adrenocortical carcinoma portends a much better progno-
sis, the ability to fully remove the lesion should not be
compromised solely for decreasing patient morbidity. The
additional patient morbidity endured following an open
surgical procedure is insignificant if a more thorough exci-
sion is possible. The threshold to convert from a laparo-
scopic procedure to an open one should be low when there
is a clinical suspicion of a malignant adrenal neoplasm.
Laparoscopic adrenalectomy for suspected malignant neo-
plasm should be performed only by those with great expe-
rience in laparoscopic surgery, so that the surgeon can feel
that an equivalent or even more thorough excision can be
achieved by the laparoscopic approach.
PREOPERATIVE PATIENT EVALUATION
AND PREPARATION
Careful preoperative control and management of hor-
monally active tumors is critical prior to performing
adrenal surgery, whether laparoscopic or open.
Inadequate preoperative control of hormonally active
lesions can lead to catastrophic intraoperative conse-
quences. Close collaboration with an endocrinologist and
anesthesiologist experienced with adrenal disorders is
helpful. The urologist should have an understanding of
the physiology of adrenal disorders in order to appropri-
ately manage patients in the peri- and postoperative
period with regard to fluid management, electrolyte
abnormalities, and blood pressure control. Hormonally
functional tumors must be adequately evaluated and
appropriate preoperative interventions initiated in con-
cert with an endocrinologist.
Preoperatively, all patients should receive a mechani-
cal bowel preparation. Clear liquids should be started the
day before surgery. A broad-spectrum antibiotic should
be administered on call to the operating room.
OPEN SURGICAL TECHNIQUES
Surgical Anatomy
A thorough knowledge of the anatomy of the adrenal
gland and its relationship to adjacent organs is essential
to avoid intraoperative complications. Familiarity with
the vascular supply of the adrenal gland is important in
minimizing the chances of intraoperative hemorrhage.
The adrenal gland, like the kidney, is enveloped by
Gerota’s fascia; it is however located in a distinct fascial
compartment that is separate from the kidney. The arte-
rial supply to the adrenal gland arises from the inferior
phrenic artery, aorta, and renal artery. A complex arcade
of small arteries enters the adrenal gland from the medial
and superior border of the gland, and thus the anterior,
posterior, and inferolateral surfaces of the adrenal gland
are relatively avascular.
The right and left adrenal glands have key anatomic
differences in location and vasculature. The main right
adrenal vein exits the gland from the superomedial sur-
face and enters the inferior vena cava (IVC) directly. The
longer left main adrenal vein exits the inferomedial
aspect of the gland and drains into the left renal vein at
an oblique angle. The right adrenal gland is more inti-
mately related to the IVC than the left gland is related to
the aorta. The capsule surrounding the adrenal gland is
very fragile, and direct grasping of the adrenal gland can
lead to parenchymal fracture resulting in persistent and
troublesome bleeding. The lymphatic drainage of the
adrenal gland includes all lateral aortic lymph node tissue
between the diaphragm and ipsilateral renal artery.
Open Surgical Approaches to the Adrenal Gland
There are a variety of approaches to the adrenal gland,
including the flank, posterior, modified posterior, trans-
abdominal, and thoracoabdominal approaches. The
choice of surgical approach is influenced by the tumor
pathology, size of the lesion, patient’s body habitus, and
surgeon familiarity and preference.
Lateral Flank Approach
The standard extrapleural, extraperitoneal lateral flank
approach offers excellent exposure to the adrenal gland.
In addition, the lateral flank approach is familiar to most
urologists. Generally, an incision above the 11th rib is
utilized with or without resection of a rib. This approach
is ideal for either left or right adrenalectomy.
After adequate general anesthesia, a Foley catheter is
inserted to decompress the bladder and an orogastric
tube to decompress the stomach. Lower extremity pneu-
matic compression stockings are placed. The patient is
then placed in the full lateral position with the flank over
the flexion point of the operating table. The operating
table is flexed 30 to 45 degrees and the kidney rest is
raised. An axillary roll is placed under the contralateral
arm. The patient is then carefully secured, and all pres-
sure points are adequately padded.
A supracostal incision above the 11th rib is made extend-
ing from the lateral border of the rectus abdominus muscle
anteriorly to the sacrospinalis muscle posteriorly. The exter-
nal oblique, internal oblique, latissimus dorsi, and serratus
posterior inferior muscles are incised. The lumbodorsal fas-
cia and transversus abdominus muscles are then incised to
expose the peritoneum and preperitoneal fat. Care is taken
to sweep away and avoid the peritoneum and the pleura.
 Chapter 9 Open and Laparoscopic Surgery of Adrenal Tumors 157
Once the flank is entered, the peritoneum and colon
are dissected away from Gerota’s fascia and the kidney is
partially mobilized. It is important to avoid dissecting the
adrenal gland off of the surface of the kidney gland until
mobilization of the adrenal gland is nearly complete. The
kidney is extremely useful for downward retraction of the
adrenal gland. The capsule of the adrenal gland is quite
friable and should not be directly grasped in order to
avoid fracturing the gland with resultant troublesome
bleeding. In patients with pheochromocytoma, the adre-
nal vein should be controlled early in the procedure to
limit catecholamine surges. The anesthesiologist should
be notified when the adrenal vein is divided because
occasionally a marked decrease in blood pressure can
occur despite adequate fluid hydration.
On the left side, the superior dissection of the adrenal
gland is performed initially, taking care to clip or ligate
the blood supply to the adrenal gland arising from the
inferior phrenic vessels. The adrenal gland is dissected
away from the diaphragm. Downward retraction on the
Figure 9-3 Flank approach to right adrenal.
kidney optimizes exposure to the superior aspect of the
adrenal gland. The lateral attachments of the left adrenal
gland are generally relatively avascular and are therefore
easily mobilized. Posteriorly, the adrenal arteries that
arise from the aorta must be carefully ligated. Generally,
the medial blood supply is taken last. Great care must be
taken to avoid injury to the renal artery and vein. Once
the left renal vein is identified, the left adrenal vein can
be safely divided. The adrenal gland is then dissected free
from the kidney and inspection should be made for
bleeding.
Dissection on the right side (Figure 9-3) differs only
slightly from the left side. Again, the kidney is useful for
downward retraction of the adrenal gland. The superior
and lateral dissection of the adrenal gland should be per-
formed initially, taking care to ligate the multiple small
adrenal vessels supplying the gland. The medial dissec-
tion of the adrenal gland is next performed, carefully
dividing small arterial vessels. The IVC must be exposed
to allow for exposure of the adrenal vein. The right adrenal
158 Part II Adrenal Gland

vein is short and broad and great care must be under-

taken to prevent inadvertent avulsion. The right adrenal
vein is ligated. Lastly, the right adrenal gland is dissected
off of the superior surface of the kidney.
In the case of adrenocortical carcinoma, en bloc radi-
cal nephrectomy is often necessary. The kidney should be
removed, adhering to the general principles of oncologic
surgery, without detaching it from the adrenal gland. If
the tumor appears to be invading the colon, then subto-
tal colectomy may be required. Because the overall sur-
vival following complete surgical excision is improved,
then every effort should be made to remove all of tumor
if possible.
After the adrenal gland is removed, inspection for
hemostasis and injury to surrounding structures is per-
formed. The flank incision is then closed in the standard
fashion in layers.

Thoracoabdominal Approach
The thoracoabdominal approach (Figure 9-4), usually
through an incision above the 9th or 10th rib, is most
commonly used for very large tumors or suspected adre-
nal carcinomas. The incision is the same as the standard
approach for a radical nephrectomy, described elsewhere
in this text. The thoracoabdominal approach offers supe-
rior operative exposure and is particularly useful for large
adrenocortical carcinomas.
Figure 9-4 Thoracoabdominal approach to left adrenal.

Transabdominal Approach
The transabdominal approach (Figure 9-5) is useful when
exposure to both adrenal glands is necessary, particularly
in pediatric patients. This approach is occasionally chosen
for patients with large adrenal tumors or pheochromocy-
tomas. The transabdominal approach allows for excellent
exposure to both adrenal glands and allows for full and
complete abdominal exploration. This is particularly help-
ful in pheochromocytomas, when tumors may be bilateral
or may occur at sites distant from the adrenal gland.
However, improved imaging techniques have allowed for
more precise localization of pheochromocytomas, thus
limiting the indications for this approach.
The anterior abdominal approach is performed usually
through a chevron incision, although a midline, subcostal,

Figure 9-5 Transabdominal approach to the adrenal.

 Chapter 9 Open and Laparoscopic Surgery of Adrenal Tumors 159

or transverse incision may also be employed. Generally,

the type of incision for the anterior transabdominal
approach is dictated by the size of the lesion, presence of
bilateral lesions, patient body habitus, and surgeon pref-
erence.
The patient is placed in the supine position with the
kidney bar slightly elevated. A subcostal chevron incision
is made in the upper abdomen, and all of the muscles of
the anterior abdominal wall are divided. The peritoneum
is then entered and the abdominal organs inspected for
metastatic disease. The hepatic flexure must be reflected
for right-sided tumors and the splenic flexure for left-
sided tumors.
On the right side, the duodenum is reflected (Kocher
maneuver) to expose the IVC (Figure 9-5A). The kidney
is used to provide traction to the adrenal gland, and
direct grasping of the adrenal gland is minimized. The
superior attachments of the adrenal gland are divided
carefully, followed by the lateral adrenal gland attach-
ments. The medial surface of the adrenal gland is freed
by dividing arterial branches. The short right adrenal
vein is divided and the remaining attachments of the
adrenal gland are divided to release the specimen. On the
left side, after identification of the adrenal gland and kid-
ney, the superior attachments of the gland are divided
first. The spleen and pancreas often must be dissected
bluntly away from the adrenal gland (Figure 9-5B). The
left adrenal vein is divided during the medial dissection of
the gland and the adrenal gland is then freed from the
superior surface of the kidney.

Posterior Approach Figure 9-6 Posterior approach to the adrenal.

The posterior approach (Figure 9-6) is rarely used

today because of improvements in diagnostic imaging.
In the past, the posterior approach was used for bilateral
adrenal exploration or for removal of small adrenal
lesions. The posterior approach is performed through a
subcostal incision and provides a limited surgical field.
It does provide for direct access to the adrenal gland
and is ideal for thin patients. The limited surgical field
makes this unsuitable for excision of large adrenal
masses and lesions that are suspicious for adrenocortical
carcinoma. With the advent of laparoscopic surgery,
there are no specific indications for the posterior
approach. Most lesions that are small enough to be per-
formed through a posterior approach should be
removed laparoscopically.
The patient is placed in the prone position with the
table slightly flexed. The incision is placed at the level
of the 11th or 12th rib. The incision is carried through
the lumbodorsal fascia and the latissimus dorsi muscles.
The pleura and peritoneum are swept away from the
11th and 12th ribs until Gerota’s fascia is identified.
Gerota’s fascia is incised, and the posterior surface of
the kidney is exposed. Inferior retraction on the kidney
allows for visualization of the adrenal gland on the
superior surface of the kidney. Similar to the flank
approach, the superior vessels supplying the adrenal
gland are divided, the adrenal vein is ligated, and the
adrenal gland is circumferentially mobilized. Again,
care must be taken to ensure that the renal hilar vessels
are not injured during the dissection.
Modified Posterior Approach for Right
Adrenalectomy
A modified posterior approach (Figure 9-7) for accessing
the right adrenal gland has been described.22 The patient
is placed in a modified prone position, and the 11th or
12th rib is resected. The primary advantage of this
approach is that the adrenal vein is identified more easily
because it is seen emerging from the IVC toward the
operating surgeon. Again, however, this approach is
rarely used because most such tumors are removed by the
laparoscopic technique.
160 Part II Adrenal Gland
Figure 9-7 Modified posterior approach to the right adrenal.
LAPAROSCOPIC SURGERY
OF THE ADRENAL GLAND
Indications for Laparoscopic Adrenalectomy
The indications for laparoscopic adrenalectomy have
expanded as more surgeons have become proficient with
the technique and the advantages of this approach have
become apparent. Laparoscopic adrenalectomy has, in
many centers, become the surgical procedure of choice
for the management of functional tumors less than 6 cm
in size. Although the presence of pheochromocytoma
was a relative contraindication for laparoscopic adrena-
lectomy in the past, it is clear that the procedure can be
performed safely as long as the same precautions are
taken as those for open surgery.14 The current indica-
tions for performing a laparoscopic adrenalectomy are
listed in Table 9-2.
There are few absolute contraindications to laparo-
scopic adrenalectomy. It is generally felt that a known or
suspected primary adrenal carcinoma, particularly with
extension into surrounding organs, should be removed
by an open technique. Given the aggressive nature of the
disease, the open approach allows for en bloc resection
 Chapter 9 Open and Laparoscopic Surgery of Adrenal Tumors 161

Table 9-2 Indications for Laparosocpic
Adrenalectomy
Aldosterone secreting adrenal gland, adenoma, or
unilateral hyperplasia
Cushing’s syndrome secondary to adrenocortical adenoma
Non-functional adrenal mass ≤ 8 cm with negative
metastatic workup
Non-functional adrenal mass ≤ 8 cm with progressive
growth on CT or MRI
Adrenal pheochromocytoma (benign) ≤ 8 cm
Solitary adrenal gland metastasis
and potential removal of surrounding organs.8 Other
contraindications to laparoscopic adrenalectomy include
uncorrectable coagulopathy and cardiopulmonary disease
precluding general anesthesia. Patients who will not tol-
erate an open operation are generally poor candidates for
laparoscopic adrenalectomy.
Relative contraindications to laparoscopic adrenalec-
tomy include previous abdominal surgery or significant
morbidity. Lesions greater than 8 cm in size, even if not
suspected to be primary adrenal carcinomas, should be
approached cautiously because of the increased risk of
hemorrhage and injury to surrounding viscera. With
increasing experience in performing laparoscopic
adrenalectomy, relative contraindications become less
of a factor. A variety of approaches to laparoscopic
adrenalectomy, including transperitoneal and retroperi-
toneal, have further decreased some relative contraindi-
cations.
Occasionally, the urologist will encounter a patient
with a suspected solitary metastatic lesion to the adre-
nal gland. If the lesion is less than 6 cm in size and not
obviously adherent to surrounding viscera, then a
laparoscopic approach is reasonable.23 The surgeon
should be skilled in laparoscopic adrenalectomy before
attempting to remove a solitary metastatic lesion given
the more difficult surgical planes that are often present.
determining the approach. Most surgeons are familiar
with the anterior transperitoneal approach, but many
who have overcome the learning curve of the anterior
transperitoneal approach are becoming skilled with the
retroperitoneal approach.25–30 Although each approach
has purported advantages and disadvantages, there is no
clear-cut evidence that one is superior.31,32
Preoperative Preparation
The preoperative evaluation and preparation of patients
prior to undergoing laparoscopic adrenalectomy is iden-
tical to that prior to open adrenalectomy. All patients
should undergo a mechanical bowel preparation on the
day prior to surgery and a broad-spectrum antibiotic
should be administered on the day of surgery. As with all
laparoscopic procedures, the stomach should be decom-
pressed with an orogastric tube and the bladder with a
Foley catheter.
Anterior Transperitoneal Approach for Right
Adrenalectomy
After general anesthetic by agents other than nitrous
oxide, the patient is positioned with the right side ele-
vated 45 to 70 degrees upward and the table slightly
flexed at the level of the umbilicus. The patient should be
positioned on a beanbag with extensive padding over
pressure points. Figure 9-8 shows the general modified
flank position used for laparoscopic adrenalectomy. Next,
the patient should be secured with tape to allow the table
to be tilted side to side so as to facilitate exposure.
For a right laparoscopic adrenalectomy, four subcostal
ports are used and placed two to three fingerbreadths
below the costal margin, as depicted in Figure 9-9. Initial

Laparoscopic Surgical Approaches

Perhaps no other urologic laparoscopic procedure has as
many different surgical approaches as does adrenalec-
tomy. Commonly used approaches to the adrenal gland
include the transperitoneal approaches, and the posterior
or lateral retroperitoneal approaches. Recently, a
transthoracic approach has been described for patients
who have undergone extensive previous transperitoneal
and retroperitoneal surgery.24 Surgeon preference and Figure 9-8 Patient positioning for right transperitoneal
experience appear to be the most important factors in adrenalectomy.
162 Part II Adrenal Gland
Figure 9-9 Port placement for right transperitoneal adrenalectomy.
entry into the peritoneal cavity is made using the Veress
needle just below the costal margin in the midclavicular
line. Three or four additional ports are placed under
direct vision; the most medial port is important for
upward and medial retraction of the right lobe of the
liver. Exposure of the right adrenal gland is dependent on
adequate mobilization of the liver.
Mobilization of the liver is the first step in exposing
the right adrenal gland. Unlike laparoscopic nephrec-
tomy, full mobilization of the ascending colon and
hepatic flexure is unnecessary. Incision of the posterior
peritoneum and extension through the triangular liga-
ments of the liver allow for upward and medial retraction
of the liver (Figure 9-10). A fixed retractor may be placed
under the liver through an additional trocar port to allow
the liver to remain out of the field of dissection for the
remainder of the case.
The IVC is eventually identified once there is ade-
quate liver mobilization. Continued and careful dissec-
tion along the lateral surface of the IVC will reveal the
right adrenal vein. The adrenal vein should then be
divided between standard clips. Dissection is further
 Chapter 9 Open and Laparoscopic Surgery of Adrenal Tumors 163
Figure 9-10 T-shaped incision through the posterior
peritoneum for left and right adrenalectomy. On right, incision
from second part of the duodenum to triangular ligaments at
liver edge and then lateral to hepatic flexure. On left, incision
developed across phrenocolic and splenocolic ligaments
and at inferior border of spleen (IVC, inferior vena cava;
R, right; L, left).
continued towards the diaphragm, and the inferior
phrenic vessels should next be identified and divided.
The inferior pedicle of the adrenal gland is then
released, separating the adrenal gland from the upper
pole of the kidney. Gerota’s fascia is next incised at the
junction of the upper pole of the kidney and the adrenal
gland. There is often an arterial branch to the adrenal
gland arising from the renal pedicle. Once the kidney is
completely mobilized away from the adrenal gland, all
that remains holding the adrenal gland in place is the rel-
atively avascular lateral attachments, which are divided.
Use of the harmonic scalpel can facilitate mobilization of
the adrenal gland once the main vascular pedicles have
been ligated.
Once the adrenal gland is completely separated, it
should be placed in a specimen retrieval bag and removed
en bloc. Assuming adequate hemostasis, the laparoscopic
ports are removed under direct vision and fascia closed
with the Carter–Thomason fascial closure device.
A drain is usually not necessary. The orogastric tube is
removed at the conclusion of the procedure.
Anterior Transperitoneal Approach
for Left Adrenalectomy
The patient is positioned with left side elevated 45 to 70
degrees with the table slightly flexed at the level of the
umbilicus. Three or four trocars are placed in a mirror
Figure 9-11 Dissection of left adrenal gland allowing
visualization of left adrenal vein.
image as for a right adrenalectomy. The important sur-
rounding structures to identify when performing a
transperitoneal left laparoscopic adrenalectomy include
the spleen, tail of the pancreas, splenic flexure of the
colon, and left kidney. Full mobilization of the splenic
flexure of the colon is necessary to provide adequate
exposure to the left adrenal gland.
The first step after diagnostic laparoscopy is to incise
the posterior peritoneum along the line of Toldt and
mobilize the splenic flexure of the colon to allow the
colon to fall medially. The splenocolic and lienorenal lig-
aments are then mobilized to allow the spleen to be safely
separated from the field of dissection (Figure 9-10). This
creates an adequate plane between the spleen and the
upper pole of the left kidney. If necessary, the tail of the
pancreas can be separated away from Gerota’s fascia to
allow the pancreas to fall away with the spleen to provide
more exposure.
Next, Gerota’s fascia is incised between the upper pole
of the left kidney and the adrenal gland. The left adrenal
gland should not be grasped directly to avoid adrenal
gland fractures, which are associated with troublesome
bleeding. Dissection continues through the perirenal
fibrofatty tissue. The inferior border of the adrenal gland
is defined and the dissection continued medially. Medial
dissection will eventually lead to the takeoff of the left
adrenal vein emanating directly from the left renal vein
(Figure 9-11). The left adrenal vein is then isolated,
clipped, and divided. In the case of a pheochromocytoma,
early exposure and ligation of the left adrenal vein is ideal
to reduce the risk of a hypertensive crisis. We have found
164 Part II Adrenal Gland
it easiest to initially identify the left renal vein and deter-
mine the take-off of the left adrenal vein. Clipping of the
adrenal vein at this juncture minimizes catecholamine
surges.
Again, the lateral attachments of the left adrenal gland
should be saved until the remainder of the gland is mobi-
lized. The superior aspect of the adrenal gland is then
mobilized, taking care to divide the phrenic vessels sup-
plying the gland. Once the superior and inferior borders
of the gland are dissected adequately, attention is
directed towards the head of the gland, which is adjacent
to the aorta. The left adrenal vein is divided if not previ-
ously done. The left adrenal artery arising from the aorta
is next divided. The adrenal gland has a highly variable
vasculature, especially in larger lesions with increased
blood supply. The use of a harmonic scalpel or hook
cautery electrode can facilitate adrenal gland mobiliza-
tion and adequately ligate small blood vessels supplying
the gland.
Lastly, the lateral attachments of the adrenal gland are
divided to fully free the gland from all surrounding tis-
sues. The specimen is then placed into a retrieval bag and
removed intact. Closure is similar to that for the right
adrenalectomy.
Retroperitoneal Technique
The retroperitoneal approach to the adrenal gland is par-
ticularly useful in the patient with a prior history of
extensive abdominal surgery. Unlike the transperitoneal
approach, the patient is positioned in the full flank posi-
tion. Three or four ports are typically used. Patient posi-
tioning and port placement are as shown in Figure 9-12.
Access into the retroperitoneum requires the creation of
a working space using a dilating balloon (U.S. Surgical,
Norwalk, CT).
A Hasson technique is used to place the first port.
A small 2-cm incision is made just below the tip of the
12th rib, and S-type retractors are used to split the mus-
cles until the lumbodorsal fascia is identified. Once the
Figure 9-12 Patient positioning and trocar placement for
retroperitoneal adrenalectomy (A = camera port; B and C =
working ports).
lumbodorsal fascia is incised, access into the retroperi-
toneal space is confirmed by inserting one finger in and
palpating the 12th rib, the iliac crest, and the psoas mus-
cle. The trocar-mounted balloon is then inserted and
inflated in order to mobilize Gerota’s fascia anteriorly
away from the posterior abdominal wall. Carbon dioxide
insufflation is then attached to the trocar to generate
pneumoretroperitoneum at a pressure of 15 mm Hg.
Once the primary port is inserted, the working ports are
placed. The second port is placed posterior to the pri-
mary port, below the angle formed by the 12th rib and
the paraspinous muscles. The third port is placed approx-
imately 3 to 4 cm medial to the primary port in the ante-
rior axillary line. The working ports are either 5 or 10 mm
in size. The optional fourth port is placed in the anterior
axillary line 5 to 7 cm inferior to the third port and may
be used to assist with retraction throughout the duration
of the case.
Once pneumoretroperitoneum is established, identi-
fication of key landmarks helps to establish the orienta-
tion. The psoas muscle is usually easily seen and
establishes longitudinal orientation. By retracting the
kidney upwards and anteriorly, subsequent medial dis-
section will eventually reveal the great vessels running
parallel to the psoas muscle. The renal artery can be
identified by identifying pulsations, although full
mobilization of the renal hilar vessels is generally not
necessary during adrenalectomy. On occasion intraop-
erative ultrasonography may be helpful in identifying a
small adrenal lesion in the midst of abundant per-
inephric fat.
Left Adrenalectomy
Dissection on the left side should be conducted along the
psoas muscle to the upper pole of the kidney.
Identification of the renal hilum allows for rapid identifi-
cation of the left adrenal vein. The adrenal vein can be
found along the inferomedial border of the adrenal
gland. If difficulty is encountered identifying the left
adrenal vein, the adrenal vein can be found by first locat-
ing the left renal vessels and noting the junction of the
left adrenal vein with the left renal vein. Unlike a
transperitoneal laparoscopic adrenalectomy, the dissec-
tion and identification of the left adrenal vein must be
done from a posterior approach. Once the left adrenal
vein is divided, the remainder of the adrenal gland can be
detached, again trying to minimize direct grasping of the
friable adrenal tissue. Generally, the lateral and inferior
surface of the gland is dissected away from the kidney.
The superior margin is dissected free by dividing the
inferior phrenic vessels. The use of the harmonic scalpel
is useful for complete mobilization of the adrenal gland.
Once detached, the adrenal gland is placed in a speci-
men retrieval bag and then removed through the primary
 Chapter 9 Open and Laparoscopic Surgery of Adrenal Tumors 165
port, the largest incision. The remaining ports are then
closed in the standard fashion.
Right Adrenalectomy
The right adrenalectomy proceeds using the same prin-
ciples of retroperitoneal laparoscopy. The dissection pro-
ceeds along the psoas muscle in a superior direction. The
kidney may be held anteriorly by an optional retractor.
The right adrenal gland is situated more medial to the
kidney than the left adrenal gland, and as such the upper
pole of the kidney may interfere with exposure of the
adrenal gland. The IVC is identified medial to the psoas.
Along the posterolateral aspect of the IVC, the main
adrenal vein is identified. Caution must be exercised
when manipulating the main adrenal vein to prevent
inadvertent avulsion. The adrenal vein is then clipped
and divided.
Once the adrenal vein is divided, then inferior and
medial borders of the adrenal gland are dissected free
from the right renal vein and the IVC. Small adrenal ves-
sels can then be effectively ligated using the harmonic
scalpel. The inferior phrenic vessels are then divided to
release the adrenal gland and the specimen removed in
the usual fashion.
Posterior Retroperitoneal Approach
The posterior retroperitoneal approach to the adrenal
gland has been described.33 Purported advantages of this
approach include less risk of injury to organs confined to
the peritoneal or retroperitoneal cavity and is better
suited for smaller tumors. With this technique, the oper-
ation is performed with the patient in the prone position.
A 3 to 4-port technique is used following standard bal-
loon dilatation. Gerota’s fascia is incised along the medial
crus of the diaphragm. The medial surface of the adrenal
gland, including the adrenal vessels, is exposed first
before mobilization of the entire gland. Once the main
vascular supply of the adrenal gland is divided, the
remainder of the gland is dissected free. Although results
with this technique are promising,34 experience with this
approach is limited.
Transthoracic Technique
Recently, the technique of thorascopic transdiaphrag-
matic adrenalectomy has been described.24 This tech-
nique has potential for use when both the transperitoneal
and retroperitoneal spaces have been violated by prior
surgery. Following double lumen endotracheal intuba-
tion, the patient is placed in the prone position. A 4-port
transthoracic technique is used.
In order to gain exposure to the adrenal gland, the
diaphragm is incised under ultrasonographic guidance
and the retroperitoneum entered. The adrenal gland is
then identified and dissected free. Once the adrenal
gland is removed, the diaphragm is repaired. A chest tube
is kept in place at the conclusion of the procedure.
Postoperative Care
The advantages of the laparoscopic approach to the adre-
nal gland are immediately apparent in the postoperative
period. The orogastric tube is removed immediately at
the end of the operation and the Foley catheter removed
as soon as the patient is ambulatory. Postoperative pain is
controlled with parenteral narcotics in the first 24 hours,
ketorolac or oral narcotics thereafter. Supplemental cor-
ticosteroids and appropriate antihypertensive medica-
tions are administered as needed depending on the type
of tumor removed. Postoperative care can be coordinated
in concert with an endocrinologist if necessary.
Discharge is usually within 24 to 48 hours from surgery
and full recovery requires 10 to 14 days.
Complications of Laparoscopic Adrenalectomy
The most significant intraoperative complication is hem-
orrhage. The adrenal gland is highly vascular which can
result in troublesome bleeding if not adequately con-
trolled.35 The use of a harmonic scalpel during dissection
of the adrenal gland can limit the amount of hemorrhage.
In addition, the adrenal gland itself is very easily frac-
tured, often resulting in bleeding.
Other intraoperative complications from laparoscopic
adrenalectomy are similar to those for any laparo-
scopic procedure and can include injuries to the colon,
small bowel, liver, gallbladder, pancreas, spleen, and
diaphragm.35 In general, major complications occur less
often as surgeon experience increases. Conversion to an
open case should be done if hemorrhage is uncontrol-
lable or intraoperative injury cannot be repaired through
a laparoscopic approach.
Results of Laparoscopic Adrenalectomy
Worldwide experience with laparoscopic adrenal surgery
has increased since its original introduction in 1992.
Several centers have now reported large series in the lit-
erature documenting the decreased blood loss, shortened
hospital stay, and faster return to normal activity.
Selected recent series in the literature are summarized in
Table 9-3.
Gagner et al.46 reported on 100 consecutive laparo-
scopic adrenalectomy procedures performed through the
transperitoneal approach. The mean operative time was
123 minutes with an estimated blood loss of 70 cc. In his
series, the open conversion rate was 3%. Average length
of hospital stay was 3 or less days, and morbidity was
 Table 9-3 Selected Laparoscopic Adrenalectomy Series
166

Number OR Time EBL Hospital Conversion

Reference of Cases Age Approach (minutes) (cc) Stay (days) Rate Complications

MacGillivray36 (2002) 60 — Transperitoneal 183 63 2 0/60

Valeri37 (2002) 91 — Transperitoneal 92–148 — 3.5 2/91 2 postoperative hemorrhage, 1 port site bleed
1 UTI, 1 death from myocardial infarction

Kebebew et al.38 (2001) 176 — Transperitoneal 168 — 1.7 0/176 5.1%

Part II Adrenal Gland

Lezoche et al.31 (2001) 216 45.9 149 transperitoneal 100 — — 4/216 1 death, 1 hemoperitoneum, 1
67 retroperitoneal wound infection

Salamon et al.30 (2001) 115 49.3 115 retroperitoneal 118 77 4 1/118 3.5% intraoperative
12.1% postoperative

Guazzoni et al.39 (2001) 161 39.4 Transperitoneal 160 — 2.8 4/161 5.5%

Suzuki et al.32 (2001) 118 51.7 78 transperitoneal 171 96.3 — 6/118 2 paralytic ileus
40 retroperitoneal 4 shoulder tip pain

Soulie et al.40 (2000) 52 46.9 52 retroperitoneal 135 80 5 1/52 5.7% intraoperative

11.5% postoperative

Mancini et al.41 (1999) 172 — Transperitoneal 132 — 5.8 12/172 8.7%, 2 deaths

Schichman et al.42 (1999) 50 54 Transperitoneal 219 142 3 0/50 10%

Winfield et al.43 (1998) 21 52.2 Transperitoneal 219 183 2.7 0/21 1 subcutaneous bleed
2 pneumothorax
1 pulmonary edema

Yoshimura et al.44 (1998) 28 42 11 transperitoneal 375 370 2.7 0/28 4 blood transfusion
17 retroperitoneal 4 subcutaneous emphysema
2 postoperative bleeding

Chee et al.45 (1998) 14 46.2 8 transperitoneal 135 Min 3 0/14 1 pneumonia

6 retroperitoneal

Gagner et al.46 (1997) 100 46 Transperitoneal 123 70 3 3/100 12%, 3 DVT, 2 pulmonary embolus

Gasman et al.29 (1997) 23 49.6 23 retroperitoneal 97 70 3.3 0/23 1 postop hematoma

Terachi et al.47 (1997) 100 — Transperitoneal 240 77 — 3/100 —

Rutherford et al.48 (1996) 67 54 Transperitoneal 124 — 5.1 0/67 3 DVT, 2 pulmonary emboli 1 port
site hernia, 1 postoperative bleed

Average 47.1 153.5 98.6 36/1567 (2.3%)

 Chapter 9 Open and Laparoscopic Surgery of Adrenal Tumors 167
encountered in 12% of patients. The lesions removed
included pheochromocytomas, aldosteronomas, Cushing’s
lesions, and others.
In the largest published series identified in the litera-
ture by Lezoche et al.,31 a total of 216 laparoscopic
adrenalectomies were performed through the anterior
transperitoneal, lateral transperitoneal, and the posterior
retroperitoneal approaches. The study was a combined
experience of surgeons in Italy and The Netherlands.
The average operating time of all approaches was 100
minutes with a conversion rate of only 1.9%. Average
hospital stay for all approaches was 3 to 4 days.
Comparison studies have been made between laparo-
scopic and open adrenalectomy to determine if there are
significant benefits in the laparoscopic approach.43,44,48–54
In general, the operative times for laparoscopic surgery
are longer than for the open technique, particularly early
in the learning curve. However, the operative times
decrease as surgeon experience increases. In addition, the
laparoscopic approach offers less blood loss, significantly
less postoperative narcotic use, overall shorter hospital
stay, and a faster return to normal activity. The cost of a
laparoscopic adrenalectomy was shown to be comparable
to that of an open adrenalectomy in one study.55
Laparoscopic Adrenalectomy for Malignant Tumors
Increased surgeon experience and comfort with laparo-
scopic adrenalectomies has led to performing laparoscopic
adrenalectomies for larger and potentially malignant
tumors. Henry et al.56 performed laparoscopic adrenalec-
tomies on 19 patients with potentially malignant tumors,
all of which were greater than 6 cm in size. Median oper-
ating time was 150 minutes, and conversion was neces-
sary in two patients because of intraoperative evidence of
invasive carcinoma. Six of the 19 patients had an adreno-
cortical carcinoma on pathologic diagnosis. One of these
patients presented with a liver metastasis 6 months after
surgery and died shortly after. The other 5 patients are
alive with a follow-up ranging from 8 to 83 months. The
authors concluded that laparoscopic adrenalectomy for
carcinoma can be performed on select patients in experi-
enced hands; however, conversion to open radical
adrenalectomy should be performed if there is evidence
of local tissue invasion observed during surgery.
Laparoscopic adrenalectomy has also been safely
performed in patients with solitary adrenal metastases.
In a recent series by Heniford et al.,23 laparoscopic
adrenalectomy was performed in 11 patients, 10 of
whom had the adrenalectomy performed for metastatic
disease. Average operative time was 181 minutes, and
blood loss was minimal at 138 cc. One patient required
conversion to an open approach due to local invasion of
the tumor into the lateral wall of the vena cava, which
was removed with the specimen. Ten of the 11 patients
were alive with a mean follow-up of 8.3 months. These
data suggest that the laparoscopic approach to some
malignant neoplasms either originating from or metas-
tasizing to the adrenal gland is reasonable, but the con-
version to an open procedure should be performed if
local invasion is present.
PARTIAL ADRENALECTOMY
Adrenal sparing surgery for benign tumors, particularly
aldosterone producing lesions, has been reported using
both the open and laparoscopic techniques. However, the
indications and techniques are unclear. Nakada et al.57
performed open partial adrenalectomy on 26 patients
with primary hyperaldosteronism and noted no cases of
recurrent disease at 5-year follow-up. Partial adrenalec-
tomy has also been performed for patients with bilateral
pheochromocytomas and the rare patient with the soli-
tary adrenal gland.
Laparoscopic partial adrenalectomy has also been
described. Keschke et al.58 recently reported on 13
patients with primary hyperaldosteronism and a radi-
ographically proven adrenal adenoma who underwent
laparoscopic partial adrenalectomy. Exclusion criteria
included tumors greater than 3 cm in size or centrally
located tumors. Laparoscopic partial adrenalectomy has
been reported for pheochromocytoma59 and may be use-
ful in patients with von Hippel-Lindau disease.
Laparoscopic instruments useful in performing partial
adrenalectomy include harmonic scissors, bipolar coagu-
lating forceps, and intraoperative ultrasound.
Although the indications for open and laparoscopic
partial adrenalectomy are unclear at this time, there are
patients for whom adrenal sparing surgery should be
considered. Possible indications for partial adrenalec-
tomy include patients with solitary adrenal glands,
aldosteronomas less than 3 cm in size, bilateral pheo-
chromocytomas, and patients at risk for multiple adrenal
tumors due to a hereditary syndrome.
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 Chapter 9 Open and Laparoscopic Surgery of Adrenal Tumors 169
44. Yoshimura K, Yoshioka T, Miyake O, et al: Comparison of
clinical outcomes of laparoscopic and conventional open
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48. Rutherford JC, Stowasser M, Tunny TJ, et al:
Laparoscopic adrenalectomy. World J Surg 1996;
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49. Schell SR, Talamimi MA, Udelsman R: Laparoscopic
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morbidity, and cost-effectiveness. Surg Endosc 1999;
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50. Vargas HI, Kavoussi LR, Bartlett DL, et al: Laparoscopic
adrenalectomy: a new standard of care. Urology 1997;
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51. Bolli M, Oertli D, Staub J, et al: Laparoscopic
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52. Hazzan D, Shiloni E, Golijanin D, et al: Laparoscopic vs
open adrenalectomy for benign adrenal neoplasm. Surg
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53. MacGillivray DC, Schichman SJ, Ferrer FA, et al: A
comparison of open vs laparoscopic adrenalectomy. Surg
Endosc 1996; 10:987–990.
54. Miccoli P, Raffaelli M, Berti P, et al: Adrenal surgery
before and after the introduction of laparoscopic
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55. Ortega J, Sala C, Garcia S, et al: Cost-effectiveness of
laparoscopic vs open adrenalectomy: .small savings in an
expensive process. J Laparoendosc Adv Surg Tech A 2002;
12:1–5.
56. Henry JF, Sebag F, Iacobone M, et al: Results
of laparoscopic adrenalectomy for large and
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26:1043–1047.
57. Nakada T, Kubota Y, Sasagawa I, et al: Therapeutic
outcome of primary aldosteronism: adrenalectomy versus
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1995; 153:1775–1780.
58. Jeschke K, Janetschek G, Peschel R, et al: Laparoscopic
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C H A P T E R
10 Diagnosis and Staging of Renal Cell
Carcinoma
Frederick A. Klein, MD, Judson R. Gash, MD,
and W. Bedford Waters, MD
Renal cell carcinoma (RCC) accounted for 3% of all
adult malignancies in 2003. Approximately 31,900 new
cases were diagnosed in 2003 and 11,900 deaths occurred
in the United States.1 Although the overall incidence of
noncutaneous cancers fell by an average of 1.1% annually
in the United States between 1992 and 1998, the inci-
dence of RCC has risen by an average of 3.7% annually
over the same period.1 This increased incidence has been
attributed to the increased use of ultrasonography (US),
computed tomography (CT) scan, and magnetic reso-
nance imaging (MRI) for the evaluation of a variety of
abdominal, back, or gastrointestinal complaints.2 RCC
has been called the “internists tumor” in the past because
of the multitude of constitutional symptoms that patients
presented with.3,4 Now it is called the “radiologist
tumor” because 25% to 40% are detected incidentally
using these radiologic imaging modalities.
INCIDENCE
Incidence rates of RCC and mortality rates of kidney can-
cer have increased steadily over time in the United
States.2,5 Between 1975 and 1995, incidence increased
annually by 2.3% among white men, 3.1% among white
women, 3.9% among black men, and 4.3% among black
women. Since the mid-1980s, the incidence rates among
blacks have exceeded those among whites of both sexes.
Rapid increases in the incidence of kidney cancer also have
been observed in other countries.5–9 Overall, approximately
one-half of the RCCs reported to the U.S. Surveillance,
Epidemiology, and End Results (SEER) program from
1975 to 1995 were diagnosed while localized, with regional
and distant tumors comprising approximately 20% and
25%, respectively. In general, approximately 60% of
patients diagnosed with RCC survive 5 years after diagno-
sis, comparable to the expected survival experience for the
general population. The survival patterns are similar for
men and women. The overall 5-year relative survival rates,
as well as survival rates by tumor stage at diagnosis have
improved substantially over time for whites but not for
blacks. The 5-year relative survival rates for black versus
white men were (75% versus 89%) for localized disease. In
contrast, black women had survival rates similar to white
women. The race and gender differentials in survival pat-
terns argue against early detection of preclinical tumors as
the sole explanation for the increasing trends of RCC.5 A
recent report analyzing population-based statistics from
the SEER registry demonstrates an increase in detection of
all stages of RCC but no change in the rate of advanced or
metastatic disease. The rates of localized, regional, and dis-
tant RCC were 45%, 23%, and 32%, respectively, during
1973–1985 and 54%, 21%, and 25%, respectively, from
1986 to 1998. Plotting incidence rate versus diagnosis by
year and by stage revealed a trend toward increased inci-
dence in all three stages. The three groups had significantly
different rates of incidence increase.10 Even with the
increased use of abdominal imaging, there was no signifi-
cant difference in renal cancer stage at presentation in
1986–1998, compared to 1973–1985. These results imply
that the increased use of abdominal imaging may be detect-
ing some indolent kidney cancers and further suggests that
other factors may be contributing to an overall increase in
the incidence of renal cancer.
ETIOLOGY/RISK FACTORS
The etiology of RCC is not known, although some risk
factors are known. Cigarette smoking has at least a 30%
173
174 Part III Kidney and Ureter
to 50% increase in men and women. The risk has been
shown to decline after smoking cessation. An association
with other tobacco products, including cigars, pipes, and
chewing tobacco, has not been consistently observed.5
Obesity, particularly in women, has a positive association.
Obese persons have experienced elevated risks of 20% to
more than 3-fold. The risks tend to rise with increasing
levels of body mass index. The mechanism by which obe-
sity predisposes to RCC is unclear. Obesity may influ-
ence risk by increasing the levels of endogenous
estrogens5,11 and may increase the bioavailability of free
insulin-like growth factors5,12 that may be involved in
renal carcinogenesis.5,13 Hypertension and the long-term
use of diuretics have been examined. The cumulative evi-
dence suggests that of the two variables, hypertension
itself, rather than diuretics, may have a role in the etiol-
ogy of RCC. The mechanism by which high blood pres-
sure may affect risk is unclear.5
Patients on long-term hemodialysis may develop cys-
tic changes of the kidney with associated carcinoma.
Ishikawa14 reported that 43% of 96 patients who were on
dialysis for less than 3 years developed cystic disease and
79.3% of those who had been on dialysis for more than
3 years also developed cystic disease. Four patients had
adenocarcinoma of the kidney; all 4 were in their 3rd and
4th decade and had been on dialysis for more than 5
years. In the United States, one series reported 17/31
(55%) developed cystic disease on hemodialysis and 3/12
(25%) on peritoneal dialysis. The incidence of develop-
ing cystic disease was 30% for patients on dialysis for less
than 2 years, 33% for 2–4 years, and 67% for those dia-
lyzed longer than 4 years. The calculated incidence
reported for hemodialysis was 0.10% per patient per year
and 0.08% per patient per year on continuous ambula-
tory peritoneal dislysis (CAPD). Solid renal tumors were
found in 3/43 (6.9%) who had nephrectomy. Adult cystic
disease of the kidney is felt to be a consequence of renal
failure or a humoral factor rather than caused by
hemodialysis itself.15 Other studies have shown the rela-
tive risk of RCC in patients with end-stage renal failure
has been estimated to be 5- to 100-fold higher than in the
general population.16–21 Current recommendations are to
screen only patients with a long life expectancy and no
major comorbidities with periodic ultrasound or CT
beginning during the 3rd year on hemodialysis.16
Twenty-seven percent of patients with RCC will have a
diagnosis of at least one other malignancy in their lifetime,
the most common malignancies are breast cancer, prostate
cancer, bladder cancer, and non-Hodgkin’s lymphoma.
CLINICAL PRESENTATION
In those patients presenting with signs or symptoms,
60% have hematuria, 50% have pain, and 30% have a
mass. The classic triad of gross hematuria, flank pain, and
palpable mass is rarely found.22 When this classic triad is
found, there is usually metastatic disease present. Before
the use of US, CT, and MRI most patients presented
with one of these signs or symptoms. Patients often pre-
sented with other signs and symptoms of advanced dis-
ease: weight loss, fever of unknown origin, and night
sweats. Physical findings included palpable mass, nonre-
ducing varicocele, bilateral lower extremity edema, pal-
pable cervical/supraclavicular lymphadenopathy, abdominal
bruit, penile/vaginal nodules, and caput medusa.
Paraneoplastic syndromes are found in approximately
10% to 40% of patients with RCC (Table 10-1) as well as
bizarre metastatic patterns with the disease.5 The presence
of a paraneoplastic syndrome does not imply metastatic dis-
ease. For example, the presence of hepatic dysfunction (i.e.,
Stauffer’s syndrome) is manifested by an elevated alkaline
phosphatase, α2-globulin, a prolonged partial thrombo-
plastin, or hypoalbuminemia. Twenty percent to thirty per-
cent have elevated serum bilirubin or transaminases.3,16
Other common findings include thrombocytopenia and
neutropenia, and typical symptoms include fever and
weight loss.3,16 Hepatic metastases must be excluded.
Biopsy, when indicated, often demonstrates nonspecific
hepatitis associated with a prominent lymphocytic infil-
trate.16,23 Elevated serum levels of IL-6 have been found in
patients with Stauffer’s syndrome, and it is believed that
this and other cytokines may play a pathogenic role.16,24
Table 10-1 Paraneoplastic Syndromes Associated
with Renal Cell Cancer
Syndrome Incidence (%)
Anemia 20–40
Cachexia, fatigue, weight loss 33
Fever 30
Hypertension 24
Hypercalcemia 10–15
Hepatic-dysfunction (Stauffer’s syndrome) 3–6
Amyloidosis 3–5
Erythrocytosis 3-4
Enteropathy 3
Neuromyopathy 3
From Chow W, Devesa SS, Fraumeni JF Jr: Epidemiology of renal
cell carcinoma. In Vogelzang NJ, Scardino PT, Shipley WU,
Coffey DS (eds): Comprehensive Textbook of Genitourinary
Oncology, 2nd edition, pp 101–110. Philadelphia, Lippincott
Williams & Wilkins, 2000.
 Chapter 10 Diagnosis and Staging of Renal Cell Carcinoma 175
Hepatic function normalizes after nephrectomy in 60% to
70% of cases. Persistence or recurrence of hepatic dysfunc-
tion is almost always indicative of the presence of viable
tumor and thus portends a poor prognostic finding.16
These paraneoplastic syndromes may be due to spe-
cific hormone production by the tumor cells or an
immune response to the tumor. Hormones produced by
RCCs include parathyroid-like hormone, gonadotropins,
placentolactogen, adrenocorticotrophic hormone-like
substance, renin, erythropoietin, glucagons, human
chorionic gonadotropin, and insulin.25,26
In general, treatment of paraneoplastic syndromes
associated with RCC has required nephrectomy and/or
systemic immunotherapy, and, except for hypercalcemia,
medical therapies have not proven helpful.16
SERUM MARKERS
Serum ferritin,27 erythropoietin,28 calcium,25 and renin3
levels have been shown historically to be significantly
elevated and higher than controls in patients with
RCC.29 Hematocrit and platelet levels can also prove
credible in regards to prognosis and recurrence. Symbas
et al.30 report a mean difference in survival of 59 months
with pathologic stage IV RCC and a normal platelet
count versus those with thrombocytosis (>400,000) when
controlling for pathologic stage, nuclear grade, and cell
type.29,30,31 Anemia and serum iron have also been useful
as tumor markers for initial evaluation and follow-up.29,32
Normochromic and normocytic anemia and anemia of
chronic diseases are the most common hematologic
abnormalities associated with RCC.29
MOLECULAR MAKERS
The search for better markers has increasingly moved
toward the molecular level. The prognosis for patients
with locally confined RCC is known to be variable and
emphasis on morphologic character, proteins, antigens
and other prognostic markers is being sought to aid in
the diagnosis and prognosis of RCC.29 Molecular mark-
ers of proliferation like Ki-67, silver staining nucleolar
organizer regions (AgNOR), and proliferating cell
nuclear antigen (PCNA) are present in cycling cells and
therefore have potential utility in estimating the biologic
aggressiveness of a given tumor. AgNOR reflect tran-
scription activity of ribosomal RNA and cellular mitotic
activity. For some authors the AgNOR score is an inde-
pendent prognostic factor associated with survival,33–35
whereas for others it is associated with histologic grade
but is not an independent factor.36 PCNA is a protein
synthesized during the late G1 and S phases of the cell
cycle. For some authors a low PCNA index (less than
10%) is an independent positive predictor of disease-free
survival but not of overall survival,37 whereas for others it
is associated with good survival.35,38,39 Ki-67 identifies an
antigen of 395 kDa whose expression is detectable during
the G1 phase, increases during S phase and rapidly
decreases after mitosis. There is an agreement that Ki-67
is an excellent maker of proliferation in histologic mate-
rial analyzed immunohistochemically. According to the
result of several studies, the Ki-67 index is correlated
with the histologic grade and stage,35,36,37 and might be a
more powerful prognostic factor than the PCNA index.
Rini and Vogelzang39 concluded that because Ki-67 is
present in cells during all cell cycle phases, it provides a
more accurate determination of the proliferation rate
than the PCNA index but more multivariate studies are
needed.29,35,39,40
Cell adhesion molecules and angiogenesis factors have
also been evaluated. Cadherins are a large family of trans-
membrane proteins responsible for mediating cell-to-cell
adhesion, and when expression decreases, their inherent
ability to modulate and preserve epithelial integrity
diminishes. Lack of E-cadherin expression correlates
with aggressiveness in several tumors, but in RCC, only
20% express this glycoprotein.41 E-cadherin is localized
to Bowman’s capsule and other tubular segments rather
than the proximal tubular epithelium, calling into ques-
tion whether it plays an integral role in RCC carcino-
genesis.29 Shimazui42 has shown that cadherin-6 is the
major one in the proximal renal tubules and the tumors
themselves. His group found that aberrant expression of
cahderin-6 connoted poor survival.29,42,43 Paul et al.44
have reproduced these data wherein the majority of
RCCs with histology-associated poor prognosis (i.e.,
high-grade clear cell cancers and sarcomatoid renal
tumors) showed aberrant expression. The tumor with a
historically good prognosis (low-grade clear cell carcino-
mas and papillary cancers) exhibited normal cadherin-6
expression.29,44
Studies investigating the role of angiogenesis, using
microvessel density (MVD) as a marker, as a correlate
with the development of metastases have not been
rewarding. There was no correlation to clinical stage,
pathologic stage, or tumor grade.29,45 RCC is a vascular
tumor, and its direct relationship to angiogenesis has yet
to be completely determined.29
The p53 protein has also been studied in RCC. The
p53 protein binds DNA and is believed to regulate tran-
scription, acting as a “checkpoint” to induce cell cycle
arrest.29,46 This tumor suppressor gene, when mutated,
inactivates the normal function of DNA damage surveil-
lance. Aneuploid cells originate, carcinogenesis occurs,
and tumor progression can ensue.47 Mutant p53 proteins
have a prolonged half-life and with accumulation are
detectable with immunohistochemical analysis.48
However, controversy exists with regards to the
frequency of the mutation in RCC, ranging from 4% to
40% of RCC specimens tested, and its resultant
176 Part III Kidney and Ureter
prognostic power. The clinical significance of p53 and
other apoptotic markers has yet to be determined.29,49,50
Carbonic anhydrase IX (CAIX) protein, a member of
the carbonic anhydrase family, is thought to play a role in
the regulation of cell proliferation in response to hypoxic
conditions and may be involved in oncogenesis and
tumor progression.51–54. Constitutive expression of
CAIX as a result of von Hippel-Lindau (VHL) protein
mutations has been described for RCC.55 Recent studies
now indicate that expression of CAIX is regulated by the
hypoxia-inducible factor (HIF) 1 transcriptional complex
that mediates expression of a number of genes in
response to hypoxic conditions.56 It has been postulated
that cell surface carbonic anhydrase regulate acid-base
balance to optimize conditions in the tumor invasive-
ness.54 Acidification of the extracellular matrix is known
to induce expression of angiogenic factors57 and may
inhibit cellular immunity,58 which additionally promotes
tumor aggressiveness. In addition, there is some evidence
for the association of CAIX with loss of contact inhibi-
tion and anchorage dependence of cancer cells.59 Bui
et al.51 have investigated CAIX as kidney cancer marker
as an independent predictor of progression and survival.
Immunohistochemical analysis using a CAIX mono-
clonal assay was performed on tissue microassays con-
structed from paraffin-embedded specimens from 321
patients treated by nephrectomy for clear cell RCC.
CAIX staining was correlated with response to treatment,
clinical factors, pathologic features, and survival. CAIX
staining was present in 94% of clear cell RCCs. Survival
tree analysis determined that a cutoff of 85% CAIX
staining provided the most accurate prediction of sur-
vival. Low CAIX (≥85%) staining was an independent
poor prognostic factor for survival for patients with
metastatic RCC, with a hazard ratio of 3.10 ( p < 0.001).
CAIX significantly substratified patients with metastatic
disease when analyzed by T stage, Fuhrman grade, nodal
involvement, and performance status ( p < 0.001, p = 0.001,
p = 0.009, p = 0.005, respectively). For patients with
nonmetastatic RCC and at high risk for progression,
low CAIX predicted a worse outcome similar to patients
with metastatic disease ( p = 0.058). CAIX status may
potentially aid in the selection of patients who might
benefit from IL-2 or CAIX-targeted therapies.
Furthermore, patients with high-risk localized RCC and
low CAIX may be potential candidates for adjuvant
immunotherapy.51
MOLECULAR GENETICS
To date, four major dominantly inherited forms of RCC
have been described. RCC occurs in association with VHL
disease. About 45% of patients with VHL disease have
RCC, which is metastatic in half of the cases at diagnosis,
often bilateral and multifocal, occurs in younger patients,
and has an equal male to female ratio. Tumors associated
with VHL are predominantly of the clear cell type and are
associated with germline mutations of the tumor suppres-
sor gene, VHL gene, located on chromosome 3p. After
extensive work, the VHL gene has been mapped to the
3p25–26 region and VHL inactivation by point mutation
and allelic loss has been reported to occur in both sporadic
and VHL-associated RCC. Specific sites or types of muta-
tions within the VHL gene appear to correlate with spe-
cific phenotypic expression of the gene: VHL type I (VHL
without pheochromocytomas) and VHL type II (VHL
with pheochromocytomas). VHL disease is characterized
by renal cysts, RCC (clear cell histology), retinal heman-
giomas, hemangioblastomas of the cerebellum and spinal
cord, pancreatic carcinomas and cysts, epididymal cysts
and cystadenomas, and pheochromocytomas.60–68
The VHL gene product forms a complex that degrades
two α subunits of HIF, an intracellular protein that plays
an important role in regulating cellular responses to
hypoxia, starvation, and other stresses.16,69 The HIFα sub-
units are transcription factors that regulate the expression
of a number of proteins, including vascular endothelial
growth factor (VEGF), the primary proangiogenic growth
factor in RCC, contributing to the pronounced neovascu-
larity associated with RCC,16,63,70 glucose transporter
(GLUT-1), and transforming growth factor (TGF)-α.
Hereditary papillary renal carcinoma (HPRC) is a
hereditary cancer syndrome, which generally develops in
older patients (50s and 60s). The affected individuals are
at risk to develop bilateral, multifocal papillary RCC.
Linkage analysis of the families led to the discovery of the
HPRC gene on chromosome 7.71–73 This syndrome,
which has an autosomal dominant inheritance pattern, is
caused by missense mutations in the tyrosine kinase
domain of the MET proto-oncogene at 7q31.73 Patients
with germline or somatic mutations in the MET proto-
oncogene develop a specific subtype of papillary renal
carcinoma—papillary renal carcinoma type 1. In vitro
and in vivo studies suggest that MET functions as a dom-
inantly acting oncogene in HPRC and in sporadic papil-
lary renal carcinoma.74
Patients with hereditary hair follicle tumors (fibrofol-
liculomas) on their face and neck have a high risk for
developing kidney cancer (20% to 30%), lung cysts
(90%), and pneumothorax (20%). Inherited fibrofollicu-
loma is called Birt-Hogg-Dubé syndrome (BHD). The
BHD gene has been localized to the short arm of chro-
mosome 17. BHD patients are at risk for the develop-
ment of chromophobe RCC, oncocytic renal carcinoma,
and oncocytoma.75–78
Familial renal oncocytoma is an entity currently
undergoing evaluation and definition, in which multiple
bilateral renal oncocytomas develop in affected family
members. The genetic defect involved in the pathogene-
sis of familial renal oncocytoma has not yet been identi-
 Chapter 10 Diagnosis and Staging of Renal Cell Carcinoma 177
fied. However, clues to the location of this gene have
come from cytogenetic studies: one characterized by the
loss of chromosomes 1 and Y,79 and the other by translo-
cations involving the breakpoint region 11q13.68,80–82
The untreated natural history of familial renal oncocy-
toma is currently being studied.83
Hereditary leiomyomatosis renal carcinoma (HLRC)
is another type of hereditary renal carcinoma. Affected
HLRC individuals are at risk for the development of
cutaneous leiomyomas, uterine leiomyomas (fibroids),
and renal carcinoma. The HLRC renal tumors are of
varying histologic type, but the predominate histologic
phenotype is type 2 papillary renal carcinoma.84
PATHOLOGY
RCCs originate from renal tubular cells. Renal cancer
has an equal frequency on the right and left and is dis-
tributed equally throughout the kidney. Fifteen percent
of tumors extend to the renal vein, and 8% extend to the
vena cava. The histologic classification of RCC has
undergone a major revision since 1990. Traditionally,
renal cancers have been classified as clear cell, granular,
sarcomatoid, and papillary types. Malignant renal epithe-
lial neoplasms are now subdivided under the new classifi-
cation system (Table 10-2) based on prominent
morphologic features.85 Major changes include the addi-
tion of a new histologic subtype, the chromophobe cell
carcinoma; the reclassification of granular cell tumors
into other categories; and the recognition that sarcoma-
toid lesions represent poorly differentiated elements
derived from other histologic subtypes, rather than a dis-
tinct tumor type.16,85–87 Common or conventional RCC
accounts for approximately 70% to 80% of all RCCs.
They are highly vascular and are typically yellow when
Table 10-2 Classification of Renal Cell Carcinoma
Incidence Affected
Subtype (%) Chromosomes
Conventional 70–80 3p, 17
Papillary 10–15 3q, 7, 12, 16, 17, 20, Y
Chromophobe 4–5 1, 2, 6, 10, 13, 17, 21
Collecting duct <1 1q, 6p, 8p, 13q, 21q
Medullary cell <1 Not defined
Oncocytoma 3–7 1, Y
From Störkel S, Ebie JN, Adlakha K, et al: Classification of renal cell
carcinoma: Workgroup no. 1, Union Internationale Contre le Cancer
(UICC) and the American Joint Committee on Cancer (AJCC).
Cancer 1997; 80:987–989.
bivalved. Microscopically they can include clear cell, gran-
ular cell, or mixed types.16 The loss of loci on the short
arm of chromosome 3 has been the predominant mutation
linked to clear cell carcinoma, the most common subtype
of RCC.66,88 Allelic loss of 3p is now thought to be an early
event in the pathogenesis of clear cell carcinoma, whereas
others now consider additional allelic losses on chromo-
some 17 to be associated with advanced disease.89
Papillary RCC represents 10% to 15% of all RCCs.
They can be inherited, multifocal, bilateral, and gener-
ally portend a more favorable prognosis. The cytogenetic
features are associated with loss of Y chromosome along
with trisomies of chromosomes 3q, 7, 12, 16, 17, and
20.85 Papillary RCC is more likely to be hypovascular,
perhaps owing to lack of VHL mutations, which regulate
VEGF, the primary proangiogenic molecule in RCC.16
The other genetic features of papillary RCC have been
discussed earlier.
Chromophobe cell carcinoma accounts for approxi-
mately 5% of all RCCs. It appears to be derived from the
cortical portion of the collecting duct. Histologically,
they are composed of two distinct cell types, those with
granular eosinophilic cytoplasm and those with pale
cytoplasm. Ultrastructural analysis shows numerous
cytoplasmic microvesicles, and characteristic cytoplasm
staining with Hale’s colloidal iron is typical.89,90 The clin-
ical behavior of patients with chromophobe carcinoma
shows that the majority of tumors appear to be localized
to the kidney at the time of diagnosis. Although some
may be large, clinical behavior seems to be similar to
respective stages of clear cell carcinoma.90,91 However,
Renshaw and colleagues92 reported a more adverse prog-
nosis associated with chromophobe RCC. In their series,
high-grade disease was common, and 7 of 25 patients
eventually developed metastatic disease.16,92
Collecting duct, or Bellini’s duct, carcinomas repre-
sent a rare group of renal neoplasms. They arise from the
distal portion of the nephron, commonly strike in a
young population, and carry a usually poor prognosis.
They are usually high grade, present at an advanced
stage, and do not respond to conventional therapy. There
is a frequent loss of heterozygosity at chromosome
regions on 1q, 6p, 8p, 13q, and 21q.93 High density map-
ping of arm 1q in 13 collecting tumors shows an area of
minimal deletion around the area located at 1q32.1–32.2
in 69% of examined specimens.94
Renal medullary carcinoma is a relatively new histo-
logic subtype of RCC that occurs almost exclusively in
association with the sickle cell trait. It is typically diag-
nosed in young African Americans often in the third
decade of life.16,95 Many cases are both locally advanced
and metastatic at the time of diagnosis. Most patients do
not respond to therapy and succumb to their disease
within several months.16,95 Histologically, this tumor
shares many features with collecting duct carcinoma.
178 Part III Kidney and Ureter
The site of origin (renal papillae) and association with
sickle cell trait suggest that a relatively hypoxic environ-
ment may contribute to tumorigenesis.16
RCC, unclassified, is a category reserved for malig-
nant epithelial tumors that do not conform to any of the
other subtypes. Of the total group of RCCs, they com-
prise approximately 4% to 5%.85,89 Specifically, compos-
ites of recognized subtypes, tumors with mucin
production, and tumors with extensive sarcomatoid
changes without recognizable epithelial elements are
examples of this classification.89
Imaging Evaluation
RCC may be radiologically discovered in one of two
ways. It may be diagnosed in patients with symptoms,
such as hematuria or pain or, alternatively, it may be
found incidentally in patients undergoing imaging stud-
ies for other reasons. With the increasing utilization of
cross-sectional modalities, such as CT and US, the
majority of renal cell cancers are now discovered
serendipitously.96 Once identified, renal masses usually
require further characterization. Although imaging does
not allow a histologic diagnosis, radiologic studies are
critical to exclude benign entities, such as cysts, abscesses,
and pseudomasses. Also, an attempt should be made to
eliminate certain neoplastic conditions, such as angiomy-
olipomas, metastases, and lymphoma. Finally, imaging is
indispensable in the staging of RCC. Many radiologic
techniques are available for the detection, characteriza-
tion, and staging of renal cell cancer, including intra-
venous urography, US, CT, MRI, nuclear medicine, and
positron emission tomography (PET) imaging. Invasive
angiography, once a bastion of renal evaluation, now
plays little role in the diagnostic evaluation of RCC.
Detection and Characterization
Intravenous Urography
For over five decades the intravenous pyelogram (IVP)
has been the workhorse of imaging the urinary tract and
detecting renal neoplasms. However, its limitations,
including lack of sensitivity and specificity for renal
masses, have been well known. Many renal masses may
not be identifiable on the IVP, including those that are
small, those that do not distort the collecting system, and
those that do not create a bulge to the renal contour
(intrasubstance lesions and lesions that are anteriorly or
posteriorly oriented). Scrupulous technique, including
nephrotomography, oblique views, and bowel prep, does
improve sensitivity yet 15% of lesions greater than 3 cm
will be missed and the insensitivity rises dramatically for
smaller lesions with between 48% of masses of 2–3 cm
and 79% of masses of 1–2 cm will not be visible.97 Most
RCCs appear as a mass lesion on the IVP, creating a
rounded bulge to the renal contour or displacing the col-
lecting system (Figure 10-1). Calcifications, although
observed in only about 10% of RCCs on the IVP, suggest
neoplasm, especially when they are chunky and centrally
located within the mass.98 Unlike cysts, which should not
enhance and therefore appear lucent, a mass with density
approaching that of surrounding renal parenchyma sug-
gests enhancement and is worrisome for neoplasm.
Uncommonly, RCC may present as diffuse enlargement
of the kidney when the tumor is large or infiltrating.
Diffuse replacement of the renal parenchyma or venous
invasion may result in lack of normal renal function and
nonvisualization on the IVP. Despite even the most
suggestive findings, virtually all parenchymal masses
identified on the IVP are nonspecific and thus require
further evaluation. Since more than 80% of suspected
renal masses on excretory urography are simple cysts or
pseudomasses, ultrasound should be performed in most
cases as the diagnosis of a cyst can usually be made with
ultrasound and the workup terminated.99 However, if
the mass has an appearance suggestive of a solid lesion,
such as calcification or increased density, then a dedi-
cated renal CT is an appropriate next test for further
evaluation.
Ultrasonography
The ease of use, safety and wide availability of ultrasound
make this an excellent and widely utilized modality for
evaluation of the abdomen and pelvis, including the uri-
nary tract. Perhaps as many as 50% of all diagnosed
RCCs, therefore, are initially detected during an ultra-
sound examination100 Ultrasound is sensitive for the
detection of renal masses, including RCC with sensitivity
Figure 10-1 4-cm RCC arising from the lower pole of the left
kidney.
 Chapter 10 Diagnosis and Staging of Renal Cell Carcinoma 179
approaching 100% for lesions larger than 2.5 cm,
although there is diminishing sensitivity for smaller
lesions.101 Tumors may be missed when they are isoechoic
to renal parenchyma, small, or when the examination is
technically difficult, such as with large patients; however,
new technologies, including harmonic imaging, have
resulted in dramatic improvements in image quality and
should result in increased sensitivity even in these set-
tings. Most RCCs at ultrasound appear as solid lesions
(Figure 10-2). Earlier ultrasound reports suggested that
most RCCs were hypoechoic; however, these were often
large lesions at an advanced stage. Although RCC may
have variable echogenicity, the majority of currently
identified and smaller RCCs are in fact hyperechoic,
sometimes markedly so, and may then be confused with
angiomyolipomas.102 Several features have been assessed
to try and distinguish RCC from the classically hypere-
choic angiomyolipoma.103 A very hyperechoic lesion sim-
ilar to renal sinus fat along with posterior shadowing
favors the diagnosis of an acute myelogenous leukemia
(AML) while a hypoechoic halo with small intratumoral
cystic components suggests RCC.104 Unfortunately,
there is too great an overlap of findings to allow a confi-
dent diagnosis and it is necessary to confirm the diagno-
sis of angiomyolipoma with CT. Along with echogenicity
that is variable but often increased, RCCs often have ill-
defined or irregular interfaces with normal renal
parenchyma and are frequently lobulated. Although
Doppler waveform and color analysis have been analyzed
with some success in differentiating renal masses at ultra-
sound, solid renal lesions remain nonspecific.105 True
solid masses, however, must be differentiated from
pseudomasses and normal variants. A prominent column
of Bertin, renal hypertrophy adjacent to an area of scar,
and fetal lobation can mimic a renal mass, although their
Figure 10-2 US demonstrating a 1.5-cm slightly hyperechoic
renal cell carcinoma arising from the mid-pole of the right
kidney.
normal echotexture and vascularity on color or power
Doppler often allow a confident diagnosis. It is uncom-
mon for RCC to appear predominately cystic on ultra-
sound. Most of these show thick septations or chunky
calcifications and are not confused with benign lesions.
Indeterminate cystic lesions should generally be evalu-
ated with dedicated renal CT as occasionally benign
lesions seen at CT may have a more malignant appear-
ance on US. Septae may be exaggerated and appear more
ominous and intervening normal renal tissue may look
like tumor. Conversely, ultrasound may clarify indeter-
minate lesions seen at CT, including the hyperdense cyst
and “too small to characterize” lesions. Hyperdense cysts
seen at CT may appear entirely anechoic at ultrasound
confirming its benign nature.106 Similarly, “too small to
characterize” lesions on CT can be shown to be simple
cysts in some circumstances, although the need to con-
firm these lesions with ultrasound or follow these is
highly debatable.107 Despite the dramatic improvement
in image quality, the role of ultrasound remains essen-
tially the same in the evaluation and characterization of
the renal mass. The study is useful for excluding moder-
ate to larger tumors as well as identifying and distin-
guishing the simple cyst from the solid mass; however,
the solid lesion remains nonspecific and requires further
evaluation, typically with CT.
Computed Tomography
It is safe to say that the CT now forms the backbone of
radiologic evaluation of the urinary tract, including the
renal mass. The advent of multidetector spiral CT
(MDCT) has further propelled CT to the forefront of
urologic imaging including near isotropic imaging with
scan thicknesses less than 1 mm and subsecond scanning
speeds allowing imaging of the kidneys in multiple
phases. This high spatial and temporal resolution com-
bined with quantifiable density values (Hounsfield units,
HU) and high contrast resolution makes CT excellent
for RCC detection and characterization. Finally, the wide
availability and relative safety of CT cinch its appeal. To
take full advantage of the strengths of CT, however, scan-
ning technique is critical. Virtually, all scans obtained for
renal indications should include noncontrast scans of the
kidneys. These scans can help to identify calcifications and
hemorrhage but are most important as a baseline to
assess lesion enhancement, a critical component to diag-
nosing malignancy. Four phases of enhancement may be
evaluated with CT, including arterial phase, corti-
comedullary phase, nephrographic phase, and excretory
phase. The nephrographic phase, occurring at approxi-
mately 90 seconds after contrast administration and
when there is uniform cortical and medullary enhance-
ment, is the most critical in mass detection and charac-
terization and should be included in all renal CT
180 Part III Kidney and Ureter
studies.108,109 Corticomedullary phase, seen between 30
and 90 seconds, when there is predominant cortical
enhancement but little contrast in the medulla, can be
occasionally valuable for detecting hyperenhancing
lesions and tumors in end stage renal disease, but may
miss centrally located masses and may underestimate
lesion enhancement.108 Excretory phase images obtained
after 3–5 minutes may be useful for evaluating the col-
lecting system for invasion or urothelial lesions. Arterial
phase scans are used for CT angiography studies to aid
surgical planning, especially when nephron sparring
surgery is contemplated. Finally, delayed images may be
used to assess lesion de-enhancement, suggesting
enhancement and vascularity in “reverse,” when noncon-
trast images have not been obtained.110
Detection of RCC is accomplished with high sensitiv-
ity by a combination of an up-to-date helical scanner,
scrupulous technique, and a careful, educated review of
the images. Sensitivities of 95% for 8–15 mm lesions and
essentially 100% for larger lesions are obtainable using
helical technique and nephrographic phase images108
(Figure 10-3). Once identified, an attempt should be
made to further characterize the mass and identify
pseudomasses and normal variants, inflammatory lesions,
benign tumors, and systemic or urothelial neoplasms.
Focal renal hypertrophy, dromedary humps, and fetal
lobulation may suggest a solid renal mass on noncontrast
images; however, they are easily recognized on multipha-
sic images where their enhancement and homogeneity
matches normal renal parenchyma on all sequences.
Occasionally, acute infarcts or focal infection may mimic
a mass but their infiltrating appearance and the clinical
history usually allow a confident diagnosis. Urothelial
neoplasms, typically transitional cell carcinoma, account
for about 10% of renal malignancy and should be differ-
entiated from RCC due to their distinct surgical thera-
Figure 10-3 Incidentally detected 1-cm RCC arising from the
right kidney.
pies. Urothelial neoplasms that invade the kidney tend to
have an infiltrating growth pattern rather than the expan-
sile rounded enlargement, typical of RCC.111
Additionally, the epicenter of the mass should be in the
renal pelvis. Retrograde pyelography, endoscopic biopsy,
and urine cytology may be used to confirm the diagnosis.
Secondary and systemic neoplastic involvement of the
kidney can be seen with lymphoma and metastatic dis-
ease. Similar to urothelial lesions, these entities tend to
have an infiltrative growth pattern maintaining the reni-
form shape of the kidneys.112 Also, these lesions are often
multiple, bilateral and there is usually evidence of disease
elsewhere. Renal medullary carcinomas, first described in
1995 and seen in African-American males with sickle cell
trait, along with collecting duct carcinomas also show an
infiltrating growth pattern, arise centrally in the
medullary region and are often large and heterogeneous
at presentation.112 Benign neoplasms account for 10% to
15% of renal tumors and are of increasing frequency with
the now common incidental detection of smaller
lesions.113 The presence of unequivocal fat (<10 HU)
within a mass generally allows a confident diagnosis of a
benign angiomyolipoma, with a few caveats. RCC can
engulf renal sinus or perinephric fat and mimic an
angiomyolipoma. Additionally, there have been a few
case reports of adipose tissue within RCCs, although
most of these also contained calcifications, which is dis-
tinctly rare in angiomyolipomas.114 Conversely, a small
percentage, about 10%, of AMLs do not contain
detectable fat and are indistinguishable from RCCs115
(Figure 10-4). Oncocytoma is the most common benign
neoplasm and is being detected with increasing fre-
Figure 10-4 CT demonstrating a 6-cm necrotic RCC of the
right kidney in a patient who also has a single 2-cm fat-
containing AML in the left kidney.
 Chapter 10 Diagnosis and Staging of Renal Cell Carcinoma 181
Figure 10-5 Large right RCC mimicking an oncocytoma.
quency.116 When large, a central scar within an otherwise
homogeneous mass may suggest the diagnosis, although
overlapping imaging findings do not allow a radiograph-
ically confident distinction from RCC and resection is
generally necessary for histologic confirmation (Figure
10-5). Smaller oncocytomas have imaging findings indis-
tinguishable from RCC. The appearance of RCC on CT
is somewhat variable depending on size, vascularity,
degree of necrosis, hemorrhage, and to some extent cell
type. Larger lesions tend to commonly have greater het-
erogeneity with necrosis and hemorrhage, whereas
smaller lesions tend to be much more homogeneous.
Vascularity and enhancement is a key feature of RCC. A
minimum of 10 to 15-HU increase in attenuation is seen
compared with baseline density, although many show
much greater enhancement117 (Figure 10-6A and B).
Chromophobe and papillary subtypes tend to be more
hypovascular, whereas the more common conventional
or clear cell types often show marked enhancement after
contrast.118 Calcification is not uncommon in RCC,
especially in papillary and chromophobe subtypes.23
Most renal cell cancers are rounded and expansile
although a small percentage may be infiltrating, mimick-
ing other infiltrating malignancies. Additionally, RCC
may present as a cystic lesion and the evaluation of the
complex renal cyst is a fairly common diagnostic problem
for the urologist and radiologist (Figure 10-7). In 1986,
Bosniak proposed a classification scheme for cystic renal
masses.119 Criteria are shown in Table 10-3.120 Lesions
meeting criteria for simple cysts and obviously malignant
cystic masses, Bosniak categories I and IV lesions, respec-
tively, are rarely problematic. Bosniak II and III lesions
Figure 10-6 Noncontrast CT (A) demonstrating a
homogeneous hyperdense lesion within the upper pole of the
left kidney mimicking a hyperdense cyst; however, after
contrast (B) there was a 45-HU increase in lesion density
typical of a RCC.
require more discussion. Bosniak II lesions are minimally
complicated with thin nonenhancing septations or thin,
linear calcifications, whereas Bosniak III lesions are more
concerning and complex with thicker septations, walls, or
calcifications. Bosniak II lesions are very likely benign
while the incidence of malignancy for class III lesions
may approach 50%, generally necessitating surgical
resection. There have, however, been problems noted
with this classification scheme. Some studies have shown
an unacceptable frequency of malignancy in lesions clas-
sified as category II.121 In 1993, Bosniak added an IIF
category for lesions slightly more complex and worri-
some than typical class II cysts. These IIF lesions are usu-
ally closely followed (thus the “F”) rather than ignored or
excised. One additional problem with the Bosniak
scheme has been interobserver variability between class
II and class III lesions. In one study, 60 of 227 lesions
182 Part III Kidney and Ureter

originally classified as class IIF or III lesions were reclas-
sified when reviewed by a different radiologist.122
Despite its difficulties, however, the Bosniak classifica-
tion of cystic renal masses remains a very useful frame-
work for these difficult lesions, allowing evidenced-based
therapy and further study.
The trend of increasing incidence and improved sur-
vival rate in RCC are related to several factors, perhaps
none more important than advances in computed tomog-
raphy, which is the standard imaging technique for eval-
uation of RCC and the solid and complex cystic renal
mass.113
Magnetic Resonance Imaging
Just as technical advances have improved US and CT in
recent years, MRI has made great strides with a primary
advance being the development of fast scanning
sequences which allow breath-hold imaging and conse-
quent motion artifact reduction, improved spatial resolu-
tion, and increased temporal resolution, including
multiphasic renal evaluation similar to CT. This com-
bined with its spectacular contrast resolution and multi-
planar capabilities strengthen the role of MRI in renal
mass evaluation and depiction as well as staging. High
cost, relative lack of availability, and experience have so
far limited its utility. The primary role for MRI has been
when CT is contraindicated (renal insufficiency, contrast
allergy), when CT is indeterminate or, in some settings,
for staging. MRI is extremely sensitive to detecting
enhancement and may therefore be especially useful in
certain settings, such as small lesions, complex cysts, and
hypovascular neoplasms. Imaging protocols should
include T1 and T2 weighted, preferably breath-held,
images along with gadolinium-enhanced sequences. The
sensitivity of MRI for detecting renal masses is similar to
CT, or perhaps slightly improved for polar lesions due to
the ability to obtain direct coronal images.123 Like CT,
the appearance of RCC on MRI is variable depending on
various factors. Typically, the lesions are isointense to
hypointense on T1 sequences, moderately hyperintense
on T2, show enhancement after gadolinium, and demon-
strate variable degrees of hemorrhage and necrosis
(Figure 10-8). MRI, as yet, offers no significant advan-
tage compared with CT for lesion characterization with
interpretative principles as described in the CT section.
In fact, objective assessment of enhancement is more
complex and arbitrary compared to CT.124 For now, MRI
remains a problem solver, however, the unceasing tech-
nologic advances sure to come, such as in MR spec-
troscopy, may propel this modality to the forefront of
renal mass imaging.

Nuclear Medicine and PET imaging

Figure 10-7 Cystic RCC arising from the lower pole of the
Traditional nuclear medicine techniques, such as
left kidney.
renograms and renal scans, play little role in the detec-

Table 10-3 Bosniak Criteria Cystic Renal Masses

Criteria I II III IV

Wall Thin Thin More than thin Thick or nodular

Calcifications None Few, thin Irregular Coarse

Septations None Few, thin More than a few Thick, numerous

Density (HU) 0–20 0–20 0–20 More than 20

Enhancement None None None Present

From Kausik S, Segura JW, King BF Jr: Classification and management of simple and complex renal cysts.
AUA Update Ser 2002; 21:82–87.
 Chapter 10 Diagnosis and Staging of Renal Cell Carcinoma 183
Figure 10-8 Axial T2 weighted MRI reveals a large
heterogeneous RCC.
tion and evaluation of renal masses. The occasional prob-
lematic pseudotumor may be confidently diagnosed as
normal renal tissue with a renal scan although CT usu-
ally has little difficulty with this situation. PET scanning
is limited in the evaluation of primary kidney lesions by
the high intrinsic renal uptake of 18-fluoro-2-deoxyglucose
(FDG), but early work has shown some promise in
lesion characterization, especially in evaluating complex
cysts where FDG uptake may be able to differentiate
benign from malignant lesions.125 In another study, PET
was 94% accurate in assessing suspicious renal masses
identified on another imaging modality, although there
was an inexplicable false negative in a patient with a 6-cm
RCC.126
Renal Cell Carcinoma—Staging
The most commonly used staging system for RCC prior
to the 1990s was that proposed by Holland in accordance
with the classification system developed by Robson,
Murphy, Flocks, and Kadesky (Figure 10-9).127 The lim-
itations of this classification scheme have been well
defined and evidenced by the grouping in stage III that
lumps lymphatic metastases (a very poor prognostic find-
ing) with venous involvement that, even though may be
extensive, can be treated with aggressive surgery and
portend a good long-term outcome. Likewise, since the
extent of nodal and venous involvement was not delin-
eated in this system, the prognostic significance of these
pathologic findings were lost.
The tumor, nodes, and metastasis (TNM) system pro-
posed by the International Union Against Cancer and
Figure 10-9 Robson classification for the staging of RCC.
modified by Hermanek and Schrott128 in 1990 repre-
sented a major improvement because it both separated
lymphatic from venous involvement and quantified the
extent of involvement of each system. After this system
was popularized, there was easy global comparison of
clinical and pathologic data that were found to correlate
well with patient outcomes.
In 1997, the International Union Against Cancer and
the American Joint Committee on Cancer proposed a
change in the TNM system that was widely adopted until
the most recently adopted TNM system in 2002 (Table
10-4).129 Division between T1 and T2 tumors was origi-
nally 2.5 cm and was changed to 7 cm because it reflected
the mean tumor size in a database where no prognostic
significance or survival differences could be shown
between cut points at 5, 7.5, and 10 cm.130 In 2002, the
widely acceptable modification was dividing stage T1 into
T1a representing tumor size of 4 cm or less and T1b rep-
resenting tumor size between 4 and 7 cm. The rationale
for this division is that tumors of 4 cm or less, unilateral
and capsular confined, have excellent outcomes and T1a
tumors are very amenable to nephron sparing procedures
184 Part III Kidney and Ureter

Table 10-4 Definition of TNM

Primary tumor (T) TX Primary tumor cannot be assessed

T0 No evidence of primary tumor

T1 Tumor 7 cm or less in greatest dimension, limited to the kidney

T1a Tumor 4 cm or less in greatest dimension, limited to the kidney

T1b Tumor more than 4 cm but not more than 7 cm in greatest dimension, limited to the
kidney

T2 Tumor more than 7 cm in greatest dimension, limited to the kidney

T3 Tumor extends into major veins or invades adrenal gland or perinephric tissues but not
beyond Gerota’s fascia

T3a Tumor directly invades adrenal gland or perirenal and/or renal sinus fat but not beyond
Gerota’s fascia

T3b Tumor grossly extends into the renal vein or its segmental (muscle-containing) branches,
or vena cava below the diaphragm

T3c Tumor grossly extends into vena cava above diaphragm or invades the wall of the vena cava

T4 Tumor invades beyond Gerota’s fascia

Regional lymph nodes (N)* NX Regional lymph nodes cannot be assessed

N0 No regional lymph node metastases

N1 Metastases in a single regional lymph node

N2 Metastasis in more than one regional lymph node

Distant metastasis (M) MX Distant metastasis cannot be assessed

M0 No distant metastasis

M1 Distant metastasis
Stage grouping

Stage I T1 N0 M0

Stage II T2 N0 M0

Stage III T1 N1 M0

T2 N1 M0

T3 N0 M0

T3 N1 M0

T3a N0 M0

T3a N1 M0

T3b N0 M0

T3b N1 M0

T3c N0 M0

T3c N1 M0
 Chapter 10 Diagnosis and Staging of Renal Cell Carcinoma 185

Table 10-4 Definition of TNM—cont’d

Stage 4 T4 N0 M0

T4 N1 M0

Any T N2 M0

Any T Any N M1

Histopathologic type

The predominant cancer is adenocarcinoma; subtypes are clear cell and granular cell carcinoma. The use of the following
grading system is recommended when feasible. Sarcomas and adenomas are not included. The histopathologic types are:

Conventional (clear cell) renal carcinoma

Papillary RCC
Chromophobe renal carcinoma
Collecting duct carcinoma

Histologic grade (G)

GX Grade cannot be assessed

G1 Well differentiated
G2 Moderately differentiated
G3–4 Poorly differentiated or undifferentiated

From Kidney. In Greene FL, Page DL, Fleming ID, et al (eds): AJCC Cancer Staging Manual, 6th edition, pp 323–328. New York, Springer, 2002.
*Laterality does not affect the N classification.
Note: If a lymph node dissection is performed, then pathologic evaluation would ordinarily include at least eight nodes.

with outcomes equivalent to those treated with radical
nephrectomy.131–133 Other changes in 1997 included sim-
plifying the classification of the extent of nodal involve-
ment and reclassifying the extent of venous tumor
thrombi. It was emphasized that adrenal gland involve-
ment by local tumor extension should be T3a because this
situation has a better prognosis than isolated adrenal
metastases that reflect hematogenous spread and por-
tends a poor prognosis.134,135 In addition, stage T3a
includes invasion of renal sinus fat because there is no
rationale for including them in another category. Finally,
it has been suggested that vena caval wall invasion has a
worse prognosis than simply the cephalad extent of the
tumor thrombus and should be classified as stage T3c.136
Clinical staging is important and has been shown to
correlate directly with prognosis as well as play a critical
role in appropriate preoperative planning. The clinical
staging of RCC begins with a thorough history, physical
examination, and selected laboratory tests. Symptoms
and signs of significant weight loss (greater than 10% of
body weight), any localized bone pain, a palpable mass,
or lymphadenopathy, and/or a poor performance status
suggest more advanced disease and a worse progno-
sis137,138 New onset of a nonreducing varicocele and
lower extremity edema suggest venous involvement.
Likewise, other constitutional symptoms of pain, fever,
night sweats, and abnormal liver function tests, such as
alkaline phosphatase, α-glutamyltransferase, glutamic
oxaloacetic transaminase, and glutamate pyruvate
transaminase, an elevated sedimentation rate, and signif-
icant anemia all point to the likelihood of advanced
disease.136,137 In the absence of either bone pain or eleva-
tions of serum alkaline phosphatase or calcium, it is
uncommon for a patient to harbor skeletal metastases.
The routine addition of a bone scan for the evaluation of
bone metastases from RCC is not indicated. In fact, in a
study by Koga et al.,139 the overall incidence of bone
metastases was 17% in a group of all stages of RCC.
Likewise, in all patients stages T1–T3, only 4 (1.8%) had
osseous metastases without other metastatic sites, lymph
node involvement, or localized bone pain.
The TNM system is felt to be inadequate by some
groups to describe prognosis in 2003. The addition of
Fuhrman’s tumor grade and Eastern Cooperative
Oncology Group (ECOG) patient performance status
(PS) has been shown to be an important prognostic
tool.140 Zisman et al.140 from University of California
Los Angeles (UCLA) have described the UCLA
Integrated Staging System (UISS). The medical records
of 477 patients undergoing nephrectomy between 1989
and 1999 were evaluated. Median age was 61 years, male-
to-female ratio was 2.2:1, and median follow-up was 37
months. Survival time was the primary end point
assessed. Sixty-four possible combinations of stage,
186 Part III Kidney and Ureter

grade, and ECOG PS were analyzed and collapsed into
distinct groups. The internal validity of the categories
was challenged by a univariate analysis and a multivariate
analysis testing for the accountability of each UISS cate-
gory against independent variable shown to have impact
on survival.140
Combining and stratifying 1997 TNM stage, Fuhrman’s
grade and ECOG PS resulted in five stratification groups
designated UISS, and numbered I–V. The overall 5-year
survival for the UISS groups I–V, respectively, are: 94%,
67%, 39%, 23%, and 0% (Table 10-5). UISS is an emerg-
ing important prognostic tool for counseling patients with
various stages of kidney cancer. It is currently being vali-
dated in two large-scale external databases.140
Imaging plays a crucial role in staging and treatment
planning; however, only tests where the results affect the
patient’s management should be performed. The diagno-
sis of RCC will most commonly be made incidentally by
ultrasound or CT.141 Therefore, performing excretory
urography is of no useful value. Although ultrasound can
yield significant staging information, it is rarely used as
the sole imaging modality. Limitations are associated
with operator ability and interference by body habitus
and overlying bowel gas.
In the majority of cases, radiographic staging of RCC
can be accomplished with the meticulous use of high
quality abdominal CT and routine chest x-ray or chest
CT. Staging accuracy for CT has been reported to be in
the 90% to 91% range.117,142 Probably the greatest limi-
Table 10-5 UCLA Integrated Staging System (UISS)
Overall
5-Year
TNM Survival
UISS Stage ECOGPS Grade (%)
I I 0 1–2 94
tation and most common staging error is determining
extracapsular tumor extension into the perinephric fat
and as such distinguishing stages T1a, T1b, and T2 from
stage T3a. Perinephric stranding adjacent to renal cancers
is a nonspecific sign and can represent edema, fibrosis,
prominent engorged vessels or tumor, and falsely suggest
capsular extension and a T3a lesion. Since, in the major-
ity of cases tumor extension is microscopic, it does not
change patient management and is of less clinical signif-
icance. Perinephric stranding has been reportedly seen in
up to 50% of confirmed T1 and T2 lesions.142 On the
other hand, to confidently suggest perinephric spread
requires nodular soft tissue beyond the capsule. Although
this finding has a 98% specificity, sensitivity is only 46%
with the findings usually seen with larger lesions.142
(Figure 10-10) Another difficult issue is for CT to distin-
guish between abuttal and invasion of adjacent organs,
such as liver, spleen, duodenum, and pancreas.
Obliteration of fat places suggesting invasion can be dif-
ficult to evaluate on CT and lead to false positive results
in 15% of cases.143 (Figure 10-11) In selected cases where
more careful surgical planning is necessary, an MRI may
be helpful.144
Regional lymph node involvement (N1–N2) portends
a poor prognosis. CT must rely on anatomic size criteria
to diagnose or exclude nodal disease and sensitivity and
specificity will vary based on the size used to consider a
node enlarged. Nodal size of 2 cm or greater usually is
associated with malignancy. Using a threshold of 1 cm,
false negative rates for microscopic metastases are low
(4%), while the false positive rates have ranged from 3%
to 43%.136,142,145,146 These false positive rates may even
be higher in patients where venous invasion and tumor
necrosis are present as a result of reactive hyperplasia.
Because of this imaging unreliability, extirpative surgery
should not be withheld without tissue confirmation of

II I 0 3–4

II Any Any 67

III 0 Any

III ≥1 1

III III ≥1 2–4 39

IV 0 1–2

IV IV 0 3–4 23

IV ≥1 1–3

V IV ≥1 4 0

From Zisman A, Pantuck AJ, Dorey F, et al: Improved

prognostication of renal cell carcinoma using an integrated staging Figure 10-10 Large right RCC with nodular soft tissue in the
system. J Clin Oncol 2001; 19:1649–1657. perinephric space consistent with transcapsular spread.
 Chapter 10 Diagnosis and Staging of Renal Cell Carcinoma 187
Figure 10-11 Very large RCC with incontrovertible invasion
of the liver.
malignancy by aspiration cytology or biopsy. MRI may
be more reliable for distinguishing lymphadenopathy
from vascular structures.
Ipsilateral adrenal gland involvement by RCC has
been found in up to 10% of radial nephrectomy speci-
mens.147 With metastatic RCC, ipsilateral adrenal
involvement has been found to be as high as 19.1% while
the contralateral gland is affected in 11.5%.148 Patients at
higher risk for adrenal involvement have an enlarged
adrenal on CT, have an upper pole tumor, and/or have
large tumors with extensive malignant replacement of the
kidney. Microscopic invasion, of course, evades detection
by any imaging modality; however, adrenal involvement
with small mid- or lower pole lesions is reported to be as
low as 1.9%.146 Therefore, with a normal adrenal gland
on CT and small mid- and lower pole tumors, routine
adrenal resection is not justified.149,150
Tumor extension or invasion into the renal vein, vena
cava, or into the heart is a unique finding associated with
RCC. The incidence of renal vein involvement and for
caval extension at the time of surgical exploration has
been reported to be between 10% and 39% and 4% and
25%, respectively.151–153 Reports of successful interior
venacavotomy and tumor thrombectomy date back to
1913.154 Since there are better outcomes with complete
surgical excision in these patients when compared to
those with lymphatic invasion, accurate venous staging
with a thorough knowledge of the extent of venous
involvement is necessary for optimal surgical planning
and management. The sensitivity and specificity of CT
detecting vascular extension of tumor thrombus have
been reported at 78% and 96%, respectively.143 Accuracy
for caval involvement is greater (86%) than for renal vein
involvement (50%).155 The CT findings suggestive of
venous involvement include venous enlargement, abrupt
change in the caliber of the vein, low density intralumi-
nal filling defects, and the presence of collateral venous
tributaries. Enhancement of the thrombus and direct
continuity with the primary tumor are typical of neoplas-
tic thrombus. Bland thrombus, commonly seen below the
level of the renal veins in lesions with large venous exten-
sion, shows no enhancement after contrast. False nega-
tives occur in patients where a mass effect on the vein
may make tumor thrombus identification difficult (more
common on the right) and in situations where tumor
hypervascularity alone causes venous enlargement and
suggests thrombus.156 The superior most extent of
venous invasion is particularly crucial to delineate espe-
cially when the thrombus extends above the diaphragm
(T3c), as this takes careful surgical planning. Finally,
venous extension into the wall of the renal vein or IVC
may make resection impossible, but this is difficult to
diagnose unless tumor is clearly seen extending beyond
the venous wall into the perivascular tissues.
Careful attention should also be paid on CT to the
remainder of the kidney as well; especially when
nephron-sparing surgery is contemplated. Multifocal
RCC occurs in as many as 25% of patients who are can-
didates for partial nephrectomy.157 Although multicentric
lesions tend to be small (from “microscopic” to 1 cm), as
many as 50% of these may be detectable on preoperative
imaging.158 Similarly, the contralateral kidney must be
closely evaluated since bilateral disease is becoming more
commonly recognized.159
Metastatic disease is not uncommonly identified at the
time of staging and most often occurs in the lungs, bone,
liver, and brain. Mediastinal and mesenteric nodes, pan-
creas, and other less common areas of distant dissemina-
tion may be seen. A careful search is prudent, especially
for small lesions. Renal cell metastatic lesions are often
hypervascular and aggressive in appearance. The ques-
tion of whether to routinely obtain a chest CT for staging
is commonly asked. In general, a routine anterio-
posterior and lateral plain chest film is sufficient to
screen for parenchymal lesions but not for mediastinal
nodes less than 2 cm.160 If enlarged lymph nodes are seen
on abdominal CT or if lymphangitic metastases are sus-
pected on plain chest film, chest CT is encouraged.
Similarly, routine use of pelvic CT has been shown to pro-
duce negligible yield and is not routinely recommended.161
MRI has some advantages over CT for staging RCC.
It is noninvasive, does not subject the patient to the
risks of intravenous contrast, and provides high intrin-
sic contrast resolution permitting improved depiction
of tumor thrombus extension and invasion, invasion of
adjacent organs, and capsular extension. This is well
shown in Figure 10-12. MRI has been advocated
because of its ability to directly image in multiple planes
although with today’s modern CT scanners, reconstruc-
tion in virtually all planes is possible without resolution
loss. A recent study by Pretorius et al.162 has shown sim-
ilar staging accuracies for CT and MRI. In addition,
188 Part III Kidney and Ureter
Figure 10-12 Axial MRI demonstrating low signal tumor
thrombus involving the right renal vein to the level of the IVC.
several logistical and practical factors hinder MRI avail-
ability, including long scan times, lack of a consistent
oral contrast agent, inability to image the lungs, claus-
trophobia issues, and contraindications, such as pace-
makers. Finally, image quality can be unpredictable
secondary to motion and other artifacts especially
related to the inability to cooperate with multiple
sequential breath-holds. MRI’s role is a problem-solver
especially when CT findings are equivocal and in
patients with renal insufficiency.
Venacavography has predominantly been abandoned.
For venous thrombus staging, it is invasive, has contrast
risks, and risks of detaching tumor, may require superior
vena cava puncture to determine the cephalad extent of
the thrombus, and is subject to the inaccuracies created
by slow flow and suboptimal contrast filling. In selected
cases where MRI may be contraindicated and other stag-
ing modalities equivocal, transesophageal echo can be
very accurate for establishing the cephalad extent of
tumor thrombus. Transesophageal echo, however, is
invasive.163
Positron Emission Tomography
PET permits noninvasive measurement of biochemical
as well as physiologic reactions. Positron-emitting
radioisotopes labeled to endogenous biochemicals or
drugs are injected intravenously and accumulate in vari-
ous organ tissues depending on their biochemical or
physiologic properties. Presently, the most commonly
used agent is the glucose analog FDG. Normally, there is
high uptake in the brain, myocardium, kidneys, and blad-
der. The increased activity in the genitourinary system is
due to the inability of the nephron to resorb filtered
FDG in the convoluted tubule.164 Although PET-FDG
has detected histologically confirmed RCCs, there have
been significant false positives. A more important role for
PET-FDG (presently under investigation) is for evalua-
tion of metastatic disease and to detect recurrence or
progression and response to systemic therapies. In one
study, 10 of 10 patients were proven to have active pro-
gressive disease whereas only 7 of these 10 cases were
positive with conventional imaging. In 5 patients with no
evidence of disease or complete remission, PET-FDG
studies were negative in all whereas conventional imag-
ing was positive in three cases.165 In another study, PET-
FDG has been used to establish a response to cancer
immunotherapy with interleukin (IL)-2. The lack of
PET activity at prior active sites suggests fibrosis or
necrosis and lack of activity within a previous active renal
mass or lymph node suggests lack of viable cells and
necrosis.166 In another recent study of the clinical role of
PET-FDG, the detection and management of RCC,
PET-FDG accurately detected local disease spread and
metastatic disease in patients with RCC and altered treat-
ment plans in 40%.116 Finally, in a study comparing
PET-FDG to routine bone scan, PET-FDG sensitivity
and accuracy were 100% and 100%, respectively, com-
pared to bone scans that were 77.5% and 59.6%, respec-
tively.167 Clearly, more data and experience are needed
before PET-FDG is recommended for routine use in
RCC. However, this technology with fusion imaging
combining CT with PET, more accurate preoperative
staging, and better patient care is on the horizon.
Monitoring for Recurrence or Progression
of Disease
Follow-up algorithms for RCC remain controversial as
there remains no systemic treatment regiment with
highly satisfactory response rates that would significantly
improve survival in an asymptomatic patient. Exceptions
to this would be isolated renal fossa recurrences that are
rare and solitary delayed metastases (also rare).168 Levy et
al.169 from M.D. Anderson Cancer Center retrospec-
tively reviewed the records of 286 patients with patho-
logic stage T1–T3 RCC of which 68 relapsed. For pT1
disease only, an annual chest x-ray and liver function tests
were recommended. For pT2 and pT3 tumors, it was rec-
ommended to obtain chest radiographs every 6 months
for 3 years, then annually, and perform surveillance
abdominal CT scans at 24 and 60 months unless the
patient becomes symptomatic. It was recommended that
bone and brain surveillance studies only be performed for
site-specific symptoms, elevated alkaline phosphatase, or
the development of metastases at other sites.169 The use
 Chapter 10 Diagnosis and Staging of Renal Cell Carcinoma 189
of periodic CT and/or ultrasound for patients with post-
partial nephrectomy, however, is warranted.170
Evaluation of these patients can prove challenging as fre-
quently there is a wedge-shaped or concave defect often
filled with fat placed to help with hemostasis and
decrease urinary extravasation. Hypodense areas of old
hemorrhage may be present as well as perfusion defects
secondary to devascularized surrounding tissue. For
patients with renal insufficiency or contrast allergy, MRI
is useful. “How often to obtain imaging” is controversial.
However, every 6–12 months is acceptable. Similarly, it
has been recommended that CT scans be done every 3–6
months postoperatively on patients having had “bench
surgery” and autotransplant for RCC.171
Periodic relapse monitoring is also important in fol-
lowing patients with small indeterminate lesions on CT
or ultrasound and on patients who have increased
comorbidities where intervention would only be under-
taken if substantial growth is documented. Birnbaum et
al.172 studied a group of patients longitudinally looking at
yearly growth rates on CT. They found the growth rate
to be between 0 and 1.6 cm in diameter in a year with a
mean growth rate of 0.5 cm. It, therefore, seems reason-
able to obtain imaging every 6 months for 1 year and if
there is no change, settle for yearly follow-up.
Percutaneous Needle Aspiration Cytology and
Biopsy for the Diagnosis of Renal Cell Carcinoma
Percutaneous renal tumor sampling continues to be
frowned on except for specific indications as outlined in
Table 10-6. Although the risk of seeding normal tissue in
the needle tract is small, it is likely that the true incidence
is undeteresteimated.173 If seeding occurs, potentially
curable organ-confined renal cancer is compromised. In
general, a CT or ultrasound guided aspiration or biopsy
is quick and safe, but may be associated with bleeding or
arteriovenous fistula formation. Furthermore, there are
significant equivocal or false negative results due to sam-
pling error and the inability to conclusively differentiate
oncocytomas from low-grade RCCs.
Table 10-6 Indications for Percutaneous Biopsy
or Aspiration of Renal Mass
● When a lesion present in a patient with lymphoma
persists after systemic response to therapy
● Distinguish between primary neoplasia and metastatic
disease
● Differentiate between an infected cyst or abscess and
neoplasm
● Obtain tissue diagnosis in a patient who is not an
operative candidate
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171. Stormant TJ, Bilhartz DL, Zincke H: Pitfalls of berch
surgery and auto-transplantation for renal cell
carcinoma. Mayo Clinic Proc 1992; 62:621–628.
172. Birnbaum BA, Bosniak MA, Megibow AJ, et al:
Observations on the growth of renal neoplasms.
Radiology 1990; 176:695–701.
173. Sheroy PP, Lakhkar BN, Ghosh MK, et al: Cutaneous
seeding of renal oncocytoma by Chiba needle aspiration
biopsy. Case Report. Acta Radiol 1991; 32(1):50–52.
C H A P T E R
11 Renal Cell Carcinoma: Localized
Disease
Kenneth Ogan, MD, and Fray F. Marshall, MD
Renal cell carcinoma (RCC) is a unique neoplasm because
currently there is no effective systemic therapy once it has
progressed beyond the kidney. Therefore, even more so
than in other malignancies, prompt and effective treatment
of localized RCC is of paramount importance. Over the
past several decades, in part due to the diagnosis of smaller
tumors with improved imaging modalities, there has been
a paradigm shift in the treatment of localized renal tumors.
First described by Robson et al.1 in 1968, open radical
nephrectomy (ORN), including removal of the ipsilateral
adrenal gland and an extended regional lymphadenectomy,
became the standard of care for surgical extirpation of renal
tumors for the following several decades. In the 1980s,
Hohenfellner, Novick and others initiated nephron-spar-
ing surgery (NSS), removing the renal tumor with a mar-
gin of normal parenchyma and sparing the remaining
normal parenchyma.2,3 While originally reserved for
patients that would be rendered functionally anephric with
radical nephrectomy, nephron-sparing surgical procedures
have been extended to the majority of patients with small
cortical renal tumors (<4 cm), even in patients with a nor-
mal contralateral kidney. Over the past decade, the intro-
duction of laparoscopic radical nephrectomy (LRN)4 and
laparoscopic partial nephrectomy (LPN)5 has provided a
minimally invasive treatment modality to the urologist’s
surgical armamentarium for the treatment of localized
renal tumors. Finally, in an effort to even further reduce the
morbidities of open and laparoscopic procedures, energy-
based ablative techniques have been developed in which
small renal tumors are destroyed and left in situ.6,7
EPIDEMIOLOGY AND CLINICAL PRESENTATION
Malignant tumors of the kidney account for greater than
2% of cancer incidence and mortality. According to the
American Cancer Society (ACS), based on the rates from
the National Cancer Institute’s (NCI) surveillance,
Epidemiology and End Results (SEER) program, the
estimated number of new cases and deaths from kidney
cancer in the United States for 2004 was 12,480. Chow
et al.8 have reported a rapidly increasing incidence of
RCC between 1975 and 1995 in the United States.
While the greatest increase was seen for localized
tumors, the incidence also increased for advanced
tumors. Thus, it is unlikely that this increased incidence
is solely due to an increased detection rate, but it more
likely represents a true increased incidence of RCC. The
incidence rate in males is approximately twice that of
females, with the peak age of diagnosis in the seventh and
eighth decades of life. While Caucasians are affected
more commonly than African Americans, the incidence
and mortality rates are increasing at a greater pace in the
African-American population.8
In the past, presentation with the classic triad of flank
pain, abdominal mass, and hematuria was rarely associ-
ated with localized disease. Due to the protected location
of the kidney within the retroperitoneum, the majority of
symptomatic tumors present at an advanced stage.
Fortunately, in the current day of routine ultrasonogra-
phy (US), computed tomography (CT) imaging, and
magnetic resonance imaging (MRI), this presentation is
rare, and in fact, the majority of tumors are discovered
incidentally.9 Incidental tumors have also been shown to
be of a lower-stage than their symptomatic counter-
parts.10,11 Thompson and Peek11 reported that 82% of
incidental tumors were stage I or stage II, whereas only
32% of symptomatic tumors were at early stage.
Consequently, following treatment these incidental
tumors also demonstrated improved 10-year survival
compared to the symptomatic tumors (90% versus 30%).
195
196 Part III Kidney and Ureter
Importantly, these smaller, lower-staged tumors are more
amenable to nephron-sparing and minimally invasive
procedures.
CLASSIFICATION AND HISTOPATHOLOGY
The majority of kidney tumors originating in the renal
cortex are adenocarcinomas, commonly called RCCs.
The first attempt to classify renal tumors was by
Grawitz12 when he attributed the origin of renal tumors
to an ectopic adrenal rest and, therefore, called them
“hypernephroma.” Since that time numerous classifica-
tion systems have been developed to characterize renal
tumors. Currently, most people adhere to the classifica-
tion system developed in 1997 by the World Health
Organization (WHO) in combination with the Union
Internationale Contre le Cancer (UICC) and the American
Joint Committee of Cancer (AJCC) (Table 11-1),13 which
separates adult renal tumors into either benign or malig-
nant categories.
Of the malignant primary tumors of the kidney cortex,
conventional clear cell carcinoma accounts for 70% to
80% of renal neoplasms.13,14 Papillary RCC is the second
most common carcinoma, accounting for 10% to15% of
renal neoplasms.15,16 Compared to clear cell carcinoma,
papillary RCC has been associated with a better progno-
sis. The overall 5-year survival rates for papillary com-
pared to conventional clear cell RCC have ranged
between 82% to 90% and 44% to 54%, respectively.16,17
Chromophobe RCC accounts for approximately 5% of
renal neoplasms. As with papillary RCC, chromophobe
has been found to be associated with a better 5-year
Table 11-1 Classification of Renal Cell Carcinoma
Malignant neoplasms
Conventional (clear cell) carcinoma
Papillary renal carcinoma
Chromophobe renal carcinoma
Collecting duct carcinoma
RCC unclassified
Benign neoplasms
Oncocytoma
Papillary adenoma
Metanephric adenoma
From Storkel S, Eble JN, Adlakha K, et al: Classification of renal cell
carcinoma: Workgroup No. 1. Union Internationale Contre le Cancer
(UICC) and the American Joint Committee on Cancer (AJCC).
Cancer 1997; 80:987–989, with permission.
cumulative survival compared to conventional clear cell
RCC.18 Collecting duct carcinoma is a rare type of RCC,
accounting for only 0.4% to 2.6% of renal neo-
plasms.14,19,20 These tumors are characterized by an
aggressive course with a high incidence of locoregional
spread and metastases.21 Similarly, Davis et al. were the
first to describe renal medullary carcinoma, which
appears to be a variant of collecting duct carcinoma. This
type of RCC is unique because it is exclusively found in
black patients with either sickle trait or sickle cell hemo-
globin disease.22,23 As with its collecting duct counter-
part, this is a very aggressive disease with a dismal mean
survival of 3.5±2.4 months following diagnosis.23–25
Finally, sarcomatoid RCC is no longer considered as a
distinct histopathologic category but rather an ominous
subtype. In the largest series to date, Mian et al.26 from
M.D. Anderson Cancer Center reported a dismal median
overall survival of only 9 months in 108 patients classified
with sarcomatoid RCC. Thus, it is apparent that the his-
tologic type of RCC strongly affects prognosis and may
act as a guide to the institution of adjuvant systemic ther-
apies. Conversely, the future of classification or identifi-
cation of renal tumors will most likely be based on
molecular, rather than histopathologic findings.27
RISK FACTORS
The increased incidence of RCC has been noted across
all stages and cannot be explained solely by the increased
detection of incidental tumors. RCC incidence rates
increased steadily between 1975 and 1995, by 2.3%
among white men, 3.1% among white women, 3.9%
among black men, and 4.3% among black women.8,28
While the greatest increase was seen for localized
tumors, there was also an increase in kidney cancer-spe-
cific mortality during this time period. Thus, this sug-
gests that there is a true increased incidence of renal
cancer rather than just an increased rate of detection.
Despite numerous epidemiologic studies, the etiology
of RCC remains largely unknown. There are definitive
genetic, dietary, and environmental risk factors for the
development of RCC. Hereditary RCC syndromes place
family members at a tremendous increased risk of RCC
and should likely prompt early screening. Table 11-2 lists
the most common inherited syndromes and the affected
chromosomes associated with increased risks of develop-
ing RCC.29 Also, acquired renal cystic disease secondary
to chronic hemodialysis has been associated with an
increased risk of RCC.30 Similarly, renal transplantation,
with its necessary immunosuppression, has been demon-
strated to confer up to a 80-fold increased risk of devel-
oping RCC.31
There are numerous studies that consistently impli-
cate smoking,32 hypertension,33 asbestos exposure,34
petroleum exposure,35 and frequent analgesic use36 as

Table 11-2 Inherited Syndromes with an Increased Risk of RCC
Inherited Disease Chromosome
von Hippel-Lindau 3p25-p26
Hereditary papillary c-MET proto-oncogene 7q31
renal carcinoma
Tuberous sclerosis 1 TSC1 on 9q34
Tuberous sclerosis 2 TSC2 on 16p13.3
Birt-Hogg-Dube 17p12-q11.2
Modified from Godley P, Kim SW: Curr Opin Oncol 2002; 14:280–285, with permission.
risk factors for the development of RCC. There is con-
flicting evidence on the risks of specific dietary sub-
stances on the increased risk of RCC. However, obesity
and a high body mass index (BMI) have been consistently
noted in several studies to connote an increased risk of
RCC.37–39
DIAGNOSIS
Localized RCC rarely causes symptoms or physical find-
ings on examination. What used to be called as the
“internist’s tumor” is now found more commonly by the
radiologist during evaluation of other ailments.
Radiologic imaging of the kidneys for a suspected renal
tumor can be performed with ultrasonography (US),
intravenous pyelography (IVP), CT, or MRI.
Angiography, which was routinely performed in the past,
is currently a rare component of the radiologic evalua-
tion. However, angiography may be a useful adjunct in
preoperative planning prior to a complex partial nephrec-
tomy and during angioinfarction of large tumors. The
advantages of ultrasound include low cost, low morbidity,
lack of potentially nephrotoxic contrast agents, and the
ability to differentiate solid from cystic masses. These
characteristics make ultrasonography the imaging
modality of choice for a potential screening program.
IVP has been the traditional imaging study of the upper
urinary tract used in the evaluation of hematuria. The
main advantage of IVP is the ability to detect small
urothelial tumors. However, due to similar costs,
increased time to perform the study, and lack of detailed
cortical imaging, this study is being replaced by CT.40
The main advantage of MRI is the ability to determine
the cranial extent of tumor thrombus extension and the
presence of contiguous organ involvement. Finally,
positron emission tomography (PET) is an emerging
technology with potential applications for staging and
detection of tumor recurrences.
Chapter 11 Renal Cell Carcinoma: Localized Disease 197
Characteristics
Hemangioblastoma of CNS/retina, pheochromocytoma, RCC
(clear cell type), renal cysts, pancreatic cysts, and cystadenomas
High incidence of bilateral papillary RCC
Facial angiofibromas, peringual fibromas, renal angiomyolipomas
Facial angiofibromas, peringual fibromas, renal angiomyolipomas
Fibrofolliculomas, different histologic renal tumors, and
pulmonary cysts associated with increased risk of pneumothorax
TUMOR BIOPSY
While the majority of solid renal tumors represent RCC,
there are certain situations in that the preoperative diag-
nosis is less certain. Review of large radical nephrectomy
series reports benign lesions in up to 20% of cases. Thus,
in an effort to avoid needless nephrectomies for benign
tumors, the debate arises whether preoperative biopsy
is warranted in a proportion of these patients.
Percutaneous biopsies can be performed by fine needle
aspiration (FNA) or with hollow-bore needles under
radiologic guidance. The FNA is less traumatic but must
be sent for cytologic versus pathologic analysis.
Opponents of renal tumor biopsies note the risk of tumor
spread due to needle tract seeding and the possibility of
obtaining false negative biopsies. With newer biopsy
needles, this occurrence is rare.
Wood et al.41 retrospectively reviewed 79 biopsies in
73 patients with renal masses. All tumors initially under-
went FNA (22 gauge) with immediate cytologic analysis,
followed by core biopsy (17 to 20 gauge). Biopsy samples
were adequate for diagnosis in 74 of 79 (94%) cases. Of
49 positive biopsies, 15 (31%) involved non-RCCs. Of
the 79 biopsies, 5 (6%) were false negative and all corre-
lated to samples with insufficient tissue for diagnosis.
The ultimate diagnosis was made on repeat biopsy or at
surgery. Biopsy results altered treatment in 32 (44%)
patients who did not undergo surgery because of biopsy
results. There were no major complications or tumor
track seeding reported at a mean follow-up or 30.4
months. Finally, the efficacy and safety of FNA was com-
parable to that of core biopsy specimens.
Lechevallier et al.42 reported on 63 consecutive
patients that underwent 18-gauge core biopsies for suspi-
cious renal masses. Biopsy material was insufficient for
analysis, suspicious for RCC and diagnostic in 15 (19%),
2 (3%), and 56 (78%) of cases, respectively. Biopsy
revealed a benign lesion in 8 (13%) patients and a non-
surgical malignant tumor in 21 (33%) of patients. Thus,
198 Part III Kidney and Ureter
in theory, 29 (46%) of patients could have avoided sur-
gery because of biopsy results. Finally, for those patients
who had a nephrectomy (26 patients) for malignant dis-
ease, the accuracy of biopsy for histopathologic and
Fuhrman nuclear grade evaluations was 89% and 78%,
respectively. Importantly, there were no complications
necessitating intervention from the biopsies and no
evidence of tumor seeding at a mean follow-up of
29 ± 11 months.
Finally, Harisinghani et al.43 looked at the accuracy of
percutaneous renal biopsy of Bosniak III renal cysts,
which are diagnostic dilemmas for the surgeon and
patient. In their series of 28 biopsied category III lesions,
17 (60.7%) were malignant (16 RCCs and 1 lymphoma)
and 11 (39.3%) were benign (6 hemorrhagic cysts, 3
inflammatory cysts, 1 metanephric adenoma, and 1 cystic
oncocytoma). Seventeen of the 28 lesions (16 RCCs and
1 inflammatory cyst) underwent surgical resection after
the biopsy. All resected lesions had pathologic diagnoses
identical to the percutaneous imaging-guided biopsy
results. The remaining 11 patients, who did not have sur-
gery, had radiologic follow-up for a minimum of 1 year,
with benign lesions showing no interval change. Thus, in
these studies, surgery could have been avoided in 39% to
46% of cases, which begs the question of whether renal
biopsies should be performed more frequently in selected
patients.
INDICATIONS FOR SURGERY
Radiation and systemic therapy (chemotherapy or
immunotherapy) are both ineffective treatment of local-
ized RCC. Similarly, the results of systemic treatment for
metastatic disease are poor. Thus, surgery is the treat-
ment of choice for locally confined or locally advanced
disease without regional or distant metastasis. There is
recent evidence to suggest that surgical removal of the
renal primary (cytoreductive surgery) in the midst of
metastatic disease may also improve survival rates in
combination with systemic immunotherapy.44,45
Therefore, one could make the argument that any
resectable renal tumor, regardless of size, or presence of
metastases, is a candidate for surgical removal if the
patient has a high performance status (PS). For those
patients with especially poor prognostic factors, some
investigators have suggested testing tumor responsive-
ness to immunotherapy prior to cytoreductive nephrec-
tomy to avoid the morbidity of surgery in patients
unlikely to respond to systemic treatment.46
SURGICAL MANAGEMENT OF LOCAL DISEASE
Robson et al.,1 in 1968, were the first to describe their
results of radical nephrectomy for RCC. In this classic
article, the authors describe the radical extirpation of the
tumor-bearing kidney and adrenal gland within Gerota’s
fascia along with an extended lymph node dissection.
Until recently, ORN, as described by Robson, was the
standard of care for localized RCC. This “gold standard”
has been challenged by the introduction of two concepts:
elective NSS for small renal tumors and laparoscopic
renal surgery, including radical and partial nephrectomy.
Elective NSS is now considered by many to represent the
standard of care for the management of small renal
tumors, with 10-year cancer-specific survival rates similar
to radical nephrectomy.47 LRN was first performed by
Clayman et al.4 in 1991 for a tumor-bearing kidney. Since
then, LRN has gained wide acceptance because of its
decreased postoperative pain, decreased hospital stay and
shortened convalescence compared to the open
approach.48–50 Only recently a significant follow-up has
been made available to demonstrate the laparoscopic
approach to be oncologically equivalent to open surgery.
Finally, ablative technologies are coming to fruition, in
that tumors are destroyed with heat or cold energy and
then left in situ following treatment.
OPEN RADICAL NEPHRECTOMY
Technique
For details on “technique” see “Textbook of Operative
Urology” by Marshall.51 Briefly, the kidney can be
approached through several different incisions (flank,
transperitoneal, thoracoabdominal), depending on the
size and location of the tumor, the patient’s body habitus,
and the surgeon’s preference. Whichever approach is
taken, early ligation of the renal pedicle and removal of
the kidney and tumor with adequate margins are manda-
tory (Figure 11-1).
The flank approach is the most commonly performed
incision for radical nephrectomy. For the flank incision,
the patient is placed laterally on the operating table with
the table flexed and the kidney rest elevated. The incision
is usually made over the 11th or 12th rib, and a rib may
need to be removed for exposure of the kidney. The goal
is to stay extraperitoneal, as well as extrapleural. Early
identification, access and ligation of the renal hilar ves-
sels, and avoidance of the intraperitoneal cavity are the
advantages of this approach. Disadvantages include risk
of pneumothorax, which can be easily repaired without
leaving a chest tube if identified intraoperatively, and rel-
atively increased pain compared to other incisions
because of division of the flank muscles.
The transperitoneal approach is accessed via a sub-
costal, midline upper abdominal or chevron incision.
The main advantages of the transperitoneal approach are
the ability to examine surrounding intraabdominal struc-
tures, including the contralateral kidney, and the
improved access to the hilar vessels for larger tumors.
Disadvantages include poor exposure of the upper pole of
 Chapter 11 Renal Cell Carcinoma: Localized Disease 199
Figure 11-1 Radical nephrectomy with division of hilar vessels.
the kidney and the increased risks of postoperative ileus
and adhesions.
Finally, the thoracoabdominal approach, while not
often necessary, arguably provides the optimal exposure
for large upper pole tumors and tumor thrombus into the
vena cava. Entrance into the pleural cavity also allows for
concomitant metastasectomy of isolated ipsilateral pul-
monary lesions. Disadvantages include the need for a
chest tube postoperatively and the risks of postoperative
atelectasis. While it has been argued that the thoracoab-
dominal approach is associated with an increased risk of
postoperative pain, Kumar et al.52 demonstrated no
increase in postoperative pain or analgesic requirements
in patients with a thoracoabdominal versus a flank inci-
sion. Thus, there are numerous approaches to the kidney
for a radical nephrectomy, and the urologic surgeon must
be familiar with each to tailor the approach to best suit
the situation.
LAPAROSCOPIC RADICAL NEPHRECTOMY
The three laparoscopic approaches to LRN are transperi-
toneal, retroperitoneal, and hand-assisted laparoscopy
(HAL). The original description by Clayman and col-
leagues4 was a transperitoneal approach. The retroperi-
toneal approach was developed to mimic the open flank
nephrectomy and allow the hilar vessels to be accessed
and controlled quickly without violating the peritoneal
cavity. Lastly, hand-assisted nephrectomy was developed
to facilitate the procedure for the novice surgeon, to
provide an alternative to open conversion and for large
renal tumors and specimens, where HAL may help to
expedite the procedure. Surgeon’s preference, laparo-
scopic procedure, patient anatomy, and history of prior
surgery all impact the approach that is taken, but the
ultimate goal of all three is to perform an adequate
oncologic operation while minimizing morbidity.
A preoperative consent form is signed, detailing the
possible complications. Specifically for laparoscopic
surgery, patients are instructed about the risks of open
conversion, hypercarbia, and neuromuscular injury
from prolonged positioning. For each of the three
techniques, bowel preparation for the day prior to sur-
gery is optional to prevent colonic distension from
obscuring visualization. Patients are administered a
second-generation cephalosporin intravenously and
200 Part III Kidney and Ureter
intraoperatively for routine prophylaxis. In case of
rapid blood loss, the anesthesiologist must have ade-
quate intravenous access with 2 large bore IV lines and,
at the surgeon’s discretion, patients are typed and
cross-matched for 2 units of packed red blood cells
(RBCs). Of note, the anesthesiologist should be edu-
cated not to use nitrous inhalant as it can cause bowel
distention and that temporary oliguria with insufflation
is common and expected.
Technique
Transperitoneal
A Foley catheter and orogastric tube are first placed
while the patient is in the supine position. Patients are
then positioned in a modified 45-degree flank position
with meticulous care taken to pad all pressure points.
The kidney rest is not elevated, and the bed is minimally
flexed. The patients are then firmly secured to the oper-
ating table with 3-inch cloth tape. Once secured, prior to
covering the patient with sterile drapes, the bed is tilted
completely to the right and left sides to assure that the
patient’s position does not change. For emergent conver-
sion to an open procedure the patient is rotated on the
bed into a supine position to make a subcostal incision
and obtain immediate access to bleeding.
Intraperitoneal access can be accomplished either with
the Veress needle or an open Hassan technique.
However, the authors use both; the Hassan technique is
used exclusively in patients with multiple abdominal scars
or when the Veress technique fails. We typically gain
access at the umbilicus where the abdominal wall is the
thinnest. The abdomen is temporarily insufflated to 20
mm Hg for trocar placement under direct laparoscopic
visualization. We typically use a 3 or 4 port configuration
for LRN. Once all trocars have been placed, the pneu-
moperitoneum is decreased to 15 mm Hg to reduce the
possible complications of hypercarbia and decreased
venous return.
Initial dissection involves incising the posterior peri-
toneum at the line of Toldt and reflecting the colon medi-
ally to gain access to the retroperitoneum. In doing so the
renocolic ligaments are divided to expose the kidney. On
the left side, the splenocolic ligaments are divided and
care is taken not to injure the tail of the pancreas. On the
right side, the duodenum is reflected medially and the
hepatocolic ligaments are divided to adequately expose
the renal hilum. The ureter is then identified and mobi-
lized superiorly with the gonadal vessels. The renal hilum
is identified and then the artery and vein are sequentially
divided using an Endo-GIA stapler (US Surgical,
Norwalk, CT; Ethicon Endosurgical, Cincinnati, OH) or
Weck locking polymer clips (Weck Closure Systems,
Research Triangle Park, NC). We no longer use a tita-
nium disposable clip appliers to control the artery. Finally,
the upper pole of the kidney is dissected free and the
ureter and lateral attachments are divided to free the
entire kidney. The kidney is placed in a specimen retrieval
bag for intact removal or morcellation.
The major advantage of the transperitoneal approach
is the increased working space and multiple landmarks to
guide the surgeon. In addition, the transperitoneal
approach allows for extraction via a Pfannenstiel incision
providing an excellent cosmetic result. Disadvantages
include the need to reflect multiple abdominal structures
to gain access to the kidney, including the spleen, pan-
creas, colon, liver, and duodenum. Manipulation of the
bowel has been thought by some investigators to increase
the risks of postoperative ileus compared to retroperi-
toneal approaches.
Retroperitoneal
The preoperative preparation is the same for the
retroperitoneal as the transperitoneal approach. As
described by Gill,53 the patient is placed in a 90-degree
full flank position with the table flexed and the kidney
rest elevated. Initial access is obtained through a 1 to
2-cm transverse incision located just below the tip of the
12th rib. The tissue layers are bluntly dissected down to
the thoracolumbar fascia, which is incised sharply, gain-
ing access to the retroperitoneum. Blunt finger dissection
is performed between the psoas muscle and the posterior
aspect of Gerota’s fascia. A balloon dilator (Origin
MedSystems, Menlo Park, CA) may be positioned into
this space and inflated to approximately 800 cm3 of air. A
laparoscope is then inserted into the transparent balloon
to confirm adequate placement within the retroperi-
toneum. The balloon is removed, a 10-mm blunt trocar
is introduced through the skin incision, and the pneu-
moretroperitoneum is established at 15 mm Hg. Two
additional trocars are placed under direct visualization at
the lateral border of the erector spinae muscle just below
the 12th rib and between the mid- and anterior axillary
line, 3 cm cephalad to the iliac crest.
Dissection begins with longitudinal incision of
Gerota’s fascia anterior to the psoas muscle in the region
of the renal hilum. The renal artery is then easily visual-
ized, circumferentially dissected, clipped/stapled, and
divided. The renal vein is anterior to the artery, exposed
and divided using an Endo-GIA vascular stapler.
Suprahilar dissection is performed along the medial
aspect of the upper pole. Finally, the ureter and gonadal
vessels are divided and the remainder of the kidney is
mobilized outside of Gerota’s fascia. As with the
transperitoneal approach the specimen is placed in a
retrieval bag for either intact removal or morcellation.
The proponents of retroperitoneal LRN have claimed
that this approach is associated with less morbidity com-
pared to transperitoneal LRN secondary to rapid access
 Chapter 11 Renal Cell Carcinoma: Localized Disease 201
to the hilum and avoidance of the peritoneal cavity. In
theory, avoiding the peritoneal cavity should decrease the
incidence of postoperative ileus and inadvertent injury to
intraperitoneal contents. McDougall et al.54 reported a
faster return to oral intake in a retrospective comparison
of patients undergoing retroperitoneal versus transperi-
toneal nephrectomy for benign disease. Conversely,
Gill et al.55 recently prospectively compared the out-
comes of transperitoneal versus retroperitoneal LRN in
88 consecutive patients. Although the retroperitoneal
approach was associated with less surgical time, there was
no significant difference in blood loss, complications,
pain requirements, or hospital stay. The main theoretic
disadvantage of this technique is the limited working
space allotted. To the novice surgeon inexperienced with
this technique, this technique may initially make orienta-
tion and dissection challenging. In addition, large renal
specimens may be difficult to handle. Abbou et al.56 still
recommend limiting retroperitoneal nephrectomy to
T1 lesions.
Hand-Assisted
Hand-assisted LRN is the latest addition to the laparo-
scopic armamentarium. It has been criticized by “pure”
laparoscopists because of the presumed increased mor-
bidity associated with the incision necessary for hand
insertion. However, Nelson et al.57 recently reviewed 22
hand-assisted and 16 standard laparoscopic radical
nephrectomies and demonstrated that there was no dif-
ference in pain scores, hospital stay, or return to normal
activity. Importantly, the operative time was significantly
less in the hand-assist group (205 versus 270 minutes)
and less of a learning curve to overcome.
The HAL technique utilizes the same presurgical
preparation as the transperitoneal technique, including
patient positioning. Typically the nondominant hand is
placed into the abdomen via an incision placed below the
umbilicus with 2 to 3 accessory trocars for laparoscopic
instruments. The initial steps of exposing the kidney are
identical to that described for the transperitoneal tech-
nique. The kidney is then mobilized except for the upper
pole, using both blunt and sharp dissection techniques.
The ureter is divided prior to dividing the hilar vessels.
This allows the surgeons hand to grasp the kidney and
place the hilum on stretch. The fingers are then able to
palpate, present, and if need be, compress the hilum dur-
ing dissection. The hilar vessels are separately controlled
and divided using an Endo-GIA stapler (US Surgical,
Norwalk, CT; Ethicon Endosurgical, Cincinnati, OH) or
Weck locking polymer clips (Weck Closure Systems,
Research Triangle Park, NC). Finally, the upper pole
attachments are released, and if the situation dictates, the
adrenal gland is removed with the specimen en bloc. The
specimen is delivered through the hand incision. All of
the new hand devices protect the extraction wound with
an impermeable barrier. Thus, there is no need for an
extraction bag device. There is no role for morcellation
since the hand port incision is large enough for almost all
specimens.
Though not embraced by all surgeons, HAL has
gained popularity within the private sector secondary to
the short learning curve and quick operative times. For
the “pure” laparoscopists, HAL may provide an alterna-
tive to conversion. Finally, having the hand in the opera-
tive field may provide distinct advantages in patients with
large renal specimens or with prior abdominal surgery.
Disadvantages to HAL include less working space sec-
ondary to the hand in the intraabdominal cavity. This is
especially true in thin, small patients. The extraction site
is limited to where the hand device is placed, typically
lower midline, but rarely in a Pfannenstiel position.
Finally, similar to the transperitoneal technique, HAL
requires multiple abdominal structures to be reflected
prior to exposing the kidney, which theoretically may
lead to an increased incidence of injury to adjacent
organs and prolonged ileus.
Comparison of Laparoscopic Radical Nephrectomy
to Open Radical Nephrectomy
Intraoperative and Postoperative Parameters
In general, the benefits of LRN have been in patient
recovery from surgery. Numerous series have demon-
strated that compared to ORN, laparoscopic patients
incur less postoperative pain and need for analgesics,
shorter hospitalization, and a reduced convalescence.
Intraoperatively, ORN is advantageous, with shorter
operative times, but also with an increased blood loss.
Finally, opponents of laparoscopy criticize the increased
costs associated with these procedures, secondary to
costly equipment and prolonged operative times.
However, Lotan et al., in a cost comparison analysis of
LRN versus ORN, found that the laparoscopic approach
was actually less costly due to reduced hospitalization
costs secondary to shorter hospital stays. The laparo-
scopic approach, with its shorter convalescence, would be
even more cost advantageous if cost from lost wages was
included in the cost analysis (Table 11-3).
Oncologic Adequacy
The goal of any laparoscopic procedure should be to
reproduce the efficacy of its open counterpart, while pro-
viding the benefits of the minimally invasive approach.
One of the earliest surrogate endpoints to compare the
oncologic adequacy of LRN to ORN was specimen
weight and margin status. The specimen weight follow-
ing LRN and ORN should be equivalent if the specimen
is removed intact and approximately 20% less if the
 Chapter 11 Renal Cell Carcinoma: Localized Disease 203

Table 11-4 Laparoscopic Radical Nephrectomy Oncologic Results

Number Clinical Tumor Port Site or Renal 5-Year Cancer Mean Follow-Up
Study of Patients Stage Fossa Recurrence Specific Survival (%) (months)

Cadeddu et al.62 157 T1-2,N0,M0 0 91 19.2

Dunn et al.48 61 T1-2,N0,M0 0 — 25

Gill et al.59 53 T1-2,N0,M0 0 — 13

Chan et al.63 67 T1-2,N0,M0 0 95 35.6

Portis et al.60 64 T1-2,N0,M0 1 98 54

Ono et al.58 147 T1-2,N0,M0 — 96 30 (median)

ogy, grade, and stage were accurately determined follow-
ing morcellation. Only tumor size was not assessed.
However, as noted, with modern imaging tumor size can
be accurately measured preoperatively and incorporated
into the tumor staging process. Meng et al.74 found that
india ink covering of the specimens prior to morcellation
allows for accurate determination of surgical margins.
Therefore, accurate staging of morcellated renal tumors
is possible following morcellation and should not be a
concern.
It is well established that specimen morcellation is a
safe alternative to intact removal as long as the morcel-
lation is performed in an impermeable entrapment sack.
Urban et al.75 tested the permeability of 18 LapSacs
(Cook Urologic, Spencer, IN) following porcine laparo-
scopic nephrectomy or nephroureterectomy with a
high-speed electrical tissue morcellator. None of the
sacks demonstrated permeability to bovine serum albu-
min, indigo carmine or mouse bladder tumor cells fol-
lowing morcellation. These results were confirmed by
Landman et al.73 in 14 of 15 LapSacs that remained
impermeable following morcellation. The one case of
perforation occurred with a specimen that had been
preserved in formalin. Clinically, Dunn et al.48 reported
a series of 39 cases where the specimen was morcellated
with no local or port site recurrences over 9 years.
However, Fentie et al.72 have reported a case with a
clinical stage T3 tumor with an isolated port site recur-
rence following laparoscopic nephrectomy and morcel-
lation. Thus, while morcellation has been demonstrated
to be safe, meticulous care must be taken to avoid tumor
contamination during morcellation. In particular, to
avoid entrapment sac violation and tumor spillage,
laparoscopic visualization during morcellation is
mandatory.
Whether there is a clinical advantage to morcellation
remains to be determined. Walther et al.76 compared
specimen morcellation to intact removal and described
decreased analgesic requirements and a shorter hospital
stay. However, Gettman et al.77 showed no significant
differences in subjective pain and activity scores, and
time to return to normal activity. Ono et al.58 also
demonstrated no significant differences in analgesic
requirements (29 mg versus 29 mg analgesics) and con-
valescence (22.7 days versus 23.3 days) in the intact
extraction group and morcellated group, respectively.
These conflicting results call into question the benefits
of specimen morcellation. This in combination with
prolonged operative times, expenses associated with
morcellation and risk of tumor spillage; all combine to
make intact specimen removal our technique of choice.
TUMOR THROMBUS
Venal caval tumor thrombus has been reported in 4% to
10% of all patients with RCC.78–80 Venous extension is
classified by the cranial extent of the tumor thrombus.
While there are numerous classification schemes avail-
able, the one proposed by Skinner et al.80 is simple to use
and has implications on the surgical approach and ulti-
mate prognosis (Table 11-5).
In 1913, Berg et al.81 were the first to remove an intra-
caval thrombus in a patient with RCC. Sosa et al.82
reported dismal results with no survivors at 1 year in
patients undergoing nephrectomy alone, without
removal of the vena caval thrombus. Conversely, numer-
Table 11-5 Classification of superior extent of RCC
in the IVC
Level 3 Level 2 Level 1
Intra-atrial Extension within Extension below the
tumor the intrahepatic insertion of the
extension IVC but not into hepatic veins
the atrium
From Skinner DG, Pritchett TR, Lieskovsky G, et al: Ann Surg 1989;
210:387–392. (Discussion 392–394.), with permission.
204 Part III Kidney and Ureter
ous investigators have demonstrated long-term survival
rates with removal of tumor thrombus at the time of rad-
ical nephrectomy, even with cranial extension into the
atrium (Figure 11-2).
There is considerable debate as to whether the pres-
ence of tumor thrombus independently portends a poor
prognosis. Numerous reports have demonstrated
encouraging 5-year survival rates of 32% to 64% in
patients undergoing radical nephrectomy with removal
of inferior vena caval thrombi.80,83,84 The survival rates
decrease dramatically when tumor thrombus is associated
with positive lymph nodes, distant metastasis and when
the tumor thrombus invades into the wall of the inferior
vena cava (IVC). The prognostic significance of the cra-
nial extent of tumor thrombus has also been the point of
contention. Skinner et al.,80 in a series of 53 patients,
demonstrated 5-year survival rates for subhepatic,
hepatic, and atrial thrombi of 35%, 18%, and 0%,
respectively. Conversely, Staehler et al.85 found no differ-
ence in survival rates among patients with levels I to IV
thrombi. Therefore, an aggressive surgical approach is
Figure 11-2 Tumor thrombus with vena caval extension into the atrium.
warranted in patients with tumor thrombi, regardless of
cranial extent, without evidence of metastatic disease.
ROLE OF ADRENALECTOMY
The adrenal gland is easily removed en bloc using an
ORN or LRN technique. However, most LRN series
reserved ipsilateral adrenalectomy for patients with evi-
dence of adrenal involvement on preoperative studies or
large upper pole lesions where removal was required to
ensure a negative margin.62 The major report that sup-
ports this practice comes from Tsui et al.,86 in that the
records of 511 patients undergoing ORN with ipsilateral
adrenalectomy were reviewed. The incidence of adrenal
metastasis was 5.7%. Importantly, tumor stage correlated
with the probability of adrenal involvement, with T4,
T3, and T1 to T2 tumors accounting for 40%, 7.8%, and
0.6% of cases, respectively. Also, preoperative CT imag-
ing demonstrated 99.6% specificity and a 94.4% negative
predictive value. Similarly, Paul et al.87 evaluated 866
consecutive patients undergoing ORN with ipsilateral
 Chapter 11 Renal Cell Carcinoma: Localized Disease 205
adrenalectomy. In their series, a total of 27 (3.1%) of
adrenal metastasis were found. Of the 27 patients, 21 had
multiple metastases at diagnosis and only 6 (0.7%) pre-
sented with solitary ipsilateral adrenal metastasis.
Univariate and multivariate analysis revealed tumor size
and M stage as best predictors of adrenal involvement.
They concluded that adrenalectomy was not necessary if
the tumor was less than 8 cm in size on preoperative CT
imaging and there was no evidence of metastasis or
extension from adjacent renal tissue.
ROLE OF LYMPHADENECTOMY
The incidence of lymph node metastasis in RCC ranges
from 13% to 32%, with increasing incidence with higher
stage tumors.88 The regional nodal drainage is different
in the right and left sides.89 The left kidney most often
drains to the para-aortic nodes in the lumbar region,
whereas the right kidney drains primarily to the interaor-
tocaval and paracaval nodes.89 Figure 11-3 demonstrates
the borders of a lymph node dissection. Regretfully, sec-
ondary to the frequently aberrant drainage pattern of the
Figure 11-3 Lymph node dissection for RCC.
lymph nodes draining the kidney, an extended lym-
phadenectomy would be necessary to potentially remove
all involved lymph nodes.
Regional lymph node dissection for the treatment of
RCC may be unnecessary in patients with no evidence of
lymph node enlargement on preoperative studies or dur-
ing surgery. Minervini et al.90 showed no difference in
5-year survival between a group of 108 patients who
underwent radical nephrectomy alone versus 49 patients
who underwent radical nephrectomy plus a regional
lymph node dissection. Of the 49 patients with no suspi-
cion of lymph node involvement, only 1 (2%) had a his-
tologically confirmed positive node. This is in agreement
with the results of the EORTC Genitourinary Group in
that only 1.0% of patients with no suspicion of involve-
ment had nodal disease.88 There is often variability in the
surgical dissection and pathologic examination of nodal
tissue. In patients with no evidence of nodal enlargement,
a regional lymph node dissection (open or laparoscopic)
is not frequently beneficial.
Whether patients with evidence of suspicious lymph
nodes garner any benefits from an extended dissection at
206 Part III Kidney and Ureter
the time of nephrectomy also remains controversial.
Improved pathologic staging does provide information
for guiding subsequent systemic immunotherapy.
However, the data demonstrating improved survival rates
in patients undergoing lymphadenectomy are based
solely on nonrandomized retrospective studies,91,92 with
multiple studies arguing against its utility.93,94 The only
prospective trial comparing radical nephrectomy with
and without lymphadenectomy (EORTC 30881) demon-
strated no increase in morbidity with lymphadenectomy,
but the results are too premature to determine any sur-
vival benefits.88 Importantly, a complete laparoscopic
lymph node dissection can be performed if the surgeon
desires. Several investigators reporting their results with
laparoscopic retroperitoneal lymph node dissections for
teste tumors have validated this.95,96
ROLE OF NEPHRECTOMY WITH ADVANCED
DISEASE
While RCC is being diagnosed at an earlier stage,
approximately 30% of patients still present with metasta-
tic disease, and 30% to 50% of initially localized tumors
eventually progressing to metastatic disease.91,97 RCC is
a unique cancer, in that removal of the primary tumor has
been associated with rare spontaneous regression of
metastasis.98 However, review of this phenomenon has
demonstrated an overall incidence of only 0.7% com-
pared to a mortality rate with nephrectomy of between
1% and 5%.99,100 Thus, nephrectomy alone in the face of
metastatic disease is not generally curative and must be
considered palliative. The debate arises whether
nephrectomy with or without metastasectomy in combi-
nation with adjuvant immunotherapy improves response
rates, and ultimately, patient survival.
Surgical removal of the primary tumor along with iso-
lated metastatic lesions has been demonstrated to be
effective for colon cancer metastatic to the liver.101
Numerous retrospective studies have suggested a survival
benefit for surgical extirpation of metastatic RCC
lesions. van der Poel et al.102 reported on 152 resections
of RCC metastases performed in 101 patients. Patients
demonstrated a median survival of 28 months after the
initial metastasectomy. Improved survival correlated with
pulmonary metastases and a tumor-free interval of more
than 2 years between primary tumor and metastasis.
Surprisingly, the number of metastases and additional
immuno- or radiation therapy did not influence survival.
Numerous studies have suggested that cytoreductive
nephrectomy prior to immunotherapy for unresectable
metastatic RCC may improve response rates.103,104
Regretfully, these studies are retrospective and nonran-
domized, making them subject to negative selection bias.
Recently, however, the SWOG conducted a randomized
prospective study examining the role of nephrectomy
prior to immunotherapy versus immunotherapy alone in
patients with metastatic RCC.105 They found that while
there was no significant difference in the radiologic
response rates of metastatic deposits between the two
groups, the nephrectomy group had a statistically signif-
icant improved survival (medial survival of 11.1 versus 8.1
months). Importantly, there was only one operative mor-
tality, low operative morbidity (4.9%), and negligible
delay to the institution of immunotherapy (median 19.9
days). Similarly, the EORTC Genitourinary Group
prospectively demonstrated a delay in time to disease
progression and an improved median survival in patients
treated with cytoreductive nephrectomy prior to sys-
temic immunotherapy.45 The only criticism with these
two studies is that they lack a group of patients that only
received nephrectomy, without immunotherapy. Thus, it
is impossible to assess the true benefit of immunotherapy
in the patients’ improved survival.
Finally, to avoid the potential surgical morbidity of
nephrectomy in patients who will not respond to
immunotherapy, several investigators have proposed
neoadjuvant immunotherapy, and reservation of surgery
only for patients that demonstrate a response.106,107
Rackley et al.108 demonstrated a slightly higher objective
response rate and longer median survival rates for
patients treated with initial immunotherapy followed
by surgery compared to patients who underwent pri-
mary nephrectomy and adjuvant immunotherapy.
Krishnamurthi et al.46 reported on a selected population
of 14 patients with metastatic RCC who underwent ini-
tial immunotherapy followed by surgical resection of pri-
mary and metastatic lesions. All 14 patients either had an
objective response to immunotherapy (9) or stable
disease (5) following immunotherapy. Their 3-year can-
cer-specific survival rate was an impressive 81.5%, sug-
gesting that patients that respond favorable to initial
immunotherapy may represent a biologically more favor-
able group.
PARTIAL NEPHRECTOMY (OPEN OR
LAPAROSCOPIC)
The first report of a partial nephrectomy was by Wells in
1884 when he described this technique for a perirenal
fibrolipoma.109 NSS was initially proposed for the surgi-
cal management of patients in that radical nephrectomy
would render them functionally anephric. This consisted
of patients with bilateral renal tumors, tumors in a soli-
tary kidney, and patients with preexisting renal insuffi-
ciency. Due to the excellent results seen in these patient
populations, the indications for NSS have expanded to
include all patients with small renal tumors (<4 cm).
Fergany et al.47 reported on their long-term results of
NSS for sporadic RCC in 107 patients treated with par-
tial nephrectomy prior to 1988. They reported 5- and
 Chapter 11 Renal Cell Carcinoma: Localized Disease 207
10-year cancer-specific survival rates of 88.2% and 73%,
respectively. Isolated recurrences in the ipsilateral kidney
were seen in only 2 patients (4%) at a mean follow-up of
104 ± 57 months. These results are even more impressive
considering that tumors were symptomatic in 68%
of cases, bilateral in 50%, and more than 4 cm in 45%.
A subset of patients (29) that met currently accepted
indications for elective NSS (unilateral tumors <4 cm)
demonstrated a 100% cancer-specific survival at 10 years.
Importantly, although almost 40% of patients had preop-
erative renal insufficiency (creatinine ≥1.5 mg/dl), renal
function was preserved in the majority of patients, with
100 patients (93%) maintaining adequate renal function
to avoid dialysis.
Technique
Open3 and LPN adhere to the same operative principle;
removal of the tumor with a margin of normal
parenchyma. The main complications of this procedure
are bleeding and urinoma formation. Bleeding can be min-
imized with hilar clamping or with the application of
parenchymal compression and renal injury can be reduced
through cold ischemia. Urinoma formation can be avoided
through direct suture repair of any entry into the collect-
ing system. Due to the inherent limitations of intracorpo-
real suturing and renal cooling, numerous adjunctive
techniques have been developed to facilitate LPN.110–113
Nonetheless, this is an advanced laparoscopic procedure,
which is best reserved for smaller exophytic tumors. With
the advent of improved instrumentation and experience
with the laparoscopic approach, Gill et al.114 have reported
on an increasing experience treating larger, more complex
central tumors, mimicking the open technique.
Surgical Margin
Historically, the surgical dictum has always been to excise
at least a 1-cm margin of normal peritumoral renal
parenchyma during partial nephrectomy to decrease the
risk of local tumor recurrences. This principle was based on
scant evidence and has recently been challenged. Lerner
et al.115 reported similar local recurrence and survival rates
in patients that underwent tumor enucleation compared to
standard partial nephrectomy. Sutherland et al.116 reported
on 41 patients, with a mean postoperative follow-up of
49 patients, who underwent partial nephrectomy for small
renal tumors (mean size = 3.2 cm). With a median surgical
margin of only 0.2 cm (range 0.05 to 0.70), no patient with
a negative parenchymal surgical margin had a local recur-
rence at the resection area. Thus, for low stage tumors,
margin size was irrelevant as long as the surgical bed was
free of residual tumor. Importantly, multiple biopsies from
the bed of the tumor resection should be performed to con-
fer margin status. These results suggest that in lieu of a
negative margin, the extent of peritumoral normal
parenchyma excised is not significant.
RENAL TUMOR ABLATION
With the advent of improved imaging modalities, the
vast majority of renal tumors detected are of low grade
and stage. In the past, options were limited to observa-
tion or partial/radical nephrectomy. While tumors less
than 3-cm rarely metastasize, the natural history of RCC
is unpredictable and observation may not be in the best
interest of the patient for a disease with no effective sys-
temic treatment.117,118 Thus, ablative therapy provides a
minimally invasive modality for the treatment of these
small tumors that minimizes the risks and morbidity tra-
ditionally associated with open or LPN.
Cryoablation
Cryoablation involves the destruction of cells by rapid-
freeze thaw cycles, with complete necrosis of renal
parenchyma occurring at temperatures of −19.4 ˚C or
lower.119 Delworth et al.120 first described open renal
cryoablation of an RCC in 1996, and since then it has
been performed by several investigators laparoscopi-
cally6,121 and percutaneously.122 Gill et al.7 and
Shingleton and Sewell123 recently reported on two large
series of laparoscopic and percutaneous renal cryoabla-
tion, respectively.
Gill et al.7 reported short-term follow-up of 32 patients
undergoing laparoscopic renal cryoablations who had exo-
phytic enhancing renal masses less than 4 cm in size.
Anteriorly located tumors were approached via a
transperitoneal route, while posterior and lateral tumors
were approached retroperitoneally. Once exposed and ver-
ified with color Doppler ultrasound, the renal tumor was
biopsied prior to cryoablation. Under direct laparoscopic
and real-time ultrasonic visualization the tumor was punc-
tured with a 4.8-mm cryoprobe, and the tumor was treated
with a double freeze–thaw cycle. Treatment was stopped
when the ice ball was seen to extend approximately 1 cm
beyond the edge of the tumor. Follow-up imaging con-
sisted of MRI scans obtained on postoperative day 1 and
then at 1, 2, 3, 6, and 12 months. CT-guided core needle
biopsies were obtained at 3 or 6 months.
All procedures were performed laparoscopically with-
out the need for open conversion. Mean tumor size by
intraoperative ultrasound was 2 cm with an average blood
loss of 66.8 ml (range 10 to 200). There were no major
intraoperative complications and two minor postopera-
tive complications that did not require surgical interven-
tion. Among 20 patients imaged with MRI at 1 year,
5 patients had no cryolesion identified and 15 patients
had a 66% reduction in cryolesion size. None of the
23 patients who had CT-guided biopsies at 3 or 6 months
208 Part III Kidney and Ureter
had evidence of residual cancer on histopathologic analy-
sis. The authors noted that while CT-guided biopsies
have a reported false-negative rate of 16%,124 the absence
of cancer on all of the 23 biopsies is encouraging.
However, they appropriately cautioned that long-term
follow-up is warranted to assess the true efficacy of
cryoablation for small renal tumors.
Shingleton and Sewell123 initially reported their series
of 20 patients treated with MRI-guided percutaneous
cryoablation with a mean follow-up of 9.1 months (range
3 to 14). For this procedure, a high Telsa open MRI unit
is necessary. The patients were administered a general
anesthetic (18) or intravenous sedation (2) and placed
prone on the interventional MRI docking table. Axial fast
spin echo images were obtained to determine probe entry
site and angle of insertion. The cryoprobe, which is 2 or
3 mm in diameter and 15 cm in length (Galil Medical, Tel
Aviv, Israel) was then activated for a total of 3
freeze–thaw cycles. Periodic reimaging was performed to
monitor ice ball propagation and to ensure treatment 5
mm beyond the edge of the mass while avoiding damage
to the collecting system and surrounding structures.
Following probe removal after the third cycle, the access
sheath was packed with absorbable knitted fabric or
absorbable gelatin sponge pledgets to facilitate hemosta-
sis. Follow-up included MRI or CT scans at 1 week, and
1, 3, 6, and 12 months.
The mean procedure time was 97 minutes (range 56 to
172) and there were no intraoperative complications.
The only postoperative complication was a wound
abscess. On follow-up CT scan or MRI imaging, only
one mass of the 22 treated demonstrated continued con-
trast enhancement. This patient was subsequently
retreated and 6-month follow-up imaging showed no
residual enhancement. Overall 20 of the 22 masses either
completely resolved or decreased in size. While routine
post ablation biopsies were not performed, two core
biopsies of tumors with rim enhancement were both neg-
ative for malignancy. As with Gill’s series, the mean fol-
low-up was short at 9.1 months (range 3 to 14).
Table 11-6 Clinical Tumor Ablation Series
Author Technique
Sung et al.126 Laparoscopic cryoablation
Shingleton et al.127 Percutaneous cryoablation
Jacomides et al.128 Laparoscopic RF ablation
McGovern et al.129 Percutaneous RF ablation
Pavlovich et al.130 Percutaneous RF ablation
*Successful ablation defined as no contrast enhancement on follow-up CT imaging.
†Negative CT-directed biopsy at 3–6 months.
Recently, Shingleton and Sewell125 reported on
longer-term follow-up of their series. A total of 65
patients were treated with percutaneous cryoablation and
followed for a mean of 18 months (range 2 to 30). While
9 patients required more than one treatment for com-
plete ablation, 60 patients were alive without evidence of
local disease recurrence at last follow-up. As longer fol-
low-up becomes available we will be better able to assess
the true efficacy of this technology (Table 11-6).
Radiofrequency Ablation
Much of the experience using radiofrequency (RF)
energy for ablative therapy has come from the treatment
of liver tumors.131,132 Zlotta et al.133 were the first to
describe the effects of RF ablation on human renal
tumors prior to nephrectomy in 1997. Since then, RF
energy has been utilized both laparoscopically111 and
percutaneously130,134 for the treatment of small renal
tumors. RF energy employs alternating electric current
to agitate tissue ions in proximity to the probe, resulting
in frictional heating of the tissue around the RF elec-
trodes. Heating of tissues to 50 to 55 ˚C for 4 to 6 min-
utes produces irreversible cell damage while
temperatures between 60 and 100 ˚C result in tissue
coagulation and almost instantaneous cell death.135
Walther et al.136 demonstrated necrosis in 10 of 11
tumors treated intraoperatively by RF ablation prior to
surgical removal.
Gervais et al.134 were the first to report their experi-
ence with percutaneous RF ablation of 9 tumors in
8 patients. The mean tumor size was 3.3 cm (range 1.2 to
5.0) and all tumors showed contrast enhancement on
preablation CT or MRI imaging. Seven of 9 tumors
treated had biopsy proven RCC prior to ablation.
Patients were anesthetized with intravenous sedation,
and tumors were localized with ultrasound or CT guid-
ance. RF ablation was performed with an RF generator
(Cosman Coagulator CC-1; Radionics, Burlington, MA)
and single (one 2.0 to 3.0-cm tip) or cluster of (three 2.5-
Mean Tumor Successful Mean Follow-up
Patients Size (cm) Ablation* (months)
50 2.1 97% (30/31)† 18.8
35 3.7 86% (30/35) 12
11 2.1 100% (11/11) 9.8
17 1–5.5 84% (15/18) 6–36
21 2.4 79% (21/24) 2.0
 Chapter 11 Renal Cell Carcinoma: Localized Disease 209
cm tip) cooled tip electrodes. Once the electrodes were
appropriately positioned, the tumor was treated for
12 minutes at a current of 1500 to 1800 mA. The elec-
trodes were repositioned in larger tumors to ensure com-
plete tumor ablation, and additional treatments at a
separate setting were necessary in 4 patients (total of
14 treatments). Unlike cryoablation, real-time ultra-
sound imaging is not effective in monitoring the RF
lesions acutely.137 Therefore, the only true measure of
treatment success is diligent follow-up imaging with or
without image-guided biopsies. Gervais et al.134 per-
formed CT or MRI at 1, 3, and 6 months, and then every
6 months thereafter.
Percutaneous RF treatments are well tolerated, and 12
of the 14 treatments reported by Gervais et al.134 were
conducted on an outpatient basis. There was one compli-
cation attributable to the RF ablation in a patient that
sustained a large paranephric and renal pelvis hematoma
necessitating a ureteral stent and blood transfusion.
Follow-up imaging at 6 months demonstrated no tumor
enhancement in all 5 exophytic tumors and all 3 tumors
less than 3 cm. Conversely, 2 of the 3 central tumors
measuring 4.4 and 5.0 cm, respectively, demonstrated
persistent contrast enhancement necessitating repeat
treatments. While these short-term results (mean follow-
up = 10.3 months) are encouraging, the authors recom-
mend this treatment only for exophytic tumors less than
3 cm in size.
Pavlovich et al.130 reported their experience at The
National Cancer Institute with percutaneous renal
tumor ablation in patients with either von Hippel-
Lindau clear cell tumors or hereditary papillary RCC.
Patients with CT scan demonstrating solid renal tumors
3 cm or less than enlarged during the previous year were
considered candidates for ablative therapy. In conjunc-
tion with an interventional radiologist, the authors local-
ized and targeted the tumors with either ultrasound
or CT guidance. Then under intravenous sedation or
general anesthesia, the RITA probe (RITA Medical
Systems, Mountain View, CA) was positioned into the
tumor and the electrodes deployed until the tumor vol-
ume was completely covered. The tumors were then
treated to a target temperature of 70 ˚C for two or three
10 to 12-minute cycles, depending on the size and loca-
tion of the tumors.
A total of 21 patients underwent RF ablation of 24
tumors. The mean diameter of the tumors treated was
2.4 cm (range 1.5 to 3.0). All patients tolerated the pro-
cedure and were medically stable for discharge from the
hospital within 24 hours. There were no major compli-
cations, though 2 patients suffered flank pain on ipsilat-
eral hip flexion and 2 complained of skin numbness on
the ipsilateral flank. Follow-up CT imaging at 2 months
revealed absence of contrast enhancement in 19 of the 24
(79%) tumors treated. Of the 5 tumors that continued to
demonstrate persistent contrast enhancement, 4 did not
reach target treatment temperature at each of the elec-
trodes for the entire treatment period. While results are
promising, 79% successful ablation is less than ideal.
Recently, we have reported successful RF ablation in 12
of 13 tumors (93%) at a short-term follow-up of only 4.9
months.
Laparoscopic RF ablation can also be performed for
renal tumors that are not amenable to percutaneous abla-
tion or for tumors that cannot be safely treated with LPN
because of location. Yohannes et al.138 were the first to
describe retroperitoneoscopic RF ablation of a solid renal
mass in an 83-year old man. The tumor was 2.0 cm in
size and located on the anterior surface of the kidney.
Due to extensive comorbidities and renal insufficiency,
laparoscopic RF ablation was performed rather than par-
tial nephrectomy. The advantages of the laparoscopic
approach are that it allows biopsy of the renal mass and
overlying fat prior to ablation, and also provides direct
visualization of the surrounding structures minimizing
potential injury.
Jacomides et al.128 have performed laparoscopic
transperitoneal RF ablation of 11 tumors in 8 patients.
The mean tumor size was 2.1 cm (range 1.0 to 3.6) with
an average blood loss of only 44 cc (range 20 to 100).
Biopsy of the tumors following ablation revealed RCC in
6 patients, acute myelogenous leukemia (AML) in
1 patient and 4 oncocytomas in a single patient who
underwent multiple ablations. The only complication
was transient elevation in serum creatinine to 1.8 mg/dl
in the patient with multiple ablations. Follow-up CT
imaging at 6 weeks lack of contrast enhancement in all of
the tumors treated. The advantages of the laparoscopic
approach are that anterior tumors can be safely treated,
surrounding structures can be directly visualized and
avoided, and adequate tissue specimens can be obtained
for pathologic analysis. There have been reports of vary-
ing efficacy of RF, but this likely represents engineering
and technical problems rather than a primary deficiency
of RF.
High-Intensity Focused Ultrasound
High-intensity focused ultrasound (HIFU) is a nonin-
vasive technique of delivering ultrasonic energy to a
specific area within the body. The ultrasound energy
can be focused into a small volume (1 cc) so that tem-
perature at the treatment site reaches 90 ˚C and the
intervening tissue between the transducer and target is
theoretically unaffected. As with the other ablative
technologies, the cells at the treatment site undergo
coagulative necrosis and cell death. HIFU was first
investigated as a nonsurgical treatment for experimen-
tal liver tumors in the rabbit model.139 Soon afterward,
Foster et al.140 investigated the creation of prostatic
210 Part III Kidney and Ureter
lesions in the canine prostate with transrectally deliv-
ered HIFU. Subsequently, HIFU has been utilized
clinically for the treatment of benign141 and malignant
diseases142 of the prostate.
Chapelon et al.143 were the first to explore the tissue
effects of transcutaneous delivery of HIFU to kidneys
in the canine model. Adams et al.144 subsequently
investigated the feasibility of treating renal tumors with
HIFU in the rabbit model. In their study, renal tumors
were induced and then treated with HIFU by placing
the transducer either on the kidney or transcuta-
neously. With the transducer on the kidney surface
opposite the tumor location, the HIFU was able to cre-
ate well-defined areas of necrosis of the tumor and
renal parenchyma. Transcutaneous delivery resulted in
less well-defined treatment areas, with only 7 of 9 rab-
bits demonstrating ablation of the tumors. Four of the
rabbits suffered 1 cm skin burns in areas where the
probe contacted the skin. Of note, there were no
injuries to adjacent organs. Similar problems of incon-
sistent treatment zones and injuries to the skin have
been noted in transcutaneous HIFU in the porcine
model.145
In a phase 1 study in humans, Vallancien et al.146
treated 4 patients with T2 and T3 kidney tumors with
pyrotherapy (HIFU) 2, 6, 8, and 15 days prior to
nephrectomy. In all cases, histology demonstrated coag-
ulative necrosis in the targeted tumor areas. As in the
previous animal studies, there was one case of a superfi-
cial skin burn attributed to an error in dosimetry calcula-
tion. While HIFU represents the ultimate in minimally
invasive treatment of small renal tumors, the problems of
imprecise targeting and thermal burns to the overlying
skin have prevented its widespread use. The Cyberknife,
which has been extensively used for the treatment of
brain tumors, is an additional extracorporeal means of
renal tissue ablation currently being evaluated in animal
models.147
PROGNOSTIC FACTORS
A prognostic factor is a marker that can be used to
determine progression of a disease or its arrest.
Reliable prognostic factors for RCC would allow
physicians to avoid ineffective treatment and enroll
patients earlier in either conventional treatments or
therapeutic trials. A recent review article by Mejean
et al.148 separated prognostic factors into three sepa-
rated subgroups of those associated with the tumor, the
patient, and the treatment.
Tumor stage, which reflects the anatomic extent of the
tumor, is the most widely utilized prognostic factor for
RCC. While there have been numerous staging systems
developed, the TNM classification system (Table 11-7)
has become the gold standard for most tumors, including
Table 11-7 2002 TNM Classification
Primary Tumor (T)
Tx: Primary tumor cannot be assessed
T0: No evidence of primary tumor
T1: Tumor 7 cm or less in greatest dimension, limited to
the kidney
T2: Tumor extends more than 7 cm in greatest dimension,
limited to the kidney
T3: Tumor extends into major veins or invades adrenal
gland or perinephric tissues but not beyond Gerota’s
fascia
T3a: Tumor directly invades adrenal gland or perirenal
and/or renal sinus fat but not beyond Gerota’s fascia
T3b: Tumor grossly extends into the renal vein or its
segmental (muscle-containing) branches, or vena cava
below the diaphragm
T3c: Tumor grossly extends into vena cava diaphragm or
invades the wall of the vena cava
T4: Tumor invades beyond Gerota’s fascia
Regional Lymph Nodes (N)
Nx: Regional lymph nodes cannot be assessed
N0: No regional lymph node metastases
N1: Metastases in a single regional lymph node
N2: Metastasis in more than one regional lymph node
Distant Metastasis (M)
Mx: Distant metastasis cannot be assessed
M0: No distant metastasis
M1: Distant metastasis
From Javidan J, Stricker HJ, Tamboli P, et al: Prognostic significance
of the 1997 TNM classification of renal cell carcinoma. J Urol 1999;
162:1277–1281, with permission.
RCC. In 1997, the classification system was modified so
that the transition point between T1 and T2 tumors was
changed from 2.5 cm to the current size of 7 cm. This
change was initially undertaken because multivariant
analysis demonstrated improved survival stratification
with the 7 cm cutoff.149,150 Subsequent analyses have sug-
gested that 7 cm may be too high and that the T1 classi-
fication should be subclassified into T1a and T1b groups.
However, the exact cutoff between these subgroups is
debated, with studies proposing values of 4.0,151 5.5,152
 Chapter 11 Renal Cell Carcinoma: Localized Disease 211
and 6.6 cm,150 respectively. A range between 4.0 and
4.5 cm seems most reasonable from pathologic, techni-
cal, and prognostic considerations. These issues will most
likely be represented by modifications in The American
Joint Committee on Cancer 6th Edition of TNM
Staging.
Venous involvement with tumor thrombus is relatively
common in RCC compared to most tumors. The prog-
nostic significance of tumor thrombi has been debated,
most likely due to difficulties in differentiating tumor
thrombus from blood clot and quantifying vascular inva-
sion. Some investigators believe that tumor thrombus, no
matter the level, is independently associated with a
decreased prognosis.153,154 Others have demonstrated no
differences in overall survival with the presence of tumor
thrombi.155,156 The presence of gross, as well as
microvascular, vascular invasion has been unanimously
associated with an increased incidence of metastasis and
reduced cancer-specific survival.157
Metastatic disease is associated with a poor prognosis.
Prognostic factors identified by multivariant analysis
include PS, number of sites, time to appearance, and
location. Poor PS has been demonstrated to be inde-
pendently associated with a decreased cancer-specific
survival.158 Multiple metastatic sites have a worse prog-
nosis compared to single metastatic deposits.159,160 The
appearance of metastases within 12 months from the
original diagnosis is associated with a poor progno-
sis.161,162 Finally, isolated metastatic disease within the
lung tends to have a better prognosis compared to other
organs.102
Complex histologic and molecular analysis of tumor
specimens is becoming a routine part of determining
tumor biology and ultimate prognosis. Histologic tumor
type is readily available, with poor prognosis associated
with collecting duct carcinoma,163 renal medullary carci-
noma,24 and the presence of sarcomatoid features.164
Grading as described by Fuhrman and colleagues, which
is based on nucleolar aspect, size and content, has been
shown to be an independent determinant of prognosis in
multiple studies.165,166 Nuclear morphometric studies
have been demonstrated to correlate with prognosis, but
most investigators have been disappointed with the abil-
ity of these parameters to offer independent prognostic
information.167–169 Finally, molecular markers are an
exciting area of research but none have reached common
use in the clinical setting.
Patient factors seem to be very important to the over-
all prognosis. As would be expected, patients present with
“incidentalomas” were found to have tumors of lower
stage and grade, with a lower incidence of metastases and
longer survival compared to patients presenting with
symptomatic tumors.170 As stated above, PS, which com-
bines symptoms and comorbidities, has been noted as an
independent prognostic variable in most series. The
Eastern Cooperative Oncology Group (ECOG) PS of 2
or greater has been associated with a poorer response to
immunotherapy171,172 and shorter survival.153,159,173
Biologic factors, such as an increased erythrocyte sedi-
mentation rate,174 elevated platelet counts,175 and hemo-
globin concentration of less than 10 mg/dl,176 have been
found to be poor prognostic factors.
Finally, numerous investigators have attempted to
combine multiple prognostic factors to further improve
the overall accuracy. Kattan et al.177 from Memorial
Sloane-Kettering Cancer Center developed a nomogram
to predict recurrence after surgery for RCC combining
the following predictor variables: patient symptoms,
including incidental, local or systemic, histology, includ-
ing chromophobe, papillary or conventional, tumor size,
and pathologic stage. Similarly, Zisman et al.178 at the
University of California at Los Angeles developed the
UCLA Integrated Staging System (UISS) to stratify
patients into survival groups after surgery. Combining
and stratifying TNM staging, Fuhrman’s grade and
ECOG PS resulted in five separate survival groups. The
projected 2- and 5-year survival rates for the five groups
were, respectively: I, 96% and 94%; II, 89% and 67%;
III, 66% and 39%; IV, 42% and 23%; V, 9% and 0%.
Both of these systems, compared to individual prognostic
factors, provide the physician and patient a more accurate
means of predicting survival. This will help better deter-
mine candidates for adjuvant therapy and enrollment in
experimental trials.
SCREENING
The high proportion of incidentally discovered renal
tumors combined with improved survival of these lower
stage tumors suggests the possibility of screening for
RCC. However, it must be remembered that RCC
accounts for only 2% of solid renal tumors, and even in
selected populations of patients with hematuria, the
prevalence is only 3% to 6%.179,180 The US Preventative
Services Task Force (1996) and the Canadian Task Force
on the Periodic Health Examination both recommend
against routinely screening asymptomatic patients for
hematuria to identify those with urologic malignan-
cies.181 Tosaka et al.182 performed screening ultrasounds
in a population of 41,364 asymptomatic people and
found only 19 (0.04%) renal adenocarcinomas. They cal-
culated that for every cancer detected, 2177 ultrasounds
had to be performed. Thus, they concluded that the
immense cost incurred would be prohibitive, and that
screening should be reserved for patients at risk, such as
von Hippel-Lindau disease, hereditary RCC, and
acquired renal cystic disease. Therefore, population-
based screening for renal cancer with urinalysis and renal
imaging can only be recommended for patients at risk for
a renal malignancy.
212 Part III Kidney and Ureter
SUMMARY
The treatment of RCC has undergone a dramatic change
over the past several decades. While the systemic treat-
ment of advanced disease has made relatively little
progress, surgical treatment of local RCC is continuously
evolving. Recent studies have indicated that radical
nephrectomy is warranted for certain patients in the face
of metastatic disease. For all but the largest of renal tumors
or the presence of renal vein thrombi, ORN has been
replaced with LRN. Even these cases are starting to be
tackled laparoscopically by some surgeons. Additionally,
small renal tumors are being treated with nephron-sparing
surgery, despite normal contralateral kidneys. Even open
partial nephrectomy is now being challenged by exciting
new laparoscopic and ablative techniques. While the long-
term results of these techniques are still maturing, the ini-
tial results are very promising.
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216 Part III Kidney and Ureter
129. McGovern FJ, McDougal WS, Gervais D, et al:
Percutaneous radiofrequency ablation of human renal
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130. Pavlovich CP, Walther MM, Choyke PL, et al:
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131. Curley SA, Izzo F, Ellis LM, et al: Radiofrequency
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132. Wood TF, Rose DM, Chung M, et al: Radiofrequency
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134. Gervais DA, McGovern FJ, Wood BJ, et al: Radio-
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135. Rhim H, Goldberg N, Dodd GD, et al: Essential
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136. Walther MC, Choyke PL, Libutti SK: A phase 2 study of
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137. Dupuy DE, Goldberg SN: Image-guided radiofrequency
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139. Yang R, Reilly CR, Rescorla FJ, et al: High-intensity
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140. Foster RS, Bihrle R, Sanghvi N, et al: Production of
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141. Bihrle R, Foster RS, Sanghvi NT, et al: High intensity
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142. Gelet A, Chapelon JY, Bouvier R: Treatment of organ
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143. Chapelon JY, Margonari J, Theillere Y, et al: Effects of
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144. Adams JB, Moore RG, Anderson JH, et al: High-
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145. Watkin NA, Morris SB, Rivens IH, et al: High-intensity
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146. Vallancien G, Chartier-Kastler E, Harouni M, et al:
Focused extracorporeal pyrotherapy: experimental study
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147. Ponsky LE, Crownover RL, Rosen MJ, et al: The initial
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148. Mejean A, Oudard S, Thiounn N: Prognostic factors of
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149. Javidan J, Stricker HJ, Tamboli P, et al: Prognostic
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150. Gettman MT, Blute ML, Spotts B, et al: Pathologic
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151. Hafez KS, Fergany AF, Novick AC: Nephron sparing
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152. Kinouchi T, Saiki S, Meguro N, et al: Impact of tumor
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153. Giberti C, Oneto F, Martorana G, et al: Radical
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154. Tongaonkar HB, Dandekar NP, Dalal AV, et al: Renal
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155. Elfving P, Mandahl N, Lundgren R, et al: Prognostic
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156. Medeiros LJ, Gelb AB, Weiss LM: Renal cell carcinoma.
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157. Griffiths DF, Verghese A, Golash A, et al: Contribution
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158. Palmer PA, Vinke J, Philip T, et al: Prognostic factors for
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159. Elson PJ, Witte RS, Trump DL: Prognostic factors for
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160. Miyao N, Oda T, Shigyou M, et al: Pre-operatively
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161. Kavolius JP, Mastorakos DP, Pavlovich C, et al:
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162. Negrier S, Escudier B, Lasset C, et al: Recombinant
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 Chapter 11 Renal Cell Carcinoma: Localized Disease 217
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C H A P T E R
12 Surgery of Renal Cell Carcinoma,
Including Partial Nephrectomy
Andrew C. Novick, MD
Notwithstanding recent advances in our understanding
of the genetics and biology of renal cell carcinoma
(RCC), surgery remains the mainstay of curative treat-
ment for this disease. Nevertheless, the role of surgery is
changing with respect to both localized RCC and
patients with metastatic disease. Nephron-sparing sur-
gery has assumed an increasing role in the management
of localized tumors. The advent of promising
immunotherapy regimens and their adjunctive use with
surgery offers new hope for patients with disseminated
malignancy. This chapter will review the contemporary
role of surgery and specific operative techniques in the
management of patients with RCC.
RADICAL NEPHRECTOMY
Indications and Evaluation
Radical nephrectomy is the treatment of choice for
patients with localized RCC.1 The preoperative evalua-
tion of patients with RCC has changed considerably in
recent years due to the advent of new imaging modalities,
such as ultrasonography, computed tomography (CT)
scanning, and magnetic resonance imaging (MRI). In
many patients, a complete preliminary evaluation can be
performed using these noninvasive modalities. Renal
arteriography is no longer routinely necessary prior to
performing radical nephrectomy. All patients should
undergo a metastatic evaluation including a chest X-ray,
abdominal CT scan, and occasionally a bone scan; the
latter is only necessary in patients with bone pain or an
elevated serum alkaline phosphatase. Radical nephrec-
tomy is occasionally done in patients with metastatic dis-
ease to palliate severe associated local symptoms, to allow
entry into a biologic response modifier protocol, or con-
comitant with resection of a solitary metastatic lesion.
218
Involvement of the inferior vena cava (IVC) with
RCC occurs in 3% to 7% of cases and renders the task
of complete surgical excision more complicated. Yet,
operative removal offers the only hope for cure and,
when there are no metastases, an aggressive approach is
justified. Five-year survival rates of 40% to 58% have
been reported after complete surgical excision.2–5 The
best results have been achieved when the tumor does
not involve the perinephric fat and regional lymph
nodes. The cephalad extent of vena caval involvement
is not prognostically important and, even with intraa-
trial tumor thrombi, extended cancer-free survival is
possible following surgical treatment when there is no
nodal or distant metastasis.6 In planning the appropri-
ate operative approach for tumor removal, it is essen-
tial for preoperative radiographic studies to define
accurately the distal (craniad) limits of a vena caval
tumor thrombus.
RCC involving the IVC should be suspected in
patients who have lower extremity edema, a varicocele,
dilated superficial abdominal veins, proteinuria, pul-
monary embolism, a right atrial mass, or nonfunction of
the involved kidney. Currently, MRI is the preferred
diagnostic study for demonstrating both the presence
and distal extent of IVC involvement.7 Transesophageal
echocardiography (TEE) and transabdominal color flow
Doppler ultrasonography have also proven to be useful
diagnostic studies in this regard. Inferior vena cavogra-
phy is reserved for patients in whom an MRI or ultra-
sound study is either nondiagnostic or contraindicated.
Renal arteriography is particularly helpful in patients
with RCC involving the IVC since in 35% to 40% of
cases, distinct arterialization of a tumor thrombus is
observed. When this finding is present, preoperative
embolization of the kidney often causes shrinkage of the
 Chapter 12 Surgery of Renal Cell Carcinoma, Including Partial Nephrectomy 219
thrombus that facilitates its intraoperative removal.
When adjunctive cardiopulmonary bypass with deep
hypothermic circulatory arrest is considered, coronary
angiography is also performed preoperatively.4 If signif-
icant obstructing coronary lesions are found, these can
be repaired simultaneously during cardiopulmonary
bypass.
Radical nephrectomy encompasses the basic princi-
ples of early ligation of the renal artery and vein,
removal of the kidney outside Gerota’s fascia, removal
of the ipsilateral adrenal gland, and performance of a
complete lymphadenectomy from the crus of the
diaphragm to the aortic bifurcation.1 Perhaps the most
important aspect of radical nephrectomy is removal of
the kidney outside Gerota’s fascia, because capsular
invasion with perinephric fat involvement occurs in
25% of patients. Removal of the ipsilateral adrenal
gland is not routinely necessary unless the malignancy
either extensively involves the kidney or is located in the
upper portion of the kidney.8 Although lymphadenec-
tomy allows for more accurate pathologic staging, the
therapeutic value remains controversial. A study from
Giuliani and associates suggests that a subset of patients
with micrometastatic lymph node involvement may
benefit from performance of a lymphadenectomy.9 At
the present time, the need for routine performance of a
complete lymphadenectomy in all cases is unresolved,
and there remains a divergence of clinical practice
among urologists with respect to this aspect of radical
nephrectomy.
Figure 12-1 The anatomic relationship of the kidneys to the surrounding structures. The
liver is retracted superiorly in this illustration.
Surgical Anatomy
The anatomic relationship of the kidneys to surrounding
structures is illustrated in Figure 12-1. The kidneys are
located on either side of the vertebral column in the lum-
bar fossa of the retroperitoneal space. Each kidney is sur-
rounded by a layer of perinephric fat that is in turn
covered by a distinct fascial layer termed Gerota’s fascia.
Posteriorly, both kidneys lie on the psoas major and
quadratus lumborum muscles. Posteriorly and superiorly,
the upper pole of each kidney is in contact with the
diaphragm.
A small segment of the anterior medial surface of the
right kidney is in contact with the right adrenal gland.
However, the major anterior relationships of the right
kidney are the liver, which overlies the upper two-
thirds of the anterior surface, and the hepatic flexure of
the colon, which overlies the lower one-third. The sec-
ond portion of the duodenum covers the right renal
hilum.
A small segment of the anterior medial surface of the
left kidney is also covered by the left adrenal gland. The
major anterior relationships of the left kidney are
the spleen, body of the pancreas, stomach, and splenic
flexure of the colon.
Surgical Incisions
The surgical approach for radical nephrectomy is deter-
mined by the size and location of the tumor as well as by
the habitus of the patient.10 The operation is usually per-
220 Part III Kidney and Ureter

formed through a transperitoneal incision to allow

abdominal exploration for metastatic disease and early
access to the renal vessels with minimal manipulation of
the tumor. Occasionally, an extraperitoneal flank incision
is employed in elderly patients or in patients with small
tumors who are also classified as poor risks.
The author prefers an extended subcostal or a bilateral
subcostal incision for most patients undergoing radical
nephrectomy (Figure 12-2). This incision provides better
access to the lateral and superior portion of the kidney
than a midline abdominal incision. When employing an
anterior subcostal incision, the patient is in the supine
position with a rolled sheet beneath the upper lumbar
spine. The incision begins approximately one to two fin-
gerbreadths below the costal margin in the anterior axil-
lary line and then extends with a gentle curve across the Figure 12-2 Patient positioning for anterior subcostal
midline, ending at the midportion of the opposite rectus transperitoneal incision.
muscle. The incision is carried through the subcutaneous
tissues to the anterior fascia, which is divided in the
direction of the incision. In the lateral aspect of the inci- from the tumor mass. The patient is placed in a semi-
sion, a portion of the latissimus dorsi muscle is divided. oblique position, with a rolled sheet placed longitudinally
The external oblique muscle is divided, exposing the beneath the flank. The incision is begun in the 8th inter-
fibers of the internal oblique muscle (Figure 12-3A). The costal space, near the angle of the rib, and is carried
rectus, internal oblique, and transversus abdominous across the costal margin to the midpoint of the opposite
muscles are divided along with the posterior rectus rectus muscle, above the umbilicus. The latissimus dorsi,
sheath (see Figure 12-3B and C). The peritoneal cavity is external oblique, rectus, and intercostal muscles are
entered in the midline, and the ligamentum teres is divided in the direction of the incision (Figure 12-5A).
divided (see Figure 12-3D). The pleura is then opened to obtain complete exposure of
The thoracoabdominal approach is preferable for per- the diaphragm (see Figure 12-5B and C).
forming radical nephrectomy in patients with large The diaphragmatic incision is made at the periphery
tumors involving the upper portion of the kidney (Figure about 2 cm inside its attachment at the chest wall with
12-4). It is particularly advantageous on the right side, the incision then being carried around circumferentially
where the liver and its venous drainage into the upper to the posterior aspect of the diaphragm (see Figure 12-5D).
vena cava can limit exposure and impair vascular control Circumferential incision of the diaphragm obviates dam-
as the tumor mass is being removed. Less need exists for age to the phrenic nerve and also creates a diaphragmatic
a thoracoabdominal incision on the left side because the flap, which can be pushed into the chest to provide com-
spleen and pancreas can usually be readily elevated away plete exposure of the liver, which is then retracted

Figure 12-3 A and B, The various steps in performing an anterior subcostal transperitoneal
incision are illustrated (see text for details).
 Chapter 12 Surgery of Renal Cell Carcinoma, Including Partial Nephrectomy 221
Figure 12-3 cont’d C and D, The various steps performing an anterior subcostal
transperitoneal incision are illustrated (see text for details).
upward (see Figure 12-5E). If further mobilization of the
liver is needed, the right triangular ligament and coro-
nary ligament can be incised to mobilize the entire right
lobe of the liver upward. This maneuver provides excel-
lent additional exposure of the suprarenal vena cava.
Medial to the ribs, the internal oblique and transversus
abdominous muscles are divided and the peritoneal cav-
ity is entered. The kidney and great vessels may then be
exposed by upward retraction of the liver and medial vis-
ceral mobilization (see Figure 12-5F ).
Left Radical Nephrectomy
After the peritoneal cavity is entered, a thorough explo-
ration is done to rule out metastatic disease. The poste-
Figure 12-4 Patient positioning for a right thoracoabdominal
incision.
rior peritoneum lateral to the left colon is incised verti-
cally and the incision is carried upward to divide the
lienorenal ligament. Care must be taken to avoid tearing
the delicate capsule of the spleen. The plane between the
kidney and adrenal gland posteriorly, and the pancreas
and spleen anteriorly, is developed by blunt dissection.
The left colon and duodenum are reflected medially, and
the pancreas and spleen are reflected cephalad, with care
taken not to injure the spleen or the pancreas (Figure
12-6). When adequate exposure of the kidney and great
vessels has been obtained, a self-retaining ring retractor
is inserted to maintain the operative field (Figure 12-7).
The operation is initiated with dissection of the renal
pedicle. The left renal vein is quite long as it passes over
the aorta. The vein is mobilized completely by ligating
and dividing gonadal, adrenal, and lumbar tributaries.
The vein can be retracted to expose the artery posteri-
orly, which is then mobilized toward the aorta (Figure
12-8). The renal artery is ligated with 2.0 silk ligatures
and divided, and the renal vein is then similarly managed.
The kidney is mobilized outside Gerota’s fascia with
blunt and sharp dissection as needed (Figure 12-9).
Remaining vascular attachments are secured with nonab-
sorbable sutures or metal clips. Visualization of the upper
vascular attachments is facilitated by downward retrac-
tion of the kidney. The ureter is then ligated and divided
to complete the removal of the kidney and adrenal gland
(Figure 12-10).
The classic description of radical nephrectomy
includes the performance of a complete regional lym-
phadenectomy. The lymph nodes can be removed en
bloc with the kidney and adrenal gland or separately, fol-
lowing the nephrectomy. The lymph node dissection is
222 Part III Kidney and Ureter

Figure 12-5 The various steps in performing a thoracoabdominal incision are illustrated (see
accompanying text).

begun at the crura of the diaphragm just below the origin
of the superior mesenteric artery. A readily definable
periadventitial plane is seen close to the aorta that can be
entered. The dissection may then be carried along the
aorta and onto the origin of the major vessels, to remove
all the periaortic lymphatic tissue. Care must be taken to
avoid injury to the origins of the celiac and superior
mesenteric arteries superiorly, as they arise from the
anterior surface of the aorta. The dissection of the
periaortic and pericaval lymph nodes is then carried
 Chapter 12 Surgery of Renal Cell Carcinoma, Including Partial Nephrectomy 223
downward en bloc to the origin of the inferior mesenteric
artery. The sympathetic ganglia and nerves are removed
together with the lymphatic tissue. The cisterna chyli is
identified medial at the right crus. Entering lymphatic
vessels are secured to prevent the development of chylous
ascites.
Right Radical Nephrectomy
On the right side, after entering the peritoneal cavity, the
posterior peritoneum lateral to the right colon is incised
vertically and the incision is carried high up along the
vena cava to the level of the hepatic veins. The right
colon and duodenum are reflected medially, and the liver
and gallbladder are retracted upward (Figure 12-11).
Care is taken to avoid trauma to the delicate hepatic
veins, which may enter the vena cava at this level. When
adequate exposure of the kidney and adrenal gland is
obtained, a self-retaining ring retractor is inserted to
maintain the operative field.
The vena cava and renal vein are retracted medially
and downward to expose the right renal artery.
Alternatively, with a large medial tumor, the renal artery
may be exposed between the vena cava and the aorta
(Figure 12-12). Ligation of the renal artery and vein is
performed as described on the left side with 2.0 silk liga-
tures. Since the right renal vein is usually short, ligation
should take place at the level of its entrance to the vena
cava. The remainder of the radical nephrectomy is per-
formed as described for left-sided tumors.
Radical Nephrectomy with Infrahepatic Vena Caval
Involvement
There are four levels of vena caval involvement in RCC
that are characterized according to the distal extent of the
tumor thrombus (Figure 12-13). A bilateral subcostal
transperitoneal incision usually provides excellent expo-
sure for performing radical nephrectomy and removal of
a perirenal or infrahepatic IVC thrombus. For extremely
large tumors involving the upper pole of the kidney, a
thoracoabdominal incision may alternatively be used.
After the abdomen is entered, the colon is reflected
medially and a self-retaining ring retractor is inserted to
maintain exposure of the retroperitoneum (Figure
12-14A). The renal artery and the ureter are ligated and
divided, and the entire kidney is mobilized outside
Gerota’s fascia leaving the kidney attached only by the
renal vein (see Figure 12-14B,C ). During the initial dis-
section, care is taken to avoid unnecessary manipulation
of the renal vein and vena cava.
The vena cava is then completely dissected from sur-
rounding structures above and below the renal vein, and
the opposite renal vein is also mobilized. It is essential to
obtain exposure and control of the suprarenal vena cava
above the level of the tumor thrombus. If necessary, per-
forating veins to the caudate lobe of the liver are secured
and divided to allow separation of the caudate lobe from
the vena cava. This maneuver can allow an additional 2 to
3 cm length of vena cava to be exposed superiorly. The
infrarenal vena cava is then occluded below the thrombus
with a Satinsky venous clamp, and the opposite renal vein
is gently secured with a small bulldog vascular clamp.
Finally, in preparation for tumor thrombectomy, a curved
Satinsky clamp is placed around the suprarenal vena cava
above the level of the thrombus (see Figure 12-14D).
The anterior surface of the renal vein is then incised
over the tumor thrombus and the incision is continued
posteriorly with scissors, passing just beneath the throm-
bus (see Figure 12-14E). In most cases, there is no attach-
ment of the thrombus to the wall of the vena cava. After
the renal vein has been circumscribed, gentle downward
traction is exerted on the kidney to extract the tumor
thrombus from the vena cava (see Figure 12-14F ). After
removal of the gross specimen, the suprarenal vena caval
clamp may be released temporarily as the anesthetist
applies positive pulmonary pressure; this maneuver can
ensure that any small remaining fragments of thrombus
are flushed free from the vena cava. When the tumor
thrombectomy is completed, the cavotomy incision is
repaired with a continuous 5-0 vascular suture (see
Figure 12-14G).
In occasional cases, there is direct caval invasion of the
tumor at the level of the entrance of the renal vein and
for varying distances. This requires resection of a portion
of the vena caval wall. Narrowing of the caval lumen by
up to 50% will not adversely affect maintenance of caval
patency. If further narrowing appears likely, caval recon-
struction can be performed with a free graft of peri-
cardium.
In some patients, more extensive direct growth of
tumor into the wall of the vena cava is found at surgery.
The prognosis for these patients is generally poor, par-
ticularly when hepatic venous tributaries are also
involved, and the decision to proceed with radical surgi-
cal excision must be carefully considered. Several impor-
tant principles must be kept in mind when undertaking
en bloc vena caval resection. Resection of the infrarenal
portion of the vena cava usually can be done safely,
because an extensive collateral venous supply will be
developed in most cases. With right-sided kidney
tumors, resection of the suprarenal vena cava is also pos-
sible provided the left renal vein is ligated distal to the
gonadal and adrenal tributaries, which then provide col-
lateral venous drainage from the left kidney with left-
sided kidney tumors. The suprarenal vena cava cannot be
resected safely owing to the paucity of collateral venous
drainage from the right kidney. In such cases, right renal
224 Part III Kidney and Ureter

Figure 12-6 After entering the peritoneal cavity, the colon is Figure 12-8 The left renal vein is mobilized by ligating its
reflected medially to expose the left kidney and great vessels. major branches to expose the artery posteriorly.

Figure 12-7 A self-retaining ring retractor is inserted to Figure 12-9 After securing the pedicle and dividing the
maintain exposure of the operative field. ureter, the kidney is mobilized outside Gerota’s fascia.
 Chapter 12 Surgery of Renal Cell Carcinoma, Including Partial Nephrectomy 225
Figure 12-10 Remaining medial vascular attachments are
secured and divided to complete the nephrectomy.
Figure 12-11 After entering the peritoneal cavity, the right
colon and duodenum are reflected medially to expose the
right kidney and great vessels.
venous drainage can be maintained by preserving a
tumor-free strip of vena cava augmented, if necessary,
with a pericardial patch; alternatively, the right kidney can
be autotransplanted to the pelvis or an interposition graft
of saphenous vein may be placed from the right renal vein
to the splenic, inferior mesenteric, or portal vein.
Figure 12-12 The right renal artery may be mobilized either
lateral to the vena cava (below) or between the vena cava
and the aorta (above).
Radical Nephrectomy with Intrahepatic
or Suprahepatic Vena Caval Involvement
In patients with RCC and an intrahepatic or suprahepatic
IVC thrombus, the difficulty of surgical excision is sig-
nificantly increased. In such cases, the operative tech-
nique must be modified because it is not possible to
obtain subdiaphragmatic control of the vena cava above
the tumor thrombus. Several different surgical maneu-
vers have been used to provide adequate exposure, pre-
vent severe bleeding, and achieve complete tumor
removal in this setting.4
One described technique for obtaining vascular con-
trol involves temporary occlusion of the suprahepatic and
intrapericardial portion of the IVC. To reduce hepatic
venous congestion and troublesome backbleeding, the
porta hepatis and superior mesenteric artery are also
temporarily occluded. A disadvantage of this approach is
that occlusion of the latter vessels can be safely tolerated
for only 20 minutes. This approach is also not applicable
in cases of tumor extension into the right atrium. At the
Cleveland Clinic, we have preferred to employ car-
diopulmonary bypass with deep hypothermic circulatory
arrest for many patients with supradiaphragmatic tumor
thrombi and for all patients with right atrial tumor
thrombi. We initially reported a favorable experience with
this approach in 43 patients,4 and a subsequent study has
shown excellent long-term cancer-free survival following
its use in patients with right atrial thrombi.6 The relevant
technical aspects are subsequently described.
226 Part III Kidney and Ureter
Figure 12-13 Classification of inferior vena caval thrombi according to the distal extent of
the thrombus as perineal, infrahepatic, intrahepatic, and suprahepatic.
A bilateral subcostal incision is used for the abdominal
portion of the operation. After confirming resectability, a
median sternotomy is made (Figure 12-15). Intraoperative
monitoring is accomplished with an arterial line, a multiple-
lumen central venous pressure catheter, and a pulmonary
artery catheter. Nasopharyngeal and bladder temperatures
are monitored. Anesthesia is induced with either fentanyl,
sufentanil, or thiopental and maintained with a narcotic
inhalation agent.11
The kidney is completely mobilized outside Gerota’s
fascia with division of the renal artery and ureter, such
that the kidney is left attached only by the renal vein. The
infrarenal vena cava and contralateral renal vein are also
exposed. Extensive dissection and mobilization of the
suprarenal vena cava are not necessary with this approach.
Adequate exposure is somewhat more difficult to achieve
for a left renal tumor. Simultaneous exposure of the vena
cava on the right and the tumor on the left is not readily
accomplished simply by reflecting the left colon medially.
We have dealt with this by transposing the mobilized left
kidney anteriorly through a window in the mesentery of
the left colon while leaving the renal vein attached. This
maneuver yields excellent exposure of the abdominal vena
cava with the attached left renal vein and kidney. Precise
retroperitoneal hemostasis is essential before proceeding
with cardiopulmonary bypass due to the risk of bleeding
associated with systemic heparinization.
The heart and great vessels are now exposed through
the median sternotomy. The patient is heparinized,
ascending aortic and right atrial venous cannulae are
placed, and cardiopulmonary bypass is initiated (Figure
12-16). When the heart fibrillates, the aorta is clamped
and crystalloid cardioplegic solution is infused. Under
circulatory arrest, deep hypothermia is initiated by reduc-
ing arterial inflow blood temperature as low as 10 ˚ C .
The head and abdomen are packed in ice during the cool-
ing process. After approximately 15 to 30 minutes, a core
temperature of 18 to 20 ˚C is achieved. At this point, flow
through the perfusion machine is stopped and 95% of the
blood volume is drained into the pump with no flow to
any organ.
The tumor thrombus can now be removed in an
essentially bloodless operative field. An incision is made
in the IVC at the entrance of the involved renal vein, and
the ostium is circumscribed. When the tumor extends
into the right atrium, the atrium is opened at the same
time (Figure 12-17). If possible, the tumor thrombus is
removed intact with the kidney. Frequently, this step is
not possible because of the friability of the thrombus and
its adherence to the vena caval wall. In such cases, piece-
meal removal of the thrombus from above and below is
necessary. Occasionally, a venous Fogarty catheter can be
inserted into the vena cava to assist in extraction of the
thrombus. Under deep hypothermic circulatory arrest,
the entire interior lumen of the vena cava can be directly
inspected to ensure that all fragments of thrombus are
completely removed. Hypothermic circulatory arrest can
be safely maintained for at least 40 minutes without
incurring a cerebral ischemic event.12 In difficult cases,
this interval can be extended either by maintaining
“trickle” blood flow at a rate of 5 to 10 ml/kg/minute13 or
by adjunctive retrograde cerebral perfusion.14
Following complete removal of all tumor thrombus,
the vena cava is closed with a continuous 5-0 vascular
 Chapter 12 Surgery of Renal Cell Carcinoma, Including Partial Nephrectomy 227

Figure 12-14 Technique of radical nephrectomy and vena cava thrombectomy with
infrahepatic tumor thrombus (see text for details).
228 Part III Kidney and Ureter
Figure 12-15 Surgical incision for performing radical
nephrectomy with removal of suprahepatic vena caval tumor
thrombus.
suture and the right atrium is closed. As soon as the vena
cava and right atrium have been repaired, rewarming of
the patient is initiated. If coronary artery bypass grafting
is necessary, this procedure is done during the rewarming
period. Rewarming takes 20 to 45 minutes and is contin-
ued until a core temperature of approximately 37 ˚C is
obtained. Cardiopulmonary bypass is then terminated.
Decannulation takes place, and protamine sulfate is
administered to reverse the effects of the heparin.
Platelets, fresh-frozen plasma, desmopressin acetate, or
their combination may be provided when coagulopathy is
suspected. Aprotinin has also proven effective in revers-
ing the coagulopathy associated with cardiopulmonary
bypass but may induce thrombotic complications.
Mediastinal chest tubes are placed but the abdomen is
not routinely drained.
In patients with supradiaphragmatic vena caval tumor
thrombi that do not extend into the right atrium, veno-
venous bypass in the form of a caval-atrial shunt may be
employed.15 In this approach, the intrapericardiac vena
cava, infrarenal vena cava, and opposite renal vein are
temporarily occluded. Cannulas are then inserted into
the right atrium and infrarenal vena cava. These cannu-
las are connected to a primed pump to maintain adequate
flow from the vena cava to the right heart (Figure 12-18).
This avoids the obligatory hypotension associated with
temporary occlusion alone of the intrapericardiac and
infrarenal vena cava. Following the initiation of ven-
ovenous bypass, the abdominal vena cava is opened and
the thrombus is removed. If bleeding from the hepatic
veins is troublesome during extraction of the thrombus,
Figure 12-16 Cannulae are placed in the ascending aorta
and right atrium in preparation for cardiopulmonary bypass.
the porta hepatis may also be occluded (Pringle maneuver).
After removal of the thrombus, repair of the vena cava is
performed as previously described. This technique is sim-
pler than cardiopulmonary bypass with hypothermic circu-
latory arrest but may entail more operative bleeding.
PARTIAL NEPHRECTOMY
Recent interest in partial nephrectomy or nephron-
sparing surgery for RCC has been stimulated by advances
in renal imaging, improved surgical techniques, the
increasing number of incidentally discovered low-stage
RCCs, and good long-term survival in patients undergo-
ing this form of treatment. Partial nephrectomy entails
complete local resection of a renal tumor while leaving
the largest possible amount of normal functioning
parenchyma in the involved kidney.
Accepted indications for partial nephrectomy include
situations in which radical nephrectomy would render
the patient anephric with subsequent immediate need for
dialysis. This encompasses patients with bilateral RCC or
RCC involving a solitary functioning kidney. The latter
circumstance may be present due to unilateral renal age-
nesis, prior removal of the contralateral kidney, or irre-
versible impairment of contralateral renal function
represented by patients with unilateral RCC, and a func-
tioning opposite kidney, when the opposite kidney is
affected by a condition that might threaten its future
function, such as calculus disease, chronic pyelonephritis,
renal artery stenosis, ureteral reflux, or systemic diseases,
such as diabetes and nephrosclerosis.15
 Chapter 12 Surgery of Renal Cell Carcinoma, Including Partial Nephrectomy 229
Figure 12-17 The ostium of the renal vein is circumferentially
incised and the right atrium is opened. Following removal of
the tumor thrombus, the atriotomy and vena cavotomy
incisions are closed.
Recent studies have clarified the role of partial
nephrectomy in patients with localized unilateral RCC
and a normal contralateral kidney. The data indicate that
radical nephrectomy and partial nephrectomy provide
equally effective curative treatment for such patients who
present with a single, small (<4 cm), and clearly localized
RCC.16 The results of partial nephrectomy are less satis-
factory in patients with larger (>4 cm) or multiple local-
ized RCCs, and radical nephrectomy remains the
treatment of choice in such cases when the opposite kid-
ney is normal. The long-term renal functional advantage
of partial nephrectomy with a normal opposite kidney
requires further study.
The technical success rate with partial nephrectomy is
excellent, and long-term patient survival rates free of
cancer are comparable with those obtained after radical
nephrectomy, particularly for low-stage RCC (Table
12-1).17–20 The major disadvantage of partial nephrec-
Figure 12-18 Technique of venovenous bypass for removal
of supradiaphragmatic vena caval tumor thrombus.
tomy for RCC is the risk of postoperative local tumor
recurrence in the operated kidney, which has occurred in
4% to 6% of patients. These local recurrences are most
likely a manifestation of undetected microscopic multifo-
cal RCC in the remnant kidney. The risk of local tumor
recurrence after radical nephrectomy has not been studied,
but it is presumably very low.
We recently reviewed the results of partial nephrec-
tomy for treatment of localized sporadic RCC in 485
patients managed at the Cleveland Clinic before
December 1996.20 A technically successful operation with
the preservation of function in the treated kidney was
achieved in 476 patients (98%). The overall and cancer-
specific 5-year patient survival rate in the series were 81%
and 93%, respectively. Recurrent RCC developed postop-
eratively in 44 of 485 patients (9%). Sixteen patients
(3.2%) developed local recurrence in the remnant kidney,
whereas 28 patients (5.8%) developed metastatic disease.
230 Part III Kidney and Ureter
More recently, we received the long-term (10-year)
results of partial nephrectomy in 107 patients with local-
ized sporadic RCC treated before 1988.21 All patients
were followed up for a minimum of 10 years or until
death. Cancer-specific survival was 88.2% at 5 years and
73% at 10 years. Long-term preservation of renal func-
tion was achieved in 100 patients (93%). These results
attest that partial nephrectomy is an effective therapy for
localized RCC that can provide both long-term tumor
control and the preservation of renal function.
Evaluation of patients with RCC prior to partial
nephrectomy must include a detailed history and physi-
cal examination, a laboratory evaluation including serum
creatinine, liver function tests, and urinalysis or urine
dipstick check to screen for preoperative proteinuria.
Radiographic testing is used to rule out locally extensive
or metastatic disease, including chest X-ray and abdomi-
nal CT, as well as possible bone scan and chest or head
CT depending on the clinical circumstances.
Partial nephrectomy is more technically challenging
than en bloc removal of the kidney by radical nephrectomy,
and it therefore requires a more detailed understanding
of renal anatomy. Knowledge of the relationship of the
tumor and its vascular supply to the collecting system and
adjacent normal renal parenchyma is essential for preop-
erative assessment, which must include a plan for com-
plete tumor removal and reconstruction of the renal
remnant. Therefore, more extensive and invasive preop-
erative imaging studies are often obtained before partial
nephrectomy, compared with radical nephrectomy. In
some instances, this includes arteriography and occasion-
ally venography. Arteriography has been used to delin-
eate the intrarenal vasculature and may aid in the excision
of the tumor while minimizing blood loss and injury to
normal adjacent parenchyma. It is most useful for non-
peripheral tumors encompassing two or more renal arte-
rial segments. Selective renal venography is performed in
patients with large or centrally located tumors to evalu-
ate for intrarenal venous thrombosis and to assess the
adequacy of venous drainage of the planned renal rem-
nant. However, these radiographic studies provide only
two-dimensional views, and the risks and costs of con-
Table 12-1 Results of Partial Nephrectomy for Renal Cell Carcinoma
Series No. Patients
Steinbach et al.17 121
Lerner et al.18 185
Belldegrun et al.19 146
Cleveland Clinic20 485
ventional arteriography and venography are significant.
Furthermore, these studies yield limited anatomic spatial
interrelationships between the tumor, normal
parenchyma, collecting system, and vascular supply.
Advances in helical CT and computer technology now
allow the production of high quality, three-dimensional
images of the renal vasculature and soft tissue anatomy in
any plane. New volume-rendering software allows real-
time interactive stereoscopic viewing of these images and
provides a topographic road map of the renal surface and
multiplanar views of the intrarenal anatomy. This per-
mits the complex renal anatomy to be evaluated by using
a single unified study in a format that is familiar to the
surgeon and consistent with intraoperative findings,
thereby obviating mental reconstruction of several two-
dimensional imaging studies. A detailed prospective
study at the Cleveland Clinic showed the utility of
three-dimensional volume-rendering CT in accurately
showing the renal parenchyma and vascular anatomy
necessary for the performance of partial nephrectomy.22
The data from three-dimensional CT integrate essential
information from angiography, venography, excretory
urography, and conventional two-dimensional CT into a
single preoperative staging test that diminishes the need
for more invasive imaging. The use of a 3 to 5-minute
videotape in the operating room provides concise, accu-
rate, and immediate three-dimensional information to the
surgeon during the dissection, allowing him or her to anti-
cipate the subtleties of the anatomy. Three-dimensional,
volume-rendered CT has become the imaging modality
of choice before partial nephrectomy, allowing hilar dis-
section, tumor removal and reconstruction to proceed
quickly and confidently.
In patients with bilateral synchronous RCC, the kid-
ney most amenable to a partial nephrectomy is usually
approached first by the author. Then, approximately
1 month after a technically successful result has been
documented, radical nephrectomy or a second partial
nephrectomy is performed on the opposite kidney.
Staging surgery in this fashion obviates the need for tem-
porary dialysis if ischemic renal failure occurs following
nephron-sparing excision of RCC.
Local Tumor 5-Year Cancer
Recurrence (%) Specific Survival (%)
4.1 90
5.9 89
2.7 93
3.2 92
 Chapter 12 Surgery of Renal Cell Carcinoma, Including Partial Nephrectomy 231
It is usually possible to perform partial nephrectomy
for malignancy in situ by using an operative approach
that optimizes exposure of the kidney and by combining
meticulous surgical technique with an understanding of
the renal vascular anatomy in relation to the tumor. In
the author’s experience, extracorporeal partial nephrec-
tomy is rare if ever indicated. We employ an extraperi-
toneal flank incision through the bed of the 11th or 12th
rib for almost all of these operations; we occasionally use
a thoracoabdominal incision for very large tumors
involving the upper portion of the kidney. These inci-
sions allow the surgeon to operate on the mobilized kid-
ney almost at skin level and provide excellent exposure of
the peripheral renal vessels. With an anterior subcostal
transperitoneal incision, the kidney is invariably located
in the depth of the wound, and the surgical exposure is
simply not as good.
When performing in situ partial nephrectomy for
malignancy, the kidney is mobilized within Gerota’s fas-
cia while leaving intact the perirenal fat around the
tumor. For small peripheral renal tumors, it may not be
necessary to control the renal artery. In most cases, how-
ever, partial nephrectomy is most effectively performed
after temporary renal arterial occlusion. This measure
not only limits intraoperative bleeding but, by reducing
renal tissue turgor, also improves access to intrarenal
structures. In most cases, we believe that it is important
to leave the renal vein patent throughout the operation.
This measure decreases intraoperative renal ischemia
and, by allowing venous backbleeding, facilitates hemo-
stasis by enabling identification of small transected renal
veins. In patients with centrally located tumors, it is helpful
to occlude the renal vein temporarily to minimize intraop-
erative bleeding from transected major venous branches.
When the renal circulation is temporarily interrupted,
in situ renal hypothermia is used to protect against postis-
chemic renal injury. Surface cooling of the kidney with ice
slush allows up to 3 hours of safe ischemia without per-
manent renal injury. An important caveat with this
method is to keep the entire kidney covered with ice slush
for 10 to 15 minutes immediately after occluding the
renal artery and before commencing the partial nephrec-
tomy. This amount of time is needed to obtain core renal
cooling to a temperature (approximately 20 ˚ C ) that
optimizes in situ renal preservation. During excision of
the tumor, invariably large portions of the kidney are no
longer covered with ice slush and, in the absence of ade-
quate prior renal cooling, rapid rewarming and ischemic
renal injury can occur. Cooling by perfusion of the kidney
with a cold solution instilled via the renal artery is not rec-
ommended due to the theoretical risk of tumor dissemi-
nation. Mannitol is given intravenously 5 to 10 minutes
before temporary renal arterial occlusion. Systemic or
regional anticoagulation to prevent intrarenal vascular
thrombosis is not necessary.
A variety of surgical techniques are available for per-
forming partial nephrectomy in patients with malig-
nancy.23 These include simple enucleation, polar
segmental nephrectomy, wedge resection, transverse
resection, and extracorporeal partial nephrectomy with
renal autotransplantation. All of these techniques require
adherence to basic principles of early vascular control,
avoidance of ischemic renal damage, complete tumor
excision with free margins, precise closure of the collect-
ing system, careful hemostasis, and closure or coverage of
the renal defect with adjacent fat, fascia, peritoneum, or
Oxycel. Whichever technique is employed, the tumor is
removed with a surrounding margin of grossly normal
renal parenchyma. Recent studies suggest that the width
of the margin need not be more than 2 to 3 mm.
Intraoperative ultrasound is very helpful in achieving
accurate tumor localization, particularly for intrarenal
lesions that are not visible or palpable from the external
surface of the kidney.24 The argon beam coagulator is a
useful adjunct for achieving hemostasis on the transected
renal surface. If possible, the renal defect created by the
excision is closed as an additional hemostatic measure. A
retroperitoneal drain is always used as an additional
hemostatic measure. A retroperitoneal drain is always left
in place for at least 7 days. An intraoperative ureteral
stent is placed only when major reconstruction of the
intrarenal collecting system has been performed.
In patients with RCC, partial nephrectomy is con-
traindicated in the presence of lymph node metastasis,
because the prognosis for these patients is poor. Enlarged
or suspicious looking lymph nodes should be biopsied
before initiating the renal resection. When partial
nephrectomy is performed, after excision of all gross
tumor, absence of malignancy in the remaining portion
of the kidney should be verified intraoperatively by
frozen-section examinations of biopsy specimens
obtained at random from the renal margin of excision. It
is unusual for such biopsies to demonstrate residual
tumor but, if so, additional renal tissue must be excised.
Segmental Polar Nephrectomy
In a patient with malignancy confined to the upper or
lower pole of the kidney, partial nephrectomy can be per-
formed by isolating and ligating the segmental apical or
basilar arterial branch while allowing unimpaired perfu-
sion to the remainder of the kidney from the main renal
artery. This procedure is illustrated in Figure 12-19 for a
tumor confined to the apical vascular segment. The api-
cal artery is dissected away from the adjacent structures,
ligated, and divided. Often, a corresponding venous
branch is present, which is similarly ligated and divided.
An ischemic line of demarcation will then generally
appear on the surface of the kidney and will outline the
segment to be excised. If this area is not obvious, a few
232 Part III Kidney and Ureter
milliliters of methylene blue can be directly injected dis-
tally into the ligated apical artery to better outline the
limits of the involved renal segment. An incision is then
made in the renal cortex at the line of demarcation,
which should be several millimeters away from the visi-
ble edge of the cancer. The parenchyma is divided by
sharp and blunt dissection, and the polar segment is
removed. In cases of malignancy, it is not possible to pre-
serve a strip of capsule beyond the parenchymal line of
resection for use in closing the renal defect.
Often a portion of the collecting system will be
removed with the cancer during a segmental polar
nephrectomy. The collecting system is carefully closed
with interrupted or continuous 4-0 chromic sutures to
ensure a watertight repair. Small transected blood vessels
on the renal surface are identified and ligated with shal-
low figure-of-eight 4-0 chromic sutures. The edges of
the kidney are reapproximated as an additional hemosta-
tic measure, using simple interrupted 3-0 chromic
sutures inserted through the capsule and a small amount
of parenchyma. Before these sutures are tied, perirenal
fat or Oxycel can be inserted into the defect for inclusion
in the renal closure. If the collecting system has been
entered, a Penrose drain is left in the perinephric space.
Wedge Resection
Wedge resection is an appropriate technique for remov-
ing peripheral tumors on the surface of the kidney, par-
ticularly ones that are larger or not confined to either
renal pole. Because these lesions often encompass more
than one renal segment, and because this technique is
generally associated with heavier bleeding, it is best to
perform wedge resection with temporary renal arterial
occlusion and surface hypothermia.
In performing a wedge resection, the tumor is
removed with a surrounding margin of grossly normal
renal parenchyma (Figure 12-20). The parenchyma is
divided by a combination of sharp and blunt dissection.
Invariably, the tumor extends deeply into the kidney, and
the collecting system is entered. Often, prominent
intrarenal vessels are identified as the parenchyma is
being incised. These may be directly suture-ligated at
that time, while they are most visible. After excision of
the tumor, the collecting system is closed with inter-
rupted or continuous 4-0 chromic sutures. Remaining
transected blood vessels on the renal surface are secured
with figure-of-eight 4-0 chromic sutures. Bleeding at this
point is usually minimal, and the operative field can be
kept satisfactorily clear by gentle suction during place-
ment of hemostatic sutures.
The renal defect can be closed in one of two ways.
The kidney may be closed on itself by approximating the
transected cortical margins with simple interrupted 3-0
chromic sutures, after placing a small piece of Oxycel at
the base of the defect. If this is done, there must be no
tension on the suture line and no significant angulation
of kinking of blood vessels supplying the kidney.
Alternatively, a portion of perirenal fat may simply be
inserted into the base of the renal defect as a hemostatic
measure and sutured to the parenchymal margins with
interrupted 4-0 chromic. After closure or coverage of the
renal defect, the renal artery is unclamped and circula-
tion to the kidney is restored. A Penrose drain is left in
the perinephric space.
Transverse Resection
A transverse resection is done to remove large tumors that
extensively involve the upper or lower portion of the kid-
ney. This technique is performed using surface hypother-
mia after temporary occlusion of the renal artery (Figure
12-21). Major branches of the renal artery and vein sup-
plying the tumor-bearing portion of the kidney are identi-
fied in the renal hilus, ligated, and divided. If possible, this
should be done before temporarily occluding the renal
artery to minimize the overall period of renal ischemia.
After occluding the renal artery, the parenchyma is
divided with blunt and sharp dissection, leaving a margin
of grossly normal tissue around the tumor. Transected
blood vessels on the renal surface are secured as previ-
ously described, and the hilus is inspected carefully for
remaining unligated segmental vessels. An internal
ureteral stent may be inserted if extensive reconstruction
of the collecting system is necessary. If possible, the renal
defect is sutured together with one of the techniques pre-
viously described. If this suture cannot be placed without
tension or without distorting the renal vessels, a piece of
peritoneum or perirenal fat is sutured in place to cover
the defect. Circulation to the kidney is restored, and a
Penrose drain is left in the perirenal space.
Simple Enucleation
Some RCCs are surrounded by a distinct pseudocapsule
of fibrous tissue. The technique of simple enucleation
implies circumferential incision of the renal parenchyma
around the tumors simply and rapidly at any location,
often with no vascular occlusion and with maximal
preservation of normal parenchyma.
Initial reports indicated satisfactory short-term clini-
cal results after enucleation with good patient survival
and low rate of local tumor recurrence. However, most
recent studies have suggested a higher risk of leaving
residual malignancy in the kidney when enucleation is
performed.25
These latter reports include several carefully done
histopathologic studies that have demonstrated frequent
microscopic tumor penetration of the pseudocapsule that
surrounds the neoplasm. These data indicate that it is not
 Chapter 12 Surgery of Renal Cell Carcinoma, Including Partial Nephrectomy 233

Figure 12-19 Technique of segmental (apical) polar nephrectomy with preliminary ligation
of apical arterial and venous branches.
234 Part III Kidney and Ureter

Figure 12-20 Technique of wedge resection for a peripheral tumor on the surface of the
kidney. The renal defect may be closed on itself or covered with perirenal fat.

Partial Nephrectomy for Renal Angiomyolipoma

always possible to be assured of complete tumor encap-
sulation prior to surgery. Local recurrence of tumor in
the treated kidney is a grave complication of partial
nephrectomy for RCC, and every attempt should be
made to prevent it. Therefore, it is the author’s view that
a surrounding margin of normal parenchyma should be
removed with the tumor whenever possible. This pro-
vides an added margin of safety against the development
of local tumor recurrence and, in most cases, does not
appreciably increase the technical difficulty of the opera-
tion. The technique of enucleation is currently employed
only in occasional patients with von Hippel-Lindau dis-
ease and multiple low-stage encapsulated tumors involv-
ing both kidneys.26
Renal angiomyolipomas (AMLs) are benign hematomas
whose course may be complicated by pain, hematuria,
hemorrhage, rupture, and even death. They may
develop spontaneously or be part of the tuberous scle-
rosis complex, where they are often multiple and bilat-
eral. These tumors have a propensity to grow, and
treatment has been recommended for asymptomatic
AMLs larger than 4 cm and symptomatic AMLs of any
size.27 Partial nephrectomy and selective angioem-
bolization are two renal-preserving treatment modali-
ties available for patients with these benign neoplasms.
Currently, there are few data reporting the efficacy and
ability to preserve renal function by using selective

Figure 12-21 Figure of transverse resection for a tumor involving the upper half of the
kidney.
 Chapter 12 Surgery of Renal Cell Carcinoma, Including Partial Nephrectomy 235
embolization, and it is therefore best suited when a dis-
tinct and accessible renal arterial branch supplies the
tumor exclusively and not the adjacent normal
parenchyma. Partial nephrectomy is considered the pre-
ferred treatment in cases of bilateral tumors or tumors
in a solitary kidney. AMLs are well suited to a nephron-
sparing approach for several reasons. Because these
lesions are benign, the risk of residual microfocal dis-
ease is of less long-term significance. Furthermore,
most AMLs are exophytic and maintain a distinct
pseudocapsule that is readily identified and can be dis-
sected to a narrow base. The amount of renal
parenchyma that can be spared with an open procedure
is usually much greater than one would predict radi-
ographically. There are few published studies evaluating
the efficacy of partial nephrectomy for patients with
AMLs. Fazeli-Matin reported the largest series of 27
patients undergoing partial nephrectomy for renal
AMLs ranging in size up to 26 cm.28 All kidneys main-
tained good function postoperatively, no patient
required dialysis, and there were no recurrent AMLs or
related symptoms identified at a mean follow-up time of
39 months. When surgical treatment for renal AMLs is
indicated, partial nephrectomy can be performed with a
high-rate of success, even in patients with larger tumors
involving a solitary kidney.
REFERENCES
1. Robson CJ, Churchill BM, Anderson W: The results of
radical nephrectomy for renal cell carcinoma. J Urol 1969;
101:297.
2. Schefft P, Novick AC, Straffon RA, Stewart BH: Surgery
for renal cell carcinoma extending into the vena cava.
J Urol 1978; 120:28.
3. Libertino JA, Zinman L, Watkins E: Long-term results of
resection of renal cell cancer with extension into inferior
vena cava. J Urol 1987; 137:21.
4. Novick AC, Kaye M, Cosgrove D, et al: Experience
with cardiopulmonary bypass and deep hypothermic
circulatory arrest in the management of retroperitoneal
tumors with large vena caval thrombi. Ann Surg 1990;
212:472.
5. Neves RJ, Zincke H: Surgical treatment of renal cancer
with vena cava extension. Br J Urol 1987; 59:390.
6. Glazer AA, Novick AC: Long-term follow-up after
surgical treatment for renal cell carcinoma extending into
the right atrium. J Urol 1996; 155:448.
7. Goldfarb DA, Novick AC, Lorgi R, et al: Magnetic
resonance imaging for assessment of vena caval tumor
thrombi: a comparative study with vena cavography and
CT scanning. J Urol 1990; 144:1110.
8. Sagalowaky AI, Kadesky KT, Ewalt DM, Kennedy TJ:
Factors influencing adrenal metastasis in renal cell
carcinoma. J Urol 1994; 151:1181.
9. Giuliani L, Giberti C, Martorama G, Rovida S: Radical
extensive surgery for renal cell carcinoma. J Urol 1990;
143:468.
10. Novick AC: Surgery of the kidney. In Campbell’s
Urology, edited by Walsh PC, Retik AB, Stamey
TA, Vaughan ED. W.B. Saunders Co., Philadelphia,
2002.
11. Welch M, Bazaral MG, Schmidt R, et al: Anesthetic
management for surgical removal of renal cell carcinoma
with caval or atrial tumor thrombus using deep
hypothermic circulatory arrest. J Cardiothoracic
Anesthesia 1980; 3:580.
12. Svenson L, Crawford E, Hess K, et al: Deep hypothermia
with circulatory arrest. J Thoracic Cardiovascu Surg 1993;
106:19.
13. Mault J, Ohtake S, Klingensmith M, et al: Cerebral
metabolism and circulatory arrest: effects of duration
and strategies for protection. Ann Thoracic Surg 1993;
55:57.
14. Pagano D, Carey JA, Patel RL, et al: Retrograde
cerebral perfusion: clinical experience in emergency
and elective aortic operations. Ann Thorac Surg 1995;
59:393.
15. Burt M: Inferior vena caval involvement by renal cell
carcinoma: use of venovenous bypass as adjunct during
resection. Urol Clin N Am 1991; 18:437.
16. Butler BP, Novick AC, Miller DP, Campbell SA, Licht
MR: Management of small unilateral renal cell
carcinomas: radical versus nephron-sparing surgery.
Urology 1995; 45:34.
17. Steinbach F, Stockle M, Muller SC, et al: Conservative
surgery of renal cell tumors in 140 patients: 21 years of
experience. J Urol 1992; 148:24–29.
18. Lerner SE, Hawksin CA, Blute ML, et al: Disease
outcome in patients with low-stage renal cell carcinoma
treated with nephron-sparing or radical surgery. J Urol
1996; 155:1868–1873.
19. Belldegrun A, Tsui KH, deKernion JB, et al: Efficacy of
nephron-sparing surgery for renal cell carcinoma: analysis
based on the new 1997 tumor-node-metastasis staging
system. J Clin Oncol 1999; 17:2868–2875.
20. Hafez KS, Fergany AF, Novick AC: Nephron-sparing
surgery for localized renal cell carcinoma: impact of
tumor size on patient survival, tumor recurrence and
TNM staging. J Urol 1999; 162:1930–1933.
21. Fergany AF, Hafez KS, Novick AC: Long-term results of
nephron-sparing surgery for localized renal cell
carcinoma: 10-year follow-up. J Urol 2000; 163:442–445.
22. Coll DM, Uzzo RG, Herts BR, et al: 3-dimensional
volume-rendered computerized tomography for
preoperative evaluation and intraoperative treatment of
patients undergoing nephron-sparing surgery. J Urol
1999; 161:1097–1102.
23. Novick AC: Anatomic approaches in nephron-sparing
surgery for renal cell carcinoma. Atlas of Urol Clin N Am
1998; 6:39.
24. Campbell SC, Fichtner J, Novick AC, et al: Intraoperative
evaluation of renal cell carcinoma: a prospective study of
the role of ultrasonography and histopathological frozen
sections. J Urol 1996; 155:1191–1195.
236 Part III Kidney and Ureter

25. Marshall FF, Taxy JB, Fishman EK, Chang R: The
feasibility of surgical enucleation for renal cell carcinoma.
J Urol 1986; 135:231.
26. Spencer WF, Novick AC, Montie JE, Streem SB, Levin
HS: Surgical treatment of localized renal carcinoma in
von Hippel-Lindau disease. J Urol 1988; 139:507.
27. Oesterling JE: The management of renal
angiomyolipoma. J Urol 1986; 135:1121–1124.
28. Fazeli-Matin S, Novick AC: Nephron-sparing surgery for
renal angiomyolipoma. Urol 1998; 52:577–583.
C H A P T E R
13 Laparoscopic Radical and Partial
Nephrectomy
Sidney C. Abreu, MD, and Inderbir S. Gill, MD, MCh
At specialized centers worldwide, laparoscopic radical
nephrectomy is now becoming established as routine
practice for management of indicated patients with local-
ized renal cell carcinoma.1,2 Current data indicate that,
compared to open radical nephrectomy, the laparoscopic
approach is associated with comparable operative time,
decreased blood loss, superior recovery, improved
cosmesis, and equivalent cancer control over an interme-
diate and long-term follow-up.3–5
While laparoscopic radical nephrectomy, practiced for
over a decade now, has become an established procedure,
laparoscopic partial nephrectomy, a considerably more
technically challenging procedure, is a more recent inno-
vation. However, ongoing advances in laparoscopic tech-
niques and operator skills have allowed the development
of a reliable technique of laparoscopic partial nephrec-
tomy.6 Thus, laparoscopic partial nephrectomy is emerg-
ing as an attractive minimally invasive nephron-sparing
option at select institutions.
In this chapter, we present an update on laparoscopic
radical and partial nephrectomy for the management of
renal tumors. For each procedure, we describe the current
indications and contraindications, laparoscopic operative
technique, intraoperative and perioperative data, compli-
cations, oncologic outcome, and additional specific facets.
In the future, it appears likely that minimally invasive
techniques will become an established treatment option
for treatment of a majority of kidney tumors, with open
surgery being reserved for specific important indications.
LAPAROSCOPIC RADICAL NEPHRECTOMY
Current Indications and Contra-indications
In the decade since the first laparoscopic radical nephrec-
tomy, standardization of technique has allowed surgeons
to apply this minimally invasive approach to many
patients with organ-confined kidney cancer who are can-
didates for radical nephrectomy. Even circumstances ear-
lier considered relative contraindications, such as
previous abdominal surgery,7 morbid obesity,8 tumors
with level I renal vein thrombus,9 and cytoreductive sur-
gery,10 are now amenable to this laparoscopic approach.
In 2004, laparoscopic radical nephrectomy could be
performed for most patients with organ-confined
T1-T3aN0M0 renal tumors, who are not candidates for
nephron-sparing surgery.5,11 Specific contraindications
in 2004 include vena caval involvement, bulky lym-
phadenopathy, and locally invasive tumors.5,11 Large
tumor size was earlier considered a relative contraindica-
tion. However, we believe this to be a decision based on
the experience of the individual surgeon, and consider
tumors as large as 15 cm to be amenable to laparoscopic
excision.12 General contraindications for major abdomi-
nal laparoscopic surgery apply.
Approach Selection
From a technical standpoint, laparoscopic radical
nephrectomy can be performed safely and efficaciously
by either the transperitoneal or the retroperitoneal
approach. The transperitoneal approach has been
employed more commonly, primarily because of its
“familiar” anatomic landmarks and the larger working
space offered by this route. Nonetheless, since the kidney
is a retroperitoneal organ, a direct “retroperitoneo-
scopic” approach has considerable logical appeal, thus
avoiding the peritoneal cavity completely. Critics of the
retroperitoneal approach point to its somewhat smaller
initial working space, and a steeper learning curve. At the
Cleveland Clinic we are equally technically comfortable
237
238 Part III Kidney and Ureter
with either approach. It is obvious to us that balloon dila-
tion affords an adequate working space, and a sound
knowledge of retroperitoneal surgical anatomy allows
rapid identification of anatomic landmarks.13
Retroperitoneoscopy has the remarkable advantage of
direct access to, and rapid control of, the renal artery and
vein prior to any tumor manipulation.14,15 A prospective
randomized study comparing transperitoneal and
retroperitoneal approaches to laparoscopic radical
nephrectomy at the Cleveland Clinic has shown both
approaches to be comparable as regards blood loss, hos-
pital stay, analgesia requirements, and convalescence.
However, the retroperitoneal approach had the inherent
advantages of a quicker renal hilar control and a shorter
operative time.16 We believe that equal facility with both
approaches will allow the experienced laparoscopic sur-
geon to select the appropriate technique for the particu-
lar case based on the individual patient’s characteristics.
Two clinical situations where we prefer the retroperi-
toneal approach include morbid obesity and multiple
prior abdominal surgeries.8,17
Surgical Technique
The techniques of transperitoneal and retroperitoneal
laparoscopic radical nephrectomy have been previously
Figure 13-1 Port placement for transperitoneal left side radical nephrectomy.
reported1,18,19 Herein, we briefly describe both
approaches.
Transperitoneal Approach
Typically, a 3- or 4-port approach is employed (Figure
13-1). The line of Toldt is incised to mobilize the colon,
and this incision is transversally carried medially along
the undersurface of the liver or spleen. On the right side,
sharp dissection is used to mobilize the duodenum medi-
ally until the anterior aspect of the vena cava is exposed.
The gonadal vein and ureter are identified and retracted
laterally. Blunt dissection is performed between the infe-
rior vena cava and the laterally retract gonadal vein/
ureter, to identify the psoas muscle. The ureter and
gonadal vein are secured, divided, and tautly retracted
laterally. Progressive cephalad dissection is performed
along the lateral border of the inferior vena cava with the
psoas muscle in clear view at all times until the renal vein,
which is mobilized circumferentially. Anterolateral rota-
tion of the completely free lower pole brings the posteri-
orly located renal artery into view. A single hemlock clip
(Weck Closure Systems, Triangle Park, NC) is placed on
the renal artery in-continuity at this time to arrest renal
arterial inflow. The renal vein is controlled and transected
with an Endo-GIA stapler (US Surgical, Norwalk, CT)
 Chapter 13 Laparoscopic Radical and Partial Nephrectomy 239
(Figure 13-2). The clip-occluded renal artery, now in
clear view, is circumferentially mobilized, three clips are
applied proximally towards the aorta and two towards
the kidneys, and the renal artery is transected. During
upper pole dissection, the adrenal gland is taken en
bloc, if necessary. The adrenal vein is dissected and con-
trolled with clips. The en bloc specimen is then com-
pletely freed and placed in an Endocatch bag for intact
extraction.
For a left-side procedure, it is again important (as on
the right side) to enter the correct avascular fascial plane
between the anterior surface of Gerota’s fascia and the
posterior aspect of the descending mesocolon. It is also
important to obtain complete mobilization of the spleen
along its lateral border, which facilitates its medial dis-
placement by gravity alone throughout the procedure.
Occasionally, a distended descending colon and the
spleen must be retracted medially with a fan retractor in
order to expose the renal hilum. For this purpose, an
additional port can be placed in the lower abdomen
through a Pfannenstiel incision, the site of subsequent
specimen extraction. Psoas muscle identification and
renal hilar control are performed as described for the
right-side procedure.
Figure 13-2 Renal artery and vein are sequentially controlled with clip-applier and Endo-GIA
vascular stapler.
Retroperitoneal Approach
Initially a horizontal 1.5-cm skin incision is made just
below the tip of the 12th rib to gain entry into the
retroperitoneal space. A trocar-mounted balloon dissec-
tion device (Origin Medsystems, Menlo Park, CA) is
inserted immediately anterior to the psoas muscle and
posterior to the Gerota’s fascia. Typically 800 to 1000 ml
of air are instilled into the balloon for rapid and atrau-
matic creation of the working space in the retroperi-
toneum. The balloon dilatation outside and posterior to
Gerota’s fascia effectively displaces the Gerota’s fascia
covered kidney anteromedially, allowing direct access to
the posterior aspect of the renal hilum (Figure 13-3).
Laparoscopic examination from within the transparent
balloon confirms adequate expansion of the retroperi-
toneum. Secondary cephalad or caudad balloon dilata-
tion, as required by the clinical situation, further enlarges
the retroperitoneal working space (Figure 13-4).
Following balloon dilatation and removal, a 10-mm
Bluntip trocar (Origin Medsystems, Menlo Park, CA) is
placed as the primary port to prevent air leakage. Two
secondary ports are placed under 30-degree laparoscopic
visualization. A 10/12-mm port is placed three fingers
breadths cephalad to the iliac crest, between the mid and
240 Part III Kidney and Ureter
Figure 13-3 Balloon dissection of the retroperitoneum. Upon
inflating the balloon, the kidney is displaced anteromedially,
allowing direct access to the renal hilum.
Figure 13-4 Secondary cephalad balloon dilation is performed to further enlarge the initial
retroperitoneal working space.
anterior axillary lines. For this purpose, the lateral peri-
toneal reflection must be clearly visualized laparoscopi-
cally and avoided. A second 10/12-mm port is placed at
the lateral border of the erector spinae muscle just
below the 12th rib (Figure 13-5). The kidney is
retracted anterolaterally, placing the renal hilum on
traction. Dissection is performed parallel to, and 1 to 2
cm anterior to, the psoas muscle, exposing the vertically
pulsating renal artery. Visualization of the vertically ori-
ented, distinct arterial pulsations indicates the location
of the renal artery, which is circumferentially mobilized,
clip-ligated, and divided. Next, the renal vein is con-
trolled with an Endo-GIA stapler (US Surgical,
Norwalk, CT). The specimen is then circumferentially
mobilized en bloc with or without the adrenal gland.
During mobilization of the specimen from the under-
side of the peritoneal envelope, use of electrocautery
must be minimized in order to avoid the possibility of
transmural thermal damage to the bowel. The entire
dissection is performed outside Gerota’s fascia, mirror-
ing established oncologic principles of open surgery.
Organ entrapment is rapidly performed by using an
Endocatch II bag (US Surgical, Norwalk, CT). The
intact specimen is extracted extraperitoneally through a
low, muscle-splitting Pfannenstiel incision.
 Chapter 13 Laparoscopic Radical and Partial Nephrectomy 241

Figure 13-5 Port placement during retroperitoneoscopy. A, Primary 10 mm port is placed at

the tip of 12th rib. B, 10/12 mm port is placed at junction of lateral border of the erector
spinae muscle with underside of 12th rib. C, 10/12 mm port is placed three fingers breadths
cephalad to iliac crest, between mid and anterior axillary lines.

Results
cera are out of sight during retroperitoneoscopy, they
Worldwide intraoperative and perioperative results on must never be out-of-mind, since they are separated
laparoscopic radical nephrectomy are summarized in only by the peritoneal layer, and are therefore suscepti-
Table 13-1. ble to direct or transmural injury.

Complications Specimen Extraction (Morcellate or Leave Intact)

In the hands of urologists with reasonable experience in
minimally invasive techniques, laparoscopic radical
nephrectomy is a safe procedure with a low incidence of
complications similar to open surgery. Both the transperi-
toneal and retroperitoneal laparoscopic approaches are
associated with a low incidence of open conversion vary-
ing from 0% to 8%.20–22 Worldwide intraoperative com-
plications following laparoscopic radical nephrectomy are
summarized in Tables 13-2 and 13-3.
During laparoscopic radical nephrectomy, one must
always be mindful of aberrant major vessels arising from
the aorta.2,23 The superior mesenteric artery arises from
the aorta more medially and superiorly than the left
renal artery, and it is not accompanied by the respective
vein. If there is any concern whether or not the isolated
vessel is indeed the renal artery, it should be dissected
and traced distally up to its entrance in the renal hilum.
Injuries to intraperitoneal organs (i.e., liver, spleen,
colon, duodenum) are rare. It is evident that lack of vio-
lation of the peritoneal cavity during retroperitoneal
laparoscopy may minimize the chances of intraperi-
toneal organ injury. However, although peritoneal vis-
The author’s routine practice for extraction of the cancer-
ous specimen aims to provide an intact specimen for accu-
rate pathologic staging while achieving a superior
cosmetic result. Valuable histopathologic information
regarding the tumor stage, and completeness of tumor
resection with negative surgical margins, cannot be
reliably obtained following specimen morcellation.
Although some argue that CT scanning can be used effec-
tively for clinical tumor staging, it is well known that CT
scan can overestimate tumor size and, more worrisomely,
underestimate tumor stage when compared to final
pathology in the individual patient.5,11 Moreover, data
from many institutions, including ours, confirm that over-
all patient morbidity (analgesic requirement, hospital stay,
convalescence) are similar between the intact extraction
and morcellation techniques.25 Currently, we routinely
perform intact specimen extraction through a low muscle-
splitting Pfannenstiel incision for male patients and
through the vagina in the appropriate female patient. This
approach minimizes any practical cosmetic disadvantage
of intact extraction, while maintaining oncologic sanctity
of the intact pathologic specimen.11,25
 242

Table 13-1 Intraoperative and Perioperative Data on Laparoscopic Radical Nephrectomy: Worldwide Experience
Author/Series Dunn et al.2 Gill et al.11 Ono et al.3 Chan et al.20 Barrett et al.21 Janetschek et al.22

Number of patients 60 100 103 67 72 73

Part III Kidney and Ureter

Age (years) 63.5 61.8 57.2 61 35–92 63.3

Male (%) 53 55 77 60 — 44

Right side (%) 47 54 53 45 50 53

Tumor size (cm) 5.3 5.1 (1.7–14) 3.1 (1.1–4.8) 5.1 (1–13) 4.5 (1–9)* 3.8 (3–6)

Transperitoneal/retroperitoneal 55/3† 27/73 85/18 66/1 72/0 73/0

OR time (hour) 5.5 2.8 4.7 4.4 2.5 2.3

EBL (cc) 172 212 254 289 — 170

Morcellate/intact 39/21 0/100 78/25 40/27 66/0 0/73

Specimen weight (g) 452 554 305 — 402

LOS (days) 3.4 1.6 — 3.8 4.4 7.2

Complications (%)

Intraoperative/postoperative — — 10/3 3/12 — —

Minor/major 34/3 11/3 — — 11/8 8/4

Open conversion 1 2 4 1 6 0

*Excluding 6 cases of open conversion.

†Intentionally combined approached was used in 3 patients.
 Table 13-2 Complications Following Laparoscopic Radical Nephrectomy
Author/series Siqueira et al.23 Dunn et al.2 Barret et al.21 Ono et al.3 Gill et al.11 Chan et al.20

Number of patients 61 60 72 103 100 67

Approach Transperitoneal Transperitoneal Transperitoneal Transp(85)/ Transp(27)/ Transperitoneal

Retrop (18) Retrop(73)

Complications (%) 4 3 2 9 2 2

Vascular Superior mesenteric Superior mesenteric Vena cava injury (2)/

artery division/ artery ligation/ open surgical
open graft openreanastomosis suture repair
revascularization, to the aorta
death

Hemorrhage Aberrant right lower Bleeding from renal Bleeding in the Bleeding from renal Bleeding from renal
pole artery/open vein; Bleeding from hilar region artery (1), renal artery; Generalized
conversion the gonadal vein/ precluding vein(1)/open oozing in a patient
laparoscopic adequate conversion; Bleeding with ESRD/both
hemostasis without visualization/ from adrenal gland (1), cases* required open
blood transfusion open conversion periureteric artery (1)*/ conversion, an open
laparoscopic splenectomy was
control and blood also performed in
transfusion second case

Visceral Liver laceration Injury to spleen/ Injury to spleen/ Injury to spleen/

during port conservative conservative conservative
placement/oxidize treatment treatment treatment
cellulose packing

Bowel Partial ischemia Duodenal perfuration/ Bowel injury during

colitis/conservative reintervention morcellation/open
treatment for open conversion for
duodenojejunostomy; bowel resection and
Descending colon extensive irrigation
injury/open surgical
repair

*Retroperitoneal approach.
Chapter 13 Laparoscopic Radical and Partial Nephrectomy 243
244 Part III Kidney and Ureter
Table 13-3 Perioperative Complications Following
Laparoscopic Radical Nephrectomy—Multicenter
Experience with 157 Cases
Ileus 4 (2.5%)
Urinary tract infection 2 (1.2%)
Pulmonary embolus* 2
Congestive heart failure† 1 (0.6%)
Transfusion 1 patients with pelvic adhesions from any etiology.27
Incisional hernia 1
Wound infection 1
Seroma 1 principles of renal cancer surgery must be respected. The
Postoperative surgical exploration‡ 1
Duodenal perforation§ 1 intact specimen extraction or morcellation are safe
Splenic injury¶ 1 is employed, care should be taken to avoid rare compli-
Total 16 (10%)
Adapted with permission from Cadeddu JA, Ono Y, Clayman, RV:
Urology 1998; 52:773.
*Intraoperative mortality: postmortem examination indeterminate
(possible carbon dioxide embolus).
†One patient died of heart failure one month postoperatively.
‡Postoperative hemorrhage requiring exploratory laparotomy.
§Perforation discovery on postoperative day 1.
¶Minor splenic injury identified intraoperatively and managed
conservatively.
Specimen Extraction in Males
During a transperitoneal approach, a Pfannenstiel skin
incision is made at, or just below, the level of the pubic hair-
line. Straightforward access is gained into the peritoneal
cavity after the anterior rectus fascia is incised transversally
and the rectus muscle is separated at the midline. During a
retroperitoneal approach, a similar low Pfannenstiel skin
incision is performed although slightly lateralized towards
the nephrectomy side.26 In order to avoid violation of the
peritoneal cavity, the anterior fascia is incised obliquely at
the lateral border of the rectus abdominis. Subsequently,
the rectus muscle fibers are retracted medially, the poste-
rior rectus fascia is incised, and the peritoneal membrane is
reflected cephalad using finger dissection. Access is gained
to the retroperitoneal space, and entrapped specimen is
extracted. Alternatively, a muscle-splitting Gibson incision
can be performed for intact specimen extraction during
either the transperitoneal or retroperitoneal approach.
Transvaginal Extraction in Females
With the table set in a steep Trendelenburg position,
bowel loops are retracted cephalad out of the pelvis.
A sponge-stick is externally inserted into the sterilely
prepared vagina and tautly positioned in the posterior
fornix. Laparoscopically, a transverse posterior 3-cm
colpotomy is created at the apex of the tented-up poste-
rior fornix, and the drawstring of the entrapped specimen
is delivered into the vagina (Figure 13-6). After laparo-
scopic exit is completed, the patient is placed in a supine
lithotomy position. The specimen is extracted intact per
vagina, and the posterior colpotomy incision repaired
transvaginally. This approach is contraindicated in
Oncologic Outcome
To achieve optimal oncologic outcomes, established
excised surgical specimen must be removed in a hermetic
sac to avoid contact with the abdominal wall.28 Either
regarding oncologic outcomes. However, if morcellation
cations, such as sack perforation, with potential for bowel
injury and tumor spillage. In the aggregate, laparoscopic
radical nephrectomy does not result in an increased risk
of port site seeding, local recurrence, or metastasis3,5,11,28
(Table 13-4).
Cancer-free patient survival is the ultimate criterion of
oncologic outcome. Portis et al.5 reported 5-year cancer
specific survival for the laparoscopic radical nephrectomy
similar to open surgery: 98% versus 92%. The authors
also reported 5-year cancer specific survival of 97% fol-
lowing laparoscopic radical nephrectomy for T1Nx dis-
ease. These data compare favorably with existing reports
of survival after conventional open total/radical nephrec-
tomy for T1N0: 91% to 95%. Cicco et al.29 have
reported a Kaplan–Meyer actuarial disease-free survival
rate of 91% at 54 months following retroperitoneal
laparoscopic radical nephrectomy.
Wound seeding after open radical nephrectomy,
although extremely rare, has been reported in 2 of 518
patients (0.4%). Similarly, a few port site recurrences have
been reported following laparoscopic radical nephrec-
tomy.28 Fentie et al.30 observed one port site seeding 25
months after radical nephrectomy for a grade 4 renal cell
carcinoma. Castilho et al.31 reported multiple port site
abdominal masses 5 months after the laparoscopic proce-
dure in a patient with ascites. Although the etiology of port
site recurrence remains unclear in these cases, in both pro-
cedures the specimens were extracted with morcellation.
Local recurrence occurs occasionally following open
radical nephrectomy and appeared to be related to the
initial pathologic stage.30 As regards local recurrence fol-
lowing laparoscopic radical nephrectomy, Fentie et al.30
have reported an incidence of 5% (3/57), including the
case with port site recurrence. Ono et al.3 have reported
 Chapter 13 Laparoscopic Radical and Partial Nephrectomy 245

Figure 13-6 The drawstring of the closed Endocach II bag, previously grasped by the
laparoscopic clamp, is delivered into the vagina.

1 case of local recurrence 43 months after the laparo-
scopic procedure. Although no concomitant port site
seeding was observed in this case, the intact specimen
could not be entrapped and was therefore removed with-
out a bag through an additional incision.
Distant metastases have been reported following
laparoscopic radical nephrectomy. Cicco et al.29 reported
1 patient with metastatic disease 9 months after the
laparoscopic procedure. Hepatic tumor metastasis fol-
lowed a local recurrence in a patient who had a pT2G3
renal cell carcinoma and tumor-free surgical margins.
Gill et al.11 reported 2 patients with dialysis-dependent,
end-stage renal disease and pT1N0M0 renal cancer with
negative surgical margins that had metastatic disease at 8
and 12 months, respectively.11
Larger Renal Tumors
With increasing experience, laparoscopic radical
nephrectomy for larger (≥7 cm) can be performed effica-
ciously.12 Of the senior author’s overall experience with
over 300 laparoscopic radical nephrectomies at our insti-
tution, 33 patients had larger, clinical stage T2 tumors,
7 cm or greater in size. Mean tumor size was 9.8 cm, with
17 tumors between 7 and 10 cm in size, and 16 tumors
>10 cm in size.12 This group was compared to a contem-
porary group of 34 patients undergoing open radical
nephrectomy for tumors >7 cm in size. Tumors >14 cm
or with IVC thrombus were excluded from this
study. Estimated blood loss (294 cc—lap; 837 cc—open;
p-value: <0.001) and hospital stay (1.8 days—lap; 6.1
days—open; p-value: <0.001) were reduced in the laparo-
scopic group. Although there was a trend to less surgical
complications in the laparoscopic group, this finding was
not statistically significant (6.2% versus 23.5%; p-value:
0.08) (Table 13-5).
Concomitant Adrenalectomy
Performance of concomitant adrenalectomy depends
on the site and size of the renal tumor and the pres-
ence of any abnormality in the adrenal gland on preop-
erative CT. Generally, ipsilateral adrenalectomy is
not necessary if the preoperative CT scan clearly
246 Part III Kidney and Ureter

Table 13-4 Laparoscopic Radical Nephrectomy: Intermediate and Long-term Follow-up

(Pathologically Confirmed RCC)
Author/series Cicco et al.29 Gill et al.11 Portis et al.5 Ono et al.3 Chan et al.20

Number of patients 41 80 64 103 67

Transperitoneal/retroperitoneal All retroperitoneal All retroperitoneal 52/12 85/18 All transperitoneal

Morcellate/intact 0/41 0/80 25/39 78/25 40/27

Pathologic tumor size (cm) 5.26 (2–9) 4.6 (1.7–14) 4.3 (2–10) 3.1 (1.1–4.8) 4.8 morcellate;
5.5 intact

Tumor grade 2.3±1.0 2±0.8 1.88 1.8±0.4 2.1±0.6

Pathologic tumor classification

pT1 25 61 102 46

pT2 2 6 — 8

pT3a 9 9 1 8

pT3b 3 3 — 5

pT4 — 1 — —

Port site recurrence 0 0 0 0 0

Local recurrence 1 0 1 1 0

Time after operation (months) 9.1 — 12 43 —

Metastasis 1 2 3 3 2

Cancer specific mortality 2* 1 1 0 2

Five-year disease-free (%) — — 98 89.7 95

Follow-up (months) 24.76 (2.4–52.7) 16.1 (1–36) 54 (0–94) 29 (3–95) 35.6 (12–111)

*One patient was M+ at the time of diagnosis.

demonstrates the adrenal gland to be normal in size,
shape, contour, and location, thereby showing it to be
uninvolved by the renal tumor.32 In our initial series, en
bloc adrenalectomy was performed in 72% of the
patients. Adrenal-sparing was performed in the setting
of bilateral radical nephrectomy, previous contralateral
adrenalectomy, or elective preservation of the adrenal
gland.11
Renal Vein Involvement
We recently reported a series of 16 patients who under-
went laparoscopic radical nephrectomy for pathologically
confirmed renal cell cancer with either microscopic
(8 patients) or gross (8 patients) tumor involvement of
the renal vein. Microscopic involvement was incidentally
identified on postoperative histopathology. Gross
involvement was identified on preoperative CT scan.33 In
the group of patients with gross involvement of the renal
vein, mean tumor size was 12.4 cm (6 to 20 cm). CT scan
detected renal vein thrombus floating within the vein in
7 patients and invading the renal vein wall in 1 patient.
All procedures were successfully completed laparoscopi-
cally, except for one open conversion due to intraopera-
tive hemorrhage (1000 ml) (Table 13-6). Either the
transperitoneal or retroperitoneal techniques were
employed to perform right or left laparoscopic radical
nephrectomy. After the renal artery was clipped and tran-
sected, the renal vein was dissected proximally towards
the inferior vena cava. While the renal vein segment con-
taining the thrombus clearly appeared full and bulky, the
uninvolved, free-of-thrombus proximal renal vein seg-
ment was flat on laparoscopic examination. This estab-
lished a clear line of demarcation, where the articulating
 Chapter 13 Laparoscopic Radical and Partial Nephrectomy 247

Table 13-5 The Large (>7 cm, pt2) Renal Tumor—Laparoscopic Versus Open Radical Nephrectomy
Laparoscopic Radical Open Radical
Nephrectomy Nephrectomy
(>7 cm) N=33 (>7 cm) N=34 p-value

Mean tumor size (cm) 9.8 10 0.52

Clinical status 0.66

Localized (%) 91.4 88.2

Metastatic (%) 8.6 11.8

Mean OR time (min) 199 200 0.35

Mean EBL (ml) 294 837 <0.001

Intraoperative complications (%) 6 18 0.12

Conversion to open surgery (%) 0 N/A N/A

Mean LOS (days) 1.8 6.1 <0.001

MSO4 equivalent 22 400 <0.001

Postoperative complications (%) 20 26 0.52

Convalescence (weeks) 4 8 0.018

Specimen weight (g) 890 719 0.17

RCC (%) 82 88 0.15

pT1 13 0 0.08

pT2 29 50

pT3 54 50

Positive surgical margins 1 0 0.32

Adapted with permission from Steinberg AP, Desai MM, Kaouk JH: J Endourol 2002; 16:A160 (abstract P28-21).

endoscopic gastrointestinal anastomosis (GIA) stapler
was safely fired (Figure 13-7).
Intraoperative laparoscopic ultrasonography with
color Doppler is helpful to precisely delineate the proxi-
mal extent of the thrombus and should be used routinely.
Placing the ultrasound probe over the thrombus-bearing
distal segment of the renal vein reveals the intraluminal
mass without venous blood flow. This is in remarkable
contrast with the sonographic findings of the proximal
thrombus-free segment of the renal vein, which shows
evidence of turbulent flow from the vena cava without
any intraluminal mass.
Histologic evaluation confirmed renal cell carcinoma in
all 8 cases, in which gross tumor was found within the
renal vein. Inked surgical renal vein vascular margins were
negative for cancer in all these 8 patients with gross venous
involvement. Over a mean follow-up of 9.5 months (5 to
16) no patient showed evidence of local recurrence, and
1 patient developed pulmonary metastasis.33
Cytoreductive Nephrectomy
Laparoscopic radical nephrectomy has been performed
in the setting of cytoreductive surgery as preparation for
systemic immunotherapy. Walther et al.10 reported a
series of 11 patients undergoing laparoscopic cytoreduc-
tive nephrectomy. Three procedures were converted to
open surgery. The major complication rate in these
series was significantly greater than current series of
laparoscopic radical nephrectomy for organ-confined
disease. The authors concluded that laparoscopy afforded
quicker recovery and more rapid implementation of
248 Part III Kidney and Ureter

Table 13-6 Pre and Perioperative Data on Laparoscopic Radical Nephrectomy for Renal Tumor
with Renal Vein Involvement
Microscopic Renal Vein Level I Gross Renal Vein
Thrombus±SD (Range) Thrombus±SD (Range) p-value

Number of points 8 8 N/A

Mean age (years) 62.8±9.7 (48–72) 55.9±6.7 (44–64) 0.15

Mean BMI 29.4±4.6 (25–37) 25.9±5.5 (21–36) 0.17

Number of men/women 6/2 5/3 N/A

Number of left/right 3/5 4/4 N/A

Mean centimeter tumor size 7.8±2.9 (4.7–13) 12.4±5.4 (6–20) 0.09

Number of tumor thrombus visible on

preoperative imaging 1 8 N/A

Mean centimeter renal vein diameter on CT N/A 3.3±6.5 (3–4) N/A

Number of renal vein thrombus type

Floating intraluminal 0 7 N/A

Invasive into vessel wall 1* 1

Number of renal vein thrombus enhancement 0 2 N/A

Approach transperitoneal/retroperitoneal 2/6 7/1 N/A

Mean minutes operative time 188.8±87.3 (75–330) 195.7±39.1 (150–270) 0.68

Mean milliliter estimated blood loss 381.9±393.7 (30–1125) 353.6±334.3 (75–1000) 0.91

Number of conversion to open surgery 0 1 >0.99

Mean days hospital stay 1.9±1.1 (1–4) 2.3±0.8 (1–3)† 0.33

Postoperative complications (Number) Wound infection (1) 0 0.78

Adapted with permission from Desai MM, Gill IS, Ramani AP: J Urol 2003; 169:487.
*Questionable appearance on preoperative CT.
†Excludes patient treated with open conversion.

treatment with interleukin-2 (37 days—laparoscopy with
morcellation versus 67 days—open surgery; p-value:
0.006). Moreover, since accurate staging of the primary
tumor is not a primary concern in the setting of metasta-
tic disease, the authors suggested that tumor morcella-
tion should be performed to further reduce surgical
trauma.10
Financial Analysis
Financial implications of laparoscopic radical nephrec-
tomy are important factors in determining its wide dissem-
ination within the urologic community. At our institution,
we recently addressed this issue of cost-effectiveness of
laparoscopic radical nephrectomy. After overcoming the
learning curve, laparoscopic radical nephrectomy was
shown to be 12% less expensive than open radical
nephrectomy. Nonetheless, the intraoperative costs,
mainly related to disposable instrumentation and a
slightly longer operative time, were 33% greater in
comparison to the open radical nephrectomy. Post-
operatively, the reduced nursing care and decreased hos-
pitalization time resulted in a 68% lower postoperative
costs.34 Furthermore, when the intangible nonhospital
economic factors are considered, such as earlier patient
return to the work-force, and increased productivity
laparoscopic approach becomes even more financially
advantageous and attractive.
 Chapter 13 Laparoscopic Radical and Partial Nephrectomy 249

Figure 13-7 Thrombus bearing distal renal vein is clearly demarcated from uninvolved,
proximal, flattened vein, and transected with a GIA stapler adjacent to the Vena Cava.

LAPAROSCOPIC PARTIAL NEPHRECTOMY

Current Indications and Contraindications
Initially, laparoscopic partial nephrectomy was reserved
for only the select patient with the favorably located,
small, peripheral, superficial, exophytic tumor.35–38 After
gaining experience, we have carefully expanded our indi-
cations to include select patients with more complex
tumors; those invading deeply into the parenchyma up to
the collecting system or renal sinus, completely
intrarenal tumor, tumor abutting the renal hilum, tumor
in a solitary kidney, or a tumor substantial enough to
require hemi-nephrectomy.6,39 Laparoscopic partial
nephrectomy for these complex tumors is performed
only in the setting of compromised or threatened global
nephron mass wherein nephron preservation is an impor-
tant consideration. In 2004, our absolute contraindica-
tions for laparoscopic partial nephrectomy include renal
vein thrombus, multiple (>3) renal tumors, and 2 mid-
pole, central, completely intrarenal tumor.40 Patients
with a bleeding diathesis or renal failure-induced platelet
dysfunction, and those on anticoagulant therapy, are at
significantly increased risk for postoperative hemor-
rhage, and should be approached only with great caution
and adequate preoperative correction. Morbid obesity
and a history of prior renal surgery may prohibitively
increase the technical complexity of the procedure, and
should be considered a relative contraindication for laparo-
scopic partial nephrectomy at this time.
Three-dimensional computed tomography, with vol-
ume-rendered video reconstruction, is an important tool
to determine candidacy for laparoscopic partial nephrec-
tomy and to aid in preoperative planning.40 Finally, a
substantive laparoscopic partial nephrectomy involves
renal hilar control, transection of major intrarenal ves-
sels, entry into and repair of the collecting system (usu-
ally), suture-control of parenchymal blood vessels, renal
parenchymal reconstruction, all under ischemia condi-
tions. Therefore, significant laparoscopic experience,
including expertise with time-sensitive intracorporeal
suturing is essential.
Technique
Laparoscopic partial nephrectomy (Table 13-7) can be
performed either transperitoneally or retroperitoneally.
Our technique has been described elsewhere.6,39
250 Part III Kidney and Ureter
Table 13-7 Technical Steps of Laparoscopic
Partial Nehprectomy
Cystoscopy, ureteral catheterization
Port placement
Hilar dissection/preparation for cross-clamping
Mobilize kidney
Identify tumor
Laparoscopic ultrasonography and circumferential scoring
Renal hypothermia (if needed)
Hilar cross-clamping (preceded by IV Mannitol)
Tumor excision
Pelvicaliceal repair (if necessary)
Specific figure-of-8 sutures to control transected
parenchymal vessels
Hemostatic renorrhaphy over bolsters
Unclamp hilum, confirm hemostasis
Jackson–Pratt drain
Adapted with permission from Gill IS, Desai MM, Kaouk JH, et al:
J Urol 2002; 167:469.
Selection of laparoscopic approach depends on location
of the tumor. The transperitoneal approach is preferred
for anterior, lateral, and upper-pole tumors. Posterior
or posterolaterally located tumors may be better
approached retroperitoneoscopically. A ureteral catheter
is inserted cystoscopically up to the renal pelvis.
Essentially, our operative strategy involves preparation
of the renal hilum for cross clamping, followed by
mobilization of the kidney and isolation of the tumor.
Transperitoneally, a Satinsky clamp is employed to
occlude the renal hilum en bloc (Figure 13-8).
Conversely, during retroperitoneoscopy, the renal artery
and vein are dissected separately for individual placement
of Bulldog clamps (Figure 13-9). Laparoscopic ultra-
sonography precisely delineates tumor size, intra-
parenchymal extension, distance from renal sinus, and
rules out any preoperatively unsuspected secondary renal
masses. An adequate margin of normal renal parenchyma
is scored circumferentially around the tumor under sono-
graphic guidance. The hilum is clamped, and the tumor
is excised and entrapped within an Endocatch bag
(USSC, Norwalk, CT). Injection of dilute indigo
carmine through the ureteral catheter identifies any
pelvicaliceal entry (Figure 13-10), which is suture
repaired by intracorporeal laparoscopic techniques.
Figure-of-8 sutures are specifically placed at the site of
visible transected intrarenal vessels. Finally, the renal
parenchyma is reconstructed using 0 Vicryl suture over
prefashioned surgicel bolsters to complete a hemostatic
renorrhaphy (Figure 13-11). A Jackson–Pratt drain is
placed in all patients undergoing pelvicaliceal repair or if
there is any concern about hemostasis.
Laparoscopic Renal Hypothermia
At the Cleveland Clinic, we have recently developed a
laparoscopic technique of renal hypothermia with ice-
slush by laparoscopic techniques and evaluated its effi-
cacy in 10 initial patients.41 An Endocatch-II bag is
placed around the completely mobilized and defatted
kidney, and its mouth is closed around the intact renal
hilum. The renal hilum is occluded en bloc with a
Satinsky clamp. The bottom of the bag is retrieved
through a 12-mm port site and cut open. Finely crushed
ice-slush is rapidly introduced into the bag to completely
surround the kidney, thereby achieving renal hypother-
mia (Figure 13-12). Pneumoperitoneum is reestablished,
and laparoscopic partial nephrectomy is performed after
opening the bag and removing the ice from the vicinity
of the tumor. Mean time required to introduce 600 to
750 cc of ice-slush around the kidney was 4 minutes.
Using a needle thermocouple probe core renal tempera-
ture was documented to drop to the 5 to 19 ˚C range.
Our laparoscopic technique of renal surface contact
hypothermia with ice-slush mirrors the method routinely
used during open partial nephrectomy.41 Further refine-
ments in the laparoscopic ice delivery system are neces-
sary to increase the efficiency of introduction of ice
around the kidney.
Results
In our initial 50 patients, mean tumor size was 3 cm
(range 1.4–7), and partial nephrectomy was performed
for an imperative indication in 48% of patients. Warm
ischemia time was 23 minutes, mean operative time was
3 hours, and mean hospital stay was 2.2 days. On pathol-
ogy, renal cell carcinoma was confirmed in 68% of
patients, all with a negative surgical margin.6
More recently, we have retrospectively compared 200
patients undergoing partial nephrectomy at The
Cleveland Clinic either by the laparoscopic (n = 100) or
open (n = 100) approach.42 Median tumor size was 2.8 cm
in the laparoscopic group and 3.3 cm in the open group
( p = 0.005), and a solitary kidney was present in 7 and 28
patients, respectively ( p = 0.001). The tumor was located
centrally in 35% and 33% of cases ( p = 0.83) and the indi-
cation for a partial nephrectomy was imperative in 41%
and 54% of cases, respectively ( p = 0.001). Comparing
the laparoscopic versus open groups, median surgical
Figure 13-8 Transperitoneal partial nephrectomy. A Satinsky clamp is used to obtain en
bloc control the renal hilum.

Figure 13-9 Retroperitoneal partial nephrectomy. Bulldog clamps are used for individual
control of mobilized renal artery and vein.
252 Part III Kidney and Ureter
Figure 13-10 Retrograde injection of diluted methylene blue via retrograde ureteral catheter
clearly identifies the site of leakage.
time was 3 hours versus 3.9 hours ( p < 0.001), blood loss
was 125 cc versus 250 cc ( p < 0.001), and warm ischemia
time was 28 minutes versus 18 minutes ( p < 0.001). In the
laparoscopic and open groups, analgesic requirement was
20.2 mg morphine sulfate equivalent versus 252.5 mg ( p
< 0.001), hospital stay was 2 days versus 5 days ( p <
0.001), and convalescence averaged 4 weeks versus 6
weeks ( p < 0.001). No laparoscopic patient was converted
to open surgery. The laparoscopic group had a higher
incidence of intraoperative complications (5% versus
0%; p = 0.02) including hemorrhage (n = 3), ureteral
injury (n = 1), and bowel serosal injury (n = 1).
Postoperative complications (9% versus 14%; p = 0.27).
Renal/urologic complications occurred in 7 patients in
the laparoscopic group and 2 patients in the open group.
Median preoperative serum creatinine (1.0 mg/dl versus
1.0 mg/dl) and postoperative serum creatinine (1.0 mg/dl
versus 1.1 mg/dl) were similar ( p = 0.99). Pathology con-
firmed renal cell carcinoma in 75% of patients in the
laparoscopic and 85% in the open group ( p = 0.003).
Parenchymal margin of resection was positive in two
laparoscopic cases and no open cases ( p = 0.11); median
width of margin was 4 mm in each group ( p = 0.11).42 No
patient in the laparoscopic group developed a local or
port site recurrence. No kidney was lost due to warm
ischemic injury in this study of 200 patients. The world-
wide single institutional experiences with laparoscopic
partial nephrectomy are detailed in Table 13-8.
Complications
In the first 100 consecutive patients undergoing laparo-
scopic partial nephrectomy at the Cleveland Clinic, com-
plications occurred in 29% of patients: intraoperative
5%, postoperative 9%, and late 15%.42 Intraoperative
complications consisted of parenchymal hemorrhage in 3
patients, which were controlled laparoscopically without
open conversion in each instance. Likely causes for the
hemorrhage included an unoccluded renal artery, which
was unsuspected in the setting of multiple vessels, and
inadequate occlusion by the laparoscopic bulldog clamp.
Additional intraoperative complications included a
 Chapter 13 Laparoscopic Radical and Partial Nephrectomy 253
Figure 13-11 Renal parenchymal repair over bolsters.
ureteral injury repaired laparoscopically by ileal replace-
ment (1), and a small, superficial, serosal bowel abrasion
repaired laparoscopically without sequelae (1). All 100
partial nephrectomies were completed laparoscopically
without open conversion.42 Postoperatively, urologic
complications occurred in 7 patients: urine leak (3) of
which 1 subsided spontaneously within 7–10 days, and 2
required restenting and percutaneous CT-guided needle
aspiration; delayed nephrectomy for secondary hemor-
rhage 5 days postoperatively (1); an enlarging perineal
hematoma successfully managed by percutaneous
embolization (1); and hematuria which subsided sponta-
neously with bed rest (1). Late complications after dis-
charge from the hospital occurred in 15% of patients:
incisional hernia (3), wound infection (2), percutaneous
embolization for perineal hematoma (1), congestive heart
failure (1), hematuria (1), urine leak (1), wound dehis-
cence (1), pneumonia (1), and pulmonary embolism (1).42
A worldwide literature review of 97 patients undergoing
laparoscopic partial nephrectomy revealed a major com-
plication rate of 10%.6 In a multicenter European experi-
ence in 53 patients, 4 cases (8%) were converted to open
surgery, and urine leak was noted in 5 patients (10%).44
Financial Analysis
Recently, we reviewed the financial data of 30 patients
undergoing partial nephrectomy: laparoscopic (n = 15)
and open (n = 15).45 All 30 patients in this retrospective
study had a normal contralateral kidney and an uncom-
plicated perioperative course. Cost data, collected by the
financial department of our institution, were divided into
intraoperative and postoperative categories. Laparoscopic
and open groups were comparable as regards tumor size
(2.4 cm versus 2.5 cm; p = 0.50). Intraoperative costs were
20.1% greater for the laparoscopic group ( p < 0.001) and
postoperative costs were 55% lesser for the laparoscopic
group ( p < 0.001). Overall, hospital costs for laparoscopic
partial nephrectomy were 15.6% less compared to open
surgery ( p = 0.002).45
254 Part III Kidney and Ureter

Figure 13-12 The kidney is enclosed within the deployed Endocatch II bag. Finely
crushed ice slush is being inserted into the mouth of the bag with a 30 cc syringe.
The nozzle of the syringe has been cut off to facilitate rapid ice injection.
 Table 13-8 Worldwide Single Institutional Experience with Laparoscopic Partial Nephrectomy for Tumor
Postoperative Complications (Number) Wound Infection (1) 0 0.78

Mean Mean
References Mean Hilar Number Estimated Operating Mean Number Number Follow
(Number Tumor Control of Calyceal Blood Room Time Hospital Urine Complication up
of Points) Size (cm) (Number) Repair (%) Hemostasis Loss (cc) (hour) Days Leak (%) (%) (months)

McDougall37 (2) 2.5 No 0 Argon beam coagulator, 225 7.1 7 1 (50) — 17

snare

Hoznek38 (5) 2.7 Yes (4) 0 Harmonic, bipolar, glue 225 2.6 8 1 (20) 1 (20) 22
No (1)

Janetschek22 (25) 1.9 No 0 Bipolar, argon beam 287 2.7 5.8 0 3 (12) 22.2
coagulator, glue

Harmon43,* (15) 2.3 No 3 Argon beam coagulator, 368 2.8 2.6 0 0 8

bolster

Gill6 (50) 3.0 Yes 18 Suture over bolsters 270 3.0 2.2 1 (2) 6 (12) 7.2

Overall (97) — No (43) 21 (22) — 275 — — 3 (3) 10 (10) 15.3

Yes (54)

Adapted with permission from Gill IS, Desai MM, Kaouk JH, et al: J Urol 2002; 167:469.
*Two institutional experience.
256 Part III Kidney and Ureter
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partial nephrectomy: initial case report for benign disease.
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36. Gill IS, Delworth MG, Munch LC: Laparoscopic
retroperitoneal partial nephrectomy. J Urol 1994;
152:1539.
37. McDougall EM, Elbahnasy AM, Clayman RV:
Laparoscopic wedge resection and partial
nephrectomy—the Washington University experience
and review of literature. J Soc Laparoendosc Surg 1998;
2:15.
38. Hoznek A, Salomon L, Antiphon P, et al: Partial
nephrectomy with retroperitoneal laparoscopy. J Urol
1999; 162:1922.
 Chapter 13 Laparoscopic Radical and Partial Nephrectomy 257
39. Desai MM, Gill IS, Kaouk JH, et al: Laparoscopic partial
nephrectomy with suture-repair of the collecting system.
Urology 2003; 61:99.
40. Gill IS: Minimally invasive nephron-sparing surgery. Urol
Clin North Am 30(3):551–579.
41. Gill IS, Abreu SC, Desai MM, et al: Laparoscopic ice
slush renal hypothermia for partial nephrectomy: the
initial experience. J Urol 170(1):52–56.
42. Gill IS, Matin SF, Desai MM, et al: Comparative analysis
of laparoscopic vs. open partial nephrectomy for renal
tumors in 200 patients. J Urol 170(1):64–68.
43. Harmon WJ, Kavoussi LR, Bishoff JT, et al: Laparoscopic
nephron-sparing surgery for solid renal masses using the
ultrasonic shears. Urology 2000; 56:754.
44. Rassweiler JJ, Abbou C, Janetschek G, et al: Laparoscopic
partial nephrectomy. The European experience. Urol Clin
North Am 2000; 27:721.
45. Steinberg AP, Desai MM, Gill IS, et al: Financial analysis
of laparoscopic versus open partial nephrectomy.
J Endourol (in press).
C H A P T E R
14Treatment of Advanced
Renal Cell Carcinoma
Tracey Krupski, MD, Hyung Kim, MD,
Robert A. Figlin, MD,
and Arie Belldegrun, MD
Advanced renal cell carcinoma (RCC) continues to pres-
ent a major challenge for physicians. Approximately 20%
to 30% of patients have metastatic RCC at the time of
diagnosis, and metastatic RCC remains resistant to con-
ventional oncologic therapies.1 Immunotherapy with
interleukin-2 (IL-2) and interferon-α (IFN-α) remains
the standard of care for metastatic RCC, however,
response rates remain modest at 10% to 30%, and the
median survival for patients presenting with metastatic
RCC is 12 to 18 months. Despite the poor prognosis
generally associated with advanced RCC, a unique char-
acteristic of RCC is that in a small subset of patients
durable remissions and long-term survival is possible.
Spontaneous regression of primary and metastatic
lesions in RCC is second only to melanoma in terms of
regression rates. The most common pattern of disease
regression is resolution of pulmonary metastasis after
nephrectomy.2 Freed et al.3 found 51 cases of regression
of RCC. Of these, 3 had no treatment of the primary
lesion and 18 had histologic confirmation of regression.
A review of the available literature by Snow and
Schellhammer4 in 1982 found regression of metastatic
renal tumors in fewer than 1% of cases. However, regres-
sion prior to primary therapy has also been documented.
Disease stabilization, defined as a failure of sustained
growth, has been documented in both primary RCC and
metastatic foci.5 Oliver et al.6 observed 73 patients with
metastatic RCC who received no treatment. In this
series, 3 patients had complete regression and 2 patients
had partial regression of disease. In addition, 5% of
patients had stable disease.
To treat RCC better, efforts have been directed at
delineating the variables important in determining prog-
nosis. Patients most likely to progress and die from RCC
258
can now be identified. Treatments associated with signif-
icant toxicities can be reserved for patients most likely to
benefit from the therapy. An accurate stratification of
patients based on risk factors will allow physicians to bet-
ter interpret the results of clinical trials. As in the treat-
ment of any malignancy, the ultimate goal is complete
cure, and the remarkable examples of spontaneous
regression of advanced RCC hold out the hope that with
the right medical intervention, this is possible.
EPIDEMIOLOGY OF RENAL CELL CARCINOMA
RCC is the third most common genitourinary malig-
nancy. It is estimated that 31,500 new cases of RCC, rep-
resenting 3% of all cancers, will be diagnosed in the
United States in 2003.7 In the United States since 1950,
there has been a 126% increase in the incidence of RCC
accompanied by a 36.5% increase in annual mortality.8
This phenomenon may partially be explained by the
increased number of incidental tumors detected by wide-
spread use of radiologic imaging. However, other
unidentified factors are important, as the incidences of
both localized and advanced RCC have increased. Not
until the year 2002 did this trend stabilize. The rise in
incidence for all stages from 1973 to 1997 was three
times greater than rise in the rate of mortality.
Consequently, the 5-year survival for all cases has nearly
doubled from 34% in 1954 to 62% in 1996.8,9 Recently,
obesity has been found to be a risk factor for death in sev-
eral cancers, including kidney cancer. Calle et al.10 exam-
ined how obesity influenced the death rate from kidney
cancer. A patient’s degree of obesity was determined by
their body-mass index and categorized according to the
World Health Organization’s classification system of
 Chapter 14 Treatment of Advanced Renal Cell Carcinoma 259
normal range, grades 1, 2, and 3 overweight. As the
degree of obesity increased, so did the relative risk of
death from cancer with patients in the highest group hav-
ing a 1.7 relative risk.
Prognosis
The natural history of RCC is complex and many factors
impact the biologic behavior of these tumors. Various
prognostic models that integrate clinically relevant vari-
ables have been proposed. The evaluation of biomolecu-
lar markers for staging and determining prognosis is an
active area of investigation. However, until these biomol-
ecular markers have been rigorously tested and validated,
clinical variables, such as stage, grade and performance
status, will continue to be the most important variables
for assessing prognosis.
Tumor Stage
Stage categorizes the anatomic spread of RCC and is rec-
ognized as the most important prognosticator for RCC.
Currently, the two most commonly used staging systems
are the stages described by Flocks and Kadesky11 and
modified by Robson12, and the TNM system proposed
by the Union Internationale Contre le Cancer (UICC).13
The TNM system has been modified twice since its
introduction. The change in 1997 entailed expanding the
T1 stage from <2.5 to <7 cm. Tumor thrombus above the
diaphragm became T3c instead of T4 and thrombus
below the diaphragm was changed to T3b.14 Several
studies have validated the latest modification of the
TNM system.15–17 However, others have suggested that
further changes to the 1997 modification will increase
the discriminatory power of the staging system.18,19
The 1997 TNM staging system uses a 7-cm cutoff
between T1 and T2 tumors. The T1 tumors are further
stratified into those <4 cm, which are T1a, and those
greater than 4 cm, which are T1b. Using the UCLA
database, various cutoffs for separating T1 and T2 pri-
mary tumors were evaluated. Patients were optimally
stratified when a 4.5-cm cutoff was used (Figure 14-1). In
addition, the difference in survival was not statistically
different between patients with 4.5 and 7-cm tumors and
patients with tumors >7 cm.18 In a similar analysis of
patients who underwent a partial nephrectomy, Hafez et
al.20 suggested that a 4-cm cutoff should be used in the
TNM staging system. Recently, collecting system inva-
sion has been analyzed with respect to survival rates.
Analysis of 895 patients found 124 patients with collect-
ing system invasion. Multivariate analysis revealed a 1.4
times increased risk of death after controlling for tumor
grade and stage. The difference in 3-year survival is most
apparent in stage 1 tumors, where noninvaders had an
81% survival versus 67% for invaders.21 The Cleveland
Survival Using 4.5 cm Cut-off
100
ⱕ4.5 cm
75
P = 0.0001
Survival (%)
P = NS 4.5 –7.0 cm
60
>7.0 cm
25
0
0 12 24 36 48 60 72
Time from Nephrectomy (months)
Figure 14-1 The 4.5-cm cutoff provides optimal stratification
of early-stage kidney cancer. This modification has been
proposed to the TMN system.
Clinic’s experience with collecting system invasion is sim-
ilar. Clear cell carcinoma most commonly invades, and
when the stage is high, urothelial involvement has little
impact on prognosis. However, low stage T2 lesions have
a worse prognosis when urothelial invasion is involved.22
Grade and Histology
The initial report correlating grade and patient outcome
was published in 1932.23 In 1971, Skinner and colleagues
noted the correlation between nuclear features and sur-
vival, and Fuhrman et al.24 subsequently developed the
findings into a 4-tier grading system. Grade 1 has no
observable nucleoli, grade 2 has small nucleoli, grade 3
has prominent nucleoli, and grade 4 has large pleomor-
phic atypical cells with prominent nucleoli. Analysis of
patients from UCLA found the 5-year cancer-specific
survival based on tumor grade is 89% for grade 1, 65%
for grade 2, and 46% for grades 3 and 417 (Figure 14-4).
Inspection of the Mayo clinic data revealed similar 5-year
crude survival rates based on histologic grade (Zincke,
personal communication).
While nuclear grading clearly impacts outcome, the
effect of histologic subtype on outcome is more variable.
There are five main histologic subtypes of RCC recog-
nized as a result of a collaborative effort between the
UICC and the American Joint Committee on Cancer
(AJCC) in 1997.14 Clear cell carcinomas account for 70%
to 80% of RCC tumors while papillary tumors account
for 10% to 15% and both arise from the proximal
tubules. Chromophobe tumors arise from the interca-
lated cells of the collecting ducts and account for 5% of
kidney cancers. Collecting duct or medullary carcinomas
of the kidney are a rare and very aggressive form of kid-
ney cancer. Chao et al.25 reported on 6 patients with col-
lecting duct tumors. Tumors affected patients at a
260 Part III Kidney and Ureter

younger age, presented with stage IV disease, and had an action between multiple prognostic factors. Using the
average survival of 11.5 months. Renal medullary carci- UCLA kidney cancer database, 14 clinical variables were
noma occurs almost exclusively in African-Americans assessed for inclusion in a prognostic model. The 1997
with sickle cell trait or disease and has a very poor prog- TNM stage, tumor grade, and ECOG-PS were identi-
nosis. Sarcomatoid RCC is no longer considered a dis- fied as strong predictors of prognosis and were combined
tinct histologic subtype but rather a high-grade form of to develop the 5-tiered UCLA integrated staging system
RCC that portends poor prognosis. Sarcomatoid features (UISS) (Figure 14-2). Using the UISS the projected 2-
are present in <5% of RCC and are typified by a spindle and 5-year survivals for patients in groups are: I, 96% and
cell growth pattern.26 Ro et al.27 noted that in low stage 94%; II, 89% and 67%; III, 66% and 39%; IV, 42% and
disease, 2 factors independently predictive of a poorer 23%; V, 9% and 0% (Figure 14-3). This novel system for
prognosis were the amount of tumor necrosis and pro- staging and predicting survival for patients with RCC is
portion of sarcomatoid tumor. Renal tumors that do not simple to use and superior to using stage alone in pre-
fit into one of the five histologic categories are desig- dicting survival.36
nated as unclassified renal tumors.28 As molecular classi- More recently, a simplified UISS algorithm has been
fication becomes available, it is expected that these developed that assigns patients with localized and
tumors will either be categorized as one of the estab- metastatic RCC into either low, intermediate or high-
lished subtypes or a new subtype will be defined. risk groups.33 For each of the risk groups, a relevant set
Each subtype has distinctive characteristics and biol-
ogy that predict tumor behavior. Amin et al.29 reviewed ULCA Integrated Staging System (UISS)
405 cases of renal tumors and assessed the role of histol-
ogy in predicting outcome. They reported 5-year dis- TNM ECOG Overall
UISS Grade
ease-specific survivals of 100%, 86%, 76%, and 24% for Stage PS 5 Yr Survival (%)
chromophobe, papillary, clear cell, and unclassified 0 1– 2
I I 94
tumors, respectively. However, the limited number of
I 0 3–4 67
histologic cases in each group precluded controlling for II
II any any
stage. Motzer et al.30 recently analyzed 64 patients with
III 0 any
metastatic non-clear cell RCC and reported that patients
III ≥1 1
who had chromophobe tumors also fared better than
III III ≥1 2–4 39
patients who originally had collecting duct or papillary
IV 0 1–2
histology. In 12 patients with chromophobe histology, 4
IV 0 3–4
patients had survivals of over 3 years. IV 23
IV ≥1 1–3
V IV ≥1 4 0
Patient Performance Status
Figure 14-2 From 14 possible variables, TMN stage, tumor
The Karnovsky performance scale and the Eastern grade and ECOG-PS proved to optimally stratify patient
Cooperative Oncology Group performance status prognosis.
(ECOG-PS) scale measure the impact of multiple objec-
tive and subjective symptoms on the patient’s overall
UCLA Integrated Staging System
functional status. The ECOG-PS scale at the time of (UISS)
presentation is an important prognostic factor in patients 100
I
with metastatic RCC and it is useful for selecting patients
for treatments.31,32 ECOG-PS is an independent predic-
75
tor for survival in patients with both metastatic and local-
ized disease. Patients with RCC and an ECOG-PS score II
of 0 had a 81% 5-year survival while patients with an 50
III
ECOG-PS score 1 to 4 had a 51% 5-year survival.33
Performance status was found by Elson34 to be one of the
25
primary determinants of prognosis. Further, a decreased IV
performance status was associated with reduced survival
P = 0.001 V
in a Memorial Sloan Kettering study by Motzer et al.35 0
0 12 24 36 48 60 72 84 96
The UCLA Integrated Staging System Months

Recent studies suggest that the ultimate clinical behavior Figure 14-3 The UISS stratifies patients beyond stage alone.
of RCC can be predicted by considering a complex inter- The difference in survival curves is clearly shown.
 Chapter 14 Treatment of Advanced Renal Cell Carcinoma 261
of clinical outcome data was generated, including overall
survival, disease-specific survival, freedom from recur-
rence in nonmetastatic (NM) patients, outcome after
recurrence in NM patients, and freedom from progres-
sion in metastatic (M) patients undergoing cytoreductive
nephrectomy and immunotherapy. This outcome data
can now be used to predict prognosis of other patients.
The Mayo Clinic also has developed an outcome predic-
tion model called the SSIGN score. SSIGN represents
stage, size, grade, and necrosis. Stage relates to the 1997
TMN system, while size refers to tumors >5 cm. This
scoring system is designed to predict outcomes of patients
with clear cell carcinoma.37 A postoperative nomogram
also exists for RCC. Kattan’s nomogram predicts the 5-
year freedom from failure and utilizes the factors symp-
toms, histology, pathologic stage, and tumor size.38
Other stratification systems that address prognosis
have been described. In 1998 Elson et al.34 developed a
scoring system to determine the prognosis of advanced
RCC by stratifying patients into 5 groups based on
ECOG-PS performance status, time from diagnosis to
metastasis, weight loss, previous chemotherapy, and
number of metastatic sites.34 Most recently, Motzer et
al.35 developed a model based on a study of 670 patients
with advanced RCC treated at Memorial Sloan Kettering
Cancer Center by defining the relationship of pretreat-
ment clinical features and survival. Features associated
with shorter survival on multivariate analysis included
decreased performance scale, increased serum lactate
dehydrogenase level, hypercalcemia, and having the pri-
mary tumor in place.
Paraneoplastic signs and symptoms occur in 20% of
patients diagnosed with RCC. Polycythemia, hypercal-
cemia, and hepatic dysfunction are the results of proteins
elaborated by the tumor and constitute a paraneoplastic
syndrome. Anemia of hypoalbuminemia is thought to be
related to tumor volume. While in univariate analysis
each of these impacts disease-specific survival signifi-
cantly, multivariate analysis found only hypoalbumine-
mia, weight loss, anorexia, and malaise correlated with
disease-specific survival. This analysis controlled for
TMN stage, ECOG-PS, and Fuhrman grade. The pres-
ence of any one of these findings constitutes cachexia and
impacts survival. Patients with localized RCC had a sig-
nificantly worse disease-specific survival if they had a
cachexia-related finding, as did those patients with
metastatic RCC.39
Evaluation of Patient
All patients diagnosed with RCC require a thorough
workup for metastatic disease. In addition to a meticu-
lous history and physical exam, the abdomen and pelvis
should be imaged with a CT scan. A CXR or chest CT
should be obtained to rule out pulmonary metastasis. Any
patient with metastatic RCC to the chest or abdomen
should have an MRI or CT of the brain. A bone scan
should be obtained in any patient with bone pain, ele-
vated serum calcium or metastasis noted elsewhere.
Paraneoplastic findings are common in RCC, and the
history and laboratory evaluation should be directed to
assess for cachexia, fever, night sweats, hypercalcemia,
polycythemia, anemia, and hepatic dysfunction.
A brain metastasis has the potential for producing
severely debilitating and crippling effects. Any brain
metastasis, regardless of the total extent of the disease,
should be treated with radiation, surgery or both, prior to
administering any further treatment. Regardless of
organ, solitary metastatic lesions amenable to surgery
should be resected. Although randomized studies are not
available, surgical extirpation provides palliative benefits
and may extend survival.40–42 One study found 66% of
patients treated with immunotherapy and surgical resec-
tion of lung metastasis were alive with a median follow-
up of 48 months.43 Slaton et al.44 reported on 15 patients
who underwent resection of the primary tumor with con-
current resection of a metastatic site (8 lung, 3 bone, 2
nodal, 1 liver, and 1 contralateral adrenal). Nine received
adjuvant immunotherapy. Seven had no evidence of dis-
ease, and 4 had stable metastasis at 17 months.
Inferior Vena Cava Involvement
Extension of tumor thrombus into the inferior vena cava
(IVC) often poses a challenge to surgeons. However, sev-
eral studies show it can be safely done.44,45 Zisman et al.45
compared surgical complications in patients with
metastatic disease undergoing resection of the kidney
and caval thrombus with patients undergoing a radical
nephrectomy alone. There was no increase in surgical
complications. Zisman et al.45 further found that in
patients who had isolated caval involvement but no
metastasis, the survival was not statistically different from
those without the thrombus. In another retrospective
analysis, patients with IVC thrombus and metastatic
RCC who underwent both a nephrectomy and received
immunotherapy had better survival than patients treated
with either therapy alone.46
Lymph Node Involvement
The older literature regarding lymphadenopathy reported
conflicting results.47–49 The only randomized phase III
trial to address the benefits of lymph node dissection
during radical nephrectomy for patients with resectable,
nonmetastatic RCC was performed by the European
Organization for the Research and Treatment of Cancer
Genitourinary Group in study # 30881. In this study, the
dissection extended from the crus of the diaphragm infe-
riorly to the bifurcation of the aorta. The study random-
262 Part III Kidney and Ureter
ized 772 patients to undergo standard nephrectomy or
nephrectomy with node dissection. The preliminary
results have been reported. After preoperative staging, the
incidence of unsuspected lymph node metastasis was
3.3%. The complication rates were not increased in the
group undergoing lymph node dissection.50
Retrospective studies evaluating the role of lym-
phadenectomy in patients with clinically bulky lymph
nodes suggest that lymph node dissection will improve
survival. Vasselli et al.51 examined survival in patients
with metastatic RCC. The patients without clinical evi-
dence of lymphadenopathy had a 14.5-months survival as
compared to an 8.5 median survival of those with positive
nodes. Furthermore, survival was 3 months longer in
those who underwent complete, or even incomplete, sur-
gical extirpation of nodes as opposed to those deemed
unresectable. The UCLA experience confirms the find-
ing that clinically positive nodes in the setting of metasta-
tic disease are associated with poor prognosis. In those
patients, lymphadenectomy improves survival when per-
formed on carefully selected patients undergoing cytore-
ductive nephrectomy prior to immunotherapy. It was
noted that bulky lymph nodes almost never respond to
immunotherapy and should be resected when possi-
ble52,53 (Figure 14-4).
METASTATIC RENAL CELL CARCINOMA
Role of Nephrectomy
Before the era of immunotherapy, the natural history of
metastatic RCC was not improved by debulking
nephrectomy. deKernion et al.2 published the survival
rates in patients with metastatic disease treated with
nephrectomy alone. The 2- and 5-year survival rates
were 25% and 13%, respectively. Nephrectomies were
reserved for palliation of local symptoms, such as pain
and hematuria. However, with the advent of modern
immunotherapy, the role of cytoreductive nephrectomies
Metastatic Patients and LND
1.00
0.75
Survival
0.50 Treated with IMT
LND LND 63%
No LND 71%
0.25 P = 0.0002
n = 107
0.00 No LND n = 22
0 12 24 36 48 60 72 84 96
Months
Figure 14-4 Among patients with metastatic RCC who are
treated with immunotherapy, lymphadenectomy appears to
confer a survival advantage.
for patients with metastatic RCC became a source of
debate. In the 1980s, IFN-α was established, an effective
therapy for metastatic RCC.54 In 1992, the Food and
Drug Administration approved recombinant human IL-2
monotherapy for RCC.
Several authors have noted a response to IL-2
immunotherapy with the primary tumor in place.55
However, advocates of neoadjuvant nephrectomy argued
that the primary tumor may produce an immunosuppres-
sive effect and that neoadjuvant nephrectomy will further
improve the response to immunotherapy. Another argu-
ment for neoadjuvant nephrectomy was that the primary
tumor rarely responses to immunotherapy. Wagner
et al.56 at the National Cancer Institute reported a 6%
extrarenal response to immunotherapy; however, there
were no responses of the primary tumor.
One of the primary concerns with neoadjuvant
nephrectomy was that surgery would delay or even pre-
clude administration of immunotherapy.57 However,
several studies have examined this issue and found that
immunotherapy can be given in a timely manner fol-
lowing surgery. The median time to delivery was
40 days.58 Laparoscopic nephrectomy has also been
advocated as a modality that would decrease time to
immunotherapy.59
Recently, the results of two multi-institutional ran-
domized studies have been published and they establish
cytoreductive nephrectomy, and immunotherapy
improves survival in advanced RCC. Southwest
Oncology Group (SWOG) trial 8949 began in 1989 and
randomized 246 patients with metastatic RCC into 2
arms. Patients in first arm were treated with radical
nephrectomy and IFN-α, and patients in the second arm
were treated with IFN-α alone. Although the response
rates were similar, the median survival was 8 months in
the interferon-only arm compared to 12 months in the
surgery in first arm (p = 0.02). The trend for increased
survival was maintained for all stratification factors,
including measurable disease, performance status, and
site of metastasis.60
A multi-institutional, phase III study from Europe
reached a similar conclusion. The EORTC-GU trial
30947 applied the same protocol as the SWOG study.
The two arms included a combination arm consisting of
nephrectomy followed by immunotherapy and a control
arm that received immunotherapy alone. Both time to
progression (p = 0.04) and survival (p = 0.3) were signifi-
cantly improved in the combination arm over the control
arm. Median survival was only 7 months in the interferon
only arm and it was 17 months in the surgery plus inter-
feron arm.61 These two trials are the first prospective
studies demonstrating the benefit of nephrectomy in the
modern immunotherapy era.
Following the publication of the SWOG study,
Pantuck et al.62 studied patients treated with nephrectomy

and IL-2-based immunotherapy at UCLA. They retro-
spectively identified 89 patients who met the preopera-
tive eligibility criteria used in the SWOG study. The
median survival in these patients was 16.7 months with a
5-year survival of 19.6%. Figure 14-5 shows the
Kaplan–Meier survival curve for this group superim-
posed on survival curves for the two groups in the
SWOG study. An important caveat is that these studies
enrolled and evaluated patients with favorable clinical
features, such as good performance status and minimal
number of metastatic sites. Therefore, the results of
these studies may not apply to patients with higher-risk
features.
SYSTEMIC THERAPY
RCC is refractory to chemotherapy and radiation
therapy. However, it is responsive to systemic cytokine
therapy. The most commonly used agents include IFN-α
and IL-2.
Interferon-α
IFN-α, originally described as an antiviral agent, has
broad immunoregulatory properties and has been shown
to be effective in metastatic RCC. In one study, 1042
patients treated with IFN-α demonstrated an overall
response rate of 12% with an average response time of
4 months.63 The dosing regimen of 5 to 20 million U/d of
IFN-α appears to be effective with minimal toxicity.64 The
toxicity associated with INF-α is usually seen several
weeks after initiating treatment and includes malaise,
myalgia, fever, chills, anorexia, weight loss, depression, and
decreased cognitive function. Prophylactic use of aceta-
minophen, NSAIDs, and antihistamines is routine, and
SWOG & UCLA
100 Retrospective
P < 0.05
80
60
Survival
40
Nx + IL-2
20
Nx + IFN
IFN
0
0 24 48 72
Figure 14-5 Kaplan–Meier survival curves for patients
undergoing cytoreductive nephrectomy followed by either
interferon or interleukin immunotherapy.
Chapter 14 Treatment of Advanced Renal Cell Carcinoma 263
antidepressants are often used prophylactically as well. In
an effort to minimize toxicity, various combinations of
agents at various dosing schedules have been proposed.
In the only randomized study to demonstrate a sur-
vival advantage for IFN-α, patients were randomized to
receive vinblastine alone versus IFN-α and vinblastine.
The median survival for the vinblastine only arm was
37.8 weeks and for the combination arm was 67.6 weeks
(p = 0.0049).65 In an early report of a randomized trial
comparing IFN-α versus medroxyprogesterone acetate
(MPA), the 1-year survival in the IFN-α group was 43%
compared to 31% in the MPA group.66
In other phase III trials, the addition of 5-fluorouracil
(5-FU) or 13-cis-retinoic to IFN-α-based regimens did
not significantly impact survival.64,67 In a randomized
trial, 284 patients were treated with IFN-α alone or IFN-α
plus 13-cis-retinoic acid. While progression free rates and
overall survival were not statistically different, the
median duration of response was higher in the group that
received both IFN-α and 13-cis-retinoic acid, suggesting
and 13-cis-retinoic acid may enhance the durability of the
response to IFN-α68 An ongoing phase III ECOG trial is
evaluating IFN-α alone versus IFN-α and thalidomide.
The role of IFN-α as adjuvant therapy for high risk,
localized RCC has also been evaluated in a randomized
trial. An Italian study randomized 264 patients to IFN-α
three times a week for 6 months or to observation fol-
lowing nephrectomy. After 62 months, the overall sur-
vival was 66% for both groups but disease-free survival
was slightly lower in the IFN-α group.69 Therefore,
there is currently no role for adjuvant immunotherapy in
patients without documented metastatic disease.
Interleukin-2
IL-2 was approved in 1992 by the Food and Drug
Administration (FDA) for the treatment of mRCC based
on a 14.5% response rate in 255 patients treated with
high-dose IL-2. A follow-up study of the 255 patients
originally presented to the FDA was published 8 years
later. The median survival for all 255 patients was 16.3
months and 10% of all patients remained alive and dis-
ease free.70 IL-2 does not have any direct cytotoxic
effects; however, it induces the immune system to pro-
duce a cytotoxic response against RCC.
IL-2 is associated with significant toxicity due to vas-
cular permeability.71 Major toxicities include vascular
collapse, vascular leak syndrome, cardiac arrhythmias,
fever, chills, diarrhea, hepatic dysfunction, and renal fail-
ure. IL-2 is administered either as low- or high-dose reg-
imen. The high-dose regimen needs to be administered
96
in a closely monitored inpatient setting with ready access
to vasopressors. Patients should have normal or mini-
mally impaired cardiac, renal, and pulmonary function.
Approximately 50% of patients required vasopressor sup-
264 Part III Kidney and Ureter
port in one study.72 The high-dose regimen should
preferably be used at referral centers with experience in
administering high-dose IL-2 and managing related
complications. The low-dose IL-2 regimen is associated
with significantly less toxicity and can be administered on
an outpatient basis.
A review of 10 trials with over 500 patients involving
high-dose intravenous IL-2 revealed a response rate of
19% with a median duration of 22 months.73 The
response rates in studies using low-dose IL-2 with or
without IFN-α were 11% to 17%74,75 These results are
comparable to those seen with high-dose IL-2; however,
high-dose IL-2 was more likely to produce complete
responses that resulted in longer disease-free intervals. In
a randomized 3 arm comparison of high-dose intra-
venous, low-dose intravenous and intermediate-dose
subcutaneous IL-2 regimens, the response rates were
16%, 4%, and 11%, respectively.57 However, long-term
survival results, which may confirm the improved dura-
bility of responses seen with higher-dose regimens, are
not yet available. Recent work by the Cytokine Working
Group examined the role of high-dose IL-2 in patients
with locally advanced as well as M1 disease who were
completely resected. They found no improvement in
survival with the addition of IL-2 in these high-risk pop-
ulations (ASCO 2003).
NOVEL THERAPIES
Passive Immunotherapy
Immunotherapy is characterized as active when the agent
induces a state of immune responsiveness against the
tumor in the host or as passive when the immunologic
agents are directly active against the tumor. Examples of
passive immunotherapy include monoclonal antibody
therapy and adoptive immunotherapy. The transfer of
cells, which can mount an antitumor response, is coined
adoptive immunotherapy. An example of adoptive ther-
apy utilizes tumor-infiltrating lymphocytes (TIL), which
are derived from the tumor and adoptively transferred to
the tumor-bearing host. In 1980, the NCI isolated infil-
trating lymphoid cells from solid tumors.76 These cells
were expanded ex vivo using IL-2 and shown to have
direct antitumor activity.77 In a murine model, TIL were
effective in eliminating micrometastases.78
The initial single-institution studies showed great
promise. Figlin et al.79 reported a 34.6% overall response
rate to treatment with TIL. This lead to a multicenter
randomized trial comparing CD8+TIL combined with
IL-2 versus IL-2 alone. The response rate in the combi-
nation arm was 9.9% compared to 11.4% in the IL-2
alone arm. This lead the investigators to conclude that
the combination of TIL and IL-2 was no better than IL-2
alone.80 However, it should be noted that 41% of the
subjects randomized to the TIL arm did not receive the
TIL cells due to processing failure. At the present time,
it may not be technically feasible to consistently deliver
TIL-based treatment in a multi-institutional fashion.
Active Immunotherapy
Active immunotherapies sensitize effector cells (T lym-
phocytes) to target tumor antigens. A major obstacle in
the search for an effective agent is the lack of tumor-spe-
cific antigen.81 However, carbonic anhydrase IX (CA-9)
has recently been identified as a potential target. CA-9 is
the only characterized protein that is widely expressed in
RCC with 95% to 100% of the clear cell variant demon-
strating expression. Further, this expression is specific to
the primary tumor and metastatic deposits.82,83 The rea-
son for this overexpression is a direct consequence of a
mutation in the von Hippel-Lindau gene, which nor-
mally suppresses CA-9.
A better understanding of the immune system and the
molecular changes involved in tumor formation provide
insight into better treatment strategies. An effective
tumor vaccine needs to recruit cytotoxic T cells specific
for RCC and antigen presentation is the first step.
Dendritic cells (DC) are the primary antigen presenting
cells for stimulating T cell mediated immune responses,
and thus, manipulation of DC ex vivo to express tumor-
specific antigen may yield a potent vaccine.84,85 In animal
studies, DC-based tumor vaccines were more effective
when combined with systemic cytokines. An elegant
solution to avoid the toxicity of systemic therapy yet
retain the synergy with a vaccine would be to engineer
the DC ex vivo to express tumor antigen, as well as an
immunomodulatory cytokine, such as GM-CSF. This
allows for lower systemic levels of cytokine yet keeps
high levels in the tumor itself. At UCLA, preclinical
studies designed to assess the effectiveness of a fusion
protein consisting of CA-9 and GM-CSF are currently
underway.
Heat shock protein represents another potential tar-
get for treating RCC. Heat shock protein normally
functions to allow proper folding of intracellular
polypeptides and aids with intracellular transport. They
have been associated with degraded proteins from
tumor. Heat shock protein vaccines have been shown to
be effective against RCC in a clinical trial.86 A pivotal,
500-subject phase III trial of adjuvant HSP vaccine
(Oncophage-Antigenic) in high-risk RCC is underway.
Future studies will likely combine the heat shock pro-
tein with IL-2 or GMCSF.
Antiangiogenic
In RCC, increase in vascular endothelial growth factor
(VEGF) and angiogenesis is a direct consequence of the
VHL mutation commonly found in clear cell RCC. An
 Chapter 14 Treatment of Advanced Renal Cell Carcinoma 265
understanding of this mechanism provides a straightfor-
ward rationale for targeting angiogenesis in RCC.
Bevacizumab is a monoclonal antibody designed to neu-
tralize VEGF. A randomized placebo-controlled study is
ongoing to evaluate the effectiveness of high- and low-
dose bevacizumab.87 In an early report of 110 patients
randomized on the study, there was a highly significant
prolongation in time to progression of high-dose beva-
cizumab compared to placebo. Three partial responses
were seen in the high-dose group and none in the low-
dose or placebo groups.
Chemotherapy
Gemcitabine is the latest chemotherapeutic agent to be
used in clinical trials. A phase I trial initially evaluated
multiple dosing regimens of 5-FU with weekly gemc-
itabine. The results of this work suggested antitumor
activity against RCC, in particular. The most efficacious
dosing regimen was defined by this study as well.88 A
multiinstitutional phase II study used gemcitabine 600
mg/m(2) on days 1, 8, and 15 with continuous infusion of
5-FU 150 mg/m(2)/day for days 1 to 21. While no
patient had a complete response, 7 of 39 had a partial
response (17%).89 To increase this objective response
rate, additional agents have been added to the regimen in
a search for synergy.
Neri et al.90 combined 1000 mg/m gemcitabine intra-
venously on days 1, 8, 15, and 28 with intramuscular
IFN-α (1 MU) and 4.5 million IU of IL-2 subcuta-
neously for 6 months. The overall response rate was 28%
and median survival was 20 months. No toxicity greater
than grade 2 was noted and therefore this appears to be a
well-tolerated regimen. Daily thalidomide was also
added to the gemcitabine and 5-FU regimen with no
improvement in response rate. Further, the addition of
thalidomide was associated with an unacceptable rate of
deep venous thrombosis.91 However, none of these trials
was prospective nor have they employed a control arm or
immunotherapy alone arm.
Bone Marrow Transplantation
Researchers at the National Heart, Lung and Blood insti-
tute expanded their research on graft-versus-leukemia
reactions to graft-versus-tumor effects. Because mRCC
is partially responsive to immunotherapy, the authors
postulated that allogeneic lymphocytes from healthy
donors would attack metastatic RCC. Nineteen patients
underwent immunosuppression with cyclophosphamide
and fludarabine followed by infusion of peripheral blood
stem cell allograft from an HLA identical or single mis-
match sibling. Transplantation-related deaths occurred
in 2 patients, and 8 patients died of disease progression.
However, 53% experienced disease regression. The three
complete responders remained in remission for an aver-
age of 22 months.92
SUMMARY
Advanced RCC remains as a difficult problem for physi-
cians. For metastatic RCC, immunotherapy with IFN-α
or IL-2 remains as the standard of care, with typical
response rates of about 20%. While nephrectomy fol-
lowed by immunotherapy appears to be the most effica-
cious treatment, careful patient selection is imperative.
Improved ability to define patient prognosis allow us to
better select patients for various treatments. In an effort
to improve response rates and minimize toxicity, novel
approaches continue to be explored. Active areas of
investigation include vaccines therapies, bone marrow
transplantation and targeted pharmaceuticals.
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C H A P T E R
15 Transitional Cell Carcinoma of the
Renal Pelvis and Ureter: Evaluation
and Treatment
Badrinath R. Konety, MD, MBA,
and Richard D. Williams, MD
Transitional cell carcinoma (TCC) of the upper urinary
tract occurs less frequently than bladder cancer. The pre-
cise incidence of renal pelvic and ureteral cancers is diffi-
cult to discern since they are grouped with other kidney
cancers. Ureteral cancers are less common than renal
pelvic cancers. Renal pelvic tumors comprise 5% to 7%
of all renal tumors.1–5 Worldwide statistics vary and are
not accurate, since renal pelvis tumors are not reported
separately. The highest incidence is found in Balkan
countries (Bulgaria, Greece, Romania, and Yugoslavia),
where urothelial cancers account for 40% of all renal
cancers. The majority of renal pelvic and ureteral cancers
are transitional cell in origin with squamous cell carci-
noma (SCC) and adenocarcinoma forming a small
minority.2,6,7 Ureteral tumors most frequently involve
the lower-third of the ureter.7–10 Bilateral involvement or
metachronous renal pelvic tumor development in the
contralateral kidney occurs in about 2% of patients.11,12
The estimated incidence of TCC arising in the ureter
and other portions of the urinary tract other than renal
pelvis or bladder in the United States is 2450 cases for
the year 2004, with 690 deaths occurring as a result of
these tumors.3 TCC of any origin is uniformly fatal
unless treated since it is almost never discovered inciden-
tally at autopsy.13 Patients with Balkan nephropathy have
a higher incidence of upper tract TCC and there is also
an increased incidence of bilaterality in 10% of these
patients but the tumors tend to be low grade.2,8,11,12,14
Patients with upper tract TCC are at risk of developing
bladder TCC, with an estimated incidence of 15% to
60% within 5 years following the upper tract TCC.15,16
Patients with primary bladder TCC will develop upper
tract TCC in 2% to 4% of cases, with a mean interval of
17 to 170 months.17,18 Based on karyotypic similarities
between bladder and upper tract TCC, it is likely that
similar risk factors affect both upper and lower tract
tumors.19 The risk factors associated with increased inci-
dence of upper tract TCC include recurrent bladder car-
cinoma in situ (CIS) after intravesical BCG therapy,20,21
and multifocal CIS in the bladder at the time of cystec-
tomy.22–24 Up to 19% of patients with upper urinary tract
TCC have been reported to initially present with
metastatic disease.25
ETIOLOGY
Workers in chemical, petrochemical, and plastic indus-
tries, aniline dye workers, and those exposed to coal,
coke, tar, and asphalt are at increased risk for renal pelvis
and ureteral TCC (relative risk = 4 to 5.5). Aniline dyes,
β-naphthylamine and benzidine compounds have all
been implicated as causative agents for upper tract
TCC.26,27 TCC in various locations in the urinary tract
can develop up to 18 years after exposure.27 However,
most of these chemicals are more commonly associated
with lower urinary tract tumors because it is believed that
prolonged contact with parent compounds or metabo-
lites in urine is required for induction of carcinogenesis.
Cigarette smoking is a major risk factor for upper tract
TCC. Cessation of smoking somewhat decreases the risk
but does not eliminate it completely. Duration of smok-
ing is the strongest predictor of risk.28 Balkan endemic
nephropathy is a chronic tubulointerstitial disorder con-
fined to the Balkan countries, which ultimately results in
renal failure. Cancer of the renal pelvis is 100 to 200
times more frequent in these countries than in control
269
270 Part III Kidney and Ureter
regions.29 Analgesic abuse is another predisposing factor
for the development of upper tract TCC. One study
found the relative risk for abusers of phenacetin contain-
ing analgesics was 2.4 for men and 4.2 for women.29 The
dose–effect relationship was noted for both phenacetin
and aspirin. The latency period was 24 to 26 years. While
phenacetin is no longer available in the United States,
acetaminophen has similar metabolites to phenacetin and
is widely used as an antipyretic. Case control studies have
not revealed any significant association between routine
acetaminophen use and bladder TCC or upper tract
TCC.30 However, abuse of the drug has not been stud-
ied. Both Balkan nephropathy and phenacetin abuse are
associated only with renal pelvis TCC. Renal papillary
necrosis itself is not a necessary factor for the develop-
ment of renal pelvis TCC, but the combination of
phenacetin use and papillary necrosis causes a 20-fold
increased risk for renal urothelial tumors, indicating that
both are probably independent risk factors. Chronic bac-
terial infection with urinary calculi and obstruction may
predispose to the development of urothelial cancer. SCC
is the most common entity in these cases. Schistosomiasis
may also predispose to SCC. Cyclophosphamide has also
been implicated in the development of renal pelvis TCC.
About 6 cases have been reported occurring after an
average of 5 years following chemotherapy.31 Thorium
dioxide (Thorotrast), which was used as a contrast agent
for retrograde pyelograms about 70 years ago, is also
known to be a causative factor since it supposedly causes
vascular insufficiency and a foreign body response.
Cancers tend to occur after a latency period of 20 years.32
DIAGNOSIS
Upper tract TCC can present with ureteral obstruction
or hematuria (gross or microscopic). It can be asympto-
matic and discovered during upper tract surveillance
after development of bladder TCC. An increased index
of suspicion, especially in patients who have undergone
BCG or other intravesical therapy for bladder TCC, is
prudent since the incidence of upper tract cancer in these
patients can be as high as 38%.33 These tumors can occur
up to 15 years following successful treatment of bladder
TCC, which mandates at least yearly surveillance of the
upper tracts in these patients.34 Hematuria is the most
common presenting symptom, occurring in 56% to 98%
of patients.8,35,36 Flank pain is usually a sign of upper tract
obstruction. Systemic symptoms, such as weight loss,
anorexia, and lethargy, are late findings that can occur in
10% to 15% of patients.36–38
Radiographic Evaluation
The traditional evaluation of the upper tract has included
an intravenous pyelogram (IVP). While the IVP may
yield more precise anatomic information regarding the
upper tract urothelium, it is laborious to perform and not
all centers have the same level of expertise in performing
and interpreting these studies. A well-performed IVP
will reveal an abnormality in the majority of cases (Figure
15-1A,B). The finding of a non-functional kidney on
IVP, which occurs in up to 50% of cases,8,37 can portend
a worse prognosis.39 Classic signs for upper tract urothe-
lial carcinoma on IVP include the “goblet” or
“Bergmann’s sign,” which is a meniscus-shaped filling
defect in the ureter. A “stipple” sign may be observed
with contrast being trapped in the fronds of a papillary
tumor, either in the renal pelvis or ureter. Retrograde
pyelograms will demonstrate evidence of tumor in the
form of filling defects or an intrinsic narrowing or stric-
ture of the ureter in almost all cases (Figure 15-2).39
Stricture or stenosis more commonly occurs at the
ureteropelvic junction or ureter and can indicate infiltra-
tive disease.8 In patients who have undergone a cystec-
tomy for prior bladder TCC, a loopogram or
pouchogram obtained by instilling contrast into the ileal
conduit or neobladder may be required to adequately
visualize the upper tracts. Conventional upper tract
imaging can yield false positive results in 36% to 60% of
cases.40,41 An alternative to the IVP is a contrast-
enhanced CT scan, which is often required to optimally
evaluate the renal parenchyma. Presence of a mass lesion
protruding into the contrast-filled collecting system can
usually be identified on the CT scan especially in cases of
papillary tumors >1 cm in size (Figure 15-3). CT scan-
ning is easier to perform and less labor-intensive, with
greater standardization of technique, and has the specific
advantage of distinguishing intrarenal stones from
tumors if films are obtained before and after intravenous
contrast administration. The curvilinear pattern of calci-
fication occasionally observed in upper tract TCC is usu-
ally distinguishable by CT scan. A single shot (IVP) in
the form of a plain abdominal X-ray immediately follow-
ing the CT scan can capture an image of the contrast
filled renal pelvis and ureters. More recently, CT uro-
grams have been performed in order to obtain a three-
dimensional view of the calyces and ureters. They appear
to be equivalent to an IVP in imaging the ureters.42
Thinly collimated axial images obtained during a single
breath hold using a multirow detector CT scan are then
reformatted to obtain a coronal image of the collecting
system. The images are of higher resolution than those
obtained using standard single detector helical CT scan-
ning. CT urography can detect the majority of ureteric
tumors with a sensitivity as high as 94%.43 CT urogra-
phy, however, does expose the patient to a greater dose of
radiation. Sensitivity for detecting upper tract malig-
nancy can approach 100% with a specificity of 60%. The
negative predictive value was 100% in one reported
study.43 However, more experience with this technique is
 Chapter 15 Transitional Cell Carcinoma of the Renal Pelvis and Ureter 271

Figure 15-1 IVP with tomographic and excretory phase images of a patient with invasive
TCC of the right upper pole who presented with gross hematuria and pyelonephritis.
272 Part III Kidney and Ureter

needed before it can be widely employed. MR urography

has also been used in a similar manner with slightly lower
reported sensitivity of 80%.44 CT scanning or MRI can
also be used to assess local extent of tumor and presence
of metastatic disease.

Cytology and Other Markers

Urine cytology is a very specific method that can be used
to diagnose TCC of the upper and lower urinary tracts
(Figure 15-4A,B). It is very sensitive for high-grade papil-
lary tumors and CIS but less so for low-grade disease7,45
and is also operator dependent. Positive upper tract cytolo-
gies in the absence of bladder disease identify the presence
of upper tract TCC. Often retrograde pyelography and
ureteroscopy fail to reveal a lesion in the upper tract even
in the presence of frankly positive urine cytology. Upper
tract or urine cytologies that do not revert to negative
6 months following a completely negative urologic workup
may indicate indolent or latent disease that will be discov-
ered subsequently.46 The value of obtaining upper tract
washing for cytology in the presence of bladder TCC is
questionable. Contamination from tumor cells in the blad-
der make it very difficult to accurately interpret these
results, especially in the absence of a radiologic abnormal-
ity in the upper tracts.47 However, properly performed
studies with simultaneous specimens being obtained from Figure 15-2 Retrograde pyelogram obtained in the patient
from Figure 15-1 demonstrating a filling defect in the right
the bladder and upper tracts with the use of normal saline
upper pole due to an infiltrative TCC.
to keep the ureteral catheter clear of bladder urine until it
has been placed in the ureter can be successful.
Several urine-based markers have been studied to
increase the accuracy of diagnosing upper tract cancer.
Urinary levels of NMP22, a nuclear matrix protein-based
Direct Endoscopic Evaluation
marker, are found to be elevated in patients with upper
tract cancer.48 However, the numbers of patients in these Endoscopic evaluation, including retrograde pyelograms
studies are small and the specificity is low, yet the sensi- and brush biopsies, are usually performed to obtain a
tivity is higher than cytology for low-grade disease. The more definitive diagnosis following the detection of a
BTA stat test (Mentor Corp., Santa Barbara, CA) has a positive upper tract cytology. Brush biopsy through an
sensitivity of 82% and specificity of 89% compared to open-ended ureteral catheter was originally described by
voided urine cytology (11% and 54%, respectively) or Gill et al.52 Brush biopsy has a sensitivity of up to 90%
ureteral wash cytology (48% and 33%, respectively) for and a specificity of up to 88%.7,53,54 Ureteroscopic visu-
upper tract tumors.49 In one study, telomerase was alization using a flexible or semirigid ureteroscope and
detected using cells obtained from upper tract wash- direct biopsy is also effective in diagnosing these tumors,
ings and measured using the telomeric repeat amplifica- with a sensitivity of 86% and specificity of 90%.53
tion protocol (TRAP) assay in 14 of 17 patients.50 In Complications of brush biopsy or ureteroscopy include
comparison, voided urine cytology detected only 2 of the risk of infection, ureteral or renal pelvic perforation,
13 cases and ureteral washing cytology detected only 8 of bleeding, mucosal flap injury, and mucosal edema with
15 cases.50 Studies conducted thus far have included small resultant ureteral obstruction.
numbers of patients and more data are required from
larger studies before any of these tests can be routinely
HISTOPATHOLOGY
recommended. Other markers, such as p27 (cyclin-
dependent kinase inhibitor) expression in tumor tissue, TCC is the most common histologic type of upper uri-
can also help to predict prognosis of upper tract tumors. nary tract cancer. Cancers may be papillary or sessile and
Low levels of p27 staining in tumors can be indicative of multifocality is common. CIS can be particularly difficult
worse disease-free survival in these patients.51 to identify grossly and may vary from a whitish-appearing
 Chapter 15 Transitional Cell Carcinoma of the Renal Pelvis and Ureter 273

Figure 15-3 Contrast enhanced CT scan of a patient with a large papillary Ta TCC (arrow)
arising from the left renal pelvis, which led to spontaneous bleeding and a perinephric
hematoma (arrow).

Figure 15-4 A, Urine cytology, low-grade papillary TCC. (Modified from Kleer E, Osterling
JE: Prob Urol 1992; 6(3):531, with permission.) B, Urine cytology, high-grade papillary TCC.
(Modified from Kleer E, Osterling JE: Prob Urol 1992; 6(3):531, with permission.)
274 Part III Kidney and Ureter

plaque, due to epithelial hyperplasia, to a velvety red Table 15-1 Staging Systems for Upper Tract
patch from increased submucosal vascularity.2 Progression Urothelial Tumors
to invasive TCC can occur from a papillary, low-grade TNM staging system
lesion or by transformation of CIS.2,55 Multiple tumors Primary tumor (T)
can occur by implantation of tumor cells onto mechani- Tx Primary tumor cannot be assessed
cally disrupted mucosa or due to the “field effect” on the T0 No evidence of primary tumor
entire urothelium, which is believed to contribute to the Ta Papillary noninvasive carcinoma
multifocal nature of TCC. CIS or atypia of the lower Tis Carcinoma in situ
ureters is found in 7% to 25% of patients undergoing cys- T1 Tumor invades subepithelial connective tissue
tectomy for bladder cancer.56 Presence of upper tract CIS T2 Tumor invades the muscularis
is also more common in heavily pretreated patients who T3 (For renal pelvis only) Tumor invades beyond
muscularis into peripelvic fat or the renal
have failed multiple courses of intravesical agents, such as
parenchyma
BCG.57 These tumors can occur long after treatment of T4 Tumor invades adjacent organs, or through
bladder disease, which suggests that these patients will the kidney into the perinephric fat
benefit from long-term follow-up. Many of these instances
of upper tract CIS may be asymptomatic and diagnosed on Lymph nodes (N)
work-up of positive urine or selective ureteral cytology. Nx Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in a single lymph node, 2 cm or
STAGING AND GRADING less in greatest dimension
The most commonly used staging system for upper tract N2 Metastasis in a single lymph node, more than
cancer is the TNM staging system (Table 15-1). Upper 2 cm but not more than 5 cm in greatest
dimension; or multiple lymph nodes, none
tract TCC spreads by direct invasion, mucosal seeding,
more than 5 cm in greatest dimension
hematologic and lymphatic routes. The most common N3 Metastasis in a lymph node, more than 5 cm
sites of metastases are lung, bone, and liver. The likeli- in greatest dimension
hood of nodal metastases increases with increasing stage,
with 48% of T3 tumors and 78% of T4 tumors present- Distant metastasis (M)
ing with nodal metastases.58 Mx Distant metastasis cannot be assessed
The traditional grading system for bladder TCC is M0 No distant metastasis
also applicable to TCC of the upper urinary tract. M1 Distant metastasis
Broder’s original grading system, as modified by Ash,
grades tumors on a scale of 1 to 4, with grade 1 tumors AJCC staging system in comparison to TNM
being mainly papillomas and grade 4 tumors being AJCC stage TNM staging
Stage 0 T0
highly anaplastic and poorly differentiated.2,59 The
Stage I Ta, Tis, T1, N0, M0
World Health Organization’s grading system, proposed Stage II T2, N0, M0
by Mostofi, eliminates papillomas and grades tumors Stage III T3, N0, M0
from grade 1 to grade 3. The most recent grading sys- Stage IV T4 or any T, N+, M+
tem now divides tumors into low grade or high grade.60
Papillomas and papillary urothelial neoplasms of low
malignant potential (PUNLMP) are separated out as
CONSERVATIVE SURGICAL MANAGEMENT
well. Low-grade tumors include those previously con-
Endoscopic Management
sidered grade 1 and grade 1-2, while high-grade tumors
are those considered grade 2, grade 2-3, and grade 3. The established standard of care for the management of
Prognosis of upper tract tumors is clearly dependent upper tract TCC, regardless of stage or grade, is a radical
on tumor stage. There is a progressive decrease in sur- nephroureterectomy with resection of a generous cuff of
vival with increasing stage with the most significant drop bladder. The first radical nephroureterectomy was
being observed in stage T3 tumors, which involve perire- reported by LeDantu and Albarran.64 This approach is
nal or periureteral fat.61 When matched stage for stage, based on the characteristic biologic behavior of these
there does not appear to be a significant difference in sur- tumors. They tend to be multifocal, contralateral tumors
vival between renal pelvis and ureteral tumors.62 Other are uncommon (<5%), and there is a high incidence of
factors correlated with survival in these patients include ipsilateral tumor recurrence after partial resection.65
tumor grade, multifocality, concomitant bladder carci- Furthermore, prior to the advent of the smaller caliber and
noma, and ploidy.56 Tumor ploidy may be predictive of flexible endoscopes, conservative endoscopic management
survival with aneuploid tumors, demonstrating 5- and of these tumors was extremely difficult and fraught with
10-year survivals of 25% and 0%, respectively.63 errors in diagnosis and complications, rendering it obvi-
 Chapter 15 Transitional Cell Carcinoma of the Renal Pelvis and Ureter 275
ously unpopular. Vest first reported the successful man-
agement of papillary ureteric tumors with local resection
alone in 1945.66 Over the past two decades a number of
authors have reported successful long-term endoscopic
management of upper tract TCC. There are certain basic
tenets that must be observed while adopting this approach.
The patient must agree to submit to long-term close sur-
veillance with repeated upper tract endoscopy, tumors
should be of low grade and stage and the patient must
understand that nephroureterectomy may still become
necessary if there is evidence of stage or grade progression.
Upper tract tumors can be visualized using ureteral
contrast studies and ureteroscopy. Biopsies can be
obtained using a 2.4Fr flat wire basket or a 3Fr flexible
cup biopsy forceps, which can be placed through a flexi-
ble 7Fr ureteroscope or a 6.9Fr semirigid ureteroscope.
This approach can successfully confirm the presence of
upper tract TCC in up to 98% of cases.67 In their series
of 51 patients, Keeley et al.68 found that ureteroscopic
biopsy yielded a diagnosis of cancer in 94.1% of cases and
histologic grading was possible in 82.4%. The 11.5Fr
resection loop can also be used through the ureteroscope,
particularly in sampling and/or treating distal ureteric
tumors.69 Upper tract tumors are akin to bladder tumors
in terms of the correlation between pathologic grade and
stage. Low-grade tumors predominantly tend to be low
stage and very few high-grade tumors are of low stage
(Ta-T1).38,70 Previous studies indicate that almost all
grade 1 tumors are Ta.70 Keeley et al.71 found that even
low- to moderate-grade tumors tend to be of lower stage
(Ta-T1) while 67% of high-grade tumors were muscle
Table 15-2 Results of Endoscopic Ablation of Upper Urinary Tract Tumors
No. of Complication
Author Patients Rate
Englemeyer and Belig75 10 2/10 (20%)
Elliott et al.74 37 8/37 (22%)
Martinez-Pinero et al.76 28 12/28 (43%)
Keeley et al.68 41 2/41 (5%)
Chen et al.67 23 2/23 (9%)
Blute et al.53 13 (ureteral) 0%
8 (renal pelvis) 0%
Johnson77 3 33%
Schilling et al.78 10 0%
Modified from Chen GL, Bagley DH: J Endourol 2001; 15:399.
P, renal pelvis; U, ureter; B, bladder.
invasive (T2-T3). Correlation between grade and stage
determined on ureteroscopic biopsy samples and final
pathologic grade/stage determined from the
nephroureterectomy specimen tend to be more accurate
in the case of proximal ureteral tumors than distal
ureteral tumors.69 Following adequate biopsy sampling,
the tumors are ablated using either a Nd:Yag laser or
Holmium laser delivered through a 200 or 365 μm fiber.
The holmium laser is used at a setting of 1 J and 10 Hz
while the Nd:Yag is used at a 30 W setting.72 The holmium
laser has a penetration depth of 0.5 mm while the Nd:Yag
can penetrate 5 to 6 mm below the surface, which can
result in ureteral wall damage and may go unnoticed until
later.73 Some experienced endoscopists advocate using a
combination of the two types of laser to achieve a more
complete ablation of all of the tumors. A ureteral stent is
left in place for 1 to 2 weeks following the procedure. In
situations where postablation instillation of a chemother-
apeutic agent, such as mitomycin is anticipated, an open-
ended ureteral catheter can be left in place attached to a
Foley catheter to facilitate upper tract access.
Complications reported with this approach have been
minimal. Ureteral perforation, ureteral strictures and
incomplete tumor resection have all been reported. The
incidences of ureteral perforation in the two largest
recent series of endoscopic management of upper tract
tumors have been 0%68 and 5.4%.74 Ureteral strictures
tend to occur more frequently in patients who suffer a
ureteral perforation, with an overall incidence of 8.6%
(Table 15-2). This is higher than that observed with
nononcologic ureteroscopy and laser use. One potential
Subsequent
Recurrence Nephrouret- Follow-Up
(Site) erectomy (Months)
2 (P), 5 (U) — 24–66
8 (P), 9 (U), 19 (B) 6 3–132
2 (P), 6 (U) 3 2–119
3 (P), 5 (U), 15 (B) 8 3–116
5 (P), 8 (U), 7 (B) 4 8–103
2 (U); 4 (B) 0 6–50
1 (P) 0 12–48
1 (U), 2 (B) 0 5–22
1 (B) 0 3–31
276 Part III Kidney and Ureter
reason for this may be that in the case of tumor ablation
the laser energy is being directed against the urothelium,
directly permitting a greater amount of damage to occur,
while in the case of laser lithotripsy, the beam is directed
away from the urothelium. TCC recurrence rates after
endoscopic ablation have been comparable to those
obtained with open resection of renal pelvis TCC (50%
versus 45% to 65%, respectively).8 Overall, the recur-
rence rate of tumors in the renal pelvis is 37% and of
those in the ureter is 43% after endoscopic management
(see Table 15-2). Recurrences appear to be grade related,
with 76% of kidneys with grade 1 tumors being cleared
of all disease at one point, 64% of kidneys with grade 2
tumors being cleared of disease and only 40% of kidneys
bearing grade 3 tumors being cleared of disease.68
However, in this same report, local recurrences occurred
in 25% of those with grade 1 tumors and 44% of those
with grade 2 tumors requiring repeat endoscopic treat-
ment at mean follow-up times of 40.3 months and 27.6
months, respectively.68 Tumors smaller than 1.5 cm can
also be cleared more effectively compared to larger
tumors as evidenced by the difference in recurrence
rates—25% versus 50%.68
An alternative endoscopic approach in patients with
bulky renal pelvis tumors is percutaneous resection or
ablation. While this approach has demonstrated equiva-
lence with more traditional surgical approaches in terms of
cancer control, case selection is critical.79 Percutaneous
access is obtained through the upper or midpole calyx to
gain easy access to the collecting system as well.
Alternatively, the involved calyx can also be accessed and
the tract dilated and a working sheath placed. The tumor
is debulked using cold cup forceps and the base is resected
using a standard resection loop. The base can also be ful-
gurated with electrocautery or a laser. A second look
nephroscopy is typically performed 3 to 7 days later and
the resection base biopsied again to rule out the presence
of residual tumor.80 Disease-specific survival at a mean fol-
low-up of 51 months using this approach is reported to be
100% for grade 1, 94% for grade 2, and 62% for grade 3
TCC.80 The procedure is invasive with increased risk of
hemorrhage, extravasation, and possible tumor dissemina-
tion along the nephrostomy tract or into the retroperi-
toneum. The incidence of percutaneous tract seeding after
nephrostomy and upper tract TCC resection is low. Most
reports involve recurrences that have occurred following
percutaneous access after nephroscopy81 or prolonged
nephrostomy tube drainage.82–84 Very few reported cases
in the literature have occurred after percutaneous resec-
tion of an upper tract TCC.85,86 Suggested methods to
prevent nephrostomy tract or local recurrence after percu-
taneous access include maintaining low intrarenal pres-
sures, using a 30Fr working sheath, use of sterile water,
and keeping the irrigating solution at a height <40 cm
above the patient.86 Resecting the nephrostomy tract and
performing adjuvant radiation after nephroureterectomy
in this situation are also viable options.87 The percuta-
neous nephrostomy can also be utilized for instillation of
chemotherapeutic/immunotherapeutic agents following
the resection.88,89 Percutaneous resection is effective for
low-grade tumors but the outcome of local resection for
high-grade disease is dismal with 80% of patients dying of
their disease in spite of subsequent nephroureterectomy in
one series.90 Multiple resections may be required to clear
the renal pelvis of disease. Seeding of the nephrostomy
tract does not appear to be a significant occurrence as evi-
denced by absence of tumor in the tract resected at subse-
quent nephroureterectomy.90 Renal salvage is possible in
60% of patients with low-grade disease at a follow-up of
64 months.90
In patients who have biopsy-proven CIS or positive
upper tract cytologies, instillation of BCG into the upper
tract can be an effective therapy. This approach could also
be used, in solitary kidneys or in poor surgical candidates for
nephroureterectomy, as adjuvant therapy following either
percutaneous or retrograde resection of renal pelvis
tumors. Instillation can be performed either antegrade via a
percutaneous nephrostomy tube or retrograde through a
4Fr or 5Fr ureteral catheter inserted temporarily. The BCG
is instilled as a continuous infusion over 30 to 60 minutes (1
ml/minute) with the bag hanging 20 cm above the
patient.88,89 The dose of BCG used is usually up to three
times the intravesical dose91 and instillation is avoided in the
presence of gross hematuria. Patients void following instil-
lation and the treatment is repeated weekly for 6 weeks. In
an analysis of data from at least eight previous studies, it
appears that an initial response rate of 79% can be achieved
with a follow-up ranging from 4 to 82 months. The
response can be durable in several of these patients as
observed by Okubo et al.,89 who obtained a long-term
response over a median follow-up of 49 months in 6 of 9
(66%) of their initial responders. Other series have found a
long-term response rate with renal preservation of around
50% for patients with CIS.91 Fever appears to be a common
side effect in these patients and septicemia due to bacterial
dissemination or systemic BCGosis can occur in these
patients and could be lethal. In one series, the incidence of
sepsis was 2 of 37 patients (5%).91 This mandates emergent
evaluation with resuscitation, starting of triple antitubercu-
lous drug therapy with isoniazid (plus pyridoxine), rifampin,
and ethambutol. Steroids may need to be used in addition if
the patient is not responding to this regimen in the acute
setting. Mitomycin instillation can also be used as initial
treatment in place of BCG with similar results.92
Surgical Approaches
Partial Ureterectomy
Segmental ureteral resection is a viable curative option
for tumors of the ureter. Judicious use of this option is
 Chapter 15 Transitional Cell Carcinoma of the Renal Pelvis and Ureter 277
important, keeping in context the stage and grade of
tumor. It is most applicable to low-grade, distal ureteral
tumors. The 5-year survival for patients with grade
1 tumors, who have undergone partial ureterectomy, is
100%.93 The ipsilateral recurrence rate following seg-
mental resection is low and the recurrent tumors also
tend to be low grade94 (Table 15-3). Recurrent tumors
usually tend to occur distal to the original tumor, though
occasional proximal recurrences have been noted.95,99
Potential explanations for this include the presence of
adjacent CIS that is undetected at the time of primary
resection, seeding of the upper tract due to vesico-
ureteric reflux, or de novo occurrence of new tumors.
Patients with grade 2, stage Ta or T1 tumors can also be
managed by segmental resection of the ureter containing
the tumor. Anderstrom et al.39 found a 100% survival
rate in 16 patients managed in this manner at 83 months
follow-up. The success of conservative resection for
muscle invasive or high-grade disease is not as clear-cut.
Leitenberger et al.100 found that 4 of 13 patients man-
aged with partial ureterectomy or nephrectomy alone for
high stage (≥pT2) disease developed ipsilateral recur-
rences. Other studies have found a low rate of ipsilateral
recurrence in patients managed with conservative resec-
tion of high-grade tumors.38 However, it is possible that
the lower duration of subsequent survival in these
patients is too short to permit appearance of locally
recurrent tumors.
Removal of the kidney and only a portion of the ureter
for a renal pelvic or proximal ureteric TCC has a high
rate of recurrence in the remaining ureteric stump.8,37,101
The incidence of tumor recurrence is proportional to the
residual length of ureter left behind, suggesting that it is
a function of potentially affected urothelium left in
situ.57,102,103 This observation has provided the impetus
for complete ureterectomy in these patients. Zincke
et al.93 found that recurrence rates following segmental
resection for distal ureteral TCC was much lower than
that for renal pelvis TCC following nephrectomy with
partial ureterectomy (15% versus 62%, respectively).
Table 15-3 Results of Segmental Ureteral Resection and Reimplantation
for Localized Ureteric Tumors
No. of
Study Patients (n)
Johnson and Babaian95 6 1/6 (16.6)
Zungri et al.96 35
Maier et al.97 17
Wallace et al.98 7 1/7 (14.3)
Anderstrom et al39 21
Recurrent TCC are also more likely to be of higher
grade and stage when they are located in the renal
pelvis.8,104 Renal pelvis TCC also appear to have a higher
likelihood of developing systemic disease subsequently
(0%) as compared to ureteral TCC (19%). Hence, the
more traditional nephroureterectomy is a better
approach for renal pelvis or proximal ureteral TCC espe-
cially if they are of high grade or stage.
Open Nephroureterectomy
One of the major drawbacks of the open nephroureterec-
tomy is the need for two separate incisions to enable
complete excision of the distal ureter with a cuff of blad-
der mucosa. Typically, this is achieved by using a flank
incision for the nephrectomy and an additional Gibson
incision to access the distal ureter and bladder. It should
also be noted that prior to proceeding with an open
nephroureterectomy, it is essential to ensure that the
bladder is tumor-free by means of a cystoscopy and pos-
sible biopsy. Several urologists have advocated an endo-
scopic approach to excising the distal ureter and bladder
cuff transvesically, thereby avoiding the need for a second
incision.105 The two principal endoscopic approaches
have been a “stripping” technique wherein a ureteral
catheter is placed and secured with a tie around the dis-
tal ureter. Following resection of the kidney and proxi-
mal two-thirds of the ureter, a resectoscope is used to
circumscribe the mucosa around the ureteral orifice
while applying upward traction on the catheter through
the flank incision. This allows the intramural ureter to be
detached from the bladder along with a rim of surround-
ing bladder mucosa.106,107 There are multiple variations
to this approach with the orifice being cauterized to
encourage closure or simply ligated. Another commonly
used technique is the “pluck” approach. The ureteral ori-
fice is circumscribed endoscopically using a resectoscope
loop or a hook electrode until perivesical fat is visi-
ble.108,109 This denotes that the distal ureter is free from
surrounding attachments and can then be extracted in
Local Ureteral Duration of
Recurrences (%) Follow-Up (Months)
44.4
3/35 (8.5) 86
3/17 (17.6) 41.4
93.6
1/21 (4.7) 83
278 Part III Kidney and Ureter
continuity with the renal specimen through the flank
incision. The mucosa around the opening in the bladder
wall is fulgurated to cause scarring and sealing of this
area. A drain is left in place postoperatively. Mean blad-
der recurrence rates using the two different approaches
are comparable (19.3% versus 24%, respectively).105
However, a total of 9 patients (7%) have developed local
recurrence at the site of the ureteral orifice with the
pluck technique, which is of significant concern.
Complication rates are higher with the stripping tech-
nique (10% versus 2.7%) and it may not be applicable in
all cases.105 The main complications with the pluck tech-
nique are the risk of intraperitoneal extravasation, while
ureteral catheter-related problems, such as breakage/dis-
lodgement or retention of the catheter, are the main
problems following the stripping approach. Prognosis
and survival following traditional management of TCC
of the renal pelvis and ureter are very dependent on stage
and grade. The presence of renal parenchyma around the
renal pelvis acts as an anatomic barrier and this impacts
prognosis. Stage T3 renal pelvis TCC is associated with
a 54% 5-year survival rate, while that of ureteral T3
tumors is 24%.8,36 Metastatic upper tract TCC has a dis-
mal prognosis, with the majority of patients dying by 3
years and 0% of patients survive for 5 years, even with
administration of adjuvant therapy.37,62 Overall reported
stage-specific 5-year survival rates for upper tract TCC
are 100% for Ta/CIS tumors, 92% for T1, 73% for T3,
and 41% for T4 tumors.38 Median survival for those with
stage T4 disease can be as short as 6 months. Overall
median survival does not appear to differ significantly
between patients who undergo segmental ureterectomy
for a ureteral tumor compared to those who undergo a
nephroureterectomy, and is reported to be as high as 58
months.38 Previous studies indicate a clear effect of both
stage and grade on 5-year survival, with rates ranging
from 54% to 75% for stage I/A/Tis, 43% to 87% for
stage II/T1 or T1, 0% to 54% for stage III/C/T3, and
0% to 19% for stage IV/D/T4/N+ or M+.36 Most large-
scale studies for treatment outcomes for upper tract
TCC using reported epidemiologic data from the
American College of Surgeons or the Surveillance
Epidemiology and End Results (SEER) program con-
sider mainly renal pelvis TCC, which is grouped with
kidney cancers and which renders the data hard to inter-
pret. Most recent data from the American College of
Surgeons National Cancer Database indicate that overall
survival for cancers of the kidney and renal pelvis is 76%
(Figure 15-5).
Laparoscopic Nephroureterectomy
Since the first report of a laparoscopic nephroureterec-
tomy in a child by the Washington University group in
1991,110 this approach has rapidly gained acceptance and
is now considered the standard of care by many. Cancer
control and complication rates are reported to be compa-
rable to the open approach. The morbidity, as with other
laparoscopic procedures, is significantly lower with
shorter hospital stays and recovery times (Table 15-4).
The efficacy of both transperitoneal and retroperitoneal
laparoscopic nephroureterectomy appear to have similar
advantages over the traditional open approach.111,119 A
hand-assisted approach has been advocated by some as
easier for traditional surgeons to master and as a means
to allow better control and manipulation during the
removal of large tumors or more complex cases. Using
this approach Keeley et al.120 observed better retraction,
dissection, and tactile feedback, which translated to
shorter operative times than standard “pure” laparoscopic
nephroureterectomy. The hand-assisted laparoscopic nep-
hroureterectomy still requires a longer operative time
compared to the traditional open nephroureterectomy
but hospital stay, time to oral intake, time to resuming
normal activity, and quality of life are better with the
hand-assisted approach as determined by prospective
studies.121 In a prospective comparison of the standard
laparoscopic nephroureterectomy to the hand-assisted
approach, Landman et al.111 found that complication
rates were slightly lower with the hand-assisted approach
(45% versus 31%). Operative time was shorter with the
hand-assisted approach and there were no differences in
hospital stay or postoperative pain medication require-
ments. Return to work times were 1 to 3 weeks longer in
the hand-assisted group though this was not statistically
significant. All three approaches appear to be oncologi-
cally equivalent as assessed by the incidence of recurrent
tumors. Based on these data the laparoscopic or hand-
assisted approaches are considered by many to be the
standard of care.
There is still some controversy about the best method
of excising the lower ureter with a cuff of bladder mucosa
while performing a laparoscopic nephroureterectomy.
The methods described in the open nephroureterectomy
section for endoscopic resection of the distal ureter
transvesical to avoid a second incision are applicable to,
or have been adapted for, use in conjunction with laparo-
scopic nephroureterectomy. Gill et al.122 have used an
intravesical approach with needlescopic (2 mm) instru-
ments. Small-sized laparoscopic instruments are placed
transvesically and the bladder cuff around the ureteric
orifice is circumscribed with electrocautery and dissected
around a previously placed ureteral balloon catheter,
which occludes the ureter and prevents tumor spillage.
Dissection is carried out until the intramural portion of
the ureter is free of all attachments and the lower ureter
and bladder cuff can be extracted in continuity with the
rest of the specimen. Shalhav et al.123 have proposed a
combined laparoscopic and endoscopic approach. An
occluding balloon catheter is placed in the ureter. The
 Chapter 15 Transitional Cell Carcinoma of the Renal Pelvis and Ureter 279

100
90
80
70
60
Percent

50
40
30
20
10
0
At diag After 1 year. After 2 year. After 3 year. After 4 year. After 5 year.
SURVIVAL
When diagnosed on stage: I II III
IV Overall
Source: NCDB, Commission on Cancer, ACoS. Survial Reports, v2.0 −− March 9, 2004

Five Year Survival Table fo Kidney and Renal Pelvis Cancer Cases Diagnosed in 1995 &
1996
All States/Data Reported from 1653 Hospitals
Hospitals of type: All

Stage Cases At dx 1 year 2 year 3 year 4 year 5 year 95% Confidence Interval

I 5147 100 93.10 87.96 82.87 77.66 73.91 72.53 - 75.29

II 15158 100 92.94 87.10 82.35 77.12 72.31 71.47 - 73.15

III 6334 100 82.76 70.78 62.79 55.96 50.59 49.17 - 52.01

IV 9423 100 33.75 17.66 11.22 8.17 6.49 5.91 - 7.07

Overall 39944 100 75.00 65.22 59.30 54.28 50.35 49.79 - 50.91

Source: NCDB, Commission on Cancer, ACoS/ACS. Survival Reports, v2.0—March 9, 2004

Figure 15-5 Stage specific 5-year survival rates for kidney and renal pelvic tumors
diagnosed 1995–1996. (Data from the National Cancer Database maintained by the
American College of Surgeons, with permission.)

intramural ureter is unroofed using a hot Collins knife
and a 1-cm cuff of bladder mucosa is circumscribed
around the ureteric orifice using a resectoscope until
perivesical fat is clearly visible. A rollerball electrode is
used to fulgurate the edges of the ureter. A balloon
catheter is replaced in the renal pelvis to prevent leakage
of tumor into the retroperitoneum. The lower ureter is
thus freed of all attachments and can then be extracted in
continuity with the rest of the specimen. Other authors
have reported simply resecting the ureteral orifice trans-
vesically using a resectoscope.108 The availability of
hand-assisted laparoscopy has also permitted a more
standard approach using hand traction on the lower
ureter to dissect it down to the bladder extravesically and
excise it along with a cuff of mucosa. All of the minimally
invasive approaches run the risk of leaving a portion of
the intramural ureter intact.
CHEMOTHERAPY FOR ADVANCED DISEASE
Upper tract urothelial cancers are fairly chemosensitive.
Given the relatively low frequency of upper tract TCC
compared to bladder TCC, very few trials have focused
on developing chemotherapeutic regimens specific for
upper tract disease. Single-agent and combination regi-
mens that have shown activity in bladder TCC have been
generally used to treat upper tract disease with similar
efficacy. Most of the data cited below pertain to bladder
 280

Table 15-4 Comparison of Outcomes from Laparoscopic Nephroureterectomy with Open Nephroureterectomy
Part III Kidney and Ureter

Number of Mean Mean Local

Cases/Open Method of Distal Mean LOS Follow-up Recurrence
Study Approach Conversions Ureter Resection Pathology EBL (cc) (days) (Months) Rate

Chung et al.112 Retroperitoneal 6/14 Open bladder cuff NS NS 9 12.6 15% (B)

Salomon et al.113 Retroperitoneal 4/0 Open bladder cuff PT2-T3, grade 2-3 220 5.7 18 25% (local)

Keeley and Tolley114 Transperitoneal 18/3 Pluck NS NS NS NS 11%

Hobart et al.115 Retroperitoneal 17/2 Transvesical PTa-T4, grade 1-3 278 2.2 6.4 NS

Shalhav et al.116 Transperitoneal 25/0 Stapled PTa-T3, grade 1-4 199 3.6 39 40% (28% B,
12% local)

McNeill et al.117 Transperitoneal 25/3 Open bladder cuff PT1-T3, grade 1-3 5 35 16%*

Yoshino et al.118 Retroperitoneal 23/1 Stapled 2.5 cm cuff PTa-T4, Grade 1-3 304 NS 19* 17.4% (B)

Landman et al.111 Transperitoneal 11/0 Cystoscopic unroofing, PTa-T1, Grade 1-4 190 3.3 27.4 30% (B)
(1 retroperitoneal) cauterization

NS, Not significant; B, bladder.

*Median follow-up.
 Chapter 15 Transitional Cell Carcinoma of the Renal Pelvis and Ureter 281
TCC but has served as a basis for the chemotherapeutic
approaches adopted for upper tract TCC.
Single-agent chemotherapy with cisplatin, methotrex-
ate, cyclophosphamide, or gemcitabine has yielded
responses ranging from 25% to 35%.124,125 The methotrex-
ate, vinblastine, adriamycin, cyclophosphamide (MVAC)
regimen, which has a reported response rate as high as
70% in bladder TCC, can also be used for upper tract
TCC.126,127 In direct comparisons, it is clear that combi-
nation therapy is more effective than single-agent ther-
apy such as cisplatin.128 In one report, 20 patients with
upper tract TCC were included in a randomized trial
comparing MVAC with the cisplatin, cyclophosphamide,
adriamycin (CISCA) regimen.129 There was no differ-
ence in response rates between these patients and those
with primary bladder TCC. In spite of observed com-
plete responses, there is a tendency for patients to relapse.
Duration of response varies from 8.5 to 39 months.128
Alternative newer regimens, such as gemcitabine with
cisplatin or paclitaxel with carboplatin have yielded
response rates of 50% to 60%.130 A randomized trial
comparing MVAC to gemcitabine with cisplatin obtained
similar response rates, median overall survival, and dura-
tion of response.131 The gemcitabine/cisplatin regimen
was much less toxic and better tolerated. It is now con-
sidered the de facto standard for the treatment of most
urothelial cancers. A sequential approach has also been
used to treat urothelial cancers. Adriamycin/gemcitabine
followed by ifosfamide/paclitaxel/cisplatin has been used
in an effort to maximize response while limiting toxic-
ity.132 Results of randomized trials are awaited.
Neoadjuvant chemotherapy has been used in upper
tract disease and more so in bladder cancer. Large ran-
domized trials have failed to show a clear survival benefit
to this approach. One study using the cisplatin,
methotrexate, vinblastine (CMV) regimen demonstrated
a 5.5% higher survival in the neoadjuvant chemotherapy
group at 3 years of follow-up, which was not statistically
significant.133 The theoretical advantage of neoadjuvant
chemotherapy in downstaging the tumor and allowing
organ preservation by conservative surgery does not
really exist for upper tract disease since the only candi-
dates for such surgery are those with superficial disease.
Data supporting the use of adjuvant chemotherapy in
urothelial cancers are also weak and this applies to upper
tract disease as well. Most trials have not shown a clear
benefit and the advantage of routine adjuvant
chemotherapy over salvage therapy at the time of recur-
rence is not well established.134–137
RADIATION THERAPY FOR UPPER TRACT TCC
The use of radiation therapy as an adjuvant to surgery in
patients with locally advanced upper tract TCC has been
reported with variable results. Original studies suggested
that the use of adjuvant radiation may decrease the like-
lihood of local recurrence after nephroureterectomy in
patients with locally advanced T3/T4 disease.138–140
Brookland and Richter139 treated 23 patients determined
to have poor risk disease with surgery alone or surgery
followed by adjuvant radiation. They found that 1 of 9
(11%) evaluable patients treated with adjuvant radiation
developed local and distant recurrence, while 5 of 11 (42%)
evaluable patients who were treated with surgery alone
developed local or local and distant recurrence. Other
authors report similar low rates of local recurrence with
the use of adjuvant radiation therapy.138,141 The reported
doses of radiation used have ranged from 40 to 50 Gy.
Adequate and complete local control of tumor is impor-
tant considering the fact that it can be an independent
predictor of survival.142 Maulard-Durdux et al.143
reported the largest retrospective series, with 26 patients
treated with adjuvant radiation of 45 Gy following com-
plete surgical resection of primary tumor in patients with
locally advanced disease, of whom 42% had regional
nodal metastases. They noted a low local recurrence rate
of 15% but the overall 5-year survival rate was not dif-
ferent than that obtained in historic series using surgery
alone. These results highlight the fact that while local
failure is important, most patients who die succumb to
metastases, which is not in areas addressed by radiation.
Hence, it is difficult to recommend routine adjuvant
radiation even in patients with evidence of residual local
disease. These individuals may benefit from adjuvant
combination chemotherapy or a combination of radiosen-
sitizing single-agent chemotherapy with cisplatin fol-
lowed by radiation to optimize local control.
OUTCOME
Overall risk of recurrence after initial standard treatment
of upper tract TCC, which has traditionally been open
nephroureterectomy, has been related to stage and grade
of tumor. Five-year survival can range from 100% for
low-stage disease to 0% for T4 disease.70 More recent
series have indicated a local recurrence rate of 23% to
27%.38,141 Almost 50% of these recurrences are in the
bladder, with 9% occurring in the retroperitoneum, 18%
in the remaining upper tract, and 22% being distant.38 In
multivariate analysis, tumor stage and surgical procedure
were related to the risk of recurrence.38 Only patient age
and stage were indicative of survival in multivariate
analysis. Local disease relapse tends to occur early and
the median time to such recurrence can be 12 months.38
Follow-up of patients with upper tract TCC involves
obtaining periodic IVP and/or CT scans to image the
upper tracts and rule out local disease recurrence. While
there is no established follow-up schedule that is known
to be optimal, it is reasonable to base it on stage/grade of
primary tumor and type of surgical procedure performed.
282 Part III Kidney and Ureter
We typically recommend obtaining an IVP 3 months
postoperatively and a CT scan 6 months following sur-
gery if the renal unit is left intact. Subsequent follow-up
will include annual IVP and/or CT scan. In those who
undergo nephroureterectomy, CT scans are obtained at
yearly intervals for stage T2 or higher and biannual stud-
ies for lower stage disease. We also obtain a voided urine
cytology and perform office cystoscopy to rule out the
presence of bladder TCC in patients at 3-month intervals
for the first 2 years, every 6 months for the following
2 years, and yearly thereafter following treatment of
upper tract TCC.
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79. Smith AD, Orihuela E, Crowley AR: Percutaneous
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80. Jabbour ME, Smith AD: Primary percutaneous approach
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81. Tomera KM, Leary FJ, Zincke H: Pyeloscopy in
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82. Sengupta S, Harewood L: Transitional cell carcinoma
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83. Sharma NK, Nicol A, Powell CS: Track infiltration
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84. Huang A, Low RK, DeVere White R: Nephrostomy
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85. Fulgsig S, Krarup T: Percutaneous nephroscopic
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86. Oefelein MG, MacLennan G: Transitional cell
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87. Clark PE, Streem SB: Endourologic management of
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88. Studer UE, Casanova G, Kraft R, et al: Percutaneous
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89. Okubo K, Ichioka K, Terada N, et al: Intrarenal bacillus
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90. Goel MC, Mahendra V, Roberts JG: Percutaneous
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91. Thalmann GN, Markwalder R, Walter B, et al: Long-
term experience with bacillus Calmette–Guerin therapy
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92. Eastham JA, Huffman JL: Technique of mitomycin C
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93. Zincke H, Neves RJ: Feasibility of conservative surgery
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95. Johnson DE, Babaian RJ: Conservative surgical
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97. Maier U, Mertl G, Pummer K, et al: Organ-preserving
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98. Wallace DMA, Wallace DM, Whitfield HN, et al: The
late results of conservative surgery for upper tract
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99. Palou J, Salvador J, Millan F, et al: Management of
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100. Leitenberger A, Beyer A, Altwein JE: Organ sparing
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101. Booth CM, Cameron KM, Pugh RCB: Urothelial
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102. Kakizoe T, Fujita J, Kishi K, et al: Transitional cell
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103. Strong DW, Pearse HD, Hodges CV, et al: The
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104. Charbit L, Gendreau MC, Cukier J, et al: Tumors of the
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110. Clayman RV, Kavoussi LR, Figenshau RS, et al:
Laparoscopic nephroureterectomy: initial case report.
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111. Landman J, Lev RN, Bhayani S, et al: Comparison of
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115. Hobart MH, Gill IS, Sung GT, et al: Radical
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124. McCaffrey JA, Dodd PM, Herr H, et al: Nonbladder
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126. Sternberg CN, Yagoda A, Scher HI, et al: Preliminary
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286 Part III Kidney and Ureter
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C H A P T E R
16Management of Upper Urinary Tract
Transitional Cell Carcinoma
Andrew J. Dreslin, MD, and Graeme S. Steele, MD
Transitional cell carcinoma (TCC) is a malignant disease
that affects the urothelium of the urinary tract. Although
TCC of the upper urinary tract accounts for only 5% of
urothelial tumors, this incidence is increasing.1 This may
be due in part to improved treatment and survival of
patients with TCC of the bladder. In general, clinical
symptoms and signs, such as dysuria and hematuria, do
not differentiate between tumors of the upper and lower
urinary tracts. However, patients with upper tract tumors
may present with flank pain due to obstruction by tumor
or blood clot (Figure 16-1). Constitutional symptoms of
weight loss, fatigue, and anemia may indicate more
advanced disease.
Initial evaluation of suspected upper urinary tract
tumors includes complete urinary tract imaging, urinary
cytology, and direct endoscopic visualization. Traditio-
nally, the intravenous pyelogram (IVP) was employed to
detect filling defects within upper urinary tract. However,
with increasing availability and decreasing costs, the com-
puted tomography (CT) urogram provides detailed images
not only of the urinary tract but also of the other abdom-
inal structures, including regional lymph nodes. As a
result, CT urography has replaced the IVP in many cen-
ters, where CT technology is readily available. In addition,
retrograde pyelography at the time of cystoscopy to evalu-
ate gross hematuria is widely employed to evaluate upper
tract morphology (Figure 16-2).
Technologic improvements in visual optics have
allowed direct endoscopic visualization of the entire uri-
nary tract. This advancement has readily provided the
ability by visual inspection to differentiate soft tissue fill-
ing defects from renal and ureteral stones, in addition to
the option of biopsy of suspected lesions and in some
cases definitive treatment.
Multiple treatment options now exist for tumors of
the renal pelvis and ureter. Treatment decisions are based
largely on the histology of the tumor. Merely 20% to
30% of upper tract urothelial tumors are low-grade, pap-
illary lesions with favorable prognosis.2 Multifocal
tumors are common, the incidence of that is directly
related to tumor grade.2 TCC has a high rate of ipsilat-
eral recurrence following conservative management.
Proximal-to-distal ipsilateral recurrence is common,
while recurrence in a distal-to-proximal direction
remains rare.3 In a retrospective study of 252 patients
treated for upper tract TCC, tumor stage was a signifi-
cant predictor of recurrence on multivariate analysis.4
This observation lends support to radical treatment of
these tumors, although increasing evidence supports the
use of more conservative approaches for low-grade and
low-stage tumors.
TCC of the renal pelvis and ureter can invade local
structures or spread by lymphatic and hematogenous
routes. Common sites of hematogenous metastasis
include the lungs, liver, and bones. Lymphatic spread is
initially to regional hilar, paraaortic, and paracaval nodes
for renal pelvis and proximal ureteral tumors, while dis-
tal ureteral tumors invade pelvic nodes. Thus, a thorough
preoperative evaluation is necessary prior to any decision
on treatment strategy. This includes chest x-ray, abdom-
inal CT, liver function tests, and occasional bone scans.
In this chapter, several treatment strategies are discussed,
including open radical nephroureterectomy (NU),
laparoscopic NU, open nephron-sparing surgery, and
endoscopic or percutaneous management. The technical
aspects, as well as the indications, and advantages of each
procedure are also discussed.
OPEN RADICAL NEPHROURETERECTOMY
Traditionally, open radical NU with excision of bladder
cuff has been regarded as the gold-standard therapy for
287
288 Part III Kidney and Ureter
Figure 16-1 Left retrograde pyelogram (RPG) in a 66-year
old male who presented with left flank pain and gross
hematuria. RPG revealed a renal pelvic filling defect, which
proved to be a well-differentiated TCC, and was managed by
percutaneous resection.
TCC of the upper urinary tract in patients with a normal
functioning contralateral kidney. While this approach
has some advantages in certain situations, laparoscopic
NU is now regarded as the more appropriate approach in
the majority of patients requiring NU for upper tract
TCC.
Open NU with excision of bladder cuff is still appropri-
ate in very large, invasive tumors with possible local exten-
sion, including renal vein or vena caval involvement and
gross lymphadenopathy. Furthermore, cytoreductive sur-
gery in the setting of metastatic disease is often best accom-
plished by an open, rather than a laparoscopic, approach.
Open NU with resection of bladder cuff can be per-
formed through one or two incisions. The patient is
placed in a flank-torque position allowing access to the
kidney and lower abdomen. The surgical prep includes
the flank, abdomen, and genitalia, providing for sterile
bladder catheter placement at the beginning of the pro-
cedure. Table flexion or the use of a kidney rest usually
provides improved surgical exposure of the kidney. An
initial flank incision is made over the 11th or 12th rib,
removing the tip of the 11th or 12th rib usually enhances
access to the kidney and renal pedicle. This incision may
Figure 16-2 Left retrograde pyelogram in a patient with
gross hematuria showing filling defects due to transitional cell
in the proximal ureter and renal pelvis. Metastatic evaluation
revealed pulmonary parenchymal metastatic disease.
be extended towards the pelvis allowing dissection of the
distal ureter and bladder cuff. Conversely, a second lower
abdominal midline incision may be used for this part of
the procedure. The use of an ipsilateral Gibson or
Pfannenstiel incision may be substituted for a lower mid-
line incision, although the increased muscle dissection
with this approach may contribute to further postopera-
tive morbidity. The flank dissection proceeds in a
retroperitoneal or intraperitoneal fashion. Thoraco-
abdominal surgical exposures are hardly ever required.
Either intraperitoneal or retroperitoneal dissection can
easily accomplish exposure and dissection of the distal
ureter and bladder.
Open NU with resection of bladder cuff is com-
menced with radical nephrectomy, which includes
removal of the kidney and surrounding Gerota’s fascia.
The renal vessels are identified and tagged with a vessel
loop prior to ligation. The renal artery is ligated and
transected first, followed by the renal vein. A combina-
tion of nonabsorbable suture tie and hemostatic clips or
suture ligature is used to secure the vessel stumps. As the
incidence of adrenal involvement is low with renal pelvis
and ureteral tumors, ipsilateral adrenalectomy may be
 Chapter 16 Management of Upper Urinary Tract Transitional Cell Carcinoma 289
Figure 16-3 Open NU includes resection of the ureteral
orifice and bladder cuff, usually accomplished with a ureteric
catheter in situ to provide traction and ureteric exposure.
avoided in patients with distant tumors and normal pre-
operative imaging.
After mobilizing the kidney and Gerota’s fascia, the
ureter is dissected along its course to the bladder. To
reduce the risk of tumor spillage, transection of the kid-
ney from ureter is avoided. The distal ureteral dissection
should include removal of the intramural ureter and a
cuff of bladder mucosa. Recurrent TCC is seen in the
ureteral stump of 23 % to 64% of patients following
incomplete ureteral dissection.5-7 An anterior cystotomy
allows access to the ureteral orifice and transmural
ureter. Needlepoint electrocautery and counter-traction
facilitate this portion of the dissection.
Upon removing the kidney, ureter, and bladder cuff,
the bladder defects are closed in two layers with
absorbable suture. Alternatively, extravesical dissection of
the intramural ureter avoids the creation of an anterior
cystotomy. Traction on the dissected ureter brings the
surgical plane into the field. Care must be taken to
remove completely the transmural ureter and ureteral
orifice as these may be the sites of recurrence. Again, the
bladder defect is closed in two layers with absorbable
sutures. A bladder catheter is left in situ for 7 to 10 days,
then a cystogram determines adequate healing. An
extravesical closed suction drain is used to detect a urine
leak postoperatively (Figure 16-3).
Regional lymphadenectomy should be performed dur-
ing radical NU. For the tumors of renal pelvis and prox-
imal ureter ipsilateral hilar lymph nodes are dissected.
The paraaortic nodes extending from the renal hilum to
the aortic bifurcation are included with left-sided tumors.
For right-sided tumors, paracaval and retrocaval nodes
are dissected. With distal ureteral tumors, ipsilateral
common iliac, external iliac, internal iliac, and obturator
nodes are excised. Inclusion of a regional lymphadenec-
tomy adds little additional operative time and postopera-
tive morbidity, while it may provide therapeutic benefit
for patients with local disease and identify patients who
may benefit from adjuvant chemotherapy.8 Additional
series suggest a possible therapeutic benefit for patients
with lymph node positive disease.9
In general, NU (open or laparoscopic) remains the
gold-standard therapy for patients with upper urinary
tract TCC and a normal functioning contralateral kid-
ney. Hall et al.4 reported decreased local recurrence fol-
lowing radical versus nephron-sparing surgery. In a
review of 100 patients treated for upper urinary tract
TCC, the 15-year cancer-specific survival was 69% for
patients treated with radical NU compared to 25% for
patients treated with nephron-sparing surgery.5 A 5-year
survival advantage following radical NU was also seen in
patients with low-grade disease, while the advantage was
lost with high-grade tumors owing to the high incidence
of metastatic disease.10 The importance of nephrectomy
with total ureterectomy was seen in a series comparing
simple nephrectomy versus radical NU in patients with
TCC of the renal pelvis.11 The authors of the above-
mentioned references demonstrated a 5-year survival
advantage of 84% versus 51% for the radical surgery.
Contrary to the previous study, further benefit was seen
in patients with high-grade tumors, with a 5-year survival
of 74% versus 37% for radical NU and simple nephrec-
tomy, respectively. The benefit of NU is well defined for
patients with high-grade, organ-confined disease and
may be of value in patients with locally advanced disease
without evidence of systemic metastasis. In the setting of
bilateral tumors, solitary kidney, or poorly functioning
contralateral kidney, the benefit of NU must be
weighed against the quality of life changes following radical
surgery.
LAPAROSCOPIC RADICAL
NEPHROURETERECTOMY
Laparoscopic NU has emerged as an effective alternative
to open surgery in most patients with upper urinary tract
TCC. Clayman et al.12 initially reported the use of
laparoscopic technique for NU in a patient with TCC of
the renal pelvis. Subsequently, multiple techniques have
been described and include transperitoneal,13 retroperi-
toneal,14 and hand-assisted laparoscopy.15 The preferred
290 Part III Kidney and Ureter

approach is largely surgeon’s preference, although body
habitus and tumor characteristics of the patient may
guide this decision. The patient is positioned supine or
oblique and is prepped in a similar fashion to the open
procedure, again allowing access to a bladder catheter on
the surgical field. In laparoscopic surgery, the use of table
flexion or a kidney rest can make access to the upper pole
kidney more difficult as the surgeon’s reach is limited by
the length of the laparoscopic instruments. If total
laparoscopic surgery is planned, cystoscopy with electro-
cautery dissection of the ureteral orifice and intramural
ureter is performed at the beginning of surgery. At the
Cleveland Clinic, laparoscopic radical NU comprises
transvesical needlescopic-assisted cystoscopy detachment
of the en bloc bladder cuff and ureter, followed by
retroperitoneal removal of the kidney and ureter16
(Figure 16-4). Under cystoscopic control 2.2-mm
needlescopic ports are inserted suprapubically into the
bladder
A ureteral catheter is cystoscopically passed into the
ureteral orifice up to the renal pelvis, and the ureteral
orifice is grasped with a needlescopic grasper inserted
through the contralateral suprapubic port and retracted
anteriorly. A 24Fr resectoscope with a pointed coagulat-
ing electrode is inserted per urethra alongside the
ureteral catheter to resect a bladder cuff around the
ureteral orifice. Anterior traction by the suprapubic
grasper facilitates this dissection.
For renal and ureteric dissection trocar site placement
varies by surgeon preference, but usually involves the use
of four or five trocars. A periumbilical trocar is placed
initially by the Veras needle or open technique, and
pneumoperitoneum is established to 15 mm Hg. A 30-
degree telescope is inserted through this port and the
remaining trocars are placed under direct vision.
Additional port sites may include ipsilateral lower quad-
rant, midline supraumbilical, or mid-axillary subcostal.
This latter site is particularly of benefit in right-sided
tumors to assist with retraction of the liver. Initially, the
colon is mobilized medially by releasing the renocolic
ligaments, allowing access to the kidney. The ureter is
now identified at the lower pole of the kidney. By tracing
the ureter towards the kidney, the renal hilum comes into
view. First the renal artery then the renal vein are ligated
and transected using a vascular stapling device. On freeing
the kidney from its vessels, the remaining superior and
lateral dissections of the kidney are performed. With the
kidney completely mobilized, the dissection continues in
a caudal direction along the ureter. Distal to the iliac ves-
sels, the vas deferens in men or round ligament in women
is encountered and ligated. The ureteral dissection is con-
tinued to the bladder. Traction on the ureter will evert the
ureteral orifice and enable a vascular stapling device to
ligate and transect the distal margin. The umbilical trocar
site can be extended to allow removal of the specimen.
Alternatively, the specimen can be morcellated in a speci-
men bag and removed through the trocar site. Finally, the
fascial and skin layers of the port sites are closed.
For hand-assisted laparoscopic NU, a lower midline
or ipsilateral Gibson incision is used to place the hand-
port (Figure 16-5). The surgery is continued in a manner
similar to the total laparoscopic procedure. The sur-
geon’s hand is used for tactile sensation, retraction, and
blunt dissection. When the dissection reaches the level of
the iliac vessels, the surgeon may choose to release the
pneumoperitoneum and complete the distal ureterec-
tomy in an open technique through the hand-port.17
This hand-port also allows easy extraction of the intact
specimen from the abdomen. In comparison to the total
laparoscopic procedure, the hand-assisted approach
decreases operating time without altering postoperative
analgesic requirements or hospital stay.18

Figure 16-4 A, Laparoscopic NU can be performed via a retroperitoneal approach. Initially

the balloon is inflated in a cephalad direction towards the kidney to create a working space.
Finally the balloon is inflated along the anterior surface of the psoas muscle, displacing the
ureter anteriorly and creating a working space towards the iliac vessels. B, Right
laparoscopic NU showing patient position and three-port trocar approach.
 Chapter 16 Management of Upper Urinary Tract Transitional Cell Carcinoma 291

The advantages of laparoscopic surgery compared to its

open counterpart include the reports of decreased analgesic
requirements, shorter hospital stay, and shorter convales-
cence.17,19-22 The efficacy of this procedure as a definitive
cancer therapy is more difficult to establish given the lim-
ited number of series reporting long-term outcomes.
McNeill et al.23 reported a series of 25 patients with upper
urinary tract TCC treated by laparoscopic NU. With a
mean follow-up of 33 months, there was no difference in
overall survival compared to those patients treated with
open surgery. In a comparable series, the crude and cancer-
specific survivals for patients treated with open versus
laparoscopic NU were similar after 24 months of follow-
up.21 This study did note a greater number of patients with
grade 4 tumors who had local retroperitoneal recurrence
following laparoscopic surgery, suggesting that the open
procedure may provide additional therapeutic benefit for
patients with high-grade tumors. For patients with upper
urinary tract TCC without local invasion, laparoscopic
techniques of NU are proving to be a safe and effective
alternative to open surgery with the advantage of shorter
hospital stays and quicker recovery (Figure 16-6).

OPEN NEPHRON-SPARING SURGERY

Figure 16-5 Trocar and abdominal incisions for right and left Open nephron-sparing surgery, including partial
hand-assisted laparoscopic NU. nephrectomy for renal pelvis tumors and partial

Laparoscopy Open p Value

Mean surgical time (mins):* 224.8 ± 64.3 280.2 ± 73.8 0.003

Cystoscopy (mins) 58.9 (35–120) —
Laparoscopy (mins) 173.5 ± 54.2 —

Mean blood loss (cc) 242 ± 267.4 696 ± 953.2 <0.0001

Mean intravenous fluids (l) 3.6 ± 1.0 5.4 ± 2.7 0.002

No. concomitant adrenalectomy (%) 28 (67) 4 (11) <0.001

Mean extraction incision (cm) 7.0 — —

Mean time to ambulation (days) 1.4 ± 1.0 2.5 ± 1.5 0.0003

Mean time to oral intake (days) 1.6 ± 1.2 3.2 ± 1.9 0.0004

Mean hospital stay (days) 2.3 ± 1.6 6.6 ± 1.9 <0.0001

Mean analgesics (mg morphine sulfate equivalent) 26 ± 24.3 228 ± 207.2 <0.0001

Mean duration Foley catheter (days) 7.6 ± 4.9 7.4 ± 3.6 0.97

Mean time to normal activities (weeks) 4.7 ± 9.4 8.2 ± 7.6† 0.002

Mean time of convalescence (weeks) 8.0 ± 10.1 14.1 ± 8.3† 0.007

*Does not include time (approximately 45 minutes) to reposition patient.

†Only available in 13 patients.

Figure 16-6 Intraoperative and postoperative data.

292 Part III Kidney and Ureter

ureterectomy for ureteral tumors, is a treatment option
for patients in whom preservation of renal function is
important. Indications for conservative surgery include
solitary kidney, bilateral tumors, or baseline renal insuf-
ficiency. The patient is placed in the flank-torque posi-
tion and prepped in a similar fashion to the open NU.
For partial nephrectomy, an incision is made superficial
to the 10th or 11th rib, and the dissection proceeds in a
retroperitoneal, extrapleural, or thoracoabdominal
manner. Gerota’s fascia is incised, and the kidney is
mobilized completely. The renal vessels and ureter are
identified and tagged with vessel loops. Cooling the
kidney in a crushed ice slurry can reduce ischemic
injury. Similarly, mannitol diuresis prior to vascular
clamping can decrease parenchymal injury due to free
radical formation. Upon clamping the renal vessels, the
margin of dissection is defined with electrocautery of
the renal capsule. In dissection, the blunt end of a
scalpel blade is used to excise the tumor, the involved
renal calyces, and surrounding margin of normal renal
parenchyma. Areas of brisk bleeding are controlled with
hemostatic microclips or over-sewn with 4-0 Prolene
suture. Following adequate hemostasis, the remaining
renal pelvis is closed with 4-0 chromic sutures. The bed
of dissection is cauterized with electrocautery or argon
beam coagulator, and the parenchymal defect is closed
with a series of 2-0 chromic mattress sutures. A closed
suction drain is used to detect a urine leak postopera-
tively (Figure 16-7).
Open segmental ureterectomy is a treatment option
for invasive ureteral tumors when nephron-sparing sur-
gery is required or for local low-grade tumors, which are
too large for endoscopic management. Patients are
placed in a flank position for proximal and mid-ureteral
tumors or supine for distal ureteral tumors. The type of
incision depends on the location of the tumor. For prox-
imal and mid-ureteral tumors, a flank incision provides
adequate exposure, while a Gibson or lower midline
abdominal incision is used for distal tumors. Upon iden-
tifying the ureter and palpating the lesion, the ureter is
clamped and ligated 2 cm proximal and distal to the
affected area. Frozen sections of each free end are per-
formed prior to ureteroureterostomy to ensure complete
resection of the diseased segment. The ureter is mobilized

Laparoscopy Open p Value

Number of points with complete followup greater than 1 month 35 30 —

Mean months followup (range) 11.1(1–27) 34.4 (2.5–87) <0.0001

No. bladder recurrence (on followup cystoscopy) (%) 8 (23) 11 (37) 0.42
Multifocal 5 8
Solitary 3 3

Mean months to recurrence (range) 6.6 (3–15) 10.5 (2–37)

No. subsequent bladder treatment

Transurethral bladder tumor resection 2 1
Transurethral bladder tumor resection, bacillus Calmette-Guerin 6 10
Cystectomy 0 2

Number of points with distant metastasis (%) 3 (8.6) 4 (13) 1.00

Lung 2 1
Liver 1 0
Bone 0 2
Lymph nodes 0 1

No. adjuvant systemic chemotherapy (%)* 4 (11) 4 (13) 1.00

No. deaths (%) 2 (6) 9 (30) 0.39

Mean months to death (range) 4 (2–6) 24 (2.5–67)

% Crude survival 97 94 0.59

% Ca specific survival 97 87 0.59

There were no retroperitoneal or port site/incisional recurrences with either technique.

*Comprises 3 to 4 cycles of methotrexate, vinblastine, doxorubicin and cisplatin therapy.

Figure 16-7 Follow-up data comparing laparoscopic NU to open NU.

 Chapter 16 Management of Upper Urinary Tract Transitional Cell Carcinoma 293

to allow sufficient length to enable a tension-free repair
(Figure 16-8). If necessary, the kidney or bladder can be
mobilized to provide additional ureteral length.
Ureteroureterostomy is performed by spatulating each
free end and anastomosing around a ureteral stent with
4-0 absorbable suture. When performing a distal
ureterectomy, the repair proceeds with creation of an
ureteroneocystostomy. This is performed through an
anterior cystotomy in a refluxing or nonrefluxing manner
using 4-0 absorbable suture. The use of a psoas bladder
hitch may be required to lessen tension across the
anastomosis.24 Again, a closed suction drain is used to
monitor for a urine leak postoperatively (Figure 16-9).
In the setting of a solitary kidney, bilateral tumor, or
baseline renal insufficiency, nephron-sparing surgery
may be employed for the treatment of upper urinary tract
TCC. Ziegelbaum et al.25 reported the use of nephron-
sparing surgery for patients with TCC of the renal pelvis.
The indication for conservative surgery was a solitary
kidney in the majority of patients, and the tumors were
primarily of low grade and low stage. In this series, 62%
of patients remained disease-free up to 5 years postoper-
atively. For distal ureteral tumors, 83% disease-free sur-
vival has been observed following distal ureterectomy.24
In a large series of 224 patients with low-stage upper uri-
nary tract TCC treated by NU, nephrectomy, or seg-
mental ureterectomy, no difference in overall survival
was observed.26 The use of open nephron-sparing sur-
gery is a viable treatment option for patients with low-
grade, low-stage TCC of the upper urinary tract who
require preservation of renal function.
ENDOSCOPIC MANAGEMENT
Endoscopic evaluation of the upper urinary tract by ante-
grade or retrograde approach is useful for evaluation of
symptoms, diagnosis of pathology, and more recently,
definitive therapy of upper tract malignancy. Diagnostic
ureteroscopy is performed on patients with lateralizing
hematuria or abnormal cytology, a filling defect observed
on radiographic evaluation and tumor at the ureteral ori-
fice.2 It is also a critical tool employed for surveillance of
patients treated for upper tract malignancy with renal-
sparing methods. With the advances in optical technol-
ogy, smaller and flexible ureteroscopes are able to access
most areas of the upper urinary tract including the renal
pelvis and calyces.
Ureteroscopy provides access to the upper urinary
tract for evaluation and treatment of pathology while
maintaining a closed urinary system. The rigid uretero-
scope provides excellent visualization of the distal and
mid-ureter, while flexible ureteroscopes are used to

Figure 16-8 Surgical technique for uretero-ureterostomy. Ureteral spatulation of well-

vascularized ureteral ends and tension-free reapproximation with fine absorbable suture
material usually results is a good surgical result. Intraoperative frozen section analysis is
imperative to establish negative surgical margins.
294 Part III Kidney and Ureter
Figure 16-9 Distal ureterectomy and psoas hitch ureteral reimplantation is a well-recognized
surgical option for patients with distal ureteral tumors, when the proximal upper tract is
tumor free. Surgical principles once again include well-vascularized distal ureter and a
tension free anastomosis.
access the proximal ureter and renal pelvis. Access to the
lower pole calyx may be limited by the infundibulopelvic
angle, which can exceed the deflection capability of flex-
ible ureteroscopes. Patients are placed in the lithotomy
position. Cystoscopy is performed initially for evaluation
of the bladder mucosa and to gain access to the ureter
using a guide wire. Although not always necessary with
the use of small diameter instruments, atraumatic dila-
tion of the ureteral orifice and intramural ureter allows
easy passage of ureteroscopes into the upper urinary
tract. This is accomplished by inserting an inflatable bal-
loon dilator over a guide wire across the ureteral orifice.
The balloon is inflated to 14 cm H2O for 1 to 2 minutes.
Following dilation, a rigid ureteroscope is passed into the
ureter under direct vision, or the flexible scope is passed
over a guide wire using fluoroscopic guidance. High-
pressure irrigation or pulse-irrigators used at a maximum
of 40 cm H2O allows good visualization without the risk
of ureteral perforation.
The entire intraluminal ureter and renal pelvis are
inspected on initial and subsequent evaluations. Several
biopsy instruments are available for sampling areas of
pathology. These include brush-biopsy forceps, cold-cup
biopsy forceps, and resectoscopes, in which use is limited
to larger rigid ureteroscopes. Complete resection of
abnormal lesions can be accomplished with the biopsy
forceps or resectoscope. Bugbee electrocautery of the
resected tissue bed fulgurates residual tumor and mini-
mizes bleeding. Alternatively, various laser fibers may be
used to ablate tumors following tissue biopsy. The
neodymium:yttrium-argon-garnet (Nd:YAG) and
holmium:YAG laser sources are commonly used. The
200 or 365 μm flexible fibers pass easily through the
working channel of both rigid and flexible ureteroscopes,
without significantly altering deflection. The holmium:
YAG laser at 0.6 to 1 J and 10 Hz provides tissue ablation
to a maximum of 5 mm.27 This is especially well suited
for the thin-walled ureter. The Nd:YAG laser induces
coagulation necrosis with subsequent sloughing of
necrotic tumor. Dose characteristics of this laser source
have been described following studies in the canine
ureter.28 Consistent transmural necrosis and ureteral
perforation were observed at doses of 20 W for 2 sec-
onds. At higher power (60 W) and shorter duration
(0.5 seconds), thermal injury extended into the muscle of
the ureter without perforation and resulted in nonstric-
tured healing. In humans, settings of 20 W for 1 to 2
seconds are commonly used for tissue penetration of 5
to 6 mm.29 At the completion of treatment, a double-J
ureteral stent is placed and left in situ until the tumor bed
is completely healed, typically for 4 to 6 weeks (Figure
16-10).
 Chapter 16 Management of Upper Urinary Tract Transitional Cell Carcinoma 295
Figure 16-10 Therapeutic options for upper tract TCC also
include ureteroscopy and laser ablation, using an
holmium:YAG laser. Careful follow-up, including ureteroscopy,
brushings and cytology, is important to ensure a good
outcome.
Percutaneous antegrade access to the renal sinus is
employed to evaluate lesions inaccessible by flexible
ureteroscopy or to resect large tumors of the renal pelvis.
Under fluoroscopic guidance, a percutaneous nephros-
tomy tract is established. With placement of a 34F
Amplatz sheath, the renal pelvis is accessed with a rigid
or flexible nephroscope. Again, cold-cup biopsy forceps
or a resectoscope is used to sample and resect the lesion.
As with ureteroscopy, electrocautery or laser ablation is
used to fulgurate the tumor bed following resection.
Insertion of a 24F reentry nephrostomy tube allows easy
access to the pelvis on a second-look procedure.
Nephroscopic examination of the renal pelvis with ran-
dom biopsies should always be performed within 4 weeks
of tumor resection. The nephrostomy tube is removed
after no suspicious areas are noted on nephroscopic
examination and all random biopsies are negative.30
Percutaneous management is best reserved for tumors
with a low risk of recurrence. These include solitary, pap-
illary tumors that are less than 2 cm, low-grade, and low-
stage.30 Other tumors are most appropriately managed
by ureteroscopy if possible (Figure 16-11).
Endoscopic management of upper urinary tract TCC
is reserved for patients with previously mentioned indica-
Figure 16-11 Nephrostomy tract puncture sites. Peripheral
calyceal tumor sites are best approached directly, while renal
pelvic tumors are usually easily approached via lower or
interpolar calyces.
tions for nephron-sparing surgery or who have a solitary,
low-grade, and superficial tumor. Endoscopy is used only
for biopsy and tissue diagnosis in patients who have sus-
pected invasive disease, high-grade or multifocal tumor.
In a comparison of patients with TCC of the upper uri-
nary tract treated by percutaneous resection or open NU,
there was no difference observed in the cancer-specific
survival rates (Figure 16-12).31 Following tumor treat-
ment, a high rate of recurrence is observed with reported
rates ranging from 24% to 65%.1,3,30,32-35 The rate of
recurrence has been directly associated with increasing
grade of tumor in a several studies.1,2 The development
of subsequent bladder tumors is also a concern with
reported rates of 30% to 43% of patients, similar to other
renal-sparing procedures.1,32 With a high rate of tumor
recurrence, a strict surveillance protocol is employed for
all patients treated with nephron-sparing surgery. This
includes cystoscopy with retrograde pyelography and
ureteroscopy every 3 months until tumor-free. This is fol-
lowed by cystoscopy and retrograde pyelography every 3
months and ureteroscopy every 6 months.1 NU remains a
treatment option for those patients with multiple recur-
rences. Overall, the preservation of renal units by complete
endoscopic management ranges from 73% to 86% when
primary tumors are low-grade and noninvasive.30,32,36
296 Part III Kidney and Ureter

Figure 16-12 Endoscopic technique for percutaneous removal of renal pelvic

tumors. A, The bulk of the tumor is removed with grasping forceps. Following
that the remaining tumor is resected using a standard resectoscope and
cutting loop. B, Medial tumors pose increased risk because of renal
vasculature and are therefore best managed by debulking biopsy followed by
holmium:YAG laser ablation. C, Finally, ureteroscopy and laser ablation can
be achieved with the flexible cystoscopy and a standard lower pole
approach. D, Intraoperative and postoperative data comparing laparoscopic
NU to open NU.
 Chapter 16 Management of Upper Urinary Tract Transitional Cell Carcinoma 297
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5. Racioppi M, D’Addessi A, Alcini A, Destito A, Alcinin E:
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8. Miyake H, Hara I, Gohji K, Arakawa S, Kamidono S: The
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9. Komatsu H, Tanabe N, Kubodera S, Maezawa H, Ueno
A: The role of lymphadenectomy in the treatment of
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10. Murphy DM, Zincke H, Furlow WL: Management of
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tract. J Urol 1981; 125:25–29.
11. Johansson S, Wahlquist L: A prognostic study of
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12. Clayman RV, Kavoussi LR, Figenshau RS, Chandhoke PS,
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13. Shalhav AL, Elbahnasy AM, McDougall EM, Clayman
RV: Laparoscopic nephroureterectomy for upper tract
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14. Gill IS, Soble JJ, Miller SD, Sung GT: A novel technique
for management of the en bloc bladder cuff and distal
ureter during laparoscopic nephroureterectomy. J Urol
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15. Keeley FX Jr, Sharma NK, Tolley DA: Hand-assisted
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17. Chen J, Chueh SC, Hsu WT, Lai MK, Chen SC:
Modified approach of hand-assisted laparoscopic
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18. Landman J, Lev RY, Bhayani S, et al: Comparison of hand
assisted and standard laparoscopic radical
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19. Goel A, Hemal AK, Gupta NP: Retroperitoneal
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20. Seifman BD, Montie JE, Wolf JS Jr: Prospective
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26. Murphy DM, Zincke H, Furlow WL: Primary grade 1
transitional cell carcinoma of the renal pelvis and ureter.
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28. Smith JA Jr, Lee RG, Dixon JA: Tissue effects of
neodymium:YAG laser photoradiation of canine ureters.
J Surg Oncol 1984; 27:168–171.
29. Schmeller NT, Hofstetter AG: Laser treatment of ureteral
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30. Orihuela E, Smith AD: Percutaneous treatment of
transitional cell carcinoma of the upper urinary tract. Urol
Clin North Am 1988; 15:425–431.
31. Lee BR, Jabbour ME, Marshall FF, Smith AD, Jarrett
TW: 13-year survival comparison of percutaneous
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collecting system: equivalent outcomes. J Endourol 1999;
13:289–294.
32. Elliott DS, Segura JW, Lightner D, Patterson DE, Blute
ML: Is nephroureterectomy necessary in all cases of upper
tract transitional cell carcinoma? Long-term results of
conservative endourologic management of upper tract
transitional cell carcinoma in individuals with a normal
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urinary tract tumors. J Clin Las Med Surg 1998;
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34. Martinez-Pineiro JA, Matres JG, Martinez-Pineiro L.
Endourological treatment of upper tract urothelial
carcinomas: analysis of a series of 59 tumors. J Urol 1996;
156:377–385.
35. Elliott DS, Blute ML, Patterson DE, Bergstralh EJ,
Segura JW: Long-term follow-up of endoscopically
treated upper urinary tract transitional cell carcinoma.
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C H A P T E R
17 Diagnosis and Staging of Bladder
Cancer
Michael J. Droller, MD
The standard approach in diagnosing and staging bladder
cancer initially incorporates cystoscopic examination of the
bladder and examination of urinary cytology to determine
the presence of malignancy. Once the presence of a lesion
is established, resection and pathologic evaluation of the
tumor specimen (and occasionally of mucosal biopsies) are
needed to document disease and characterize grade and
stage (extension of the neoplasm into the bladder wall).
Preliminary information on prognosis is inferred by the
“snapshot” obtained through histopathologic examination
and staging of the resected specimen (Figure 17-1).1,2
However, a deeper understanding of the implications of a
particular tumor is based on an appreciation of where this
snapshot fits into the natural history and pathogenesis of
the specific diathesis represented by this lesion in the con-
text of different developmental pathways of bladder cancer
(Figure 17-2).3 Further, these are ultimately determined by
genetic and molecular changes that correspond to intrinsic
biologic behaviors of specific tumors and the potential for
recurrence or progression (Figure 17-3).4 Characterization
of a particular tumor’s pathogenesis may thus be as impor-
tant clinically as the pathologic stage at the time of its
resection in the individualization of treatment approaches,
assessment of results of various “standardized” treatments,
and design of new therapeutic approaches.
This chapter discusses standard methods used to diag-
nose and stage bladder cancer. It will also review con-
cepts that are being used increasingly to assess the
intrinsic biologic potential of various forms of bladder
cancer and to enhance our understanding of molecular
changes that may determine their pathogenesis.
INITIAL DIAGNOSIS OF BLADDER CANCER
Bladder cancer is the fourth most prevalent noncuta-
neous malignancy in the United States.5 Over 54,000
new cases are diagnosed annually and over 12,000 indi-
viduals die of bladder cancer each year.5
Efforts to diagnose the possible presence of a urothe-
lial cancer are generally initiated by occurrence of either
gross or microscopic hematuria.6 The degree of hema-
turia has not been observed to correlate with either size,
grade, or stage of a particular tumor. On the other hand,
the presence of a bladder tumor may be more likely when
gross hematuria, rather than microscopic hematuria, is
the inciting event.
Irritative symptoms suggestive of a cystitis with a
sense of increased urgency and urinary frequency may
occasionally be reported by a patient with bladder cancer,
most often in the setting of carcinoma in situ (see later).
The location of this entity at the trigone of the bladder,
the bladder neck, or in the urethra should be suspected
when irritative symptoms occur in the setting of urothe-
lial cancer.
Most often, however, hematuria is not accompanied
by other symptoms. It is therefore referred to as “silent.”
The occurrence of hematuria requires evaluation of the
entire urinary tract since its source may not be exclusive
to the bladder. Nor is the occurrence of hematuria nec-
essarily indicative of the presence of a malignancy.7
Therefore, general imaging studies are performed to
evaluate the kidney cortex, the renal pelvis, the ureters,
and the bladder to search for malignancy or to identify
another possible etiology. Although it has become
increasingly common to perform sonography initially in
such an evaluation, the efficacy of ultrasound in detecting
upper tract urothelial lesions depends on the extent of
the abnormality, as well as the experience and thorough-
ness of the radiologist performing the procedure.8 The
major value of sonography in this setting lies in its ability
to detect a renal mass and to determine whether it is solid
or cystic. Additionally, it may be useful in identification
301
302 Part IV Bladder

Figure 17-1 Staging systems for bladder cancer are based on correlations between the
layer to which a particular cancer has penetrated the bladder wall and the prognosis of that
type of cancer. The original staging system (developed by Jewett HJ, Strong GH: J Urol
1946; 55:366) suggested distinctions between superficial and muscle-invasive disease. The
superficial classification was subsequently divided into tumors confined to the mucosa
(stage Ta) and tumors that penetrate the lamina propria (stage T1). Carcinoma in situ (stage
Tis) is a superficial disease composed of neoplastic cells that replace the normal urothelium
or undermine the normal urothelium and extend along the plane of the urothelium. Deep
bladder tumors penetrate the muscularis propria either superficially (stage T2a) or deeply
(stage T2b) or penetrate through the muscularis propria into the perivesical soft tissue either
microscopically (stage T3a) or extensively (stage T3b). These distinctions are a change in the
World Health Organization (WHO) classification system, which now combines all muscle-
invasive tumors into one category (stage T2) rather than maintaining the separation that
formerly had characterized the staging system (stage T2 for superficial invasion and stage
T3a for deep muscle invasion). The involvement of lymph nodes is designated by the N
category and involvement of adjacent structures is categorized as stage T4. This format
implies a simple pattern of sequential development according to which early cancers appear
as lower stages, and then progress to higher stages in sequence. However, this is not
necessarily what characterizes the different forms of bladder cancer seen clinically. Rather, a
variety of pathways that do not necessarily occur in sequence but are possibly interrelated
may more accurately reflect the biology of the different forms of bladder cancer.

of a lesion within the renal pelvis or within the course of
the ureter, a dilated possibly obstructed ureter, or an
intraluminal-filling defect of the bladder itself (largely
for tumors larger than 1 cm).9
Intravenous pyelography (IVP) provides definition of
the contours of the upper tracts better than that obtained
with sonography. However, pyelography may not reliably
permit identification of small lesions of the renal
parenchyma or renal pelvis or of bladder lesions <1 cm in
diameter.10 Imaging of the bladder in various positions as
it fills with contrast may allow visualization of one or
multiple bladder tumors, and full distention of the blad-
der may be of particular usefulness to the radiologist in
imaging a tumor on ultrasound.
Retrograde pyelography may be useful in a patient
with renal compromise or with contrast allergy in defin-
ing the anatomy of the upper tracts and in characterizing
any areas that appear abnormal or may not have been
adequately visualized on IVP.
Computed tomography (CT)11-13 and magnetic reso-
nance imaging (MRI)14-17 can also be used to identify
upper tract lesions, the presence of dilated ureter(s), and
masses in the bladder. To this point, neither has been
used as initial means of evaluating the cause of hematuria
or as a first-line method in diagnosing bladder cancer.
However, recent interest has focused on the use of CT
scanning in providing 3D imaging of the urinary tract.
Spiral CT scanning provides not only the quality of
images achievable to visualize the kidney, ureter, and
bladder on intravenous pyelogram but also provides
cross-sectional imaging and 3D reconstruction, which
can be used as an advantage in possibly staging a lesion if
one is uncovered. The use of air insufflation to facilitate
imaging of lesions in the bladder has been suggested to

the upper tracts or the bladder and penetrated through to
the soft tissues.
MRI enhancement has been attempted by the use of
gadolinium, T-weighted spin modalities, and use of a
number of other agents in imaging a primary tumor and
assessing its extent and penetration. MRI (and positron
emission tomography [PET] scanning) has been used in
identifying whether enlarged lymph nodes represent
metastatic disease.15-21 In such instances, fine needle
aspiration has been used to confirm whether or not
metastatic disease is present (see later).22,23
Former teaching held that when an upper tract source
of gross hematuria was suspected, upper tract imaging
studies should be followed immediately by cystoscopy to
facilitate localization of disease by visualizing blood ema-
nating from a ureteral orifice. However, as upper tract
lesions can now be visualized with greater reliability
using current imaging techniques, the immediate need
for cystoscopy has become less pressing.
On initial imaging evaluation of a patient with hema-
turia, it may be of value to obtain urine for cytologic
assessment. Although not particularly efficacious in the
detection of low-moderate-grade disease (with sensitivi-
ties ranging between 10% and 50%), urinary cytology is
useful in diagnosing urothelial cancers that are of high
grade.24,25 Therefore, if a urinary cytology is positive,
and upper tract imaging is negative, it may be expedient
to proceed directly to cystoscopy under anesthesia so that
multiple biopsies (see later) and resection of visible
lesions can be performed. The same approach may be
reasonable if a bladder tumor has been visualized on
imaging studies. Further assessment with barbotage irri-
gation specimens may produce clusters of cells that sug-
gest low-moderate-grade malignancy, but this may also
correspond to instrumentation artifact. Therefore, barb-
otage has generally been used more specifically to provide
increased numbers of cells for analysis by flow cytometry,
which may detect abnormalities in individual cells when a
urinary cytology has been interpreted as negative.26-28
Two products have recently been introduced to
enhance detection of low-moderate grade urothelial can-
cers and to complement cytology in diagnosis of high-
grade disease by employing fluorescent enhancement.
The ImmunoCyt assay employs fluorescent-labeled anti-
bodies to tumor antigens, obtaining a sensitivity of 70%
to 80% in detecting low-moderate-grade tumors (versus
that of urinary cytology with reports of sensitivity as low
as 10% to 15% for grade 1 tumors and 50% to 60% for
moderate-grade disease).29 The second assay, Vysion,
incorporates fluorescent in situ hybridization (FISH)
technology in identifying chromosomal abnormalities in
voided or barbotage urinary specimens.30 The antibodies
used in each assay are directed against molecules that
may identify cancers with specific biologic pathways.
Both assays may, therefore, offer the possibility of distin-
Chapter 17 Diagnosis and Staging of Bladder Cancer 305
guishing between tumors that are of low malignant
potential and those that are of high malignant potential
(see later). The substantial overlap in labeling, however,
may currently prevent full exploitation of this possibility.
At the same time, use of these assays in conjunction with
urinary cytology may permit the more reliable detection
of urothelial cancers of all grades.
Both the ImmunoCyt and the Vysion assays have a
lower specificity than does urinary cytology. In this, uri-
nary cytology remains the gold standard.31 It is therefore
the balance between enhanced sensitivity of these assays
in detecting disease of low malignant potential versus the
increased sensitivity and specificity of urinary cytology in
detecting disease of high malignant potential that must
be considered in using these assays appropriately.
During the past decade, much interest has been focused
on the use of assays that detect tumor “markers” in the
urine. One prominently advocated was an assay for blad-
der tumor “antigen” (BTA), a complement-related protein
released from the lamina propria in the presence of tumor
and inflammation.32 Unfortunately, the latter condition
severely compromised this assay’s specificity.33 Moreover,
the BTA assay also had inadequate sensitivity in detecting
higher-grade disease.32 This led to the development of a
point-of-care assay (BTA stat) and then a double-antibody
sandwich assay (BTA trac) in assessing a complement-
related factor released into the urine in association with
the presence of a urothelial malignancy.33 However, speci-
ficity of these assays was also affected by inflammation,
compromising their usefulness.
A urinary assay for nuclear matrix protein (NMP-22)
had an improved sensitivity for detecting low-moderate-
grade disease and its specificity was better than that
obtained with either of the BTA tests.34 Its validation in
the detection of high-grade disease and its use in the set-
ting of inflammatory conditions, however, appeared simi-
larly to limit its use. Other assays (microsatellites,
telomerase, hyaluronic acid/hyaluronidase, DD-23, fibrin
gradation products [FDP], and many others) have shown
promise in preliminary studies.35 However, validation
regarding their reliability, their consistency, and their role
in the diagnosis and assessment of urothelial cancer
remains to be obtained. An evolving consensus is that their
use may ultimately be found in monitoring for tumor
recurrence in patients with a history of bladder cancer, and
particularly in the setting of tumors that have low malig-
nant potential, so that the interval between sequential
invasive procedures for surveillance can be lengthened.
After preliminary imaging of the upper tracts and
bladder and an analysis of urinary cytology, cystoscopic
examination is required to confirm the presence of
malignancy, characterize its architecture, determine the
multiplicity of disease, and determine whether there is
diffuse mucosal involvement. Each helps assess the
nature of the cancer diathesis.
306 Part IV Bladder
The sine qua non of diagnosis in urothelial cancer is
transurethral resection of the tumor and pathologic eval-
uation of the surgical specimen. In addition, biopsies may
be taken in the setting of positive urinary cytology ran-
domly from several sites or directed on visualization of
abnormal areas of the bladder mucosa. Directed biopsies
typically include areas adjacent to the presenting lesion,
areas of mucosal erythema, and areas at the bladder neck
and within the prostatic urethra. Random biopsies of
endoscopically normal areas of the urothelium are no
longer taken routinely as part of the standard diagnostic
approach in the evaluation of a bladder cancer diathesis
when a preliminary cytology has been negative. Several
studies have shown that such random biopsies are not
likely to be informative and that the characterization of
the tumor diathesis by pathologic evaluation of the
resected specimen is generally sufficient for decisions
regarding subsequent treatment.36 Thus, random biop-
sies are now generally only obtained when there is no
endoscopically visible lesion, when upper tracts and ure-
thra have no radiologic or visual abnormality, and urinary
cytology is persistently positive. In these instances, biop-
sies are needed to identify the source of the positive cells.
The configuration of the tumor as characterized
endoscopically may suggest whether the tumor is super-
ficially or more deeply invasive. A papillary lesion is more
likely to be “superficial.” However, this alone does not
permit a distinction to be made between those tumors
that are mucosally confined (stage Ta) and those that
infiltrate the lamina propria (stage T1) (see later).37
Occasionally, mucosally confined disease may be identi-
fied by being able to remove the lesion by “scraping” it
with a cold loop. This can often be done with multiple
very small papillary lesions, in which a well-developed
fibrovascular core has not formed. Generally, however,
electroresection is necessary to excise a papillary lesion.
It is important that muscle fibers be visualized and sam-
pled for accurate staging, particularly when a papillary
tumor may have invaded the lamina propria. Several
studies have observed an at least 20% involvement of the
muscularis propria on repeat resection when initial resec-
tion suggested only lamina propria invasion and no mus-
cle was present for accurate analysis.38 A vigorous
resection, however, with its risk for penetration of the
bladder wall, is generally not necessary to obtain ade-
quate levels of tissue for staging.
Papillary tumors should initially be resected flush with
the bladder mucosa. Somewhat deeper resection can then
be done to permit separate evaluation of the lamina pro-
pria and the superficial level of the muscularis propria.
Care should be taken not to resect too deeply to avoid
perforation of the bladder wall. In the setting of papillary
disease the bladder wall may be quite thin and electrore-
section need not be carried more deeply than is required
for accurate staging of the superficial bladder layers.
A “solid” or nodular (as distinct from papillary) tumor
appearance implies a more deeply infiltrative diathe-
sis.39,40 In such instances, the superficial (or intraluminal)
portion of the solid tumor should be resected flush with
the plane of the mucosa. Deeper resection to include the
muscularis propria should then be done to determine the
depth of infiltration and possibly distinguish between
superficial and deep muscle invasion. Some have advocated
even deeper resection to the level of the perivesical fat.
However, extensiveness of disease can generally be deter-
mined without an aggressive resection such as this, and
risk of perforation can be avoided.
Bimanual examination of the bladder under anesthesia
before and after transurethral resection may provide addi-
tional information on the extent of the tumor invasion. This
is most informative when there is a large nodular or sessile
tumor that may have extended through the bladder wall, or
possibly involved adjacent structures. Inability to palpate a
tumor mass prior to resection suggests that the tumor is
possibly less extensively invasive. Palpation of a mass that
is mobile suggests the presence of a nodular, infiltrative can-
cer that does not involve adjacent structures. Palpation of a
mass that is fixed suggests that the cancer may have involved
adjacent structures or the pelvic sidewalls. Palpation follow-
ing resection that suggests less fixation may indicate a less
extensive involvement of adjacent structures than had been
surmised. However, any degree of palpability is generally an
ominous finding. In attempting to assess the extent of inva-
sive disease, bimanual palpation is highly subjective. Its
greatest value may be in cases of large tumors that are exten-
sively infiltrative, since these are more likely to be palpable
and generally indicate an adverse prognosis, especially if
they are palpable after resection.
STAGING OF BLADDER CANCER
Transurethral ultrasound,41 pelvic CT,42 and pelvic or
endorectal (endovaginal) MRI43 imaging can be used to
assess tumor extent prior to transurethral resection.
Transurethral ultrasound examination has been reported
to have a sensitivity of 90% and a specificity of 76% in
determining whether a tumor is muscle-invasive.44 One
report described that 24% of tumors staged as T1 by
transurethral ultrasound had been overstaged and that
10% of tumors staged as T2 had been understaged.
Correspondingly, 29% of stage T3b tumors (deep muscle
invasion) were understaged and 5% of stage T3a tumors
were overstaged by this modality.
The sensitivity of CT scanning in detecting extravesi-
cal extension of a bladder cancer has ranged between 60%
and 96%.12,14,42,45 Its specificity has ranged between
66% and 93%. Cumulative sensitivities and specificities
have been calculated at 83% and 82%, respectively,
implying that extravesical extension remains undetected
in 17% of instances and is over-diagnosed in 18% of

instances. CT scanning has had limited success in distin-
guishing between mucosally confined (stage Ta) and lam-
ina propria-invasive tumors (stage T1) and between
superficial and muscle-invasive (stage T2) diseases. It has
been more useful in distinguishing between lesions that
are only minimally invasive of the extravesicular soft tissues
(stage T3a) and those that have involved these tissues exten-
sively (stage T3b) or adjacent organs (stage T4). However,
overstaging has occurred in two-thirds of patients with
superficial disease, while understaging has been found in
30% of patients with muscle-invasive tumors.
MRI has several features that theoretically would
make it more accurate than CT scanning in the staging
of bladder cancer. Its major advantage lies in images that
can be obtained in multiple planes and in the demonstra-
tion of perivesical fat planes and boundaries of the
prostate and seminal vesicles.15-17,42,43 T1-weighted
images of the primary tumor can be contrasted with low-
signal intensity images of urine and high-signal intensity
images of perivesical fat. T2-weighted images can be
used to assess disruption of the muscle wall and invasion
of other organs. The sensitivity for MRI in identifying
extravesical tumor extension ranges between 60% and
100%, with a cumulative average of 73%. Specificity
ranges between 60% and 100% with a cumulative aver-
age of 84%. Recent reports have described improved
sensitivity and specificity in detecting muscle invasion
(96.2% and 83.3%, respectively) with the use of gadolin-
ium-DTPA enhanced MRI for tumor staging.43 In addi-
tion, improved accuracy has been obtained with newer
MRI techniques. Improved staging accuracy with sub-
millimeter pixel MRI, fast dynamic first pass MRI, fast
low-angle shot images, oblique contrast-enhanced T1
weight, and rapid gradient echo sequence MRI have been
used in attempts to improve the accuracy of staging both
in terms of identifying depth of penetration into and
through the bladder wall and identifying abnormalities in
the pelvic lymph nodes.15-18
PET scanning in bladder cancer has not been studied
extensively, and its role in staging is therefore unclear.19-
21 The radionuclides used are 18F-2-fluoro-2-deoxy-D-
glucose (FDG) and L-(methyl)-11C-methionine (LCM).
Both are primarily glucose derivatives and are used for
PET scanning that exploits the hypermetabolic state of
malignant tissues when compared with normal tissues.
FDG is taken up by normal and malignant cells, and the
glucose is phosphorylated for passage through the
Embden-Meyerhof pathway.20 However, phosphorylated
FDG cannot leave the cell and cannot be metabolized.
This allows its detection by PET scanning.
Since FDG is excreted in the urine, the bladder must
be irrigated continuously to permit delineation of the
bladder wall from the urine. Diagnosis of a primary blad-
der tumor and its separation from possible urinary arti-
fact, however, may be difficult. In diagnosis of a bladder
Chapter 17 Diagnosis and Staging of Bladder Cancer 307
cancer, studies have described a sensitivity of 86% to
100% and a specificity of 63% to 100%. The diagnosis of
lymph node involvement or extension outside of the
bladder may also be achieved using PET scanning with
FDG. However, studies reported to this date have
involved only small numbers of patients.
Other studies have used LCM for diagnosis of bladder
cancer and have employed calculations of specific uptake
values in attempts to enhance discrimination between
muscle invasion and extravesical extension of disease.21
Uptake of LCM by normal bladder tissue is low.
Therefore, staging of disease is limited. Some have sug-
gested that PET scanning with LCM may be useful in
monitoring for responses to neoadjuvant chemotherapy
or assessing regression of metastatic foci by evaluating
persistence of uptake on PET scanning after treatment.
Further study to assess these possibilities and definition
of the costs involved in the use of this technique will
determine its future usefulness.
The staging of bladder cancer by each of these imag-
ing modalities is limited by their inability to discern
microscopic extension of disease and the relative
dependence of each on disruption of normal “radi-
ographic” tissue planes in identifying the extension of
the cancer. The former may lead to understaging of dis-
ease, since extension of the cancer, even if only micro-
scopic, may be associated with a greater likelihood of
metastasis. The latter can lead to overstaging, since
images suggesting disruption of the muscularis can be
created by prior resection, inflammatory processes, or
other therapeutic interventions.
The critical element in ultimate characterization of a
bladder cancer is its histopathologic appearance. The
extent to which the cancer penetrates the bladder micro-
scopically,46 the histologic appearance of the tumor cells
and the architectural configuration of those cells (papil-
lary versus nodular),40,47 whether or not bladder lymphat-
ics or vasculature are involved by the cancer,40 and the
nature of the urothelium adjacent to and at sites distant
from the presenting lesion(s) (dysplasia or carcinoma in
situ)48,49 are important in considering a tumor’s prognosis.
Currently, staging of bladder cancer is based on the
depth to which the cancer has penetrated the bladder
wall.1,50 Although transurethral resection may be per-
formed so as to provide specimens that permit determina-
tion of the extent of involvement by the cancer of different
levels, inaccuracies generally prevail and tumors are often
understaged.51 More definitive assessment may only be
possible by analyzing a full thickness of the bladder wall
obtained by partial cystectomy or total cystectomy speci-
mens. This is clearly impractical in the majority of
patients. Several reports have described transabdominal
CT-guided needle biopsies to provide full-thickness blad-
der wall specimens to evaluate the depth of cancer infiltra-
tion.52 This technique has not gained general usage.
308 Part IV Bladder
Early attempts to characterize the prognosis of various
forms of bladder cancer were based more on an analysis of
their cellular appearance than their depth of penetration.
Broders53 described different grades of disease and corre-
lated those that were poorly differentiated with a more omi-
nous prognosis and those that were well differentiated with
a more benign prognosis. Although Aschner54 subsequently
correlated an increasing depth to which a tumor had pene-
trated the bladder wall with a progressively worse progno-
sis, this system did not obtain widespread currency.54
It was not until the mid-1940s that Jewett and Strong55
proposed a classification of bladder cancer based on the
depth of involvement of the bladder wall in association
with the “curability” of the tumor by cystectomy. Initial
observations were based on an autopsy series, in which
those tumors that had penetrated deeply into the bladder
wall were found in retrospect to have been “incurable.” In
a subsequent study of cystectomy specimens, Jewett and
Lewis56 proposed that tumors that had invaded only super-
ficially were curable by cystectomy whereas those that had
invaded the bladder wall more deeply were not.
Subsequent refinements in staging have been based on
more precise correlations between the depths of invasion of
a tumor through the different layers of the bladder wall in
association with prognosis, giving rise to the TNM classi-
fication.1,50 This consists of characterization of depth of
penetration of the tumor (T), involvement of pelvic lymph
nodes (N), and whether or not metastases were present
(M). The objectives of such a system are to suggest prog-
nosis, to form a basis for selecting treatment, to provide a
standard for evaluating treatment results, and to facilitate
the exchange of information through standardization of the
classification of the disease being treated.
The TNM system consists of a pretreatment clinical
(c) classification and a postsurgical histopathologic (p) clas-
sification. The pretreatment clinical classification is
based on imaging studies and impressions obtained both
by endoscopic visualization of the cancer and bimanual
examination. The histopathologic classification is based
on specimens obtained by transurethral resection.
Differences between these two classifications within indi-
vidual categories may be substantial. Moreover, the latter
may often be in substantial error (generally by under-
staging) when compared to assessments determined by
full thickness bladder wall cystectomy specimens.57-59
Although correlating well with stage and biologic poten-
tial of disease, tumor grade has not been included in
these classification systems.
The most recent TNM classification for bladder
tumors (1998)50 maintained the classifications for superfi-
cial tumors that were described in the 1992 TNM classifi-
cation subsequently reviewed at the 4th International
Consensus Meeting on bladder cancer in 1993.60 These
classifications included carcinoma in situ (TIS), mucosally
confined cancers (stage Ta), and cancers that had infiltrated
the lamina propria (stage T1). The classification for mus-
cle invasive bladder tumors was unified in a single category
of stage T2 disease (with subcategorization into stage T2a
representing superficial invasion into muscularis propria
and stage T2b representing invasion into the deeper com-
ponent of the muscularis propria) and this was distin-
guished from stage T3 disease that represented either
microscopic penetration into the perivesical soft tissues
(stage T3a) or disease that had extensively infiltrated the
soft tissues surrounding the bladder (stage T3b). These
staging systems are identical to those that have been pre-
sented in the current American Joint Committee on
Cancer’s (AJCC) staging system for 2002.
In addition, various modifiers that characterize the
tumor diathesis can be included in describing the stage and
character of disease that is present at any particular time.
For example, multiplicity of disease as this may be indica-
tive of the increased risk for recurrence can be indicated by
stating the number of tumors in parentheses following the
pathologic stage of disease. The presence of lymphatic
invasion or vascular invasion in the wall of the bladder,
while not officially recognized as a component of the stag-
ing system, can be indicated as a modifier of either “l” or
“v” in parentheses following the indication of pathologic
stage. Ultimately, incorporation of molecular markers may
be used to modify staging based on depth of invasion, and
grade may also be useful in determining risk of progres-
sion. It is important to recognize in each of these that a
particular stage provides only a snapshot as part of the
pathogenesis of disease that may evolve with time. A more
detailed discussion of a schema indicative of the different
pathways of tumor development that represents the
pathogenesis of disease in bladder cancer is provided in
detail at the end of this chapter.
Biologic Activity of Different Stages of Bladder
Cancers
Mucosally confined tumors (stage Ta), comprising 50%
of all urothelial cancers at initial diagnosis (70% of all
superficial cancers that are diagnosed as such in 70% to
75% of all urothelial cancers initially), have the best
prognosis.61,62 A 70% recurrence rate has been associated
with larger and multiple tumors at diagnosis. This could
represent inadequate resection, increased likelihood of
tumor cell implantation, or sites that were not endoscop-
ically visible initially but that then “recurred” (becoming
apparent clinically).
Most mucosally confined tumors found likely to
progress have been of high grade. These have comprised
only 2% to 4% of all stage Ta cancers.62 Additionally,
they have often been observed as a more diffuse
micropapillary diathesis,63 or to have been accompanied
by flat carcinoma in situ (see later) adjacent to or else-
where in the bladder.48

“Superficial” cancers that have invaded the lamina
propria (stage T1) comprise 20% of all urothelial cancers
on initial presentation (30% of all superficial cancers
[70%] as staged initially).61 As with mucosally confined
(stage Ta) tumors, these have a 70% rate of recurrence.
Unlike the mucosally confined diathesis, however, stage
T1 disease has a 20% to 30% possibility of progres-
sion.64,65 The high-grade tumors in this category (com-
prising 50% of all T1 cancers) appear most likely to
progress.62 This is seen in 50% of these cancers, or in
25% of the entire group.66,67 High-grade lamina propria
invasive tumors are often associated with urothelial
abnormalities (dysplasia or carcinoma in situ) adjacent to
the presenting lesion or at distant sites.48,68,69 These
appear more likely to be aggressive, particularly if they
are rapidly recurrent or do not respond to adjunctive
intravesical BCG (see Chapter 18).
It is highly important that the resection specimen
includes the muscularis propria in the staging of these
lesions. Several studies have documented muscle invasion
on repeat resection in 10% to 20% of tumors initially staged
as having only involved the lamina propria, particularly
when extensive lamina propria invasion has been seen.38,70,71
In addition, the submucosal connective tissue (lamina
propria) contains a muscle layer (muscularis mucosae),
the thickness of which can vary from being either virtu-
ally absent to being quite prominent.72 In the latter
instance, this muscle layer may be confused with the
muscularis propria. Several reports have suggested the
muscularis mucosae as a staging boundary, above which
(stage T1a) tumors do not have a strong risk of progres-
sion and beneath which (stage T1b) there is a higher risk
of progression to muscle invasive disease.73 Penetration
of the muscular mucosae as an indication of a more
aggressive cancer and its use in staging remains to be val-
idated. At the same time, many of those tumors that
invade more deeply appear to be more extensive while
those that are more superficially invasive appear to be less
extensive and may have invaded in only microscopic
foci.74 This in itself may be more indicative of the intrin-
sic biologic potential of the particular tumor diathesis
rather than of its topographically “prognostic” relation to
muscularis mucosae fibers.
In considering distinctions in the biologic potential of
various forms of superficial bladder cancer, grade of the
individual cells may be highly important as the manifes-
tation of a particular biologic capability.75 This may be
manifested in the development of generalized changes in
the urothelium leading to expression of a more diffuse
neoplastic diathesis known as carcinoma in situ.76 The
ultimate natural history of this entity may reflect
the intrinsic biology of the neoplastic diathesis and
should be taken into account in the staging of a particu-
lar bladder cancer and in the implementation of the
TNM staging system.
Chapter 17 Diagnosis and Staging of Bladder Cancer 309
It is as yet unclear whether there are different forms of
carcinoma in situ, and whether the variability and the
manner in which carcinoma in situ presents may affect
the heterogeneity of response of superficial disease
(whether mucosally confined or invasive of the lamina
propria) to different types of treatments.3,77 One form of
carcinoma in situ is characterized by highly abnormal
cells that involve the bladder mucosa diffusely and may
actually undermine the normal mucosa in spreading in
pagetoid fashion to cover broad areas of the bladder wall,
possibly extending as well into the prostatic urethra and
the lower ureters.78-80 Patients often present with symp-
toms of irritability, and urinary cytology is likely to be
positive. Other forms of carcinoma in situ may be unifo-
cal and occasionally more well differentiated. These may
theoretically represent a less malignant form of this
diathesis.81
The ominous prognosis ascribed to carcinoma in situ
may have originally been based on its association with
concomitant muscle-invasive transitional cell cancer.82
The muscle-invasive cancer rather than the carcinoma in
situ, at least as diagnosed at that phase of its course, was
probably the component that progressed and that was
responsible for metastasis in the majority of such cases.
However, knowing what we now know of the biology of
this diathesis, the specific pathway in which neoplastic
transformation had originally occurred and had led to
this diathesis may in turn have led to the formation of
nodular or sessile muscle-invasive disease with penetra-
tion into the bladder wall that was the form in which can-
cer was diagnosed on presentation.3,83,84
Once the entity of carcinoma in situ was appreciated
and urinary cytology came into more common use, the
diagnosis of this entity in association with more superfi-
cially invasive disease (a secondary form of diathesis) or
as the only (primary) form of cancer that was present
became more common. It therefore should not have been
surprising to see an apparently prolonged and possibly
nonprogressive course of carcinoma in situ when muscle-
invasive cancer was not present. Indeed, several studies
suggested that this form of cancer by itself might not
pose a major threat as the cancer cells forming carcinoma
in situ might lack the biochemical machinery necessary
to become invasive.76,77,81 However, it is also possible
that these observations represented lead-time biases in
describing the course and risk of this diathesis.
The ultimate ominous potential of carcinoma in situ
has been more fully appreciated on the basis of molecu-
lar changes that characterize this diathesis.77,85-87 This
has been supported further by its association with those
forms of high-grade papillary cancer that may not have as
yet invaded the muscularis propria. These have an omi-
nous prognosis, rapid recurrence, and progression to
muscle-invasion and metastasis soon after initial diagno-
sis. In long-term follow-up of carcinoma in situ, the
310 Part IV Bladder
incidence of progressive disease has been reported as
75% to 80% in patients with diffuse disease.
Several additional observations are relevant. First, car-
cinoma in situ has been found to penetrate the lamina
propria microscopically in 20% to 30% of cases.83
Second, high-grade carcinoma in situ appears to be more
commonly associated with papillary and papillo-nodular
tumors that are invasive of the lamina propria than with
papillary tumors that are mucosally confined.48,76,84 When
associated with the latter, the tumors may be micropapil-
lary, and usually are high grade. Since those tumors that
have invaded the lamina propria are more likely to
become progressive, the carcinoma in situ associated
with these may reflect a more aggressive diathesis as well.
Third, several reports have suggested the development of
solid or nodular tumors from foci of carcinoma in situ.84
If carcinoma in situ is the direct antecedent of nodular
tumors, which are more deeply invasive when they
become clinically apparent than are papillary tumors, the
diagnosis of this type of carcinoma in situ may signify a
particularly ominous neoplastic diathesis.
The correct placement of carcinoma in situ within the
generally accepted staging system remains unclear. All
forms of bladder cancer have their origin in intraepithelial
neoplastic transformation, which, by definition, produces
“carcinoma in situ.” Indeed, pathologists often identify
papillary mucosally confined tumors as papillary carcinoma
in situ, notwithstanding low-moderate grade cells and the
implication of disease with low malignant potential.
However, despite its confinement technically to the
mucosa, this diathesis is clearly quite different from the
form of flat carcinoma in situ that is associated with lamina
propria-invasive high-grade or muscle-invasive disease.
Descriptions of cancers as “invasive” have generally
implied their penetration of the bladder wall muscle
(muscularis propria). Progressive depth of penetration
into and through this layer has been correlated with an
increased likelihood of metastasis. A majority of patients
diagnosed with muscle invasive disease are diagnosed at
this stage of disease at their initial presentation.88,89
These comprise 20% to 30% of all urothelial cancers at
initial presentation. Muscle invasive cancers that arise
from initially superficial tumors comprise only an addi-
tional 10% to 12%. This reflects calculations based on
observations in stage T1 disease (since only 2% to 4% of
stage Ta tumors progress) as follows:
1. 20% to 30% of T1 tumors (comprising 30% of all
superficial tumors on initial diagnosis) are actually
muscle-invasive on repeat resection (equals 6% to
9% of all superficial tumors or 4% to 6% of all
urothelial cancers);61,62
2. 40% of initially high-grade T1 cancers are at risk for
progression (representing an original 50%, less 20%
which are already muscle invasive) but only 50% of
these progress, leaving 20% of stage T1 tumors
(equaling 6% of all superficial tumors or 4% of all
urothelial cancers).62,65,67
Approximately 50% of patients who present with muscle
invasive disease are thought to have occult metastasis at
diagnosis, these generally being expressed within 2 years
regardless of aggressive locoregional treatment.89
The directness of these associations and inaccuracies
of staging have led to a broad variability in suggested cor-
relations. For example, tumors that have penetrated only
the superficial muscle (stage T2) may have a better prog-
nosis than those that have penetrated only the lamina
propria (stage T1) but have done this extensively.90 Those
that have a papillary configuration and have invaded in a
broad front may have a better prognosis than those that
have a nodular configuration and that have manifested a
tentacular form of infiltration.91,92 Furthermore, cancers
staged as T2 may have been infiltrative of only the mus-
cularis mucosae (the muscle layer within the lamina pro-
pria) and not of the muscularis propria. And, even if truly
invasive of the muscular propria, many of these may only
have been very superficially invasive. Thus, despite hav-
ing had the ability to infiltrate, they may have invaded at
a less rapid rate and may have lacked the ability to pene-
trate lymphatics and vasculature and metastasize.92
Correspondingly, cancers staged as T1 may have been
understaged in 10% to 20% of instances, since repeat
resection has found residual cancer that was actually
invasive of the muscularis propria.38,70,71 These, as well as
those staged as T1 that are extensive in their penetration,
may have a particularly aggressive biologic potential.65-67
When recurrent (or persistent) they may already have
extended into the muscularis and even metastasized.
At the 1993 bladder cancer consensus conference in
Antwerp, a proposal was made that stage T3a tumors
(those with deep muscle invasion) and stage T2 tumors
(those with superficial muscle invasion) be combined in a
single category of T2.93 Stage T2a would then comprise
those tumors that had invaded only the superficial muscle
(less than one-half the depth of the muscle layer) and stage
T2b would comprise those that had invaded the deep mus-
cle (deeper than half the depth of the muscle layer). Stage
T3 would then designate tumor penetration into the
perivesical tissue. Stage T3a would comprise those tumors
that demonstrated only microscopic invasion beyond the
muscularis and stage T3b would comprise those that had
invaded more extensively into the extravesical tissues.
The rationale for including all muscle-invasive cancers
in one category reflected in part the problem of accu-
rately determining the depth of muscle invasion by
transurethral resection, as well as the impression that all
cancers invading the muscle wall were likely to behave in
a similar aggressive fashion regardless of their depth of
penetration.94-96 It also reflected the concept that

muscle-invasive tumors did not exhibit the same poten-
tial biologic behavior as did tumors that had extended
through the full thickness of the bladder wall into the
perivesical fat.97-99
Some have suggested that this new categorization fails
to take into account several observations. First, those
tumors that have penetrated only the superficial muscle
appear to be less likely to be associated with metastasis
and appear also to be more likely to be cured by a variety
of surgical approaches.97,98 For example, many of these
have shown no remaining cancer in the cystectomy
specimen after initial extensive transurethral resec-
tion.89,100,101 In addition, treatment outcomes have often
been more successful either in terms of time to disease
recurrence or survival as for more deeply invasive dis-
ease.101-103 That more superficial muscle invasion has
been associated more often with a papillary configura-
tion, invasion in a broad front, and less frequent involve-
ment of bladder wall lymphatics and vasculature than
deep muscle-invasive cancer is supportive of distinctions
between these diatheses (see later).91,92 Second, those
tumors that have invaded the muscle layer more deeply
appear to have an ominous prognosis similar to that of
tumors that have involved perivesical soft tissues micro-
scopically.93,94,99 This harks back to earlier staging cate-
gories that combined deep muscle invasion with extension
into perivesical fat.55 Differences in clinical manifestation
and treatment outcomes may be less restrictive than dis-
tinctions between these categories imply.
Superficial muscle invasion has been associated with a
papillary configuration and a pattern of infiltration that
has been described as “broad front,” in which tumor cells
penetrated the bladder wall muscle in large clusters of
cells with a broad infiltrative margin.91,92 Such tumors
have appeared to involve the bladder wall vasculature and
lymphatics in only one-third of cases.47 In contrast,
tumors that have invaded more deeply have been associ-
ated with a more nodular type of configuration and a pat-
tern of infiltration that has been described as
“tentacular,” in which tumor cells have appeared to “per-
colate” through the bladder wall in smaller clusters or as
finger-like projections.47,91,92 Such tumors have been
found to involve the bladder wall lymphatics and vascu-
lature in at least two-thirds of instances.47
Stage T4 disease has been compartmentalized into
stage T4a, representing tumor invasion of the prostate,
uterus, or vagina, and stage T4b representing tumor
invasion of the pelvic or abdominal wall. Conflicting
observations have made definitive staging in these cate-
gories somewhat unclear. For example, 40% of cystec-
tomy specimens have cancer involvement of the
prostate.80,104 Traditionally thought to indicate an omi-
nous prognosis, prostatic involvement may actually influ-
ence outcomes in a variable manner. If the cancer is
mucosally confined while extending into the prostatic
Chapter 17 Diagnosis and Staging of Bladder Cancer 311
urethra and prostatic ducts, prognosis will be less omi-
nous than if the cancer has infiltrated into the prostatic
stroma.80 An analogous situation may pertain in women.
If there has been direct penetration only to the outer
aspect of the anterior vaginal wall, prognosis may be less
ominous than if there has been more extensive involve-
ment of the vagina or penetration of the uterus. Evidence
validating this suggestion has not been obtained. Direct
involvement of other adjacent structures or fixation to
the pelvic sidewalls is generally tantamount to the cancer
being incurable. Distant metastatic disease is nearly
invariably present in these situations even if only occult.
Therefore, locoregional treatments generally fail.99,105,106
Involvement of regional lymph nodes has generally
been interpreted as indicating an ominous prognosis.107
Several recent reports have suggested that prognosis may
not be as grave when only microscopic metastases are
found and only involve 1 to 2 regional lymph nodes.108,109,111
Under these circumstances, aggressive surgery with
meticulous lymphadenectomy has been reported to pro-
duce 5-year survivals as high as 35%.108 Moreover, although
gross involvement of the lymph nodes or involvement of
more than two lymph nodes has previously been associ-
ated with a poor prognosis, recent studies have suggested
that more extensive dissection of lymph nodes beyond
the pelvis and inclusive of all pelvic nodes resulted in
improved outcomes.110 Whether staging subdivisions
according to the degree of lymph node involvement,
number of lymph nodes involved, proportion of nodes
involved per total number of lymph nodes removed, or
differences between macroscopic versus microscopic dis-
ease play a role in outcomes and should adjust surgical
treatment approaches remains to be validated.
Distinctions in organ involvement by distant metas-
tases have not been associated with variability of out-
comes and survival. Therefore, staging subdivisions
according to organ involvement have not been included
in standard staging systems.
PATHOGENIC PATHWAYS IN BLADDER CANCER
Schematic depictions of bladder cancer staging systems
in association with likelihood of progression have created
the impression that the various cancer diatheses fall into
a sequence of stages in their pathogenesis (see Figure
17-1). This has implied further that progression from the
most superficial appearance histologically to the most
extensive invasion is inexorable.
Such schema, however, as they imply a sequence of
stages, do not take into account issues in the pathogene-
sis of disease. The natural history of various forms of
bladder cancer may instead reflect developmental path-
ways that, although interrelated, may be distinct from
one another (see Figure 17-2). A schema that incorpo-
rates the concept of a variety of different developmental
312 Part IV Bladder
pathways can complement the standard concept of a
sequence of stages in understanding the pathogenesis of
different forms of bladder cancer.
In this construct, stage of disease can be viewed as a
snapshot in the evolving pathogenesis of disease. Although
stage may remain consistent with time, changes may also
occur. The stage at resection as manifest in the snapshot
provided by the resection specimen may be used to suggest
prognosis, but this may profitably be understood in the
context of the potential pathogenesis of a particular tumor
diathesis. Distinctions in the potential biologic behavior of
a particular cancer at a specific point in time (either at ini-
tial diagnosis or at the time of recurrence) may be of use in
determining whether aggressive treatment is indicated
(even if a tumor appears to be at an “early” stage) or
whether conservative treatment may be appropriate (even
if a tumor appears to be more advanced).
In considering a schema in which different pathways
portray the biology of various types of bladder cancer,
several developmental terms may be applied to describe
the different processes that give rise to various forms of
tumor diathesis. For example, papillary tumors may arise
through a process that can be described as proliferative.
Accordingly, transformed epithelial cells proliferate and
produce tumors with a multilayered epithelium in papil-
lary configuration surrounding a central fibrovascular
core. The process of proliferation by itself may produce
tumors that contain cells with a histologically normal
appearance (low grade). Such tumors may lack the
machinery necessary to invade the lamina propria aggres-
sively, progress, and metastasize.
Tumors that are comprised of histologically abnormal
(high grade) cells may occur as the result of a process that
can be termed “dysplasia” superimposed on the prolifer-
ative process. It is unusual to see papillary tumors that are
high grade and truly mucosally confined. Indeed, this has
been reported to occur in only 2% to 4% of all mucos-
ally confined tumors.61,62
A high-grade histologic appearance in papillary
tumors is more commonly seen when penetration of the
basement membrane and invasion of the lamina propria
has occurred.64–66 This difference in appearance concep-
tually suggests a developmental process that can be
termed dysplasia. It may indicate a different biologic
capability of these tumors such that they can proliferate
but also infiltrate. Although low-grade, mucosally con-
fined tumors could conceivably change during the course
of their proliferation to become high-grade tumors that
have acquired the biochemical machinery to penetrate
into the sub-epithelial stroma, dysplasia may hypotheti-
cally have been the primary result of neoplastic transfor-
mation, leading to the development of a papillary
high-grade urothelial cancer capable of invasion.
The neoplastic pathway characterized predominantly
by dysplasia could also lead to the development of cancer
cells that extend along the plane of the bladder
mucosa,75,76,79 possibly undermine it, cause it to slough,
and then themselves slough. Such cells lack cohesive and
adhesive ability. Through proliferation and continued
pagetoid spread, a high-grade flat neoplastic diathesis
could occur that in some instances might lead to the
development of either papillary tumors that extend into
the lumen of the bladder or, more likely, nodular tumors
that penetrate into the lamina propria and muscu-
laris.59,68,81,83 Some have suggested that carcinoma in situ
leads directly to infiltration of nodular disease into the
bladder wall, so that silent carcinoma in situ is diagnosed
initially in its muscle-invasive manifestation.84
The various staging systems have not as yet incorpo-
rated the genetic changes that characterize different can-
cers. Although many reports have focused on specific
chromosomal and molecular changes that correlate with
the propensity either towards proliferation or to invasion
and metastasis,112–116 these have not as yet been fully val-
idated. Therefore, they have not been incorporated into
staging systems.
They have, however, been correlated with different
developmental pathways as suggested in schema for tumor
pathogenesis.2,4,77,85 For example, aberrations of chromo-
some 9 have been seen in both low-grade, low-stage blad-
der tumors and higher grade, invasive tumors. This has
suggested that loss of heterozygosity of chromosome 9
may occur early in the genesis of a variety of bladder can-
cers.117–120 It has also been shown that chromosome 9 is
lost in each of several multifocal tumors within an individ-
ual patient, supporting the concept of a field change in the
genesis of bladder cancer.121,122 Abnormalities in chromo-
some 9 have been associated with a proliferative diathe-
sis.117,120 Specific foci for these changes have been variable,
but all have been correlated with neoplastic transforma-
tion that is reflected in a proliferative diathesis and that
characterizes the course of these tumors as one of recur-
rence rather than progression.120
Loss of heterozygosity of chromosomes other than
chromosome 9 has been observed in high-grade, high-
stage tumors.77,86,87 Mutations in chromosome 17 with
expression of higher levels of p53 have been identified in
approximately half of all high-grade high-stage bladder
cancers.86,123 Abnormalities in chromosome 17 have also
been associated with tumors more likely to invade and
metastasize.124–126
Several studies have also shown that carcinoma in situ
expresses high levels of p53 mutations, and that it is not
characterized by loss of heterozygosity of chrom-
osome 9.86,87,127 This is in keeping with the apparently
aggressive course implied by the presence of carcinoma
in situ either alone as “primary” or in the setting of high-
grade lamina propria or muscle invasive cancer as “sec-
ondary.”81,83,84 Other studies have demonstrated that
only those lamina propria invasive tumors that express
 Chapter 17 Diagnosis and Staging of Bladder Cancer 313
p53 progress to muscle invasion suggesting a commonal-
ity of pathways with the more aggressive tumor diatheses
expressing abnormalities in chromosome 17.
Most studies have been based on immunohistochemical
studies. Some have been validated with analysis of selected
sequence conformational polymorphisms. Taken together,
initial changes in chromosome 9 may be followed by mul-
tiple sequential changes of other genes that may then lead
to an invasive and potentially metastatic phenotype.
Although these situations are complex, it may ulti-
mately be possible to superimpose a molecular profile for
a particular cancer on the snapshot stage of a tumor as
determined by histopathologic analysis to determine not
only the type of therapy that may be effective in a partic-
ular cancer diathesis but also to predict the outcome of
particular treatment regimens in the context of the natu-
ral history and propensity of that diathesis based on its
predicted pathogenesis.
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98. Wishnow KI, Levinson AK, Johnson DE, et al: Stage B
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99. Roehrborn CG, Sagalowsky AI, Peters PC. Long-term
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100. See WA, Fuller JR: Staging of advanced bladder cancer:
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101. Herr HW, Whitmore W Jr, Morse MJ, et al:
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102. Herr HW: Conservative management of muscle
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103. Solsona E, Iborra I, Ricos, JV, et al: Feasibility of
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104. Schellhammer PF, Bean MA, Whitmore WF: Prostatic
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107. Smith JA Jr, Whitmore WF Jr: Regional lymph node
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119. Stadler WM, Steinberg G, Yang X, et al: Alterations of
the 9p21 and 9q33 chromosomal bands in clinical
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aberrations of chromosome 9 in bladder cancer. A
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chromosome 17p distinguishes high grade from low
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associations of p53 gene mutations in invasive bladder
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C H A P T E R
18Superficial Transitional Cell Carcinoma
of the Bladder: Management and
Prognosis
Murugesan Manoharan, MD, FRCS, and Mark S. Soloway, MD
Superficial transitional cell carcinoma (TCC) of the uri-
nary bladder refers to tumor confined to the mucosa (Ta,
Tis) or submucosa (T1). This is a heterogeneous disease
with a variable natural history. At one end of the spec-
trum, low-grade Ta tumors have a low progression rate
and require initial endoscopic treatment and surveillance
but rarely represent a threat to the patient. At the other
extreme, high-grade T1 tumors have a high malignant
potential with significant progression and cancer death
rates. Seventy percent of bladder tumors present as
superficial disease. Approximately 70% of these tumors
present as Ta lesions, 20% as T1, and 10% as Tis (carci-
noma in situ). The true natural history of untreated non-
invasive disease is not fully known.
Many characteristics of TCC have been studied in an
attempt to predict this variable tumor behavior. These
include pathologic features, cytologic analysis, and bio-
logic and molecular markers. Although thorough endo-
scopic tumor resection remains the principal treatment,
intravesical agents have become important in the sub-
group of tumors that are at risk of progression. In order
to tailor treatment appropriately, the urologist should
review the various prognostic factors and define the
behavior of the tumors as precisely as possible.
INITIAL EVALUATION
Patient evaluation begins with a thorough history includ-
ing exposure to smoking and other known carcinogens,
physical examination, and urine analysis. Endoscopic
assessment of the entire urethra and urinary bladder
remains the most important diagnostic procedure.
Modern flexible endoscopes with high-quality optics
allow this to be performed safely, with minimal patient
discomfort, as an office examination.1 The anterior blad-
der wall and bladder neck regions are well visualized with
flexible cystoscopy. Cold-cup biopsy is possible, although
sufficient tissue to determine depth of invasion is difficult
to obtain with small forceps. Hence, we prefer cys-
toscopy under anesthesia to obtain satisfactory biopsy.
Upper tract radiologic visualization should be per-
formed in all cases. Intravenous urography is sensitive in
detecting papillary tumors, as well as in providing func-
tional and anatomic information. Ultrasound has also
been used for upper tract assessment, with the advantages
of avoiding contrast reactions, radiation, and intestinal
preparation. However, ultrasound is less sensitive in
detecting small tumors. Retrograde ureteropyelography,
with cytologic washings at the time of tumor resection, is
useful to further assess suspicious or poorly imaged areas.
In selected cases, CT scan may be useful in the initial
evaluation. It is more sensitive in detecting small renal
masses, urinary calculi and nonurologic lesions. The dis-
advantages include inability to visualize small urothelial
lesions, cost, availability issues, and the need for contrast
agents.
If there is suspicion of a high-grade tumor, cytologic
assessment is important. Bladder washings have a better
yield than voided urine cytologies.2 Gentle barbotage
using 50 ml of sterile saline with prompt cytology evalu-
ation is suggested.
ENDOSCOPIC MANAGEMENT
Well-performed transurethral resection (TUR) remains
the most important method for the diagnosis and
treatment of primary and recurrent bladder tumors,
despite the evolving role of intravesical therapy.
317
318 Part IV Bladder
Technologic improvements have dramatically improved
this procedure.3
Videoendoscopy has been a major advance in all areas
of endourology but particularly for bladder tumor resec-
tion. In addition to minimizing the surgeon’s exposure to
body fluids, it allows all areas of the bladder, including
the dome and anterior wall, to be resected with greater
ease and improved magnification. It also provides docu-
mentation and improved teaching opportunities.
Continuous-flow resection allows the urologist to con-
trol the degree bladder filling, thus reducing the risk of
perforation, obturator nerve excitation, and resection
time.
Adequate anesthesia is important for safe, controlled
resection, and patient comfort. In males, we prefer
beginning the procedure with an optical dilator that pro-
vides calibration and dilation of the urethra with visual
assessment prior to placement of the resectoscope.4
Saline barbotage for cytologic analysis should be per-
formed first if high-grade tumor is suspected. The entire
bladder should be examined using the 12-degree or 30-
degree and 70-degree lenses. The nature, number, loca-
tion, and size of the lesions should be noted. The
capacity of bladder, ureteral orifices and adjacent urothe-
lium should be assessed.
Papillary tumors should be systematically resected
with a right angle or bladder wall loop, as appropriate.
The bladder wall or angled loop is designed for resecting
tumors located on the high lateral or posterior walls. The
aim is to achieve complete resection of all tumors. Biopsy
of the tumor base should be done either with cold-cup
forceps or formal resection, which may involve the mus-
cle. Specimens should be retrieved for histopathology.
Suspicious mucosal areas should be biopsied with a cold-
cup forceps to minimize cautery artifact. The roller ball
electrode is used to fulgurate all suspicious areas and to
achieve hemostasis.
A history or the presence of a high-grade tumor
necessitates transurethral biopsy of the prostatic urethra.
This is best performed with the resectoscope, as opposed
to cold-cup forceps. One should sample the mucosa and
underlying stroma from the bladder neck to the veru-
montanum. A bimanual examination should be per-
formed. Catheter drainage is necessary if there is
bleeding requiring irrigation, or if a deep resection has
been performed. The majority of procedures can be per-
formed on an outpatient or overnight basis.
PATHOLOGIC PROGNOSTIC FACTORS
After complete endoscopic resection, approximately 30%
to 80% of patients will develop additional tumors, usually
of similar grade and stage. The majority of these lesions
are new occurrences, as opposed to true recurrences,
reflecting a generalized instability of the urothelium.
Although close follow-up with endoscopic management
of recurrences is appropriate for most low-grade Ta
tumors, the adjuvant use of intravesical chemotherapeu-
tic and immunotherapeutic agents is appropriate for
high-grade T1 and CIS. In order to identify patients at
higher risk of progression and recurrence, who may ben-
efit from such therapy, numerous prognostic factors have
been proposed (Table 18-1). These include well-
established pathologic features, such as grade and stage,
endoscopic features, cytologic characteristics, tumor cell
products, and molecular genetic markers, such as p53.
Although some of these prognostic factors have an estab-
lished clinical role, some of the newer markers remain
investigational.
TUMOR GRADE
Tumor grade is well established as an important prognos-
tic factor for both new tumor occurrence and progression
to invasion.5,6 Mostofi et al.7 introduced a World Health
Organization’s (WHO) classification system for grading
TCC as grades 1, 2, and 3 based on the degree of cellular
differentiation. The WHO/International Society of
Urologic Pathology (ISUP) consensus classification of
1998 distinguishes between papilloma, papillary urothe-
lial neoplasm of low-grade potential (PUNLMP), low-
and high-grade carcinoma. A solitary papillary, tumor
with a fibrovascular core and no more than either seven
or eight normal-appearing cell layers, is regarded by
some as a papilloma. Others include these with grade 1
papillary carcinomas.8,9 The WHO’s grading system
takes into account the degree of anaplasia as determined
by increased cellularity, nuclear crowding, disturbance of
Table 18-1 Prognostic Factors for Superficial
Bladder Cancer
Number of tumors
Tumor size
Tumor grade
Tumor T stage
Lymphatic invasion
Carcinoma in situ
Urine cytology
DNA ploidy
Blood group antigens
Tumor cell products-EGFR, AMFR, PCNA
Molecular genetic markers-p53; c-erb B-2; c-myc
 Chapter 18 Superficial Transitional Cell Carcinoma of the Bladder 319
cellular polarity, the absence of differentiation from base
to surface, pleomorphism, variations in nuclear shape and
chromatin pattern, mitotic counts, and the presence of
giant cells.7 This pattern is reproducible at the extremes
(grades 1 and 3) but leaves grade 2 as a heterogeneous
intermediate group.10,11
There is a strong correlation between higher grade
and invasion, disease progression, metastases, and sur-
vival.5,6 Mortality from progression of grade 1 tumors is
low (0% and 4% at 10 years).6,12 Another 3% recur as
grade 3 tumors.1 Grade 3 tumors frequently progress to
muscle invasion, however. This has been documented in
50% and 62% of cases, with a 35% 10-year actuarial sur-
vival rate.6
Predicting the behavior of grade 2 tumors is less well
defined. For all grade 2 tumors, between 18% and 33%
are reported to progress, with a 10-year actuarial survival
of 87%.5,6 In an attempt to clarify the behavior of these
heterogeneous tumors, Carbin et al.10,11 subclassified
them into 2a and 2b based on nuclear pleomorphism and
the number of mitoses. When progression was assessed,
grade 2a tumors faired much better, with a 92% 5-year
survival compared with 43% for grade 2b. This prognos-
tic discrimination has been demonstrated elsewhere.13
Nuclear size (area) has also been used to stratify interme-
diate-grade tumors.14
The major criticism of multiple subclassification for
clinical application has been subjectivity. The subclassifi-
cation of Carbin et al.10 was demonstrated to be highly
reproducible, with an interobserver agreement of 90%.
However, inter- and intraobserver errors ranging from
50% to 87% have been reported for grade using reference
pathologists in controlled trials.15 In clinical practice, most
pathologists describe the tumor as low or high grade.
The categorization of grade becomes increasingly
important for T1 tumors. This group has a much higher
risk of progression to muscle invasion than Ta tumors. In
a series of T1 tumors, 50% of grade 3 and 22% of grade 2
tumors have progressed.12
Histologic Stage
Depth of tumor invasion was first included as a marker of
outcome by Jewett and Strong.16 It is now commonly
used as a prognostic indicator and incorporated into stag-
ing systems including the current American Joint
Committee on Cancer (AJCC) system.17
There is a significant difference in prognosis between
Ta tumors, which are confined to the mucosa (not pene-
trating the basement membrane), and T1 tumors, which
infiltrate the lamina propria. This difference has been
documented for both tumor recurrence and progression.
The difference in recurrence risk between the two stages
is minimal. Grade, multiplicity, and size are more impor-
tant in determining the recurrence rate.18 However, the
risk of stage progression is clearly higher for T1 tumors.
Between 0% and 4% of Ta tumors and 27% to 46% of
T1 tumors will progress to muscle invasion at 3
years.12,19–22 Long-term survival for Ta tumors is excel-
lent. Ten-year survival rates are 95% for grade 1, 89% for
grade 2, and 84% for grade 3 tumors.23 Twenty-year
cancer-specific survival for Ta tumors is 89%, compared
with 30% for T1 tumors.
Clearly, careful evaluation for lamina propria invasion
is important. Muscularis mucosa is identifiable as a land-
mark in 70% to 80% of TUR specimens.25 When absent,
the larger arteries of the deep lamina propria are a useful
landmark. The surgeon should attempt to minimize
cautery artifact by using cold-cup biopsies or reducing
the coagulation current. With papillary disease, the
tumor base should be sampled carefully, submitting the
underlying tissue as a separate specimen if necessary.
The significance of the depth of lamina propria inva-
sion has varied mainly due to difficulties in identifying
the muscularis mucosae. In a series with three review
pathologists, the concurrence rate for depth of invasion
was only 50%.26 Despite this interobserver error, two
series have used T1 subclassification and found it useful
for prognostic discrimination. Younes et al.27 used the
presence of invasion to, and beyond, the muscularis
mucosae to subclassify T1 tumors. Superficial invasion,
termed T1a, had a 75% 5-year survival compared with
14% for deep invasion (T1b). Using the same classifica-
tion system, Hassui et al.25 reported a 7% progression
rate for T1a and 53% for T1b, independent of tumor
grade, number, and size. The deep lamina propria is rich
in lymphatics, and this may explain why it is an important
factor in progression to deep muscle invasion. The prac-
tical role of T1 subclassification needs further study to
clarify its clinical application.
Vascular and lymphatic invasion in general confer a
poorer prognosis. In a study including Ta and T1 tumors,
7% had documented vascular or lymphatic invasion, with
a 30% 6-year survival. These results were independent of
grade.23 Clearly, it is important to exclude muscularis
propria invasion. If there is any doubt, the urologist
should resect the tumor site again to be certain of the
stage. In a series of 46 patients who had a second TUR
within 2 weeks of their first resection, 43% demonstrated
residual tumor in the deep resection.28 Given the impli-
cation of muscle invasion, adequate tissue sampling to
include muscle is essential.
Reproducibility of Grade and Stage
As indicated, there are limitations with the current stag-
ing and grading system for superficial tumors. This has
implications for tailoring treatment for an individual
patient, and for the analysis of prognostic factors in clin-
ical trials.
320 Part IV Bladder
Ooms et al.15 with seven review pathologists, reported
a high inter- and intraobserver error of grade. A similar
discrepancy in stage with an intraobserver error of 50%
has also been demonstrated.11,29–31 In reviewing a series
of multicenter trials by tile Dutch Uro-Oncology Group,
which utilized review pathology, the error of grading was
30%, with a tendency for local pathologists to under-
grade.32 The error in T stage was 20%, with a tendency
for local pathologists to overstage.
The same problem has been reported in interpreting
biopsies of normal-appearing urothelium in patients with
superficial tumors. In one study, biopsies reported as
“dysplasia” were reproduced only 60% of the time.33
In randomized trials, such distortion of pathologic
results is balanced in both treatment and control arms
and hence does not have a major impact on the outcome
of a study.32 This variation becomes more significant,
however, when comparing results between studies of
“similar” pathologic stage. It also has an important impli-
cation in the management of an individual patient, par-
ticularly when identifying muscle-invasive disease. These
limitations in staging and grading must be recognized.
The important lesson is for the clinician to review the
slides with the pathologist prior to any major treatment
decision.
Status of Bladder Mucosa Distant from the Tumor
Any abnormality of the mucosa distant from the primary
tumor provides prognostic information on recurrence
rates. Recently, there has been increasing support for
tumor cell implantation as one explanation for high
recurrence rates.34,35 In general, any abnormal-appearing
mucosa should be biopsied. A cold-cup technique is
preferable, as it allows adequate tissue sampling without
diathermy artifact. More controversial is the role of
biopsy of normal-appearing mucosa. The incidence of
associated changes in normal-appearing mucosa is
between 10% and 50%.5,36,37 Dysplasia is reported in
approximately 15%, with carcinoma in situ more variable
(10% to 50%).37In general, CIS is more common with
grade 3 tumors.37 The incidence of concurrent CIS in
the prostatic urethra is reported to be between 16% and
30%.39,40 We believe that the magnification associated
with videoendoscopy lessens the likelihood of CIS being
found in normal-appearing bladder mucosa.
Less well defined is the accuracy and reproducibility
of dysplasia reported in a biopsy, and the true risk of pro-
gression for dysplasia.41–44 Progression for Ta and T1
tumors has been shown to increase from 8% to 30%
when moderate or severe mucosal dysplasia was also
present on biopsy.5 Others have suggested that moderate
dysplasia like mild dysplasia is not a risk factor.41
More widespread use of cytology and improved endo-
scopic optics, particularly video magnification, have
reduced the role of mucosal biopsies. In an attempt to define
the role of random biopsies in predicting recurrence and
progression, Kiemeney et al.8 demonstrated that random
biopsies did not significantly influence patient outcome.
Biopsies gave no additional information to predict tumor
behavior beyond stage, grade, tumor size, and number.
Most patients with high-grade tumor will receive
adjuvant treatment, regardless of the information from
mucosal biopsies. Therefore, we infrequently perform
mucosal bladder biopsies outside of clinical trials.
ENDOSCOPIC FEATURES
The number of primary tumors is a strong predictor of
recurrence. The presence of two or more tumors
increases the recurrence rate approximately 2-fold, and
decreases the time to first recurrence.5,45–48 Heney et al.5
showed that the recurrence rate for multiple tumors
increased from 18% to 43% for Ta disease and from 33%
to 46% for T1 disease. Multiple primary tumors are also
associated with a tendency for increasing grade with
recurrence.48 There is an approximately 1.5-times
increased risk of progression for multiple tumors.12,45
Tumor size is also a predictor of recurrence and progres-
sion. The risk of stage progression increases from 9% to
25% for tumors >5 cm.5
The time to first recurrence is also prognostic. A
recurrence or new occurrence at 3 months has been
shown to increase the risk of subsequent recurrence from
20% to between 70% and 85%.47,48 This emphasizes the
importance of the disease status at the first follow-up
cystoscopy.18
CYTOLOGIC PROGNOSTIC FACTORS
Urine Cytology
Urinary cytology performed on exfoliated urothelial cells
in urine or bladder washings can be used to detect TCC.
Care must be taken with specimen collection and han-
dling to preserve exfoliated cells and avoid bacterial con-
tamination.
The yield for diagnosis of low-grade tumors is low,
generally <30%.50 Recognition of subtle malignant fea-
tures requires a skilled cytopathologist. However, cytol-
ogy is highly sensitive for high-grade disease for both
CIS and papillary tumors. Greater than 60% of papillary
tumors and 90% of cases of CIS have positive cytology.
The reduced cellular adherence of high-grade tumors
results in a higher proportion of cells shed into the urine
and thus detectable with cytology. This complements
cytoscopy in the detection of high-grade TCC. Bladder
wash cytology may provide more information on the
presence or absence of CIS than random biopsies. It is
important to provide relevant clinical history for accurate
interpretation by the cytopathologist.
 Chapter 18 Superficial Transitional Cell Carcinoma of the Bladder 321
In addition to identifying the method of specimen
collection, it is important to note any history of
previous treatment (radiation, chemotherapy, or
immunotherapy), urinary infection, stones, recent sur-
gery, or catheterization. All of these conditions may
produce cells with nuclear features that may be con-
fused with malignancy.57
The interpretation of a positive urine cytology
requires knowledge of tumor status of the bladder. The
absence of cancer in the bladder requires exclusion of
CIS or high-grade disease in the upper tracts or prostatic
urethra. Cytology also has a valuable role in follow-up of
high-grade superficial tumors.
DNA Ploidy
DNA ploidy as assessed by flow cytometry has been used
to assess TCC. In general, all grade 1 and most of the
grade 2 tumors are diploid. Some grade 2 tumors are
tetraploid, while others, and most of the grade 3 tumors
are nontetraploid aneuploid. Variation in DNA content
within a tumor is a significant limitation in the applica-
tion of ploidy studies.
There is a correlation between ploidy and tumor
behavior. Of 229 grade 1 and grade 2 superficial tumors,
Gustafson et al.53 showed that none of the diploid tumors
progressed, while 35% of the aneuploid tumors pro-
gressed with a 21% death rate. Aneuploid tumors have
also been shown to recur more frequently.54
There is conflicting evidence as to the ability of ploidy
to independently predict progression over grade
alone.55,56 Ploidy remains expensive, and has yet to estab-
lish a clinical role. We do not use this in decision-making.
BIOLOGIC PROGNOSTIC MARKERS
Blood Group Antigens
There has been long-standing recognition of the prog-
nostic importance of the loss or absence of blood group
antigens from the tumor cell surface.57,58 This can be
assessed by immunohistochemistry or red-cell adherence
tests. However, the results are usually qualitative and the
methodology subjective. The result is also dependent on
the patient’s blood group, with group O being prone to
false-negative results. An increased risk for progression
has been documented with loss of antigen expression.58
This information appears to be independent of grade and
stage.59 There is also an association with tumor recur-
rence rate60 and response to bacille Calmette-Guérin
(BCG) treatment.61
Other cell surface antigens have also been correlated
with prognosis. These include the Lewis surface antigens
and the Thompson-Friedenreich antigen.62,63 Advances
in immunostaining with monoclonal antibodies have
allowed assessment of these antigens in urine, with
improved sensitivity and specificity64 They have not as
yet found a role in clinical practice.
Tumor Cell Products
There have been numerous cell proteins that appear to
correlate with tumor behavior. They perform various
functions but often act as cell receptors. These include
desmosomal glycoprotein,65transferrin receptor,66 and
human milk fat globulin.67 Epidermal growth factor
(EGF) receptor and basement membrane tissues have
been more extensively studied.
EGF receptor is reported to be an independent pre-
dictor for stage progression in Ta and T1 tumors.68 In
addition, an increased recurrence rate from 7% to 17%
has been noted for receptor-positive patients.69 This
marker would appear to have potential clinical applica-
tion on the basis of results to date.
Various connective tissue components of the basement
membrane have been studied as potential markers. The
loss of laminin and type IV collagen in the basement
membrane underlying noninvasive tumors correlates
with increasing tumor progression.70
Cytogenic and Molecular Genetic Markers
Although the majority of invasive bladder tumors com-
monly contain nondiploid and morphologically abnor-
mal DNA, most superficial tumors are near diploid.
Sandberg71 first identified abnormal DNA in Ta and T1
tumors, and demonstrated a relationship with risk of
recurrence and progression. Chromosomal analysis for
solid tumors has been simplified with the development of
specific probes, such as fluorescent in situ hybridization
(FISH) for DNA sequence analysis. RNA amino acid
sequencing with polymerase chain reaction (PCR) has
also contributed to the understanding of TCC. Both
FISH and PCR can be performed on paraffin sections.
Specific chromosomal abnormalities for bladder can-
cer have been identified on chromosomes 1, 5, 7, 9, 11,
and 17.72–75 Abnormalities of chromosome 7 include
alteration to the c-erb B oncogene, which codes for the
EGF receptor.
Loss of heterozygosity at chromosomes 9q, 11p, and
17p correlates with known tumor suppressor genes,
namely, the Wilms’ tumor gene (WTG) and p53. Studies
on the role of oncogenes and carcinogenesis have tradi-
tionally used rodent tumors, particularly the ras fam-
ily.78–80 Unfortunately, it has not proven useful in the
study of human TCC.
Promising results have been demonstrated through
molecular genetic work with oncogenes. The p53 onco-
gene (17p13-1 locus) codes for a nuclear phosphoprotein,
whose major role appears to be in transcriptional regula-
tion. The p53 is involved in DNA repair or induction of
322 Part IV Bladder
apoptosis for irreversibly damaged DNA. Hence, it is
thought to function as a tumor suppressor gene.86 There
are two forms of this gene product—the wild, or unal-
tered type, and the mutant form.82 Mutation of wild type
results in the accumulation of mutant p53 protein within
the tumor cell nucleus, due to a prolonged half-life. This
leads to alterations in modulating activity.83 Mutant p53
can be easily detected immunohistochemically using
monoclonal antibodies on fresh or fixed tumor speci-
mens.84 Immunohistochemical changes have been shown
to correspond to abnormalities with DNA sequence
analysis.85–88 It must be recognized that the limitation of
monoclonal immunohistochemistry is false-negative
results,89 although this is reduced with the monoclonal
antibody Pab-1801.89
Changes in p53 are the most commonly recognized
genetic alterations in human malignancy, and correlate
with tumor behavior.90 Mutations have been observed in
50% of high-stage bladder tumors.85–87,91
However, p53 changes and their relationship to tumor
behavior in superficial tumors are less clear. Studies have
utilized both immunohistochemistry and nucleic acid
sequence analysis for assessment of Tis, Ta, and T1
tumors. Mutations have been observed in up to 65% of
biopsies of primary Tis (pTis).92 Positivity for p53 has
been demonstrated as an independent predictor of
progression in a series of 33 pTis patients followed for
124 months.89
The results for Ta and T1 diseases are more variable.
Positive mutant p53 staining has ranged between 8% and
95%,85,93–97 with a strong correlation between positivity
and tumor grade.94,95,98 Several recent institutional
reviews of Ta and T1 tumors utilizing multivariate analy-
sis have demonstrated p53 status as a statistically signifi-
cant prognostic factor for progression-free and overall
survival.99,100 The disparity between numerous investiga-
tors is difficult to explain. Technical factors may play a
role. In summary, the oncogene p53 is an encouraging
prognostic marker for bladder cancer. Its clinical role in
superficial disease will remain unclear until further large
series with multivariate analyses are performed. The
overexpression of other oncogenes, c-erb B-2 and c-myc,
has also been observed and is more frequently in high-
grade, high-stage TCC.101–103 Their role in superficial
TCC has not been defined.
INTRAVESICAL THERAPY
Rationale
The high incidence of subsequent tumors after initial
TUR, whether true recurrences or new occurrences, has
led to the use of intravesical instillation of antineoplastic
agents. This form of treatment can be used either thera-
peutically, to eradicate residual tumor after an incom-
plete TUR, or prophylactically, after all visible tumor has
been resected and urinary cytology, if performed, is neg-
ative. Intravesical therapy can be subdivided into
chemotherapy and immunotherapy. The decision to use
intravesical treatment is dependent on numerous factors,
including: tumor stage, grade, size, and multiplicity; the
presence of CIS or positive urinary cytology; the side-
effect profile of each agent; and other patient-specific
factors (Table 18-2). Economic factors may also play a
part in the decision process.
The ideal intravesical agent would have an antitumor
effect against TCC, show no phase specificity in the cell
cycle and have limited systemic and local toxicity on an
acute and chronic basis. Much of the systemic toxicity
associated with intravesical therapy is due to drug
absorption. Factors associated with increased absorption
include low molecular weight of the instilled drug, tem-
poral relationship to the TUR, and extent of resection.
Local toxicity with intravesical therapy is frequent and
usually consists of irritative voiding symptoms or hema-
turia.104 Delaying the initiation of intravesical therapy for
10 or more days after resection will allow healing of the
resected urothelium and may lessen the local and sys-
temic side effects.
Increasing exposure of the urothelium to the intraves-
ical agent would seem to be important. This can be done
by increasing the concentration and contact time of the
drug. Some advocate asking the patient to lie in the
prone position for part of the treatment.105 Others sug-
gest that sterile water, instead of saline, as the diluent
decreases the osmolality of the solution, thereby increas-
ing the intracellular concentration of the drug.106
Recommended dosages, administration schedule, and
duration of intravesical therapy have varied and are
largely based on empiric data. Patients who receive
intravesical therapy should be monitored for response.
This includes endoscopy and bladder wash cytology.
Appropriate end-points include recurrence, time to
recurrence, progression in grade or stage, and time to
progression. Patients are monitored for response 3
months after initiation of treatment. A complete
response (CR) to treatment is defined as no tumor on
endoscopy, negative cytology, and negative bladder biop-
Table 18-2 Indications for Intravesical Therapy
Cumulative tumor size >5 cm
Multiple tumors
Multiple recurrences
Stage T1 or high-grade TCC
CIS or positive cytology
Residual tumor
 Chapter 18 Superficial Transitional Cell Carcinoma of the Bladder 323
sies. Anything less than a CR is considered as a treatment
failure, as partial responders have the same incidence of
progression as nonresponders.107
If any question exists as to the persistence of tumor,
resection or biopsy is performed. In the face of a positive
biopsy or cytology after intravesical treatment, it is less
likely that another course with the same agent will be
effective, and an alternative treatment should be used.
BCG may be an exception, as a second 6-week course is
beneficial in some instances. The stage and grade of the
tumor recurrence will ultimately be the determinant of
future treatment (e.g., cystectomy, TUR alone).
Intravesical Chemotherapy
Thiotepa
Thiotepa is an antineoplastic alkylating agent related to
nitrogen mustard that has been shown to eradicate exist-
ing tumors and delay the development of new tumors.
The usual dosage is 30 to 60 mg in 30 to 60 ml of distilled
water. The National Bladder Cancer Study Group found
that the CR rate for 30 mg was equal to that for 60 mg.
Hence, the lower dose is recommended.12 Duration of
treatment is usually weekly for 6 to 8 weeks when given
therapeutically and weekly for 4 to 6 weeks when given pro-
phylactically. If maintenance is given, a monthly schedule
is usually selected. A randomized cooperative study by
the Medical Research Council found no statistically
significant difference in tumor recurrence rates in
patients receiving: (1) no intravesical therapy, (2) a single
instillation of thiotepa at the time of resection, or (3) a
single thiotepa instillation at the initial resection and
3-month intervals for a total of 5 treatments in a year.
Median follow-up was almost 9 years. Thus, it appears
that it is necessary to give more than 5 treatments of
thiotepa in a year to make a significant difference in
tumor recurrence.
When used as a therapeutic agent, CR rates of 35% to
45% have been reported.14,115 Long-term use of thiotepa
prophylaxis was evaluated by the National Bladder
Cancer Collaborative Group.112 They reported that 53%
of patients were tumor free at 2 years compared to only
27% of untreated patients. The benefits were only noted
in patients with grade 1 lesions (51% treated with
thiotepa were tumor free at 2 years versus 14% of the
control group). Recurrence rates of grade 2 and grade 3
tumors were not significantly different than controls,
suggesting that thiotepa is most effective in treating
patients with low-grade tumors.
Due to thiotepa’s low molecular weight (189 Da), it is
absorbed more than any other intravesical agent.
Myelosuppression occurs in up to 9% of patients, usually
in the form of leukopenia or thrombocytopenia. Thus,
white blood cell and platelet counts must be monitored
during the course of therapy. In a study of 670 patients,
Soloway and Ford116 found that only 4% of patients suf-
fered this side effect and none of the consequences were
severe. Irritative voiding symptoms are common as with
other intravesical agents. Overall, thiotepa is relatively
safe and inexpensive, and is most effective for low-grade
tumors. We believe that it is a reasonable choice for pro-
phylaxis in patients with multiple, recurrent grade 1, Ta
bladder tumors.
Mitomycin C
Mitomycin C (MMC) is a 329-kDa antitumor antibiotic,
which inhibits DNA synthesis. There has never been a
thorough dose response study with MMC. Most studies
have used from 20 to 40 mg in 20 to 40 ml of water,
weekly, for 8 weeks. Many studies have used MMC for
residual TCC after incomplete resection (i.e., treatment
rather than prophylaxis). Most patients in these studies
were at high risk for recurrence, having a history of prior
TCC. A study by the National Bladder Cancer Group
involved treatment with 40 mg of MMC for 8 consecutive
weeks.117 The study included 117 patients with CIS or
grade 1 to grade 3 Ta or T1 disease. Each patient had
failed a course of intravesical thiotepa. At 3 months, 27%
of patients had a CR as defined by negative endoscopy,
biopsy, and cytology. Another 9% had negative endoscopy
and cytology but were not biopsied again. Despite a neg-
ative endoscopy, an additional 12% were not considered
as complete responders, since their cytology was positive.
Overall, 18% of patients with T1 disease, 29% with Ta
disease, and 35% with CIS were rendered tumor free.
The National Bladder Cancer Collaborative Group
also compared MMC and thiotepa for treatment of
TCC.118 Study participants received either 40 mg of
MMC in 40 ml or 30 mg of thiotepa in 30 ml of sterile
water, weekly, for 8 weeks. MMC patients had a statisti-
cally significant higher CR rate (39% versus 27% with
thiotepa, p = 0.02). Ta grade 1 tumors responded best as
in previously reported thiotepa studies.
Soloway119 reported a series of 80 patients who
received 8 weekly 40-mg instillations of MMC for treat-
ment with evaluation for response at 12 weeks. All com-
plete and some partial responders received monthly
MMC for 1 year. Average follow-up was 40 months.
Complete responses were noted in 37% (15 of 41) of Ta
patients, 33% (7 of 21) of CIS patients, and 44% (8 of 18)
of T1 patients. Twenty-six percent of patients eventually
had a cystectomy and 15% developed muscle invasion.
Nine percent (7 of 80) of the patients eventually died of
bladder cancer.
The initial response to MMC was predictive of the
patient’s eventual outcome. Of those who had persistent
TCC at 3 months, 34% later required cystectomy com-
pared to only 13% of initial complete responders. Death
from carcinoma of the bladder occurred in 12% of early
324 Part IV Bladder
treatment failures compared to only 3% of initial com-
plete responders. It thus may be prudent to consider cys-
tectomy for patients with high-grade TCC who do not
have a CR with intravesical treatment.
Huland et al.120 reported a randomized prospective
study of MMC used for prophylaxis. Patients received
either 20 mg of MMC in 20 ml every other week for up
to 18 months or had a TUR alone. Only 10% of MMC-
treated patients recurred compared to 51% of controls.
Maier and Hobarth121 reported a study of 63 patients
who received MMC prophylaxis over a 2-year period.
The mean follow-up was 50 months. Fifty-two percent
developed a recurrence. One-third (21 of 63) died while
receiving MMC. Of the remaining 42 patients, 26%
recurred at an average of 14 months after MMC was dis-
continued. The remaining 31 patients (48% of the origi-
nal 63) remained tumor free for a mean 26 months after
MMC was completed.
The Medical Research Council has reported the
7-year follow-up of a 502-patient randomized multicen-
ter trial involving the use of early instillation of MMC.
After complete resection of Ta and TI tumors, patients
were randomized to receive either no further treatment
until the next endoscopy, a single instillation of 40 mg
MMC within 4 hours of resection, or an instillation
within 24 hours of resection and at 3-month intervals for
1 year (5 total doses). They found that the overall recur-
rence rates were lower and the interval to recurrence
prolonged in patients receiving 1 or 5 instillations of
MMC compared to controls. The estimated 5-year
reduction in recurrence risk was 5% and 23% for the
1- and 5-dose regimens, respectively.122
Due to MMC’s molecular weight, systemic toxicity is
rare. Local symptoms, primarily chemical cystitis, are
relatively common (10% to 17%).117,120,123 A desquamat-
ing rash of the palms and genitalia is unique to MMC. It
occurs in approximately 5% of patients and is thought to
be a form of contact dermatitis. Occasionally, the rash is
diffuse. Severe bladder contracture requiring cystectomy
(4%) has also been reported myelosuppression is
rare.104,119,124
In summation, MMC appears to be more effective
than thiotepa. The toxicity of MMC is acceptable. The
widespread use of MMC as a first-line therapy, however,
is limited in the United States by its cost.
Doxorubicin
Best known as a systemic chemotherapeutic drug, this
antitumor antibiotic has been shown to be an active intrav-
esical agent. Doxorubicin is a 380-kDa intercalating agent.
The vast majority of the literature comes from Japan,
where doxorubicin is the most frequently used intravesical
agent. The doses varied widely from 10 to 100 mg at var-
ious intervals. Therefore, there is no standard dose.
There have been a number of randomized studies
using doxorubicin for prophylaxis. Niijima et al.125
reported findings from a randomized study of doxoru-
bicin (30 mg in 30 ml, twice a week, for 4 weeks) plus
TUR versus TUR alone. At a minimum 12 months’ fol-
low-up, 70% (104 of 149) of patients receiving doxoru-
bicin were recurrence free compared to 55% (77 of 139)
who had a TUR alone. Kurth et al.126 found that 64% (58
of 86) of patients randomized to receive doxorubicin
(50 mg in 30 ml, weekly, for 1 month then monthly for
1 year) in addition to TUR were recurrence free versus
52% (39 of 69) in the control group. Doxorubicin was
not shown to be superior to thiotepa for prevention of
superficial tumor recurrence in other controlled double-
blind studies.127,128
In a randomized trial comparing the efficacy of dox-
orubicin and BCG for CIS, Lamm et al.129 reported a
34% CR rate for doxorubicin. Median length of time to
failure was 5 months. BCG was superior for treatment of
CIS. Others have demonstrated up to a 70% CR rate
with doxorubicin, but follow-up was short.130
Due to doxorubicin’s high molecular weight, absorp-
tion is low and myelosuppression rare. Cystitis is the pri-
mary toxicity, occurring in 25% of patients.104,124,131
Diminished bladder capacity occurs in up to 9% of
patients and anaphylactic reactions have been seen.124,130
Overall, doxorubicin has been shown to be an effective
agent for treatment and prophylaxis of TCC.
Valrubicin (AD-32)
AD-32 (N-trifluoroacetyladriamycin-14-valerate), an
anthracycline derivative, is a semisynthetic analog of dox-
orubicin. AD-32 (MW 723) differs from doxorubicin
(Adriamycin) in that it lacks cardiotoxicity, it is associated
with less local toxicity, and it is lipophilic. AD-32 does
not bind DNA but is an active inhibitor of DNA and
RNA syntheses.
Studies have focused on treating patients with CIS or
superficial disease who failed with BCG treatment. Phase 1
trials of patients treated with AD-32 have been com-
pleted. Of the 35 courses given, 69% had some local tox-
icity, 31% grade 2 or grade 3. Irritative voiding
symptoms accounted for all but three adverse events.
Reducing the alcohol content in the diluent decreased
these symptoms. There was negligible systemic absorp-
tion.133 Valrubicin has been approved by the FDA for
treatment of BCG refractory carcinoma in situ, and fur-
ther clinical trials in this group are in progress.
Immunotherapy
Bacille Calmette-Guérin
Since BCG was initially identified as an effective intrav-
esical agent for superficial bladder cancer, much has been
 Chapter 18 Superficial Transitional Cell Carcinoma of the Bladder 325
learned about its actions. Still more remains to be eluci-
dated.134 BCG is a live attenuated tuberculosis organism
first developed from cultures at the Pasteur Institute of
Lille.135 Its mechanism of action remains ill defined, but
at least part of its effectiveness is due to an immunologic
host response. T-cell-deprived animals do not respond to
BCG. Furthermore, BCG must bind to urothelial cells to
be active and binds by attaching to fibronectin.136 An
immunologic cascade of events occurs causing a strong
inflammatory response. The inflammatory response itself
may have a deleterious effect on tumor cells. In addition,
various cytokines are released including interleukins,
which have known antineoplastic activity.134,136
The urologic literature is replete with reports on the
efficacy of BCG. There is marked variability. This vari-
ability may be due to differences in the completeness of
resection, tumor stage and grade, prior history of TCC,
prior intravesical therapy, associated CIS, the number of
instillations, the BCG substrain used, host immunologic
factors, and length of follow-up.
The optimal schedule for BCG administration has yet
to be established. The number of milligrams per colony
count differs among the numerous BCG substrains. The
concept of 6 weekly instillations is arbitrary. An induc-
tion phase is necessary for the development of the
immunologic response in the bladder. While most
patients develop an inflammatory response with 6 instil-
lations, some will require fewer and some may require
more.137 Studies have shown that 19% to 26% of patients
treated, who do not respond to an initial 6-week course
of BCG, will respond to 6 additional weekly doses.108,109
Maintenance therapy is also controversial. Early studies
showed no clear benefit to maintenance BCG to justify
the increased risk of side effects.137 However, Lamm
et al.129 recently reported results of a randomized,
prospective Southwest Oncology Group’s (SWOG) trial
of maintenance BCG for CIS, Ta, and TI diseases. After
a 6-week induction course, patients received BCG in
3 weekly doses at 3 months, 6 months, and every 6 months
for 3 years. In this study, maintenance therapy further
reduced the tumor recurrence rate.138 However, the opti-
mal timing of these maintenance doses whether monthly,
3-monthly, or even yearly has not been established.
BCG for CIS
The literature strongly supports the use of BCG for
treatment of CIS. CR rates of 70% have been
reported.139–142 Dejager et al.141 reported on 123
patients from 6 phase 11 studies; patients received at
least 6 weekly instillations of TICE BCG and 12
monthly maintenance doses. A 76% complete remission
rate was reported, including a 71% (45 of 63) CR rate
for patients who failed intravesical chemotherapy. A
durable CR was seen in 50% of responders at a mean
follow-up of 48 months. Only 117 of responders subse-
quently required cystectomy versus 55% of nonrespon-
ders. However, no survival difference was noted between
responders and nonresponders. Lamm et al.129 in the
aforementioned randomized study of BCG versus dox-
orubicin for CIS, reported a 70% CR rate for BCG ver-
sus 34% for doxorubicin. The mean interval to
treatment failure was 39 months for BCG compared to
5 months for doxorubicin.
BCG for Prophylaxis
Several randomized studies have compared the efficacy of
TUR alone versus TUR plus BCG. Herr142 recently
summarized the results of 5 such studies encompassing
437 patients. Overall, 70% of patients who received BCG
prophylaxis were tumor free compared to 31% of
patients who had TUR alone. Follow-up ranged from 12
to 60 months.
To address the impact of BCG on disease progression,
Herr et al.143 reviewed the 10-year follow-up of 86
patients with recurrent Ta, T1, and Tis diseases, who
were randomized to either TUR plus 6 weeks of Armand-
Frappier BCG or TUR alone. Crossover was available for
patients in the TUR group who recurred. The 10-year
progression-free and overall survival were 62% and 75%,
respectively, for patients who received BCG and 37% and
53% for patients who had a TUR alone. The median pro-
gression-free survival was not reached for the BCG group
and was 46 months for the “control” group. Fifteen of 18
patients who crossed over and received BCG did not have
tumor progression. The authors concluded that BCG
delayed both tumor progression and death in patients
with superficial bladder cancer.
BCG has also been compared to the most commonly
used intravesical chemotherapeutic agents. Brosman144
and Marfinez-Pineiro,145 in separate studies, found BCG
to be superior to thiotepa in reducing tumor recur-
rence.109 Lamm et al.146 reported the results of a
SWOG’s comparison of BCG and doxorubicin in
patients with rapidly recurring superficial TCC. The
mean interval to recurrence in the patients with papillary
tumors receiving BCG was 22 months versus 110 months
in patients receiving doxorubicin.
Vegt et al.147 recently reported the results of a ran-
domized prospective study of 435 patients with pTa or
pT1 disease comparing the efficacy of TICE BCG,
RlVM-BCG, and MMC. Mean follow-up was 36
months. Patients underwent TUR followed by either 6
weeks of TICE or RIVM-BCG or 4 weeks of MMC fol-
lowed by monthly doses for 6 months. Results are shown
in Table 18-3. They concluded that MMC was equivalent
to BCG in efficacy. Drug-induced cystitis, the most com-
mon local toxicity, and systemic side effects were signifi-
cantly less in the MMC group.
326 Part IV Bladder
Table 18-3 Randomized Trial of TICE and RIVM BCG and MMC
TICE BCG
Recurrence Ta/TI 75 of 117 (64%)
Recurrence CIS 17 of 23 (74%)
Progression at recurrence 7 (5%)
From Vegt PDJ, Witjes JA, Wities WPJ, et al: J Urol 1995; 153:929, with permission.
In regard to T1 disease, Eum et al. reported a series of
30 patients with high-grade T1 disease treated with a
6-week course of Armand-Frappier BCG. After one
course, 47% (14 of 30) had a negative cytology and
biopsy at 6 months. Another 6 patients responded to a
second 6-week course, for an overall CR rate of 66%.
Four patients required a cystectomy for progression or
recurrent TI tumor, and one patient had metastasis. All
had failed a first course of BCG. Thus, the overall pro-
gression rate was 17%.
Cookson and Sarosdy148 studied BCG for T1 disease
in 86 patients. Patients underwent TUR prior to receiv-
ing a 6-week course of Pasteur BCG. Some patients
received booster doses at 3, 6, and 12 months. Patients
with recurrence had a repeat TUR followed by additional
BCG either weekly or monthly. At a median follow-up of
59 months (range 9 to 149), 9170 were disease free. Of
the 91%, 69% responded to the initial induction course
and 22% were recurrence free after reresection and addi-
tional BCG. Progression to T2 disease occurred in only
7% of patients. They concluded that BCG was effective
in the treatment of T1 tumors. Some patients in their
study, however, were listed as having grade 1, T1 tumors.
Grade 1, TI disease rarely, if ever, exists. This under-
scores the importance of pathology review.
Nadler et al.149 reported that 23 of 66 (35%) patients
who were disease free 2 years after treatment with BCG
had tumor recurrence after 2 to 11 years of follow-up.
Thus, lifelong monitoring after BCG is essential even
with an excellent initial response to treatment.
Cystitis is the most common side effect of BCG,
occurring in up to 90% of patients. Hematuria occurs in
up to one-third of patients and can be problematic.
Major adverse reactions include fever over 103 ˚F (3%),
granulomatous prostatitis (0.9%), and pneumonitis or
hepatitis (0.7%). BCG sepsis, the most serious complica-
tion, occurs in 0.4% of patients. Thus far, 10 deaths from
BCG sepsis have been reported. Caution should be used
in administering BCG to patients who are immunocom-
promised or have liver disease. Treatment depends on the
clinical situation but includes isoniazid 300 mg and
rifampin 600 mg daily. In advanced cases, ethambutol
1200 mg daily is useful. Cycloserine 250 to 500 mg twice
daily in combination with isoniazid and rifampin should
RIVM-BCG MMC
62 of 134 (46%) 58 of 136 (43%)
9 of 15 (60%) 8 of 12 (67%)
8 (6%) 8 (6%)
be used if the patient is septic. In addition, the coadmin-
istration of antituberculin agents with BCG to lessen side
effects of treatment has been proposed.150
Interferon
Interferons (IFN) are biologic response modifiers that
are integrally associated with the immunologic cascade.
IFN has antiproliferative and antiviral properties. It stim-
ulates cytokine release and inhibits nucleotide synthesis.
It stimulates macrophage function, enhances natural
killer (NK) cell cytolytic activity, and activates B and T
lymphocytes.151
The success of IFN-α-2b has been limited in several
previously reported series of superficial TCC. The
Northern California Oncology Group reported that 4 of
16 patients (25%) with superficial TCC had a CR with
intravesical recombinant IFN-α-2b. In the same study, 6
of 19 patients with CIS had a CR. Of the 10 CRs in the
study, 5 were durable at 18 to 37 months.153
Glashan154 reported on a series of 87 patients with
CIS. Patients received either high-dose (100 million
units) or low-dose (10 million units) IFN-α-2b, weekly
for 12 weeks, then monthly up to a year. In the high-dose
group, 20 of 47 (43%) had a CR compared to only 2 of
38 (5%) in the low-dose group. Interestingly, 6 of 9
patients who failed a course of BCG had a CR with IFN-
α2b. Seven patients in each group eventually required a
cystectomy, 13 for disease progression. The median
interval to cystectomy was 32 weeks for the high-dose
group and 18 weeks for the low-dose group. The primary
toxicity was a flulike syndrome occurring in 17% of high-
dose and 8% of low-dose patients. Local symptoms did
not occur and no patient discontinued therapy due to
side effects. Though the efficacy of IFN is inferior to
BCG, it is being used more commonly in BCG failure
patients.
Keyhole-Limpet Hemocyanin
Keyhole-limpet hemocyanin (KLH) is a high molecular-
weight immunogenic protein collected from the
hemolymph of the mollusk Megathura crenulata. In
humans, KLH induces both cell-mediated and humoral
 Chapter 18 Superficial Transitional Cell Carcinoma of the Bladder 327
responses. KLH was initially used as a skin test to evalu-
ate delayed-type hypersensitivity responses in humans.152
Olsson et al.155 first reported the use of KLH
immunotherapy for superficial TCC of the bladder.
Patients immunized with KLH were noted to have fewer
tumor recurrences. In a prospective trial of 19 patients
with a history of superficial TCC, prophylactic KLH
injections were given after TUR. Of the 9 immunized
patients, only 1 had a recurrence over 204 patient-months.
In the nonimmunized group, 7 of 10 had a recurrence
over 228 patient-months.
In a randomized controlled study, Jurinic et al.156
found that KLH was more effective than MMC in pro-
phylaxis against recurrent TCC. KLH (10 mg) was given
intravesically following a 1-mg intracutaneous dose.
Twenty-three patients received 20 mg of intravesical
MMC. Fourteen percent of KLH patients recurred com-
pared to 39% in the MMC group. In a subsequent non-
randomized single arm study, Jurinic et al. reported that
17 of 81 patients (21%) had recurrence of TCC after the
same KLH regimen. No adverse effects were reported.152
Bropirimine
Bropirimine is a pyrimidine that induces interferon, pre-
sumably leading to antineoplastic and immunomodulatory
activities.157 Bropirimine is a unique agent for urothelial
neoplasms, since it can be given orally in a phase 1 trial for
treatment of CIS and papillary TCC; Sarosdy et al.158
reported that 6 of 26 patients who could be evaluated had
a CR at 3 months. Five of 11 patients with CIS had a CR.
The drug was most effective when given at high doses, 3
g/day for 3 consecutive days, weekly for 12 weeks. Only 1
of 10 papillary tumors regressed completely.
In a subsequent phase 2 trial using high-dose bropir-
imine, 20 of 39 patients (51%) with CIS had a CR. This
included 6 of 13 patients (46%) who were BCG failures.
CRs lasted as long as 17 months. Flulike symptoms were
the most common adverse effect occurring in 62% of
patients.159 Further phase 2 trials of bropirimine alone
and in combination with BCG are in progress.
Combination Therapy
Recent studies have shown that BCG and IFN-α have
complementary and synergistic immunomodulatory and
antitumoral activity. This allows reduction in the BCG
dose used. This combination is efficacious in patients
who failed BCG therapy. O’Donnell et al.189 reported
63% and 53% disease-free rates at 12 and 24 months in
BCG refractory patients.189
Clinical studies suggest that combination of BCG and
MMC is not advantageous over mitomycin alone. In
high-grade tumors, complete resection of the tumor
should be followed by immediate instillation of MMC
and subsequent 6-week BCG instillation. The immediate
instillation of MMC decreases the tumor cell implanta-
tion and BCG should further reduce the recurrence and
progression rate.190
Recommendations
From the above data it is clear that BCG plus TUR is
more beneficial than TUR alone for patients with high-
grade TCC and T1 disease. Furthermore, BCG has been
shown to prolong the interval to progression, while
intravesical chemotherapy has not. BCG or MMC
appears to be the agent of choice for CIS.
For recurrent, low-grade Ta tumors, the optimal
treatment is less clear. The likelihood of progression to
muscle-invasive disease is very low (<5%). We recom-
mend either no adjuvant therapy or intravesical
chemotherapy. In this situation, the role of intravesical
chemotherapy would be to prolong the tumor-free inter-
val and decrease the cost and morbidity of frequent sur-
gical procedures. Some studies show no significant
difference between BCG and chemotherapy for low-
grade, low-stage disease,139 and as described above, the
side-effect profile of BCG is not insignificant. Thus, we
do not suggest BCG for grade 1 TCC.
For grade 2 or grade 3 Ta tumors treatment should be
individualized based on recurrence patterns. Either BCG
or intravesical therapy may be appropriate in these situa-
tions. If intravesical chemotherapy fails, BCG would be a
reasonable next step. If a patient were to fail a course of
BCG, a second 6-week course could be considered. This
may help avoid the morbidity of cystectomy in a sub-
group of patients. Yet, this delay may allow disease pro-
gression and loss of curability with radical treatment.
Herr et al.160 reported a series of 61 patients with high-
grade superficial bladder cancer who were initially
treated with BCG. At a follow-up ranging from 10 to 13
years, 12 patients (20%) died of metastatic urothelial can-
cer. Thus, in many cases, despite diligent follow-up,
patients progress and die of bladder cancer.
Biologic immune response modifiers other than BCG
have been used to treat TCC. These cytokines can be
administered orally or intravesically. Their mechanisms
of action are not clearly defined. A host response appears
to be central to their efficacy. Further elucidation of the
mechanism of action of these agents, as well as controlled
studies of various drug combinations at various doses,
will better define their role in the treatment of Ta and TI
TCC and CIS.
TRANSITIONAL CELL CARCINOMA
OF THE PROSTATIC URETHRA
TCC of the prostatic urethra is usually found concomi-
tant with or subsequent to TCC of the bladder. It is
328 Part IV Bladder
rarely primary. Analysis of cystoprostatectomy specimens
has identified TCC of the prostate in 10% to 50% of
cases. Involvement is more common with high-grade
bladder tumors, occurring in 70% of men with primary
CIS of the bladder. Since the presence of TCC of the
prostate may alter the treatment strategy, a TUR biopsy
of the floor of the prostatic urethra should be performed
in all men with high-grade TCC of the bladder.162
The management and prognosis of TCC of the pro-
static urethra depend on stage and grade. Although the
UICC staging system indicates that all TCC of the
prostate is stage T4, it seems prudent to substratify
patients based on involvement of the prostatic urethra,
ducts, or stroma.165 The prognosis for prostatic mucosal
CIS and ductal involvement differs from that of stromal
invasion. Furthermore, TCC involving the prostatic ure-
thra primarily may be less lethal than the disease from
the bladder infiltrating through the bladder wall to
involve the prostate.
Treatment of TCC of the prostatic urethra must take
into consideration the status of the bladder (i.e., current
TCC or prior history of TCC and treatment).
Therapeutic options include intravesical chemotherapy,
immunotherapy, or cystoprostatectomy (Figure 18-1).
BCG has been the most widely studied agent for topical
therapy. Initial concerns about obtaining effective con-
tact with the prostatic urethra arose from observations of
recurrence in the prostatic urethra after BCG therapy for
TCC of the bladder. However, bladder neck incompe-
tence following TUR would seem to allow adequate tis-
sue contact for treatment. For disease confined to the
High-grade bladder TCC (Ta, T1, CIS)
TUR biopsy of the prostatic urethra
CIS only Ductal
Intravesical therapy Cystoprostatectomy
(if fails, cystoprostatectomy with urethrectomy
with urithrectomy) or intravesical therapy
Figure 18-1 Algorithm for evaluation and treatment of prostatic urethral TCC. (From Matzkin H,
Soloway MS, Haredeman S: J Urol 1991; 146:1210, with permission.)
prostatic urethra, several series have documented CRs
using BCG.168,169
Cystoprostatectomy is recommended for most cases
of TCC involving the prostatic ducts or stroma.162
Concurrent urethrectomy is recommended because
there is a 30% to 50% risk of urethral recurrence.171
The prognosis for urethral involvement relates to dis-
ease stage, with high-T-stage lesions associated with a
grim outcome.
PARTIAL AND RADICAL CYSTECTOMY
With the current efficacy of quality endoscopic instru-
ments and multiple intravesical agents, the majority of
patients with superficial bladder cancer will not require
radical surgery. The indications for cystectomy include
failed intravesical therapy for high-grade disease (papil-
lary or CIS), persisting or recurrent high-grade tumor, or
progression to bladder muscle or prostatic stromal inva-
sion (Table 18-4). Persistently positive urine cytology
after intravesical treatment requires a thorough reevalu-
ation of the bladder, in addition to reassessment of the
upper tracts and the prostatic urethra in men.
Localization and accurate restaging is necessary before
considering cystectomy.
Cystectomy should also be strongly considered when
pathologic understaging is suspected. Hydronephrosis
associated with a bladder tumor usually indicates muscle
invasion. Staging error rates as high as 55% have been
reported for T2 tumors.172,173 This reinforces the impor-
tance of careful pathologic review of all biopsy material.
stromal invasion Negative
Cystoprostatectomy Treat bladder tumor as
with urethrectomy indicated
 Chapter 18 Superficial Transitional Cell Carcinoma of the Bladder 329
Table 18-4 Indications for Cystectomy
for Superficial Bladder Cancer
Persistent or recurrent high-grade papillary tumor
Persistent or recurrent CIS
Progression to muscularis propria or prostatic stromal
invasion
TCC involving prostatic ducts
Consideration should be given to concurrent ure-
threctomy with cystectomy if there is widespread multi-
focal CIS, involvement of the prostatic urethra in men,
or bladder neck and trigone in women. This probably
precludes orthotopic urinary reconstruction to the ure-
thra for these individuals, although some suggest that this
is not an absolute contraindication with limited prostatic
urethral involvement.
Partial cystectomy has a limited role. There is a sub-
group of superficial tumors in which this may be consid-
ered, such as tumors within bladder diverticula.
Diverticulectomy should be performed with care to
obtain adequate surgical margins and avoid tumor cell
spillage.
Surgery alone achieves a high cure rate for superficial
TCC. Amling et al.174 reported cancer-specific 5-year
survival rates of 88% for Ta, 76% for T1, and 100% for
CIS. Pelvic lymph node metastases were present in 5.9%.
Similar survival figures have been reported in other large
series.175–177
FOLLOW-UP
Since 30% to 80% of tumors will recur, close follow-up
is important to diagnose and treat recurrence early.
Flexible endoscopy and urinary cytology (for high-grade
disease) are essential for follow-up. Historically this has
been performed at 3-month intervals, and then tailored
according to patterns of recurrence. The disease status at
the initial 3-month cystoscopy is important in predicting
future tumor behavior, and has become the basis of fol-
low-up protocols.18–48
Treatment of papillary recurrence, or suspicious areas,
is ideally performed under anesthesia, with rigid instru-
mentation, allowing adequate biopsies and thorough
visual assessment. The mucosa distant from the tumor
and the prostatic urethra in males should be sampled as
previously outlined for high-grade primary tumors.
Laser ablation via flexible endoscopy under topical
anesthesia has been used to manage recurrences in
selected cases.178,179 Laser is well tolerated, although
there is a recognized risk of bowel injury.178 Diathermy
has also been used180; 4-French electrodes are available
to treat small lesions. Care must be taken to pass the elec-
trode at least 1 cm beyond the tip of the endoscope to
avoid thermal damage to the fiberoptic system. Both
techniques require a cooperative patient. There is con-
siderable cost benefit for this strategy in appropriate
individuals. It must be emphasized that representative
histopathology is necessary to avoid undertreatment of
innocent-appearing high-grade lesions.181
Protocols for cystoscopic follow-up have been pro-
posed based on known prognostic factors, such as tumor
size, number, histologic grade and stage, urine cytology,
and DNA ploidy. Parmar et al.18 concluded that the like-
lihood of recurrence, and hence the need for follow-up
cystoscopy, could be predicted simply and accurately by
the number of tumors at initial presentation and the
presence of recurrent tumor at the first 3-month cys-
toscopy risk categories and appropriate follow-up are
summarized in Table 18-5. The power of this classifica-
tion lies in the objectivity and reliability of these two
prognostic factors. The safety and efficacy of this proto-
col have been demonstrated in a retrospective review of
232 patients.182
The duration of endoscopic follow-up for patients free
of recurrence for many years has been debated. Morris
et al.,183 in a longitudinal follow-up study of 179 patients
with Ta and T1 TCC, documented recurrence risk over
time. They reported that after a tumor-free interval of 2,
5, and 10 years, the risk of recurrence is 43%, 22%, and
2%, respectively. No patient had a recurrence after
remaining tumor free for 12 years. No patient free of
recurrence for 2 years progressed to muscle invasion or
metastases. Holmang et al.24 reported that only 1 of 59
patients tumor free for 5 years progressed. They also
observed that patients who had recurrences on 10 or
more cystoscopic studies, or multiple recurrences over
more than 4 years, continued to have recurrences until
death or cystectomy.
Urinary markers and cytology may have a role in long-
term follow-up. Table 18-6 lists sensitivities and speci-
ficities for potentially useful urinary markers. The ideal
Table 18-5 Follow-Up for Superficial Bladder Cancer
Risk Category Recommended Follow-Up
Single tumor with no Annual cystoscopy
recurrence at 3 months
Single tumor with 3-monthly cystoscopy
recurrence at 3 months,
or multiple tumors
with no recurrence
Multiple tumors with Adjuvant treatment
recurrence at 3 months
From Parmar MKB, Friedman LS, Hargreave TB, et al: J Urol 1989;
142:284–288, with permission.
330 Part IV Bladder

Table 18-6 Urinary Markers for Follow-up of Superficial Bladder Cancer

Number Sensitivity Specificity
Marker Technique of Patients (%) (%)

LewisXantigen64 Immunocytology (bladder wash) 101 81 86

LewisXantigen184 Immunocytology 89 85 85

Basement membrane complex Latex agglutination 499 40 82

(Bard BTA)185

Autocrine motility factor (AMF) Qualitative immunoassay 70 80 75

receptor186

Nuclear matrix protein (NMP-22)* Quantitative immunoassay 69 74 78

Hyaluronidase† Quantitative ELISA assay 104 63 (high grade-99) 94

ELISA, enzyme-linked immunosorbent assay.

*Data derived from Soloway MS, Briggman J, Carpinito G, et al: Use of a new tumor marker, urinary NMP22, in the detection of occult or rapidly
recurring transitional cell carcinoma of the urinary tract following surgical treatment. Personal communication, 1995.
†Data derived from Lokeshwar BL: Personal communication, November, 1995.

noninvasive bladder tumor marker would need to be
nearly 100% sensitive before replacing follow-up cys-
toscopy. Voided urine cytology has excellent specificity
and reasonable sensitivity in high-grade lesions. But in
low-grade lesions, the sensitivity is low (25%). At present
none of these tests can completely replace cystoscopy for
surveillance. A positive cytology and a negative cys-
toscopy should prompt the clinician to investigate the
patient further including random biopsies of the bladder,
prostatic urethra and careful assessment of upper tracts.
The frequency of radiologic follow-up depends on the
individual’s risk of developing upper urinary tract tumors.
This risk varies from 0.5% with low-grade bladder
tumors24,187 to 15% with CIS.188 Intravenous pyelogra-
phy should be performed every 2 to 5 years, accordingly.
CASE HISTORIES
Case 1
A 74-year old female presented with a 4-cm papillary
bladder tumor. TUR confirmed a grade 3 T1 tumor with
invasion to the level of the muscularis mucosae but not
involving deep muscle (stage T1a).
Case 1 Discussion
Accurate staging is important when evidence of lamina
propria invasion is present on initial biopsy. Restaging
biopsy is essential. Confirmed lamina propria invasion
and high grade puts this patient at high risk for both
recurrence and progression. Intravesical BCG was
administered weekly for 6 weeks, without evidence of
recurrence.
Case 2
A 48-year-old woman presented with a 2-cm papillary
tumor on the bladder trigone, near the ureteric orifice,
with negative mucosal biopsies. Pathology confirmed a
grade 3 Ta lesion that was strongly positive for p53 on
immunohistochemical staining. Small papillary recur-
rences were resected at 13 and 21 months, all of which
remained grade 3 Ta and p53-positive. Intravesical mito-
mycin (20 mg weekly for 5 weeks) was administered. The
patient remains tumor free at 10 months following the
last TUR.
Case 2 Discussion
Recent data suggest that p53-positive papillary tumors
may be at increased risk for progression. These tumors
initially recurred as high-grade noninvasive lesions,
although they appear to have responded to a prophylac-
tic course of mitomycin. BCG would have been an
equally reasonable alternative and will be used with
recurrence. Intravesical therapy could have been used at
the time of diagnosis given the high tumor grade.
Case 3
A 66-year-old male underwent a TUR of the prostate for
symptoms associated with benign prostatic hyperplasia.
Surprisingly, the pathology noted grade 3 TCC involving
the prostatic ducts. No bladder disease was detected on
biopsy at a subsequent cystoscopy. The patient declined
further treatment. A TUR biopsy at 24 months again
demonstrated CIS involving prostatic ducts with no stro-
mal invasion and no TCC of the bladder.
 Chapter 18 Superficial Transitional Cell Carcinoma of the Bladder 331
Case 3 Discussion
The management options for prostatic ductal involve-
ment include intravesical BCG or cystoprostatectomy. A
cystoprostatectomy with urethrectomy was performed
confirming prostatic ductal CIS with extensive CIS of the
bladder and one focus of lamina propria invasion. This
demonstrates the problems of disease understaging,
which is the major concern with intravesical treatment
for both bladder and prostatic urethral TCC.
Case 4
A 65-year old male presented with a 1-cm grade 3 Ta
tumor involving the left wall of the bladder, which was
completely resected. A large, wide-mouthed bladder
diverticulum located on the right wall of the bladder was
filled with a second grade 3 papillary tumor. Random
bladder and prostatic urethral biopsies were negative. A
TUR biopsy at 8 weeks revealed no evidence of tumor in
the left wall. A partial cystectomy removing the bladder
diverticulum was performed, confirming a grade 3 Ta
tumor with associated CIS but negative surgical margins.
Case 4 Discussion
Residual or high-grade noninvasive tumor involving a
bladder diverticulum could be managed with divertic-
ulectomy or cystoprostatectomy. Care must be taken to
exclude and treat other foci of tumor, if bladder preser-
vation is chosen.
Case 5
A 74-year old female presented with a history of CIS and
T1 grade 3 TCC of the bladder. After resection she was
treated with 6 weeks of BCG.
Case 5 Discussion
This case prompts consideration as to whether to give
maintenance BCG. Early randomized studies showed no
clear-cut advantage to giving maintenance BCG over a
standard 6-week inductive course. Lamm et al.138 recently
reported that not only can maintenance therapy reduce
tumor recurrence but may also increase survival. The
optimal timing of maintenance doses has not been clearly
established. Given the patient’s age and risk of side effects,
no maintenance therapy was given in this case.
Case 6
A 77-year old woman was diagnosed with multifocal CIS
in 1990. She was treated with 6 weekly doses of intraves-
ical MMC. At that time she had frequency and urgency,
as well as perineal discomfort. In 1993, she had a right
distal ureter stricture treated with distal ureterectomy
and reimplantation. In follow-up she had a positive cytol-
ogy but no evidence of tumor on bladder biopsy She
received 6 weeks of BCG. Her irritative symptoms wors-
ened. She later had dysplasia in the bladder documented
by biopsy and received another 6-week course of MMC.
She remained tumor free but presented with incapacitat-
ing irritative voiding symptoms and incontinence and a
severely contracted bladder. She underwent a cystectomy
and ileal conduit for severe bladder contracture. There
was no cancer in the specimen.
Case 6 Discussion
This is a classic case of overtreatment with intravesical
therapy and incapacitating iatrogenic morbidity. While
intravesical agents may prolong recurrence-free survival,
the side effects of treatment should not be underestimated.
Case 7
A 75-year old woman presented with a history of super-
ficial, low-grade TCC in 1983. She had been treated pre-
viously for interstitial cystitis. In 1988, she underwent a
left nephroureterectomy for T1, grade 2 TCC of the
ureter. In 1991, she was found to have CIS in the bladder
and superficial tumor in the right distal ureter. A stent
was placed and she received intravesical MMC. Four
months later she had a resection of a T1, grade 3 bladder
tumor. She was given a second 6-week course of BCG.
Nine months later she had a TURBT, with pathology
revealing a high-grade, muscle-invasive tumor with
involvement of the right ureteral orifice and invasion of
the bladder neck and urethra. Cystectomy with urinary
diversion was performed. Pathology revealed a grade 3
T3 TCC. No adjuvant chemotherapy was given.
Case 7 Discussion
This case illustrates the progression of a superficial lesion
to a high-grade invasive tumor despite intravesical
MMC, BCG, and close surveillance.
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334 Part IV Bladder
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C H A P T E R
19Prognosis and Management of
Invasive Transitional Cell Carcinoma
J. Matthew Hassan, MD, Sam S. Chang, MD,
Michael S. Cookson, MD, and Joseph A. Smith, Jr, MD
Fifty-four thousand new cases of bladder cancer are diag-
nosed each year. It is the second most common genitouri-
nary cancer and results in over 12,000 cancer-related
deaths annually.1 Twenty percent to 25% of newly diag-
nosed bladder cancer consist of muscle-invasive disease,2
with the majority of these invasive bladder cancers
demonstrating invasion at the time of diagnosis.3 While
tumor grade and stage do influence progression, only
approximately 15% of superficial tumors will eventually
develop the characteristic features of muscle-invasion.4–6
For those that become muscle-invasive, however, the risk
of metastasis and mortality unquestionably and dramati-
cally rises.7
More than 90% of invasive and noninvasive bladder
tumors are transitional cell carcinomas (TCCs). Invasive
bladder cancer, however, can be of squamous cell carci-
noma (3%), adenocarcinoma (2%), or small cell
carcinoma (<1%) origin. TCCs may also contain focal
areas of squamous or glandular differentiation. These
have been traditionally classified and managed as TCC,
but future investigation may demonstrate that these his-
tologic variants are in fact associated with different out-
comes and should be treated as different pathologic
entities. This chapter will deal specifically with the prog-
nosis and management of invasive TCC of the bladder.
The management of muscle-invasive and metastatic
TCC continues to evolve. The advent of multimodality
therapy has begun to challenge the traditional view of
radical cystectomy as the “gold standard” treatment for
muscle-invasive bladder cancer. A multitude of new
information about the cellular mechanisms and biology
of bladder cancer has led to trials ultimately designed to
improve patient outcome and survival. Herein, we will
review the principles and concepts behind the biology of
338
muscle-invasive TCC, as well as current treatment rec-
ommendations with regards to surgery, adjunctive sys-
temic therapy, and alternative therapies.
TUMOR EXTENT EVALUATION
Stage and Grade
Transurethral resection (TUR) of a bladder tumor yields
vital information to the urologist. The objective is to
remove all visible tumors, if possible, and obtain tissue
for pathologic evaluation. The two most commonly used
prognostic indicators, clinical stage and histologic grade
of the cancer, can be determined from this operative pro-
cedure. TUR under anesthesia is both diagnostic and
therapeutic, especially in cases of superficial disease.
Invasive bladder cancer consists of malignant transitional
epithelial cells that extend beyond the connective tissue
of the lamina propria and into the muscularis propria
(T2) and surrounding perivesical fat and soft tissues
(T3,4). For this reason, the presence of muscle detrusor
cells in the resected tissue is essential to provide patho-
logic evidence of muscle invasion.
Local muscular invasion classically has been described
by three mechanisms.8 The majority (60%) advance “en
bloc,” as a broad face below the primary epithelial lesion.
Twenty-five percent spread with tentacle-like fronds.
The remainder (10% to 15%) spread by laterally
encroaching under normal adjacent mucosa. A more
modern biochemical interpretation involves concepts of
stimulation of neovascularization, the regulation of cellu-
lar motility, and the avoidance of detection from cellular
surveillance mechanisms.
The presence and degree of local invasion has been
closely linked to poor outcomes both in time to metastasis
 Chapter 19 Prognosis and Management of Invasive Transitional Cell Carcinoma 339
and time to cancer-related death. According to the
National Cancer Data Base, the overall 5-year survival
rates for Ta, T1, T2, T3, and T4 tumors are 90%, 87%,
65%, 48%, and 23%, respectively.7 In other studies, the
median survival for T2 tumors is 85 months, whereas
for T4 tumors, the median survival is 29 months.9
Furthermore, a recent review of 1636 cases demonstrated
a significant variation with stage and survival following
radical cystectomy; 63% of patients with T2 disease sur-
vived 5 years, while only 18% of those with T4 disease
survived as long.10 There is clear and persuasive evidence
to suggest that the depth of infiltration correlates with
curability of TCC.
While this review focusses on muscle-invasive bladder
cancer, there are forms of non–muscle-invasive TCC
that have such a high propensity to invade that they merit
inclusion. Carcinoma in situ (CIS) is confined to the
urothelium, but 20% of patients treated with cystectomy
for CIS are found to contain some elements of micro-
scopic invasion.11 Between 40% and 83% of CIS tumors
will ultimately progress to muscle-invasion.5 Likewise,
T1 tumors have been shown to become invasive about
one-half of the time.12 In addition, one-third have
involvement of the posterior urethra, which, as discussed
later, affects surgical treatment options.13
Pathologic T1 tumors may require a different surgical
management than other noninvasive bladder tumors
because of their propensity for invasion.14 Recently
revised recommendations of management of high-grade
(II and III) T1 cancers include transurethral re-resection
of the previous tumor bed because incomplete resec-
tion is closely linked with invasion15,16 and because of the
risk of understaging.17
In addition to tumor depth, the grade, or the degree of
differentiation, of the tumor cells is of critical prognostic
significance.18 Grading has traditionally been applied to
superficial tumors to predict recurrence or progres-
sion.19,20 Patients with grade 1 and grade 2 tumors have
approximately 10% risk of developing muscle-invasion,
whereas one-third of patients with grade 3 tumors will
eventually have invasive disease.21 More recently, efforts
to grade muscle-invasive components have not demon-
strated any prognostic significance in T2 disease.22
Other less commonly used methods to detect invasive
disease and predict its course, such as the use of DNA
ploidy and the expression of various growth factors and
cell-cycle regulators, will be addressed in detail later.
Metastatic Evaluation
Prior to proceeding with management of locally invasive
bladder cancer, the physician must determine the systemic
extent of the tumor, specifically, if the cancer has metas-
tasized. A close correlation between muscle-invasion and
distant metastasis has been well documented.23 The most
frequent sites of metastasis are the pelvic lymph nodes.
Among the pelvic lymph nodes, the obturator nodes and
the external iliac nodes are involved most commonly in
cases with positive nodes, 74% and 65% of the time,
respectively. The presacral nodes (25%), common iliac
nodes (20%), and paravesical nodes (16%) are involved
with TCC less often.24 Other distant sites of metastasis
for TCC include bone, lung, skin, liver, and less com-
monly, the brain and meninges.25 Few patients with
distant metastases survive 5 years.26 Clearly, the identifi-
cation of metastasis affects the decision-making process
for tumor thought to be locally invasive.
In order to complete the pretreatment clinical staging,
the urologist must survey the patient to detect the most
common metastatic lesions. In addition to performing a
full physical examination, including bimanual palpation
of the bladder before and after tumor resection,27 labora-
tory studies, such as renal and hepatic function panel,
should be performed. In addition, a chest radiograph is
appropriate to document evidence of pulmonary nodules
consistent with tumor metastasis.
Often, the initial test performed in evaluation of TCC
is a computerized tomographic (CT) scan of the
abdomen and pelvis.28,29 While this is a simple test and
may assist in the detection of distant metastatic lesions,
bulky retroperitoneal adenopathy, or obstructive hydro-
ureteronephrosis, it has repeatedly been shown to be
inaccurate in assessing the stage of the primary cancer,
especially with small volume pelvic nodal disease.30,31 In
addition to understaging tumors by not reliably detecting
pelvic lymphadenopathy, CT also can overstage tumors
because of the difficulty in distinguishing postbiopsy
edema from residual tumor. Despite these shortcomings,
CT scan remains the standard preoperative staging test.
Because CT scanning is inadequate to detect pelvic
nodes, MRI has been studied to determine better the
extent of tumor.32,33 MRI can be particularly beneficial in
patients who have renal insufficiency or a contrast allergy
and cannot tolerate CT. The rate of detection of micro-
scopic metastasis has compared similarly to CT,34 but
some advocate its use in the staging of patients with
deeply invasive TCC.35 There is still a significant amount
of “mis-staging” (40%) of bladder tumors with MRI.36
Combined with its high cost, these doubts reduce the fre-
quency of its use. Future advances in MRI, including
endorectal coil enhancement37 and dynamic contrast
imaging,38 may make it more accurate, but they have not
been validated.
The role of PET scanning has also been investigated
for use in invasive TCC.39–41 An intrinsic problem is that
fluoro-deoxy-glucose (FDG), the most commonly used
radiopharmaceutical, is unsuitable for evaluation of blad-
der cancer due to intense accumulation in the urine.42
Because of this inability to image the bladder, efforts have
been made to employ more specific tracers, which are not
340 Part IV Bladder
excreted in the urine. Early studies indicate that carbon-11
labeled choline may be helpful.43 Again, the cost of the
study and current inaccuracies, however, make PET
impractical for routine use. The most likely use of PET
scanning in invasive bladder cancer may be to assist in
detection of positive lymph nodes or distant metastatic
lesions.
The most accurate method to stage regional lymph
nodes remains surgical, regional lymph node dissection.
Performed as a separate procedure, it can reliably distin-
guish N+ from N0 patients and can be performed laparo-
scopically.44 While most believe there is an insignificant
risk of port site tumor recurrence,45 others have argued
that the risk may be greater in patients with bladder can-
cer. One study shows a 4% risk of port site recurrence
following pelvic node dissection for bladder cancer com-
pared to a negligible risk following lymphadenectomy for
prostate cancer.46 The reason for this discrepancy
between TCC and other genitourinary malignancies is
unclear. The majority of time, however, regional lymph
node dissection is performed at the time of radical cys-
tectomy at a single operative setting.
PROGNOSIS OF INVASIVE TRANSITIONAL CELL
CARCINOMA
Even in organ-confined, muscle-invasive bladder cancer
(stage pT2N0M0) treated by radical cystectomy, approx-
imately 50% of patients ultimately develop recurrences.
In one recent study of 594 patients with organ-confined
invasive cancer treated locally, 44% relapsed.47 Others
have also shown 5-year survival rates following cystec-
tomy for locally invasive bladder cancer to be 38% to
64%.7,48–51 Most patients with occult metastases develop
overt clinical evidence of distant metastasis within
1 year.25
The above data imply that the current clinical staging
and histologic grading systems on which urologists rely
are insufficient. Except for the patients with extensive
local disease or bulky lymphadenopathy, contemporary
preoperative evaluation continues to understage patients
with invasive TCC. While significant thought has been
devoted to which superficial tumors will progress to inva-
sion, equally intense research effort has been devoted to
predicting which invasive tumors will metastasize. What
has been shown is that there is a vast degree of biological
heterogeneity to urothelial cancer. By combing through
this cellular variability, it may be possible to identify par-
ticular genetic characteristics that will predict failure of
conventional therapy. The identification of any prognos-
tic factors for muscle-invasive bladder cancer would be of
critical clinical utility.
Advances in molecular genetics may provide the
opportunity to better determine an invasive bladder
tumor’s biological potential.52 One of the newest tech-
niques used in the investigation of TCC is cDNA
microarrays. This is a high output method of studying the
expression of thousands of genes on one tumor extract on
a single slide rapidly and reproducibly. Many groups are
employing this technique to try and determine the molec-
ular profile of TCC.53–55 It is becoming apparent that
there may not be a uniform treatment for every patient
with muscle-invasive bladder cancer. Rather, clinically
relevant subsets of bladder cancer patients may be identi-
fied, and selective treatments may be required for patients
with specific tumor characteristics.56
While many correlations have been made with tumor
progression, the use of markers has not been accepted
into standard practice yet.57 The molecular changes that
occur in the progression of invasive bladder cancer have
been examined as potential prognostic factors and can be
organized into 3 categories: (1) chromosomal alterations;
(2) cell adhesion molecules and angiogenesis; and (3) loss
of cell-cycle regulation involving tumor suppressor genes
and oncogenes.
Chromosomal Abnormalities
As in many malignancies, the role of chromosomal
abnormalities and DNA cytometry has been evaluated
for bladder cancer.58 Abnormal number of chromosomes
and chromosomes of abnormal morphology have been
associated with an increased risk of bladder cancer recur-
rence and progression.59,60 Several studies correlate
polysomy, especially of chromosome 7, or aneuploidy
with progression of superficial bladder cancer.61–64 There
has been very little work, however, that can demonstrate
the same prognostic significance for muscle-invasive
transitional carcinoma. In invasive cancer, DNA ploidy
does not appear to statistically correlate with invasive
cancer in stage, tumor recurrence, lymph node metasta-
sis, or survival.65–67 In addition, abnormal chromosomal
number or configuration has not been correlated with
response to treatment. In patients with muscle-invasive
disease, DNA ploidy has not predicted outcome for those
receiving either preoperative radiation therapy68,69 or
neoadjuvant chemotherapy.70
Growth Events
The progression of TCC to invasion and metastasis
requires a cascade of molecular events. Malignant cells
must extend beyond their boundaries into the lamina
propria and subsequently, the muscularis mucosa and
perivesical fat. This process relies on cellular motility,
proteolysis, proliferation, and angiogenesis. There is
mounting evidence to suggest that alterations in the mol-
ecules that govern cell growth enable this progression. In
addition, if one is able to detect at the molecular level
these processes, one may identify a real-time marker for
 Chapter 19 Prognosis and Management of Invasive Transitional Cell Carcinoma 341
progression. The two most investigated of these growth
control markers as indicators of prognostic significance
in invasive TCC are cell adhesion molecules and angio-
genesis factors.
Cell Adhesion Molecules
Various properties of neoplastic cells are altered, which
enables invasion. These involve the relationship between
cells, components of the extracellular matrix, and the
underlying basal lamina. The physical relationships
between cells are controlled by cell adhesion molecules
like cadherins. E-cadherin, in particular, has been inves-
tigated and has been demonstrated to be a critical factor
in facilitating the progression of bladder cancer.71 Not
only is loss of E-cadherin associated with an invasive phe-
notype but also its normal expression decreases in direct
proportion to the tumor stage.72 Others have also shown
abnormal E-cadherin expression to be an independent
predictor of disease progression following cystectomy,
demonstrating an inverse relationship with stage, grade,
likelihood of lymph node metastasis, and even overall
survival.73
Investigation is also being performed on the prognos-
tic value of E-cadherin-related cytoplasmic molecules.
Cadherin function requires an intact network of catenins
to network through the cytoskeleton. Abnormal expres-
sions of alpha-, beta-, and gamma-catenin have been
shown to significantly correlate with tumor stage, grade,
and survival in patients with invasive bladder cancer.74
Other cellular adhesion molecules include the inte-
grins family, which are transmembrane proteins that link
epithelial cells to each other and the basal membrane.
Critical cell–cell interaction occurs via integrins and the
anchoring complex of desmosomes. In addition to con-
tributing to the spread of CIS,75 abnormal expression of
integrins have been linked to the proliferation of invasive
bladder cancer. It has been shown that loss of the coex-
pression of alpha-6-beta-4 integrin and collagen VII, a
component of this extracellular network, is prominent in
progressively invasive urothelial cancer.76
Malignant urothelium has also been associated with
abnormal expression of other cell-surface molecules like
epidermal growth factor receptors. The interaction of
these signaling molecules induces a wide variety of
changes within the cell nucleus, including mitosis.
Abnormal expression or production of these gene prod-
ucts may therefore upregulate growth and promote can-
cer cell motility.77 Multiple groups have demonstrated
that the traditional signs of tumor aggressiveness, such as
stage, grade, and survival, correlate with abnormal
expression of epidermal growth factor.78–81
Cellular motility through the extracellular matrix relies
on an array of enzymes like collagenases, which provide
proteolysis. One such family of enzymes is the matrix
metalloproteinases, that contribute to the destruction of
the basement membrane. Their role in the process of
invasion of superficial tumors has been well described.82
Matrix metalloproteinases, however, have been suggested
to play a role in the progression of invasion to metastasis
as well.83 Their expression has been shown to be of prog-
nostic significance in those patients who develop recur-
rence of their TCC following what appeared to be
complete extirpation of their invasive cancers.84
Angiogenic Factors
Like all solid tumors, TCC of the bladder requires angio-
genesis to promote progression and growth. The angio-
genic phenotype—the sum of the balance of stimulatory
and inhibitory signals to the endothelium—not only
determines the degree of neovascularity but also is evolv-
ing into an important prognostic factor in the outcome of
bladder cancer.85 Some of the variables, which have been
studied, include vascular endothelial growth factor
(VEGF), thrombospondin-1 (TSP-1), and microvascular
density.
Several groups have looked at VEGF as a mediator of
tumor angiogenesis. The VEGF serum level in patients
with bladder cancer was significantly associated with
tumor stage, grade, vascular invasion, and metastasis.86
VEGF expression has also been identified by multivariate
analysis as a significant predictor of disease recurrence in
patients who have undergone cystectomy with neoadju-
vant chemotherapy.87
Thrombospondin-1 (TSP-1), an important compo-
nent of the extracellular matrix, has also been identified
as a potential prognostic angiogenic factor. It is a potent
inhibitor of neovascularity and a reduction in its gene
expression has been associated with disease progression
of superficial TCC.88 Other groups have examined TSP-
1 expression in invasive disease. TSP-1 was significantly
associated with disease recurrence and overall survival
but not seen to behave independently of other tumor
markers like p53.89 This may indicate that TSP-1 may
have some inhibitory function but may be one mecha-
nism of action of p53.
A different method of quantifying vascular develop-
ment is to evaluate microvessel density (MVD). MVD
has been shown to be independently influential to disease
recurrence and survival in muscle-invasive bladder can-
cer.87,90–92. In patients with an elevated MVD, there is a
significantly higher rate of occult lymph node metastases
in patients with clinically localized disease.93 Histologic
efforts to assess other shape-related morphometric char-
acteristics of the microvascularization as indicators of sig-
nificant neovascularity have been demonstrated in
superficial disease. In muscle-invasive disease, however,
MVD is the only significant histologic indicator of prog-
nosis that has been identified.94
342 Part IV Bladder
While a majority of studies have found a positive cor-
relation between MVD and worsening prognosis, not all
reports concur. Some have found MVD to be not signif-
icantly associated with lymph node status in patients with
high-stage, high-grade bladder cancer.66 As will be
addressed, many of the intergroup outcome variability
may be secondary to differing treatments. It remains to
be seen how treatment affects the upregulation of these
various markers of progressive invasion.
Cell-Cycle Regulators—p53
TCC is thought to develop from genetic changes, which
affect cell growth and proliferation. Two such genes,
which can regulate the cell cycle, are tumor suppressor
genes and proto-oncogenes. Both have been extensively
studied in TCC.95
The p53 is a tumor suppressor gene located on chro-
mosome 17p. It encodes a 5-kD protein that induces
apoptosis in cells with evidence of DNA damage.
Approximately one-half of all human cancers have evi-
dence of mutations in the p53 gene.96 These mutations
permit unabated cell growth by disrupting normal cell-
cycle checkpoints and apoptosis.97 There is evidence to
support that p53 may also act by promoting other angio-
genic factors already mentioned, such as VEGF and
TSP-1,98 although this is debated particularly in the
angiogenesis of bladder cancer.99
There is a vast amount of evidence to suggest that the
dysregulation of p53 is critical in the development of
TCC.100 When p53 undergoes mutation, its half-life typ-
ically increases, which causing accumulation of p53 in the
cell nuclei. Advances in immunohistochemistry and
molecular genetics have allowed researchers to detect
easily the cellular buildup of abnormal p53.
p53 mutations occur in the pathogenesis of TCC rel-
atively early, and researchers have attempted to corre-
late varying expressions of abnormal p53 with patient
outcome.101 While p53 has been associated with high
rate of tumor progression in high-risk superficial dis-
ease,102 there has been inconsistent evidence to suggest
the same for invasive bladder cancer. The nuclear over-
expression of mutant p53 does appear to be more com-
mon in muscle-invasive disease according to a large
meta-analysis from the International Study Initiative on
Bladder Cancer. Of 1706 patients, p53 mutations
appeared in only 25% of superficial disease versus 48%
of muscle-invasive disease.103 It has been shown that
nuclear overexpression in T2 or greater disease is asso-
ciated with a worse prognosis, resulting in higher stage
and grade, earlier development of metastases, and
decreased survival.104,105 In other studies, p53 status was
the only independent predictor of survival in those
patients with clinically localized disease at the time of
cystectomy.106
As suggested earlier, not all investigators have found a
direct link between p53 expression and prognosis in
patients with muscle-invasive disease. One group found
no correlation between mutation in the p53 and cancer-
specific survival. Also, it has held no prognostic value in
patients with T3b or greater disease106 or node-positive
disease.107 These varying results may be due to multiple
reasons including differences in assays, technique, and
tumor heterogeneity.
Cell-Cycle Regulators—Others
Other molecules that regulate the cell cycle have been
associated with bladder cancer, and thus, have been
investigated for their potential prognostic significance
when detected in abnormal levels. One such gene is the
retinoblastoma gene. It appears on chromosome 13q and
when its protein product is phosphorylated by cyclin-
dependent kinases, it activates genes critical to DNA
replication.
The retinoblastoma gene appears mutated in approxi-
mately one-third of bladder tumors.108 Loss of normal
retinoblastoma function has been shown to result in sta-
tistically significant higher grade of TCC, along with a
higher likelihood of invasion.109 Others have shown that
abnormal expression of retinoblastoma in patients who
have undergone radical cystectomy for muscle-invasive
disease has a significant higher rate of recurrence and
decreased survival.110 Interestingly, in the same study,
those with both retinoblastoma dysregulation and p53
mutation fared more poorly than either individually. This
may suggest a synergistic relationship between retinoblas-
toma and p53 in the promotion of tumor progression.
Similarly, any other genetic mutation that affects the
cyclin-dependent kinase systems, which phosphorylate
the retinoblastoma gene product, may also promote cel-
lular proliferation and malignant transformation.111 The
p21 is a ras oncogene that transduces signals from the cell
membrane to the nucleus and is actually induced by wild-
type p53.112 This particular kinase inhibitor, under
altered expression, has been shown to contribute to
tumor progression. Mutated p21 emerges in several stud-
ies as an independent indicator of increased likelihood of
recurrence and of decreased disease-free survival in
patients undergoing radical cystectomy for muscle-inva-
sive disease.113,114 A deficiency of p21 expression has also
been shown to be correlated with poor response follow-
ing systemic chemotherapy115 and radiation therapy.116
Another oncogene that has been suggested as a useful
prognostic index for bladder cancer is erb-B-2. This
oncogene codes for a growth factor receptor, which is
functionally related to epidermal growth factor receptor.
Its amplification and overexpression have been impli-
cated as prognostic markers for recurrent superficial
bladder tumors.117 Researchers, however, have been
 Chapter 19 Prognosis and Management of Invasive Transitional Cell Carcinoma 343
unable to link protein overexpression to tumor stage,
grade, or disease progression in invasive bladder cancer
patients.118,119. In terms of invasive TCC, erb-B-2
appears to not possess much predictive value at the pres-
ent time.
Transforming growth factor (TGF) is both a cellular
regulator and a potent angiogenic factor. Serum levels of
TGF have been shown to be more elevated in patients
with muscle-invasive cancer than with superficial can-
cer.120 A recent work suggests that preoperative TGF-
beta was an independent predictor of lymph-vascular
invasion, lymph node metastasis, disease recurrence, and
cancer-specific survival.121
Genetic Determinants of Treatment Response
While the cellular components of TCC may someday
elucidate its degree of aggressiveness, these markers may
also serve to predict and determine tumor responsiveness
to systemic chemotherapy. Theoretically, the molecules
critical to cellular proliferation could modify tumor
response by impairing apoptosis and altering cell-cycle
kinetics. Thus, they may provide further prognostic
information for patient management.
The p53 tumor suppressor gene, by preventing pro-
grammed cell death, can enable cells to undergo malig-
nant transformation. Likewise, if certain drugs rely on
p53-mediation to achieve apoptosis, subtle mutations in
p53 may render that bladder cancer line more chemoresis-
tant for those medications. For example, the overexpression
of p53 has been shown to be an independent prognostic fac-
tor for methotrexate, vinblastine, doxorubicin, and cisplatin
(MVAC) failure and decreased survival in patients with T2
or T3a bladder cancer.122 In fact, it has been suggested that
other agents like paclitaxel and gemcitabine be used in blad-
der cancer patients with p53 mutations.123
While some studies predict p53 as a marker for
chemoresistance for certain cytotoxic agents, there have
been equal data to suggest that p53 overexpression is
associated with good treatment response. Some have
identified p53-mutated tumors to respond better to adju-
vant cis-platinum-based chemotherapy prior to cystec-
tomy.56,124 Likewise, there have been several studies that
demonstrate no correlation between p53 expression and
response to chemotherapy. The p53 expression did not
affect response to chemotherapy and did not predict over-
all survival for patients with invasive bladder cancer.125
In summary, the p53 status and response rate are con-
flicting regarding systemic chemotherapy and may
depend on the particular chemotherapeutic agent. One
particular reason for this may be the fact that p53 may be
induced by exposure to chemotherapeutic agents.
Therefore, uniform timing of the sampling and adminis-
tration of the chemotherapy are essential for completely
evaluating this prognostic parameter.
Investigators have evaluated the prognostic signifi-
cance of p53 alteration and overexpression with regards
to radiation therapy as well. As compared to chemother-
apy, there is less evidence to suggest that there is a reli-
able correlation in treatment outcomes. Several groups
have indicated no correlation of p53 status to local con-
trol, delay to metastasis, or overall survival.126–128 Others
have suggested that p53 overexpression is associated with
radiosensitivity,129,130 while yet others have argued for a
correlation between radioresistance and overexpres-
sion.131 These varying reports indicate that p53 is not a
reliable prognostic indicator for response to radiation
therapy for invasive bladder cancer.
Another molecule to consider regarding prognosis of
treatment is P-glycoprotein, formerly known as the mul-
tidrug resistance (MDR) gene. Certain cytotoxic drugs
have been demonstrated to be exported from tumor cells
through a multidrug effusion pump. This pump activity
is characterized by expression of P-glycoprotein, and can
theoretically result in decreased efficacy of chemothera-
peutic agents. While the phenomenon of upregulation of
P-glycoprotein has been well documented following sys-
temic chemotherapy for bladder cancer,132 the data con-
cerning drug resistance and P-glycoprotein expression
have been variable.133
Another molecule with possibly some prognostic sig-
nificance for therapy is the intracellular scavenger, glu-
tathione (GSH). GSH has been shown to react with free
cisplatin, thus reducing the intracellular availability of
the drug. The levels of GSH are upregulated in some
lines of TCC and it is possible that this contributes to the
mechanism of cisplatin resistance.134 In other cancer
models, the administration of GSH inhibitors has been
shown to increase response to cisplatin,135,136 but this has
not yet been applied to bladder cancer.
Conclusion
The ultimate importance of the aforementioned data on
clinical decision-making is still unclear. TCCs are clearly
variable and complex. The continued unveiling of the
intricacies of the cancer’s cellular biology will likely one
day help determine prognosis and direct appropriate ther-
apy. For now, the knowledge produced from investiga-
tions of the past will more specifically direct future clinical
studies, thus, making them more clinically applicable.
RADICAL CYSTECTOMY
Radical cystectomy remains the gold standard therapeu-
tic option for patients with muscle-invasive bladder car-
cinoma, and in the U.S., it is the most common
treatment option. Despite alternatives that may appear
appealing and may be appropriate for certain individuals,
surgical removal still provides local control and chance
344 Part IV Bladder
for cure, to which other treatments attempt to compare
themselves.
Preoperative Evaluation and Preparation
Patients with invasive bladder cancer often are elderly
with significant competing comorbidities who require
careful preoperative evaluation, and it is often the sur-
geon’s responsibility to ensure that an appropriate work-
up has been performed. Recently, Miller et al.137 have
demonstrated an association between comorbid illness
and adverse pathological and survival outcome following
radical cystectomy. It is ultimately the surgeon’s respon-
sibility to try and optimize the patient’s health status
prior to cystectomy, and to determine if a patient is not a
candidate for major surgery. It is important to realize that
the goal of the preoperative assessment is to assess risk
among these potential surgical candidates. Several
reports have now confirmed the procedure that it can be
performed safely with acceptable morbidity among the
elderly, including those with high perioperative
risk.138–140 Despite more “conservative” approaches, such
as bladder sparing, age and even comorbidities should
not be used as absolute deterrents when considering rad-
ical cystectomy as therapy for a potentially lethal cancer.
Patients are seen preoperatively by an enterostomal
nurse for counseling and optimal stoma site marking.
This is recommended regardless of diversion type
planned in the event that an orthotopic diversion is not
technically feasible or contraindicated. Prior to surgery,
patients undergo a mechanical and antibiotic bowel
preparation usually performed in the outpatient setting
after 1 to 2 days of a clear liquid diet. Patients are rou-
tinely admitted on the day of surgery with an estimated
length of stay of between 5 and 7 days.
Radical Cystectomy in Males
Radical cystectomy is the standard treatment in the sur-
gical management of male patients with muscle-invasive
bladder cancer.141 In a male, the prostate and seminal
vesicles are removed routinely along with the bladder and
is the equivalent of an anterior exenteration. Reasons for
routine removal of the prostate include direct extension
of the bladder cancer into the prostatic urethra, as well as
prostatic ductal or stromal involvement. There is also a
risk of secondary malignancy, namely, prostatic adeno-
carcinomas, which has been detected in up to 40% of
specimens in historical series.142,143
Recently, however, a series of 100 men who under-
went prostate sparing at the time of radical cystectomy
was reported.144 After careful patient selection, patients
underwent TUR of the prostate with frozen section
analysis at the time of cystectomy. In the absence of can-
cer in the TUR specimen, local recurrence occurred in
4.5%, 5%, and 8% of men with pTa/T1, pT2, and pT3,
respectively. At 1-year follow-up, 97% are fully continent
during the day and 95% are continent at night.
Additionally, 82% of patients maintained potency with
retrograde ejaculation due to the TUR, while 10% are
partially potent and 8.1% are impotent. Clearly, long-
term follow-up will be required to ensure continued
excellent cancer control. As with other carcinomas, the
importance of achieving a negative surgical margin is
paramount to obtaining local cancer control and should
not be compromised.145
A better understanding of the anatomic relationships
of the neurovascular bundles with respect to the prostate
combined with improved surgical technique has led
to major improvements in functional outcomes.146
Retaining potency in men following radical cystectomy is
also technically feasible and involves careful attention to
the area of the prostatic pedicles, where nerve bundle
injury is most likely.147–149 Currently, it has been reported
that potency is preserved in about 50% of men with
nerve-sparing techniques and there has been no apparent
compromise in cancer control.149
Urinary reconstruction following cystectomy involves
the reconnection of the ureters to an intestinal segment
that allows for the drainage of urine. There are essen-
tially three methods in which this can be accomplished:
an ileal conduit, a continent cutaneous reservoir, or an
orthotopic urinary diversion. Historically, the majority of
patients underwent an ileal conduit, an incontinent form
of urine drainage. Over the past decade, however, conti-
nent urinary diversions, especially orthotopic bladder
reconstruction, have evolved from experimental surgery
to become a commonly preformed method of urinary
diversion. The detection of cancer in younger patients,
the desire to maintain a normal body image, and the real-
ization that quality of life can be improved by maintain-
ing near-normal function after radical surgery, and
improved surgical techniques have all contributed to the
realization that continent urinary diversion is an option
for a significant percentage of patients.150,151
Patient selection criteria include both patient factors
and cancer factors. Relative contraindications to ortho-
topic urinary diversion include renal insufficiency (serum
creatinine > 2 ng/dl), hepatic dysfunction, and the inabil-
ity to perform self-catheterization should the need arise.
An absolute contraindication in a male patient is the
inability to achieve a negative cancer margin in the prox-
imal urethra (prostatic apex). Although controversial, age
alone is not a contraindication to orthotopic diversion
and thus can be performed judiciously in men over the
age of 70 years, and even in men with significant comor-
bidities.152 Prior pelvic radiation therapy is again a rela-
tive contraindication; however, there have been reports
of successful orthotopic diversion in the setting of salvage
cystectomy for failed radiation.153
 Chapter 19 Prognosis and Management of Invasive Transitional Cell Carcinoma 345
Increasing experience has expanded the possible appli-
cability of orthotopic diversion. The impact of local recur-
rence on ileal neobladder function and survival was recently
reported in a series of 357 men.154 Local recurrence devel-
oped in 43 patients (12%). Of the 43 patients with local
recurrence at follow-up, 36 had local advanced cancer on
the final pathological evaluation (stage pT3a or node-posi-
tive or greater), yet 40 maintained good neobladder func-
tion. The neobladder was removed only in 1 patient due to
a neobladder to intestinal fistula. These data imply that
most patients may anticipate normal neobladder function
even in the presence of recurrent disease or until death. In
addition, although it is unclear what the real likelihood is,
the retained urethra in any form of urinary diversion must
be carefully followed as a possible site of recurrence.
Orthotopic neobladder construction involves the cre-
ation of an internal reservoir from some segment of bowel,
most commonly this is 45 to 60 cm of ileum, detubularized
and fashioned in either a “W configuration” (Hautmann)
or “U shaped or J shaped” (Studer).150,155 While in the past
there was a fear that orthotopic diversion would be associ-
ated with significantly higher rate of complication as com-
pared to an ileal conduit, recent reports suggest that in
properly selected patients the early complications rates are
similarly acceptable.151,156
The functional results following orthotopic urinary
reconstruction have been excellent. Daytime urinary
continence rates range from 80% to 95% with differ-
ences largely due to definition of continence, methods in
which the data are obtained, and length of follow-
up.157–160 Nighttime continence is more problematic,
with rates of 65% to 85% reported. The incidence of
hyper-continence or urinary retention requiring self-
catheterization is approximately 3% to 5%. Men should
be counseled preoperatively that while most men are
continent in the day, they may experience some degree of
incontinence at night and a protective pad may be
required. Overall patient satisfaction with orthotopic
neobladder substitution remains high with >95% of
patients satisfied with their choice of diversion.161
Radical Cystectomy in Females
In women, radical cystectomy for muscle-invasive blad-
der cancer has historically been the equivalent of an ante-
rior exenteration. This includes removal of the uterus,
fallopian tubes, ovaries, bladder, urethra, and a segment
of anterior vaginal wall. This remains the gold standard.
However, early detection combined with a desire to
improve the functional outcomes, including sexual abili-
ties and urinary control, has led surgeons to modify their
techniques in selected patients, where preservation of
disease-free urethra is possible.
Although the majority of women still undergo ileal
conduit urinary diversion or continent cutaneous diver-
sion, orthotopic urinary diversion has become increas-
ingly viable as an option. Stein et al.162 and others subse-
quently have demonstrated the oncologic safety of
orthotopic reconstruction in properly selected female
patients. Exclusion criteria for orthotopic neobladder
reconstruction include tumor involving the bladder neck,
diffuse CIS, and a positive bladder neck margin at the
time of radical cystectomy.162 In addition, females with
large, palpable tumors along the anterior vaginal wall are
not appropriate candidates. In properly selected patients,
local recurrence rates have been extremely low and func-
tional outcomes have been comparable to those reported
among male patients.163–167
The technique and outcomes of orthotopic diversion
in females have been well described.164,165 These techni-
cal refinements include avoidance of overlapping suture
lines, the interposition of a vascularized omental pedicle,
and preservation of the anterior vaginal wall.163 In
patients with nonpalpable tumors, the plane between the
posterior bladder wall and the anterior vaginal wall can
be developed while ligating the posterior-lateral pedicles.
The plane is developed to the level of the bladder neck,
and the anterior and posterior dissections are connected
with preservation of the bladder neck.
It was recently reported that there is a very low inci-
dence of secondary gynecologic malignancies at the time
of cystectomy.168 In this series, only a single gynecologic
malignancy was found and involvement of the uterus by
direct extension of bladder cancer was discovered in only
2 patients, both of whom had clinical suspicion based on
bimanual examination or preoperative imaging. Thus, in
most women, the risk of gynecologic involvement of uro-
logic malignancy is small and can usually be determined
either preoperatively or at the time of surgery. The
potential for improved functional outcomes and quality
of life through preservation of gynecological organs, par-
ticularly among young women with invasive bladder can-
cer, is currently an area of ongoing research, and these
younger women are more likely to be concerned about
preservation of fertility and continuation of normal hor-
monal status.169
In properly selected patients, functional outcomes
have been comparable to those reported among male
patients.163–167 Daytime continence rates range from
70% to 95%, with high rates of overall satisfaction.
There may be a higher rate of urinary retention regard-
ing intermittent catheterizations, and all patients
undergoing diversion should receive preoperative
counseling regarding this, as well as other possible
complications.
Role of Lymphadenectomy
Although it has long been a standard part of radical cys-
tectomy, pelvic lymph node dissection has garnered more
346 Part IV Bladder
attention recently. This is derived in part from data
demonstrated long-term disease-free survival among
node-positive patients and benefit implied from the com-
pleteness of the lymph node dissection. It has been pro-
posed that the therapeutic benefit of lymphadenectomy
may be extended beyond the confines of the traditional
pelvic template arguing in favor of a more extended node
dissection.47,170,171 Recent studies have proposed that the
actual number of nodes harvested may play a role in
patient outcomes, and the greater the lymph nodes
removed the better the survival.172,173
The concept of lymph node density, defined as the
total number of positive lymph nodes divided by the total
number of lymph nodes removed, has recently been
reported to be an important prognostic indicator among
patients with node-positive bladder cancer.174 The bene-
fit of an extended dissection may be derived from both
the removal of clinically apparent pathologic nodes
and/or from undetected micrometastatic disease. Future
studies that carefully document the overall number and
location of lymph nodes removed (mapping) along with
the number and location of positive nodes removed at the
time of cystectomy using defined templates of dissection
and possibly molecular staging will be important.
Outcomes of Radical Cystectomy
The long-term efficacy of radical cystectomy among
patients with invasive bladder cancer has been demon-
strated in terms of local control and disease-specific sur-
vival. Numerous series have demonstrated excellent local
control and excellent 5- and 10-year survivals for patients
with invasive bladder cancer treated with cystec-
tomy.149,175–178 Long-term survival is best among those
with organ-confined disease, and consistently 5-year sur-
vival is >70%.47,179,180
The presence of locally advanced or lymph node
metastases is associated with a high rate of recurrence
and argues in favor of combined neoadjuvant or adjuvant
chemotherapy. In the largest contemporary series to
date, investigators at the University of Southern
California (USC) recently reported results in 1054
patients with a median follow-up of 10.2 years.47 In this
series, the overall recurrence-free survival at 5- and 10-years
was 68% and 60%, respectively. In patients with muscle-
invasive disease (P2a and P3a), lymph node negative
tumors had 89% and 87%, and 78% and 76% 5- and 10-year
recurrence-free survival, respectively. In patients with
nonorgan-confined bladder cancer (P3b, P4), lymph
node-negative cancer demonstrated a significantly higher
probability or recurrence with 5- and 10-year recur-
rence-free survival rates for P3b tumors were 62% and
61% and for P4 tumors were 50% and 45%, respectively.
Clearly, these data support the aggressive surgical man-
agement of invasive bladder cancer. Durable local control
can be achieved with excellent long-term survival
afforded as well.
Complications of Radical Cystectomy
Despite significant decrease in overall mortality and
morbidity rates associated with cystectomy, complica-
tions can occur as an exacerbation of the patients preex-
isting comorbid conditions, arising from the bladder
removal and those arising from the use of an intestinal
segment. The mortality rate for radical cystectomy
remains 1% to 2%, with a an overall early complication
rate of about 25% to 30%.47,140,181–183 In one recent
series of 304 patients, the overall major and minor com-
plication rates were 4.9% and 30.9%, respectively, within
the first 30 days.184 Postoperative ileus was the most
common minor complication, affecting 18% of patients,
which resolved with conservative management in all
cases. Despite these improved results, the serious life-
threatening major complications, such as pulmonary
emboli, myocardial infarction, and stroke, do occur and
prompt recognition with appropriate intervention may
avoid mortality.
Radical cystectomy has been associated with significant
blood loss and/or transfusion requirement, and compli-
cating the surgical treatment of these patients is the sig-
nificant number that have preoperative anemia. In one
series, 45% of patients had anemia preoperatively.
Median estimated blood loss was 600 ml (range 100 to
3000). Increased estimated blood loss was related to
patient age; American Society of Anesthesiologists (ASA)
score longer operative time and paralytic ileus. Overall,
transfusion was required in 30% of patients with a median
requirement of 2 units (range 1 to 10). The transfusion
rate in male and female patients was 26% and 40%,
respectively.185 These data support the need for continued
refinement in surgical techniques designed to decrease
blood loss, as well as for strategies designed to lower the
need for blood transfusion during radical cystectomy.
Role of Chemotherapy: Neoadjuvant Versus
Adjuvant
The rationale for including chemotherapy regimens
before or after radical cystectomy is based on the pre-
sumption that this therapy may increase patient survival.
Clearly, TCC is a chemosensitive malignancy and
patients with metastatic disease can achieve a long-term
cure.186–189 Even patients with large, bulky unresectable
disease that cannot be cured by surgery alone can survive
with the addition of chemotherapy for their treatment.190
Neoadjuvant chemotherapy in patients with advanced
disease is becoming increasingly touted as the possible
standard approach. This is based largely on two recent
trials that have reported a benefit. An intergroup trial
 Chapter 19 Prognosis and Management of Invasive Transitional Cell Carcinoma 347
conducted by the Medical Reserve Crops (MRC) and the
EORTC is the largest randomized trial (976 enrolled
patients) examining neoadjuvant chemotherapy (CMV).
The patients underwent some form of localized therapy
(cystectomy alone, radiation therapy alone, or cystec-
tomy and radiation therapy) after 3 cycles of CMV.
Although initially there was no survival difference, the
updated results did demonstrate a survival difference
in those patients receiving neoadjuvant chemotherapy
(p = 0.048).191 The second large trial that took almost
10 years to enroll its 307 patients was the SWOG-initiated
Intergroup 0080 trial.192 The results are compelling; but
as in most trials, criticisms can be made of methodology,
as well as interpretation of results. The SWOG study uti-
lized a one-sided testing and when two-sided hypothesis
testing was performed, there was no statistical advantage
in survival with neoadjuvant chemotherapy. Other stud-
ies that in themselves had viable criticisms have not
demonstrated a survival benefit.193–195
Arguments exist for both approaches when consider-
ing chemotherapy regimens. With adjuvant chemother-
apy, there is better pathologic staging and assessment of
true disease burden within each patient.196 Recently,
Herr et al.197 updated the Memorial Sloan-Kettering
experience with postchemotherapy surgery in patients
with unresectable or lymph node positive bladder can-
cer. Of 207 patients with unresectable or regionally
metastatic bladder cancer, 80 (39%) underwent
postchemotherapy surgery after treatment with a cis-
platin-based chemotherapy regimen. No viable cancer
was present at postchemotherapy surgery in 24 of the 80
cases (30%), pathologically confirming a complete
response to chemotherapy. Of the 24 patients without
residual cancer, 14 (58%) survived 9 months to 5 years
after salvage surgery. Residual viable cancer was com-
pletely resected in 49 patients (61%), resulting in a com-
plete response to chemotherapy plus surgery and 20
(41%) survived.
Unfortunately, randomized trials with small numbers
have given mixed results. The two studies that did not
show a benefit to adjuvant chemotherapy examined non-
metastatic disease patients.198,199 Stockle et al.200 reported
on 166 patients and demonstrated that those patients
most likely to gain benefit from immediate chemotherapy
were those with small volume lymph node involvement.
Trials are currently in progress, including an examination
of the impact of p53 status. Other trials looking at more
advanced and node-positive patients are also accruing
patients, including an EORTC trial examining surveil-
lance versus immediate chemotherapy (M-VAC or gemc-
itabine plus cisplatin) after surgery. The CALGB 90104
study treats all patients with extravesical and/or node-
positive disease with a cis-platinum-based regimen.
As with any treatment modality, proper patient selec-
tion is essential but in TCC it can be difficult. Delaying
radical cystectomy in itself clearly has a negative impact
on patient pathology and survival.201–203 This negative
impact on delay is true even in patients who undergo
some type of therapy, such as radiation therapy, as veri-
fied by better survival in patients who undergo early cys-
tectomy as opposed to late cystectomy.204
BLADDER-SPARING THERAPY: A MULTIMODALITY
PARADIGM
Rationale for Bladder Preservation
In certain patients, radical cystectomy may not be the
best option, and bladder preservation strategies for the
treatment of invasive cancer have evolved for several rea-
sons. Advances in the treatments of other malignant
processes, such as breast and esophageal cancer, have
demonstrated the effectiveness of this strategy. In bladder
cancer, the majority of patients with recurrent and
metastatic disease die of disease that is distant in location
as opposed to local. In addition, despite its accepted stan-
dard as the treatment of choice, radical cystectomy does
not ultimately result in a cure in a large number of
patients and still represents a significant operative proce-
dure with associated complications. Many bladder cancer
patients are elderly, and although the number is decreas-
ing with improvements in surgical techniques and peri-
operative care, there are patients who are “too ill” to
undergo radical cystectomy.
Although this approach has its appeal it remains only
an option, and radical cystectomy continues to be the
standard treatment of choice. Survival data for bladder-
sparing approach presented in a certain light can first
appear promising, but it is difficult to compare directly
how patient survival rates differ between bladder-sparing
regimens and initial radical cystectomy. This is especially
true when a significant number of patients do eventually
require cystectomy, which is in fact only delayed by the
bladder sparing approach. This strategy often requires a
multitude of visits to different physicians requiring often-
invasive procedures to attempt to monitor closely the
patient’s condition and tumor status. In addition, blad-
der-sparing protocols are not in themselves inherently
risk-free and have associated possible complications. To
date, no prospective randomized trial has been per-
formed comparing a multimodality bladder-sparing
approach with radical cystectomy.
Single Modality Approaches
The success of TUR as a single modality has been used
for many years depends on clinical stage and proper
patient selection. Although an option, TUR alone can-
not adequately treat the majority of patients with inva-
sive carcinoma. Barnes et al.205 reported a 27% 5-year
survival in patients with T2 bladder cancer. In highly
348 Part IV Bladder
selected series, 5-year survival rates have varied but
have been as high as 67% in patients still with their
bladder.206–208
Clearly, this approach is predicated on accurate evalu-
ation and staging of the true and limited extent of muscle
invasion. Even after repeated resections, however, occult
invasive disease may still be present that would not be
adequately treated by TUR alone.209 A single TUR, thus,
would be an inadequate therapy. One of the major pitfalls
to only endoscopic management of these tumors is the
continued limitations of clinical understaging, which is
present in 30% to 50% of cases.17 This is also true in
patients treated with radiation therapy or neoadjuvant
chemotherapy.196,210 In a selected few patients with lim-
ited disease of minimal depth and with no residual dis-
ease on repeat resection, this modality does have a role.15
By extending the boundaries of TUR, another blad-
der-sparing therapy approach using surgery is partial cys-
tectomy. Once again, this approach could be advocated
in a limited group of patients. Those patients who may
be reasonable candidates would include small, single
tumors, away from the trigone without related
CIS.211–213 Although bladder capacity may be enough to
maintain normal voiding patterns, this remaining bladder
tissue serves as an area for recurrent disease or previously
unrecognized disease. Localized recurrence in the form
of new tumors or recurrent tumors occur anywhere
between 15% and 75% of the time.211,212,214 This form of
therapy should not be accepted as a standard treatment
choice.
Radiation therapy as a single modality is commonly
employed in Europe and has been studied in the U.S.
Conventional radiation therapy has local control rates of
30% to 50%.215–218 At M.D. Anderson, 135 patients were
treated with primary external beam radiation therapy,
with a 26% 5-year survival rate. Those patients with
more advanced disease had a poor survival rate and less
than a third achieved long-term local control.219 Similar
survival rates have been demonstrated overseas.220,221
Patients who receive monotherapy radiation treat-
ment tend to be older with greater comorbidities. But
significant side effects, such as radiation cystitis, cannot
be ignored.222 Unfortunately, as opposed to TUR or par-
tial cystectomy, any type of salvage surgery is difficult, in
one large series, <30% of patients who did not achieve a
complete response to radiation underwent salvage cystec-
tomy.215 Radiation as the only primary therapy has not
been considered as equal treatment modality to cystec-
tomy. Similarly, the role of chemotherapy continues to
evolve but in no way should it be considered as a single
treatment choice or as an acceptable alternative treat-
ment choice to cystectomy. It cannot consistently eradi-
cate the primary bladder tumor. This is the case even
when there is an impressive response to disease outside of
the bladder.
Multimodality Approach
Single modality bladder-sparing therapy for muscle-inva-
sive bladder cancer, including TUR, partial cystectomy,
systemic chemotherapy, or radiation therapy have been
demonstrated to result in insufficient local control when
compared to cystectomy.223 In an attempt to maximize
the efficacy of less invasive approaches and overcome
their deficiencies, bladder-sparing approaches have com-
bined different strategies to offer a comparable alterna-
tive to radical cystectomy. This inclusion of more than
one approach seems to offer better oncologic cure rates
and achieves bladder preservation at a higher rate than a
single treatment choice.193,224–228 TUR and radiation
therapy hopefully provide local control with chemother-
apy providing a synergistic additive component and
treating possible micrometastatic disease.
Multiple variations of treatment algorithms have been
studied. This large number of studies makes comparisons
difficult. In general, however, after patients are diagnosed
with muscle-invasive bladder cancer, they undergo “com-
plete” resection of their tumor for local control, as well
as attempting as accurate staging as possible. This is then
followed by chemotherapy and external beam radiation.
Oftentimes, the chemotherapy includes a platinum-based
radiosensitizing chemotherapeutic agent (e.g., cisplatin).
Patients are then carefully reevaluated by repeat cys-
toscopy and TUR. Only those patients with a complete
response are candidates for continued bladder-sparing
approach; those without complete response are recom-
mended to undergo radical cystectomy. If bladder spar-
ing is viable, patients receive additional radiation and
chemotherapy with continued careful surveillance by cys-
toscopy, physical exam, and radiographs.
Outcomes of Bladder-Sparing Approach
Approximately 40% of patients survive 5 years with a
bladder-sparing approach.193,224–228 In one of the largest
randomized trials evaluating the role of chemotherapy in
multimodality bladder preservation, the Radiation
Therapy Oncology Group (RTOG) reported an overall
49% 5-year survival with an intact functioning bladder in
38%.193 The local recurrence rate in this series was 28%,
and the study was stopped prematurely due to severe
complications from the chemotherapy, including
3 deaths. Among these patients treated with bladder
preservation strategies, life-long surveillance is required
not only to monitor for progressive disease but also for
superficial recurrences that may culminate in cystectomy
in up to a third of these patients.229 Importantly, recur-
rence can occur after 5 years of disease-free survival.
Also, induction treatment many times is not successful as
up to 40% have an incomplete response and are recom-
mended to undergo cystectomy.193 One recent study of a
 Chapter 19 Prognosis and Management of Invasive Transitional Cell Carcinoma 349
bladder-sparing approach, although not prospectively
randomizing patients, did find better overall survival in
those patients who did at some point undergo cystectomy
(65% versus 40%).230
Complications of Bladder-Sparing Approach
Bladder-sparing approaches may also be associated with
adverse therapy-related side effects that can result in sig-
nificant morbidity that negatively impacts on quality of
life. Many patients cannot complete the recommended
protocol of chemotherapy because of toxicity. This
include nausea, fatigue, neutropenia, and GI complaints,
such as diarrhea in up to 70% of patients.193 Also, there is
mortality associated with only the induction portion of
this algorithm (4% in one series193). This is actually a
higher mortality rate than most cystectomy series.
Furthermore, the long-term effects of these multimodal-
ity therapies may result in significant increased morbidity
among those patients who demonstrate recurrent or pro-
gressive disease and ultimately require radical cystectomy.
One important point is that although a patient may toler-
ate the chemotherapy and radiation changes to the blad-
der, symptoms that the patient may have caused by the
disease process and/or previous therapy (e.g., TURBTs,
intravesical therapies) are not at all altered or improved by
bladder sparing. Such bladder dysfunction may be better
addressed by bladder removal and urinary diversion. In
addition, bowel symptoms and effect on small bowel and
the rectum must also be considered. Moderate or severe
symptoms can affect up to one-third of patients.231
In its present form, multimodality therapy aimed at
bladder-preservation is best performed at select centers
that have a dedicated and cooperative multidisciplinary
team that can provide these patients with close clinical fol-
low-up. Patients should also be made aware of the selec-
tion criteria and specifics of the associated with the various
treatment protocols, including cost, before making an
informed decision. Finally, the results of these various
strategies should be objectively balanced against the results
of contemporary radical cystectomy and orthotopic diver-
sion. Attempting to spare the bladder requires complex
and constant surveillance and assessment of patient status.
There has to be a coordinated effort between patient and
a number of disciplines, including surgery, radiation
oncology, and oncology. This requires a dedicated effort
by a team approach.225 Although not a primary concern,
this approach is costly regardless of preservation of the
bladder or ultimately requiring cystectomy.232
Quality of Life Concerns
Increasingly, health-related quality of life (HRQOL) has
been recognized as an important outcome measure fol-
lowing the treatment of urologic malignancies. For many
patients, quality of life may be as important as length of
life or survival. Furthermore, among the long-term sur-
vivors of cancer therapy, the impact of cancer treatment
on the HRQOL is even more profound, especially with
radical cystectomy, one of the most potentially stressful
and life-altering.233 One of the key reasons for bladder
sparing approach is an attempt to avoid the morbidity
and possible complications associated with loss of the
bladder. Patients oftentimes do maintain adequate blad-
der function after chemotherapy and/or radiation, but
the different types of urinary diversion now available
make cystectomy and urinary diversion at least somewhat
more acceptable if not desirable.231,234
Although more studies have been performed examin-
ing the impact of cystectomy on quality of life, many of
these are inherently flawed.161,235–239 Most of these stud-
ies have compared quality of life in patients undergoing
various types of urinary diversion and have been criti-
cized for flaws in methodology. In addition, most are ret-
rospective and so the actual quality of life comparison
from baseline is not known. Also, as investigators have
started realizing the value of validated instruments when
gauging outcome after treatment,233,240 it has become
clear that one does not yet exist for bladder cancer. It is
important, therefore, to keep in mind that despite the
perception that patients with neobladders enjoy a better
quality of life compared to those with ileal conduits, the
definitive study remains to be performed.228 Large,
prospective longitudinal studies using both generic and
disease-specific validated instruments are required.
SUMMARY
The diagnosis and treatment of muscle-invasive TCC
continues to evolve. With each patient, multiple issues
including patient selection, complexity of care, cost, sur-
vival outcomes, and quality of life measures must be care-
fully evaluated. An improved understanding of tumor
biology coupled with a multimodality approach treat-
ment strategy will hopefully provide continued improved
results. Radical cystectomy currently remains the gold
standard for patients with invasive bladder cancer; and
modifications of surgery, urinary diversion, and perioper-
ative care continue to translate into improved quality of
life for patients. Continued research to discover and val-
idate accurate tumor markers will provide further benefit
for these patients.
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208. Henry K, Miller J, Mori M, et al: Comparison of
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C H A P T E R
20 Transurethral Surgery of Bladder
Tumors
Rabi Tiguert, M.D., Louis Lacombe, M.D., F.R.C.S.C.,
and Yves Fradet, M.D.
Cancers originating from the urothelium are responsible
for 8% of all diagnosed tumors in men and 4% in women.
In the United States alone, this corresponds to more than
56,000 new cases yearly,1 transitional cell carcinoma
(TCC) accounting for approximately 90% of all cases.2 At
the time of diagnosis, about 80% of bladder tumors are
superficial and limited to the mucosa or submucosa (Ta,
T1), while 20% invade the muscular layer of the bladder
wall. In recent cohort studies of patients newly diagnosed
with Ta, T1 tumors, a 55% recurrence rate was observed
within 3 years,3,4 but previous studies had reported up to
70% recurrence within 5 years of the initial diagnosis.5
The majority of these recurrent tumors will remain super-
ficial and progression to muscle invasive or metastatic can-
cer will occur in <10% of recurrent cases. These statistics
underscore the overall importance of transurethral surgery
as the primary and often only treatment modality for blad-
der cancer. Obviously, intravesical immunotherapy and
chemotherapy have become important therapeutic modal-
ities to prevent recurrence and progression of superficial
bladder tumors. Nevertheless, the quality of the
transurethral surgery has an important influence on the
risk of tumor recurrence, since up to 41% of recurrent
tumors were reported to occur at the site of the original
resection in the National Bladder Cancer Collaborative
Group study.6 Recent EORTC studies on variability of
recurrence were linked to the experience of the surgeon.
Endoscopic resection or fulguration of bladder tumor is
usually effective, has low morbidity, and is associated with a
rapid postoperative recovery. Transurethral resection
(TUR) is the standard method for the initial diagnosis and
staging of bladder cancer, as well as for the eradication of
low-stage bladder tumor. Some infiltrating bladder cancers
can also be treated primarily by TUR, with or without
adjuvant radiation therapy or systemic chemotherapy.
358
Laser therapy, either as thermocoagulation of bladder
tumors or as photodynamic therapy, is an alternative that
has become part of the treatment armamentarium. Recent
advances in fluorescent cystoscopy may influence visualiza-
tion of tumors and enhance the completeness of resection.
This chapter will review the indications, techniques, and
outcomes of TUR, LASER thermocoagulation, and pho-
todynamic therapy in the management of bladder cancer.
TRANSURETHRAL RESECTION
Preparation
Before TUR of the first tumor, it is mandatory to study
the upper urinary tract either by retrograde pyelogram or
intravenous pyelogram (IVP) to rule out any associated
tumor of the renal pelvis and/or ureters and to identify
any hydroureteronephrosis, which is most often the
result of tumor invasiveness. The IVP is usually normal
in the presence of superficial bladder tumor with the
exception of tumors directly overlying the ureteral orifice
and causing obstruction. About 3% of patients with blad-
der cancer will concurrently or subsequently have an
upper tract urothelial neoplasm. The presence of ureteral
obstruction, particularly in the absence of intravesical
involvement of the ureteral orifices, suggests a high-
stage, muscle-invasive, and metastatic tumor in more
than 90% of the patients. If parameters of the preopera-
tive work-up are suspicious for advanced stage disease or
muscle invasive disease, then computed tomography
(CT) scan of the abdomen and pelvis with injection may
be a suitable alternative to IVP if thin cuts through the
kidney and ureter are obtained. CT scan has the advan-
tage of determining size of the bladder tumor and, to
some extent, presence of local invasion or regional lym-
phadenopathy. Ureteral obstruction is a significant risk

factor of poor prognosis and has been associated with sig-
nificantly lower, overall, and stage-specific, survival rates,
despite radical surgery. More than 90% of patients with
bilateral obstruction had disease with extravesical exten-
sion. One-third of patients with unilateral hydronephro-
sis had disease confined to the bladder, of whom 42% had
tumor confined to the mucosa with no muscle invasion
(p0-p1). These findings suggest that a significant propor-
tion of patients with unilateral obstruction may have
good outcome with cystectomy alone.7
Anesthesia
Following the diagnosis of a bladder tumor, which is usu-
ally made in an office setting, the formal endoscopic eval-
uation, including biopsy-resection, is performed in the
operating room and requires that the patient have an
adequate anesthesia for the pelvic floor and bladder
relaxation and thus a prior consultation with the anesthe-
siologist is required to provide a successful outcome.
Anesthesia could be attempted either with spinal or gen-
eral anesthesia. Other methods of anesthesia have been
reported for removal of small tumors or performing
cold-cup biopsies, including local anesthesia with intrav-
esical instillations of lignocaine or with electromotive
drug administration system (EMDA) that enhances blad-
der wall penetration of lidocaine. This approach has not
been widely accepted.8,9
Bimanual Examination
The bimanual examination is an integral part of the oper-
ative procedure for patients undergoing treatment for
Figure 20-1 Bimanual examination.
Chapter 20 Transurethral Surgery of Bladder Tumors 359
bladder cancer. It is performed with the patient under
anesthesia before tumor resection and should be repeated
after the endoscopic procedure is completed. In the male
patient, the urologist puts a finger in the rectum with the
other hand placed suprapubically and palpates for any
mass (Figure 20-1). In the female patient, bimanual exam-
ination is performed with two fingers in the vagina and
the other hand placed suprapubically. The presence of a
mass should be noted, along with the evidence of indura-
tions or fixation to the adjacent organs or the pelvis walls.
The disappearance of a movable mass after TUR is more
likely consistent with a superficial tumor. When the mass
is fixed or indurated or persists after TUR, it is more
likely to be muscle-invasive tumor. Bimanual examination
cannot distinguish benign from malignant bladder fixa-
tion in patients who underwent previous radiation ther-
apy or had pelvic inflammatory disease.
Instrumentation and Equipment
Several instruments are potentially useful for the surgical
removal of bladder tumors. At the time of the operative
procedure, the urologist should have sufficient lenses,
which consist of either a 12-degree or 30-degree lens, and
a 70-degree lens. On the other hand, several loops may be
available, including the 90-degree loop, which is usually
used for resecting a tumor along the floor of the bladder,
the trigone, or near the bladder neck. The angled loop is
preferable to resect tumors located along the lateral walls,
posterior wall, or dome. The roller or ball electrode is
helpful to achieve hemostasis at the end of tumor resec-
tion and to cauterize small noninvasive papillary tumors
or areas of diffuse carcinoma in situ (CIS).
360 Part IV Bladder
Video Endoscopy
The new generation of endoscopic video equipment is
very attractive and its use is quickly becoming routine in
private and teaching hospitals as instruction during endo-
scopic procedures takes on a new dimension. The advan-
tage of the endoscopic video system is that all of the staff
in the operating room feels that they are taking part in
the procedure, which no longer isolates the urologist
from the other members of the team. The likelihood of
contamination of body fluids is negligible with endo-
scopic video procedures.
Flexible Cystoscope
Flexible cystoscope is often used for the initial diagnosis
and follow-up of patients with bladder tumors in the
office setting. It has less discomfort than rigid endoscopy
especially in men. The entire urinary bladder mucosa can
be examined with a single instrument, as well as bladder
neck, by retrograde view. Small laser fibers or Bugbee
electrode devices can be inserted through a flexible
cystoscope to allow destruction of small, low-grade, non-
invasive papillary tumors in the office setting.
Cold-Cup Biopsy
Cold-cup biopsy is used primarily to remove papillary
tumors or to sample multiple areas of the bladder
mucosa. The small size of the cup limits its indication to
tumors generally <0.5 cm. Biopsy forceps exist for flexi-
ble cystoscope but most often a rigid cystoscope is used.
The cup is closed over a papillary tumor, and with a
twisting and pulling motion, the tumor is avulsed from
Figure 20-2 Transurethral resection of a bladder tumor.
the bladder wall.10 Some cup biopsy forceps have an
attachment for electrocautery that allows immediate
coagulation of the bladder wall. A Bugbee electrode or
resectoscope or roller may be used to cauterize bleeding
vessels.11 Suspicious erythematous areas for CIS can be
sampled by cold biopsy. There is almost no risk of blad-
der perforation, and the absence of electrocautery during
removal helps preserve the architecture of the urothe-
lium for pathology evaluation. The role of a cold-cup
biopsy in normal appearing areas of the bladder is con-
troversial.
Technique for Transurethral Resection
The first step of TUR is to visualize the whole bladder
mucosa, the trigone, ureteral orifices, bladder neck, and
prostatic urethra (Figure 20-2). Sometimes it is difficult
to visualize the dome especially in obese patient. In such
circumstances, suprapubic manual pressure toward the
resectoscope should be applied, the mucosa in the begin-
ning of bladder filling is to be observed. The second step
includes the report of any abnormality, such as erythe-
matous areas, that could correspond to CIS or dysplasia.
In our institution, we used a diagram to report the loca-
tion, appearance (papillary or sessile), and size of all
tumors, which is a part of the patient’s record. The sites
of mucosal biopsies are also recorded on the diagram, as
well as all the observed abnormalities during cystoscopy
were also noted. Photographs of initial tumors and
abnormal areas can be taken in order to be compared
with the recurrent one. Following endoscopy, a resecto-
scope is used to remove all visible tumors. A continuous
flow resectoscope has the advantage to maintain the

bladder at a reduced capacity and thus minimize the risk
of bladder perforation or stimulation of the obturator
nerve. A 70-degree lens is used prior and after tumor
resection to review the bladder, since there are locations
in the bladder that are difficult to visualize with the
12-degree or 30-degree lens used with a resectoscope. After
the resectoscope has been inserted, the resecting loop
should be readily visible and the instrument should be
checked for full excursion of the loop. The resecting loop
should be passed beyond the tumor and then pulled back
toward the viewing eye while applying the electrocautery.
At some point, it is necessary to maintain the resecto-
scope loop in an extended fixed position and to move the
resectoscope downward with a rocking motion parallel to
the base of the tumor, similar to scraping a wall. Constant
orientation is necessary during these maneuvers. With
papillary tumors, the resecting loop is often used to ele-
vate the tumor off the bladder wall before application of
the electric current. The base of bladder tumors with
small pedicle can often be resected in a whole piece. In
larger tumors, however, early attempt to resect its base
will result in a nonfixed tumor rendering the resection
difficult. Resection of bladder tumors should ideally be
performed in two steps: resection of the tumor and its
base, which must include muscle wall. Care should be
taken to limit coagulation artifact on the specimen for a
better pathologic analysis. In patients with possible mus-
cle invasive tumors or suspicion of CIS, a TUR of the
prostatic urethra should be performed to rule out CIS
or intraductal neoplasia in the prostate. Such information
is important for counseling the patient in planning
intravesical therapy, or cystectomy with orthotopic
neobladder. Prostatic urethral sampling could be
attempted either with superficial resection immediately
proximal to the verumontanum on both sides at 5 and
7 o’clock, or by resection of the whole prostatic urethra
for a complete sampling if cystectomy with prostate spar-
ing is indicated.12
Irrigation Fluid
The choice of irrigation fluid is important during a TUR
of a bladder tumor, because of problems with electrical
conduction, saline solution should not be used. The
amino acid solutions used for TUR of the prostate are an
option but are expensive and unnecessary, since the
absorption of large amounts of irrigation fluids is rarely
encountered with bladder tumor resection. Sterile water
or isotonic irrigation fluid are mostly used.
Management of Intraoperative Problems
Some tumors may be difficult to resect because of their
location, such as anterior bladder wall tumors, especially
those located close to the bladder neck. By using differ-
Chapter 20 Transurethral Surgery of Bladder Tumors 361
ent techniques, a better exposure of these tumors could
be obtained. By pushing down the anterior lower wall of
the abdomen with the opposite hand, these tumors are
usually brought to a better view. An assistant can carry
out this manipulation if the surgeon prefers the two-
handed instrument. However, even with the use of a
long resectoscope, such tumors may remain inaccessible
in a morbidly obese patient. In this uncommon setting,
the resectoscope can be inserted by a perineal urethros-
tomy performed in the bulbar urethra over a metal
sound to circumvent the suspensory ligament of the
penis. After the TUR a Foley catheter is inserted into
the penile urethra or through the perineal urethrostomy,
which heals within 24 hours of removal of the catheter.
Another method to remove these anterior bladder wall
tumors has been described, which consists to perform a
2-cm incision in the skin that is deepened by blunt dis-
section to the fascial level. A nasal speculum is used to
refract the fat and allow an incision to be made on the
fascia. A finger is inserted to localize the bowel. A peanut
or empty sponge stick holder is introduced through the
opening and the TUR began with control of the tumor
position. This technique has been used in 9 patients by
the author who reported this technique. It is mandatory
to carry out the TUR with usual precautions to avoid
bladder perforation.13
Deep resection in the bladder neck area must be care-
fully performed. In females, TUR in such areas can cre-
ate a vesicovaginal fistula. In men, it may result in
trigonal undermining hampering further resection and
even bladder catheterization. If an undermining trigone
is apparent at the end of surgery, the catheter should be
inserted with the help of a catheter guide.
Tumors involving the ureteral orifice occur in approx-
imately 10% to 15% of cases. Noninvasive tumors should
be resected aggressively and resection may be pursued to
remove the whole intramural ureter if a papillary tumor
is found to extend in this area. Complete resection of a
noninvasive papillary tumor will leave a bulging ureteral
mucosa. To prevent stenosis of the orifice, fulguration
and coagulation should be minimized in this area. If
extensive coagulation is required or the ureteral mucosa
does not appear to protrude satisfactorily, a ureteral
catheter should be placed for a few days to allow initial
healing and prevent ureteral obstruction. Resection of a
ureteral orifice and the intramural portion of a ureter will
result in vesicoureteral reflux. While reflux may increase
the risk of upper urinary tract seeding, it also allows pas-
sage of endovesical immunotherapy or chemotherapy
and ensuing preventive effect.
TUR of tumors arising in an acquired bladder diver-
ticulum is limited, since the absence of an underlying
muscular component will result in a perforation. Only
small superficial tumors should be resected or fulgurated
in a diverticulum with a wide mouth. Otherwise, we can
362 Part IV Bladder
rely on laser therapy or intravesical immunotherapy or
chemotherapy. If there is a doubt or a persistent tumor, a
diverticulectomy by an extravesical approach should be
performed after proper control of any present tumor.
The goal of TUR treatment for superficial bladder
tumors should be complete eradication of the tumors. If
there are numerous tumors or bad visibility hampered by
uncontrolled bleeding, surgery should be aborted and
resumed 1 or 2 weeks after. Laser therapy and endovesi-
cal therapy may be an option for residual superficial blad-
der tumors.
Sometimes, concurrent benign prostatic hyperplasia
may be too large or protruding into the bladder and thus
impeding TUR of bladder tumors. Ideally, the bladder
tumor should be resected first and allow the healing
before the prostate is resected in order to prevent tumor
seeding in the prostatic fossa. In rare instances, the resec-
tion of the prostatic lobe is performed prior to the blad-
der tumor. There is a lack of increase of transitional cell
tumors seeding of the prostatic fossa in previous reports
when concomitant TUR of bladder tumor and prostate
were performed. Mitomycin C has been shown to
decrease the likelihood of bladder tumors seeding and it
may be safe to administer a single instillation of 40 mg
after the surgery.
Second Look Resection
On occasion, the pathologist will have difficulty deter-
mining whether the tumor has invaded the muscularis
propria. As this is important to dictate therapy, these
patients need to undergo a re-resection of the base of the
tumor. In some instances, a second look resection is per-
formed to resect any residual tumor left behind in 37%
of cases.13 This maneuver will decrease the rate of blad-
der tumor recurrences and increase the number of blad-
der spared. We perform a second look resection usually
4 weeks after the initial one in the presence of T1G3
tumor invading more than 50% of the depth of the
muscularis mucosa.14
TUR as Primary Treatment of Muscle Invasive
Tumors
TUR has been mainly reserved to treat superficial blad-
der tumors. However, some select patients with muscle
invasive bladder cancer could be treated with TUR alone
or associated with chemotherapy and radiation therapy.
Several studies show that in selected patients, TUR
achieves 5-year survival rates comparable to those
achieved with radical cystectomy,15–17 and approximately
10% of cystectomy patients have no residual tumor (p0)
found in the cystectomy specimen.16 This suggests that
TUR can control some muscle-invasive bladder cancers.
For patients with primary muscle-invasive bladder can-
cer, radical TUR is an acceptable bladder-sparing treat-
ment strategy. TUR alone is justified only when the blad-
der tumor is clinically limited to the superficial muscle
layer and when re-resection biopsies of the periphery and
deep muscle in the tumor bed are negative for invasive
carcinoma. Patients who have any evidence of residual
tumor invasion are more likely to undergo incomplete
resection and be understaged, which predisposes them to
early local relapse or metastatic disease and higher risk of
developing new invasive cancers in the bladder. Lifelong
surveillance cystoscopy seems necessary to detect recur-
rent invasive tumors that can be successfully treated with
salvage cystectomy. Even with close follow-up, patients
who elect treatment by TUR alone assume some risk (at
least 8% and possibly as high as 16%) that a recurrent
invasive tumor in the retained bladder may eventually
cause death from TCC.
Postoperative Management
Resection of smaller bladder tumors with very minimal
bleeding may not require postoperative catheterization
unless postoperative administration of mitomycin C is
indicated. Furthermore, most endoscopic resections
require a short period of bladder catheterization with a
Foley catheter. The catheter can be removed when the
hematuria has resolved and this is routinely observed on
postoperative day one. Catheterization helps quantify both
urine output and degree of hematuria. With a catheter in
place, the bladder does not have to contract to empty, and
this may beneficially reduce the amount of postoperative
bleeding. On the other hand, bladder spasms may occur
with the Foley catheter in place responding to anticholin-
ergic therapy. Bleeding should be controlled at the time of
surgery. When bleeding control is adequate, there is gen-
erally no need for three-way bladder irrigation. Catheter
drainage may be indicated for longer periods of time if
perforation has occurred or if tumor resection extends up
to the limit of the bladder wall. Antibiotics are not required
postoperatively; however, many urologists prescribe prophy-
lactic oral antibiotics for a period of 3 to 5 days.
Complications
The most frequent encountered complications following
TUR of bladder tumors are intra- and immediate post-
operative bleeding with an incidence ranging from 2% to
13%. In a recent study, the complication rate was 5.1%
in a series of 2821 patients.18
Hemorrhage
The incidence of hemorrhage following TUR of bladder
tumors ranges between 2% and 13%.18–20 This variability
of incidence is due to the differences of the definition of

hemorrhage. The best way to prevent this bleeding is to
perform a careful coagulation in the beginning of bladder
filling after TUR to avoid the intravesical high pressure
that stops temporarily the bleeding by compression of
the vessels. Nevertheless, it is not uncommon to have an
important postoperative bleeding in patients with crys-
tal-clear irrigation fluid at the end of surgery. The risk of
hemorrhage exists until the third week postoperative fol-
lowing scare sloughing. These secondary hemorrhages
are seen when the coagulation of the tumor is extensive
leading to a necrosis of the bladder wall.
Bladder Perforation
Bladder perforation was encountered in 0.9% to 5% of
patients undergoing TUR of bladder tumors. It is prob-
ably underestimated since it is less reported in the litera-
ture. Many factors have been implicated including deep
TUR, bad vision of the site to be resected, tumor located
in a diverticulum, stimulation of the obturator nerve by
an electrical current, and overdistension of the bladder.
Thin bladder wall secondary to multiple TUR of bladder
tumors is also at risk for perforation. Perforation of the
bladder should be recognized whenever there is difficulty
to distend the bladder; the quantity of fluid instilled in
the bladder is greater than the recuperated one and also
in the presence of an abdominal distension associated
with a tachycardia. When there is a doubt a cystogram
under fluoroscopy could be performed during the TUR.
Perforations of the bladder are divided into two groups,
intraperitoneal and extraperitoneal; the treatment is differ-
ent in the two categories. Management of extraperitoneal
bladder perforation is conservative, consisting of drainage
of the bladder by a urethral catheter and administration of
large spectrum antibiotics. Surgical or percutaneous
drainage is rarely indicated and is dictated when there is an
important urine leakage or a pelvic abscess. Intraperitoneal
bladder perforation is classically managed surgically. The
indication of exploratory surgery relies on the importance
of the perforation, presence of a bowel traumatism, and
the risk of infection. In some selected cases, it is possible to
manage it conservatively in the absence of bowel perfora-
tion. Draining the bladder with a urethral catheter during
a week together with antibiotic administration is sufficient.
However, if there is no improvement with the conservative
treatment, a surgical or laparoscopic exploration is manda-
tory to repair the bladder as a whole, as well as any con-
comitant bowel perforation.
Urinary Infection
The reported incidence of urinary infection following
TUR of bladder tumor (TURBT) ranged from 2% to
39%. The etiology of urinary infection is controversial. It
has been suggested that the bladder tumor is the reser-
Chapter 20 Transurethral Surgery of Bladder Tumors 363
voir site of the germs and during the TUR, the germs are
dislocated and may be the source of infection.21
However, this observation was not confirmed by others
who held the endoscopy maneuver responsible for uri-
nary infection by inoculating germs into the bladder.22,23
Urethral Stricture
The incidence of urethral stricture was 15% in males and
4% in females but less than one-third were symptomatic.
The strictures were found distally in the urethra in 83% of
the patients and could be treated with optical urethrotomy.
The risk factors of urethral stenosis include longer duration
of postoperative catheterization and use of larger size resec-
toscope. Furthermore, repeated transurethral instrumenta-
tions may increase the risk of stricture development.24
Obturator Nerve Reflex
Obturator nerve reflex may be evoked while resecting
lesions on the lower lateral wall and neck of the bladder,
particularly in thin patients. This reflex will result in
adductor spasms of the leg, as well as inward movement
of the bladder wall during resection that could result in
its perforation and to some extent in trauma to major
pelvic vessels. The obturator reflex may be prevented by
lowering the cutting current and avoiding distension of
the bladder during resection of this area. If these maneu-
vers are not successful, d-tubocurarine and succinyl-
choline can be used during general anesthesia, or to block
the obturator nerve as it passes through the obturator
canal with infiltration by a local anesthetic as described
previously by Augspurger.25
Ureteral Orifice Injury
Ureteral orifices could be damaged when the tumor is
localized inside the orifice or close to it, raising the risk
of stricture and reflux vesicoureteral. Excretory urogra-
phy should be performed within a few weeks after a TUR
that has involved the periureteral area to detect
hydronephrosis due to ureteral injury. Management of
ureteral stricture post-TUR consists of antegrade or ret-
rograde intraluminal dilatation with a risk of reflux. The
risk of tumor seeding is 22-fold greater when there is a
vesicoureteral reflux. No consensus has been reached to
treat the reflux in patients with history of bladder tumors,
but it seems reasonable to treat patients with reflux grade
III, or having multiple recurrences of bladder tumors or
tumors located near the orifices.26–28
Reabsorption Syndrome
This is a rarely encountered complication when non-
saline irrigating fluid was used. This appears usually fol-
364 Part IV Bladder
lowing intraperitoneal bladder perforation. An extracel-
lular hyper hydration was observed leading sometimes to
severe hyponatremia causing cerebral edema with nau-
sea, vomiting, and visual disturbances. The treatment
consists of water restriction and diuretics.29
Bladder Explosion
Intravesical explosion during endoscopic resection are
rare but may be devastating. The formation of explosive
gas, essentially an air–hydrogen mixture, results from
carbonization of tissues (particularly with the coagula-
tion current) and the introduction of air into the blad-
der during manipulation of the resectoscope. The
nature of the bladder infusion liquid does not appear to
play an important role. Prevention implies the use of a
coagulation current of moderate power, the avoidance
of air entering the bladder accidentally, and the contin-
uous or repeated evacuation of the air bubble under the
bladder vault.30–32
LASER SURGERY
LASER is an acronym that stands for “light amplification
by the stimulated emission of radiation.” It describes the
physical process by which light energy is produced. A
laser is a device that generates an intense beam of light
that falls between the longest and the shortest wave-
lengths, in the infrared, visible, and the ultraviolet por-
tions of the electromagnetic spectrum. The lasers are
named by the laser medium (solid, liquid dye, or gas
component), which when stimulated produces photons
(laser light). During the last two decades, when the FDA
approved the use of the Neodymium:YAG (Nd:YAG)
(1984), Argon (1987), KTP (1988), and in 1992 the
Holmium:YAG (Ho:YAG) lasers in urology, these surgi-
cal tools have been used to treat various urologic diseases,
including superficial bladder tumors. The first reported
study using lasers to treat superficial bladder tumors
occurred more than 20 years ago.33, 34 The most of the
clinical experience in the treatment of bladder cancer has
been obtained using an Nd:YAG laser with an end-fire
Table 20-1 Different Laser Types Used in Urology Practice
Laser Type Wavelength (nm) Energy Delivery
KTP 532 Continuous wave
Diode 800–1.1 Continuous wave or pulsed
Nd:Yag 1064 Continuous wave
Ho:YAG 2100 Pulsed
CO2 10,600 Continuous wave
noncontact fiber with a 5-degree to 15-degree angle of
divergence (Table 20-1).
Surgical Techniques
Laser fibers could be inserted through standard cysto-
scopes either flexible or rigid. For rigid cystoscope a
modified Albarran apparatus is available. Energy emis-
sion is usually controlled with a foot pedal; 35 to 40 W
is ample for necrosis. After visualization of the tumor,
the laser fiber is introduced into the cystoscope and the
tip is positioned 2 to 3 mm from the surface of the
tumor. Often, the best way to appreciate the distance
between the fiber tip and the tumor is to start approxi-
mately 1 cm away and slowly move closer to the tumor
until the thermal changes become apparent. The end
point of treatment is determined by visible changes in
the tumor, which is characterized by a white discol-
oration (Figure 20-3).
Advantages and Disadvantages of Laser Use
One of the most important advantages of laser treatment
is the lack of bleeding during surgery and in the postop-
erative period. Whether energy is applied directly to the
center of the tumor initially or to the periphery, bleeding
simply does not occur unless there is trauma to the treated
area from the tip of the cystoscope or fiber. Catheter
insertion is not required. Patients treated with Nd:YAG
laser can immediately resume their daily activity with an
extremely low risk of bleeding. Laser treatment appears to
be less painful than electrocautery resection. Patients are
able to perceive the laser energy and often describe it as a
burning discomfort. Laser energy does not stimulate the
obturator nerve. Therefore, contraction of the adductor
muscles of the thigh is avoided. This helps to prevent
bladder perforation.
Laser treatment can be effective for tumors located in
bladder diverticulum by delivering energy with either a
flexible or rigid cystoscope. Even though the penetration
depth of the laser energy exceeds the thickness of the
diverticulum wall, free perforation rarely occurs.
Endoscopic Uses Tissue Penetration
Yes 1.0 mm
Yes Varies with wavelength
Yes 5.0 mm
Yes <0.5 mm
No 0.1 mm
 Chapter 20 Transurethral Surgery of Bladder Tumors 365

Figure 20-3 Nd:YAG laser-induced coagulation necrosis of a

bladder tumor. (Courtesy of Dr. Guy Drouin.)

Disadvantages of laser fulguration include lack of

histopathologic specimens for diagnosis. It is recom-
mended to obtain tissue with TUR for proper grading
and staging of the tumor. It requires some training and
some manipulation with safety applications concern for
the patient and the surgeon. The most feared complica-
tion of laser treatment is forward scatter of the energy
with perforation of an adjacent organ even in the absence
of bladder perforation.

Bladder Tumor Recurrence Rate

The clinical results achieved with laser treatment of
superficial bladder cancer are comparable with the
results of electrocautery resection. In a prospective
study of 122 patients randomized for Nd:YAG laser (n =
62) or TUR (n = 60), new tumors in nontreated areas
occurred in 12 patients in the laser group and in 13
patients in the TUR group. Thus, no difference in the
recurrence rate was observed for laser and electro-
cautery treated patients.34
Fluoroscopic Cystoscopy
The porphyrins are intermediate in the synthesis of
heme,35 which all mammalian nucleotide cells have the
ability to synthesize as HAEME-containing enzymes
that are required for energy metabolism. The derivative
of hematoporphyrins, like Photofrin, a derivative puri-
fied form of hematoporphyrin, can be used for photode-
tection of malignant cells, as well as photodynamic
therapy. However, the latter product needs to be taken
by mouth several days before treatment and one poten-
tial side effect of such medication is a skin photosensiti-
zation, which can last for 6 to 8 weeks. Another way to
Figure 20-4 A, Superficial TCC of the bladder on white light
cystoscopy. B, Same tumors seen by fluorescence
cystoscopy.
increase production of porphyrin is the use of
5-aminolevulinic acid (5-ALA), which could be adminis-
trated intravesically without any major side effects. The
5-ALA is a well-known precursor in the synthesis of pro-
toporphyrin IX, the latter being the immediate precur-
sor of heme. Accumulation of protoporphyrin IX is
found in urothelial tumor tissue compared with unaf-
fected urothelium (ratio 17:1). Thus, tumors fluoresce
red under excitation with violet light at wavelength of
375 to 440 nm36 (Figure 20-4). The neoplastic cells can
then be used as an endogenous photosensitizer under
excitation with blue light, which produces red fluores-
cence. The use of porphyrin fluorescence has been stud-
ied to improve the diagnosis of superficial bladder
cancer.37–39 Results from these publications have shown
that fluorescence cystoscopy improved the detection
rate of all malignant/dysplastic lesions by approximately
366 Part IV Bladder
18% to 76%. In cases of lesion of dysplasia/CIS, detec-
tion rate was improved from 50% to 140%.37–39
Furthermore, three recent studies have prospectively
shown a decrease risk of residual tumor after TUR and
a significantly improved recurrence-free survival at fol-
low-up.40–42 Larger multicenter studies are ongoing to
further evaluate the exact role of fluorescence cys-
toscopy in superficial bladder tumors.
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Endoscopic neodymium-YAG laser application
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34. Beisland HO, Seland P: A prospective randomized study
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35. Moore MR, Disler PB: Biochemical diagnosis of the
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36. Koenig F, McGovern FJ: Fluorescence detection of
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37. Koenig F, McGovern FJ, Larne R, et al: Diagnosis of
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39. Jichlinski P, Forrer M, Mizeret J, et al: Clinical evaluation
of a method for detecting superficial transitional cell
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40. Kriegmair M, Zaak D, Rothenberger KH, et al:
Transurethral resection for bladder cancer using
5-aminolevulinic acid induced fluorescence endoscopy
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41. Riedi CR, Daniltchenko D, Koenig F, et al: Fluorescence
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165:1121–1123.
42. Filbeck T, Pichhmeier U, Knuechel R, et al: Clinically
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C H A P T E R
21Partial and Radical Cystectomy
John P. Stein, MD, and Donald G. Skinner, MD
Radical cystectomy has traditionally been considered the
standard of therapy for high-grade, invasive bladder can-
cer with the best survival results and lowest local recur-
rence rates reported to date.1,2 Radical cystectomy
provides accurate pathologic staging of the primary blad-
der tumor and the regional lymph nodes that may then
influence the decision for adjuvant chemotherapy based
on clear pathologic criteria.3 Furthermore, advances in
urinary diversion and lower urinary tract reconstruction
to the urethra (orthotopic neobladder) have provided
patients a more socially acceptable means to store urine,
allowing volitional voiding per urethra without the need
for a urostomy appliance, cutaneous stoma, or the need
for catheterization in most instances. Currently, most
men and women undergoing radical cystectomy are
appropriate candidates for this form of urinary diversion.4
Improvements over the past several decades in med-
ical, surgical, and anesthetic techniques have dramatically
reduced the morbidity and mortality associated with rad-
ical cystectomy. Prior to 1970, the perioperative compli-
cation rate of radical cystectomy was reportedly close to
35%, with a mortality rate of nearly 20%. This has dra-
matically diminished to less than a 10% perioperative
complication rate and 2% mortality rate reported in con-
temporary cystectomy series.1,2 In addition, radical cys-
tectomy with en bloc pelvic lymphadenectomy provides
optimal local control of the bladder tumor. Pelvic recur-
rence rates in patients following radical cystectomy are
less than 10% for patients with node-negative bladder
tumors, and 10% to 20% for patients with resected pelvic
nodal metastases.1,2,5 Furthermore, transitional cell carci-
noma (TCC) is generally resistant to radiation therapy
even at high doses. To date, chemotherapy alone or as
adjuvant therapy, coupled with bladder-sparing surgery,
has yet to demonstrate equivalent recurrence and long-
term survival rates compared to radical cystectomy
alone.6,7
A dedicated effort has been made to improve the tech-
nique of radical cystectomy and provide an acceptable
form of urinary diversion without compromise of a sound
cancer operation.8–10 Certain technical issues regarding
the surgical procedure of a radical cystectomy are critical
in order to minimize local recurrence and positive surgi-
cal margins, and maximize cancer-specific survival. In
addition, attention to surgical details is important in opti-
mizing the successful outcomes of orthotopic diversion:
maintaining the rhabdosphincter mechanism and urinary
continence in these patients.10
PARTIAL CYSTECTOMY
Although radical cystectomy is the standard therapy for
high-grade, invasive bladder cancer, partial cystectomy
may be an option in a few, very carefully selected indi-
viduals. Partial cystectomy has been considered an alter-
native surgical procedure to radical cystectomy in an
attempt to preserve the bladder and maintain sexual
function. Many of these quality-of-life issues have been
significantly reduced with the development of continent
urinary diversion (orthotopic reconstruction) and nerve-
sparing approaches to radical cystectomy.4 Furthermore,
when one considers the fact that bladder cancer is gener-
ally considered a panurothelial disease and rarely an iso-
lated phenomena, this makes partial cystectomy an even
less desirable surgical option.
Despite the potential limitations of partial cystec-
tomy, certain patients may not be suitable candidates
for radical cystectomy, or simply refuse this form of
therapy. Partial cystectomy may be considered in indi-
viduals with the following selection criteria: a unifocal
tumor without evidence of atypia, or carcinoma in situ
(cis) in the bladder; the ability to obtain at least a 2-cm
circumferential margin around the tumor; a bladder
tumor in a diverticulum; no previous history of bladder
368

cancer. Relative contraindications to a partial cystectomy,
multiple tumors, include: multiple tumors, cis of the pro-
static urethra or ureters, and tumors involving the trigone
and bladder neck or those with potential extravesical
tumor extension. Patients with a small bladder capacity
are also not ideal candidates for a partial cystectomy.
Considering the aforementioned selection criteria,
only a small percent of patients with bladder cancer are
appropriate candidates for a partial cystectomy. Most
reported studies of partial cystectomy are those
reported prior to the era of orthotopic lower urinary
tract reconstruction. In a 20-year experience at the
Mayo clinic, only 199 of 3454 patients (6%) were con-
sidered appropriate candidates.11 Similarly, in a 10-year
experience at the Cleveland Clinic, only 50 of 2000
patients (2.5%) underwent partial cystectomy for inva-
sive bladder cancer.12 Although the role of a pelvic lym-
phadenectomy is controversial in partial cystectomy, it
is becoming apparent that a meticulous, extended lym-
phadenectomy is important in patient outcome follow-
ing radical cystectomy.13–16 An additional consideration
in patients with bladder tumors undergoing partial cys-
tectomy is the potential for significant tumor recur-
rence,17 and tumor spill and wound implantation
occurring in at least 10% to 20% of patients without
preoperative radiation therapy.18 This may be prevented
with a high-dose, short course of preoperative radiation
therapy.19
RADICAL CYSTECTOMY
Preoperative Evaluation
Complete clinical staging for bladder cancer should eval-
uate the retroperitoneum and pelvis along with the most
common metastatic sites, including the lungs, liver, and
bone. A chest x-ray, liver function tests, and serum alka-
line phosphatase should be obtained routinely. Patients
with an elevated serum alkaline phosphatase or with/
without complaints of bone pain should undergo a bone
scan. A CT scan of the chest is obtained when pulmonary
metastases are suspected by history, or because of an
abnormal chest x-ray. A CT scan of the abdomen and
pelvis is routinely performed to evaluate the pelvis and
retroperitoneum for any significant lymphadenopathy or
local contiguous spread. This radiographic study should
also be performed in patients with suspected metastases,
elevated liver functions tests, a bladder tumor associated
with hydronephrosis, or in patients with an extensive pri-
mary bladder tumor that is either nonmobile or fixed; the
results of which may impact on the decision for neoadju-
vant therapy. However, CT scan of the primary bladder
is neither sensitive nor specific enough to evaluate the
degree of bladder wall tumor invasion, or to accurately
determine pelvic lymph node involvement with
tumor.20,21
Chapter 21 Partial and Radical Cystectomy 369
En Bloc Radical Cystectomy and Pelvic-Iliac
Lymphadenectomy: Surgical Technique
Preoperative Preparation
Patients undergoing radical cystectomy are admitted the
morning prior to surgery. All patients receive a mechan-
ical and antibacterial bowel preparation the day prior to
surgery. Intravenous hydration must be considered in
these patients to prevent dehydration on arrival to the
operating room. In addition, all patients should be eval-
uated and counseled by the enterostomal therapy nurse
prior to surgery. A clear liquid diet may be consumed
until midnight, at which time the patient takes nothing
per mouth. A standard modified Nichols bowel prepara-
tion22 is initiated the morning of admission: 120 ml of
Neoloid per mouth at 9:00 a.m.; 1 g of neomycin per
mouth at 10:00 a.m., 11:00 am, 12:00 noon, 1:00 p.m.,
4:00 p.m., 8:00 p.m., and 12:00 midnight; and 1 g of
erythromycin base per mouth at 12:00 noon, 4:00 p.m.,
8:00 p.m., and 12:00 midnight. This regimen is generally
well tolerated, obviates the need for enemas and main-
tains nutritional and hydrational support. Intravenous
crystalloid fluid hydration is begun in the evening prior
to surgery in those patients admitted to the hospital the
day prior to surgery and maintained to ensure an ade-
quate circulating volume as the patient enters the operat-
ing room. This may be particularly important in the
elderly or frail patient with associated comorbidities.
Patients over 50 years of age routinely undergo pro-
phylactic digitalization prior to cystectomy unless a spe-
cific contraindication exists. Patients younger than 50
years of age are not routinely digitalized. Digoxin is given
orally; 0.5 mg at 12:00 noon, 0.25 mg at 4:00 p.m., and
0.125 mg at 8:00 p.m. Our experience with preoperative
digitalization in patients undergoing cystectomy has been
positive and there is evidence suggesting that preopera-
tive digitalization may decrease the risk of perioperative
dysrhythmias and congestive heart failure in the elderly
patient undergoing an extensive operative procedure.23,24
Attention to fluid management is important in these eld-
erly patients particularly on postoperative days 3 and 4
when mobilization of third-space fluid is highest, subse-
quently necessitating liberal use of diuretics. In addition,
intravenous broad-spectrum antibiotics are administered
en route to the operating room, providing adequate tis-
sue and circulating levels at the time of incision.
Preoperative evaluation and counseling by the
enterostomal therapy nurse is a critical component to the
successful care of all patients undergoing cystectomy and
urinary diversion. Patients determined to be appropriate
candidates for orthotopic reconstruction are instructed
how to catheterize per urethra should it be necessary
postoperatively. All patients are site marked for a cuta-
neous stoma, instructed in the care of a cutaneous diver-
sion (continent or incontinent form), and instructed in
370 Part IV Bladder
proper catheterization techniques should medical, tech-
nical, or oncologic factors preclude orthotopic recon-
struction. The ideal cutaneous stoma site is determined
only after the patient is examined in the supine, sitting,
and standing position. Proper stoma site selection is
important to patient acceptance, and to the technical suc-
cess of lower urinary tract reconstruction should some
form of cutaneous diversion be necessary. Incontinent
stoma sites are best located higher on the abdominal wall,
while stoma sites for continent diversions can be posi-
tioned lower on the abdomen (hidden below the belt
line) since they do not require an external collecting
device. The use of the umbilicus as the site for catheter-
ization may be employed with excellent functional and
cosmetic results.
Patient Positioning
The patient is placed in the hyperextended supine posi-
tion with the superior iliac crest located at the fulcrum of
the operating table (Figure 21-1). The legs are slightly
abducted so that the heels are positioned near the corners
of the foot of the table. In the female patient considering
orthotopic diversion, the modified frogleg or lithotomy
position is employed allowing access to the vagina. Care
should be taken to ensure that all pressure points are well
padded. Reverse Trendelenburg position levels the
abdomen parallel with the floor and helps to keep the
small bowel contents in the epigastrium. A nasogastric
tube is placed, and the patient is prepped from nipples to
mid-thigh. In the female patient the vagina is fully
prepped. After the patient is draped, a 20-F Foley
catheter is placed in the bladder and left to gravity
drainage. A right-handed surgeon stands on the patient’s
left-hand side of the operating table.
Incision
A vertical midline incision is made extending from the
pubic symphysis to the cephalad aspect of the epigas-
trium. The incision should be carried lateral to the
umbilicus on the contralateral side of the marked cuta-
neous stoma site. When considering the umbilicus as the
site for a catheterizable stoma, the incision should be
directed 2 to 3 cm lateral to the umbilicus at this location.
Figure 21-1 Proper patient positioning for cystectomy in the male patient. Note, the iliac
crest is located at the break of the table.
The anterior rectus fascia is incised, the rectus muscles
retracted laterally, and the posterior rectus sheath and
peritoneum entered in the superior aspect of the incision.
As the peritoneum and posterior fascia are incised inferi-
orly to the level of the umbilicus, the urachal remnant
(median umbilical ligament) is identified, circumscribed,
and removed en bloc with the cystectomy specimen
(Figure 21-2). This maneuver prevents early entry into a
high-riding bladder and ensures complete removal of all
bladder remnant tissue. Care is taken to remain medial
and avoid injury to the inferior epigastric vessels (lateral
umbilical ligaments), which course posterior to the rectus
muscles. If the patient has had a previous cystotomy or
segmental cystectomy, the cystotomy tract and cutaneous
incision should be circumscribed full-thickness and
excised en bloc with the bladder specimen. The medial
insertion of the rectus muscles attached to the pubic
symphysis can be slightly incised, maximizing pelvic
exposure throughout the operation.
Abdominal Exploration
A careful, systematic intraabdominal exploration is per-
formed to determine the extent of disease, and to evalu-
ate for any hepatic metastases, or gross retroperitoneal
lymphadenopathy. The abdominal viscera are palpated to
detect any concomitant unrelated disease. If no con-
traindication exists at this time, all adhesions should be
incised and freed.
Bowel Mobilization
The bowel is mobilized beginning with the ascending
colon. A large right angle Richardson retractor elevates
the right abdominal wall. The cecum and ascending
colon are reflected medially to allow incision of the lat-
eral peritoneal reflection along the avascular/white line
of Toldt. The mesentery to the small bowel is then
mobilized off its retroperitoneal attachments cephalad
(toward the ligament of Treitz) until the retroperitoneal
portion of the duodenum is exposed. This mobilization
facilitates a tension-free ureteroenteric anastomosis if
orthotopic diversion is performed. Combined sharp and
blunt dissection facilitates mobilization of this mesen-
tery along a characteristic avascular fibroareolar plane.

Figure 21-2 Wide excision of the urachal remnant and medial umbilical ligaments en bloc
with the cystectomy specimen.
Conceptually, the mobilized mesentery forms an
inverted right triangle; the base formed by the third and
fourth portions of the duodenum, the right edge repre-
sented by the white line of Toldt along the ascending
colon; the left edge represented by the medial portion of
the sigmoid and descending colonic mesentery; and the
apex represented by the ileocecal region (Figure 21-3).
This mobilization is critical in setting up the operative
field and facilitates proper packing of the intraabdominal
contents into the epigastrium.
The left colon and sigmoid mesentery are then mobi-
lized to the region of the lower pole of the left kidney by
incising the peritoneum lateral to the colon along the
avascular/white line of Toldt. The sigmoid mesentery is
then elevated off the sacrum, iliac vessels, and distal aorta
in a cephalad direction up to the origin of the inferior
mesenteric artery (Figure 21-4). This maneuver provides
a wide mesenteric window through which the left ureter
will pass (without angulation or tension) for the
ureteroenteric anastomosis at the terminal portions of
Chapter 21 Partial and Radical Cystectomy 371
the operation. This sigmoid mobilization also facilitates
retraction of the sigmoid mesentery while performing
the lymph node dissection. Care should be taken to dis-
sect along the base of the mesentery and avoid injury to
the inferior mesenteric artery and blood supply to the
sigmoid colon.
Following mobilization of the bowel, a self-retaining
retractor is placed. The right colon and small intestine
are carefully packed into the epigastrium with three
moist lap pads, followed by a moistened towel rolled to
the width of the abdomen. The descending and sigmoid
colon are not packed, and they remain as free as possible,
providing the necessary mobility required for the ureteral
and pelvic lymph node dissection.
Successful packing of the intestinal contents is an art
and prevents their annoying spillage into the operative
field. Packing begins by sweeping the right colon and
small bowel under the surgeon’s left hand along the right
sidewall gutter. A moist open lap pad is then swept with
the right hand along the palm of the left hand, under the
372 Part IV Bladder

Figure 21-3 View of the pelvis from overhead; after the ascending colon and peritoneal
attachments of the small bowel mesentery have been mobilized up to the level of the
duodenum. This mobilization allows the bowel to be properly packed in the epigastrium and
exposes the area of the aortic bifurcation, which is the starting point of the lymph node
dissection.

viscera along the retroperitoneum, and sidewall gutter. In
similar fashion, the left sidewall gutter is packed ensuring
not to incorporate the descending or sigmoid colon. The
central portion of the small bowel is packed with a third
lap pad. A moist rolled towel is then positioned horizon-
tally below the lap pads but cephalad to the bifurcation of
the aorta. Occasionally, prior to placement of the first
moist lap pad, a mobile greater omental apron can be
used to facilitate packing of the intestinal viscera in a sim-
ilar fashion to the lap pad. After the bowel has been
packed, a wide Deaver retractor is placed with gentle
traction on the previous packing to provide cephalad
exposure.
Ureteral Dissection
The ureters are most easily identified in the retroperi-
toneum just cephalad to the common iliac vessels. They
are carefully dissected into the deep pelvis (several cen-
timeters beyond the iliac vessels) and divided between
two large hemoclips. A section of the proximal cut
ureteral segment (distal to the proximal hemoclip) is sent
for frozen section analysis to ensure the absence of carci-
noma in situ or overt tumor. The ureter is then slightly
mobilized in a cephalad direction and tucked under the
rolled towel to prevent inadvertent injury. Frequently, an
arterial branch from the common iliac artery or the aorta
needs to be divided to provide adequate ureteral mobi-
lization. In addition, the rich vascular supply emanating
laterally from the gonadal vessels should remain intact
and undisturbed. These attachments are an important
blood supply to the ureter, which ensure an adequate vas-
cular supply for the ureteroenteric anastomosis at the
time of diversion. This is particularly important in irra-
diated patients. Leaving the proximal hemoclip on the
divided ureter during the exenteration allows for hydro-
static ureteral dilation and facilitates the ureteroenteric
anastomosis. In women, the infundibulopelvic ligaments
are ligated and divided at the level of the common iliac
vessels.
 Chapter 21 Partial and Radical Cystectomy 373

Figure 21-4 View of the pelvis from overhead; after the ascending colon and small bowel
have been packed in the epigastrium. Note that the sigmoid mesentery is mobilized off the
sacral promontory and distal aorta up to the origin of the inferior mesenteric artery.

Pelvic Lymphadenectomy
A meticulous pelvic lymph node dissection is routinely
performed en bloc with radical cystectomy. The extent of
the lymphadenectomy may vary depending on the
patient and surgeon preference. An accumulating body of
evidence suggests that an extended lymphadenectomy
may be beneficial in patients undergoing cystectomy for
high-grade, invasive bladder cancer.13–16 When perform-
ing a salvage procedure following definitive radiation
treatment (>5000 rads), a pelvic lymphadenectomy is
usually not performed because of the significant risk of
iliac vessel and obturator nerve injury.25
For a combined common and pelvic iliac lymphadenec-
tomy, the lymph node dissection is initiated 2 cm above
the aortic bifurcation (superior limits of dissection), and
the dissection extends laterally over the inferior vena cava
to the genitofemoral nerve, representing the lateral limits
of dissection. Distally, the lymph node dissection extends
to the lymph node of Cloquet medially (on Cooper’s liga-
ment) and the circumflex iliac vein laterally.
The cephalad portion (2 cm above the aortic bifurca-
tion) of the lymphatics are ligated with hemoclips to pre-
vent lymphatic leak, while the caudal (specimen) side is
ligated only when a blood vessel is encountered.
Frequently, small anterior tributary veins originate from
the vena cava just above the bifurcation, which should be
clipped and divided. In men, the spermatic vessels are
retracted laterally and spared. In women, the infundibu-
lopelvic ligament along with the corresponding ovarian
vessels has been previously ligated and divided at the
pelvic brim as previously described.
All fibroareolar and lymphatic tissues are dissected
caudally off the aorta, vena cava, and common iliac vessels
over the sacral promontory into the deep pelvis. The ini-
tial dissection along the common iliac vessels is performed
over the arteries, skeletonizing them. As the common iliac
veins are dissected medially, care is taken to control small
arterial and venous branches coursing along the anterior
surface of the sacrum. Electrocautery is helpful at this
location, which allows the adherent fibroareolar tissue to
374 Part IV Bladder
be swept off the sacral promontory down into the deep
pelvis with the use of a small gauze sponge. Significant
bleeding from these presacral vessels can occur if not
properly controlled. Hemoclips are discouraged in this
location as they can be easily dislodged from the anterior
surface of the sacrum, resulting in troublesome bleeding.
Once the proximal portion of the lymph node dissec-
tion is completed, a finger is passed from the proximal
aspect of dissection under the pelvic peritoneum (ante-
rior to the iliac vessels), distally toward the femoral canal.
The opposite hand can be used to strip the peritoneum
from the undersurface of the transversalis fascia and to
connect with the proximal dissection from above. This
maneuver elevates the peritoneum and defines the lateral
limit of peritoneum to be incised and removed with the
specimen. The peritoneum is divided medial to the sper-
matic vessels in men and lateral to the infundibulopelvic
ligament in female patients. The only structure encoun-
tered is the vas deferens in the male or round ligament in
females; these structures are clipped and divided.
A large right-angled rake retractor (e.g., Israel) is used to
elevate the lower abdominal wall, including the spermatic
cord or remnant of the round ligament, to provide distal
exposure in the area of the femoral canal. Tension on the
retractor is directed vertically toward the ceiling, with care
taken to avoid injury to the inferior epigastric vessels. This
provides excellent exposure to the distal external iliac ves-
sels. The distal limits of the dissection are then identified:
the circumflex iliac vein crossing anterior to the external
iliac artery distally, the genitofemoral nerve laterally, and
Cooper’s ligament medially. The lymphatics draining the
ipsilateral leg, particularly medial to the external iliac vein,
are carefully clipped and divided to prevent lymphatic leak-
age. This includes the lymph node of Cloquet (also known
as Rosenmüller), which represents the distal limit of the
lymphatic dissection at this location. The distal external
iliac artery and vein are then circumferentially dissected
and skeletonized with care taken to ligate an accessory
obturator vein (present in 40% of patients) originating
from the inferomedial aspect of the external iliac vein.
Following completion of the distal limits of dissection,
the proximal and distal dissections are joined. The proxi-
mal external iliac artery and vein are skeletonized circum-
ferentially to the origin of the hypogastric artery (Figure
21-5A). Care should be taken to clip and divide a com-
monly encountered vessel arising from the lateral aspect
of the proximal external iliac vessels coursing to the psoas
muscle. The external iliac vessels (artery and vein) are
then retracted medially, and the fascia overlying the psoas
muscle is incised medial to the genitofemoral nerve. On
the left side, branches of the genitofemoral nerve often
pursue a more medial course and may be intimately
related to the iliac vessels, in which case they are excised.
At this point, the lymphatic tissue surrounding the iliac
vessels are composed of a medial and lateral components
attached only at the base within the obturator fossa. The
lateral lymphatic compartment (freed medially from the
vessels and laterally from the psoas) is bluntly swept into
the obturator fossa by retracting the iliac vessels medially
and passing a small gauze sponge lateral to the vessels
along the psoas and pelvic sidewall (Figure 21-5B). This
sponge should be passed anterior and distal to the
hypogastric vein, directed caudally into the obturator
fossa. The external iliac vessels are then elevated and
retracted laterally, and the gauze sponge is carefully with-
drawn from the obturator fossa with gentle traction using
the left hand (Figure 21-6A). This maneuver effectively
sweeps all lymphatic tissue into the obturator fossa and
facilitates identification of the obturator nerve deep to the
external iliac vein. The obturator nerve is best identified
proximally and carefully dissected free from all lymphat-
ics. The obturator nerve is then retracted laterally along
with the iliac vessels (Figure 21-6B). At this point, the
obturator artery and vein should be carefully entrapped
between the index finger (medial to the obturator nerve)
laterally and the middle finger medially with the left hand.
This isolates the obturator vessels exiting the obturator
canal along the pelvic floor. These vessels are then care-
fully clipped and divided ensuring to stay medial to the
obturator nerve. The obturator lymph node packet is then
swept medially toward the sidewall of the bladder, ligating
small tributary vessels and lymphatics from the pelvic
sidewall. The nodal packet will be removed en bloc with
the cystectomy specimen.
Ligation of the Lateral Vascular Pedicle
to the Bladder
Following dissection of the obturator fossa and dividing
the obturator vessels, the lateral vascular pedicle to the
bladder is isolated and divided. Developing this plane iso-
lates the lateral vascular pedicle to the bladder; a critical
maneuver in performing a safe cystectomy with proper
vascular control. Isolation of the lateral vascular pedicle is
performed with the left hand. The bladder is retracted
toward the pelvis, placing traction and isolating the ante-
rior branches of the hypogastric artery. The left index fin-
ger is passed medial to the hypogastric artery, posterior to
the anterior visceral branches, and lateral to the previ-
ously transected ureter. The index finger is directed cau-
dally toward the endopelvic fascia, parallel to the sweep of
the sacrum. This maneuver defines the two major vascu-
lar pedicles to the anterior pelvic organs: the lateral pedi-
cle—anterior to the index finger, composed of the visceral
branches of the anterior hypogastric vessel; the posterior
pedicle—posterior to the index finger, composed of the
visceral branches between the bladder and rectum.
With the lateral pedicle entrapped between the left
index and middle fingers, firm traction is applied verti-
cally and caudally. This facilitates identification and
 Chapter 21 Partial and Radical Cystectomy 375

Figure 21-5 A, Technique of skeletonizing the external iliac artery and vein. Note, the
vessels are completely dissected free up to the level of the origin of the hypogastric artery.
This allows for the vessels to be carefully retracted medially and the psoas fascia incised to
allow passage of a gauze sponge. B, Technique of passing a small gauze sponge lateral to
the external iliac vessels and medial to the psoas muscle.

allowing individual branches off the anterior portion of
the hypogastric artery to be isolated (Figure 21-7). The
posterior division of the hypogastric artery, including the
superior gluteal, iliolumbar, and lateral sacral arteries, is
preserved to avoid gluteal claudication. Distal to this pos-
terior division, the hypogastric artery may be ligated for
vascular control but should not be divided since the lat-
eral pedicle is easier to dissect if left in continuity. The
largest and most consistent anterior branch to the blad-
der, the superior vesical artery, is usually isolated and
individually ligated and divided easily. The remaining
anterior branches of the lateral pedicle are then isolated
and divided between hemoclips down to the endopelvic
fascia, or as far as is technically possible. With blunt dis-
section the index finger of the left hand helps identify this
lateral pedicle and protects the rectum as it is pushed
medially. Right angle hemoclip appliers are ideally suited
for proper placement of the clips. Each pair of hemoclips
is positioned as far apart as possible to ensure that 0.5 to
1 cm of tissue projects beyond each clip when the pedicle
is divided. This prevents the hemoclips from being dis-
lodged resulting in unnecessary bleeding. Occasionally,
in patients with an abundance of pelvic fat, the lateral
pedicle may be thick and require division into two man-
ageable pedicles. The inferior vesicle vein serves as an
excellent landmark as the endopelvic fascia is just distal to
this structure. The endopelvic fascia just lateral to the
prostate may then be incised, which helps to identify the
distal limit of the lateral pedicle.
Ligation of the Posterior Pedicle to the Bladder
Following division of the lateral pedicles, the bladder spec-
imen is retracted anteriorly exposing the cul-de-sac (pouch
of Douglas). The surgeon elevates the bladder with a small
gauze sponge under the left hand, while the assistant
376 Part IV Bladder

Figure 21-6 A, Technique of withdrawing the gauze sponge with the left hand. This aids in
dissecting and clearing the obturator fossa, sweeping all fibroareolar and lymphatic tissue
toward the bladder. B, Obturator fossa cleaned. This allows proper identification of the
obturator nerve passing deep to the external iliac vein.

retracts on the peritoneum of the rectosigmoid colon in a
cephalad direction. This provides excellent exposure to the
recess of the cul-de-sac and places the peritoneal reflection
on traction facilitating the proper division. The peri-
toneum lateral to the rectum is incised and extended ante-
riorly and medially across the cul-de-sac to join the
incision on the contralateral side (Figure 21-8).
An understanding of the fascial layers is critical for the
appropriate dissection of this plane. The anterior and
posterior peritoneal reflections converge in the cul-de-
sac to form Denonvilliers’ fascia, which extends caudally
to the urogenital diaphragm (Figure 21-9, large arrow).
This important anatomic boundary in the male separates
the prostate and seminal vesicles anterior to the rectum
posterior. The plane between the prostate and seminal
vesicles, and the anterior sheath of Denonvilliers’ will not
develop easily. However, the plane between the rectum
and the posterior sheath of Denonvilliers’ (Denonvilliers’
space) should develop easily with blunt and sharp dissec-
tion. Therefore, the peritoneal incision in the cul-de-sac
must be made slightly on the rectal side rather than the
bladder side (see Figure 21-9, small arrow). This allows
proper and safe entry and development of Denonvilliers’
space between the anterior rectal wall and the posterior
sheath of Denonvilliers’ fascia (Figure 21-10).
Employing a posterior sweeping motion of the fingers,
 Chapter 21 Partial and Radical Cystectomy 377

Figure 21-7 Isolation of the lateral vascular pedicle. The left hand is used to define the right
lateral pedicle, extending from the bladder to the hypogastric artery. This plane is developed
by the index finger (medial) and the middle finger (lateral), exposing the anterior branches of
the hypogastric artery. This vascular pedicle is clipped and divided down to the endopelvic
fascia. Traction with the left hand defines the pedicle, allows direct visualization, and
protects the rectum from injury.

the rectum can be carefully swept off the seminal vesicles,
prostate, and bladder in men and off the posterior vagi-
nal wall in women. This sweeping motion, when
extended laterally, helps to thin and develop the posterior
pedicle, which appears like a collar emanating from the
lateral aspect of the rectum. Care should be taken as one
develops this posterior plane more caudally as the ante-
rior rectal fibers often are adherent to the specimen and
can be difficult to bluntly dissect. In this region, just
cephalad (proximal) to the urogenital diaphragm, sharp
dissection may be required to dissect the anterior rectal
fibers off the apex of the prostate in order to prevent rec-
tal injury at this location.
Particular mention should be made concerning several
situations that may impede the proper development of
this posterior plane. Most commonly, when the incision
in the cul-de-sac is made too far anteriorly, proper entry
into Denonvilliers’ space is prevented. Improper entry
can occur in between the two layers of Denonvilliers’ fas-
cia, or even anterior to this, making the posterior dissec-
tion difficult, increasing the risk of rectal injury.
Furthermore, posterior tumor infiltration, or previous
high-dose pelvic irradiation can obliterate this plane
making the posterior dissection difficult. To prevent
injury to the rectum in these situations, only sharp dis-
section should be performed under direct vision. To pre-
vent a rectal injury is to avoid blunt dissection with the
finger in areas where normal tissue planes have been
obliterated by previous surgery or radiation. Sharp dis-
section under direct vision will dramatically reduce the
potential for rectal injury. If a rectotomy occurs, a 2- or
3-layer closure is recommended. A diverting proximal
colostomy is not routinely required unless gross contam-
ination occurs, or if the patient has received previous
pelvic radiation therapy. If orthotopic diversion or vaginal
reconstruction is planned, an omental interposition is rec-
ommended to prevent fistulization between suture lines.
Once the posterior pedicles have been defined, they
are clipped and divided to the endopelvic fascia in the
male patient. The endopelvic fascia is then incised adja-
cent to the prostate, medial to the levator ani muscles (if
not done previously), to facilitate the apical dissection. In
the female patient, the posterior pedicles, including the
cardinal ligaments, are divided 4 to 5 cm beyond the
cervix. With cephalad pressure on a previously placed
vaginal sponge stick, the apex of the vagina can be iden-
378 Part IV Bladder

Figure 21-8 The peritoneum lateral to the rectum is incised down into the cul-de-sac and
carried anteriorly over the rectum to join the opposite side. Note that the incision should be
made precisely so the proper plane behind Denonvilliers’ fascia can be developed safely.

tified and incised posteriorly just distal to the cervix. The
vagina is then circumscribed anteriorly with the cervix
attached to the cystectomy specimen. If there is concern
about an adequate surgical margin at the posterior or
base of the bladder, then the anterior vaginal wall should
be removed en bloc with the bladder specimen; subse-
quently requiring vaginal reconstruction if sexual func-
tion is desired. It is our preference to spare the anterior
vaginal wall if orthotopic diversion is planned. This elim-
inates the need for vaginal reconstruction, and helps
maintain the complex musculofascial support system and
helps prevent injury to the pudendal innervation to the
rhabdosphincter proximal urethra, both important com-
ponents to the continence mechanism in women. The
anterior vaginal wall is then sharply dissected off the pos-
terior bladder down to the region of the bladder neck
(vesicourethral junction), which is identified by palpating
the Foley catheter balloon. At this point, the specimen
remains attached only at the apex in men and vesi-
courethral junction in women.
Anterior Apical Dissection in the Male Patient
Once the cystectomy specimen is completely freed and
mobile posteriorly, attention is directed anteriorly to the
pelvic floor and urethra. All fibroareolar connections
between the anterior bladder wall, prostate, and under-
surface of the pubic symphysis are divided. The
endopelvic fascia is incised adjacent to the prostate and
the levator muscles are carefully swept off the lateral and
apical portions of the prostate. It must be emphasized
that minimal dissection is to be performed along the
pelvic floor. The innervation to the rhabdosphincter and
continence mechanism arises from the pudendal innervation
 Chapter 21 Partial and Radical Cystectomy 379

Figure 21-9 Illustration of the formation of Denonvilliers’ fascia. Note that it is derived from a
fusion of the anterior and posterior peritoneal reflections. Denonvilliers’ space lies behind the
fascia. To successfully enter this space and facilitate mobilization of the anterior rectal wall
off Denonvilliers’ fascia, the incision in the cul-de-sac is made close to the peritoneal fusion
on the anterior rectal wall side, and not on the bladder side.

and courses along the pelvic floor.10 Therefore, any
unnecessary dissection may disrupt this delicate innerva-
tion and may compromise the continence mechanism in
patients undergoing orthotopic reconstruction.
The superficial dorsal vein is identified, ligated, and
divided. With tension placed posteriorly on the prostate,
the puboprostatic ligaments are identified, and only
slightly divided just beneath the pubis, lateral to the dor-
sal venous complex that courses between these ligaments.
Care should be taken in avoiding any extensive dissection
in this region along the pelvic floor. The puboprostatic
ligaments need only to be incised enough to allow for a
proper apical dissection of the prostate. The apex of the
prostate and membranous urethra now becomes palpable.
380 Part IV Bladder
Figure 21-10 After the peritoneum of the cul-de-sac has
been incised, the anterior rectal wall can be swept off the
posterior surface of the Denonvilliers’ fascia. This effectively
defines the posterior pedicle that extends from the bladder to
the lateral aspect of the rectum on either side.
Several methods can be performed to properly control
the dorsal venous plexus. One may carefully pass an
angled clamp beneath the dorsal venous complex, ante-
rior to the urethra (Figure 21-11). The venous complex
can then be ligated with a 2-0 absorbable suture and
divided close to the apex of the prostate. If any bleeding
occurs from the transected venous complex, it can be
oversewn with an absorbable (2-0 polyglycolic acid)
suture. In a slightly different fashion, the dorsal venous
complex may be gathered at the apex of the prostate with
a long Allis clamp (Figure 21-12). This may help better
define the plane between the dorsal venous complex and
anterior urethra. A figure-of-eight 2-0 absorbable suture
can then be placed under direct vision anterior to the
urethra (distal to the apex of the prostate) around the
gathered venous complex (Figure 21-13). This suture is
best placed with the surgeon facing the head of the table
and holding the needle driver perpendicular to the
patient. The suture is then tagged with a hemostat. This
maneuver avoids the unnecessary passage of any instru-
ments between the dorsal venous complex and rhab-
dosphincter, which could potentially injure these struc-
tures and compromise the continence mechanism. After
the complex has been ligated, it can be sharply divided
with excellent exposure to the anterior surface of the ure-
thra. Once the venous complex has been severed, the
suture can be used to further secure the complex. The
suture is then used to suspend the venous complex ante-
riorly to the periosteum to help reestablish anterior fixa-
tion of the dorsal venous complex and puboprostatic
ligaments (Figure 21-14). This may enhance continence
recovery. The anterior urethra is now exposed.
Regardless of the aforementioned technique to control
the dorsal venous complex, the urethra is then incised 270
degrees just beyond the apex of the prostate. A series of 2-
0 polyglycolic acid sutures are placed in the anterior ure-
thra, carefully incorporating only the mucosa and
submucosa of the striated urethral sphincter muscle ante-
riorly. The catheter is clamped and divided, allowing two
posterior sutures to be placed in the urethra, which should
incorporate the rectourethralis muscle or the caudal extent
of Denonvilliers’ fascia posteriorly. Following this, the
posterior urethra is divided and the specimen removed.
Alternatively, the dorsal venous complex can be
sharply transected without securing vascular control of
the dorsal venous complex. Cephalad traction on the
prostate elongates the proximal and membranous ure-
thra, and allows the urethra to be skeletonized laterally
by dividing the so-called “lateral pillars,” extensions of
the rhabdosphincter. The anterior two-third of the ure-
thra is divided, exposing the urethral catheter. The ure-
thral sutures are then placed. Six 2-0 polyglycolic acid
sutures are placed, equally spaced, into the urethral
mucosa and lumen anteriorly. The rhabdosphincter, the
edge of which acts as a hood overlying the dorsal venous
complex, is included in these sutures if the dorsal venous
complex was sharply incised. This maneuver compresses
the dorsal vein complex against the urethra for hemosta-
tic purposes. The urethral catheter is then drawn
through the urethrotomy, clamped on the bladder side,
and divided. Cephalad traction on the bladder side with
the clamped catheter occludes the bladder neck, prevents
tumor spill from the bladder, and provides exposure to
the posterior urethra. Two additional sutures are placed
in the posterior urethra, again incorporating the rec-
tourethralis muscle or distal Denonvilliers’ fascia. The
posterior urethra is then divided and the specimen is
removed. Bleeding from the dorsal vein is usually mini-
mal at this point. If additional hemostasis is required, 1 or
2 anterior urethral sutures can be tied to stop the bleed-
ing. Regardless of the technique, frozen section analysis
of the distal urethral margin of the cystectomy specimen
is then performed to exclude tumor involvement.
If a cutaneous form of urinary diversion is planned,
urethral preparation is slightly modified. Once the dorsal
 Chapter 21 Partial and Radical Cystectomy 381

Figure 21-11 Control of the dorsal venous complex. A right-angled clamp can be passed
posterior to the venous complex and anterior to the urethra. An absorbable suture can be
passed to ligate the complex distal to the apex of the prostate.

Figure 21-12 The dorsal venous complex is gathered with Figure 21-13 An absorbable suture is carefully passed in a
an Allis clamp distal to the apex of the prostate. This figure-of-eight fashion anterior to the urethra around the
maneuver will define the plane between the dorsal venous gathered dorsal venous complex to control the vascular
complex and urethra. structure.
382 Part IV Bladder
Figure 21-14 The dorsal venous complex is completely
divided. The previously placed suture is then used to further
secure the venous complex. The complex is then fixed
anteriorly to the periosteum.
venous complex is secured and divided, the anterior ure-
thra is identified. The urethra is mobilized from above as
far distally as possible into the pelvic diaphragm. With
cephalad traction, the urethra is stretched above the uro-
genital diaphragm, a curved clamp is placed as distal on the
urethra as feasible and divided distal to the clamp. Care
must be taken avoid rectal injury with this clamp. This is
prevented by placing gentle posterior traction with the left
hand or index finger on the rectum and ensuring that the
clamp is passed anterior. The specimen is then removed.
This mobilization of the urethra will facilitate a late ure-
threctomy. The levator musculature can then be reapprox-
imated along the pelvic floor to facilitate hemostasis.
Anterior Dissection in The Female
The wide female pelvis allows for better anterior expo-
sure in women, particularly at the vesicourethral junc-
tion. However, urologists may be less familiar with pelvic
surgery in women than in men. In addition, paravaginal
vascular control may be troublesome in women, and the
venous plexus anterior to the urethra is less well defined
in women. When considering orthotopic diversion in
female patients undergoing cystectomy, several technical
issues are critical to the procedure in order to maintain
the continence mechanism in these women.10
When developing the posterior pedicles in women,
the posterior vagina is incised at the apex just distal to the
cervix (Figure 21-15). This incision is carried anteriorly
along the lateral and anterior vaginal wall forming a cir-
cumferential incision. The anterolateral vaginal wall is
then grasped with curved Kocher clamps. This provides
countertraction and facilitates dissection between the
anterior vaginal wall and the bladder specimen. Careful
dissection of the proper plane will prevent entry into the
posterior bladder and also reduce the amount of bleeding
in this vascular area (Figure 21-16). Development of this
posterior plane and vascular pedicle is best performed
sharply and carried just distal to the vesicourethral junc-
tion (Figure 21-17). Palpation of the Foley catheter bal-
loon assists in identifying this region. This dissection
effectively maintains a functional vagina.
In the case of a deeply invasive posterior bladder
tumor in women, with concern of an adequate surgical
margin, the anterior vaginal wall should be removed en
bloc with the cystectomy specimen. After dividing the
posterior vaginal apex, the lateral vaginal wall subse-
quently serves as the posterior pedicle and is divided dis-
tally. This leaves the anterior vaginal wall attached to the
posterior bladder specimen. The Foley catheter balloon
again facilitates identification of the vesicourethral junc-
tion. The surgical plane between the vesicourethral
junction and the anterior vaginal wall is then developed
distally at this location. A 1-cm length of proximal ure-
thra is mobilized, while the remaining distal urethra is
left intact with the anterior vaginal wall. Vaginal recon-
struction by a clam shell (horizontal) or side-to-side (ver-
tical) technique is required. Other means of vaginal
reconstruction may include a rectus myocutaneous flap,
detubularized cylinder of ileum, a peritoneal flap, or an
omental flap.
It is emphasized that no dissection to be performed
anterior to the urethra along the pelvic floor. The
endopelvic fascia should remain undisturbed and not to
be opened in women considering orthotopic diversion.
This prevents injury to the rhabdosphincter region and
corresponding innervation, which is critical in maintain-
ing the continence mechanism. Anatomic studies have
demonstrated that the innervation to this rhabdosphinc-
ter region in women arises from branches off the puden-
dal nerve that course along the pelvic floor posterior to
the levator muscles.26,27 Any dissection performed ante-
riorly may injure these nerves and compromise the con-
tinence status. This surgical principle similarly applies to
the male patients as previously described.
When the posterior dissection is completed (ensuring
to dissect just distal to the vesicourethral junction), a
Satinsky vascular clamp is placed across the bladder neck.
The Satinsky vascular clamp placed across the catheter at
the bladder neck prevents any tumor spill from the blad-
der. With gentle traction the proximal urethra is com-
pletely divided anteriorly, distal to the bladder neck and
clamp. The female urethra is situated more anteriorly
than in men, and the urethral sutures can be placed easily
after the specimen is completely removed (Figure 21-18).
A total of 10 to 12 sutures are placed. Frozen section
analysis is performed on the distal urethral margin of the
cystectomy specimen to exclude tumor. Once hemostasis
 Chapter 21 Partial and Radical Cystectomy 383

Figure 21-15 In women, the vagina is incised distal to the cervix. Note that cephalad
traction on the posterior aspect of the vagina facilitates the incision of the anterior vaginal
wall. Slight dissection of the posterior vaginal wall off the rectum provides mobility to the
vaginal cuff.

is obtained, the vaginal cuff may be closed in 2 layers with
absorbable sutures. The vaginal cuff is then anchored
via a colposacralpexy using a strut of Marlex mesh to
the sacral promontory. This fixates the vagina without
angulation or undo tension. Note, at the terminal por-
tions of the operation, a well-vascularized omental
pedicle graft is placed between the reconstructed
vagina and neobladder, and secured to the levator ani
muscles to separate the suture lines and prevent fis-
tulization (Figure 21-19).
If a cutaneous diversion is planned in the female
patient, the posterior pedicles are developed as previ-
ously mentioned. Attention is then directed anteriorly
and the pubourethral ligaments are divided. A curved
clamp is placed across the urethra, and the anterior vagi-
nal wall is opened distally and incised circumferentially
around the urethral meatus. The vaginal cuff is closed as
previously described and suspended. Alternatively, a per-
ineal approach is to be used for this dissection with com-
plete removal of the entire urethra.
Following removal of the cystectomy specimen, the
pelvis is irrigated with warm sterile water. The presacral
nodal tissue previously swept off the common iliac vessels
and sacral promontory into the deep pelvis is collected,
and sent separately for pathologic evaluation. Nodal tis-
sue in the presciatic notch, anterior to the sciatic nerve,
is also sent for histologic analysis. Hemostasis is obtained
and the pelvis is packed with a lap pad, while attention is
directed to the urinary diversion.
The use of various tubes and drains postoperatively is
important. The pelvis is drained for urine or lymph leak
with a 1-in. Penrose drain for 3 weeks, and a large suc-
tion Hemovac drain for the evacuation of blood for
24 hours. A gastrostomy tube with an 18 French Foley
384 Part IV Bladder
Figure 21-16 Dissection of the anterior vaginal wall off of the bladder. Note caudal traction
of the cystectomy specimen with countertraction applied to the vagina in a cephalad
direction.
catheter is routinely placed utilizing a modified Stamm
technique, which incorporates a small portion of omen-
tum (near the greater curvature of the stomach) inter-
posed between the stomach and the abdominal wall.28
This provides a simple means to drain the stomach and
prevents the need for an uncomfortable nasogastric tube,
while the postoperative ileus resolves.
POSTOPERATIVE CARE
A meticulous, team-oriented approach to the care of
these generally elderly patients undergoing radical cys-
tectomy helps reduce perioperative morbidity and mor-
tality. Patients are best monitored in the surgical
intensive care unit (ICU) for at least 24 hours or until sta-
ble. Careful attention to fluid management is imperative
as third space fluid loss in these patients can be tremen-
dous and deceiving. Patients with compromised cardiac
function or pulmonary function may require invasive car-
diac monitoring with a pulmonary artery catheter placed
prior to surgery to precisely ascertain the cardiac
response to fluid shifts. A combination of crystalloid and
colloid fluid replacement is given on the night of surgery,
and converted to crystalloid on postoperative day 1.
Prophylaxis against stress ulcer is initiated with an H2
blocker. Intravenous broad-spectrum antibiotics are con-
tinued in all patients and subsequently converted to oral
antibiotics as the diet progresses. Pulmonary toilet is
encouraged with incentive spirometry, deep breathing,
and coughing.
Prophylaxis against deep vein thrombosis is impor-
tant in these patients undergoing extensive pelvic oper-
ations for malignancies. The anticoagulation is initiated
in the recovery room with 10 mg of sodium warfarin via

Figure 21-17 Dissection continues only slightly distal to the vesicourethral junction. This can
be identified by palpation of the Foley balloon in the bladder.
a nasogastric or the gastrostomy tube. The daily dose is
adjusted to maintain a prothrombin time in the range of
18 to 22 seconds. If the prothrombin time exceeds 22
seconds, 2.5 mg of vitamin K is administered intramus-
cularly to prevent bleeding. No systemic anticoagula-
tion is used. Pain control by a patient-controlled
analgesic system provides comfort and enhances deep
breathing, and early ambulation. If digoxin was given
preoperatively, it is continued until discharge. The gas-
trostomy tube is removed on postoperative day 7, or
later if bowel function is delayed. The catheter and
drain management is specific to the form of urinary
diversion. Some patients may develop a prolonged ileus
or some other complication that delays the quick return
of oral intake. In such circumstances, total parenteral
nutrition (TPN) is wisely instituted earlier rather than
Chapter 21 Partial and Radical Cystectomy 385
later, in which situation the patient may become farther
behind nutritionally.
DISCUSSION
Improvements in medical, surgical, and anesthetic ther-
apy have reduced the morbidity and mortality associated
with radical cystectomy. An anticipated perioperative
mortality rate following cystectomy is 1% to 3%.1,2 The
administration of preoperative therapy (radiation and/or
chemotherapy) and the form of urinary diversion per-
formed (continent or incontinent) do not appear to alter
the mortality rate or the perioperative complication
rate.1 Strict attention to perioperative details, meticulous
surgery, and a team-oriented surgical and postoperative
approach is the key to minimize morbidity and mortality,
386 Part IV Bladder

Figure 21-18 View of the female pelvis from above with open vaginal cuff and urethral
suture placement.

Figure 21-19 Sagittal section of the female pelvis. Not a vascularized omental pedicle graft
is situated between the reconstructed vagina/vaginal cuff and the neobladder. The graft is
secured to the pelvic floor to prevent fistulization.

and to ensure the best clinical outcomes following radical
cystectomy.
The development of orthotopic lower urinary tract
reconstruction has dramatically lessened the impact of
cystectomy on the quality of life of patients following
removal of their bladder.7 Orthotopic diversion has elimi-
nated the need for a cutaneous stoma, urostomy appliance,
and the need for intermittent catheterization. Continence
rates following orthotopic diversion are excellent, provid-
ing patients a more natural voiding pattern per urethra.
Currently, orthotopic diversion should be considered the
diversion of choice in all cystectomy patients and the urol-
ogist should have a specific reason why an orthotopic
diversion is not performed. Patient factors, such as frail
general health, motivation, associated comorbidity, and
the oncologic issue of a positive urethral margin, will dis-
qualify some patients. Nevertheless, the option of lower
urinary tract reconstruction to the intact urethra has been
shown to decrease physician’s reluctance and increase
patient’s acceptance to undergo earlier cystectomy when
the disease may be at a more curable stage.29
Currently, no equally effective alternative form of ther-
apy for high-grade, invasive bladder cancer has evolved.
Bladder cancer appears to be resistant to radiation therapy,
even at high doses. Other bladder-sparing techniques
employing chemotherapy alone, or in combination with
radiation therapy have substantially higher local recur-
rence rates and do not appear to result in long-term
survival or recurrence rates comparable to radical cystec-
tomy.6,7 Whether patients have a better quality of life fol-
lowing cystectomy or following bladder-sparing
protocols that require significant treatment to the bladder
with the potential for tumor recurrence, has not been
clarified. However, the authors firmly believe that the
argument for bladder-sparing protocols has diminished
with the advent and successful application of orthotopic
diversion following radical cystectomy.
Unlike any other therapy, radical cystectomy patho-
logically stages the primary bladder tumor and regional
lymph nodes. This histologic evaluation will provide
important prognostic information and may help identify
high-risk patients who could benefit from adjuvant ther-
apy. Patients with extravesical tumor extension, or with
lymph node positive disease, are at risk for recurrence
and should be considered for adjuvant treatment strate-
gies. Additionally, the recent application of molecular
markers, based on pathologic staging and analysis, may
also serve to identify patients at risk for tumor recurrence
who may benefit from adjuvant forms of therapy.30
In conclusion, a properly performed radical cystec-
tomy with en bloc lymphadenectomy provides the best
survival rates, with the lowest reported local recurrence
rates for high-grade invasive bladder cancer. The surgical
technique is critical to optimize the best clinical and
technical outcomes with this procedure. Technical
Chapter 21 Partial and Radical Cystectomy 387
advances in lower urinary tract reconstruction have
allowed a reasonable alternative for patients following
removal of the bladder and have improved the quality of
life of these patients requiring removal of their bladder.
REFERENCES
1. Stein JP, Lieskovsky G, Cote R, et al: Radical cystectomy
in the treatment of invasive bladder cancer: long-term
results in 1054 patients. J Clin Oncol 2001; 19:666–675.
2. Ghoneim MA, El-Mekresh MM, El-Baz MA, El-Attar IA,
Ashamallah A: Radical cystectomy for carcinoma of the
bladder: critical evaluation of the results in 1026 cases.
J Urol 1997; 158:393–399.
3. Skinner DG, Daniels J, Russell C, et al: The role of
adjuvant chemotherapy following cystectomy for invasive
bladder cancer: a prospective comparative trial. J Urol
1991; 145:459–467.
4. Stein JP, Skinner DG: Orthotopic bladder replacement. In
Walsh PC, Retik AB, Vaughan ED, Wein AJ (eds):
Campbell’s Urology, 8th edition, Chapter 108,
pp 3835–3864. Philadelphia, WB Saunders, 2002.
5. Lerner SP, Skinner DG, Lieskovsky G, et al: The
rationale for en bloc pelvic lymph node dissection for
bladder cancer patients with nodal metastases: long-term
results. J Urol 1993; 149:758–765.
6. Thrasher JB, Crawford ED: Current management of
invasive and metastatic transitional cell carcinoma of the
bladder. J Urol 1993; 149:957–972.
7. Montie JE: Against bladder sparing surgery. J Urol 1999;
162:452–457.
8. Stein JP, Skinner DG: Radical cystectomy in the female.
In Montie JE (ed): Atlas of Urologic Clinics of North
America, Vol 5, No 2, pp 37–64. Philadelphia, WB
Saunders, 1997.
9. Stein JP, Skinner DG, Montie JE: Radical cystectomy and
pelvic lymphadenectomy in the treatment of infiltrative
bladder cancer. In Droller MJ (ed): Bladder Cancer:
Current Diagnosis and Treatment, Chapter 10,
pp 267–307. Totowa, NJ, Humana Press, 2001.
10. Stein JP, Quek MD, Skinner DG: Contemporary surgical
techniques for continent urinary diversion: continence
and potency preservation. In Libertino JA, Zinman LN
(eds): Atlas of the Urologic Clinics of North America, Vol
9, pp 147–173. Philadelphia, WB Saunders, 2001.
11. Utz DC, Schmitz SE, Fugelso PD, et al: A
clinicopathologic evaluation of partial cystectomy
for carcinoma of the urinary bladder. Cancer 1973;
32:1075.
12. Novick AC, Stewart BH: Partial cystectomy in the
treatment of primary and secondary carcinoma of the
bladder. J Urol 1976; 116:570.
13. Herr HW, Bochner BH, Dalbagni G, et al: Impact of the
number of lymph nodes retrieved on outcome in patients
with muscle invasive bladder cancer. J Urol 2002;
167:1295–1298.
14. Leissner J, Hohenfellner R, Thuroff JW, Wolf H.K:
Lymphadenectomy in patients with transitional cell
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carcinoma of the urinary bladder; significance for staging
and prognosis. Brit J Urol Int 2000; 85:817–823.
15. Poulsen AL, Horn T, Steven K: Radical cystectomy;
extending limits of pelvic lymph node dissection improves
survival for patients with bladder cancer confined to the
bladder wall. J Urol 1998; 160:2015.
16. Stein JP, Cai J, Groshen S, Skinner DG: Risk factors for
patients with pelvic lymph node metastases following
radical cystectomy with en bloc cystectomy: the concept
of lymph node density. J Urol 2003; 170:35–41.
17. Faysal MH, Frieha FS: Evaluation of partial cystectomy
for carcinoma of the bladder. Urology 1979; 14:352.
18. Magri J: Partial cystectomy: review of 104 cases. Br J Urol
1962; 32:74.
19. van der Werf-Messing B: Carcinoma of the bladder
treated by suprapubic radium implants: the value of
additional external irradiation. Eur J Urol 1969; 5:277.
20. Voges GE, Tauschke E, Stockle M, Alken P, Hohenfellner
R: Computerized tomography: an unreliable method for
accurate staging of bladder tumors in patients who are
candidates for radical cystectomy. J Urol 1989;
142:972–974.
21. Pagano F, Bassi P, Galetti TP, et al:: Results of
contemporary radical cystectomy for invasive bladder
cancer: a clinicopathological study with an emphasis on
the inadequacy of the tumor, nodes and metastases
classification. J Urol 1991; 145:45–50.
22. Nichols RL, Broido P, Condon RE, Gorbach SL, Nyhus
LM: Effect of preoperative neomycin-erythromycin
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23. Pinaud MLJ, Blanloeil YAG, Souron RJ: Preoperative
prophylactic digitalization of patients with coronary artery
disease: a randomized echocardiographic and
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24. Burman SO: The prophylactic use of digitalis before
thorocotomy. Ann Thorac Surg 1972; 14:359–368.
25. Crawford ED, Skinner DG: Salvage cystectomy after
radiation failure. J Urol 1980; 123:32–34.
26. Colleselli K, Stenzl A, Eder R, et al: The female urethral
sphincter: a morphological and topographical study.
J Urol 1998; 160:49–50.
27. Grossfeld GD, Stein JP, Bennett CJ, et al: Lower urinary
tract reconstruction in the female using the Kock ileal
reservoir with bilateral ureteroileal urethrostomy: update
of continence results and fluorourodynamic findings.
Urology 1996; 48:383–388.
28. Buscarini M, Stein JP, Lawrence MA, Skinner DG: Tube
gastrostomy following radical cystectomy and urinary
diversion: surgical technique and experience in 709
patients. Urology 2000; 56:150–152.
29. Hautmann RE, Paiss T: Does the option of the ileal
neobladder stimulate patient and physician decision
toward earlier cystectomy? J Urol 1998; 159:1845–1850.
30. Stein JP, Grossfeld GD, Ginsberg DA, et al: Prognostic
markers in bladder cancer: a contemporary review of the
literature. J Urol 1999; 160:645–659.
C H A P T E R

22 Selective Bladder Preservation by

Combined Modality Treatment
Donald S. Kaufman, MD, Alex F. Althausen, MD,
Niall M. Heney, MD, FRCS, Anthony L. Zietman, MD, M. Dror
Michaelson, MD, PhD, and William U. Shipley, MD

In the United States, the standard treatment of muscle-
invasive transitional cell cancer of the bladder is radical
cystoprostatectomy. This is an approach that results in
90% local control at 5 years but only 40% to 60% 5-year
overall survival. The usual cause of death is the result of
systemic spread of the primary tumor with the strong
presumption that in the majority of cases micrometasta-
tic disease is present at the time of cystectomy and the
patients so afflicted are therefore destined to die of dis-
tant metastases. An analysis of cystectomy performed at
Memorial Sloan Kettering Cancer Institute demon-
strated a disease-specific survival of 67% with a median
follow-up of 65 months and a median overall survival of
only 45%.1 The clinical and pathologic stage of the dis-
ease is important in predicting long-term survival. The
5-year recurrence-free survival for muscle-invasive blad-
der cancer at the University of Southern California was
89% in P2 node-negative tumors, 50% in P4 node-negative
tumors, and 35% in patients with node-positive tumors.2
The effects of cystoprostatectomy on quality of life
have been carefully studied. The newest surgical tech-
niques of nerve-sparing that may preserve male potency
and help increase the likelihood of continence with
orthotopic urinary diversions have made cystectomy
more tolerable, but even the most enthusiastic propo-
nents of orthotopic bladder construction would agree
that a well-functioning natural bladder is superior in
function to any of the technologic advances in bladder
construction and reconstruction devised in the past
decade.
Present day combined modality treatment and selec-
tive bladder preservation by early response evaluation
differ from previous approaches utilizing monotherapy.
These older approaches included: (1) transurethral resec-
tion alone done selectively for patients with small
tumors, which represented less than 20% of all muscle-
invading bladder tumors; (2) external beam radiation
therapy as monotherapy; (3) systemic multidrug
chemotherapy as monotherapy. Local control rates with
radiation alone for muscle-invading tumors have been
disappointingly low, and radiation as monotherapy has
largely been abandoned.3–6
It is now clear that monotherapies of various types are
in general unsuccessful in curing patients of invasive
bladder cancer. Barnes et al.7 reported a 27% 5-year sur-
vival in 85 patients with well-and moderately differenti-
ated T2 transitional cell carcinomas (TCCs) treated with
transurethral resection alone. Sweeney et al.8 found that
only 19% of patients with muscle-invasive tumors were
selected for treatment by partial cystectomy, and these
had a local recurrence rate of 38% to 78%. Hall et al.9
reported a 19% 3-year freedom from recurrence with
chemotherapy alone in 27 patients with localized disease,
utilizing cisplatin, methotrexate, vinblastine, and epiru-
bicin. The local control rates for the monotherapies
noted above are inadequate (Table 22-1) when compared
to radical cystectomy with its local control rate of 90%.
Attempts at bladder sparing must be selective, as not all
patients are candidates for that approach. Favorable selec-
tion criteria include tumors that can be substantially
removed by transurethral resection and making certain
that a complete response following initial chemoradiation
induction is achieved, as measured by follow-up cytology
and cystoscopic biopsies. Only if there is a complete
response of induction therapy, consolidation chemother-
apy is recommended and that followed by adjuvant

389
390 Part IV Bladder

Table 22-1 Bladder Sparing with Monotherapy The results of trimodality therapy for muscle-invasive
bladder cancer have led to further studies utilizing tri-
No. Recurrence
No. of an Invasive modality treatment with improved radiation techniques
Treatment Patients Tumor (%) and the use of newer chemotherapeutic agents in innova-
tive combinations in attempts to improve on the com-
Transurethral resection 331 2010 plete response rate and the long-term control rate in the
alone treatment of muscle-invasive bladder cancer.
Despite promising results there is reluctance among
Radiation alone 949 4011
urologic surgeons to accept trimodality therapy as an
Chemotherapy alone 27 199 alternative to cystectomy even in selected patients. In
part, this is due to improvements in urinary diversion
in patients undergoing cystectomy, but, more impor-
chemotherapy in those patients who have negative blad- tantly, concern persists among urologists that only cys-
der biopsies following consolidation radiochemotherapy. tectomy has the potential to rid the patient of the
If residual disease is found, cystectomy is recommended. disease permanently. Urologists have expressed the fol-
The combination of transurethral resection, radiation, lowing widely held views as arguments against bladder
and chemotherapy has yielded better results than any of sparing:
the monotherapies with an improved clinical complete
response rate (Tables 22-2 and 22-3). Substantial 1. Superficial relapse is common and very difficult to
improvements in local control have been reported with treat after radiochemotherapy.
combined modality therapy.12–14,19 This generally con- 2. Radiation burns the bladder rendering it useless,
sists of transurethral resection of the tumor for debulking with bleeding and scarring associated with frequency,
with the goal a visibly complete tumor removal followed urgency, nocturia, and perineal pain.
by radiation treatment with concurrent radiosensitizing 3. Innovative surgical techniques, including
chemotherapy. In the studies reported, the most com- neobladders, continent diversion, and other technical
monly used radiosensitizing drugs have been cisplatin, advances, have been successful and are subject to
5-fluorouracil (5-FU), and paclitaxel, used either singly continuing improvement, making bladder-sparing
or in various combinations. efforts unnecessary.

Table 22-2 Recent Results of Multimodality Treatment for Muscle-invasive Bladder Cancer
5-year 5-year Survival
Number of Overall with Intact Study
Multimodality Therapy Used Patients Survival (%) Bladder (%) Location References

External beam radiation + 42 52 42 RTOG 85-12 Tester et al.12

cisplatin

TURBT, external beam radiation 79 52 41 University of Dunst et al.13

+ cisplatin Erlangen

TURBT, MCV, external beam

radiation + cisplatin 91 51 44 (4 years) RTOG 88-02 Tester et al.14

TURBT, 5-FU, external beam 120 63 NA University of Housset et al.15,16

radiation + cisplatin Paris

TURBT, external beam radiation 162 (93-cisplatin; 55 44 University of Sauer et al.17

+ cisplatin or carboplatin 69-carboplatin) Erlangen

TURBT, ± MCV, external 123 49 38 RTOG 89-03 Shipley et al.18

beam radiation + cisplatin

TURBT, MCV, external beam 190 54 45 MGH Shipley et al.19

radiation + cisplatin

TURBT, external beam 123 49 NA RTOG 97-06 Hagan et al.20

radiation + cisplatin
 Chapter 22 Selective Bladder Preservation by Combined Modality Treatment 391

Table 22-3 RTOG Bladder Protocols (1985–2001): Trimodality Therapy with Cystectomy for Poorly
Responding/Relapsing Patients
Protocol Induction Treatment Patients 5-year Survival Complete Response

85-12 TURBT, CP + XRT 42 52% 66%*

88-02 TURBT, MCV, CP + XRT 91 51% 75%*

89-03 TURBT, ± MCV then CP + XRT 123 49% 59%

95-06 TURBT, 5-FU plus CP + XRT 34 n.a. 67%

97-06 TURBT, CP + BID XRT adj. MCV 52 n.a. 74%

99-06 TURBT, TAX plus CP + XRT; adj. CP + GEM 84 n.a. n.a.

TURBT, transurethral resection of bladder tumor; XRT, external beam irradiation; CP, cisplatin; 5-FU, 5-fluorouracil; MCV, methotrexate,
cisplatin, vinblastine; TAX, paclitaxel; GEM, gemcitabine; n.a., not available.
*Urine or bladder wash cytology not included in the evaluation of the bladder tumor response.

4. Once the patient has been treated with
chemotherapy and radiation therapy to the bladder,
radical cystectomy becomes more difficult to perform
and is associated with considerable morbidity.
5. Chemotherapy with its attendants nausea, anorexia,
weight loss, and malaise is permanently destructive of
the quality of life.
6. Delay in cystectomy risks patients’ lives.
der cancer (Tables 22-4 and 22-5). The list includes, in
addition to cisplatin, methotrexate, vinblastine, ifos-
famide, doxorubicin, gemcitabine, paclitaxel, and others.
Not surprisingly, combinations of these drugs have been
shown to be more effective than single agents in the per-
centage of complete remissions (CR) achieved. With the
use of combination chemotherapy in advanced measurable
disease, CR became a common achievement compared to

Each of these concerns is dealt with in this chapter.

Table 22-4 Single Agent Activity in Bladder
In the past 15 years, the Radiation Therapy Oncology Cancer—Older Agents
Group (RTOG) has completed six prospective protocols
of combined modality therapy for patients with muscle- Drug Response Rate (%)
invasive cancer who are considered to be cystectomy can- Cisplatin 12–28
didates (see Table 22-3). Bladder preservation with
intravesical surgery, chemotherapy, and radiation therapy Methotrexate 29–45
are combined as initial treatment with radical cystectomy
recommended for all incomplete responders. Five of the Doxorubicin 17
RTOG protocols were phase I to phase II trials of con- 5-fluorouracil 15–17
current chemotherapy and radiation therapy and one
protocol was a phase III trial testing the efficacy of adju- Vinblastine 15
vant methotrexate, cisplatin, and vinblastine (MCV)
chemotherapy. A total of 426 patients were entered on Mitomycin C 13–20
these trials with 5-year overall survival of 50%, with
3-quarters of those patients being cured of their bladder
cancer, while maintaining a functioning bladder.21 Table 22-5 Single Agent Activity in Bladder
Cancer—Newer Agents
Current protocols are directed towards potentially more
effective chemotherapeutic regimens that will result in a Drug Response Rate (%)
high protocol compliance rate and possibly a higher
Paclitaxel 42–56
overall survival rate. A bladder-sparing strategy may be
offered to highly selected patients with the understand- Ifosfamide 20–31
ing that radical cystectomy is still an available option in
those patients who fail combined radiation therapy and Gemcitabine 23–28
chemotherapy.
Carboplatin 13–15
Investigators have become interested in clinical trials
with the demonstration that some older, as well as newer Docetaxel 13
drugs, have considerable activity against metastatic blad-
392 Part IV Bladder
a 15% to 20% rate of partial remission only utilizing a
variety of single drugs, and with CR only rarely observed
with single-agent treatments.
Successful bladder-sparing treatment is, and should be,
very selective with frequent examinations of patients’
bladders for signs of persistence or recurrence of disease.
Several protocols have been written explicitly directing
discontinuation of the bladder-sparing effort in favor of
radical cystectomy at the earliest sign of failure of local
control. All of the protocols have required for acceptance
that patients be medically fit and willing to undergo cys-
tectomy immediately on recognition that the disease is
found to be active in the bladder. Available data clearly
indicate that one-third of patients entering potential blad-
der-sparing protocols require radical cystectomy either
during or after the completion of radiochemotherapy.
Over the years since the initial report of the effective-
ness of cisplatin as a single agent in 1980 and the report
of cisplatinum given concurrently with radiation, it has
become appreciated that bladder cancer is a heteroge-
neous disease, one with a rapid doubling time and with
micrometastases often present at the time of cystectomy.
It is important to review the evolution of the
Massachusetts General Hospital (MGH) and national
cooperative group approaches to bladder conservation.
From 1981 to 1986, in a National Bladder Cancer Group
protocol, cisplatin was first used as a radiation sensitizer.
From 1986 to 1993, a phase II and phase III protocol uti-
lized MCV as neoadjuvant drugs. From 1994 to 1998,
twice daily (b.i.d.) radiation was introduced with concur-
rent cisplatin and 5-FU as radiation sensitizers and with
adjuvant MCV. From 1999 to 2002, b.i.d. radiation was
used, with cisplatin and paclitaxel as radiosensitizers and
with adjuvant cisplatin/gemcitabine. In 2003, a new pro-
tocol was then opened, a randomized phase II program
utilizing b.i.d. radiation in all patients with randomiza-
tion in the radiosensitizing drugs to either cisplatin plus
5-FU or cisplatin/paclitaxel. The adjuvant regimen is to
consist of cisplatin, gemcitabine, and paclitaxel, a three-
drug regimen proven effective in the treatment of
advanced measurable bladder cancer.22
The current eligibility criteria for bladder sparing
include: (1) histologic proof of invasion of the muscularis
propria; (2) normal upper tracts; (3) the absence of
hydronephrosis; (4) adequate renal function; (5) a normal
hemogram; (6) medical fitness for cystectomy; and (7) the
absence of malignant lymphadenopathy on imaging stud-
ies utilizing CT or MRI, with biopsy as necessary.
Protocols carried out between 1986 and 2002 at
the MGH Cancer Center included as complete a
transurethral resection of the tumor as safely as possible
and with the exception of one study, in which neoadjuvant
chemotherapy was employed, patients were treated fol-
lowing a transurethral resection with radiation and con-
comitant chemotherapy.23 From 1986 to 1993, we studied
the question of neoadjuvant multidrug systemic
chemotherapy to reduce the appearance of distant metas-
tases and increase cure rates. However, the 5-and 10-year
metastasis-free survival rates were not influenced in any
patient subgroup by the addition of two cycles of neoad-
juvant MCV chemotherapy. The lack of efficacy of
neoadjuvant MCV was confirmed in a previously reported
phase III trial.18 We have not used neoadjuvant
chemotherapy in subsequent protocols, directing our
attention instead to adjuvant chemotherapy.
The MGH experience with 190 patients with invasive
bladder cancers with clinical stages T2–T4a entered on
successive prospective protocols has recently been
updated.19 A common feature of all of the protocols was
early bladder tumor response evaluation and the selec-
tion of patients for bladder conservation on the basis of
their initial response to transurethral resection of bladder
tumor (TURBT) combined with chemotherapy and radi-
ation therapy. Bladder conservation was reserved for
those who had a complete clinical response at the mid-
point in therapy (after a radiation dosage of 40 Gy).
Approximately two-thirds of the total then received con-
solidation with additional chemotherapy and radiation
therapy to a total tumor dose of 64 to 65 Gy. Incomplete
responders were advised to undergo radical cystectomy,
as were patients whose invasive tumors persisted or
recurred after treatment.
In these phase II and phase III protocols, the schedul-
ing of the chemoradiation varied. In phase III study, mul-
tidrug chemotherapy as neoadjuvant treatment was
evaluated compared without it and with all patients given
TURBT plus concurrent cisplatin, and radiation therapy.
The median follow-up for all surviving patients was 6.7
years with 81 patients having been followed for 5 years or
more and 28 patients for 10 or more years.19 The 5- and
1-year actuarial overall survival rates were 54% and 36%,
respectively (stage T2 62% and 41%, stages T3–T4a 47%
and 31%). The 5-and 10-year disease-specific survivals are
63% and 59%, respectively (stage T2 74% and 66%,
stages T3–T4a, 53% and 52%). The 5-and 10-year dis-
ease-specific survivals with an intact bladder are 46% and
45%, respectively (stage T2, 57% and 50%, stages
T3–T4a 35% and 34%). The pelvic failure rate was 8.4%.
No patient required cystectomy due to bladder morbidity.
The overall survival rate is provided in Figure 22-1,
and the disease-specific survival rate is stratified by clini-
cal stage in Figure 22-2. The current schema for multi-
modality treatment of muscle-invasive bladder cancer is
provided in Figure 22-3, and the risk of relapse with a
superficial tumor following multimodality treatment is
shown in Figure 22-4.
The actuarial 5- and 10-year overall survivals and dis-
ease-specific survivals for all 190 patients and for some
clinically important subgroups are shown in Table 22-6.
The clinical stage (see Figures 22-1 and 22-2) signifi-
 Chapter 22 Selective Bladder Preservation by Combined Modality Treatment 393

Overall survival versus 68%, p = 0.002. The 5- and 10-year disease-specific

survivals for all 66 patients undergoing cystectomy are
100 48% and 41%, respectively, indicating the important
contribution of this procedure in those patients treated
75 with this approach. The tumor stage did not influence
62% the 5- and 10-year disease-specific survivals in the 66
Stage T2 (n  90) patients who are undergoing either an immediate cystec-
50 tomy or a salvage cystectomy (stage T2, 57% and 39%,
47% stages T3–T4a, 42% and 42%).
Seventy-three (60% of 121) patients who were com-
25 p  0.02 Stage T3−4a (n  100) plete responders after induction therapy developed no
90 41 11 further bladder tumors. Twenty-four percent subse-
0 100 40 17 quently developed only a superficial occurrence and 16%
developed an invasive tumor.
0 1 2 3 4 5 6 7 8 9 10 Twenty-nine patients with superficial recurrence were
Time from protocol enrollment (years) managed conservatively by transurethral resection and
intravesical therapy. With a median follow-up of 4.1
Figure 22-1 Overall Survival. (From Shipley WU, Kaufman years since conservative treatment of the superficial
DS, Zehr E, Heney NM, Lane SC, Thakal HK, Althausen AF,
recurrence 18 (62%) have tumor-free bladders. Thus, 91
Zietman AL: Urology 2002; 60:62–68, with permission.)
of the 121 initially complete responding patients (or
75%) have tumor-free bladders. Seven of the 29 required
a subsequent cystectomy for further superficial or inva-
Disease-specific survival
sive recurrence. For these patients, the overall survival is
100 comparable to the 74 who had no failure, but one-third
of these patients required a salvage cystectomy.24
74 % Stage T2 (n  90) While there has been an understandable concern that
75 bladder-sparing treatment with high-dose radiation
53 % might cause irreparable damage to bladder function,
nearly all patients reported normal or near-normal func-
50
Stage T3−4a (n  100) tion and this is borne out by objective measurements of
bladder function, recently reported by Zietman et al.25
25 The quality of life in patients whose bladders have been
p  0.01
preserved has been studied in several centers with the
90 40 11
results summarized in Table 22-7. As reported by
0 100 40 17
Zietman et al. in the study of the long-term results of tri-
0 1 2 3 4 5 6 7 8 9 10 modality therapy for invasive bladder cancer, 78% of
patients had compliant bladders with normal capacity
Time from protocol enrollment (years)
and flow parameters. Eighty-five percent had no urinary
Figure 22-2 Disease-specific survival. (From Shipley WU, urgency or only occasional urgency. Twenty-five percent
Kaufman DS, Zehr E, et al: Urology 2002; 60:62–68, with had occasional to moderate bowel control symptoms and
permission.) 50% of men had preserved erectile function.
The MGH QOL questionnaire results of the late
cantly influences overall survival (p = 0.02) and disease- effects of chemoradiation on bladder function are very
specific survival (p = 0.01), as well as CR rate (stage T2, similar to two European cross-sectional studies recently
71%, stages T3–T4a, 50%, p = 0.04) and the rate of sub- reported. In both the studies, over 74% of the patients
sequent distant metastases (stage T2, 22%, stages reported good urinary function. In one of the studies all
T3–T4a, 37%, p = 0.03). We also found higher 5- and patients received concurrent chemotherapy and radiation
10-year disease-specific survivals with an intact bladder treatment as in the MGH series,26 while in the other,27
for stage T2 patients, 57% and 50%, respectively, than the patients received radiation alone. Concurrent
for stages T3–T4a patients, 35% and 24%, respectively, chemotherapy might, therefore, be inferred to add little
with a p value of 0.008. Neither the tumor grade nor the in terms of bladder morbidity.
use of neoadjuvant chemotherapy significantly improved Comparing our results to those of contemporary radi-
the CR rate (64%), overall survival, disease-specific sur- cal cystectomy series is confounded by the discordance
vival, or distant metastasis-free survival. The presence of between the clinical TURBT staging and pathologic (cys-
hydronephrosis significantly reduces the CR rate, 37% tectomy) staging. A recent prospective evaluation from
394 Part IV Bladder

Biopsy-proven muscle-invasive bladder cancer

Transurethral resection of all visible tumor, if possible

Induction therapy with external beam radiation and radiosensitizing chemotherapy (weeks 1 to 3)

Repeat cystoscopy with transurethral biopsy (week 7)

Complete response (T0) OR only a Any residual tumor at the original site OR a tumor
superficial tumor (Ta, Tcis) at a new site (T1 or greater) at a new site

Proceed with consolidation chemoradiation therapy (weeks 8 to 9) Radical cystectomy (week 9)

Repeat cystoscopy with transurethral biopsy (week 17) Adjuvant chemotherapy

Complete response Superficial persistence Muscle-invasive disease

Intravesical therapy or Radical cystectomy

radical cystectomy

Adjuvant chemotherapy

Adjuvant chemotherapy

Long-term cystoscopic surveillance

Figure 22-3 Current schema for multimodality treatment of muscle-invasive bladder cancer.
(From Michaelson MD, Zietman AL, Kaufman DS, Shipley WU: Invasive bladder cancer: the
role of bladder-preserving therapy and neoadjuvant chemotherapy. Urologia Integrada Y De
Investigacion (in press).
 Chapter 22 Selective Bladder Preservation by Combined Modality Treatment 395

T2-4 TCC bladder

Trimodality therapy
n  190

Complete responders
n  121

No bladder Invasive
relapse relapse
n  73 n  16

Superficial
relapse
n  32

Cystectomy No treatment
n3 n1
Local therapy
n  28

No further relapse Invasive

n  18 n3
Further superficial cystectomy  3
n7
cystectomy  4

Figure 22-4 Outcome of 121 patients with clinical stages T2–T4 TCC of the bladder who
had a CR to trimodality therapy (chemotherapy, induction radiation, and transurethral
resection). (From Zietman AL, Grocela J, Kaufman DS, et al: Urology 2001; 58:380–385,
with permission.)

Stockholm28 has documented that clinical staging is more
likely to understate the extent of the disease with regard
to penetration into muscularis propria or beyond than is
pathologic staging. Thus, if any favorable outcome bias
exists, it is in favor of the pathologically reported radical
cystectomy series. The University of Southern California
recently reported on 633 patients undergoing radical cys-
tectomy with pathologic stages T2–T4a with an actuarial
overall survival rate at 5 years of 48% and 10 years of
32%.2 The Memorial Sloan Kettering Cancer Center
Contemporary Radical Cystectomy series showed that in
184 patients with tumors of pathologic stages P2–P4, the
5-year overall survival rate was 36%. The actuarial 5-year
survival rate of all 269 patients undergoing radical cystec-
tomy with pathologic stages ranging from P0 to P4 in this
series was 45%.1
The results of these contemporary cystectomy series
for muscle-invading bladder cancer are similar to the
MGH series, as well as those from the University of
Erlangen29 and the RTOG18 (Table 22-8). This similar-
ity in survival is likely in part due to the prompt use of
salvage cystectomy when necessary in the selective blad-
der preservation series. The disease-specific survival rate
of 40% at 10 years in the MGH series for patients having
cystectomy underscores the need for close urologic fol-
low-up with cystoscopic surveillance and prompt bladder
removal when necessary.
One of the concerns with bladder-sparing therapy is
the risk of subsequent superficial relapses within the
intact bladder, which could progress to life threatening
malignancy once again. Long-term follow-up from the
MGH series has examined this issue in detail in 121
patients with a complete response (see Figure 22-4). Sixty
percent of patients did not have evidence of relapse after
a median follow-up of 7.1 years. Of the 32 superficial
recurrences, 10 have required cystectomy and 18 have
been treated conservatively tumor-free bladders. Thus,
91, or 75%, of the 121 complete responding patients
with a median follow-up of over 7 years have tumor-free
bladders. The overall survival of those patients with a
superficial recurrence is the same as those CR patients
without a bladder recurrence.24
396 Part IV Bladder

Table 22-6 Survival Outcomes by Patient and Tumor Characteristics

OVERALL SURVIVAL (%) DISEASE-SPECIFIC SURVIVAL (%)

Patient Group No. 5 year 10 year 5 year 10 year

All patients 190 54 ± 7.5* 36 ± 8.3* 63 ± 7.5* 59 ± 8.0*

Age at entry

<75 years 155 55 40 p = 0.04 65 60 n.s.

>75 years 35 51 22 56 56

Gender

Female 47 59 40 p = 0.67 60 52 p = 0.50

Male 143 52 34 64 62

Clinical Stage

T2 90 62 41 p = 0.02 74 66 p = 0.01

T3–T4a 100 47 31 53 52

Hydronephrosis

No 163 55 37 p = 0.15 64 61 p = 0.09

Yes 27 48 29 53 49

From Dunst J, Sauer R, Schrott KM, et al: Int J Radiol Oncol Biol Phys 1994; 30:261-266.
*95% confidence interval.

Table 22-7 Results of a Urodynamic/QOL Analysis
Long-term results of trimodality therapy for invasive bladder
cancer
1. 78% have compliant bladders with normal capacity and
flow parameters
2. 85% have no urgency or occasional urgency
3. 25% have occasional to moderate bowel control
symptoms
4. 50% of men have normal erectile function
Thus, lifelong surveillance with cystoscopy is crucial
in patients treated with bladder-sparing therapy.
Prompt salvage therapy for either superficial or recur-
rent invasive disease likely has prevented a survival
disadvantage.
In an attempt to improve safety, as well as to increase
efficacy, newer studies of multimodality therapy, utilizing
newer chemotherapeutic agents, have recently shown a
high degree of activity in metastatic transitional cell
tumors. The major drugs in this category are gemc-
itabine and paclitaxel. Many recent studies have sug-
gested that paclitaxel is an active agent in TCCs and a
phase II study of the combination of cisplatin and pacli-
taxel demonstrated a 50% response rate in 52 patients
with metastatic disease.30 Three phase II trials demon-
strated that gemcitabine combined with cisplatin is a
well-tolerated active regimen.31–33 The combination of
cisplatin and gemcitabine has been compared to
methotrexate, vinblastine, doxorubicin, and cisplatin
(MVAC) in a phase III study and the two combinations
were shown to have similar efficacy in metastatic disease.
The gemcitabine/cisplatin combination, however, was
better tolerated and led to fewer hospital days for the
treatment of toxic side effects.32 It is, therefore, consid-
ered by many to represent the new standard of care for
metastatic TCC and is under investigation in the adju-
vant setting as well.
The latest national protocol for bladder-sparing treat-
ment (RTOG 02-33) was approved in January 2003. This
is a randomized phase II study comparing two combina-
tions of radiosensitizing chemotherapy, each given con-
currently with a short course of b.i.d. radiation
treatment. Patients received either the combination of
fluorouracil and cisplatin or paclitaxel and cisplatin. This
is followed, in patients whose tumors are successfully
controlled with chemotherapy and radiation, by a three-
 Chapter 22 Selective Bladder Preservation by Combined Modality Treatment 397
Table 22-8 Invasive Bladder Cancer Survival Outcomes in
Contemporary Series
Series Stages Number
Cystectomy
USC2 (2001) P2–P4a 633
MSKCC1 (2001) P2–P4a 181
Selective bladder preservation
Erlangen29 (2002) cT2–T4 326
MGH19 (2001) cT2–T4a 190
RTOG18 (1998) cT2–T4a 123
drug adjuvant treatment program utilizing cisplatin,
gemcitabine, and paclitaxel. This regimen has shown the
highest response rate yet observed in published reports in
advanced measurable bladder cancer.22
The 10-year overall survival and disease-specific sur-
vival rates in our bladder-sparing protocols are compara-
ble to the results reported with contemporary radical
cystectomy. For patients of similar clinical and patho-
logic stage, one-third of patients treated on protocol with
the goal of bladder sparing ultimately required a cystec-
tomy. A trimodality approach with bladder preservation
based on the initial tumor response is therefore safe and
appropriate treatment with the majority of long-term
survivors retaining functional bladders. It is clear, how-
ever, that lifelong bladder surveillance is essential
because only prompt salvage therapy can prevent a focus
of new or recurrent bladder cancer from disseminating.
We would conclude that selective bladder sparing
should be one of the approaches considered in the treat-
ment of invasive bladder cancer. While it is not sug-
gested that it will replace radical cystectomy, sufficient
data now exist from many international prospective
studies to demonstrate that it represents a valid alterna-
tive. This approach contributes significantly to the
quality of life of patients so treated and represents a
unique opportunity for urologic surgeons, radiation
oncologists, and medical oncologists to work hand in
hand in a joint effort to provide patients with the best
treatment for this disease.
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13. Dunst J, Sauer R, Schrott KM, et al: Organ-sparing
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14. Tester W, Porter A, Heaney J, et al: Neoadjuvant
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15. Housset M, Maulard C, Chretien YC, et al: Combined
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16. Housset M, Dufour E, Maulard-Durtux C: Concomitant
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17. Sauer R, Birkenhake S, Kuhn R, et al: Efficacy of
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20. Hagan MP, Winter KA, Kaufman DS, et al: RTOG
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retained bladder. Urol 2001; 58:380–385.
25. Zietman AL, Sacco UE, Skowronski E, et al: Organ
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28. Wijkstrom H, Norning U, Lagerkvist M, et al: Evaluation
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C H A P T E R
23 Noncontinent and Continent
Cutaneous Urinary Diversion
Tracy M. Downs, MD, Maxwell V. Meng, MD,
and Peter R. Carroll, MD
Urinary diversion is necessary in patients who undergo
cystectomy for bladder cancer, as well as in some patients
with severe functional or anatomic abnormalities of the
lower urinary tract. Alternative urinary drainage may be
either temporary or permanent. Permanent forms of uri-
nary diversion can be accomplished by establishing direct
continuity between the urinary tract and the skin or,
more commonly, by interposing a segment of bowel
between the urinary tract and skin. Nearly all segments
of bowel have been described for use in urinary diversion,
and despite extensive study, no single method or portion
is ideal for all patients and clinical settings. The specific
method of urinary diversion should be selected based on
the indication for diversion, individual patient prefer-
ence, anatomy, renal function, and overall health.
Urinary diversions can be broadly categorized into
those that are continent (i.e., store urine with intermit-
tent drainage) and those that are noncontinent (i.e., con-
tinuous urine output). Continent forms of urinary
diversion are achieved with either a continence mecha-
nism to an abdominal stoma or with an orthotopic blad-
der substitute relying on intrinsic continence after
anastomosis to the native urethra. Noncontinent types of
urinary diversion generally act simply as a conduit
through which the urine exits the body, thus requiring an
external appliance to collect the urine. Although conti-
nence after reconstruction permits freedom from an
external collection bag, these operations may be techni-
cally more difficult and associated with higher complica-
tion rates. Continent diversion, however, can benefit the
patient with regard to psychologic aspects, with pre-
served self-image and sexuality. Overall, patients report a
high level of satisfaction with both continent and non-
continent forms of urinary diversion.1 This chapter
describes permanent forms of cutaneous urinary diver-
sion, both noncontinent and continent. Temporary forms
of urinary diversion, such as percutaneous nephrostomy,
are discussed elsewhere.
PREOPERATIVE PREPARATION
Preoperative counseling is crucial. The discussion should
include the specific goals and complications of the
planned procedure, as well as what the patient should
expect after surgery in terms of changes in lifestyle.
Noncontinent diversion may be the most appropriate
alternative in the debilitated patient and those who lack
the manual dexterity or motivation to care for a conti-
nent reservoir. In addition, a thorough history should be
obtained, including previous surgical procedures, associ-
ated medical conditions, systemic diseases, and previous
irradiation. The patient should be specifically questioned
regarding a history of regional enteritis, ulcerative colitis,
diverticulosis and diverticulitis, and other gastrointestinal
problems; this helps identify which segment of bowel can
be used or avoided. Although the ileal conduit is most
popular, use of the colon has several advantages.
Antireflux mechanisms are possible using the ileocecal
valve or tenia, and the large lumen reduces the incidence
of stomal stenosis.
An assessment of renal function is important and pre-
operative imaging of the upper urinary tract can reveal
abnormalities, such as nephrolithiasis, hydronephrosis,
and renal scarring. Additional evaluation of the bowel by
contrast imaging or endoscopy should be considered in
patients with a history of gastrointestinal diseases or signs
and symptoms suggesting such diseases. The patient’s
overall state of health and fitness for surgery needs to be
399
400 Part IV Bladder
evaluated, especially in the older individual with bladder
cancer and typical comorbidities.
It is essential to address issues of stomal care before
surgery. Patients who are physically or mentally chal-
lenged may need assistance from a family member or vis-
iting nurse. In general, the collecting device is changed
every 4 to 5 days. The stoma site should be carefully
selected prior to surgery, and consultation and subse-
quent follow-up with an enterostomal therapist can be
valuable. The patient is evaluated in both the sitting and
standing position to ensure that the stoma is located away
from bony prominences, fat folds, prior abdominal scars,
and clothing waistbands (i.e., belts), all of which can
make it difficult for the external appliance to fit securely.
The usual site is located along a line from the anterior
superior iliac spine and the umbilicus, at the lateral edge
of the rectus abdominus muscle. It is important to bring
the stoma through the rectus muscle to help prevent the
development of a parastomal hernia.
Adequate preoperative bowel preparation is important
for reducing infectious complications. Patients are typi-
cally placed on a clear liquid diet 2 days prior to their
scheduled procedure. A mechanical bowel prep (Go-
lytely) is started one day prior to surgery and oral antibi-
otics (neomycin + erythromycin) are given after
completion of the mechanical bowel prep. Systemic
antibiotics are administered during the perioperative
period.
POSTOPERATIVE CARE
Several general principles of postoperative care apply
to the various types of urinary diversion. As with most
intra-abdominal operations, paralytic ileus commonly
occurs after using intestinal segments for urinary diver-
sion. Thus, a nasogastric tube is routinely placed for gas-
tric decompression and removed when bowel function
returns. More recently, the nasogastric tube is removed
immediately after the operation with infrequent need for
replacement and improved patient’s comfort. In order to
minimize antibiotic-associated complications, prophylac-
tic antibiotics should be continued for only 24 hours after
surgery. Fluid balance should be closely monitored and
postoperative fluid replacement should be calculated
from maintenance requirements, third-space loss, drain
output, and systemic conditions leading to hypermetabo-
lism. Serum electrolytes are checked for imbalances.
Patients undergoing pelvic surgery are at risk for venous
thromboembolic events, which can be reduced with the
use of sequential compression devices and early ambula-
tion. Incentive spirometry can improve pulmonary func-
tion and lessen respiratory complications. If ureteral
stents are used, they are typically removed on the fifth
postoperative day and after 3 weeks for an ileal conduit
and continent diversion, respectively. Evidence of urinary
leak is provided by the volume of drain output and quan-
titation of fluid creatinine. In patients with a continent
cutaneous or orthotopic diversion, a Foley catheter is
used to drain the pouch. Manual irrigation of the catheter
(60 to 100 ml saline) is performed at 4- to 6-hour inter-
vals to prevent mucus obstruction. While hospitalized,
patients become familiar with the catheterization and
irrigation process. Plain radiography with instillation of
iodinated contrast into the pouch is performed prior to
removing the Foley catheter to ensure watertight
integrity. If a suprapubic tube is placed at the time of sur-
gery, it can be removed after the contrast imaging study
or left as a safety valve, while the patient demonstrates
adequate emptying by catheterization. At home, the
patient continues to irrigate the pouch 2 to 3 times per
day, helping eliminate mucus debris. Since continent
reservoirs develop chronic bacteriuria, antibiotics should
only be given if the patient is symptomatic.
NONCONTINENT URINARY DIVERSIONS:
SURGICAL TECHNIQUE
Urinary Diversion to the Abdominal Wall
Cutaneous Pyelostomy
Cutaneous pyelostomy was originally reported by
Immergut et al.2 as a method of diverting urine in chil-
dren with tortuous, dilated ureters. The relative lack of
subcutaneous fat, underdevelopment of the flank muscu-
lature, and renal mobility in children facilitate the oper-
ation.3 Although useful as a temporizing procedure in
children with gross infection, urinary obstruction, and
especially in the setting of renal failure, current indica-
tions are limited. The technique requires the presence of
an extrarenal pelvis. Pyelostomy is an alternative to per-
cutaneous nephrostomy in small infants, where place-
ment of a nephrostomy tube can be difficult and
long-term maintenance may pose a problem for parents.4
Technique. The renal pelvis is identified and mobi-
lized through a subcostal incision. There is no need to
mobilize the ureter or disrupt its collateral circulation.
The kidney is rotated anteriorly, and a 3-cm incision is
made in the renal pelvis well away from the ureteropelvic
junction (Figure 23-1A). The renal pelvis is brought out
to the skin incision and anastomosed to the skin using
interrupted absorbable sutures (Figure 23-1B). The
remainder of the incision is closed in the usual fashion.
Cutaneous Ureterostomy
The first cutaneous ureterostomy was performed by
LeDentu in 1889 and represents a simple method of uri-
nary diversion.5 End cutaneous ureterostomy has been
used as a means of temporary diversion in infants and pal-
liative diversion in adults6,7; delayed reconstruction after
cutaneous ureterostomy can be successfully performed.8
 Chapter 23 Noncontinent and Continent Cutaneous Urinary Diversion 401
Figure 23-1 A, The renal pelvis is incised for approximately 3 cm. B, The renal pelvis is
anastomosed to the skin using interrupted sutures.
The advantages of cutaneous ureterostomy include
decreased operative and recuperative times, as well as the
use of an extraperitoneal approach.9 In addition, compli-
cations associated with the use of bowel, such as intestinal
anastomosis and absorption of urinary constituents, are
avoided.10 Disadvantages of cutaneous ureterostomy
include the risk of stomal stenosis, chronic bacteriuria,
and stone formation.
A dilated ureter is usually necessary for a successful
outcome, facilitated by the thick-walled, well-vascular-
ized ureter.11 If both ureters are dilated and have ade-
quate length, each can be brought out to the skin. If only
one ureter is dilated, this should be used for the cuta-
neous ureterostomy with proximal transureteroureteros-
tomy of the contralateral, nondilated ureter.8,12
Technique. When both ureters are dilated, a double-
barreled cutaneous ureterostomy is fashioned with the
stoma on the side of the shorter ureter. In the case of
unilateral ureteral dilation, the stoma is created on that
side. Only a single stoma site, with one appliance, is
required whether one or both ureters are brought to the
skin.
The ureter is mobilized extraperitoneally with careful
preservation of the collateral blood supply. If possible,
the ureter should be freed to the level of the bladder to
maximize length. Prior to transecting the ureter, the
ureter is measured to ensure that it is adequate.
If only a single ureter is obstructed, a simple stoma can
be created by sewing the end of the ureter flush with the
skin at the stoma site. Another option, when the ureter is
narrow, is to create a V-flap stoma (Figure 23-2A–C). If
both ureters are dilated, a single stoma can be created by
suturing the ureters together, everting them and anasto-
mosing the ends to the skin. Alternatively, a Z-plasty can
be performed when the ureters are not adequately dilated
(Figure 23-3A–C).12 When a single ureter is dilated,
transureterostomy with retroperitoneal passage of the
smaller ureter to the contralateral side is combined with
the cutaneous ureterostomy. Both ureters need to be free
from angulation and tension. The larger ureter is incised
2 cm on its medial aspect, and the smaller ureter is
trimmed to the appropriate length and spatulated. The
ureteral–ureteral anastomosis is performed using a run-
ning absorbable suture; ureteral stents may be placed
prior to this portion. The stoma is fashioned as previ-
ously described for a single ureter.
Conduits to the Abdominal Wall
Ileal Conduit
Seiffert13 first described an ureteroileocutaneous diver-
sion in 1935. The procedure was subsequently popular-
ized by Bricker14 and remains the most commonly used
method of noncontinent urinary diversion in the United
402 Part IV Bladder

Figure 23-2 A, The ureter is brought through the skin and spatulated. B, C, The Ureter is
everted and the anastomosis is performed using several interrupted absorbable sutures.

Figure 23-3 A–C, After making a Z-shaped incision, the ureters are spatulated on their
lateral aspects and sutured to the skin.
 Chapter 23 Noncontinent and Continent Cutaneous Urinary Diversion 403
States. Patient selection, proper stoma location, and
careful technique in creating a well-vascularized stoma
are all important to the success of the procedure.
An ileal conduit may be contraindicated in patients
with a history of regional enteritis or extensive pelvic
irradiation.15 In these situations, a colon conduit may be
preferable. The typical stoma is located in the right lower
quadrant, as previously described. In order to minimize
the absorptive surface of the bowel in contact with urine,
the ileal segment should be as short as feasible.
Reabsorption of urinary constituents does not cause a
significant problem in patients with normal renal func-
tion but metabolic abnormalities may develop in those
with renal insufficiency.16
Technique. The conduit is usually constructed using a
segment of ileum approximately 15 cm proximal to the
ileocecal valve. The exact length of the conduit varies
with patient habitus but averages between 15 and 20 cm
in most patients (Figure 23-4A). Preservation of the vas-
cular supply to the ileal segment is vital. Transillumination
of the mesentery helps identify the blood vessels supply-
ing the bowel, and at least two major vascular arcades
should be included with the ileal segment. Once the
appropriate area of ileum is identified and isolated, the
mesentery is divided proximally and distally with individ-
ual ligation of vessels. The bowel is divided between
clamps or using a GIA stapler. Bowel continuity is
reestablished by suturing or with the aid of stapling
Figure 23-4 A, An appropriate segment of ileum is selected, containing two major vascular
arcades. B, The conduit is positioned in the right lower quadrant and the ureters are
reimplanted into the base of the conduit.
devices. The ileal segment is brought below the level of
the ileoileal reanastomosis. The conduit is positioned cau-
dally, usually with the end in the right lower quadrant in
an isoperistaltic direction; the base of the conduit is closed
with either absorbable sutures or a stapler (Figure 23-4B).
The left ureter is brought under the sigmoid mesocolon
and both ureters are spatulated and reimplanted into the
base of the conduit. The various types of ureteral anasto-
moses will be discussed later. Ureteral stents are placed
and brought out via the abdominal stoma to facilitate uri-
nary drainage and stent the anastomoses. The mesentery
is reapproximated using nonabsorbable sutures to prevent
internal bowel herniation.
To create the stoma, a small circle of skin is excised at
the premarked site, and the underlying cylinder of fat
is removed. A cruciate incision is made in the anterior
fascia, large enough to accommodate two fingers (Figure
23-5A). The stents and the end of the conduit are brought
through the rectus abdominus muscle and fascia; the end
of the conduit is then secured to the fascia (Figure 23-5B).
If present, the distal staple line is excised and the stoma is
everted to create a “rosebud” (Figure 23-5C). The stoma
should ideally protrude, without tension, 2 to 3 cm above
the surface of the skin. In patients with short mesentery or
thick abdominal wall, a Turnbull loop can be created to
maximize stomal vascularity.17 When properly con-
structed, both end- and loop-cutaneous stomas have com-
parable long-term results in patients with ileal conduits.18
404 Part IV Bladder
Figure 23-5 A, The rectus fascia is incised in a cruciate fashion. B, The end of the conduit
is brought through the rectus muscle and anchored to the fascia. C, The stoma is everted
and sutured to the skin.
Jejunal Conduit
Jejunal conduit urinary diversion should be reserved for
patients in whom other, more suitable options are
unavailable. These include those with prior pelvic radia-
tion, inflammatory bowel disease, or loss of the middle
and distal ureters. Electrolyte disturbances are common
in those with urinary conduits using the jejunum.19
Technique. As with other bowel segments incorpo-
rated into the urinary tract, the length of jejunum should
be as short as possible to reduce metabolic abnormalities;
in some cases, the stoma can be placed above the umbili-
cus. The site, distant from the belt line, should be care-
fully considered and marked before surgery.
Patients who have received significant pelvic radiation
may require transection of the ureters at the level of the
true pelvis (pelvic inlet). The ureters are brought out
from the retroperitoneum below the ligament of Treitz.20
An appropriate segment of jejunum is identified and iso-
lated, as described for ileal conduits. It is important to
preserve an adequate blood supply to the segment. The
jejunum is divided between either clamps or the GIA sta-
pler and then continuity is restored. In contrast to the
ileal conduit, the isolated jejunum should lie above the
reanastomosed jejunum. The proximal end of the con-
duit is directed towards the retroperitoneum and the
conduit is oriented in an isoperistaltic direction. The
ureters are anastomosed to the jejunum, with placement
of stents to reduce early postoperative electrolyte abnor-
malities.15 The mesenteric window is closed using non-
absorbable sutures. The stoma is created in the same
fashion as described for an ileal conduit; the stoma is usu-
ally located in the right upper quadrant when using
jejunum.
Colonic Conduits
The colon conduit was popularized by Turner-
Warwick21 in 1960. Urinary conduits constructed from
large intestine have several potential advantages when
 Chapter 23 Noncontinent and Continent Cutaneous Urinary Diversion 405
compared to those made using small intestine. First, non-
refluxing ureteral anastomoses are possible using either a
short tunnel through the teniae coli or the ileocecal
valve. Second, stomal stenosis is less common due to the
larger lumen of the colon. Third, a suitable segment of
colon outside of the field of previous abdominal or pelvic
irradiation is usually available. When use of the colon is
anticipated, a preoperative contrast imaging study of the
large bowel or colonoscopy should be considered.
Ileocecal Conduit
The ileocecal conduit was first described by Zinman and
Libertino22 in 1975. This method utilizes the ileocecal
valve as an antireflux mechanism for the ureters. Other
advantages of this portion of bowel include the constant
and abundant blood supply and location in the right
lower quadrant, facilitating stoma formation.3 The ileo-
cecal segment is rarely affected by generalized bowel dis-
orders, such as diverticulitis.
Technique. The blood supply of the ileocecal region
is based on the ileocolic artery. The segment, including
10 cm of terminal ileum, is isolated and the appendix is
removed. After restoring continuity between the ileum
and ascending colon, the ureters are anastomosed
directly into the ileal portion of the segment. The antire-
Figure 23-6 A, An appropriate segment of transverse colon is selected. B, After
colocolostomy, the ureters are brought into the abdominal cavity and the ureteral
anastomoses are performed.
flux mechanism depends on the competency of the ileo-
cecal valve, which can be reinforced by wrapping the
redundant cecum around the ileum and securing this
configuration with seromuscular sutures.22 The proximal
portion of the conduit is fixed to the retroperitoneum,
and the distal cecal portion is brought out to the skin. An
everted stoma is created in the standard rosebud fashion.
Transverse Colon Conduit
The transverse colon conduit is well suited for patients
who have received extensive pelvic irradiation, making
the small bowel suboptimal, or situations where the dis-
tal ureters are damaged or absent. In situations of inade-
quate ureteral length, the transverse colon segment can
be directly anastomosed to both renal pelves.
Technique. A 15-cm segment of transverse colon is
used for the conduit. The blood supply is based on the
middle colic artery, and transillumination of the trans-
verse mesocolon assists in identifying the appropriate
segment (Figure 23-6A). The greater omentum is dis-
sected from the superior aspect of the transverse colon
and the mesentery is incised, with ligation of individual
blood vessels. The colon is divided both proximally
and distally, and bowel continuity is restored. The iso-
lated transverse colonic segment should lie below the
406 Part IV Bladder
reanastomosed transverse colon. Mobilization of the
right colon can ensure that the colocolostomy is created
without tension. The proximal end of the colon conduit
is closed and fixed posteriorly. The ureters are mobi-
lized and then the ends are spatulated and brought
through the posterior peritoneum into the abdominal
cavity. The ureters are reimplanted into the base of the
conduit in either a direct or nonrefluxing manner and
ureteral stents are placed (Figure 23-6B). A flap of peri-
toneum is fashioned to cover the ureteral anastomoses.
A standard rosebud technique is used to create the
stoma, which can be positioned on either side in the
upper or lower quadrant.
Sigmoid Colon Conduit
The sigmoid colon conduit should be avoided in patients
with a history of pelvic irradiation. In these cases, the
superior hemorrhoidal artery is often injured, leaving an
inadequate blood supply to the sigmoid segment. A sig-
moid conduit is also questionable in those undergoing
cystectomy because the vascular supply to the rectum
may be compromised if the internal pudendal artery is
ligated. However, the sigmoid can be used after pelvic
exenteration, since it obviates the need for intestinal
reanastomosis. A sigmoid colon conduit is commonly
used for the management of benign conditions of the
lower urinary tract, such as neurogenic bladder, requiring
urinary diversion.
Technique. The sigmoid colon is mobilized by lateral
incision along the white line of Toldt; adequate mobiliza-
tion makes the bowel reanastomosis easier. The optimal
segment is identified, typically 10 to 12 cm in length.
After short incisions in the mesentery are made, the prox-
imal and distal ends of the colonic segment are divided.
The superior hemorrhoidal artery can be divided for
increased mobility. Bowel continuity is reestablished, with
the conduit placed laterally to the anastomosis. The right
ureter is brought under the sigmoid colon, and the ureters
are sewn using either a direct or nonrefluxing technique.
The preferred stoma site, created as previously described,
is on the left side of the abdomen.
CONTINENT URINARY DIVERSIONS: SURGICAL
TECHNIQUE
Continent cutaneous (i.e., nonorthotopic) techniques can
be divided into two major categories: (1) urinary diver-
sion into the rectosigmoid and (2) continent urinary
pouches requiring clean intermittent catheterization.
Because numerous variants of continent urinary diver-
sion are used worldwide, a complete review of all opera-
tive techniques is beyond the scope of this chapter. This
chapter focuses on the most commonly utilized and
described continent urinary diversions.
RECTAL BLADDER URINARY DIVERSION
The rectal bladder urinary diversions allow excretion of
urine my means of evacuation. Innovative techniques
have been advocated for separating the fecal and urinary
streams, but all still employ the principle of ureterosig-
moidostomy. Variations of the original ureterosigmoi-
dostomy include the ureter ileosigmoidostomy, folded
rectosigmoid bladder, and augmented valve rectum pro-
cedures, in which different segments of small intestine
are anastomosed to the rectum. These operations will be
grouped and discussed together as “rectal bladder urinary
diversions.”
In each of these operations, with the exception of cer-
tain types of augmented valve rectum procedures, the
ureters are transplanted to the rectal stump and the prox-
imal colon is managed by terminal sigmoid colostomy or,
more commonly, by bringing the sigmoid to the per-
ineum, using the anal sphincter to achieve both bowel
and urinary control. Although these operations continue
to enjoy some popularity abroad, they have never been
widely accepted in the United States.
Ureterosigmoidostomy
Ureterosigmoidostomy can be regarded as the original
continent urinary diversion with reports of this procedure
dating as far back as the 1850s.23,24 Its appeal to the uro-
logic surgeon has waned given issues of transplanting the
ureters directly to an intact fecal stream and development
of malignancy, and considerable complications, including
hyperchloremic acidosis, hypokalemia with nephropathy,
and pyelonephritis. Nevertheless, ureterosigmoidostomy
offers a simple form of continent urinary diversion when
compared with the newer techniques requiring complex
refashioning of bowel segments.25,26 Currently, most
urologists reserve the procedure only for those individu-
als of advanced age where adverse long-term sequelae are
less important. Several other factors argue against the use
of ureterosigmoidostomy. In patients with neurogenic
bladder, there may be associated bowel or anal sphincter
dysfunction. Individuals with dilated ureters are at
increased risk for developing either obstruction or reflux,
while extensive prior radiation may affect both the bowel
and distal ureters. Patients with preexisting renal insuffi-
ciency are poor candidates for ureterosigmoidostomy or
any continent diversion27,28; similarly, those with underly-
ing hepatic dysfunction are at risk for developing ammo-
nia intoxication.29 Preoperative evaluation of the patient
should include barium enema and/or colonoscopy that
would detect bowel disease, such as diverticulitis, polyps,
or cancer.
Incontinence of the mixture of stool and urine is a
calamitous complication. Thus, an adequate test of pre-
operative anal sphincter integrity is mandatory and anal
 Chapter 23 Noncontinent and Continent Cutaneous Urinary Diversion 407
sphincteric tone must be judged competent before one
selects this procedure. Various tests have been proposed
to measure sphincter function. The most useful are those
that require the retention of an enema solution of both
solid and liquid material for a specified time in the
upright and ambulating positions without soilage.
Bissada et al.26 use a saline retention enema that the
patient holds for 1 hour, while Benson et al.15 advocate
the use of a 400- to 500-ml thin mixture of oatmeal and
water that the patient attempts to retain for 1 hour in the
upright position.28
Technique
If indicated, cystectomy is performed first. At the start of
urinary diversion part of the procedure, a large-caliber
(24Fr to 28Fr) red rubber catheter is placed in the rec-
tum, advanced through the anus and sutured in place to
the perianal skin. This tube should be advanced suffi-
ciently far that it can be easily reached and remains in
place after surgery to drain urine and potentially to
decrease the risk of anastomotic leakage.
A permanent end colostomy is created by dividing the
descending sigmoid colon at the junction of its middle
and lower thirds with complete closure of the distal rec-
tosigmoid segment with absorbable sutures, rather than
staples, to reduce the potential for postoperative calculus
formation in the rectosigmoid reservoir. The proximal
sigmoid colon is diverted to a premarked end colostomy
stoma site.
The most distal portion of the rectosigmoid is the pre-
ferred site for the ureteral anastomosis. In the Leadbetter
technique,30 the left ureter is brought through the sig-
moid mesentery. After both ureters have been mobilized,
stay sutures are placed proximally and distally in an
antimesenteric tenia 10 to 15 cm apart and a longitudinal
incision of 5 to 7 cm is made. The distal end of the ureter
is spatulated and a mucosal to mucosal anastomosis is
performed with fine absorbable suture material (Figure
23-7). The muscularis of the tenia is then closed over the
ureter with interrupted absorbable sutures to form the
submucosal tunnel. The contralateral anastomosis is
made in the same fashion; generally, the right ureter is
anastomosed most distally.
Goodwin and colleagues30a published their experience
with the transcolonic (open colon technique) of ureteral
anastomosis (Figure 23-8A–D). This technique differs
from Leadbetter’s method in that the rectosigmoid is
opened anteriorly and the ureters are brought through a
separate submucosal tunnel in the posterior wall into the
bowel lumen. The ureters are sutured, separately or con-
joined (i.e., Wallace technique), to the mucosa from within
the bowel lumen. After ureteral anastomosis and ureteral
stent placement have been completed, the colon is closed
with a simple 2-layer technique (see Figure 23-8C ). The
Figure 23-7 Leadbetter-Clarke ureterointestinal anastomosis.
A linear incision is made in the taenia, the taenia is raised and
the mucosa is identified. A small button of mucosa is
removed and the ureter is spatulated and then sutured to the
mucosa with 5-0 PDS. The sero-muscular layer is sutured
over the ureter with care taken not to compromise or occlude
the ureter.
inner layer is closed with a running suture of absorbable
material taken through all layers of intestine, whereas the
outer layer is closed with seromuscular nonabsorbable
material. Although intubation of the ureters and stent
placement are feasible using the Leadbetter technique of
ureteral implantation, the transcolonic approach (anterior
colotomy) (see Figure 23-8B) affords greater ease in
directing the ureteral stents to the outside.
The ureterocolonic anastomoses can be retroperi-
tonealized. In addition, it is often helpful to suture the
proximal end of the isolated rectosigmoid to the sacral
promontory to prevent excessive mobility. One or 2
intraabdominal drains are typically placed, as well as a
rectal tube.
CONTINENT CATHETERIZABLE URINARY
DIVERSIONS
Numerous operative techniques have been developed for
continent catheterizable urinary diversions. Patient
selection is important in deciding which patients are
most suitable for a continent catheterizable urinary
diversion. To perform clean intermittent catheterization,
it is paramount that one has good hand-eye coordination.
Thus, patients with spinal cord injury (e.g., quadriplegia)
or some with multiple sclerosis or other neurologic dis-
orders may not be candidates. Patient with any cognitive
condition, such as dementia, that could lead to a poor
understanding of the catheterization process would not
be an appropriate candidate.
The choice of where to place the catheterizable stoma
is based on the preference of the surgeon. The two most
common sites are at the umbilicus and in the lower quad-
rant of the abdomen, through the rectus bulge and below
408 Part IV Bladder

Figure 23-8 A, The open colostomy approach is preferred because it allows the placement
of indwelling ureteral stents bilaterally. B, The stents are directed to the outside through the
lumen of the rectal tube. C, The colon is closed with a simple two-layer technique. The
retroperitoneal windows are closed with a running suture.
 Chapter 23 Noncontinent and Continent Cutaneous Urinary Diversion 409
Figure 23-8 cont’d D, The ureteral colonic anastomoses are retroperitonealized if possible.
(From Walsh P, Retik A, Vaughn EJ, et al (eds): Campbell’s Urology, 8th ed, Philadelphia,
WB Saunders, 2002.)
the “bikini line.” The latter site affords both men and
women the opportunity to conceal the stoma. In certain
patients the umbilicus is the preferred location. For
example, in the individual confined to a wheelchair, the
umbilical stoma location may have a lower incidence of
stomal stenosis, especially when fashioning an appen-
diceal stoma. The umbilical location is also ideal in
paraplegics because it allows easier catheterization
without the need for chair transfer and disrobing.
Cosmetically, the umbilical location of a stoma is typi-
cally indistinguishable from a normal umbilical dimple.
Patients are instructed to cover the stomal site with a
gauze or square adhesive bandage to avoid mucus soil-
ing of clothing.
CONTINENCE MECHANISM
Perhaps the single most demanding technical aspect dur-
ing creation of a continent urinary diversion is construc-
tion of the continence mechanism. It is the success or
failure of this mechanism that ultimately determines the
success or failure of the urinary diversion. Four surgical
techniques have been incorporated to create a reliable,
catheterizable continence mechanism: (1) appendiceal;
(2) pseudoappendiceal tubes fashioned from ileum or
right colon; (3) intussuscepted nipple valve or flap valve,
which avoids the need for intussusception; (4) the
hydraulic valve (e.g., Benchekroun nipple).31
Two techniques of appendiceal continence mecha-
nisms have been reported. Mitrofanoff43 reported excis-
ing the appendix with a button of cecum and reversing it
on itself before tunneled reimplantation.44 Alternatively,
Riedmiller et al.45 have left the appendix attached to the
cecum and buried it into the adjacent taenia by rolling it
back onto itself. A wide tunnel is created in the taenia
extending 5 to 6 cm from the base of the appendix
(Figure 23-9A,B) and windows are created in the
mesoappendix between blood vessels. The appendix is
folded cephalad into the tunnel, and seromuscular
sutures are placed through the mesoappendix windows to
complete the tunneling. The tip of the appendix is ampu-
tated and brought to the selected stomal site.
For right colon pouches, an appendiceal tunneling
technique is the simplest to perform. The in situ or trans-
posed appendix is tunneled into the cecal taenia, similar to
that of the previously described ureterocolonic anastomo-
sis. Appendiceal continence mechanisms have been criti-
cized for three reasons. First, the appendix may be
unavailable in some patients because of prior appendec-
tomy. Second, the appendiceal stump may be too short to
reach the anterior abdominal wall or umbilicus, while still
maintaining sufficient length for tunneling. Third, the
410 Part IV Bladder
large amount of mucus produced by an intestinal reser-
voir is more easily emptied or irrigated with a larger
catheter (20 Fr to 22 Fr) rather than the typical smaller
diameter catheter (14 Fr or 16 Fr) that is accommodated
through an appendiceal stump. Several of these criticisms
have been addressed by modifying surgical technique. In
individuals who had a prior appendectomy, a pseudoap-
pendiceal tube can be fashioned from ileum32 or from the
wall of the right colon.33 In cases where the appendiceal
stump is too short to reach the anterior abdominal wall or
umbilicus, Burns and Mitchell34 lengthen the appendiceal
stump by including a tubular portion of the proximal
cecum. This has the added advantage of allowing a
slightly larger stoma made of cecum that is less prone to
stomal stenosis. Overall, the appendiceal or pseudoappen-
diceal continence mechanism remains a very attractive
and reliable continence mechanism.
The second major type of continence mechanism used
in right colon pouches is the tapered and/or imbricated
terminal ileum and ileocecal valve. The technique is
rather simple, with imbrication or plication of the ileoce-
cal valve region along with tapering of the more proximal
ileum in the fashion of a neourethra35–37 and afford a reli-
able continence mechanism.
The creation of intussuscepted nipple valves is the
most technically demanding of continence mechanisms
and also is associated with the highest rates of complica-
tion and reoperation. The procedure has a significant
learning curve and, therefore, should probably not be
chosen by the surgeon who infrequently constructs con-
tinent pouches.
A major advance in nipple valve construction includes
removal of mesenteric attachments from the middle 6 to
8 cm of bowel,38 thereby reducing the tethering effect of
Figure 23-9 A and B, The appendix is left attached to the cecum and buried into the
adjacent cecal taenia by rolling it back onto itself. A wide tunnel is created that extends 5 to
6 cm from the base of the appendix. Windows are created in the mesoappendix between
blood vessels. The appendix is folded cephalad into the tunnel, and seromuscular sutures
are placed through the mesoappendix.
the mesentery that otherwise induces eversion and
effacement of the intussusception. A second major mod-
ification has been the attachment of the nipple valve to
the reservoir wall itself. This has been achieved by 2 or 3
different stapling techniques, as well as by a suturing
technique described by Hendren38 and King.39,40 Despite
meticulous surgical technique and the most experienced
surgeons, nipple valve failure can be anticipated in 10%
to 15% of cases. In addition to being subject to slippage,
nipple valves may develop ischemic atrophy; if this
occurs, a new nipple valve must be fashioned from a new
bowel segment.
Several institutions have introduced numerous modi-
fications of the original Kock technique for constructing
a nipple valve given the disappointing long-term stability.
The group at the University of Southern California has
developed the T pouch using a flap valve.41 The proce-
dure is much simpler, avoiding the need for intussuscep-
tion, and is used to create both a continence mechanism
and an antireflux mechanism.
Benchekroun42 describes a hydraulic valve nipple. In
this procedure, a small bowel segment is isolated and a
reversed intussusception is carried out, apposing the
mucosal surfaces of the small bowel. Tacking sutures are
taken to a portion of the circumference of the intussus-
ception to stabilize the nipple valve, while allowing urine
to flow freely between the leaves of apposed ileal mucosa.
The Benchekroun hydraulic ileal valve may be the one
diversion in which reservoir detubularization actually
impairs the continence rate because the valve mechanism
depends on pouch pressure for continence. Without ele-
vated pouch pressure, there is no forceful apposition of
the serosal leaves of the valve. Although there are reports
in the literature of reasonable success, concerns regard-
 Chapter 23 Noncontinent and Continent Cutaneous Urinary Diversion 411
ing the long-term durability of this mechanism have
resulted in lack of widespread use.
INTRAOPERATIVE POUCH TESTING
Following pouch construction and completion of the
continence mechanism, it is essential that both the pouch
and continence mechanism be examined in detail in the
operating room. Typically, the pouch is filled with saline
or water, the catheter is removed, and the pouch is com-
pressed lightly as the surgeon examines the pouch for any
points of leakage, as well as observing the ability of the
pouch to contain urine. Next, the pouch is recatheterized
to ensure smooth passage of catheter passage. This is a
critical maneuver because the inability to catheterize is a
serious complication that often results in the need for
reoperation.
In general, all redundancy should be removed from
the continence mechanism. It is often useful to secure the
reservoir to the anterior abdominal wall in a manner that
allows the reservoir to surround the aditus, preventing
the development of a false passage or a kink and thereby
facilitating catheterization.
CONTINENT RESERVOIRS
Continent Ileocecal Reservoirs
Kock Pouch
In 1982, Kock et al.46 reported the first 12 cases on
their continent ileocecal reservoir, stimulating world-
wide interest in continent urinary diversion proce-
dures. However, the initial enthusiasm with this
technique is tempered by a complication rate requiring
additional surgery in half of patients, primarily for mal-
function of the efferent valve. Since then, the Kock
pouch has undergone several modifications. Skinner et
al.47,48 have carefully studied and improved the tech-
nique over the years. Although some individuals still
perform the original procedure, technical difficulties
and significant complication rates have led to the pro-
cedure being abandoned by most urologic surgeons.
This operation and the similarly constructed T pouch
are the only catheterizable continent diversions that
preserve the ileocecal valve.
Technique. An 80-cm small bowel segment is iso-
lated approximately 15 to 50 cm proximal to the ileo-
cecal valve. A stapling device is used to isolate the
segment of small bowel and the continuity of the small
bowel is reestablished with closure of the mesenteric
window to prevent incarceration of the bowel. Division
of the mesentery should extend to the base of the
mesentery to ensure sufficient mobility of the efferent
limb of the pouch. Next, the proximal and distal 15 to
20 cm of the isolated segment are preserved for cre-
ation of the afferent and efferent nipple valves, and the
remaining 40 to 50 cm of the bowel segment are
brought together as a U-shaped plate, with the apex
directed to the proposed stoma site. The U-shaped
plate is opened using electrocautery and an absorbable
suture is used to close the posterior wall of the opened
intestinal plate (Figure 23-10A–E). The proximal and
distal valves are then created by intussuscepting
approximately 10 cm of ileum at each end; the proxi-
mal 10 cm serves as the valve and the distal 5 to 10 cm
the patch (Figure 23-10A). The middle 6 to 8 cm of
the 10-cm proximal intussuscepted segment is
denuded of mesentery by electrocoagulation on each
side flush with the serosa of the ileum. Allis or
Babcock clamps are passed through the open limbs,
and intussuscepted nipple valves are created by pulling
back the intraluminal bowel wall into the opening of
the reservoir to be created (Figure 10B). In order to
maintain the intussusception, 3 to 4 parallel rows of
staples (TA-55, 4.8-mm staples) are placed along the
entire length of the nipple valves (Figure 23-10C). To
minimize the risk of stone formation, the distal 6 sta-
ples from each cartridge are removed before staple
application to ensure that the tip of the valve is free of
the staples.
The nipple valve is then fixed by 1 or 2 stapling
techniques to the back wall of the patch.39 A small but-
tonhole may be made in the back wall of the ileal plate
so that the anvil of the stapler can be passed through
the buttonhole and advanced into the nipple valve
before application of the fourth row of staples (Figure
23-10D). If this is done, the buttonhole is oversewn
with absorbable material. Alternatively, the anvil of
the stapler can be directed between the two leaves of the
intussuscipiens and the fourth row of staples used to fix
the inner leaf of the nipple valve to the pouch wall
(Figure 23-10E).
Skinner advocates the use of an absorbable polygly-
cotic acid (PGA) mesh collar to anchor the base of the
nipple valve to prevent late slippage or extussusception.
A 2.5-cm wide strip of absorbable mesh is fashioned into
a collar and passed through a separate window in the
mesentery and sewn with seromuscular stitches to
the bowel wall to secure the intussuscepted nipple from
the outside (Figure 23-10F,G). The mesh of the efferent
nipple can also be fixed to the abdominal wall to facili-
tate catheterization. The ureters are spatulated and end-
to-side, mucosa-to-mucosa anastomoses are performed
to the free portion of the afferent nipple; each ureteral
anastomosis is stented. The reservoir is then folded and
closed with a single or double layer continuous
absorbable suture. The abdominal stoma is created by
suturing the efferent nipple valve to the rectus fascia at
the predetermined site and a flush stoma is created. A
Foley catheter is passed through the efferent limb and
left inside the reservoir. Posteriorly the pouch is
412 Part IV Bladder

Figure 23-10 A, A 15-cm segment of terminal ileum is isolated and opened along its
antimesenteric wall. The proximal 10 cm will serve as the continent intussusception and the
distal 5 to 10 cm as the patch. The size of the patch varies according to the size of the
excised segment. B, An Allis clamp or Babcock clamp is advanced into the ileal terminus,
the full thickness of the intussuscipiens is grasped and it is prolapsed into the pouch. C,
Three rows of 4.8-mm staples are applied to the intussuscepted nipple valve using the TA-
55 stapler. D, A small buttonhole is made in the back wall of the ileal plate to allow the anvil
of the staples to be passed through and advanced into the nipple valve. E, The anvil of the
stapler can be directed between the two leaves of the intussuscipiens and the fourth row of
staples applied in this manner. This figure shows two valve mechanisms. In this instance,
there would be only one.
 Chapter 23 Noncontinent and Continent Cutaneous Urinary Diversion 413

Figure 23-10 cont’d F, A 2.5-cm-wide strip of absorbable mesh is placed through

additional windows of Deaver at the base of each nipple valve the mesh strips are fashioned
into collars. G, The collars are sewn to the base of the pouch, as well as to the ileal
terminus with seromuscular sutures.

attached to the sacral promontory with interrupted
sutures.
T Pouch
The group at the University of Southern California has
devised a novel continence mechanism created entirely
from ileum, based on a technique described by Abol-
Enein and Ghoneim49,50 and Bochner et al.51 Abol-
Enein and Ghoneim created an extramural serosal
tunnel into which the ureters were implanted, with the
extramural trough creating a pseudotunnel that pre-
vented reflux with, theoretically, a lower risk of obstruc-
tion than either of the techniques of direct transmural
ureteral implantation described by Goodwin, Leadbetter,
or LeDuc et al.52 Stein et al.41 first reported on the use
of a tapered ileal segment implanted into a serosal
trough as the antireflux mechanism for neobladder.53
Stein et al.54 presented the early experience with a
double T pouch as a replacement for the Kock pouch,
detailing the technique in 9 patients (2 men and 7
women) followed a mean time of 12 months.
Technique. A 70-cm segment of terminal ileum is
isolated 15 to 20 cm from the ileocecal valve. The proxi-
mal isoperistaltic 10- to 12-cm segment is isolated and
serves as the antireflux mechanism, while the distal 12- to
15-cm segment is isolated and rotated in an antiperi-
staltic fashion and becomes the cutaneous continence
mechanism (Figure 23-11A,B). A short (2 to 3 cm)
mesenteric incision is made to isolate the proximal limb
(afferent antireflux limb), and a 4-cm incision is made for
the distal limb (efferent continence limb), thereby pre-
serving the major vascular arches. The proximal and distal
segments can be of various lengths, depending on ureteral
length and the thickness of the anterior abdominal wall.
The middle 44 cm of ileum is folded into a W, with each
limb measuring 11 cm (Figure 23-11B). The afferent
antireflux mechanism is created by opening the windows
of Deaver between the mesenteric vascular arcades along
the distal 3 to 4 cm. The efferent continence mechanism
is created by opening the proximal 7 to 8 cm of vascular
arcades (antiperistaltic) (Figure 23-11C). Quarter-inch
Penrose drains are then placed in each window of Deaver
to facilitate the passage of the 3-0 silk horizontal mattress
sutures that are used to approximate the serosa of the
corresponding 11-cm limbs of the W (Figure 23-11D).
The 3- to 4-cm anchored portion of the proximal limb is
then tapered over a 30Fr catheter and the 7- to 8-cm
anchored portion of the efferent limb is tapered over a
16Fr catheter. In both portions, tapering is performed
with a GIA stapler. In the efferent limb, care must be
taken to create a gradual taper so that the catheter does
not hit a false cul-de-sac (Figure 23-11E). The portions
of the 11-cm W-limbs not forming the troughs are
sutured together with a running suture of 3-0 PGA. The
bowel is now incised along its antimesenteric border in
the portion where the serosal trough exists and in close
proximity to the medial PGA suture lines when beyond
the two limbs (Figure 23-11F). The incised mucosa is
then closed in 2 layers with a running suture of 3-0 PGA.
The incised intestinal flaps (antimesenteric incision)
are then sutured to each ostium with interrupted
sutures of 3-0 PGA and the 2 ileal flaps sutured over
each segment with a running suture of 3-0 PGA
(Figure 23-11G). The reservoir is closed side-to-side in
2 layers with 3-0 PGA, completing its construction
414 Part IV Bladder

Figure 23-11 A, 70-cm segment of terminal ileum is isolated 15 to 20 cm from the

ileocecal valve. B, Proximal 10-cm segment is isolated and rotated toward the reservoir in
an antiperistaltic direction. C, The windows of Deaver are opened to allow the walls of the W
reservoir to be apposed behind the valve mechanisms. Penrose drains are passed to guide
suture passage.
 Chapter 23 Noncontinent and Continent Cutaneous Urinary Diversion 415

Figure 23-11 Cont’d D, Some 3-0 silk horizontal mattress sutures are passed through
each window. The distal continence mechanism is longer than the proximal antireflux
mechanism. E, The proximal and distal mechanisms are tapered with a metal GIA stapler. F,
The bowel is incised along its antimesenteric border where it will overlie the two Ts. Distal to
the Ts, the bowel is incised closed to the approximated limbs of the reservoir. G, The ostia
of the valves are secured to the bowel wall with interrupted absorbable sutures. The two
flaps of ileum are closed over the Ts with running absorbable sutures.
416 Part IV Bladder
Figure 23-11 Cont’d H, The back wall of the reservoir is closed with running absorbable
sutures. I, The lateral walls are folded medially and the construction completed with running
absorbable sutures
(Figure 23-11H,I). The ureters are anastomosed end-
to-side over stents to the proximal limb, which has
been closed with a running absorbable Parker-Kerr
suture. The efferent limb is brought to the abdominal
wall stoma site, the redundant ileum resected, and the
stoma is matured. The reservoir lies immediately adja-
cent to the anterior abdominal wall.
This procedure appears to have many advantages over
the Kock pouch, but long term complications and dura-
bility of this technique cannot be assessed at this time
because of small patient numbers and short follow-up.
Mainz Pouch
In 1986, Thüroff et al.55 presented initial results with a
cecoileal reservoir (Mainz I pouch). A sutured ileoileal
intussusception valve served as the continence mecha-
nism in the first series of patients. Subsequently, the
Mainz pouch has undergone considerable modification
over the years primarily due to problems with the
intussuscepted nipple valve.56–58 The operation has
now been modified by replacing sutures with staples to
prevent deintussusception and using the intact ileoce-
cal valve as a means of further stabilizing the intussus-
ception.59 The technique described herein includes
these modifications rather than the earlier versions of
the operation.
Technique. A 10- to 15-cm segment of cecum and
ascending colon is isolated, along with two equal-sized
loops of terminal ileum and an additional portion of
ileum measuring 20 cm for the creation of the reservoir
and the continence mechanism, respectively (Figure
23-12A). The entire colonic segment and distal seg-
ment of ileum are split open along the antimesenteric
border, with care taken to preserve the ileocecal valve.
These three bowel segments are folded in the form of
an incomplete W, and the posterior aspects sutured
together to form a broad posterior plate (Figure 23-12B).
The ileal mesentery of the intact (nondetubularized)
proximal ileum is freed of its mesentery for a distance
of 6 to 8 cm and intussusception of the segment is
achieved. The ileum is intussuscepted and stabilized
with 2 rows of staples (TA 55 staples) (Figure 23-12C).
Next, the intussuscepted ileum is pulled through the
natural tunnel of the intact ileocecal valve and fixed to
the ileocecal valve with two more rows of staples. The
 Chapter 23 Noncontinent and Continent Cutaneous Urinary Diversion 417
third row of staples is applied to stabilize the nipple
valve to the ileocecal valve (Figure 23-12D) and the
fourth row of staples is applied inferiorly, securing the
inner leaf of the intussusception to the ileal wall
(Figure 23-12E).
Both ureters are implanted by means of a 5-cm long
submucosal tunnel at the uppermost part of the cecal
portion of the reservoir. Next, the reservoir is folded on
itself in a side-to-side fashion and closed with a single
layer of continuous sutures to complete the pouch con-
struction. A suprapubic tube is placed through a separate
stab incision in the pouch and abdominal wall to ensure
adequate drainage. The entire pouch is rotated cephalad
and the intussuscepted ileum is brought to the umbilicus.
A small button of skin is removed from the depth of the
umbilicus and the ileal terminus is directed through this
buttonhole (Figure 23-12F). The reservoir is secured to
the posterior fascia with interrupted absorbable sutures,
and the intussuscepted ileal limb is sewn similarly to the
anterior fascia. Extra ileal length is resected, and the
ileum is sutured to the umbilicus with interrupted
absorbable sutures. Although the cutaneous stoma can be
placed in several different locations, the preferred stoma
site by the Mainz group is the umbilicus.
The introduction of the more reliable appendiceal
continence mechanism has greatly increased the accept-
ance of the Mainz I procedure. Starting in 1988, the in
situ appendix was used for creation of the continence
mechanism.60 The advantages of this modification are
reducing of the operative time by 30 to 40 minutes, a
shorter ileal segment, eliminating nipple sliding or pro-
lapse, and reduced risk of stone formation with the
absence of staples. The Mainz group has also developed
2 new techniques for construction of a Mitrofanoff
(appendiceal) type of tube for use in patients whose
appendix is either unsuitable or absent.33,61,62
Continent Right Colon Reservoirs with
Intussuscepted Terminal Ileum
Similar to the Mainz pouch, these right colon pouches
use the nipple valve concept for continence by using the
ileocecal valve. Unlike the Mainz pouch, the right colon
is used solely for the construction of the pouch portion of
the diversion. Several right colon pouches using the valve
technology have been described—Indiana pouch, UCLA
pouch, Duke pouch, LeBag pouch, Florida pouch, and
the Penn pouch.63–65 These operations differ from one
another by only minor features, predominantly related to
the technique employed for stabilizing the nipple valve
and the amount of large intestine harvested (Table 23-1).
In this section, we discuss in detail only the Indiana and
Penn pouches. In all instances, appendectomy is per-
formed because the in situ appendix would serve as a
nidus for infection and abscess formation. Table 23-2 lists
the urodynamic and continence rates for the continent
cutaneous reservoirs from various published series.
Indiana Pouch
One of the first continent cutaneous pouches to gain
wide acceptance in the urologic community was the
Indiana pouch developed in 1985 by Rowland et al.88
The major contribution was the creation of a reliable
continence mechanism. Originally, the entire ileal seg-
ment was buttressed with imbricating sutures to establish
the continence mechanism. Pressure profile studies
demonstrated that the continence zone was confined to
the region of the ileocecal valve; therefore, imbricating
sutures were only necessary in the region of the ileocecal
valve.37
Technique. In the present form of an Indiana pouch,
20 to 25 cm of cecum and ascending colon are isolated
along with 10 to 15 cm of terminal ileum (Figure 23-
13A). After bowel continuity is reestablished, appendec-
tomy is performed and the appendiceal fat pad obscuring
the inferior margin of the ileocecal junction is removed
(Figure 23-13B). The entire right colon is detubularized
along its antimesenteric border about three-fourths of
its length starting from the distal end, and the cecum is
partially spatulated. The ureters are anastomosed
through a submucosal tunnel along the posterior colonic
tenia.
The continence mechanism consists of plicated termi-
nal ileum, which reinforces the ileocecal valve. The ileal
plication, consisting of 2 rows of Lembert sutures 8 to 10
mm apart, begins at the ileocecal valve and extends 3 to 4
cm proximally (Figure 23-13C); the continence mecha-
nism is tested and when no leakage is present, a second
layer of continuous silk sutures over a catheter (12Fr or
14Fr) is used to reinforce the suture line. Alternatively, the
University of Miami group uses purse-string sutures in the
same region of the ileum.37 In the Florida pouch, apposing
Lembert sutures are applied on each side of the terminal
ileum (Figure 23-13D). Any excess ileum is tapered over a
catheter and removed using a GIA stapler. It is important
to imbricate while the cecal reservoir is still open, allowing
one to observe the gradual closure of the ileocecal valve.
The pouch is formed by folding down the opened cecum
in a Heineke-Mikulicz configuration and closing with con-
tinuous 2-0 PGA suture. Ureteral stents are placed and a
suprapubic tube is brought through the lower abdominal
wall. A 1-cm buttonhole is made in the skin, anterior and
posterior fascia. The catheterizable ileal limb is advanced
between the rectus muscles. Excess ileum is removed and
a flush skin stoma is created.
At Indiana, as well as other institutions, it was recog-
nized that by only marsupializing a portion of the ascend-
ing colon, the cecal region maintained sufficient
418 Part IV Bladder

Figure 23-12 A, A 10- to 15-cm portion of cecum and ascending colon is isolated along
with two separate equal-sized limbs of distal ileum and an additional portion of ileum
measuring 20 cm. B, A portion of the intact proximal ileal terminus is freed of its mesentery
for a distance of 6 to 8 cm.

peristaltic integrity to generate pressures high enough to
overcome the continence mechanism. Variations on the
Indiana pouch, including the Florida pouch,36 harvest the
entire right colon and one-third to one-half of the trans-
verse colon to create the reservoir. The University of
Miami pouch37 retained the original Indiana pouch
design but marsupialized the entire ascending colon and
cecum and refashioned the pouch in a Heineke-Mikulicz
configuration.
Additional modifications to the Indiana reservoir
allow more rapid construction with a lower complication
rate,89 such as the use of absorbable staples to fashion the
reservoir. First introduced by Bejany and Politano,37 a
GIA stapler with metal staples can facilitate fashioning of
the efferent limb.
Penn Pouch
This ileocecal pouch, described by Duckett and Snyder44
in 1986, was the first continent diversion employing the
Mitrofanoff principle, wherein the appendix served as the
continence mechanism.
 Chapter 23 Noncontinent and Continent Cutaneous Urinary Diversion 419

Figure 23-12 cont’d C, The intact ileum is intussuscepted and two rows of staples are taken
on the intussuscipiens itself. D, The intussuscipiens is led through the intact ileocecal valve
and a third row of staples is taken to stabilize the nipple valve to the ileocecal valve. E, A fourth
row of staples is taken inferiorly, securing the inner leaf of the intussusception to the ileal wall.
420 Part IV Bladder

Figure 23-12 cont’d F, A button of skin is removed from the depth of the umbilical funnel
and the ileal terminus is directed through this buttonhole. Excess ileal length is resected and
ileum is sutured at the depth of the umbilical funnel.

Table 23-1 Comparison of Techniques of the Various Forms of Continent Right Colon Pouches
with Intussuscepted Terminal Ileum
Pouch Year Reservoir Continence Mechanism Ureteral Anastomosis

UCLA Pouch* 199463 Entire right colon
+ 15 cm distal ileum
Duke Pouch* 198764 Entire right colon
+ 15 cm distal ileum
Florida Pouch† 198736 Entire right colon
+ transverse colon
(right 1/3 or 1/2) + 10
to 12 cm distal ileum
LeBag* 198665 20 cm right colon
+ 20 cm distal ileum
Terminal ileum is tapered over a 14Fr LeDuc (tunneling
Foley using a GIA stapler technique)
Ileal limb (nipple) is fixed against the
wall of the continent reservoir with
continuous sutures
Ileum is intussuscepted through the Tunneling technique
ileocecal valve
Ileal limb (nipple) is stabilized with
sutures or staples
A patch of mucosa is excised from the
posterior cecal plate
One entire thickness of the intussuscipiens
is incised to reveal the inner leaf of the
intussuscipiens (serosa)
Similar to Indiana Pouch (exception: End-to-side (colonic
opposing Lembert sutures on each side segment) nonrefluxing
of the terminal ileum to buttress the
ileocecal valve
Standard nipple valve from Goodwin technique (similar
intussuscepted ileum to ureterosigmoidostomy)
Staples are used to stabilize the
nipple valve
No mesh collar for nipple valve
stabilization

*The long-term outcome of this pouch is unknown.

†Ureteral obstruction occurred in 4.9% of patients with nontunneled ureterocolonic anastomosis; hyperchloremia in 70% of patients (only 4

patients required treatment for this electrolyte imbalance).

 Table 23-2 Comparison of Continent Cutaneous Reservoirs: Reservoir Volume, Urodynamic Maximum Fill Pressures,
and Continence Rates

RESERVOIR CONTINENCE
No.
Pouch References Patients Volume (ml) Pressure (cm H2O) Overall Daytime Nighttime

Kock pouch Kock et al.66 12 500 NR NR NR NR

T pouch Stein et al.67 9 400–700 NR 100% NR NR

Mainz pouch Thuroff et al.68 100 510–620 23–33 at half capacity NR NR NR

31–41 at full capacity
Lampel et al.69 440 NR NR 90% stapled
ileocecal
intussusception
Gerharz et al.70 193 NR NR 100%

UCLA pouch* deKernion et al.71 19 560 (mean) NR 71% NR 69%

Raz63 NR 600–700 NR 88.2% NR NR

Indiana pouch Rowland et al.72 29 291–508 ≤20 intraluminal NR 93 76

Rowland et al.73 29 291–508 ≤20 intraluminal NR 93 76
Scheidler et al.74 91 NR NR 93% NR NR
Carroll et al.75 14 400–1500 24 (mean) reservoir 85.7% NR NR
675 (mean) 40 (mean) plicated ileal segment
Ahlering et al.76 70 400–800 15–25 resting pressure 98.6% NR NR
Carroll et al.77 21 NR 41 (mean) plicated ileum 85.7 NR NR
Rowland et al.78† 81 NR NR NR 98% 98%
63 (mean) stapled ileum
Bihrle et al.79‡ 50 500 (mean) NR NR 94% 94%
733 (maximum)

Continued
Chapter 23 Noncontinent and Continent Cutaneous Urinary Diversion 421
 422
Part IV Bladder

Table 23-2 Comparison of Continent Cutaneous Reservoirs—cont’d

RESERVOIR CONTINENCE
No.
Pouch References Patients Volume (ml) Pressure (cm H2O) Overall Daytime Nighttime

Florida pouch Lockhardt et al.80 11§ 400–1200 28–55 at capacity 88% NR NR

650 (mean)
Lockhardt et al.81 107 550–1200 10–58 at capacity 97.5% NR NR
747 (mean) 35 (mean)

Duke pouch* Webster et al.82 7 500–700 50 (near capacity) 42.8%¶ NR NR

U. Miami pouch Bejany et al.83 10 750–800 20 at capacity (pouch) 100% NR NR

20–30 tapered ileum (empty)
50–60 tapered ileum (at capacity)
Benson et al.84 75 ≥750 20 at capacity 98.6% NR NR

Penn pouch Sumfest et al.85 NR NR NR 96% NR NR

Gastric pouch# Adams et al.86 3 245 35 end filling pressure NR NR NR

Carr et al.87 12 309 12.9 100 NR NR

*The long-term outcome of these pouches is unknown.

†The last 81 patients operated on by Rowland and associates underwent construction of a stapled efferent limb; In the last 20 patients, the reservoir was created with absorbable

staples.
‡Mean follow-up in this study was 2.5 years.
§8/11 patients had a continent colonic reservoir performed.
¶One patient suffered incontinence due to evagination of the intussusception; three patients had intermittent incontinence secondary to cecal segment hyperactivity. This was

controlled with oxybutynin hydrochloride 5 to 10 mg TID.

#Of the 12 patients, seven had urinary reservoirs totally constructed from stomach, and five had composite reservoirs.

NR, not reported.

 Chapter 23 Noncontinent and Continent Cutaneous Urinary Diversion 423

Figure 23-13 A, Segment of terminal ileum approximately 10 cm in length along with the
entire right colon is isolated. B, Appendectomy is performed and the appendiceal fat pad
obscuring the inferior margin of the ileocecal junction is removed by cautery. C, Interrupted
Lembert sutures are taken over a short distance (3 to 4 cm) in two rows for the double
imbrication of the ileocecal valve as described at Indiana University. D, Application of
opposing Lembert sutures on each side of the terminal ileum.
424 Part IV Bladder
Technique. A segment of cecum up to the junction of
the ileocolic and middle colic arteries is isolated, in addi-
tion to a similar length of terminal ileum. The isolated
bowel is marsupialized on the antimesenteric borders and
sutured to one another. The superior margin of the pouch
is sutured transversely using absorbable material.
Mitrofanoff technique. A button of cecum surrounding
the origin of the appendix is circumscribed and the
resulting cecal aperture closed with running absorbable
suture. The mesentery of the appendix is dissected care-
fully from the base of the cecum, preserving the blood
supply. The appendix is then reversed on itself, so that
the cecal button can reach the anterior abdominal wall
and the tip of the appendix can be directed to the taenia
of the colon (Figure 23-14). The appendiceal tip is tran-
sected obliquely and spatulated prior to a tunneled
appendiceal-taenial implantation. If additional appen-
diceal length is required, the variation proposed by Burns
and Mitchell34 may be employed (cecal tube).
An alternative technique can be applied when fashion-
ing the continent catheterizable stoma. Riedmiller et al.45
leave the appendix attached to the cecum and bury it into
the adjacent taenia by rolling it back onto itself. A wide
tunnel is created in the taenia extending 5 to 6 cm from
the base of the appendix. Windows are created in the
Figure 23-14 A segment of cecum up to the junction of the
ileocolic and middle colic blood supplies along with a similar
length of terminal ileum is isolated and marsupialized on the
antimesenteric borders. A button of cecum surrounding the
origin of the appendix is circumcised. The mesentery of the
appendix is dissected carefully from the base of the cecum,
preserving its blood supply.
mesoappendix between blood vessels. The appendix is
folded cephalad into the tunnel and seromuscular sutures
are placed through the mesoappendix windows to com-
plete the tunneling. The tip of the appendix is amputated
and brought to the selected stomal site.
Gastric Pouches
The stomach has many unique properties91 and can be
used in selected circumstances. Advantages to using
stomach as a urinary reservoir include diminished elec-
trolyte reabsorption, inherent barrier to absorption of
ammonium, absence of hyperchloremic acidosis, and
reduced bacterial colonization in the acidic environment.
Situations favoring consideration of the gastric uri-
nary diversion include extensive irradiation of the lower
bowel, preexisting metabolic acidosis or renal insuffi-
ciency, and patients in whom shortening the small bowel
could result in malabsorption. Experience with gastric
pouches and composite reservoirs has been reported in
both the pediatric90 and adult populations.91,92
Technique. A 7- to 10-cm wedge-shaped segment is
isolated from the greater curvature of the stomach, typi-
cally using a 70- to 90-mm GIA stapler. The incision is
not extended to the lesser curvature because of the risk of
vagal injury and resulting problems with gastric empty-
ing. Before the gastric wedge is taken, the decision has to
be made as to which gastroepiploic artery will serve as a
pedicle for the gastric flap. The segment is preferentially
mobilized on the left gastroepiploic vascular stalk by
dividing the short gastric vessels proximal to the segment
up to the gastric fundus (Figure 23-15A,B). If the left
artery cannot be used, then the right gastroepiploic ves-
sel is used and the small gastric vessels are ligated to the
level of the pylorus. The stomach is then closed based on
surgeon’s preference.
A gastroduodenostomy or gastrojejunostomy tube is not
mandatory unless the antrum of the stomach has been used.
The gastric wedge is brought through the transverse meso-
colon and the root of the small bowel to lie in a retroperi-
toneal position. The isolated wedge is refashioned into
nearly a sphere by folding it back on itself and suturing the
edges together with running absorbable material. Before
closing the pouch, the ureters are reimplanted using the
submucosal tunneling technique (Goodwin).
A continent catheterizable reservoir can be con-
structed using appendix or the distal ureter tunneled sub-
mucosally into either the dome or posterior portion,
respectively. If the distal ureter is used to create the con-
tinence mechanism, a proximal transureteroureteros-
tomy can be performed. The free portion of the ureter
can then be brought to the skin or to the introitus
(female) or urethral stump (male) to serve as a catheteri-
zation portal. If neither option is available, a gastric tube
and nipple can be created from a gastric flap.
 Chapter 23 Noncontinent and Continent Cutaneous Urinary Diversion 425

Figure 23-15 A and B, A wedge-shaped segment of stomach whose greatest width is 7 to

10 cm is fashioned from the greater curvature. The left gastroepiploic artery is preferentially
used as the blood supply for the isolated gastric wedge by dividing the short gastric vessels
up to the gastric fundus. Alternatively, if there is a problem with the left artery, the right
gastroepiploic vessel may be employed.

Alternatively, the wedge of stomach can be incorporated
into a reservoir composed of detubularized ileum with or
without tapering (Figure 23-16A–C). When stomach is
used as a bladder augment or as a portion of a neoblad-
der, the dysuria and hematuria syndrome has been
reported, limiting use in sensate patients.93
The construction of reservoirs entirely from stomach
has not seen widespread acceptance. Rather, use of stom-
ach segments has been limited to bladder augmentation
or as part of a composite reservoir.94,95 While the use of
stomach has particular appeal in the pediatric popula-
tion,95 its various unique intrinsic properties as a reser-
voir suggest that its use will continue in only selected
clinical situations.
URETEROINTESTINAL ANASTOMOSES
Ureterointestinal anastomoses can be performed in either
a refluxing (direct) or nonrefluxing fashion. Theoretically,
a nonrefluxing anastomosis protects the upper urinary
tract from infected urine and may decrease renal deterio-
ration. This aspect, however, remains controversial.
Reflux alone does not necessarily lead to upper urinary
tract deterioration and is related to factors, such as infec-
tion, stones, and obstruction. Patients with nonrefluxing
anastomoses have not been shown to have lower rates of
bacterial colonization.96 There is no long-term evidence
that patients without reflux have a lower rate of renal dys-
function. In addition, nonrefluxing techniques of ureteral
anastomosis are associated with higher stricture rates.
Both types of ureteral anastomoses can be performed
into either the small or large bowel. In general, nonre-
fluxing anastomoses are easier to perform on the colon
because of the presence of teniae coli. Numerous tech-
niques of ureterointestinal anastomoses have been
described and we present several common methods.52,97,98
Ureteral-Small Bowel Anastomoses
Direct Anastomosis
Bricker,14 in his description of ureteroileocutaneous
diversion, used a freely refluxing, direct end-to-side
ureteral anastomosis. It remains the simplest method of
connecting the ureter to the ileum. After spatulation of
the ureters, a small ellipse of bowel serosa and mucosa is
excised from the site of implantation. The spatulated
ureter is anastomosed directly to the bowel, with care
taken to incorporate both the muscular and mucosal ele-
ments of the intestine (Figure 23-17A,B). Only small
portions of the mucosa should be included to ensure that
the mucosa everts and results in precise mucosa-to-
mucosa apposition. In contrast, if too much mucosa is
included in the anastomosis, this can narrow the lumen of
the ureterointestinal anastomosis. The anastomosis can
be performed in 1 or 2 layers using interrupted
absorbable sutures. Prior to completing the anastomosis,
the ureter may be stented, especially if the patient is at
risk for impaired wound healing.
Wallace Technique
In this method, the ureters are joined together prior to
performing the ureterointestinal anastomosis99; the cre-
ation of a single, larger urinary segment may decrease the
426 Part IV Bladder

Figure 23-16 A, An 11-cm long segment of stomach is isolated on the right gastroepiploic
blood supply with the use of a GIA-90 stapler. Usually, two staplers are required. B, A 22-
cm segment of ileum is then isolated, opened along its antimesenteric border and
refashioned in a U shape.
 Chapter 23 Noncontinent and Continent Cutaneous Urinary Diversion 427

Figure 23-16 cont’d C, The edges of the stomach are then sutured to edges of the ileum
with a running absorbable suture of 2-0 PGA.

Figure 23-17 A and B, After removing a small ellipse of bowel, the ureter is spatulated and
anastomosed directly to the bowel wall using interrupted absorbable sutures.
428 Part IV Bladder
risk of subsequent ureteroenteric stenosis. Each ureter is
spatulated for a distance approximately equal to the
diameter of the conduit. The ureters are joined together
using a running absorbable suture and then anastomosed
to the open proximal end of the bowel in a refluxing
manner (Figure 23-18A,B). The anastomosis can be per-
formed in 1 or 2 layers with absorbable sutures. The
ureters may be stented.
Tunneled Ureterointestinal Anastomosis
In this method, the ureter is brought through a submu-
cosal tunnel, creating a nonrefluxing anastomosis to the
bowel.100 A short tunnel is made between the mucosal and
seromuscular layers at each anastomotic site; saline can be
injected submucosally using a small needle to aid with the
dissection.101 Small plugs of mucosa are removed from
the ends of each tunnel where the ureter enters the bowel
lumen. After advancing each ureter through its tunnel,
the ureter is anastomosed to the mucosa of the bowel.
Ureterocolonic Anastomoses
The ureters can be implanted into the large bowel in
either a direct refluxing fashion, as previously described
for small bowel, or a nonrefluxing manner. In the latter,
a 3-cm incision is made in a tenia coli (Figure 23-19A).
The incision is carried through the muscular layer,
sparing the mucosa. At the site of entry into the colonic
Figure 23-18 A, The ureters are spatulated and joined together using a running suture.
B, The ureters are anastomosed to the open proximal end of the conduit.
lumen, a small ellipse of mucosa is excised. The ureter
is anastomosed to the bowel mucosa (Figure 23-19B)
and then the muscular layer of the tenia coli is reap-
proximated to create a tunnel over the ureter (Figure
23-19C).
COMPLICATIONS
General Complications
Numerous complications may occur after all types of uri-
nary diversion. Problems, both early and delayed, can
results from surgical technique, the incorporation of
intestine into the urinary tract, and the patient’s underly-
ing disease processes. Early postoperative complications,
such as hemorrhage, wound infection, dehiscence, uri-
nary leakage, and bowel obstruction, are uncommon.
Delayed complications, including problems with the
stoma, metabolic abnormalities, renal deterioration,
infection, and calculi, are encountered more frequently.
Stoma Complications
If patients are followed long enough, stomal complica-
tions are common and lead to significant dissatisfaction.
Training in proper stomal care, preferably by an enteros-
tomal therapist, is important in reducing these issues.
The location of the stoma is also vital in optimizing the
stoma, and guidelines for selecting the site have been
previously outlined.
 Chapter 23 Noncontinent and Continent Cutaneous Urinary Diversion 429
Figure 23-19 A, A 3-cm incision is made in a tenia coli and a small ellipse of bowel mucosa
is removed. B and C, The ureter is anastomosed to the mucosa and the muscular layer of
the tenia is reapproximated.
Stomal stenosis is a common late complication of
cutaneous ureterostomy, occurring in up to 50% of
patients.102 The incidence of stenosis is lower when
dilated, well-vascularized, thick-walled ureters are used.
If the ureter is only minimally dilated, a V-flap technique
may be beneficial. The treatment of stomal stenosis after
cutaneous ureterostomy is surgical, generally necessitat-
ing urinary intestinal diversion.
Stomal stenosis is also seen with other types of intes-
tinal urinary conduits. In ureteroileal urinary diversion,
the incidence of stenosis is as high as 42% in children and
6.7% in adults.103,104 Similar rates have been reported for
jejunal conduits.20 Because the colon has a larger lumen,
one would expect a lower rate of stomal stenosis.
However, long-term studies still demonstrate a signifi-
cant rate of stenosis, up to 61% in children.105,106 Stomal
stenosis can lead to conduit elongation and upper urinary
tract obstruction. The diagnosis can be made by passing
a catheter through the stoma and measuring the volume
of residual urine. The treatment consists of surgical revi-
sion of the stoma.
Parastomal hernias are another delayed complications
associated with intestinal urinary conduits. Parastomal
hernia occurs more frequently with colon conduits (10%
to 15%) compared with the use of small bowel. The risk
of parastomal hernias is reduced by bringing the bowel
through the rectus abdominus muscle and removing
excess fat from the mesentery of the distal conduit near
the stoma. Large parastomal hernias should be repaired
surgically.
Problems with the skin around the stoma are common
and can be categorized as infectious (i.e., fungal), irrita-
tive (e.g., urine), erosive (e.g., mechanical trauma), or
pseudoverrucous.107 Treatment depends on the type and
etiology of lesion present. In general, parastomal skin
problems are greatly reduced with meticulous and gentle
stoma care, the use of nonirritative adhesives, and a prop-
erly fitting appliance. The aperture in the appliance
should be just slightly larger than the stoma itself to min-
imize erosion and prolonged contact between the skin
and urine.
Ureterointestinal Anastomotic Complications
The use of soft Silastic stents reduces urinary extravasa-
tion, which may lead to periureteral scarring and
ureterointestinal anastomotic strictures. In general,
ureteral stents should be placed in those at risk for poor
healing. Nonrefluxing anastomotic techniques have
higher rates of stricture formation, although strictures can
occur at or distant from the intestinal anastomosis. Many
ureteral strictures can be successfully treated endoscopi-
cally with either dilation or incision; however, some will
ultimately require open surgical repair. The incidence of
ureteral obstruction and stomal stenosis for noncontinent
urinary diversions is summarized in Table 23-3.
430 Part IV Bladder

Table 23-3 Complications of Noncontinent Intestinal Urinary Conduits

No. % Ureteral % Stomal
References Patients Population % Pyelonephritis Obstruction % Stones Stenosis

Ileal conduit

Butcher et al.104 307 Adults 13.8 2.3 3.3 6.7

Johnson et al.108 181 Adults 5.5 15.5 3.3 3.9

Johnson and Lamy109 214 Adults 15.2 18.4 2.5 5.1

Sullivan et al.110 336 Adults 19.2 14.7 4.0 5.1

Middleton and Hendren103 90 Children 20 10 9 42

Shapiro et al.116 90 Children 16.7 22.3 8.9 38

Pitts and Muecke111 242 Both 10.7 4.1 5.8 14

Jejunal conduit

Golimbu and Morales20 30 Both — 3.3 — 6.6

Colon conduit

Schmidt et al.112 22 Adults — 4.5 — 0

Morales and Golimbu105 46 Both 17 13 4.3 13

Althausen et al.113 70 Both 7.1 8.6 4.3 2.8

Elder et al.106 41 Children — 22 16 61.5

Ileocecal conduit

Matsuura et al.114 147 Both 13.6 9.5 5.4 2

Renal Complications
Pyelonephritis, both early and late, can occur in all types
of urinary diversion. The incidence of pyelonephritis with
cutaneous ureterostomy has been reported to be 3%.8 A
significantly greater incidence has been found in patients
with ileal and colon conduits, as high as 20% in some
series.110 Although many ureterocolonic anastomoses are
performed using nonrefluxing techniques, even patients
without reflux of urine develop bacterial colonization of
the upper urinary tract.96 Pyelonephritis should be treated
with specific antibiotic therapy based on cultures and sus-
ceptibility of the infecting organism. The sample of urine
should be obtained by direct catheterization of the stoma
rather than simply from the collection device.
Renal deterioration has been associated with all forms
of intestinal urinary diversion. This deterioration can be
attributed to pyelonephritis, reflux, or obstruction (e.g.,
stones, ureteral stricture). The risk of renal dysfunction
increases with time, with obstruction representing a
major cause.110 The reported incidence is variable, but
ranges from 18% to 56% and from 8% to 48% for ileal
and colon conduits, respectively.103,105,106,113, 115, 116
Urinary Calculi
Any patient with an intestinal urinary diversion is at risk
for urinary stone formation, with an incidence of 5% to
10% in adults and 4% to 16% in children. Many factors
contribute to the formation of these stones.117 Staples
used during conduit construction can serve as a nidus for
stones. Bacteriuria exists in most patients with a urinary
conduit, where the presence of urease-producing organisms
 Chapter 23 Noncontinent and Continent Cutaneous Urinary Diversion 431
can lead to struvite stones. The concomitant metabolic aci-
dosis in many individuals leads to hypocitraturia and hyper-
calciuria, further exacerbating the risk of nephrolithiasis.118
In patients with an ileal conduit urinary diversion, hyper-
oxaluria and calcium oxalate stones may also result from the
use of the terminal ileum. The terminal ileum absorbs bile
salts and plays a key role in fat metabolism. When the ter-
minal ileum is excluded from the intestinal tract, faulty bile
salt and fat absorption leads to saponification of both cal-
cium and magnesium within the gut lumen. Decreased
cation binding with free gut oxalate causes increased
oxalate absorption and hyperoxaluria.
The management of stones after urinary diversion can
be difficult. Stones located in the upper tract can be treated
using a combination of percutaneous and retrograde
endoscopic techniques along with shock wave lithotripsy.119
Shock wave lithotripsy should be avoided when there
is stricture distal to the stone.119 Close monitoring is
crucial because the cause is often multifactorial and
recurrence rates are high. Those patients with struvite
stones may benefit from chronic suppressive antibiotics
and/or a urease inhibitor.
Metabolic Complications
Metabolic abnormalities are common after the introduc-
tion of bowel into the urinary system (Table 23-4). These
include electrolytes disturbances, altered drug kinetics,
osteomalacia, and nutritional disturbances. The severity
of metabolic problems is determined by length and spe-
cific segment of bowel used, renal function, concentra-
tion of urinary solutes, and degree of urinary stasis.16
Direct drainage of the urine via cutaneous ureterostomy
and pyelostomy avoids these metabolic problems.
Electrolyte Disturbances
The use of jejunum as a urinary conduit may result in
hyponatremic, hypochloremic, hyperkalemic metabolic
acidosis in up to 40% of patients.19 Clinical symptoms
include nausea, vomiting, anorexia, weakness, and
lethargy. These electrolyte changes are the expected
result of normal intestinal physiology. The jejunum is
unable to maintain a large solute gradient; therefore,
Table 23-4 Metabolic Complications Associated with Use of Bowel for Urinary Diversion
Segment Complications
Jejunum Hypochloremic metabolic acidosis
Hyperkalemia
Ileum + Colon Hyperchloremic metabolic acidosis
Hypokalemia (colon > ileum)
electrolytes move between the extracellular fluid and
urine within the conduit. The magnitude and direction
of electrolyte shifts are dependent on the differential con-
centration of the electrolytes. Sodium and chloride are lost
into the urine, while potassium and urea are reabsorbed.
The loss of sodium leads to decreased extracellular fluid
volume and reduced renal blood flow, causing activation
of the renin–angiotensin system and subsequent stimula-
tion of aldosterone production by angiotensin II.
Aldosterone increases reabsorption of hydrogen and
excretion of potassium into the distal renal tubule with
resultant acidosis and intracellular potassium release,
respectively. The reabsorption of urea and dehydration
leads to azotemia. Treatment of the jejunal conduit syn-
drome consists of oral sodium chloride replacement.
Metabolic acidosis can occur when either the ileum or
colon is used as a urinary conduit. Both sodium and chlo-
ride are absorbed across the bowel surface, with chloride
absorption greater than sodium. This results in a net loss
of bicarbonate into the urine; renal insufficiency con-
tributes to the severity of the acidosis. Excess potassium
is excreted into the urine as a result of chronic acidosis.
Since the ileum has greater capacity for absorbing uri-
nary potassium compared to the colon, patients with an
ileal conduit tend to have normal total body potassium,
while those with a colon conduit have total body potas-
sium depletion. The treatment for electrolyte abnormal-
ities associated with ileal and colon diversions is
alkalinization with oral bicarbonate or citrate.
Altered Drug Metabolism
Phenytoin toxicity has been reported in patients with
intestinal urinary conduits.120 Any drug that is excreted by
the kidneys unchanged and can be reabsorbed by the intes-
tine has the potential for toxicity. Patients with continent
urinary diversion and receiving methotrexate chemother-
apy are at risk for toxicity; a catheter should be placed in
the reservoir during methotrexate administration.
Nutritional Disturbances
Vitamin B12 is absorbed in the distal ileum. Deficiency of
this vitamin, occasionally the result of using this bowel
Treatment
Sodium chloride
Volume replacement
Alkalinizing agent (sodium or potassium citrate)
Block chloride transport (chlorpromazine, nicotinic acid)
432 Part IV Bladder
segment, results in megaloblastic anemia and peripheral
neuropathy. As mentioned earlier, loss of the terminal
ileum impairs bile salt reabsorption and leads to
decreased uptake of fat-soluble vitamins (A, D, E, K).
The patient may have chronic diarrhea from the combi-
nation of fat malabsorption, excess bile salts, and loss of
the ileocecal valve. Cholestyramine and agents that reduce
bowel motility can be used when the diarrhea persists.
Chronic acidosis leads to osteomalacia in adults and rickets
in children.121 Bone remineralization can be accom-
plished with oral alkalinization therapy and supplementa-
tion with calcium and vitamin D.
Continence Mechanism Complications
One aspect of right colon pouches that has been criti-
cized is loss of the ileocecal valve. Although some
patients experience frequent bowel movement in the
short term, the majority reports regular bowel function
through intestinal adaptation or use of pharmacologic
therapy. Nevertheless, some patients develop striking
diarrhea and/or steatorrhea after loss of the ileocecal
valve. This may be particularly true in the pediatric
patient in whom there is underlying neurogenic bowel
(e.g., myelomeningocele).
A limitation of stapled nipple valves is the potential for
stone formation on exposed staples. This has been signif-
icantly decreased by the omitting staples at the tip of the
intussuscepted nipple valve as suggested by Skinner et
al.39 However, more proximal staples occasionally erode
into the pouch and serve as a nidus for stone formation.
These stones are usually manageable with endoscopic
intact extraction with forceps or after fragmentation
using electrohydraulic, ultrasonic, or laser lithotripsy.
Although exposed staples may serve as a nidus for stone
formation, continent urinary diversion itself results in
greater urinary excretion of calcium, magnesium, and
phosphate compared with ileal conduit diversion.118
Thus, all patients undergoing continent diversion are at
an increased risk for the formation of reservoir stones.
“Pouchitis” is a condition that is manifested by pain in
the region of the pouch and increased pouch contractil-
ity. Although occurring infrequently, pouchitis may
result in temporary failure of the continence mechanism
because of the hypercontractility of the bowel segment
employed for construction of the pouch. The patient typ-
ically presents with a history of sudden explosive dis-
charge of urine through the continence mechanism,
rather than dribbling incontinence, along with discom-
fort in the region of the pouch. Appropriate antibiotic
therapy usually results in the resolution of symptoms. We
have found that a short course of antibiotics (i.e., 3 days)
is not successful in treating pouch infections, perhaps
due to the larger amount of foreign material within intes-
tinal pouches (mucus and sediment) when compared to
the native bladder. Intestinal crypts may also serve as bac-
terial sanctuaries. Therefore, a minimum 10-day course
of antibiotic administration is indicated for treating
infection; of course, pyelonephritis may require longer
courses of therapy.
Urinary retention is an infrequent but serious occur-
rence in continent pouches. It is most commonly seen
with continence mechanisms consisting of a nipple valve.
If the chimney of the nipple valve is not near the abdom-
inal surface, the catheter can be directed into folds of
bowel rather than into the nipple valve proper such that
poor drainage is achieved. Pouch urinary retention rep-
resents a true emergency, and the patient must seek
immediate attention so that catheterization and drainage
is promptly performed. The use of a coudé-tipped
catheter is often helpful in this regard, and, rarely, a flex-
ible cystoscope is needed.
After the immediate problem has been addressed by
emptying the pouch, a catheter is left indwelling for 2 to
3 days to allow the edema and trauma to the catheteriza-
tion portal to resolve. Subsequently, the patient should
be observed for the ability to successfully catheterize on
a number of occasions. The appropriate angle of entry
can be taught until the patient is comfortable with the use
of the new catheter; our preference is to routinely use
coudé catheters with nonnipple valve pouches.
Intraperitoneal rupture of catheterizable pouches has
been reported.122–125 In general, this occurs more com-
monly in the neurologic patient in whom sensation of
pouch fullness may be less distinct. Oftentimes, associ-
ated mild abdominal trauma, such as a fall, is antecedent
to the rupture. Patients with rupture require immediate
pouch decompression and radiologic studies. For
patients with large defects, surgical exploration and
repair are required. If the amount of urinary extravasa-
tion is small and the patient does not have an acute
abdomen, catheter drainage and antibiotic administra-
tion may suffice in treating intraperitoneal rupture.
However, patients managed conservatively require care-
ful monitoring. If there are any signs of progressive peri-
tonitis, surgical exploration and repair are imperative.
Complications by Specific Type of Urinary
Diversion
Overall complication rates, reoperation rates, and mor-
tality rates are reported in Table 23-5 for each different
continent cutaneous reservoir.
Ureterosigmoidostomy
The most serious immediate complication from
ureterosigmoidostomy is anuria if the anastomosis is not
 Table 23-5 Comparison of Continent Cutaneous Reservoirs: Reoperation Rate, Mortality and Complication Rates
No Reoperation COMPLICATIONS (%)
Pouch Study Patients Rate Mortality (%) Early Late Stomal Stenosis Pouch Stones

Kock Pouch Koch et al.66 12 58% 0 16.7 58 NR NR

Skinner et al.125 489 10–15% 1.9 16.2 29 NR 7.6%

T Pouch Stein et al.67 9 NR 0 0 11.1 NR 11.1%

Mainz pouch Thuroff et al.68 100 11% (nipple 0 7 18* NR NR

revision)
Lampel et al.69 440 NR NR 12 37 11.7% ileal nipple 6.8%
14.7% appendiceal stoma 3% ileal nipple
patients
Gerharz et al.70 193 24% appendix 0 NR NR 18% appendix stoma 0%
stoma
12% ileal nipple 1.9% Ileal nipple 2.8%

UCLA pouch deKernion et al.71 19 NR 0 NR NR NR NR

Indiana pouch Rowland et al.73 29 17.2% 0 20.6 NR NR NR

Scheidler et al.74 91 26% 1.1 NR NR NR NR
Ahlering et al.76 70 4% to 10% 1.4 13 17.1 NR NR
Carroll et al.77 21 4.7% 0 NR NR 4.7% 0%
Rowland et al.78† 81 17.3% 0 12.3 28.4 NR NR
Bihrle et al.79‡ 50 4% 0 20 14 0% NR

Florida pouch Lockhardt et al.80 11 NR NR NR NR NR NR

Lockhardt et al.81 107 3.7% 0 12.4 10.3 1.9%§ 1.9%

Duke pouch¶ Webster et al.82 7 28.5% 0 NR NR 14.2% NR

U. Miami pouch Benson et al.84 75 NR NR 25 21 NR NR

Penn pouch Sumfest et al.85 NR NR NR NR 10.6 19.1% NR

Complication rates are reservoir related complications.

*11 patients had valve prolapse or incontinence; none of these problems were noted in later series after the nipple valve stabilization had been modified.
†The last 81 patients operated on by Rowland and associates underwent construction of a stapled efferent limb; in the last 20 patients, the reservoir was created with absorbable staples.
‡Mean follow-up in this study was 2.5 years.
§No specific comments regarding stomal stenosis. This percentage represents the number of cases reported as having catheterization difficulties.
¶The long-term outcome of these pouches is unknown.

NR, not reported.

Chapter 23 Noncontinent and Continent Cutaneous Urinary Diversion 433
434 Part IV Bladder
stented. Anuria after removal of the ureteral stents indi-
cates bilateral obstruction, likely secondary to tissue edema.
In both cases, percutaneous nephrostomy tubes should be
placed, especially in patients with fever or flank pain.
Urinary leakage from the ureterocolonic anastomosis
or from the colostomy incision can occur early in the
postoperative period. The incidence of this complication
can be minimized by watertight ureterocolonic anasto-
moses, use of ureteral stents, and continuous drainage of
the rectal contents. Proper drainage of the rectal con-
tents can be achieved by using two rectal tubes that have
multiple perforations. Stents and tubes should be irri-
gated regularly (4 to 6 hours) to ensure patency. If the
patient is stable, it is reasonable to wait because the leak
may seal by itself. In patients in whom significant leaks
persist, treatment options include immediate reoperation
and reanastomosis, percutaneous nephrostomy tube
placement, or cutaneous diversion. Renal deterioration
can occur late secondary to obstruction, reflux, and ascend-
ing infections. When the rectal tube is removed, the patient
must be closely monitored for the development of hyper-
chloremic acidosis. Because this is common, empiric bicar-
bonate replacement may be initiated immediately. Potassium
citrate should also be considered at the outset because of the
risk for hypokalemia. In patients who cannot maintain elec-
trolyte homeostasis with oral medication, nighttime rectal
urinary drainage is mandated. The incidence of colorectal
cancer after ureterosigmoidostomy is 3.5% to 13.3%, repre-
senting an 80- to 550-fold greater risk when compared the
general population.126–128 Due to the concern for developing
malignancy, it is suggested that patients have routine moni-
toring for blood in the stool, cytologic examination of the
urine-feces mixture, and annual colonoscopy. Barium ene-
mas are contraindicated because of the potential for reflux
of this material, which could lead to a septic event.
Kock Pouch
Skinner et al. have the most experience with this tech-
nique and reported early and late complication rates of
16.2% and 22%, respectively. The reoperation rate
approaches 10% to 15% in their last series, mostly for
correction of sliding of the continence nipple or erosion
of the stabilizing efferent nipple collar into the lumen.
Upper urinary tract deterioration, electrolyte imbalance,
and stone formation are rare.
Mainz Pouch
In the mid-1990s, the 10- and 12-year experience with
the Mainz pouch and the variations created by its devel-
opers was presented.56,57 The early complication rate was
12%; complications included mechanical ileus requiring
open revision (1.6%), pouch leakage requiring revision
(0.9%), wound dehiscence (0.7%), and fatal pulmonary
emboli (0.7%). The late complication rate was 37% and
was predominantly attributable to the pouch. Stomal fail-
ure requiring open revision occurred in 45 patients (8%)
and was directly related to the continence mechanism.
Only 2 of 46 patients (1.4%) with an appendiceal conti-
nence mechanism were incontinent, but stomal stenosis
occurred in 21%. The stapled ileocecal intussusception
described previously is the current standard, with a
reduction of long-term incontinence rates to 10%. Other
late complications include ureteral reimplants in 4.9%,
stomal stenosis in 11.7% of patients with an ileal nipple,
and 14.7% of patients with an appendiceal stoma.
Patients who developed calculi within the pouch
(6.8%) were primarily treated with percutaneous proce-
dures for stone removal. Despite the loss of the terminal
ileum, it has been rare to see a significant drop in serum
vitamin B12 levels, and very few patients have developed
a macrocytic anemia or neurologic symptoms. Twenty-
five percent of patients are taking oral alkalinization
drugs to avoid metabolic acidosis. Additionally, since
1988 the incontinence rate has been only 3.2%, and less
than 2% of the patients with an appendiceal continence
mechanism have been incontinent.
Gerharz and associates58 from Marburg, Germany,
reported a single institution experience with the Mainz I
ileocecal pouch. From 1990 to 1996, 202 consecutive
patients underwent continent diversion, 96 with a sub-
mucosally embedded in situ appendix and 106 with an
intussuscepted ileal nipple. All patients had an umbilical
stoma. In 172 of 200 patients (85%), no stomal compli-
cations occurred. In 17 of 96 patients (18%) with an
appendiceal stoma, 23 revisions were performed for
stomal stenosis. In contrast, only 13 of 106 patients
(12%) with an intussuscepted ileal nipple developed a
stomal problem. However, these patients required more
invasive, major procedures for correction, and the stomas
with an appendiceal stenosis could usually be repaired
with a minor procedure. Three patients with an ileal nip-
ple (3%) developed pouch calculi, whereas none of the
patients with an appendiceal continence mechanism
developed stones. As a result, the authors concluded that
when available, the appendix should be the intestinal
continence mechanism of choice.
Indiana Pouch
The reoperation rate, mainly caused by complications
with the efferent limb, was 26%. Because of the high rate
of nighttime incontinence in Rowland’s series,35 Ahlering
and colleagues129 detubularized the entire cecum to avoid
high pressure contractions from the cecum. Complete
detubularization seems to be superior to ileal or sigmoid
colon patches.
Elegant urodynamic studies were conducted in
Indiana pouch variants by Carroll et al.130 They found
 Chapter 23 Noncontinent and Continent Cutaneous Urinary Diversion 435
only 86% of patients totally continent in a small series.
However, their pouch capacities exceeded 650 ml. Peak
contractions of 47 cm H2O were recorded at capacity.
Gastric Pouches
Over a 10-year period from January 1985 to June 1995,
Carr and Mitchell96 reported on the use of stomach in 12
patients. Seven had urinary reservoirs totally constructed
from stomach and 5 had composite reservoirs. They
report continence in all patients but that the continence
mechanisms have oftentimes required revision. The aver-
age bladder capacity was 309 ml, and average compliance
was 12.9 ml/cm H2O. When stomach is used as a bladder
augment or as a portion of a neobladder, a dysuria and
hematuria syndrome has been reported.94
QUALITY OF LIFE
With improvements in surgical technique and experi-
ence, orthotopic urinary reconstruction is a viable
alternative in many patients. The lack of a stoma or the
need for an appliance or catheterization should benefit
patient acceptance and self-image. Whether these
changes translate into an improved quality of life
remains unclear.
Early reports merely examined the impact of conduit
creation in patients receiving an ileal conduit. Overall,
these studies do not demonstrate a negative effect from a
noncontinent urinary diversion. Fossa et al.131 found that
few patients experienced a reduction in general quality of
life (13%) or restriction in professional and daily func-
tioning (16%); however, the instrument used was not a
validated survey. Similarly, Cespedes et al.132 reported
that 83% of patients had no change or an increase in
activity level after ileal conduit creation. Others have
found an improved quality of life (60% to 80%) after
surgery and ileal conduit diversion; this may reflect
improvements in urinary function in a population with-
out cancer and does not directly compare outcomes with
other forms of reconstruction.
Hart et al.133 compared quality of life after radical
cystectomy for cancer and reconstruction using an ileal
conduit, cutaneous Kock pouch, or urethral Kock
pouch. No significant differences were noted among
these groups with respect to overall quality of life,
emotional distress, and problems with social, physical,
or functional activities. Most patients (95%) rated qual-
ity of life as good to excellent, although urinary and
sexual functions were significantly affected in all
groups. Over half of patients with ileal conduits
reported frequent difficulty in caring for the collection
device and 30% had occasional problems with skin irri-
tation. The influence of disease-related factors on the
measurements of a nonvalidated questionnaire instru-
ments confounds these data. Bjerre et al.134 also com-
pared the ileal conduit with Kock pouch and found no
differences in body image, partner relations, and global
life satisfaction. Despite a higher quality of life meas-
urement in those with a neobladder, nearly all patients
in both groups (>90%) felt in good health or compara-
ble to people of similar age.
McGuire et al.135 used the validated Rand 36-Item
Health Survey (SF-36) to measure quality of life in
patients with bladder cancer undergoing cystectomy
and urinary diversion. No difference in the physical
component summary (PCS) score was apparent after
ileal conduit, neobladder, and Indiana pouch construc-
tion when compared to age- and sex-based population
norms. However, patients with ileal conduits had signif-
icantly decreased mental quality of life (p = 0.01), while
those with other forms of diversion were similar to
matched population norms. Several more recent studies
have applied validated surveys to address this question.
Fujisawa et al.136 also used the SF-36 survey to assess
effects of different forms of urinary reconstruction.
There were no significant differences between patients
with an ileal conduit and neobladder at follow-up of 45
and 31 months, respectively. Although similar in both
groups, role-physical functioning and role-emotional
function were lower than U.S. population norms. Dutta
et al.137 assessed both general health and cancer-specific
aspects in 112 patients using the SF-36 and Functional
Assessment of Cancer Therapy-General (FACT-G)
questionnaires, respectively. SF-36 scores were signifi-
cantly better for patients with a neobladder compared
with an ileal conduit (p = 0.008); however, after control-
ling for age and disease variables, the differences were
less (p = 0.09). Global satisfaction in both groups was
high (>85%). They conclude that patients with an ortho-
topic neobladder enjoy a marginal increase in quality of
life when compared with patients receiving an ileal con-
duit. Using the QLQ-C30 and an institutional question-
naires, Hobisch et al.138 provided stronger evidence that
the neobladder is associated with improved quality of life
relative to the ileal conduit. Overall satisfaction was 97%
in patients with an orthotopic neobladder and 35% in
patients with an ileal conduit, respectively. Table 23-6
summarizes the literature concerning quality of life after
ileal conduit diversion using validated instruments.
The recognition that quality of life is an important
treatment outcome in urologic malignancies is a recent
phenomenon. This is particularly true for radical cystec-
tomy, where surgery entails not only radical extirpation
for cancer cure but also requires complex reconstruction
of the urinary tract. Although the data do not demon-
strate a clear advantage to orthotopic or continent reser-
voirs, it appears that these procedures provide excellent
quality of life, with minimal increase in morbidity, and
should be strongly considered when technically feasible.
436 Part IV Bladder

Table 23-6 Studies of Quality of Life (QOL) After Urinary Diversion Utilizing Validated Instruments
(All Compared with Ileal Conduit)
References Number Type Instrument Cystectomy Results

Bjerre et al.134 67 Kock neobladder Qualitative interview Yes Higher QOL with neobladder
Similar overall satisfaction

Hart et al.133 224 Koch* Validated† Yes No differences in QOL

Urinary problems, sexual dysfunction

Fujisawa et al.136 56 Neobladder SF-36 Yes No difference in QOL

Both lower in role-physical,
emotional
Overall high satisfaction

McGuire et al.135 92 Neobladder, SF-36 Yes Conduit reduced mental health

Indiana component
Physical component similar to norms

Hobisch et al.138 102 Neobladder QLQ-C30‡ Yes High QOL with neobladder
Lower satisfaction with conduit

Dutta et al.137 112 Neobladder SF-36, FACT-G Yes No differences on multivariate

analysis
High satisfaction with both

Satoh142 45 Ileocecal rectal QLQ-C30 Yes Conduit worse in three domains

bladder

Hara143 85 Neobladder SF-36 Yes Both with lower QOL than norms
Lower role-emotional with conduit

*Both cutaneous and urethral.

†Adapted from various validated questionnaires.
‡European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core Questionnaire 30.

Conversely, the ileal conduit is preferable in some
patients and this alone does not result in a significant
reduction in overall quality of life. Patients can continue
with an active, normal lifestyle after nearly all of the
reconstructive options. Complete preoperative discus-
sion and explanation of the various forms of urinary
reconstruction are crucial factors in patient preparation
for the changes in their quality of life.
NOVEL TECHNIQUES
The realm of laparoscopy in urology has evolved from
diagnosis to simple procedures (e.g., renal biopsy) to
complete organ removal and now to complex reconstruc-
tion. Many reports have documented the use of mini-
mally invasive techniques to create noncontinent and
continent urinary drainage. The earliest descriptions of
laparoscopic urinary drainage in humans involved the
creation of cutaneous ureterostomy for palliation in
advanced pelvic malignancy. Laparoscopy, both
transperitoneal and retroperitoneal, was used to identify
and mobilize the ureter so that anastomosis to the skin
was possible. The initial model for performing the ileal
conduit was described by Sanchez de Badajoz et al.139 in
1992. Case reports describe successful operations in 2
patients requiring supravesical diversion without pelvic
exenteration. It is important to note that the bowel exclu-
sion, reanastomosis, and ureteroileal anastomoses were
performed extracorporeally via a port site.
With the development of laparoscopic devices and
experience with intracorporeal suturing, more centers
are attempting laparoscopic ileal conduits. In combina-
tion with laparoscopic radical cystectomy, most sur-
geons are performing at least a portion of the operation
through an extended port site or the specimen extrac-
tion incision. Fergany and colleagues140 have developed
a porcine model where the entire ileal conduit is per-
formed intracorporeally, demonstrating technical feasi-
bility, as well as excellent short- and long-term
outcomes in these animals. These experiences formed
the basis for the operation in 2 patients undergoing rad-
ical cystoprostatectomy with ileal conduit for bladder
 Chapter 23 Noncontinent and Continent Cutaneous Urinary Diversion 437

Table 23-7 Experience with Laparoscopic Ileal Conduit

Completely Time EBL
References Number Cystectomy Intracorporeal (hours) (ml) Follow-up Complications

Kozminski144 1 No No 6.3 NR 3 months None

Vara-Thorbeck145 1 No No 4 NR 4 months None

Sanchez de Badajoz146 1 Yes No 8 NR 1 year None

Gill147 2 Yes Yes 10.8 1100 NR None

Potter et al.141 1 No Yes 4.5 NR 5 years Ileus

Gupta148 5 Yes Yes 7.5 360 2 years Bowel

obstruction

*1 unit blood transfusion.

NR, not reported.

cancer; again, the entire operation, including bowel
manipulation and suturing, was completed entirely
within the abdomen. Potter et al.141 also reported the
long-term follow-up (5 years) in a patient, where
supravesical diversion was created by a pure laparo-
scopic ileal conduit. Table 23-7 summarizes the litera-
ture regarding surgical outcomes with laparoscopic ileal
conduit urinary diversion.
The role of minimally invasive surgery in urinary
diversion remains unclear. Although promising, further
studies are needed to confirm benefits, such as reduced
pain and shorter hospitalization. Moreover, the tech-
nique must mimic the open operation in that complica-
tions are minimal and durable results are achieved, given
the challenging nature of the operation.
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100. Starr A, Rose D, Cooper J: Antireflux ureteroileal
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101. Menon M, Yu G, Jeffs R: Technique for antirefluxing
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107. Borglund E, Nordstrom G, Nyman C: Classification of
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C H A P T E R
24 Orthotopic Bladder Substitution
in the Male and Female
Celi Varol, MD, Fiona C. Burkhard, MD,
Werner W. Hochreiter, MD, and Urs E. Studer, MD
Orthotopic bladder substitutions are here to stay and have
become the main option following cystectomy.
Improvement in cosmetic results and documented
increases in quality-of-life outcomes will encourage more
urologists to perform such surgical procedures.1,2
Excellent long-term results following orthotopic bladder
substitution can be attained, provided that attention is
given to appropriate preoperative patient selection, spe-
cific intraoperative surgical details, and, most importantly,
meticulous postoperative patient follow-up. The general
principles of patient selection and follow-up apply to both
sexes with only the obvious anatomic and operative varia-
tions to be taken into account in each case. Although blad-
der substitutions in men have been widely performed over
the past two decades and are an accepted mode of urinary
diversion, trepidation still exists when considered in
women. Currently, the majority of cystectomies per-
formed in women are for malignant bladder disease, where
the risk of metachronous or synchronous urethral transi-
tional cell tumor recurrence and voiding dysfunction are
the main factors preventing this from being a routine pro-
cedure. With evolving data over the last decade, a less cau-
tious approach to female bladder substitution is
developing. The rarity of urethral recurrence reported and
a better understanding of the natural history of transitional
cell carcinoma (TCC) has led to more appropriate patient
selection in women undergoing bladder substitution sur-
gery. Advances in surgical techniques together with
increased understanding of the pelvic anatomy, general
physiology, and female continence mechanism have
resulted in improved functional outcomes emulating those
in men. The ileal low pressure bladder substitute with an
afferent tubular segment is easily constructed and has doc-
umented good long-term functional results in both
sexes.3,4 To achieve such results, certain essential factors
need to be considered during specific time periods. These
are segregated in this chapter into the preoperative, oper-
ative, and postoperative periods.
PREOPERATIVE PATIENT SELECTION
AND ASSESSMENT
The preoperative assessment is identical to that for any
radical cystectomy case, where bone, lung, and lymph
node metastases must be excluded. Besides establishing
patient operability, major liver, renal, bowel, or mental
insufficiency must be recognized, as these may be con-
traindications for a bladder substitution.5
Mental Capacity and Compliance
A successful outcome of a bladder substitution requires
the cooperation of the patient and the willingness to
comply with long-term follow-up. Adequate mental
capacity to comprehend the basic function of the bladder
substitute with sufficient physical dexterity is needed.
The patient needs to be educated to ensure satisfactory
longevity of the bladder substitute. If this is not possible
or a question of compliance exists, an alternative form of
treatment should be discussed. A dedicated nurse who
specializes in the education and rehabilitation of patients
with bladder substitutions should be routinely involved
in the preoperative selection process.
Renal Function
The commonest biochemical abnormalities detected fol-
lowing bladder substitution are metabolic acidosis and
443
444 Part IV Bladder
electrolyte abnormalities. The frequency and severity
observed depends on the length and type of intestinal
segment used, duration of urine contact with the bowel,
and the compensatory functional reserve of the kidneys.
Preoperative renal function with a serum creatinine level
of ≤150 μmol/l is required to limit such complications.
Malignant ureteric obstruction or any other mechanical
causes of renal insufficiency, where improvement of renal
function can be expected with surgery, may be taken into
account.6,7
Hepatic Function
To maintain a metabolic equilibrium following surgery
adequate liver function is needed in bladder substitute
candidates. The bowel mucosa of the bladder substitute
allows ammonium from the urine to shift into the circu-
lation. In a urinary tract infection with a urease splitting
organism, the ammonium load becomes even more
important. In the presence of liver insufficiency hyper-
ammonemia can result in dehydration, neurologic disor-
ders and eventual coma.8
Bowel Function
The gastrointestinal tract allows up to 60 cm of ileal
resection without major repercussions, provided that the
ileocecal valve remains intact. When utilizing longer ileal
segments of 60 to 100 cm or the ileocecal valve, long-
term bowel motility disturbances may result.9 Therefore,
if ileum is resected, an attempt should always be made to
preserve the terminal ileum and the ileocecal valve, as
this not only minimizes the risk of bowel dysfunction but
also maintains vitamin B12 and bile salt metabolism.
Evidence of prior bowel disease, resection or radiation
needs to be elucidated as it results in functional bowel
shortening causing malabsorption or diarrhea when fur-
ther bowel is used for a bladder substitute. Preservation
of the right colon allows an extended length of left colon
to be used for reconstruction with lesser malabsorption
side effects. This is because fluid reabsorption occurs
predominantly in the right colon, whilst the left colon
serves more as a conduit. However, even with right colon
preservation, metabolic complications will still occur.8,10
Anastomotic Margin Biopsy and Urethral
Recurrence:
Urethral tumor recurrence is an uncommon phenome-
non following bladder substitution, with a reported inci-
dence of 2% to 4%.11–14 The main factor appears to be
the closeness of the primary tumor in the bladder to the
urethral sphincter. In men, the prostatic urethral length
allows for more separation from the bladder tumor than
in women, when the tumor is in the trigone. Positive
biopsies from the paracollicular region in the prostatic
urethra or the bladder neck in women (site of urethral
anastomosis) are associated with a high likelihood of a
urethral recurrence. These patients require a urethrec-
tomy and should not be considered for an orthotopic
bladder substitute. Infiltration by urothelial tumors
(superficial or stromal) of the proximal prostatic urethra,
carcinoma in situ, and multifocal transitional cancer in
the bladder confer a higher chance of urethral recur-
rence.11,14 These findings are not absolute contraindica-
tions to the performance of a bladder substitution but
require close follow-up with urethral wash cytology.
Management of urethral recurrence with CIS can be per-
formed with BCG therapy, attaining a success rate of
approximately 80%. These results, however, cannot be
replicated in the presence of papillary or invasive urethral
tumor recurrence where urethrectomy is advocated.14
Continence
Identification of incontinence prior to surgery, especially
in females is essential. Urge incontinence is likely to be
treated by cystectomy; however, stress incontinence,
which is due to inadequate sphincter function, needs to
be further evaluated by urodynamic assessment with an
urethral pressure profile. Patients with a grade I genuine
stress incontinence, a normal functional urethral length,
a hypermobile bladder neck and absence of a large cysto-
cele should benefit from a bladder substitute. However, if
there is documented evidence for a shortened functional
urethral length or intrinsic sphincter deficiency, inconti-
nence following an orthotopic bladder substitute can be
expected.
General Preoperative Patient Preparation
On the evening prior to the operation, a liquid diet is
implemented with two high colonic enemas. In contrast,
colonic bladder substitutes require a full mechanical
bowel preparation (Glycoprep). Application of compres-
sion stockings and subcutaneous deep venous thrombosis
prophylaxis should be commenced the evening before
surgery. Injections should be given in the upper body to
prevent pelvic lymphocele formation.
OPERATIVE TECHNIQUE
To achieve a good functional result, the bladder substitu-
tion has to have a good capacity, a low-pressure system
made of detubularized bowel segments with minimal
outlet resistance and preserved sphincter function. There
are certain critical surgical steps that need to be followed
during the cystectomy to achieve these properties. These
steps vary slightly between the genders in regards to the
obvious pelvic anatomy and the position of the respective
 Chapter 24 Orthotopic Bladder Substitution in the Male and Female 445
neurovascular bundles that supply the pelvic floor and
the urethral sphincter. The general principles, however,
remain the same in the performance of the cystectomy
with the construction of the bladder substitute not being
particular to either sex. The following points should be
noted carefully during the cystectomy and formation of
the bladder substitute for optimal surgical outcome.
Cystectomy
Nerve Preservation
Preservation of the autonomic nerves to the sphincter
and urogenital diaphragm is controversial, but we feel
that it should be attempted on the nontumor bearing side
(in bladder cancer) as it will increase the chance of
potency in the male and aid urinary continence in both
sexes.15 These nerves originate from the inferior
hypogastric plexus and continue as the pelvic plexus lying
dorsal to the bladder in the pararectal/paravaginal area,
ending as the paraprostatic neurovascular bundle or
paravaginal plexus prior to supplying the urogenital
diaphragm, sphincter, and erectile organs. Probably
equally important is the preservation of the intrapelvic
branch of the pudendal nerve.16 In benign pathology,
bilateral nerve-sparing cystectomy should be performed
with simultaneous prostatic capsule preservation in the
male.
In the male, the critical areas to preserve the pelvic
plexus and neurovascular bundles are in the dorsomedial
pedicles of the bladder, lateral to the seminal vesicles, and
Figure 24-1 The preparation goes along the dorsolateral aspect of the vaginal wall where
the anterior vaginal wall is removed en bloc with the cystetectomy specimen.
the paraprostatic neurovascular bundles. At the seminal
vesicles, minimal trauma should occur by dissecting close
to them on the lateral wall in an antegrade fashion, away
from the pelvic plexus, without touching it. The pelvic
plexus will be located dorsolateral at this point and will
continue onto the dorsomedial border of the prostatic
capsule. If the dorsomedial pedicle of the bladder is sev-
ered too far dorsally, the nerves are at risk of being tran-
sected here.17 A nerve-sparing prostatectomy should be
performed by freeing the dorsolateral neurovascular bun-
dle off the prostatic capsule. On the contralateral tumor
bearing side, the dorsomedial pedicle of the bladder
should be resected along the pararectal/presacral plane
and the prostatic neurovascular bundles removed with
the prostate if necessary.
A female nerve-sparing cystectomy requires similar
attention during ligation of the dorsomedial pedicle of
the bladder. Care is taken during the dissection of the lat-
eral vagina as the neurovascular bundles lie in the lateral
paravaginal wall. The dissection needs to be in the
anterolateral paravaginal plane, close to the bladder base
on the nontumor bearing side. This can be facilitated by
the use of sponge-holding forceps in the vagina. On the
tumor bearing side, the preparation goes along the dor-
solateral aspect of the vaginal wall where the anterior
vaginal wall is removed en bloc with the cystectomy spec-
imen (Figure 24-1). The proximal part of the paravaginal
plexus will therefore be severed here (Figure 24-2). The
intrapelvic branches of the pudendal nerve that also
innervate the external sphincter mechanism pass under
446 Part IV Bladder

the endopelvic fascia along the medial aspect of levator

ani.18 Therefore, minimal trauma to the endopelvic fas-
cia should occur by only incising it in a ring-like fashion
at the junction of the urethra and bladder neck.
On the contralateral tumor bearing side, the paravagi-
nal tissue is widely excised as far as the pararectal region
to remove the lymphatics that drain the bladder base
together with the autonomic nerves (see Figure 24-10).

Atraumatic Dissection of The Urethra

Sharp, atraumatic dissection of the urethra with limited
use of only bipolar electrocautery at the prostatic apex in
men and bladder neck in females is essential. Maximum
urethral length must be retained. Preservation of the pub-
oprostatic and pubourethral ligaments and incision of the
endopelvic fascia along the bladder neck in female patients
will allow for more urethral stability and improved conti-
nence.19 In women, preserving the autonomic nerve sup-
ply to the proximal one-third of the urethra will also
maintain its tubular shape. If this is denervated, a flaccid,
hypotonic urethra results, which tends to kink. If in doubt
of the innervation, the proximal one-third of the urethra
should be resected. This may result in dribble inconti-
nence when walking due to the shortened functional ure-
thral length. The pudendal nerve still innervating the
distal two-thirds of the urethra and pelvic floor will main-
tain continence at times of sudden increased abdominal
pressure, such as during coughing.19,20 Figure 24-2 The proximal part of the paravaginal plexus is
severed in a ring-like fashion at the junction of the urethra
and bladder neck.
Ureters
The ureters need to be mobilized en bloc with all their
paraureteric tissue. This allows for preservation of the ileum segment is measured along the border of the ileal
blood supply to the proximal ureter, whilst division of the mesentery without stretching the bowel. The distal
ureters at the level of the iliac bifurcation, allows en bloc mesenteric incision transects the main vessels, whereas
removal of the distal ureter and paraureteric lymphatic the proximal incision must be shorter in order to pre-
vessels with the cystectomy specimen. The left ureter is serve the main vessels perfusing the future reservoir seg-
mobilized retrocolic and superior to the inferior mesen- ment (Figure 24-3). A 4-0 polyglycolic acid single layer
teric artery when transposed to the paracaval side, with- seromuscular running suture is used to restore the bowel
out kinking and free of tension. Ureteric anastomoses continuity in a cephalad position, as well as close its
should not be obstructive in nature and antireflux mesenteric window. Both ends of the isolated ileal seg-
ureteric reimplantation is not required in a low pressure ment are closed with a single layer 4-0 polyglycolic acid
ileal bladder substitute.21,22 seromuscular running suture. The distal 40- to 44-cm
end of the ileal segment is opened along its antimesen-
teric border (Figure 24-4).
Orthotopic Ileal Bladder Substitute
Ileal Segment Resection
Ureteroileal Anastomosis
The intraoperative epidural anesthesia (containing local
anesthetics) will cause bowel contraction and, therefore, The ureters are spatulated 1.5 to 2 cm and anastomosed
must be switched off at least 1 hour prior to the meas- by two 4-0 polyglycolic acid running sutures using the
urement of bowel length. This is to ensure accurate Nesbit technique in an end-to-side fashion to two longi-
bowel length measurement resulting in ideal reservoir tudinal 1.5- to 2-cm long incisions along the paramedian
dimension. A 54- to 56-cm segment of ileum is isolated antimesenteric border of the afferent tubular ileal seg-
25 cm proximal to the ileocecal valve. The length of the ment (Figure 24-5). This segment is 12 to 14 cm in
 Chapter 24 Orthotopic Bladder Substitution in the Male and Female 447

Figure 24-3 Prepare 54- to 56-cm long ileal segment for the bladder substitute. Note the
different incision depths of the ileal mesentery proximally and distally, in order to preserve the
blood supply.

length. The distal ureteric adventitia is sutured to the
afferent ileal segment to remove tension on the anasto-
mosis and to cover it. The ureters are stented with 8 F
catheters. To prevent dislocation of the catheters, a rap-
idly absorbable 4-0 polyglycolic acid suture is placed
through the ureter and catheter together and loosely
tied, not compromising the ureteric blood flow (see
Figure 24-5). The ureteric catheters are passed through
the wall of the most distal end of the afferent tubular seg-
ment, where it is covered by the fat of the mesentery
(Figure 24-6). This provides a “covered” canal in the
reservoir wall following withdrawal of the ureteric
catheters.
Construction of The Bladder Substitute
and Urethral Anastomosis
For the reservoir construction, the two medial borders
of the opened U-shaped distal part of the ileal segment
are oversewn with a single continuous 2-0 polyglycolic
acid seromuscular layer. The base of the “U” is folded
over between the two limbs of the “U” (see Figure 24-6),
resulting in a spherical reservoir consisting of four cross-
folded ileal segments. After closure of the lower half
of the anterior wall and most of the upper half, the
surgeon’s finger is introduced through the remaining
opening to determine the most caudal part of the reser-
voir. An 8- to 10-mm diameter hole is cut out of the
pouch wall avoiding the suture line (Figure 24-7). The anas-
tomoses must sit flat with the pelvic floor in the male
and the pelvic floor/anterior vaginal wall in the female.
A funnel-shaped outlet, which would kink, must at all
times be avoided as it may result in outlet obstruction
(Figure 24-8).
Six 2-0 polyglycolic acid seromuscular sutures are
placed between the hole in the reservoir wall and the
membranous urethra (Figure 24-9). An 18 F urethral
catheter is inserted before tying the six sutures. A 10 F
cystostomy tube is placed into the reservoir through its
mesenteric fat prior to total closure of the reservoir
448 Part IV Bladder

Figure 24-4 Close the mesenteric window, avoiding deep sutures in the mesentery of the
terminal ileum to that of the mesentery of the bladder substitute, in order not to compromise
circulation. The distal 40- to 44-cm end of the ileal segment is opened along its
antimesenteric border.

(Figure 24-10). One 20 F silicon drain is placed into the
pelvis and one near the ureteric anastomosis.
POSTOPERATIVE MANAGEMENT
Good long-term results can only be achieved by vigilant
postoperative management and regular long-term follow-
up. This will allow potential complications to be recog-
nized early and minimize morbidity to the patient and the
bladder substitute. The in-hospital postoperative period
should be utilized for patient education and to help adjust
to their bladder substitute. A bladder substitute that func-
tions well should have no infection, no incontinence, no
acidosis, and no or minimal postvoid residual urine.7
Early Postoperative Period
The patients are stationed in a high dependency ward for
the first 24 to 48 hours. Postoperatively all patients have
a nasogastric tube, urethral catheter, suprapubic catheter,
wound drains, and two ureteric catheters. We use single
‘J’ or ureteric catheters (8 F) to stent the ureteric anasto-
moses that are exteriorized through the bladder substi-
tute. This minimizes urine contact and absorption with
the bladder substitution mucosa and allows accurate fluid
balance measurements. The suprapubic and transurethral
catheters need to be gently flushed but vigorously aspi-
rated with saline 0.9% every 6 hours. This is mandatory
to prevent any mucous clots and subsequent catheter
blockages, which may lead to bladder substitution rup-
ture. This risk is highest when bowel activity returns
whilst the urethral catheter is still in situ. Abdominal
bloating can be limited and bowel function return accel-
erated with subcutaneous neostigmine methylsulfate 3 to
6 × 0.5 mg/day commenced on the third day and addi-
tionally in smokers with nicotine patches. The ureteric
catheters are removed sequentially on the 5th to 8th
postoperative days. Total parenteral nutrition (without
 Chapter 24 Orthotopic Bladder Substitution in the Male and Female 449
Figure 24-5 Perform a simple end-to-side Nesbit technique with a 4-0 polyglycolic acid
running suture for the ureteroileal anastomosis.
lipid supplementation) is commenced and tapered once
an oral diet is reintroduced. Patients undergo regular
chest physiotherapy and are encouraged to mobilize on
the first postoperative day.
Late Postoperative Period
A cystogram is performed on the 8th to 10th postopera-
tive day. If this excludes any urinary extravasations, the
suprapubic catheter is removed first, followed by the ure-
thral catheter 2 days later. This allows for the puncture
site from the suprapubic catheter in the bladder substi-
tute to seal. A urine sample should be sent for culture
when the urethral catheter is removed. A bladder substi-
tution is not colonized with bacteria like a urinary con-
duit, so any evidence of a bacteriuria or urinary tract
infection must be treated. Following removal of all
catheters, a quinolone antibiotic is implemented as pro-
phylaxis for 5 days.
The patient is instructed to void in a sitting position
every 2 hours during the day and 3 hourly with the help
of an alarm clock at night. The normal sensory voiding
reflex is lost following a cystectomy, requiring the patient
to initially wake up twice at night. Using two alarm
clocks allows for a less interrupted sleep. Voiding needs
to occur by relaxation of the pelvic floor, followed by
slight abdominal straining. This is aided by hand pres-
sure on the lower abdomen and bending forwards.
Initially, effectiveness of reservoir emptying is monitored
with in-out catheterization and ultrasound to detect any
postvoid residual urine. This can later then be monitored
by suprapubic ultrasound alone. Effective sphincter
training is taught by performing a digital rectal examina-
tion and requesting the contraction of the anal sphincter
only and not the abdominal or gluteal muscles. The
patient reproduces this task initially 10 times hourly,
maintaining contraction for 6 seconds and as continence
is achieved on a regular daily basis. This seems to build
up resting tone and also with repetition, the patient
learns to perform it by reflex prior to certain physical
activities, thereby preventing any stress incontinence.
Men may suffer from postmicturition dribble inconti-
450 Part IV Bladder

Figure 24-6 The two medial borders of the antimesenteric opened U-shaped distal ileum
segment is oversewn with a single layer seromuscular running suture. The base of the “U” is
folded over and tied between the two limbs of the “U” as shown by the arrow.

nence, which can be managed by instructing the patient

to “milk” the urethra empty at the end of a void.23 The
voiding interval is gradually increased from 2 to 4 hourly.
This is performed in hourly aliquots and only when the
patient remains continent for the specified time period
allocated. (That is, when the patient is continent for 2
hours, the voiding period is increased to 3 hours. This is
only increased to 4 hours when continence at 3 hours is
achieved.) The patient must try not to void before the
allotted time period even if dribble incontinence ensues.
The aim is to achieve a gradually distended reservoir
capacity of 500 ml, which will result in a low-pressure
system and therefore continence. This can be best under-
stood by Laplace’s law (pressure = wall tension/radius),
where if the radius of the reservoir increases, the pressure
will decrease. As the reservoir pressure decreases below
the urethral closing pressure, continence will be attained.
The time to continence depends on good counseling
with regular and effective sphincter training, surgical
technique where nerve preservation to the urethra and
pelvic floor is achieved, and the age of the patient.
Metabolic Management
As a metabolic acidosis is the commonest biochemical
abnormality following a bladder substitution, the urolo-
gist, as well as the patient, should be aware of the symp-
toms it can cause in order to be able to rapidly implement
therapy (Table 24-1). The presence of fatigue, nausea,
vomiting, or epigastric burning should alert the urologist
to a metabolic acidosis. H2-blockers or proton pump
inhibitors should not be given for epigastric pain, as they
would worsen the metabolic acidosis. The base excess is
monitored with a venous blood gas analysis every second
day and immediately corrected if in a negative parameter.
This is performed with sodium bicarbonate 2 to 6 g/day
in ileal bladder substitutions. In virtually all patients,
short-term treatment of their metabolic acidosis with
NaHCO3 medication will be needed. This is ceased
within 3 months time, as the mucosa of the reservoir
becomes more resilient to electrolyte and fluid exchange.
In the early postoperative period, hypoosmolar urine
remains in prolonged contact with the mucosa of the
 Chapter 24 Orthotopic Bladder Substitution in the Male and Female 451

Figure 24-7 The caudal part of the reservoir is closed completely and the cranial part
almost completely by a single 2-0 polyglycolic acid running seromuscular suture. A finger is
introduced through the remaining opening of the reservoir and an 8- to 10-mm hole is cut
into the most caudal part of the reservoir, close to the mesentery and 2 to 3 cm away from
the suture edge that resulted from cross-folding the ileal segment.

Figure 24-8 The reservoir-urethral anastomosis must be flat and not funnel-shaped to
prevent subsequent kinking and outlet obstruction.
452 Part IV Bladder

Figure 24-9 Six seromuscular 2-0 polyglycolic acid sutures are placed between the
reservoir and the membranous urethra. These are tied after inserting an 18 F urethral
catheter. The catheter is used as a track to guide the reservoir onto the urethra. Cystostomy
and ureteric catheters are placed through the fat of the mesentery.

reservoir. The ileum reaches equilibrium by shifting salt
(NaCl) into the reservoir and simultaneously absorbing
acid (H+) in the form of ammonium into the blood
stream. This will result in a hypovolemic salt loosing
state with an associated metabolic acidosis.8 These
patients have a rapid drop in body weight due to dehydra-
tion and anorexia. Daily body weight monitoring is essen-
tial in the postoperative recovery period. Patients need to
consume 2 to 3 l of fluids per day that is supplemented
with increased salt intake in their diet to combat any salt-
losing syndrome.5
LONG-TERM FOLLOW-UP
The successful results of ileal low-pressure orthotopic
bladder substitution are not only due to the simplicity of
the operative technique but also the meticulous long-
term regular follow-up that is instituted. Only this way
the optimal reservoir function and prevention of poten-
tial delayed complications will be recognized and man-
aged effectively. A suggested schema is illustrated (Table
24-2). A total of 12% of patients will have positive uri-
nary cultures.24 Associated causes, such as postvoid resid-
ual urine, need to be identified, and presence of inguinal
or abdominal hernias that can prevent adequate reservoir
emptying needs to be treated. Protruding mucosa or
stricture at the urethral-reservoir anastomosis may also
be the factors that can be easily managed transurethrally.
Diurnal continence of up to 83% in women and 90%
in men with nocturnal rates over 80% at 12 months
should be achieved in both sexes.15 Incontinence rates
tend to increase in the absence of a nerve-sparing cystec-
 Chapter 24 Orthotopic Bladder Substitution in the Male and Female 453

Figure 24-10 After cystostomy tube placement into the reservoir, the cephalad part of the
pouch is closed completely; 20 F silicon drains are placed into the pelvis and near the
ureteric anastomosis.

Table 24-1 Symptoms of Metabolic Acidosis tomy, in the older patients and 5 years following a cys-
tectomy. The incontinence is generally minimal and not
Fatigue
debilitating with normal transurethral voiding achievable
Anorexia in up to 97% of patients.4
It is also important to recognize that the limited under-
Dyspepsia and heartburn standing of orthotopic bladder substitutions by other
medical professions may result in ignorant decisions
Nausea and vomiting
regarding patient care; therefore, direct referral or con-
Weight loss tact with the initial treating institution is recommended.
454 Part IV Bladder

Table 24-2 Follow-up Schema for Patients with Bladder Substitute

Months After Surgery 3 6 12 18 24 30 36 42 48 54 60

Clinical examination x x x x x x x x x x x

Urine culture x x x x x x x x x x x

Body weight x x x x x x x x x x x

Blood tests* x x x x x x x x x x x

Folic acid, vitamin B12 x x x x

Chest x-ray x x x x x x x

IVU x x x x

Renal ultrasound x x x x x x x

Bone scan (only if x x

≥pT3 and each N+)

Pelvic/abdominal x
CT-Scan (only if
≥pT3 and each N+)

Postvoid residual x x x x x x x x x x x

Urethral wash cytology x x x x x x x

*Hb, Na+, K+, Cl−, bicarb., creatinine, urea, ALP, gamma GT, AST, LDH, and venous blood gas analysis.

REFERENCES 9. Hofmann AF: Bile acid malabsorption caused by ileal

1. Hobisch A, Tosun K, Kemmler G, et al: Life after
cystectomy and orthotopic neobladder versus ileal conduit
urinary diversion. Semin Urol Oncol 2001; 19(1):18–23.
2. Yoneda T, Igawa M, Shiina H, Shigeno K, Urakami S:
Postoperative morbidity, functional results and quality of
life of patients following orthotopic neobladder
reconstruction. Int J Urol 2003; 10(3):119–125.
3. Doherty A, Burkhard F, Holliger S, Studer UE: Bladder
substitution in women. Curr Urol Rep 2001; 2(5):350–356
(review).
4. Madersbacher S, Möhrle K, Burkhard F, Studer UE:
Long-term voiding pattern of patients with ileal
orthotopic bladder substitutes. J Urol 2002; 167(5):2052.
5. Mills RD, Studer UE: Guide to patient selection and
follow-up for orthotopic bladder substitution. Contemp
Urol 2001; 2:35–40.
6. Skinner DG, Studer UE, Okada K, et al: Which patients
are suitable for continent diversion or bladder substitution
following cystectomy or other definitive local treatment?
Int J Urol 1995; 2(Suppl):105.
7. Studer UE, Burkhard F, Danuser HJ, Thalmann G: Keys
to success in orthotopic bladder substitution. Can J Urol
1999; 6(5):876.
8. Mills RD, Studer UE: Metabolic consequences of
continent urinary diversion. J Urol 1999; 161:1057–1066.
resection. Arch Intern Med 1972; 130:597.
10. Proano M, Camilleri M, Phillips SF, Brown ML,
Thomford GM: Transit of solids through the human
colon: regional quantification in the unprepared bowel.
Am J Physiol 1990; 258(6 Pt 1):G856–G862.
11. Freeman JA, Thomas A, Esrig D, et al: Urethral
recurrence in patients with orthotopic ileal neobladders.
J Urol 1996; 156(5):1615–1619.
12. Yossepowitch O, Dalbagni G, Golijanin D, et al:
Orthotopic urinary diversion after cystectomy for
bladder cancer: implication for cancer control and
patterns of disease recurrence. J Urol 2003;
169(1):177–181.
13. Hautmann RE, Miller K, Steiner U, Wenderoth U: The
ileal neobladder: 6 years of experience with more than 200
patients. J Urol 1993; 150(1):40–45.
14. Studer UE, Danuser H, Hochreiter W, et al: Summary of
10 years’ experience with an ileal low-pressure bladder
substitute combined with an afferent tubular isoperistaltic
segment. World J Urol 1996; 14:29–39.
15. Turner WH, Danuser H, MoehrleK, Studer UE: The
effect of nerve sparing cystectomy technique on
postoperative continence after orthotopic bladder
substitution. J Urol 1997; 156(6):2118.
16. Hugonnet CL, Danuser HJ, Springer JP, Studer UE:
Urethral sensitivity and the impact on urinary continence
 Chapter 24 Orthotopic Bladder Substitution in the Male and Female 455
in patients with an ileal bladder substitute after
cystectomy. J Urol 2001; 165:1502–1505.
17. Burkhard FC, Studer UE: Orthotopic bladder
substitution. Curr Opin Urol 2000; 10(4):343–349.
18. Borirakchanyavat S, Aboseif SR, Carroll PR, Tanagho EA,
Lue TF: Continence mechanism of the isolated female
urethra: an anatomical study of the intrapelvic somatic
nerves. J Urol 1997; 158(3 Pt 1):822—826.
19. Mills RD, Studer UE: Female orthotopic bladder
substitution: a good operation in the right circumstances.
J Urol 2000; 163(5):1501–1504.
20. Doherty A, Burkhard F, Holliger S, Studer UE: Bladder
substitution in women. Curr Urol Rep 2001;
2(5):350–356.
21. Thoeny HC, Sonnenschein MJ, Madersbacher S, Vock P,
Studer UE: Is ileal orthotopic bladder substitution with
an afferent tubular segment detrimental to the upper
urinary tract in the long term? J Urol 2002;
168(5):2030–2034.
22. Studer UE, Siegrist T, Casanova GA, et al: Ileal bladder
substitute: antireflux nipple or afferent tubular segment?
Eur Urol 1991; 20(4):315–326.
23. Bader P, Hugonnet CL, Burkhard F, Studer UE:
Inefficient urethral milking secondary to urethral
dysfunction as an additional risk factor for incontinence
after radical prostatectomy. J Urol 2001;
166(6):2247–2252.
24. Varol C, Burkhard FC, Thalmann GN, Studer UE:
Urethral recurrence following cystectomy for bladder
cancer; prevention and detection in patients with
orthotopic bladder substitutes. J Urol 2003; 169(Suppl
4):103.
C H A P T E R
25 Cancer of the Prostate: Detection
and Staging
Anthony V. D’Amico, MD, PhD,
and Michael W. Kattan, PhD
The goal of a staging system is to predict cancer-specific
survival as accurately as possible using readily available
pretreatment parameters. These parameters define stages
that correspond to rates of disease-specific survival fol-
lowing standard therapy that increase in a clinically sig-
nificant manner as the clinical stage decreases. Validated
algorithms1–3 currently exist that provide accurate esti-
mates of prostate-specific antigen (PSA) failure based on
pre-treatment clinical parameters following surgery or
radiation therapy (RT) for patients with clinically local-
ized disease. However, PSA failure may not translate into
death from prostate cancer for all patients because men
with prostate cancer are generally over the age of 60 and
often have competing causes of mortality.4 Therefore,
current efforts are aimed at defining a staging system
based on pretreatment factors that accurately represent
rates of prostate cancer-specific mortality (PCSM) fol-
lowing current standard therapies.
AMERICAN JOINT COMMISSION ON CANCER
STAGING SYSTEM
Historically, staging defines the anatomic extent of a dis-
ease and tumor volume remains the most important sin-
gle determinant of prognosis for many cancers. The
current 2002 American Joint Commission on Cancer
(AJCC) staging system5 for patients with adenocarci-
noma of the prostate is based solely on the findings of the
digital rectal examination (DRE) or transurethral resec-
tion of the prostate (TURP). However, the introduction
of the serum PSA has changed the presentation of
prostate cancer worldwide. The vast majority of patients
now present with nonpalpable PSA detected (i.e., clinical
category T1c) disease.6 By grouping most of today’s
patients into a single T1c-category, the 2002 AJCC stag-
ing system is limited in its ability to stratify patients into
clinically distinct groups based on cancer-specific out-
comes.
PROGNOSTIC FACTORS
Combined Modality Staging
Prior studies1,2 have confirmed that the serum PSA level,
2002 AJCC clinical T-category, and biopsy Gleason score
are independent predictors of time to PSA failure follow-
ing either radical prostatectomy (RP) or external beam RT.
Combined modality staging was developed to utilize these
independent and clinically significant predictors of PSA
outcome following definitive therapy to define prognostic
groups. Risk groups based on the PSA, biopsy Gleason
score, and the 2002 AJCC clinical T-category that stratify
the risk of PSA failure following RP or RT are illustrated
in Figures 25-1 and 25-2, respectively.3 This risk stratifi-
cation algorithm, which was originally defined based on
PSA failure rates, has also been shown to stratify time to
PCSM following RT using simply the PSA and biopsy
Gleason score as illustrated in Figure 25-3.7
Recently, a fourth parameter, the percent positive
prostate biopsies, has been shown in a validated prognos-
tic factor analysis to provide clinically useful information
regarding PSA outcome following either RP8 or external
beam RT9 for intermediate risk patients as shown in
Figures 25-4 and 25-5, respectively. This parameter has
also been shown to be predictive of time to PCSM fol-
lowing RT10 in the intermediate risk group, forming the
basis for a 2-tiered risk group stratification as shown in
Figure 25-6.
Molecular markers (such as p53, bcl-2, Ki-67, and
c-erb-b2), neuroendocrine markers (such as neuron-specific
enolase and chromogranin A), histopathologic markers
459
 100 100

Prostate cancer specific survival

90 90
% bNED Survival 80 80
70 70
60 60
50 50
40 40
30 30
Low risk Low risk
20 Intermediate risk 20 Intermediate risk
10 High risk 10 High risk
0 0
0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10
Time in years Time in years

1020 704 422 156 51 13 110 106 92 72 56 38 28 15 4 2 1

693 407 203 99 29 6 155 147 125 93 66 44 25 12 4 3 3
414 198 91 35 9 1 150 144 130 107 71 49 28 12 7 5 4

Number at risk Number at risk

Figure 25-1. Prostate-specific antigen outcome following
radical prostatectomy stratified by the pretreatment risk
group for patients with clinically localized disease. Low risk:
PSA ≤ 10 ng/ml and biopsy Gleason ≤ 6, and 2002 AJCC
category T1c or T2a. Intermediate risk: PSA > 10 to 20 ng/ml
or biopsy Gleason 7 or 2002 AJCC category T2b. High risk:
PSA > 20 ng/ml or biopsy Gleason 8 to 10 or 2002 AJCC
category T2c.
Figure 25-3. Prostate cancer-specific survival following
external beam radiation therapy stratified by the pretreatment
risk group for patients with clinically localized disease. Low
risk: PSA ≤ 10 ng/ml and biopsy Gleason ≤ 6. Intermediate
risk: PSA > 10 to 20 ng/ml or biopsy Gleason 3 + 4. High
risk: PSA > 20 ng/ml or biopsy Gleason ≥ 4 + 3.

100
90
80
100
70
PSA 0utcome

90
60
80
50
% bNED survival

70
40
60
30
Low risk 50
20 Intermediate risk 40
10 High risk
30
0 < 34%
20 34−50%
0 1 2 3 4 5 6 7 8 9 10
10 > 50%
Time in years 0
90 88 70 46 34 26 16 5 3 3 2 0 1 2 3 4 5 6 7
173 167 112 69 45 24 10 4 3 2 1 Time in years
118 115 83 47 30 18 14 8 3 1 1
366 309 259 201 149 109 79 153
150 99 75 51 31 19 13 7
Number at risk 163 104 69 44 23 12 7 4
Figure 25-2. Prostate-specific antigen outcome following
external beam radiation therapy stratified by the pretreatment risk Number at risk
group for patients with clinically localized disease. Low risk: PSA
≤ 10 ng/ml and biopsy Gleason ≤ 6, and 2002 AJCC category Figure 25-4. Prostate-specific antigen outcome following
T1c or T2a. Intermediate risk: PSA > 10 to 20 ng/ml or biopsy radical prostatectomy stratified by the percent of positive
Gleason 7 or 2002 AJCC category T2b. High risk: PSA > 20 prostate biopsies for intermediate-risk patients with clinically
ng/ml or biopsy Gleason 8 to 10 or 2002 AJCC category T2c. localized disease.
 Chapter 25 Cancer of the Prostate: Detection and Staging 461

Prostate cancer-specific survival (%)

100 100
90 90
80 80
% bNED survival

70 70
60 60
50 50
40 40
30 30
< 34% Iog rank p < 0.0001
20 34−50% 20 Low + Int  50%
10 > 50% 10 High + Int > 50%
0 0
0 1 2 3 4 5 0 1 2 3 4 5 6 7 8 9 10 11 12
Time in years Time in years

96 83 50 24 12 8 206 155 79 37 6 13
49 45 23 6 4 3 175 153 89 38 12 3
62 59 36 16 8 3

Number at risk
Figure 25-5. Prostate-specific antigen outcome following
external beam radiation therapy stratified by the percent of
positive prostate biopsies for intermediate-risk patients with
clinically localized disease.
Number at risk
Figure 25-6. Prostate cancer-specific survival following
external beam radiation therapy stratified by the percent of
positive prostate biopsies for intermediate-risk patients with
clinically localized disease.

for pelvic lymphadenopathy. A bone scan is generally rec-

(such as microvessel density and ploidy), imaging
approaches (such as color Doppler), PSA derivatives
(such as PSA velocity, PSA density, and free PSA), and
reverse transcriptase polymerase chain reaction (rtPCR)
to examine PSA-expressing cells in the peripheral blood,
bone marrow, and pelvic lymph nodes all have been
examined11–15 to assess their ability to predict PSA out-
come following definitive local therapy for patients with
clinically localized disease. While many of these factors
have been predictive of PSA outcome on univariable
analysis, they await testing in a multivariable model that
accounts for the established prognostic factors to deter-
mine their clinical significance.
Radiologic Staging
The ability of computerized tomography, pelvic coil mag-
netic resonance imaging (MRI), and transrectal ultra-
sound (TRUS) to identify extracapsular extension (ECE)
and/or seminal vesicle invasion (SVI) for patients with
clinically localized disease based on the DRE is limited.
The accuracy of these studies does not exceed 60%,16,17
and therefore none of these studies is recommended for
staging patients with clinical stage T1 or stage T2 disease.
Patients with more advanced disease (stage T3 or stage
T4) as determined by DRE should have a computed
tomographic (CT) scan or MRI scan of the pelvis to assess
ommended to identify metastatic disease and is indicated
for patients with either clinical stage T3 or stage T4 dis-
ease, biopsy Gleason score of 4 + 3 or higher, a PSA level
greater than 20 ng/ml, or clinical symptoms.
The role of endorectal MRI (erMRI) has been evalu-
ated for patients with clinical stage T1c or stage T2 dis-
ease to assess whether information regarding pathologic
stage and PSA outcome following RP was provided.18 In
experienced hands, the erMRI finding of T3 versus T2
disease was 80% accurate in predicting pathologic stage.
However, the erMRI did not add clinically meaningful
information for the vast majority of the patients (low risk
and high risk) after accounting for the pretreatment PSA
level, biopsy Gleason score, clinical T-category, and the
percent positive prostate biopsies. In the intermediate
risk patients, however, the erMRI provided a clinically
relevant stratification of 5-year PSA outcome as shown in
Figure 25-7. At present, however, outside of high risk
localized of locally advanced prostate cancer, imaging of
the pelvis with erMRI to assess for evidence of pelvic
lymphadenopathy or evidence of ECE or SVI remains
under investigation.
Pretreatment Nomograms
A popular tool for predicting outcomes in prostate can-
cer is the nomogram. Strictly speaking, a nomogram is a
series of lines with point values, which one manipulates
462 Part V Prostate Gland and Seminal Vesicles

100 nomograms have been developed and validated for pre-

90 dicting biochemical failure for patients treated with sur-
gery, brachytherapy, and external beam RT.3,21–7 They
80
are presented in Figures 25-8 to 25-10. They predict bio-
% bNED Survival

70
chemical failure, and future nomograms are necessary for
60 predicting more distant and clinically relevant endpoints,
50 such as metastasis and death. These prediction models
40 are available in software for the palm and desktop com-
30 puters from http://www.nomograms.org.
MR T2
20 MR T3
10 SUMMARY
0
The 2002 AJCC staging system is limited in its ability to
0 1 2 3 4 5 provide accurate information regarding time to PCSM
Time in years for individual patients who present with the most com-
mon clinical category of T1c disease. However, algo-
162 137 100 64 46 28 rithms for predicting PSA outcome following RP or
29 19 14 4 4 4 external beam RT that are based on pretreatment clini-
cal parameters that include the PSA level, biopsy
Number at risk Gleason score, and 2002 AJCC clinical T-category have
been validated.1–3 Nevertheless, given the competing
Figure 25-7. Prostate-specific antigen outcome following causes of mortality that exist in men undergoing defini-
radical prostatectomy stratified by the erMRI T-category for tive treatment for localized prostate cancer, many men
intermediate-risk patients with clinically localized disease. who sustain PSA failure will not live long enough to
develop clinical evidence of distant disease and far fewer
will die from the disease. Although pretreatment risk-
by drawing straight lines to obtain a prediction.19 The based staging systems predicting the endpoint of
term is attributed to Professor Maurice d’Ocagne in PCSM7,26 have been published, none has been validated
1889.20 The primary advantage of nomograms, relative in the PSA era. Studies are currently ongoing to define a
to other paper-based approach, such as tables, is that validated pretreatment staging system that can accu-
nomograms maintain a continuous prediction model, rately predict time to PCSM following surgery or RT
resulting in greater predictive accuracy. Pretreatment for prostate cancer.

Preoperative nomogram for PSA recurrence

0 10 20 30 40 50 60 70 80 90 100
Points

PSA
0.1 1 23 4 6 7 8 9 101 2 16 20 30 45 70 110
T2a T2c T3a
Clinical stage
T1c T1ab T2b

2+3 3+2 4+

Biopsy gleason sum
 2+2 3+3 3+4
Total points
0 20 40 60 80 100 120 140 160 180 200
60-month recurrence free prob.
.96 .93 .9 .85 .8 .7 .6 .5 .4 .3 .2 .1 .05

Figure 25-8. Pretreatment nomogram for patient considering surgery. (Adapted with
permission from Kattan MW, Eastham JA, Stapleton AMF, et al: J Natl Cancer Inst 1998;
90(10):766–771.)
 Chapter 25 Cancer of the Prostate: Detection and Staging 463

3D conformal radiation therapy nomogram for PSA recurrence

0 10 20 30 40 50 60 70 80 90 100
Points

Pretreatment PSA
0.3 1 2 3 4 5 6 7 910 25 50 100
T2a T3ab T3c
Clinical stage
T1c T2b T2c
357 9
Bx. gleason sum
24 6 8 10

Dose (Gy)
86.4 72 68 64.8
No
Hormones
Yes
Total points
0 20 40 60 80 100 120 140 160 180

60 month Rec. free prob.

0.99 0.98 0.95 0.9 0.8 0.7 0.5 0.3 0.1 0.01

Figure 25-9. Pretreatment nomogram for patient considering external beam radiation.
(Adapted with permission from Kattan MW, Zelefsky, Kupelian PA, et al: J Clin Oncol
2000; 18:3352–3359.

Brachytherapy nomogram for PSA recurrence

0 10 20 30 40 50 60 70 80 90 100
Points
0.8
Pretreatment PSA
0.6 1 2 3 4 5 6 8 10 15 20 30 40 60 80 100

42 7
Biopsy GI.Sum
536 8
T2a
97 clinical stage
T2b T1c
No
XRT
Yes
Total points
0 10 20 30 40 50 60 70 80 90 100 110 120 130

60-month Rec. free prob.

0.99 0.98 0.96 0.93 0.9 0.8 0.7 0.6 0.5 0.4 0.25 0.12

Figure 25-10. Pretreatment nomogram for patients considering brachytherapy. (Adapted

with permission from Kattan MW, Potters, L, Blasko JC, et al: Urology 2001;
58(3):393–399.)
464 Part V Prostate Gland and Seminal Vesicles
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prostate cancer. Int J Radiat Oncol Biol Phys 2002;
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19. Hankins TL: Blood, dirt and nomograms. Hist Sci Soc
1999; 90:50–80.
20. Banks J. Nomograms, Vol 6. New York, Wiley, 1985.
21. Kattan MW, Eastham JA, Stapleton AMF, Wheeler TM,
Scardino PT: A preoperative nomogram for disease
recurrence following radical prostatectomy for prostate
cancer. J Natl Cancer Inst 1998; 90(10):766–771.
22. Kattan MW, Potters L, Blasko JC, et al: Pretreatment
nomogram for predicting freedom from recurrence after
permanent prostate brachytherapy in prostate cancer.
Urology 2001; 58(3):393–399.
23. Kattan MW, Zelefsky MJ, Kupelian PA, et al:
Pretreatment nomogram for predicting the outcome of
three-dimensional conformal radiotherapy in prostate
cancer. J Clin Oncol 2000; 18:3352–3359.
24. Graefen M, Karakiewicz P, Cagiannos I, et al: A validation
of two preoperative nomograms predicting recurrence
following radical prostatectomy in a cohort of European
men. Urol Oncol 2002; 7(4):141–146.
25. Graefen M, Karakiewicz PI, Cagiannos I, et al:
International validation of a preoperative nomogram for
prostate cancer recurrence following radical
prostatectomy. J Clin Oncol 2002; 20(15):3206–3212.
26. Roach M, Lu J, Pilepich MV, et al: Four prognostic
groups predict long-term survival from prostate cancer
following radiotherapy alone on radiation therapy
oncology group clinical trials. Int J Radiat Oncol Biol
Phys 2000; 47:609–615.
C H A P T E R
26AClinically Localized (Stage T1a-T2c)
Adenocarcinoma of the Prostate:
Surgical Management and Prognosis
Maxwell V. Meng, MD, and Peter R. Carroll, MD
Prostate cancer remains a major health concern in the
U.S. and throughout the world. The institution of
screening protocols, based on the combination of dig-
ital rectal examination and serum prostate specific
antigen (PSA) testing, has increased the opportunity
for cancer cure by allowing earlier diagnosis at lower
stages of disease. Over the past decade, advances in
both surgical and therapeutic radiation therapy tech-
niques have revolutionized the ability to adequately
treat prostate cancer while simultaneously reducing
treatment-related morbidity. This chapter focuses on
the management and outcomes of patients with clini-
cally localized (stages T1a to T2c) cancer of the
prostate.
RADICAL PROSTATECTOMY
Rationale for Treatment
Proponents of screening for prostate cancer cite the
disease prevalence and mortality, ability to effectively
treat localized cancers, and inability to cure metastatic
disease as compelling reasons for this practice.1 Despite
the numerous factors supporting early prostate cancer
detection, controversy continues to surround the need
for, and specific choice of, intervention.2 This is partic-
ularly true for radical prostatectomy. Definitive surgery
is not only curative for most organ-confined tumors
(stages T1 to T2) but is also associated with limited
morbidity and is amenable to selective use with adju-
vant therapy in high-risk patients. Nevertheless, the
potential for operative and postoperative morbidity
exists and surgery may not be necessary in men with
lower-risk disease who may be candidates for surveil-
lance alone.
Natural History of Prostate Cancer
Ultimately, the role and necessity of surgical removal of
the prostate from men with cancer can only be deter-
mined in appropriately designed clinical trials. The most
relevant endpoint of these studies is the impact of prosta-
tectomy on overall survival. Prior published reports eval-
uating various prostate cancer treatments are not
applicable to contemporary patients. Currently, there are
several ongoing randomized trials seeking to compare
active therapy with watchful waiting.3 The results of a
recent study from the Scandinavian International Union
against Cancer provide evidence that radical prostatec-
tomy significantly reduces disease-specific mortality.4
A total of 695 men with clinical stages T1b, T1c, or T2
prostate cancer were randomized to either watchful wait-
ing or prostatectomy. During a median follow-up of 6.2
years, there was no difference between the two groups
with respect to overall survival; however, death due to
prostate cancer in the surveillance cohort (8.9%) was
greater than that observed in the surgery cohort (4.6%, p
= 0.02). In addition, men after surgery had a lower risk of
distant metastases (hazard ratio 0.63). Although there
was no reduction in overall mortality, a difference is
likely to be noted with longer follow-up given the signif-
icant reduction in metastases in those managed with sur-
gery. This important study supports the utility of early
detection and treatment of prostate cancer in selected
patients.
Although it appears that surgery for localized prostate
cancer impacts disease-specific outcomes, the rational
selection of therapy remains complex, and examination of
other data provides information regarding the natural
history of untreated prostate cancer. Chodak et al.5
analyzed the pooled data of 823 men (cT1-2) from six
465
466 Part V Prostate Gland and Seminal Vesicles
nonrandomized studies treated prior to the era of PSA
testing. The risk of metastases was significant and
dependent on tumor grade—2.1% per year, 5.4% per
year, and 13.5% per year for well differentiated, moder-
ately differentiated, and poorly differentiated tumors,
respectively. At 15 years, the fraction of patients with
metastatic disease was 40%, 70%, and 85% in these
groups, respectively (Table 26A-1).
Albertsen et al.6 analyzed the long-term outcome of
451 men with clinical stage T1-2 tumors managed with
immediate or delayed hormonal therapy. Again, tumor
grade was the important factor determining patient out-
come. The cancer-specific mortalities in men with
Gleason sums 2 to 4, 5 to 7, and 8 to 10 were 9%, 28%,
and 51%, respectively. Overall, 46% of men treated expec-
tantly living 15 years or more will die of prostate cancer
and lose approximately one-third of their remaining life
expectancy, even at older age of diagnosis (i.e. >75 years).6,7
Fleming et al.8 attempted to address questions regard-
ing the selection of surveillance or definitive therapy
using decision analysis. In their Markov model, they
incorporated estimates of progression to metastatic dis-
ease with watchful waiting from review of the literature,
efficacy of radical prostatectomy based on pathologic
stage, and arbitrary reductions in survival after surgery
due to impact on quality of life to determine which strat-
egy resulted in a greater survival advantage. Based on the
data selected for their model, the authors reported that
surgical intervention for prostate cancer provided limited
benefit to the patient, relative to expectant management,
with well-differentiated tumors. In men with moderate
or poorly differentiated tumors, they stated that treat-
ment offered less than 1-year improvement in quality-
adjusted life expectancy in those men 60 to 65 years old
and that treatment was harmful in men over age 70.
Thus, they conclude that selection of watchful waiting in
men with localized prostate cancer is a feasible alterna-
tive to radical prostatectomy. Application of the model by
other investigators, using other estimates of disease pro-
gression and efficacy of treatment, resulted in much dif-
ferent results. Beck et al.9 utilized progression data from
Table 26A-1 Development of Metastases in Men with
Localized Prostate Cancer Treated Conservatively
PERCENT WITH METASTASES
Histologic
Grade 10 Years 15 Years
1 19 40
2 42 70
3 74 85
From Chodak GW, Thisted RA, Gerber GS, et al: N Engl J Med
2002; 330: 781–789.
the work of Chodak et al. and calculated survival benefit
from surgery. In contrast to the study of Fleming et al.,
the estimated survival advantage in men with well differ-
entiated, moderately differentiated, and poorly differen-
tiated tumors increased to 1.0, 2.4, and 2.7 years,
respectively.
Selection of Patients for Radical Prostatectomy
Despite the disparate result of the various publications
and controversy regarding the “best” treatment, it is clear
that selection of therapy needs to be based on several
patient and tumor factors. In general, radical prostatec-
tomy is considered in men with a life expectancy greater
than 10 years, a duration during which an untreated can-
cer may progress and/or metastasize. In addition, the
patients should be free of serious comorbidities and be
able to tolerate a major operation. With respect to cancer
variables, the tumor should be both clinically significant
and at a stage where surgical extirpation is likely to be cur-
ative. These aspects of tumor behavior and biology are
often difficult to assess based on traditional measures, such
as digital rectal examination, serum PSA, and Gleason
grade. Thus, more accurate determinations of outcome
have been developed and are currently commonly applied
to aid in the appropriate selection of men for radical
prostatectomy, as well as other definitive treatments.
Pretreatment Risk Stratification
The most commonly used risk assessment criteria
include serum PSA, clinical tumor stage (T stage), and
Gleason grade on biopsy. Recently, the extent of disease,
assessed by systematic biopsy (e.g., percent positive biop-
sies), has been shown to have prognostic significance and
such information may be incorporated into the assess-
ment of pretreatment risk. In general, the role of imag-
ing modalities, such as transrectal ultrasonography,
computed tomography (CT), and magnetic resonance
imaging/spectroscopy, is limited in initial risk stratifica-
tion, except in those with advanced disease.
Due to widespread screening efforts, men are increas-
ingly diagnosed with early stage disease (i.e., T1c). The
risk for disease recurrence after radical prostatectomy
increases with higher clinical stage. In men with stage T1c,
5-year PSA-free survival after radical prostatectomy is
greater than 85%, while those with palpable but localized
(cT2) have disease-free rates between 70% and 80%.10
Serum PSA levels can vary within any clinical stage
but usually correlate with tumor volume and, therefore,
pathologic stage and outcome after surgery. As reported
by Ohori and Scardino,11 progression-free survival 5
years after prostatectomy in men with PSA ≤ 4.0 ng/ml,
4.1 to 10 ng/ml, 10.1 to 20 ng/ml, and >20 ng/ml was
94%, 85%, 66%, and 38%, respectively. These values are
 Chapter 26A Clinically Localized (Stage T1a-T2c) Adenocarcinoma of the Prostate 467
comparable to those reported by others. In the study
from Catalona et al.,12 7-year progression-free survival
was 93% in men with serum PSA ≤ 2.5 ng/ml, 80% with
PSA 2.5 to 4.0 ng/ml, 76% with PSA 4.1 to 10 ng/ml,
and 40% with PSA >10 ng/ml. Walsh et al.13,14 reported
10-year rates of 87%, 75%, 30%, and 28% for PSA
groups of <4 ng/ml, 4.1 to 10 ng/ml, 10.1 to 20 ng/ml,
and >20 ng/ml, respectively.
Gleason grade, as determined by biopsy, is a significant
predictor of outcomes after radical prostatectomy. With
increasing tumor grade, the likelihood of disease recur-
rence increases. Five and 10-year disease-free survival in
patients with Gleason sum 2 to 4 are approximately 90%
but drop to approximately 60% for those men with sum
of 7. Over half of men with Gleason sum 8 to 10 will
develop PSA recurrence at 5 years.10
In addition to clinical factors, pathologic information
obtained from the prostatectomy specimen can provide
prognostic information. This includes variables, such as
pathologic stage, total tumor volume, surgical margin
status, and tumor grade in the specimen. The develop-
ment of predictive nomograms and models has allowed
the prediction of both pathologic stage and clinical out-
come (i.e., PSA-free survival), based on standard pre-
treatment variables, and may increase the accuracy of risk
assessment over the use of clinical stage, PSA level, and
Gleason score alone.15–17 The nomograms published by
Partin et al.18 predict the pathologic stage of disease, thus
helping one decide the role of surgery based on the cate-
gorical estimation of organ-confined, established capsu-
lar penetration, seminal vesical invasion, and lymph node
involvement.15,16 In applying the Partin nomograms, it is
important to point out that adverse pathologic features
alone, such as seminal vesicle invasion or extracapsular
disease, may not preclude surgical therapy. From the
experience of Catalona et al.,12 over 70% of patients with
unconfined disease and 35% of those with seminal vesi-
cle invasion have long-term (10 years) cancer-free sur-
vival with prostatectomy alone (no adjuvant therapy).
Kattan and colleagues, rather than estimating patho-
logic stage as an outcome, created a continuous scale,
based on PSA, clinical stage, and Gleason grade, to cal-
culate the probability that a patient remains free of bio-
chemical recurrence at 5 years after surgery.17 They
have created a similar postoperative nomogram, pre-
dicting freedom from progression 7 years after surgery
based on PSA, Gleason sum in the prostatectomy spec-
imen, and individual pathologic features.19 These mod-
els can be easily applied in the clinical setting using a
web-based (www.mskcc.org/nomograms/prostate) or
computer calculation.
In order to simplify pretreatment risk stratification, a
three-group system has been developed based on PSA,
clinical stage, and biopsy Gleason score. One that is com-
monly applied categorizes patients as low-risk patients
(cT1c or T2a and Gleason sum 2 to 6 and PSA <10 ng/ml),
intermediate-risk (cT2b, Gleason sum 7, or PSA 10 to
20 ng/ml), or high-risk (cT2c or Gleason sum 8 to 10 or
PSA >20 ng/ml).20 In low-risk patients, it should be men-
tioned that excellent outcomes might be achieved with a
variety of modalities, including watchful waiting in
selected patients. Although progression occurs slowly
within this population, eventual active treatment is likely
in men who are young or have elevated PSA levels.21
High-risk patients can undergo radical prostatectomy
with acceptable morbidity and reasonable rates of local
control; however, long-term cure is less likely and if sur-
gery is selected, the patient must realize that adjuvant or
secondary treatment may be necessary. Although catego-
rization of patients into fewer (e.g., 3 or 4) risk groups
simplifies the situation, it is important to point out that
prognostic power can be reduced. This is particularly
true for those patients with intermediate- and high-risk
disease, where significant overlap occurs and discrimina-
tion of clinical outcome is less accurate.22,23 The develop-
ment of additional models incorporating novel and/or
molecular determinants of tumor behavior will allow
identification of patients most likely to benefit from
prostatectomy, as well as those who may benefit from
adjuvant treatments.
Pelvic Lymph Node Dissection
Contemporary series of patients undergoing radical
prostatectomy demonstrate that the risk of pelvic lymph
node metastases is low, typically between 4% and 9%.24,25
This is largely due to the earlier detection of cancers at
lower stage, as well as the refined selection of patients
undergoing surgery with reduced likelihood of nodal
involvement. Thus, pelvic lymphadenectomy may not be
routinely indicated for all patients undergoing radical
prostatectomy. However, the detection of positive lymph
nodes provides important prognostic information and
should be performed in those patients at higher risk, as
determined by nomogram or risk-group stratification.
Traditionally, it was thought that all patients with lymph
node metastases experience recurrence after prostatec-
tomy and therefore identification would spare patients an
ineffective, and potentially morbid, operation. Recent
data question the paradigm and may renew interest in
both pelvic lymphadenectomy and more aggressive sur-
gical therapy. In addition, at the time of radical retropu-
bic prostatectomy, the pelvic lymph nodes are easily
accessible and removal can be performed with minimal
morbidity; in general, unless the lymph nodes appear
grossly involved, frozen section analysis is unnecessary.
Heidenreich et al.26 extended the boundaries of the
pelvic lymphadenectomy in 103 patients, including the
external and internal iliac, obturator, common iliac, and
presacral lymph nodes. They found a high rate of nodal
468 Part V Prostate Gland and Seminal Vesicles

metastases (26%) in patients undergoing increased sam-
pling, suggesting that if lymph nodes are to be sampled,
the standard limits may be inadequate.
Nearly all men with proven pelvic lymph node metas-
tases will have biochemical relapse with 5 to 7 years after
surgery. Thus, radical prostatectomy with distant disease
has been avoided because of limited benefit to the patient.
In a retrospective, nonrandomized study, Cadeddu et al.27
compared 10-year survival in men with proven lymph
node involvement who did and did not undergo radical
prostatectomy. Overall, men fared better if the prostate
had been removed and there was a suggestion of
improved survival in this cohort. Similarly, Ghavamian
et al.28 demonstrated an overall survival advantage at 10
years in men with pTxN+ prostate cancer undergoing
prostatectomy and orchiectomy, compared with those
with orchiectomy alone. More recently, data from
Messing et al.29 indirectly address this question. In a
prospective randomized trial of 98 men undergoing rad-
ical prostatectomy and pelvic lymph node dissection, an
improvement in survival was observed in men receiving
immediate hormonal therapy for microscopic lymph
node disease compared to those men receiving delayed
hormonal therapy at the time of disease progression.
This difference, at a median follow-up of 7.1 years, was
statistically significant ( p = 0.02) with 77% of men in the
immediate-therapy group alive without disease at last
evaluation. Not only does this support the concept of
immediate androgen deprivation in those men with
node-positive prostate cancer but also raises the issue of
whether complete excision via prostatectomy and lymph
node dissection plays a role in improving cancer out-
comes even in those with regional metastases.
Results of Radical Prostatectomy
The techniques of radical retropubic and perineal prosta-
tectomy are covered elsewhere in this book. Therefore,
we describe cancer outcomes and morbidity related to
such surgery in this section. Due to an improved under-
standing of periprostatic anatomy, increased surgeon
experience, and refinement in anesthesia and periopera-
tive patient care, morbidity from prostatectomy has been
reduced from that seen in previous decades.
Early and Intraoperative Complications
Table 26A-2 summarizes perioperative data from con-
temporary series of patients undergoing radical retropu-
bic prostatectomy. Operative mortality, defined as death
within 30 days of surgery is exceedingly rare (<0.3%) but
is more common with increasing age and comorbid-
ity.30,32,35–38 In the 2001 report from Lepor et al.,32 a sin-
gle death occurred in 1000 consecutive operations

Table 26A-2 Perioperative Morbidity and Mortality of Radical Retropubic Prostatectomy

Washington
University Mayo Clinic NYU Toulouse Baylor
(n = 1870)30 (n = 1000)31 (n = 1000)32 (n = 620)33 (n = 472)34

Complication Number % Number % Number % Number % Number %

Mortality 3 0.2 0 0 1 0.1 1 0.2 2 0.4

Rectal injury 3 0.2 6 0.6 5 0.5 3 0.5 3 0.6

Colostomy — — 0 0 0 0 — — 0 0

Ureteral injury — — — — 1 0.1 0 0 1 0.2

Myocardial infarction 9 0.7 7 0.7 5 0.5 1 0.2 2 0.4

Pulmonary embolism 22 1.7 6 0.6 2 0.2 5 0.8 5 1

DVT 8 0.6 14 1.4 2 0.2 14 2.3 6 1.3

Sepsis — — — — — — 1 0.2 3 0.6

Wound problem 17 1.3 9 0.9 9 0.9 6 1 14 2.9

Lymphocele — — — — 1 0.1 14 2.3 10 2.1

Anastomotic stricture — — 87 8.7 — — 3 0.5 42 9.0

 Chapter 26A Clinically Localized (Stage T1a-T2c) Adenocarcinoma of the Prostate 469

(0.1%). The perioperative mortality rate at UCSF is
0.13%. Similarly, complications, including myocardial
infarction (0.1% to 0.4%), deep venous thrombosis
(1.1%), and pulmonary embolism (0.75%) are less fre-
quent with modern perioperative care and are likely to
decline further with continued experience and refine-
ments in technique.30,32,36,37 Begg et al.39 examined varia-
tions in morbidity after prostatectomy using the
SEER-Medicare database. In examining the record of
11,522 patients who underwent prostatectomy, neither
hospital volume nor surgeon volume was significantly
associated with surgery-related death. However, postop-
erative morbidity, as well as late urinary complications
(stricture or fistula), was lower when surgery was per-
formed in very-high-volume hospitals ( p = 0.03) and by
very-high-volume surgeons ( p < 0.001).
The most common intraoperative problem is hemor-
rhage. Significant variations in the estimated blood loss
and need for blood transfusion have been reported, with
the perineal approach associated with lower reported val-
ues (Tables 26A-3 and 26A-4).28,29,35,38 In general, the
average blood loss in recent series is less than 1000 ml
and the use of nonautologous blood transfusion is less
than 5%; our experience with current mean blood loss
and transfusion rate is 486 ml and 1%, respectively, in
our last 400 patients. However, the individual surgeon or
institutional experience dictates the need to donate autol-
ogous blood. Postoperative bleeding requiring explo-
ration is rare (<0.5%).35
Rectal injury is also uncommon, estimated to occur in
0.5% of men.35,39 These can be typically managed with
primary closure, omental coverage, dilation of the anal
sphincter, and antibiotics even without preoperative
bowel preparation. A routine diverting colostomy is rarely
performed (0% to 0.06%) but may be necessary in those
with prior radiation exposure or extensive contamination.

Table 26A-3 Estimated Blood Loss During Radical Retropubic Prostatectomy

Institution Number Mean EBL (ml) Range (ml)

Mayo Clinic40 316 1020 100–4320

Washington University41 65* 1420 200–2500

65† 1605 250–3500

Toulouse33 220 300 100–1500

Mayo Clinic35 1728 600 —

Baylor42 954 800 150–5000

NYU32 1000 819 SD 14.9

UCSF 400 486 100–1200

*
With internal iliac artery occlusion.
†
Without internal iliac artery occlusion.

Table 26A-4 Summary of Radical Perineal Prostatectomy Series

Hospitali- Positive PSA-Free Follow-Up
Blood zation Continence Potency Margins Survival (Mean
Series Number Loss (ml) (days) (%) (%) (%) (%) Months)

Frazier43 122 565 12 96 77 29 — —

Lance44 190 802 — 65 8 43 82 42.9

Sullivan45 138 416 4.5 72 — 9 70 30

Weldon46 200 — — — — 44 79 35

Weldon47 110 645 — 95 70 — — —

Parra48 500 270 1.5 94 47 16 — —

470 Part V Prostate Gland and Seminal Vesicles
Injuries to the obturator nerve and ureter are rare
(both <0.1%) and can be managed intraoperatively by
direct reanastomosis and ureteroneocystostomy,
respectively.11,32,49
Late Complications
The majority of patients experience an uneventful post-
operative course, resuming oral intake and ambulation
the first day after surgery. In the U.S., men are safely dis-
charged between 1 and 5 days after surgery with the ure-
thral catheter in place.32,38 With the interest in earlier
removal of the catheter (<10 days), rates of urinary reten-
tion have increased and may approach 20%.50
Development of an anastomotic stricture occurs in
approximately 1% to 10% of patients.11,32,38 Other com-
plications, including incisional hernia, lymphocele, ileus,
and inguinal hernia, are all less than 1%, while rates of
rehospitalization are less than 5%.11,32,38
Outcomes After Radical Prostatectomy
Cancer Control
Contemporary methods of radical prostatectomy for
patients with clinically localized disease are generally
associated with very good outcomes. Several endpoints
can be evaluated—overall survival, cause-specific sur-
vival, and biochemical relapse-free survival. Paulson
et al.51 reported a 90% cancer-specific survival at 13.5
years after radical perineal prostatectomy for patients
with organ-confined and specimen-confined diseases.
In an analysis of men treated with radical retropubic
prostatectomy at the Mayo clinic, Zincke et al.35,52
reported crude and cause-specific survival rates of 75%
and 90%, respectively. The crude survival rates at 10 and
15 years after surgery were similar to those of age-
matched men from the general population without
prostate cancer.
Despite the excellent results of radical prostatectomy,
between 22% and 50% of patients thought to have
organ-confined cancer are found to have disease beyond
the prostate on careful pathologic examination of the sur-
gical specimen.18,20,53,54 Given the protracted natural his-
tory of prostate cancer and the fact that residual and/or
recurrent disease may respond to secondary therapy,
postoperative follow-up with serum PSA testing is an
important endpoint in subsequent evaluation. Nearly all
recurrent clinical and metastatic disease is preceded by a
rising PSA, with only a few sporadic reported cases of
recurrence in the absence of a detectable serum PSA
level. Biochemical failure is defined as either the persist-
ence of a detectable PSA after surgery or the develop-
ment of a detectable PSA in those with a previously
undetectable postoperative level. The threshold consti-
tuting a detectable serum PSA varies among investiga-
tors, and the use of ultrasensitive or hypersensitive PSA
assays improves the lead-time for early detection of
recurrence.55,56 Amling et al.57 analyzed the effect of
using various PSA cut points defining biochemical failure
after radical prostatectomy in a cohort of 2782 men with
clinically localized disease (stages cT1 to T2). Five- and
10-year rates of PSA recurrence varied greatly, depend-
ing on whether the threshold was 0.2, 0.3, 0.4, or 0.5
ng/ml. Clinical progression was directly related to the
maximum PSA reached within 3 years of surgery. Using
definitions requiring multiple increases in PSA, such as
that proposed by American Society for Therapeutic
Radiology and Oncology for biochemical failure after
radiation therapy, gave misleading results with overesti-
mation of short-term failure but improved long-term
recurrence-free outcomes. They conclude that a PSA cut
point of 0.4 ng/ml may be most reasonable, with the lack
of continuation of PSA progression in many of those with
PSA values between 0.2 and 0.4 ng/ml; this may balance
the identification of patients with actual cancer recur-
rence at risk for subsequent clinical progression with
sparing unnecessary adjuvant therapy in men with low
but detectable PSA levels.
Radical retropubic prostatectomy is associated with
overall 5- and 10-year actuarial biochemical progression-
free survival rates ranging from 59% to 84% and from
47% to 75%, respectively (Table 26A-5).35,59,60,63
Biochemical relapse-free survival following radical per-
ineal prostatectomy ranges from 70% to 82% with mean
follow-up of 30 to 43 months (see Table 26A-4).43–45
Biochemical relapse typically occurs 8 years prior to any
evidence of clinical disease recurrence; this is reflected by
higher clinical disease-free rates at 5 (84% to 86%) and 10
(72% to 78%) years. The variability in outcomes across
different reports and techniques likely reflects differences
in patient selection, definition of biochemical failure, and
to a lesser extent variations in surgical technique.
In two contemporary radical prostatectomy series
from the Cleveland Clinic and The Johns Hopkins
Hospital, totaling more than 2000 men, no patient
showed signs of clinical disease in the absence of PSA
failure.56,60 Following PSA recurrence, up to 68% of men
progressed to clinical disease at a median follow-up of 19
months. The use of adjuvant therapy, such as radiation or
androgen deprivation, at the time of PSA recurrence
reduced the rate of clinical disease progression (21%).
Without adjuvant or salvage therapy, metastatic disease
developed in 34% of patients at a median actuarial time
of 8 years after PSA failure.
Han et al.61 recently reported the long-term biochem-
ical disease-free and cancer-specific survival in 2404
patients managed with radical prostatectomy at The
Johns Hopkins Hospital. Mean follow-up was 6.3 years
(range 1 to 17) and 26% of patients (n = 621) were fol-
lowed at least for 10 years. Overall actuarial PSA progres-
 Chapter 26A Clinically Localized (Stage T1a-T2c) Adenocarcinoma of the Prostate 471

Table 26A-5 Biochemical Relapse-Free Survival Following Radical Retropubic Prostatectomy

5-Year 10-Year 15-Year Follow-Up
Institution Number (%) (%) (%) Outcome (Years)

Washington University58 1778 78* — — PSA < 0.6 ng/ml Mean 4.0

Baylor20 1000 78 75 75† PSA < 0.4 ng/ml Mean 4.4

UCLA59 601 69 47 — PSA < 0.4 ng/ml Median 2.8

86 78 — Clinically free of disease

Mayo Clinic35 3170 70 52 — PSA < 0.2 ng/ml Mean 5.0

85 72 — Clinically free of disease

Cleveland Clinic60 423 59 — — PSA < 0.2 ng/ml Median 4.3

84 — — Clinically free of disease

Johns Hopkins61 2404 84 74 66 PSA < 0.2 ng/ml Mean 6.3

UCSF62 666 78 — — PSA < 0.2 ng/ml Median 3.1

*7-year results.
†
14-year results.

sion-free, metastasis-free, and cancer-specific survivals
were: 84%, 96%, and 99% at 5 years; 74%, 90%, and
96% at 10 years; 66%, 82%, and 90% at 15 years, respec-
tively. These data are similar to those reported by
Catalona et al.58 and Hull et al.20 (see Table 26A-5).
Clinical and pathologic stage, pretreatment PSA, and
pathologic Gleason score are all predictors of progres-
sion after surgery (Table 26A-6).11 Catalona et al.12
reported 79% and 66% 7-year disease-free survivals in
those with stage cT1c and stage cT2, respectively. From
the Johns Hopkins series, patients with clinical stage ≤ T2
had 5-, 10-, and 15-year recurrence-free survival rates of
86%, 76%, and 71%, respectively, compared to 60% and
49% in patients with T3a disease (15-year data unavail-
able).61 At 10 years, Hull et al.20 observed >80% and 67%
PSA-free survival in those with clinical stages T1 and T2,
respectively.
Seven-year progression-free survival was 93%, 80%,
76%, and 40% in PSA ranges of <2.5, 2.5 to 4.0, 4.1 to
10, and >10 ng/ml, respectively.12 The 10-year recur-
rence-free data from Johns Hopkins are comparable:
91% for ≤ 4 ng/ml, 79% for 4.1 to 10 ng/ml, 57% for
10.1 to 20 ng/ml, and 48% for >20 ng/ml.61
Higher Gleason grade, both on diagnostic biopsy and
in the surgical specimen, is associated with increased risk
of disease recurrence. Seven-year progression-free sur-
vival was 84% in patients with Gleason sum 2 to 4, 68%
with Gleason sum 5 to 7, and 48% with Gleason sum 8
to 10.12 Han et al.61 reported 10-year recurrence-free
rates of 91%, 79%, 57%, and 48% for Gleason sums ≤ 6,
3 + 4, 4 + 3, and 8 to 10, respectively.
Pathologic stage is one of the most important prog-
nostic factors, with increasing rates of recurrence with
extraprostatic extension with negative surgical margins,
positive surgical margins, seminal vesicle invasion, and
lymph node metastases. Actuarial recurrence-free sur-
vival in patients with organ-confined disease (i.e., ≤pT2)
is 97% at 5 years, 93% at 10 years, and 84% at 15 years.
Comparable data were reported by Hull et al.20 At 10
years, those with organ-confined and nonorgan-confined
tumors experienced 92% and 53% progression-free sur-
vivals, respectively. Men with pathologic stages T1-2,
T3a/b, T3c, and N+ had 10-year actuarial PSA-free sur-
vivals of 92%, 71%, 37%, and 7%, respectively. At
UCSF, patients with pathologically confined disease
(pT2, all grades) have a 5-year PSA progression-free
actuarial survival rate of 80%, compared with 57% in
those with higher stages.
The incidence of positive surgical margins has varied
greatly, ranging between 10% and 68%.64–66 The finding
of a positive margin on the prostatectomy specimen
would suggest incomplete removal of the tumor and is
associated with a 2- to 4-fold increased risk of progres-
sion.20 Nevertheless, those men with a positive margin
may experience reasonable long-term recurrence-free
survival (36% at 10 years) without adjuvant therapy; the
reported 10-year results for those with negative margins
is 81%. In an attempt to reduce the incidence of positive
surgical margins while performing nerve-sparing radical
retropubic prostatectomy, we examined the utility of
intraoperative frozen section analysis.67 In 101 men,
intraoperative frozen section was performed on the surgical
472 Part V Prostate Gland and Seminal Vesicles

Table 26A-6 Risk Factors for Progression After Radical Prostatectomy (Multivariate Analysis)
Variable Relative Risk (95% CI) p Value

Preoperative parameter

Clinical stage 0.0071

T1a,b versus T1c 0.6

T1c versus T2a 0.1

T1c versus T2b 2.47 (1.52–4.03) 0.0003

T1c versus T2c 1.91 (1.06–3.42) 0.0304

Biopsy Gleason sum

2–4 versus 5–6 0.15

5–6 versus 7 2.6 (1.75–3.87) <0.0001

5–6 versus 8–10 3.21 (1.72–5.97) 0.0002

Clinical and pathologic parameters

Clinical stage 0.15

Biopsy Gleason sum 0.12

Specimen Gleason sum 0.0008

2-4 versus 5-6 2.48 (1.34–4.58) 0.0038

5-6 versus 7 2.48 (1.34–4.58) 0.0038

5-6 versus 8-10 4.55 (2.19-9.42) <0.0001

Extracapsular extension 0.0019

Focal versus none 2.17 (1.20–3.92) 0.011

Established versus none 2.72 (1.56–4.74) 0.0004

Focal versus established 0.13

Surgical margin

Positive versus negative 4.37 (2.90–6.58) <0.0001

Seminal vesicle involvement

Present versus absent 2.61 (1.70–4.01) <0.0001

Lymph node metastases

Present versus absent 3.31 (2.11–5.20) <0.0001

margin thought to be at risk of tumor involvement. If the
margin was positive, additional tissue was excised.
Findings of intraoperative examination were identical to
those of final permanent section in 91% of cases. Of the
15 patients with a positive frozen section, 11 had identi-
cal findings on permanent pathologic sections. In this
group, 12 (80%) had no evidence of tumor in addition-
ally resected tissue. Overall, the positive and negative
predictive values for intraoperative frozen section analy-
sis were 73% and 94%, respectively. The risk of recur-
rence in patients with either positive or negative
intraoperative frozen section findings was similar. These
 Chapter 26A Clinically Localized (Stage T1a-T2c) Adenocarcinoma of the Prostate 473
data suggest that intraoperative frozen section analysis
may be applied during radical prostatectomy to spare the
neurovascular bundles in selected patients.
In order to improve simplify, as well as increase the
accuracy of assessment of postoperative prognosis, clini-
cal and pathologic features have been combined. A mul-
tivariate analysis from Johns Hopkins found that
pathologic stage, Gleason score, and surgical margin sta-
tus were the best predictors of the probability of cancer
recurrence.68 The risk stratification scheme, discussed
above, is able to categorize patients into low-, intermedi-
ate-, and high-risk groups with 5-year recurrence-free
survival rates of 98%, 73%, and 65%, respectively.20
Although radical prostatectomy is fairly effective even in
higher-risk patients, early identification of those at risk
for eventual primary treatment failure help select men
appropriate for adjuvant therapy and enrollment in clin-
ical trials.
Urinary Function
After radical prostatectomy, immediate postoperative
incontinence may occur in up to 80% of patients. More
contemporary series report a significantly lower rate of
immediate incontinence.30,32,69 The wide variability in
incontinence rates reported in the literature is due to
improvements in surgical technique, as well as differing
definitions of what constitutes urinary continence.
Approximately 90% of men who undergo radical
prostatectomy will be continent at 1 year, when the
definition is no regular use of pads and/or no leakage
with moderate exercise. Severe and persistent inconti-
nence, defined as leakage with normal activity or the
need for ≥ 3 pads per day, occurs in 1% to 6% of
patients.70
Most major centers report urinary incontinence
rates less than 10%. In 593 patients undergoing sur-
gery by Walsh, some degree of stress urinary inconti-
nence was present in 8%; the remaining 92% of
patients were completely continent.71 The group from
Baylor reported the median time to recovery of conti-
nence was 1.5 months, with 92% and 95% of patients
continent at 1 and 2 years, respectively.72 Factors asso-
ciated with incontinence after radical prostatectomy
are listed in Table 26A-7. At UCSF, a contemporary
cohort of patient undergoing radical retropubic prosta-
tectomy (n = 217) was surveyed anonymously using a
detailed, validated questionnaire, including the
University of California, Los Angeles/Rand Prostate
Cancer Index quality-of-life urinary domain questions.
At 1 year after surgery, overall continence (defined
above) was 98%, with immediate continence in 23%
and 55% of patients continent by 1 month. Catalona
et al.12 noted that 96% and 87% of men younger and
older than 70 years, respectively, recovered continence
Table 26A-7 Risk Factors for Urinary Incontinence
After Radical Prostatectomy
Variable p Value*
Patient weight (continuous) 0.0002
Obstructive urinary symptoms 0.004
TURP 0.001
Blood loss (continuous) 0.016
Nerve resection 0.001 (0.015)
Anastomotic stricture 0.001 (0.015)
Patient age (continuous) 0.001 (0.0001)
Anastomotic method 0.001 (0.0001)
*In univariate analysis; numbers in parenthesis represent p values in
multivariate analyses.
within 18 months; more recently, half of patients have
immediate recovery of urinary control.
In a national survey including 1796 men undergoing
radical prostatectomy who were continent before the
operation, 19% required pads daily and 3.6% were
totally incontinent.73 The National Institutes of Health-
sponsored Prostate Cancer Outcomes study found that
8.5% of men reported “severe” incontinence.74 It is
important to note that despite the presence of urinary
incontinence, most patients were minimally bothered
and highly satisfied with their treatment. This has been
confirmed in a recent randomized study comparing radi-
cal prostatectomy with watchful waiting.75 Despite a
higher incidence of urinary leakage with radical prostate-
ctomy (49%), overall well being and subjective quality-
of-life assessment were not significantly different from
the watchful waiting group.
We recently examined the impact of even minimal uri-
nary leakage after radical prostatectomy on health-
related quality of life.76 Postoperative assessment of
urinary health-related quality of life, using the urinary
function and bother subscales of the University of
California Los Angeles Prostate Cancer Index, American
Urologic Association Symptom Index, and a single ques-
tion assessing satisfaction, was performed in 168 men at
a mean of 75 weeks after surgery. Overall, 87% reported
no pad use while 12% used one pad daily. Statistically
significant differences were observed between these
groups with respect to mean function score ( p < 0.0001),
mean bother score ( p < 0.0001), and change in AUA
quality-of-life score ( p < 0.0001). Overall satisfaction was
higher in the no pad group (87.1) compared to the single-
pad group (50.9; p < 0.0001).
474 Part V Prostate Gland and Seminal Vesicles
Erectile Function
Until the description of the anatomy and location of the
autonomic branches of the pelvic plexus innervating the
corpora cavernosa, men were expected to be impotent
after radical prostatectomy.77 Identification of these
nerves allowed modification of the surgical technique
and attempted preservation of potency in men undergo-
ing removal of the prostate.78 Quinlan et al.79 reported
outcomes in 600 men aged 34 to 72 years undergoing
radical prostatectomy. Of 503 men with preoperative
sexual function followed at least 18 months, 68%
remained potent after surgery. Studies have found that
multiple factors are involved in the preservation of
potency.30,79,80 In the Johns Hopkins’ experience, these
included age, stage, and preservation or excision of the
neurovascular bundles.79 Potency was preserved in 91%
younger than 50 years, 75% in men 50 to 60 years, 58%
in men 60 to 70 years, and 25% in men older than 70
years. With increasing age, preservation of both neu-
rovascular bundles was more important in potency. After
controlling for other variables, the presence of more
advanced stage (nonorgan-confined, seminal vesicle inva-
sion) was associated with increased risk of impotence.
Similarly, Rabbani et al.80 identified patient age, preoper-
ative potency, and extent of neurovascular bundle preser-
vation as predictors of potency recovery. At 3 years
following surgery, 76%, 56%, and 47% of those aged
<60, 60 to 65, and >65 years were potent. Men with only
partial preoperative erection and unilateral neurovascular
preservation were less likely (47% and 25%, respectively)
to recover potency. Potency after radical perineal prosta-
tectomy has been documented in smaller series, with
rates near 70%.43,51
As with urinary function after prostatectomy, a wide
range of success has been reported for postoperative
potency (3% to 46%). This variability is due to patient
selection, surgeon expertise, definition of potency, and
means of assessing sexual function. In men with erectile
dysfunction after a bilateral nerve-sparing prostatectomy,
sildenafil may be efficacious.81–83 Between 43% and 75%
of such patients may respond to sildenafil; conversely,
few men benefit if both neurovascular bundles have been
excised or ligated.
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C H A P T E R
26BClinically Localized Adenocarcinoma
of the Prostate: Radiation Therapy
W. Robert Lee, MD, MS
Management of men with clinically localized (T1-2)
prostate cancer is one of the most controversial areas in
all of oncology. Treatment options include expectant
management, radical prostatectomy (RP), external beam
radiation therapy (EBRT), and interstitial brachytherapy
(IB), with or without additional EBRT.1 The results of
newer approaches, including high intensity focused ultra-
sound (HIFU) and cryotherapy, have demonstrated some
promise but they will not be discussed here.
The gold standard for treatment efficacy is consid-
ered to be the randomized clinical trial (RCT). To date
the number of RCT comparing definitive treatments in
men with T1-2 prostate cancer is very few, and in some
cases the trials have methodologic flaws that preclude
interpretation.2,3 Given the relative paucity of level I evi-
dence, clinicians and their patients rely on retrospective,
nonrandomized historic case series for treatment recom-
mendations. The potential for bias in these historic
series is well known. Several characteristics of prostate
cancer make interpretation of available information
difficult.
In the first place, the long natural history of clinically
localized prostate cancer makes it very difficult to
demonstrate a beneficial effect of any therapeutic proce-
dure. D’Amico4 has quantified prostate cancer-specific
mortality during the first decade in men with T1-2
prostate cancer treated with RP or EBRT in the prostate-
specific antigen (PSA) era. This report included more
than 7000 men (4946 treated with RP and 2370 treated
with EBRT) from 44 treating institutions. The rate of
prostate cancer specific mortality (PCSM) was dependent
on pretreatment risk grouping and primary treatment. In
men treated with EBRT, the rate of PCSM at 10 years
was <5% for men with low-risk disease, rising to approx-
imately 10% in the intermediate-risk group and nearly
25% in the high-risk group. If aggressive local treatment
is to affect the natural history of the disease, especially in
men with favorable disease, it will not be apparent for
several years following treatment.
In addition, many men with prostate cancer are
beyond the age of 65 at diagnosis and have competing co-
morbidities. In a report including more than 1400 men
treated with EBRT on Radiation Therapy Oncology
Group (RTOG) trials between 1975 and 1992, more than
50% of men died of other causes.5 Other reports of men
managed with expectant management illustrate the same
phenomenon.6 The competing risk from other causes of
mortality (cerebrovascular disease, cardiovascular dis-
ease) makes it difficult to demonstrate that treating
prostate cancer reduces overall mortality.
Finally, temporal trends confound any statements
about treatment efficacy. With the advent of PSA screen-
ing, significant stage migration has been documented.7,8
Men treated in 2003 in general have less disease than
men treated in the late 1980s. Treatment techniques have
also evolved in the past two decades. RP has been refined,
and morbidity has been reduced. Techniques of radiation
therapy (EBRT or IB) have also evolved. Thus, the
results reported from men treated 15 years ago may not
be representative of what is achievable with current
methods.
The preceding paragraphs should emphasize the
difficulties inherent in interpreting the available liter-
ature as it relates to the management of men with T1-2
prostate cancer. In this chapter, biochemical relapse-
free survival (BRFS) (incorporating PSA into the
definition of disease-free survival) will be emphasized.
The use of PSA as an endpoint has a number of advan-
tages and disadvantages, which are discussed in a pre-
vious section. Patient-reported endpoints, including
health-related quality of life (HRQOL) after definitive
treatment is considered elewhere.
477
478 Part V Prostate Gland and Seminal Vesicles

RISK STRATIFICATION
A number of variables have been reported to be inde-
pendent predictors of BRFS following radiation therapy
(EBRT or IB) for clinically localized prostate cancer.
These variables include Gleason grade, pretreatment
PSA level, and clinical T stage.9–15 In hopes of accurately
predicting biochemical outcome following definitive
treatment, a number of investigators have combined
these variables to produce risk groupings.10,16,17 One of
the more commonly used risk stratifications was first
described by D’Amico.10 In a single-institution setting
with BRFS as the endpoint, the D’Amico risk stratifica-
tion system successfully classified patients into three
groups (low, intermediate, and high) regardless of treat-
ment received (RP, EBRT, or IB). A recent report has
demonstrated that the D’Amico risk groupings also pre-
dict prostate cancer-specific survival.4 The results with
radiation therapy should be presented according to risk
grouping.

HISTORIC PERSPECTIVE, EXTERNAL BEAM

RADIATION THERAPY
Megavoltage EBRT for clinically localized prostate can-
cer has been in use since the late 1950s following the
development of Co60 teletherapy and linear accelera-
tors.18 Over the ensuing years a number of advances in
technology have allowed for modifications in the treat-
ment planning process. As late as the early 1990s most
men treated with EBRT were treated with conventional
methods. In this paradigm, the treatment planning
process relied on two-dimensional plain radiographs for
target localization and shielding of normal tissues. This
method did not allow direct visualization of the prostate
gland. The location of the prostate was estimated based
on bony landmarks and radio-opaque contrast in nearby
normal tissues. Figure 26B-1 Example of beam-shaping used for 3DCRT. A,
With the development of more sophisticated treat- Antero-posterior beam. B, Right lateral beam. C, Oblique
ment planning software, three-dimensional conformal beam
radiation therapy (3DCRT) was born. In 3DCRT, the
target organ and any relevant nearby normal tissues are
outlined on sequential computed tomography (CT)
images. These outlines are then reconstructed to allow
shaping of the radiation portal to conform to the shape of
the target organ (Figure 26B-1). As outlined later, dose gradient that results in reduced total dose to nearby
3DCRT techniques allow for an increase in dose to the normal tissues.19 IMRT is gradually being introduced
prostate gland without a significant increase in normal into community practice although the availability
tissue complications. remains somewhat limited at this time.
Intensity-modulated radiation therapy (IMRT) is a
further refinement of 3DCRT. With IMRT the fluence
TECHNIQUE OF EBRT
of linear accelerator photon beams are modulated to cre-
ate more ideal dose distributions. Potential advantages of Widespread availability of the necessary equipment
IMRT versus 3DCRT include a greater conformality of should permit all men treated with EBRT for prostate
radiation dose about the target organ and a much steeper cancer to be approached using 3DCRT. CT simulators
 Chapter 26B Clinically Localized Adenocarcinoma of the Prostate: Radiation Therapy 479
Table 26B-1 Volume Recommendations of the
International Commission of Radiation Units
and Measurements (ICRU Report 50)
Parameters Definition
GTV Palpable or visible extent of tumor
CTV GTV plus margins for subclinical disease
PTV CTV plus margins for organ motion
and daily set-up error
are becoming commonplace in radiation therapy depart-
ments, but even if conventional simulators are used, the
information obtainable from CT or magnetic resonance
(MR) should be incorporated into the treatment plan-
ning process. These newer techniques should be
approached in a systematic fashion.
With the introduction of 3DCRT, a new terminology
is required (Table 26B-1).20 In this vocabulary, the gross
tumor volume (GTV) represents the tumor which is pal-
pable or visible on imaging. The clinical target volume
(CTV) includes the GTV plus any additional structures
that are felt to be at risk for microscopic involvement
(seminal vesicles or pelvic lymph nodes). The planning
target volume (PTV) includes the CTV plus a margin
that accounts for organ motion and set-up error. In most
cases of prostate cancer, the CTV to PTV margin is 5 to
10 mm. Many clinicians will use nonuniform margins
with the smallest CTV to PTV margins posteriorly in
the vicinity of the rectum.21
A variety of beam arrangements have been described
ranging from a coplanar, four-field technique to a non-
coplanar seven-field approach. Megavoltage energies (>6
MV) are recommended. Immobilization devices are com-
monly used to decrease set-up error, reducing the CTV
to PTV margin.20,22,23 In an attempt to reduce the CTV
to PTV margin further, a number of investigators have
localized the prostate daily prior to delivering treatment.
Common techniques include transabdominal ultrasound
localization of the prostate24 and the use of implanted
fiducial markers.25
Elective irradiation of the pelvic lymph nodes has
been debated for more than 30 years. In men with a low
risk of pelvic lymph node involvement according to the
Partin tables26 or the Roach formula,27 it is difficult to
justify treating the lymph nodes. In men with more
advanced disease, a recent RTOG trial argues in favor of
including the pelvic lymph nodes.28 Patients with a risk of
pelvic lymph nodes of >15% were enrolled in this four-
arm trial. Preliminary results indicate that elective radia-
tion therapy to the pelvic lymph nodes when combined
with neoadjuvant androgen deprivation improves BRFS.
In the absence of compelling data to argue the contrary,
in patients receiving radiation therapy with a risk of
lymph nodes above 15%, elective pelvic nodal irradiation
should be strongly considered.
BIOCHEMICAL RELAPSE-FREE SURVIVAL:
EXTERNAL BEAM RADIATION THERAPY
Soon after the discovery of PSA in the serum of men with
prostate cancer this protein began to be used to monitor
the results of therapy.29 Early reports indicated that meas-
ured serum PSA would decrease in the first several
months for the majority of men with T1-2 prostate can-
cer treated with EBRT.30–32 Soon thereafter radiation
oncologists began to incorporate PSA into the definition
of disease-free survival. In the early 1990s, a number of
different definitions of BRFS following EBRT were
developed and reported in the peer-reviewed literature.
The multiple definitions led to considerable difficulties in
deciding when biochemical relapse had occurred and
made comparisons and interpretation of published reports
difficult. In an attempt to reconcile the numerous defini-
tions of biochemical relapse, the American Society of
Therapeutic Radiology and Oncology (ASTRO) con-
vened a conference to discuss the role of PSA measure-
ments after radiation therapy. The result of this
conference was the publication of the ASTRO Consensus
Definition (ACD) of biochemical failure.33 The ACD
defined biochemical failure as three consecutive rises
from a nadir value, and the time to failure was the mid-
point between the nadir value and the first rise. To date,
the utilization of the ACD is not universal.34 Weaknesses
of the present definition have been identified.35–37 Despite
these problems many investigators continue to report
their results using the ACD, and the results reported in
this chapter will rely on the ACD unless otherwise stated.
A number of series providing external beam radiation
results according to prognostic grouping are outlined in
Table 26B-2.12,16,17,38 The definition of the low-risk
group is relatively consistent between series but there are
differences in the higher risk categories across series.
This likely explains the consistent results observed in the
low-risk group, whereas the BRFS results in the higher
risk groups are slightly different. A brief summary of each
report follows.
Shipley et al.38 and others published a pooled analysis
examining BRFS following EBRT in 1999. In this report,
data from 1765 patients with T1-2 prostate cancer
treated between 1988 and 1995 at six separate institutions
were collected and analyzed. None of these patients
were treated with ADT. Fifty-one percent of patients were
treated with 3DCRT. The median follow-up was 4.1
years and the minimum follow-up was 24 months. The
ACD was used to calculate BRFS. The 5-year estimate of
BRFS for all patients was 65.8% (95% CI 62.8 to 68).
Recursive partitioning analysis of pretreatment PSA
level, clinical T-stage, and Gleason score produced four
480 Part V Prostate Gland and Seminal Vesicles

Table 26B-2 Five-year BRFS Following EBRT for T1-2 Prostate Cancer According to Prognostic Group
No. Median Median Prognostic 5-Year Reference
Authors Patients Tx Dates Follow-Ups Dose (Gy) Group BRFS No.

Shipley et al. 1765 1988–1995 4.1 years 69.4 I 81 38

II 69

III 47

IV 29

Zelefsky et al. 743 1988–1995 3 years 75.6 Favorable 85 17

Intermediate 65

Unfavorable 35

Kupelian et al. 628 1990–1998 51 months 70.2 Favorable 90* 12

Unfavorable 59*

D’Amico et al. 381 1988–2000 3.8 years 70.4 Low 78 16

Intermediate <34% 65

Intermediate >34% 35

High 40

*Eight-year BRFS.

prognostic groups. According to prognostic group the
5-year BRFS ranged from 81% to 29%. Only 5% of bio-
chemical relapses occurred beyond 5 years. This paper
provides a good benchmark of the results achievable with
EBRT in the early 1990s.
Zelefsky et al.17 have reported on 743 men treated at
the Memorial Sloan-Kettering Cancer Center between
1988 and 1995. These men were treated according to a
phase I dose-escalation study to assess the toxicity of
high-dose 3DCRT. Ninety-six men were treated to 68.4
Gy, 266 treated to 70.2 Gy, 320 to 75.6 Gy, and 61
patients treated to 81 Gy. One hundred and ninety-five
(26%) patients were in clinical stage T3. Two hundred
and thirteen patients (29%) received neoadjuvant andro-
gen deprivation therapy (ADT) to reduce the size of the
prostate gland and reduce the total dose to the bladder
and rectum. The median follow-up was 36 months with
22% of patients followed for 4 to 8 years.
The 5-year rate of BRFS was dependent on T stage
(T1-2 versus T3), pretreatment PSA (<10 versus = 10), and
Gleason score (= 6 versus >6). Patients without poor risk
features (T1-2, PSA < 10, Gleason score = 6) experienced a
BRFS of 85%. The 5-year BRFS in men with a single poor
risk feature was 65% and 35% in men with more than one
poor risk feature. Prescription dose of greater than or equal
to 75.6 Gy was also an independent predictor of BRFS.
Kupelian et al.12 have published the results of 628 men
with T1-2 treated with EBRT at the Cleveland Clinic
between 1990 and 1998. Patients were treated to doses
between 68 and 78 Gy (median 70.2 Gy). Conformal
techniques were used in 321 (51%) of patients. Twenty-
three percent of patients were treated with ADT for a
median of 6 months. The median follow-up was 51
months and an average of 8.7 PSA levels were obtained
per patient in follow-up.
The 8-year rate of BRFS for all patients was 70%. On
multivariable analysis T stage, pretreatment PSA,
Gleason score, and neoadjuvant ADT were all independ-
ent predictors of BRFS. The authors divided patients
into a favorable group (T1-2a, Gleason score < 6, and
pretreatment PSA < 10) and an unfavorable group (T2b
or T2c, or Gleason score > 6, or pretreatment PSA > 10).
The 8-year BRFS were 90% and 59% for the favorable
and unfavorable groups respectively. In the unfavorable
group, total doses above 72 Gy were associated with
improved BRFS, 75% versus 41% (p < 0.001).
D’Amico and colleagues have reported a retrospective
cohort study of 381 men treated with EBRT between
1988 and 2000.16 All men were treated with conformal
methods. The median central axis dose was 70.4 Gy. No
patient received ADT. The median follow-up is 3.8 years
(range 1 to 12.9 years).
 Chapter 26B Clinically Localized Adenocarcinoma of the Prostate: Radiation Therapy 481
The estimates of BRFS at 8 years following treatment
were dependent on prognostic group. The 8-year BRFS
in the low-risk group (T1-2a, Gleason score < 7, and pre-
treatment PSA < 10) was 78% (95% CI 72 to 83). The
intermediate-risk group (PSA > 10 but <20, Gleason score
7, or T-2b) was divided further according to the percent
positive biopsies (<34% versus >34%). The 8-year BRFS
in the low volume intermediate-risk group was 65% (95%
CI 58 to 72) compared to 35% (95% CI 12 to 55) in the
high volume intermediate-risk group. The 8-year BRFS
was 40% (95% CI 28 to 52) in the high-risk group.
Summarizing this information, it is clear that pretreat-
ment variables can be combined to create prognostic
groups. In men with favorable-risk disease, EBRT is
associated with 5-year BRFS of 78% to 90%. Men with
intermediate- and high-risk features experience 5-year
BRFS at 5 years of approximately 65% and 35%, respec-
tively. EBRT alone to conventional doses (70 Gy)
appears insufficient in men with T1-2 disease and inter-
mediate- or high-risk features.
THE EVIDENCE FOR DOSE ESCALATION
Several reports from patients treated in the pre-PSA era
suggested that improved results were possible in men
with locally advanced and/or high-grade disease with
doses above 70 Gy.39,40 In fact, a randomized trial from
Shipley and investigators at the Massachusetts General
Hospital demonstrated improved local control in patients
with high-grade disease when a proton boost [to 75.6
cobalt Gray equivalent (CGE)] was added to photon irra-
diation.41
A number of contemporary series provide evidence
that doses above 72 Gy may benefit patients with T1-2
prostate cancer.12,17,42 Results from these series are out-
lined in Table 26B-3. All of these series are nonrandom-
ized and the follow-up is generally shorter in men treated
to higher doses. The ASTRO definition is very sensitive
to length of follow-up making the conclusions from these
nonrandomized reports less than definitive.
The investigators at M.D. Anderson Hospital have
reported 5-year results from a randomized trial compar-
ing conventional dose (70 Gy) EBRT to high-dose (78
Gy) EBRT.43 Three hundred and one men were random-
ized and are eligible for analysis. Patients were treated
between 1993 and 1998. The primary endpoint of the
trial was BRFS. The two arms were well matched with
respect to known prognostic factors.
With a median follow-up of 60 months, the 6-year
BRFS was improved in the 78-Gy arm versus the 70-Gy
arm, 70% versus 64%, p = 0.03 (Figure 26B-2A). A sub-
set analysis using a stratification variable included in the
randomization process indicated that the benefit from
the high-dose treatment was restricted to patients with a
pretreatment PSA above 10 ng/ml. In those patients with
a pretreatment PSA above 10 ng/ml, the BRFS was 62%
in the 78-Gy arm versus 42% in the 70-Gy arm, p = 0.03
(Figure 26B-2B). In patients with a PSA below 10 ng/ml,
there was no evidence of a treatment effect according to
radiation dose with BRFS of 75% in both arms, p = non-
significant (NS) (Figure 26B-2C).
As the total dose to the prostate gland increases, the
possibility of increased rectal or urinary morbidity has
been examined in a number of studies. One prospective
trial has concluded that 3DCRT produces fewer late
effects than conventional techniques when similar doses
are used.44 The dose-limiting toxicity in most reports of
dose escalation appears to be rectal bleeding.45–47 The
time course of the development of gastrointestinal com-
plications is shorter than the time course of the develop-
ment of genitourinary complications so that late bladder
toxicity may not yet be evident. In the randomized trial
from M.D. Anderson Hospital of 78 Gy versus 70 Gy, the
rate of Grade 2 or greater rectal complications was
higher in the 78-Gy arm, 26% versus 12% (p = 0.001).43
The results from this trial and other reports indicate that
rectal injury following 3DCRT is a function of dose and
volume.43,45–47
The RTOG has recently completed a multi-institu-
tional phase I/phase II dose-escalation trial of 3DCRT
(RTOG 94-06). Late toxicity of the first three dose lev-
els (68.4, 73.8, and 79.2 Gy) has been published.48,49 To
date no Grades 4 to 5 toxicities have been observed and
the rate of Grade 3 toxicity is less than 5%. The rates of
GI/GU morbidity are lower than observed with historic
controls to lower dose levels using conventional
approaches. This observation has led to the development
and activation of a randomized phase III trial comparing
79.2 to 70.2 Gy (RTOG P-0126).
The improved conformality of IMRT compared to
3DCRT offers the possibility of further dose escalation
without an increase in normal tissue injury. One of the
largest experiences with this new approach has been
described by Zelefsky et al.50 In this report, the early tox-
icity and biochemical results from 772 men treated at
Memorial Hospital between 1996 and 2001 are outlined.
Ninety percent of these men were treated to a dose of 81
Gy and 10% were treated to 86.4 Gy. The late rectal and
urinary toxicity was much lower than expected. The actu-
arial probability of Grade 2 or greater rectal toxicity was
4%, while the analogous rate of Grade 2 or greater uri-
nary toxicity was 15% with most of the urinary toxicity
manifest as urethra symptoms requiring medication.
Although the follow-up is relatively short (24 months),
the BRFS is encouraging. The 3-year rates of BRFS is
92%, 86%, and 81% according to the low-, intermedi-
ate-, and high-risk groups, respectively. Preliminary
results from other institutions are available51 but longer
follow-up is required to assess 5 to 10-year BRFS and
long-term morbidity.
 Figure 26B-2 A, BRFS curves of M.D. Anderson phase III randomized trial, including all
patients. B, BRFS curves of M.D. Anderson phase III randomized trial, including only
patients with a pretreatment PSA greater than or equal to 10 ng/ml. C, BRFS curves of M.D.
Anderson phase III randomized trial, including only patients with a pretreatment PSA less
than 10 ng/ml.

Table 26B-3 Five-Year BRFS Following EBRT for Prostate Cancer According to Prescription Dose
No. Median Dose Prognostic 5-year Reference
Authors Patients Tx Dates Follow-ups Group (Gy) Group BRFS No.

Hanks et al. 618 1988–1997 53 month Low (<72.5) PSA <10, favorable 77 42

High (=72.5) PSA <10, favorable 89

Low (<76) PSA <10, unfavorable 70

High (=76) PSA <10, unfavorable 92

Low (<76) PSA 10–19.9, favorable 72

High (=76) PSA 10–19.9, favorable 86

Low (<76) PSA 10–19.9, unfavorable 51

High (=76) PSA 10–19.9, unfavorable 82

Low (<76) PSA >20, favorable 23

High (=76) PSA >20, favorable 63

Low (<76) PSA >20, unfavorable 29

High (=76) PSA >20, unfavorable 26

Zelefsky et al. 530 1988–1995 36 months Low (64–70) Low risk 83 17

High (75–81) Low risk 95

Low (64–70) Intermediate risk 55

High (75–81) Intermediate risk 78

Low (64–70) High risk 23

High (75–81) High risk 53

Kupelian et al. 738 1986–1999 45 months Low (<72) Favorable 81 12

High (=72) Favorable 98

Low (<72) Unfavorable 41

High (=72) Unfavorable 75

 Chapter 26B Clinically Localized Adenocarcinoma of the Prostate: Radiation Therapy 483
ADT AND EXTERNAL RADIATION THERAPY FOR
T1-2 PROSTATE CANCER
The results from nonrandomized historic comparisons of
patients treated with EBRT with or without ADT have
suggested a benefit to ADT,12,52 although this observa-
tion has not been universal.17 It is possible that the effect
of ADT is not observed in the Memorial series because
of the consistently high prostate doses. These results that
demonstrate a benefit to ADT combined with EBRT
in T1-2 prostate cancer must be considered hypothesis
generating as often the follow-up is shorter in the ADT
group that will lead to a perceived improvement in BRFS
using the ACD.
The results from four phase III randomized trials
comparing EBRT alone to EBRT combined with ADT
in men with locally advanced disease have been pub-
lished.53–56 In all studies, the addition of ADT has pro-
duced improved local control, decreased rates of distant
metastases, and improved disease-free survival. Overall
survival was improved in two studies.53,54 Although the
inclusion criteria are different for each of these three
studies, most patients included in these studies had
locally advanced disease. For instance, only 9% of
patients in the EORTC study had T1-2 tumors and none
of the patients in RTOG 86-10 had nonpalpable disease.
The magnitude of benefit for the addition of ADT to
EBRT in men with T1-2 prostate cancer is unknown.
Randomized trials from the RTOG and the Dana-Farber
Cancer Center investigating the impact of short-term
(4 to 6 months) neoadjuvant ADT in men with T1-2
prostate have been completed but have yet to be
reported.
HISTORIC PERSPECTIVE, INTERSTITIAL
BRACHYTHERAPY
Brachytherapy is a general term used to describe the
placement of a radioactive source(s) into or near (Gk.
“Brachy” = near) a tumor. The source can be placed per-
manently or reside temporarily. Brachytherapy is used in
the treatment of many solid tumors, including breast,
head and neck, gynecologic, and thoracic neoplasms.
The history of prostate brachytherapy extends nearly 100
years beginning in the first decade of the 20th century in
Paris. A number of renowned urologists have contributed
to the history of prostate brachytherapy.
The first technique was described by Pasteau and
Degrais in 1911.57 Their approach relied on temporary
intraurethral placement of radium capsules. Soon there-
after, Hugh Hampton Young obtained some radium and
modified the Paris technique by designing his own device
to hold the radium. A surgeon at the Memorial Hospital
in New York, Benjamin Barringer, was the first to
describe an interstitial approach using radon capsules.58
These capsules were far smaller than the radium capsules
and allowed for easier placement. In the 1960s,
Whitmore and Carlton popularized the open retropubic
approach using permanent I-125 sources.59,60 The mod-
ern closed IB procedure was originally described by
Holm et al.61 and was further developed by Blasko et al.62
The present widespread utilization of permanent
prostate brachytherapy (PPB) is the result of prostate
screening and improved technology that currently allows
for an outpatient procedure that generally can be accom-
plished in 1 to 2 hours.
The earliest prostate brachytherapy procedures using
radium or radon involved temporary sources. In the
1970s low-dose rate Ir-192 was used as a temporary
prostate brachytherapy (TPB) source.63,64 This proce-
dure required surgical exposure of the prostate. The
open procedure allowed for guidance of transperineal,
template aided after-loading needles into the prostate
gland. The needles were manually directed by way of a
suprapubic surgical incision. After the needles were posi-
tioned, Ir-192 ribbons were manually loaded. The typical
dose-rate ranged from 0.5 to 1.0 Gy per hour delivering
a total dose of 30 to 35 Gy over 2 to 3 days. EBRT (35 to
45 Gy) would follow. The initial results with this proce-
dure were encouraging but several disadvantages, includ-
ing the necessity for an open procedure and radiation
exposure from manual loading, have limited the use of
temporary LDR prostate brachytherapy to very few cen-
ters at present.
TECHNIQUE OF PERMANENT PROSTATE
BRACHYTHERAPY
The modern technique of PPB includes three compo-
nents: (1) treatment planning, (2) placement of the
sources, and (3) an evaluation of the implant quality. In
the early work of Ragde and Blasko, the three compo-
nents were separated in time but advances in imaging and
treatment planning software have led to these compo-
nents being compressed. In some centers, all three com-
ponents are completed in the operating room at the same
sitting.65 Brachytherapy treatment planning determines
the optimal radiation dose distribution for an individual
patient depending on the size and shape of the prostate
gland. A number of different dose distribution philoso-
phies have been described. Most practitioners will use
some sort of peripheral loading scheme to reduce the
dose to the urethra and maximize dose to the peripheral
zone. In patients with very low-risk features, some authors
have used MR guidance to target only the peripheral
zone of the prostate gland.66 Transrectal ultrasound
images are generally used for the treatment planning but
other imaging modalities have been described.
Two radioisotopes are in common use in the United
States: I-125 and Pd-103. Each of these isotopes possesses
484 Part V Prostate Gland and Seminal Vesicles

Table 26B-4 Prescription Doses (Gy) for PPB

According to Isotope
Dose (Gy), Dose (Gy),
Radioisotope PPB Alone PPB plus EBRT*

I-125 144 100–110

Pd-103 115–125 80–90

*Combined with EBRT (40–50 Gy).

a low-dose rate and low energy relative to the isotope

used for temporary brachytherapy (Ir-192). The radiation
dose prescribed differs according to isotope and whether
brachytherapy is used alone (monotherapy) or combined
with EBRT (combined modality therapy, CMT) (Table
26B-4).67 The low energy of the sources simplifies radia-
tion protection precautions and patients can be dis-
charged from the hospital immediately.
The radioactive sources are usually placed transper-
ineally using some form of perineal template and ultra-
sound guidance (although MR- and CT-guided
approaches have been described). Two techniques of
source deposition are commonly employed. In the pre-
loaded technique, brachytherapy needles with sources
and spacers are prepared beforehand and with each nee-
dle placement multiple sources are deposited. In the
afterloading approach, a specially designed brachyther-
apy “gun” is used to deposit one source at a time. In
either case, the needle or gun can be visualized and
placed in the desired location. Close monitoring of the
source deposition process allows the operator to recog-
nize and adjust for changes that may occur intraopera-
tively (prostate gland movement, prostate gland swelling,
and source movement).
Some form of postprocedure dosimetric evaluation is B
mandatory.68 Most investigators use CT for this assess- Figure 26B-3 Postimplant CT scan images through the mid-
ment but other methods have been described. With com- gland (A) with resulting dose-volume histogram (B). From the
mercially available software it is possible to import CT dose-volume histogram it is clear that 94% of the prostate is
images and outline the prostate gland and nearby struc- encompassed by the 100% isodose line, while the vast
tures (urethra, rectum, penile bulb, etc.). Automated majority of the urethra is receiving less than 150% of the
algorithms have been designed to identify the sources. prescription dose.
Based on the delineation of the prostate and the location
of the sources, isodose distributions can be calculated and
dose-volume histograms created (Figure 26B-3). The emerging, acceptable doses to normal tissues (urethra,
accurate delineation of prostate volumes on CT images rectum, penile bulb) are much less clear.
following brachytherapy can be difficult. Postoperative
prostate swelling and degradation of the image secondary
TECHNIQUE OF TEMPORARY PROSTATE
to the metallic sources can lead to disagreement amongst
BRACHYTHERAPY
reviewers.69
A standard definition of a “good implant” has yet to be TPB also benefitted from the advances in ultrasound and
universally accepted by the brachytherapy community. treatment planning computers in the 1980s. The simul-
There is early evidence that delivering at least 90% of the taneous development of high-dose rate afterloading
prescription dose to 90% of the prostate gland results in machines stimulated a number of investigators across the
improved BRFS.70,71 Although preliminary work is globe to refine the methods of TPB.
 Chapter 26B Clinically Localized Adenocarcinoma of the Prostate: Radiation Therapy 485

High-dose rate (HDR) afterloading machines are

devices that contain a single high-intensity Ir-192 source
(5 to 10 Ci). The source is attached to the end of a wire
that is controlled by the machine. The machine can pre-
cisely position the source and keep it there for a specified
period of time (usually measured in seconds). The source
can thus be moved within needles to a number of loca-
tions allowing the treating physician to create a dose dis-
tribution of virtually any shape or size.
Most HDR prostate brachytherapy techniques utilize
transrectal ultrasound to guide the needles into place
within and around the prostate.72 A variety of perineal
templates have been devised to assist needle placement.
In some centers, ultrasound-based treatment planning
allows treatment to be delivered at the time of the needle
placement.73 Most sites use CT images for the treatment
planning process. HDR needles are identified, and the
prostate gland is contoured on the CT images. Nearby
structures (urethra, rectum) are identified, and a the
desired dose is delivered to the prostate while limiting
the dose to the urethra and rectum.
Once a plan has been generated, the afterloading
machine delivers the treatment by moving the source to
different locations within the HDR catheters in a
sequential manner. Typical treatment times range from
5 to 10 minutes. Typically patients receive multiple treat-
ments over the course of 6 to 36 hours. Due to the high
energy of the Ir-192 source, a specially shielded room is
required for treatment.
Most clinicians have combined HDR brachytherapy
with 4 to 5 weeks of EBRT although HDR monotherapy
is taking place in a few centers. Dose-fractionation
schedules differ between institutions and despite
attempts, no consensus has been reached as to the best
treatment schedule.
BIOCHEMICAL RELAPSE-FREE SURVIVAL
FOLLOWING PROSTATE BRACHYTHERAPY
As with patients treated with EBRT, serum PSA levels
decline soon after treatment with PPB. The ACD is
commonly used to define BRFS following PPB, although
the ACD was not originally intended for this purpose.
Some advocate the use of a nadir definition following
PPB instead of the ACD.74 The results outlined in this
section use a number of different definitions to define
BRFS making comparisons problematic.
Compared to men treated with EBRT, men treated
with PPB are more likely to manifest a sudden increase in
serum PSA to be followed by a decline. Authors have
described this phenomenon as PSA bounce or PSA
spike.75–77 The incidence of this phenomenon ranges
from 17% to 35% depending on the definition utilized.
The median time to PSA spike is 18 to 24 months and
mostly occurs within the first 5 years. The magnitude of
PSA bounce has been as large as 15 ng/ml, although most
bounces are less than 3 ng/ml. Two reports find PSA
spikes to be more common in younger men, which may
reflect an increased level of sexual activity.76,77 To date in
three separate reports, there has been no correlation
between PSA bounce and subsequent BRFS.75–77
Clinicians should be aware of this phenomenon and exer-
cise caution prior to instituting salvage therapy.
The results described later are divided according to
whether patients are treated with monotherapy (PPB
alone) or CMT (PPB plus EBRT). CMT has been rec-
ommended over monotherapy for a number of reasons:
increased intraprostatic dose; treatment of extracapsular
prostate cancer; and as a form of insurance to “fill in” the
areas of reduced dose that may result from a suboptimal
implant. Some institutions use CMT selectively in men

Table 26B-5 BRFS Following PPB for T1-2 Prostate Cancer

No. Percentage Percentage of Median Follow-ups BRFS
Authors Patients P/I of T1/T2 Gleason Score > 6 PSA (months) (years)

Stock86 97 I/P 13/87 18 NS 18 76 (2)

Grado et al.83 392 I/P 6/92 20 7.3 30 80 (5)

D’Amico16 66 P 23/77 20 NS 41 0–85 (5)

Blasko9 230 P 30/70 40 7.3 41.5 83.5 (9)

Ragde85 147 I 22/78 0 8.8* 93 66 (12)

Zelefsky15 248 I 58/42 25 7 48 71 (5)

Brachman et al.82 695 I/P 17/83 15 NS 51 64 (7)

Grimm84 125 I 24/76 0 5.1 ~78 85 (10)

486 Part V Prostate Gland and Seminal Vesicles
with high-risk features,78 whereas others use CMT in all
patients regardless of T stage, PSA, and Gleason score.79
The necessity of supplemental EBRT in patients
treated with PPB has yet to be demonstrated. No ran-
domized trials have been reported. The addition of sup-
plemental EBRT to PPB increases patient’s and
physician’s time commitment with a resulting increase in
costs.80 There is also the possibility that combination
therapy will increase morbidity and decrease HRQOL
compared to PPB or EBRT alone.81 The hypothesis that
supplemental EBRT improves results is currently being
tested in a recently activated randomized trial of the
RTOG (RTOG P-0232). This trial includes measure-
ments of patient-reported HRQOL.
BIOCHEMICAL RELAPSE-FREE SURVIVAL:
PPB ALONE
Table 26B-5 summarizes the results achieved with PPB
alone in men with clinically localized prostate can-
cer.9,10,15,82–86 PSA-based disease-free survival is 63% to
93% at 5 years in selected patients treated with PB alone.
Two published reports with the longest follow-up report
10-year actuarial estimates of BRFS to be 66% to
85%.85,87 Brief descriptions of a few selected series are
provided later.
Blasko et al.9 have reported on a consecutive series of
230 men with T1-2 prostate cancer treated with Pd-103
alone at the Seattle Prostate Institute between 1988 and
1995. The majority of patients (56%) presented with pal-
pable T2a disease and 40% were classified as having a
Gleason score of 7 or higher. The median PSA was
7.3 ng/ml. Seventy-five percent of men had a pretreat-
ment PSA below 10 ng/ml. Two consecutive PSA eleva-
tions were required for biochemical recurrence. The
median follow-up was 41.5 months. The estimate of
BRFS was 83.5% (95% CI 78.3 to 88.7) at 9 years.
Pretreatment PSA and Gleason score were found to be
predictive of BRFS on univariate analysis. Grouping
patients into three risk categories according to T stage,
Gleason score and pretreatment PSA value demonstrated
significant differences in BRFS.
Zelefsky et al.15 have provided an update of the expe-
rience at Memorial Hospital. These authors reported on
248 men treated with prostate brachytherapy alone
between 1989 and 1996. All men were treated with I-125.
The median age was 65. Most men (58%) had nonpalpa-
ble disease. Twenty-four percent of men had a Gleason
score of 7 or higher. The median pretreatment PSA was
7 ng/ml, and 78% of men had a PSA of less than 10
ng/ml. Three rises in PSA was defined as evidence of
recurrence, and the median follow-up was 48 months
(range 12 to 126 months). The authors categorized
patients into previously published prognostic groups
according to T stage, Gleason score, and pretreatment
PSA. The 5-year estimate of disease-free survival for all
patients was 71%. The 5-year estimates of disease-free
survival according to prognostic risk groups were as fol-
lows: 88% for favorable risk; 77% for intermediate risk;
and 38% for high risk (p < 0.0001).
Grimm et al.87 recently published an update of the
Seattle experience with prostate brachytherapy as
monotherapy. The authors reported on 125 men treated
between January 1998 and December 1990 with I-125
prostate brachytherapy alone. These men were carefully
selected and had very favorable pretreatment characteris-
tics. The clinical T stage was less than or equal to T2a in
85% of men, and all men had a Gleason score of 6 or less.
Forty-three percent of men had a pretreatment PSA
below 4 ng/ml and more than 75% had a pretreatment
PSA below 10 ng/ml. Patients were routinely followed
with physical examination and serum PSA determina-
tions at 3 to 6-month intervals during the first 5 years
and yearly thereafter. The median follow-up was 81.4
months. These authors used two consecutive PSA rises as
evidence of failure. Disease-free survival was estimated
by the Kaplan–Meier method. Eight men were docu-
mented to have clinical failures (4 with positive prostate
biopsy and 4 with positive bone scan). All clinical failures
were diagnosed within 5 years. Eight additional patients
were found to have biochemical evidence of disease
recurrence. The Kaplan–Meier estimate of biochemical
disease-free survival in this cohort is 85.1% (95% CI 79.3
to 90.9) at 10 years. The only variable that predicted for
BDFS in this cohort was pretreatment PSA.
The authors then provided a comparison to a cohort
of 97 men treated by the same authors early in their
prostate brachytherapy experience. The authors reported
on 97 men treated between January 1986 and December
1987. The demographic characteristics of this earlier
cohort were similar to the later cohort, but the BDFS was
significantly worse in the men treated in 1986 and 1987
(10 Yr BDFS 65% versus 87%, p = 0.0002). The authors
concluded that the superior results in the later patients
were the result of refinements in the prostate brachyther-
apy technique.
In weighing the available evidence about the efficacy
of PPB, several important points should be considered.
Each and every report represents a retrospective, single-
institution experience. The extent to which the results
achieved at centers of excellence are generalizable to
general community practice is unknown. The Seattle
group has provided the best evidence that a learning
curve exists for the PB procedure in that the BRFS rates
are inferior in the group of patients treated early in their
experience despite similar pretreatment characteristics.
Differences in patient selection criteria, brachytherapy
techniques, experience of the brachytherapists, and def-
initions of biochemical relapse preclude any definitive
statements comparing techniques, isotopes, etc. From an
 Chapter 26B Clinically Localized Adenocarcinoma of the Prostate: Radiation Therapy 487

Table 26B-6 Five-Year BRFS Following PPB for T1-2 Prostate Cancer
According to Prognostic Groups
Authors No. Follow-Ups 5-Year
Patients (Months) Isotope Risk Category BRFS (%)

Blasko9 103 48.9 Pd-103 Low 94

107 39.5 Intermediate 82

20 45.5 High 65

Zelefsky15 112 I-125 Favorable 88

92 Intermediate 77

22 Unfavorable 38

Grimm84 97 I-125 Low 87*

27 Intermediate 79*

D’Amico16 32 41.0 Pd-103 Low 88

15 Intermediate 32

19 High NA

*Ten-year BRFS.

Table 26B-7 BRFS Following PPB Combined with EBRT for T1-2 Prostate Cancer
No. Implant EBRT EBRT Follow-Ups BRFS (%)
Author Patients Isotope(s) MPD* (Gy) Dose (Gy) Fields (Years) (Years)

Ragde85 82 125-I 110 45 4-field: P-SV 10 79 (10)

Blasko78 231 125-I/103-Pd 110/90 45 4-field: P-SV 5 79 (9)

Lederman et al.89 348 125-I/103-Pd 110/90 45 4-field 4 77 (6)

Critz79 689 125-I 120 45 P-SV-PPT 4 88 (6)

Dattoli et al.88 124 103-Pd 90 41 Limited Pelvic 3.8 76 (4)

*Matched peripheral dose.

evidence-based perspective, the value of these results
should be considered limited; multi-institutional,
prospective trials are required.
PSA OUTCOME STRATIFIED BY RISK GROUP
Just as in patients treated with EBRT, results following
PPB according to prognostic grouping have been pub-
lished. Table 26B-6 summarizes the available information
from those authors who reported results with PPB alone
according to risk groups.9,10,15,87 The 5-year BRFS ranges
from 88% to 94% in men with low-risk disease treated
with PPB alone. Patients with more unfavorable features
have 5-year BRFS of 32% to 65%, suggesting that PPB
alone is not adequate in these higher risk patients. This
observation has led many authors to recommend supple-
mental EBRT or ADT (or both) in these men. Results
with CMT are outlined in the following section. The use
of ADT with PPB is discussed as follows.
BIOCHEMICAL RELAPSE-FREE SURVIVAL: PPB
COMBINED WITH EBRT
The results from five centers with a significant experi-
ence with CMT (PPB plus EBRT) are outlined in Table
26B-7.78,79,85,88,89 All patients in these reports were treated
488 Part V Prostate Gland and Seminal Vesicles
after 1986 and have had continuous PSA follow-up avail-
able. The closed transperineal method of PPB was used
in all cases. Three reports originate from centers where
CMT is used in all prostate cancer cases,79,88,89 and two
are from institutions that select CMT for higher risk
patients, reserving PPB alone for patients with low-risk
disease.78,85
Ragde et al.85 have described the results in 82 men
treated with PPB (I-125, 110 Gy maximum permissible
dose [MPD]) and EBRT (45 Gy). All men were treated
between January 1987 and December 1989 so that the
follow-up is quite long (median 122 months). These
patients were selected for CMT based on high-risk fea-
tures. The vast majority of men (84%) had palpable dis-
ease, although only four men were felt to have clinical
extracapsular disease (T3). The mean PSA in this group
was 14.7 ng/ml (sd 21.2), and 18 men (24%) had a
Gleason score above 6. ADT was not used. The ACD
was used to calculate BRFS. The 10-year estimate of
BRFS was 79%.
Blasko et al.78 have reported on 231 men treated with
PPB (I-125, 110 Gy; Pd-103, 90 Gy) and EBRT (45 Gy).
The median follow-up was 58 months. During this
period, some men were treated with monotherapy, and
the use of supplemental EBRT was at the discretion of
the physician. The mean PSA was 15.6 ng/ml, and 35%
of patients presented with a Gleason score above 7. No
patients received ADT. The ACD was used to calculate
BRFS. The results of BRFS were provided according to
the prognostic groupings of Zelefsky. Ten-year BRFS
estimates were 87%, 85%, and 62% for low-, intermedi-
ate-, and high-risk groups, respectively. In this report,
the authors did compare the results with CMT to
monotherapy according to risk group and found no
group that benefitted from the addition of EBRT.
Lederman et al.89 have reported on 348 patients with
T1-3a disease treated with PPB (I-125, 110 Gy; Pd-103,
90 Gy) and EBRT (45 Gy). In this report, PPB was per-
formed prior to EBRT. No patient received ADT. The
median follow-up was 44 months. One hundred and
sixty-four (50%) men had a pretreatment PSA above 10
ng/ml and 119 (34%) were assigned a Gleason score
between 7 and 10. Only 17 (4.6%) men had T3 disease.
The ACD was not used to define BRFS. Instead, bio-
chemical failure was defined as the use of ADT anytime
following treatment, or a serum PSA > 5.0 ng/ml at last
follow-up, or two consecutive rises in serum PSA > 0.5
ng/ml. The estimated BRFS at 6 years for the entire
group was 77% (95% CI 72% to 82%). The authors
divided patients into risk groups according to pretreat-
ment PSA, T stage, and Gleason score. The estimates of
BRFS were 88%, 75%, and 51% for the low-, intermedi-
ate-, and high-risk groups, respectively.
The results from the radiation therapy clinics of
Georgia have been summarized recently.79 Six hundred
and eighty-nine men were treated between 1992 and
1996 and received an I-125 implant (120 Gy) followed in
3 weeks by EBRT (45 Gy). The median follow-up was
4 years. Twenty-eight (4%) men had a Gleason score
above 7 and 44 (6%) had a pretreatment PSA above 20.
No patient received ADT. As is the custom with these
investigators, the ACD was not used to calculate BRFS.
Instead, an absolute value of = 0.2 was used to define cure.
Patients are censored if the PSA is declining (but not
=0.2) at the time of analysis. The 5-year estimate of
BRFS is 88%.
Dattoli et al.88 have recently updated their experience
with CMT in patients with high-risk features. They have
reported on 161 men with T1-3 prostate cancer treated
with PPB (Pd-103, 80 Gy) and EBRT (41.4 Gy). The PPB
was performed for 4 weeks following EBRT. The median
follow-up for nonfailing patients was 7 years.
Approximately 25% of patients had a pretreatment PSA
above 20. Approximately 20% of the patients were assigned
a Gleason score above 7. The ACD was not used calculate
BRFS. Instead, a PSA level of =0.2 ng/ml defined the
absence of disease. The 10-year estimate of BRFS is 79%.
The BRFS from two series that provide results
according to prognostic grouping are summarized in
Table 26B-8.78,89 Although the amount of information is
small, it appears that patients with favorable (and perhaps
intermediate-) risk disease do well with CMT, but
patients with high-risk features do not fare nearly as well,
suggesting that they may benefit from effective systemic
therapy combined with local therapy.
ADT AND PERMANENT PROSTATE
BRACHYTHERAPY FOR T1-2 PROSTATE
CANCER
The use of ADT combined with PPB is common. In
recent reports, ADT has been combined with PPB in 7%
to 69% of cases.90 ADT may be utilized for three pur-
poses: (1) to downsize the prostate to facilitate PPB; (2)
to decrease morbidity; and (3) to improve cure rates. It is
clear that 3 to 6 months of ADT will lead to a 30% to
40% reduction in prostate volume on transrectal US
measurements.91 It is not clear that ADT reduces mor-
bidity. In fact there at least is an evidence that ADT prior
to PPB may increase acute urinary morbidity and
decrease sexual function.92,93 The question whether ADT
improves cure rates is more complicated.
Whether the results of randomized trials showing a
benefit for the addition of ADT to EBRT in patients with
locally advanced disease can be extrapolated to lower risk
patients treated with PPB is not known. The results from
nonrandomized historic comparisons of patients treated
with PPB with or without ADT have been inconsistent.
Some reports indicate an improvement in BRFS94,95 while
others do not.96 Given that most authors use the ACD in
 Chapter 26B Clinically Localized Adenocarcinoma of the Prostate: Radiation Therapy 489

Table 26B-8 BRFS Following PPB Combined with EBRT for T1-2 Prostate Cancer According to Prognostic Groups
No. BRFS Time Low (%) Intermediate High (%)
Authors Patients Point (years) (N) (%) (N) (N)

Blasko78 231 10 87 (75) 85 (104) 62 (52)

Lederman et al.89 348 5 88 (165) 75 (124) 51 (59)

Table 26B-9 BRFS Following HDR Brachytherapy and EBRT

No. Percentage Median Implant No. EBRT BRFS (%)
Authors Patients of T1-2 Follow-ups Dose (Gy) Fractions Dose (Gy) (years)

Borghede et al.97 50 76 45 months 20 2 50 84*

Dinges et al.98 82 26 24 months 18–20 2 45 53 (2)

Kovacs and Galalae99 144 68 8 years 30† 2 40 73 (8)‡

Mate et al.72 104 90 45 months 12–16 4 50.4 84 (5)§

Martinez100 207 91 4.4 years 16.5–23 2–3 46 74 (5)

*Eighteen-month crude rate.

†
Prescription dose to the peripheral zone.
‡
Three consecutive PSA rises, all above 1.0 ng/ml.
§
For patients with pretreatment PSA < 20 ng/ml.

these reports, any results favoring the addition of ADT
should be questioned. In all series, the follow-up is
shorter in patients receiving ADT (representing a tempo-
ral trend seen nationwide), and the ACD is extraordinar-
ily sensitive to length of follow-up. Randomized trials
examining the value of ADT combined with PPB are
required to make conclusive statements.
BIOCHEMICAL RELAPSE-FREE SURVIVAL: HDR
TEMPORARY PROSTATE BRACHYTHERAPY
To date most reports of HDR brachytherapy have
focused on men with T1-2 with intermediate- or high-
risk features (>T2b, Gleason score > 6, pretreatment PSA
>10), and the number of men with favorable disease
included in these reports is small. The BRFS results of
several series are summarized in Table 26B-9.72,97–100 The
patients included in these series are very heterogeneous.
BRFS is defined very differently with some series using
an absolute PSA level to define cure and others relying
on a rising PSA to define recurrent disease; only two of
the series use the ACD to calculate BRFS. In some series,
pretreatment ADT is given, making interpretation
difficult.
A small number of investigators have developed phase
II protocols to examine the efficacy of HDR brachyther-
apy alone (without EBRT).101,102 Follow-up is too short
to report BRFS, but the acute morbidity appears to be
tolerable.
PARTICLE BEAM THERAPY
Particle beams used in the treatment of prostate cancer
include neutrons and photons. Early randomized trials
suggested a benefit to neutron therapy in men with locally
advanced disease but an increase in complications was
noted.103 The complications were attributed to inadequate
collimation and inability to shield normal tissues near the
prostate. It is now possible to use conformal methods with
neutrons, and the results remain encouraging.104 For the
time being, however, the lack of treatment facilities with
neutron capabilities limit the use of this modality.
The number of proton facilities in the United States
is similarly small, although many new sites are under
construction. The physical characteristics of proton
beams are fundamentally different than those of pho-
ton beams. The dose gradient outside of the PTV is
much steeper with proton beams and may result in
lower morbidity. The largest experience to date is from
investigators at Loma Linda.105 The early results
appear similar to the results achieved with 3DCRT.
Comparison trials of proton beam versus photon beam
therapy are ongoing.
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69. Lee WR, Roach M III, Michalski J, et al: Interobserver
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70. Potters L, Cao Y, Calugaru E, et al: A comprehensive
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71. Stock RG, Stone NN, Tabert A, et al: A dose-response
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72. Mate TP, Gottesman JE, Hatton J, et al: High dose-rate
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73. Martinez AA, Kestin LL, Stromberg JS, et al: Interim
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76. Critz FA, Williams WH, Benton JB, et al: Prostate
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81. Brandeis JM, Litwin MS, Burnison CM, et al: Quality of
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82. Brachman DG, Thomas T, Hilbe J, et al: Failure-free
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84. Grimm PD, Blasko JC, Sylvester JE, et al: 10-year
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85. Ragde H, Korb LJ, Elgamal AA, et al: Modern prostate
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87. Grimm PD, Blasko JC, Sylvester JE, et al: 10-year
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C H A P T E R
27 Regionally Advanced Adenocarcinoma
of the Prostate (T3-4N+M0):
Management and Prognosis
Mary Frances McAleer, MD, PhD,
and Richard K. Valicenti, MD
Adenocarcinoma of the prostate is considered to be
regionally advanced once malignant cells are identified
outside the prostatic capsule (T3a), have invaded the
seminal vesicle(s) (T3b), or involve adjacent bladder, rec-
tum, musculature, or pelvic wall (T4). Also, included in
this category are tumors with nodal metastases (N1-3).1
While the overall incidence of prostate cancer in the U.S.
rose with the widespread institution of prostate-specific
antigen (PSA) screening in the early 1990s, the percent-
age of patients presenting with regionally advanced dis-
ease has decreased.2,3 Using pretreatment PSA level,
Gleason score and clinical stage, Partin et al.4 were the
first to demonstrate that the risk of regional spread of
prostate cancer can be estimated. Although the actual
diagnosis of regionally advanced prostate cancer requires
biopsy or pathology demonstrating adenocarcinoma with
extra-prostatic spread, multimodality staging (combined
use of tumor stage, pretreatment PSA, and Gleason
score) is an important and useful method to identify men
at high risk of subclinical regionally advanced disease.5
GENERAL MANAGEMENT OF REGIONALLY
ADVANCED PROSTATE CANCER
Locoregional therapy for T3 or greater adenocarcinoma
of the prostate, including radical prostatectomy (RP)
(with or without lymphadenectomy) and radiation ther-
apy alone, have not resulted in improved disease-specific
or overall survival (OS) in these patients, with the major-
ity demonstrating clinically overt metastases by 10
years.6–8 Given these poor outcomes with monotherapy,
the recent NCCN guidelines and patterns of care
prostate cancer decision tree advocate the use of andro-
gen deprivation both as neoadjuvant cytoreductive ther-
494
apy in conjunction with external beam radiation therapy
(EBRT) to enhance local control and disease-free sur-
vival, and as adjuvant systemic treatment for manage-
ment of occult metastatic disease.9,10
ANDROGEN DEPRIVATION THERAPY
Rationale
Androgens have been shown to stimulate the growth and
proliferation of neoplastic prostate cells both in vitro and
in vivo by interacting with androgen receptors on these
cells.11–14 Inhibition of this interaction by hormone ther-
apy has been shown to reduce gross tumor volume sig-
nificantly.15 This theoretically leads to increased tumor
blood flow and decreased tumor hypoxia, which, in turn,
may allow for improved treatment outcomes with locore-
gional treatment. Androgen deprivation may additionally
improve therapeutic results by eradicating distant
micrometastatic disease not controlled by surgery or
radiation therapy alone. The mechanism of these effects
is thought to involve the induction of apoptosis in the
targeted prostate cells, which may have an additive or
even synergistic effect when combined with the DNA-
damaging action of radiation.16,17
Methods of Androgen Deprivation
Orchiectomy
The most commonly used method of androgen depriva-
tion worldwide is orchiectomy. Surgical castration has
been shown to remove 95% of circulating testosterone,
with long-lasting reduction of serum levels of this hor-
mone. Orchiectomy has both economic and compliance
advantages over the other methods of androgen deprivation
 Chapter 27 Regionally Advanced Adenocarcinoma of the Prostate (T3-TN + M0) 495
discussed later.18 The psychologic ramifications of this
approach, however, have limited its widespread use in the
U.S.
Estrogen Supplementation
Estrogens are thought to act either indirectly by suppress-
ing pituitary gonadotropin, which, in turn, inhibits testic-
ular testosterone synthesis, or by directly binding to
prostate cell hormone receptors and thereby competitively
blocking receptor binding by androgens. Use of the syn-
thetic estrogen diethylstilbestrol (DES) by the Veterans
Administration Cooperative Urologic Research Group
(VACURG) was the first exogenous hormone therapy
given for prostate cancer. DES at doses of 5 mg/day
showed similar survival to orchiectomy and improved can-
cer-specific survival; however, cardiovascular mortality was
increased with DES treatment.19 Reducing the DES dose
to 1 mg/day resulted in equivalent survival as with the
higher dose, but castrate levels of testosterone were not
achieved.19,20 Side effects of estrogenic therapy, such as
fluid retention, gynecomastia, and decreased libido, have
resulted in its infrequent use in clinical practice.
Progesterone Supplementation
Medroxyprogesterone (Provera) and megestrol (Megace),
two progestins, also suppress gonadotropin release and
thus interfere with testosterone production.21 These agents
have not been found to inhibit serum androgen levels com-
pletely or for any prolonged period of time, however, and
therefore they are not used as monotherapeutic agents.
Luteinizing Hormone Releasing Hormone Analogs
Luteinizing hormone releasing hormone (LHRH)
analogs, such as goserelin (Zoladex) and leuprolide
(Lupron), function by initially inducing luteinizing hor-
mone (LH) and follicle stimulating hormone (FSH)
release by the pituitary followed by a gradual inhibition
(after 1 to 2 weeks) of these hormones. This activity
results in an initial increase (1 to 2 days) then decrease of
testosterone to castrate levels (by 20 to 28 days).22
LHRH agonists have been shown in randomized trials to
be as efficacious as orchiectomy or DES in the treatment
of advanced prostate cancer.23,24 The initial transient ele-
vation of testosterone associated with LHRH agonist use
has resulted in exacerbation of pain in approximately
10% of patients with metastatic disease and is thought to
be due to a flare reaction of tumor cell proliferation.25,26
To avoid this flare reaction, antiandrogens (see later) are
frequently coadministered either temporarily or continu-
ously with the LHRH analogues.27 The principle side
effects of LHRH agonists are impotence, decreased
libido, testicular atrophy, and hot flashes.
Antiandrogens
Antiandrogens function as competitive inhibitors of
testosterone by binding to the androgen receptors on
prostate cells. The two classes of antiandrogens include
steroidal and nonsteroidal agents. The former include
aminoglutethimide, cyproterone acetate (Androcur), and
megestrol, which additionally suppress testosterone by
hypothalamic and pituitary negative feedback mecha-
nisms. The nonsteroidal antiandrogens, namely, flu-
tamide, bicalutamide (Casodex) and nilutamide, block
androgen uptake and function in prostate cells primarily
at the level of the androgen receptor. In contrast to the
steroidal antiandrogens, the nonsteroidal agents do not
decrease gonadotropin or testosterone levels, and thus
have been shown to maintain libido and potency. Of the
nonsteroidal antiandrogens, bicalutamide has higher
binding affinity and longer area under the curve (half-life
of 7 to 10 days) with a dose of 50 mg daily being equiva-
lent to 750 mg/day (250 mg every 8 hours) of flutamide
(half-life of 5 to 6 hours).28 Diarrhea and, less frequently,
but more serious hepatic toxicity are side effects of flu-
tamide therapy.29 Bicalutamide is associated with more
breast tenderness and gynecomastia than castration.30
Preliminary results of two multi-institutional random-
ized trials comparing bicalutamide monotherapy (150 mg
daily) to surgical or medical (goserelin 3.6 mg every 28
days) castration in patients with nonmetastatic prostate
cancer demonstrated equivalent survival with median fol-
low-up of over 200 weeks.30 Although longer follow-up is
needed, bicalutamide monotherapy may provide a quality
of life advantage over castration with the preservation of
sexual function in patients treated with the antiandrogen.
ANDROGEN DEPRIVATION AND RADIATION
THERAPY
Multivariate analysis of data from a prospective trial of
the Radiation Therapy Oncology Group (RTOG study
75-06) investigating pretreatment factors associated with
disease outcome revealed that hormonal therapy either
prior to or during radiation therapy for prostate carci-
noma correlated with improved local tumor control.31 As
a result, androgen deprivation has been studied prospec-
tively in conjunction with radiation therapy in two con-
texts: (1) neoadjuvantly as cytoreductive therapy in
patients with bulky primary tumors; (2) adjuvantly in
patients at increased risk for micrometastatic disease.
Each of these approaches is presented in detail later.
Radiation Therapy with Neoadjuvant Hormonal
Therapy
Based on the promising results of RTOG 75-06 noted
earlier, as well as on the observation of >94% primary
496 Part V Prostate Gland and Seminal Vesicles
tumor clearance in both a phase II randomized study
examining the efficacy and toxicity of megestrol and DES
with definitive EBRT for locally advanced prostate can-
cer (RTOG 83-07), and a similar phase II trial (RTOG
85-19) investigating flutamide and goserelin cytoreduc-
tion with EBRT the RTOG conducted a phase III trial
(86-10) comparing EBRT with and without hormonal
therapy given prior to and during the radiation treat-
ment.31–34 The patients enrolled in RTOG 86-10 had
bulky T26-T4 prostate cancers, with 91% being lymph
node negative.35 The androgen deprivation method used
in this phase III trial consisted of two months of goserelin
(3.6 mg subcutaneously every 28 days) and flutamide (250
mg orally 3 times daily) prior to EBRT (45 to 50 Gy
pelvic RT plus 20 to 25 Gy prostate boost) with contin-
ued hormonal therapy during the radiation treatment.
There were 456 patients who could be evaluated in
RTOG 86-10, with 226 patients in the androgen depri-
vation arm and 230 patients in the EBRT-only arm. The
recently reported long-term update of this study (median
6.7-year follow-up) revealed that the 8-year local control
rate was significantly higher in the patients treated with
neoadjuvant hormonal therapy (NHT) and EBRT (42%)
than in the EBRT-only group (30%, p = 0.016).35 The
incidence of distant metastases was also significantly
lower in the patients with androgen deprivation (34%
versus 45%, p = 0.04). The actuarial and biochemical dis-
ease-free survival rates were also significantly improved
in these patients (33% versus 21%, p = 0.004; and 24%
versus 10%, p < 0.0001, respectively). While there was no
difference in OS of all patients in the two groups, a sur-
vival benefit was observed in patients with Gleason score
2 to 6 receiving the hormone treatment (70% versus
52%, p = 0.015).
The treatment delivered in both arms of RTOG 86-10
was relatively well tolerated, the highest frequency of
treatment termination being attributed to flutamide toxic-
ity (16%). The main criticism of this study is that initial
staging was based on digital rectal examination (DRE) and
not PSA or biopsy results. Nevertheless, this study set the
standard for future trials and clinical application of combi-
nation therapy for regionally advanced prostate cancer.
One such prospective randomized trial from Canada
investigated 64.8 Gy EBRT alone (n = 41), versus flu-
tamide and LHRH agonist therapy delivered either 3
months prior to EBRT (n = 43) or 3 months prior to,
during, and 6 months following EBRT (n = 36) for
patients with T2a to T4 adenocarcinoma of the
prostate.36 Trans-rectal ultrasound (TRUS)-guided biop-
sies performed at 24 months following EBRT showed
65%, 28%, and 5% residual cancer in each group,
respectively (p = 0.00001). While there is apparent local
benefit of prolonged androgen deprivation versus NHT
with EBRT, no other clinical outcome measures were
reported to support a survival advantage with the use of
neoadjuvant or prolonged hormonal therapy in these
patients.
Radiation Therapy with Adjuvant Hormonal Therapy
The use of androgen deprivation as adjuvant systemic
therapy with EBRT in patients with regionally advanced
adenocarcinoma of the prostate has been studied
prospectively by several groups. One of the earliest
reports of adjuvant hormonal therapy and radiation ther-
apy in patients with T3-4NxM0 prostate cancer was a 15-
year follow-up by Zagars et al.37 Patients in this study
were randomized either to EBRT alone or to EBRT plus
DES until relapse or death. Significant improvement in
actuarial disease-free survival was seen in patients receiv-
ing the DES with EBRT (63%) in contrast to those
treated with EBRT alone (35%). No difference in clini-
cal local tumor control or OS was detected, however, in
part because of DES use in relapsed patients receiving
EBRT-only, and also because of increased intercurrent
mortality in patients initially receiving DES with EBRT.
A phase III trial by the RTOG (study 85-31) examined
the effect of EBRT (44 to 46 Gy to pelvis with 20 to 25
Gy prostate boost or 60 to 65 Gy to prostatic bed if post-
prostatectomy) either with or without adjuvant goserelin
(3.6 mg subcutaneously every 28 days) in patients with
locally advanced prostate cancer. Goserelin was adminis-
tered to 477 patients during the last week of EBRT or at
relapse to 468 patients initially treated with EBRT-only.
Statistically significant reduction in rates of local failure
and distant metastases, and improvement in biologic and
clinical response rates were observed in patients receiving
goserelin adjuvantly versus at relapse, both were at 5- and
8-year follow-up.38,39 No difference in OS was detected
in the initial versus relapse hormonal therapy groups at
5 years (75% versus 71%) or at 8 years (49% versus
47%). Subset analysis of patients with Gleason score 8 to
10 (without prostatectomy) did demonstrate significant
benefit of adjuvant androgen deprivation with respect to
both OS and cause-specific failure compared with hor-
monal therapy at relapse.39
A similar phase III study was conducted by the
European Organization for Research on Treatment of
Cancer (EORTC) that investigated EBRT (≤50 Gy to
pelvis with 20 Gy prostate/seminal vesicle boost) with or
without hormonal therapy (cyproterone 150 mg orally
3 times daily for 4 weeks starting 1 week prior to EBRT
and goserelin starting day 1 of EBRT and continuing for
3 years) in patients with prostate cancer at high risk for
metastatic disease (high grade T1-2 or any grade T3-4,
no nodal disease at/above common iliac chains, M0).
After median follow-up of 5.5 years, statistically signifi-
cant reduction in rates of locoregional failure and distant
metastases, and improvement in biologic and clinical
response rates were again observed in the group receiving
 Chapter 27 Regionally Advanced Adenocarcinoma of the Prostate (T3-TN + M0) 497

adjuvant hormonal therapy as reported in RTOG 86- mined by TRUS and DRE, not by PSA or biopsy. Third,
10.40,41 In contradistinction to the RTOG 85-31 results, the 5-year survival results for the EBRT-only arm is
however, the use of adjuvant hormonal therapy in the lower than expected for this group (compare with RTOG
EORTC study was associated with significantly 85-31 results). Finally, the 5-year follow-up period is
improved disease-specific survival (94% with hormonal considered short for prostate cancer trials.
therapy versus 79% without hormonal therapy, p = The duration of androgen deprivation required for
0.0001) and OS (78% with hormonal therapy versus 62% therapeutic benefit in patients with regionally advanced
without hormonal therapy, p = 0.0002) (Figure 27-1). prostate cancer is not yet established. The effect of
While the EORTC study is of great importance in 2-year maintenance adjuvant goserelin therapy versus
justifying the use of early adjuvant androgen deprivation observation alone following 4 months of goserelin and
in the treatment of regionally advanced prostate cancer, flutamide therapy (2 months prior to and 2 months dur-
this study is not without its criticisms. First, patients were ing EBRT) in patients with T2b-4 disease was investi-
stratified by clinical stage and histologic grade and not by gated in RTOG study 92-02. Treatment response at
PSA or biopsy findings. Second, local control was deter- 4.8-year follow-up reflects the findings of RTOG 85-31,

100 79%
90 (72−86%)
Percentage of patients

80
70 Combined
60 treatment
50 62%
40 (52–72%)
Radiation
30
therapy
20 p = 0.001 (overall log-rank test)
10
0
0 1 2 3 4 5 6 7 8 9 10
Years
No.
No. patients at risk who died
Radiotherapy 208 183 139 96 67 39 23 10 6 1 58
Combined 207 190 144 111 82 55 39 19 7 0 35
treatment
A
85%
100
(78–92%)
90
Combined
Percentage of patients

80
treatment
70
60
50
48% Radiotherapy
40
30 (38–58%)
20 p < 0.001 (overall log-rank test)
10
0
0 1 2 3 4 5 6 7 8 9 10
Years
No. with
disease
No. patients at risk progression
Radiotherapy 208 163 107 59 38 19 11 5 3 1 78
Combined 207 189 138 108 78 51 36 16 5 0 20
treatment
B
Figure 27-1 A, Kaplan-Meier estimate of OS. B, Disease-free survivals in EORTC study.
The number of patients at risk for the event at each time point is the total number of
patients less the number of patients in whom disease progressed or who were lost to
follow-up.40
498 Part V Prostate Gland and Seminal Vesicles
with significantly decreased rates of local progression,
distant metastases, and biochemical failure in patients
receiving long-term androgen suppressive therapy com-
pared with short-term suppression. No OS benefit was
detected (79% long-term suppression versus 77% short-
term suppression, p > 0.05). Subset analysis did demon-
strate both disease-specific survival (90% versus 78%, p =
0.007) and OS (80% versus 69%, p = 0.02) advantage
with the longer duration hormonal therapy in patients
with Gleason scores 8 to 10.42 The results of this study
support the continued use and study of long-term andro-
gen deprivation in patients with poorly differentiated or
locally advanced prostate cancer.
Further support of long-duration hormonal therapy in
patients at high risk for subclinical metastatic prostate can-
cer comes from a Swedish prospective randomized trial that
investigated the effect of orchiectomy in patients receiving
EBRT (versus EBRT-only) for pelvis-confined T1-4, N0-3,
M0 disease.43 This trial, originally designed to accrue 400
patients, was terminated early after enrolling only 91
patients because of a high frequency of disease progression
in the patients receiving EBRT alone. Among patients with
nodal positive disease, a significant reduction in disease pro-
gression (61% versus 31%) and overall mortality (61% ver-
sus 38%) was observed after a median follow-up time of 9.3
years. While OS was improved in node negative patients
treated with EBRT alone than in those with lymph node
metastases, no difference was seen in either group treated
with EBRT and orchiectomy, suggesting a benefit of early
hormonal therapy in locally advanced prostate cancer.
The issue of early versus delayed hormonal therapy in
patients with T2-4 or asymptomatic M+ prostate adeno-
carcinoma was addressed by the Medical Research Council
(MRC) Prostate Cancer Working Party Investigation
Group.44 In this trial, 934 patients with expected survival
of ≥12 months were randomized at the physicians’ discre-
tion to receive hormonal therapy (orchiectomy or LHRH
agonist with flare protection) either early (within 6 weeks
of presentation) or deferred until disease progression.
There was a statistically significant reduction in disease-
specific mortality in both patients with no known metas-
tases, as well as with any M status (0, X or +) receiving
immediate hormonal therapy (54% versus 70% and 62%
versus 71%, respectively) at 10 years follow-up. There was
also an increased risk of major complications including
cord compression, extra-skeletal metastases, or ureteral
obstruction in the delayed hormone group. The OS of
patients in both treatment groups was lower than that
observed in other studies (26% at 10 years).
Timing and Duration of Hormonal Therapy
with Radiation
Although the studies outlined earlier demonstrate
improved local and distant control with both neoadjuvant
and adjuvant hormonal therapy in conjunction with
EBRT, OS time was increased only in patients or subsets
of patients receiving androgen deprivation early and for
prolonged duration. One phase III trial conducted by the
RTOG (94-13) was designed to compare NHT (andro-
gen deprivation using goserelin or leuprolide with flu-
tamide 2 months before and during EBRT, arms 1 and 2)
directly with adjuvant therapy (androgen deprivation
4 months after EBRT, arms 3 and 4) to patients with
high-risk localized prostate cancer irradiated either 70.2
Gy to the prostate only (arms 2 and 4) or 50.4 Gy to the
whole pelvis with a 19.8 Gy prostate boost (arms 1 and
3). Roach et al.45 reported initial results in 1323 patients
after median follow-up of 59.3 months. Significant pro-
gression-free survival (PFS) at 4 years was observed in
patients receiving NHT and whole pelvis irradiation ver-
sus NHT and prostate-only irradiation (59.6% versus
44.3%, p = 0.001). Four-year PFS in patients receiving
adjuvant hormonal therapy with either whole pelvis or
prostate-only RT was comparable to that of patients
given NHT and prostate-only RT. While OS was similar
in all 4 treatment arms (88%, 83%, 81%, and 82%,
respectively), there is a trend for improved OS in the
NHT/whole pelvis RT group. Longer duration follow-
up is needed, however, since the median survival in these
patients is not likely to be reached for several years.
There are several other phase III trials currently
ongoing designed to address the issue of timing and
duration of androgen deprivation in patients with locore-
gionally advanced prostate cancer. These are discussed in
the section “Future Directions.”
ANDROGEN DEPRIVATION
AND PROSTATECTOMY
RP is typically reserved for patients with clinically organ-
confined disease (T1-2, N0, M0); pelvic lymph node dis-
section being recommended for those with Gleason score
5 to 6 and PSA ≥ 20 ng/ml, Gleason score ≥ 7 and PSA ≥
15 ng/ml, or clinical T3N0M0.9 Clinical assessment of
extent of disease in prostate adenocarcinoma has been
found to underestimate the actual degree of disease
spread in approximately 50% of cases.46–49 Additional
therapy for patients with known or suspected extra-
glandular disease includes preoperative hormonal ther-
apy or postoperative hormonal therapy with or without
radiation treatment.
Prostatectomy and Neoadjuvant
Hormonal Therapy
Preoperative androgen deprivation has been investigated
in several prospective randomized trials to test the
hypothesis that tumors initially considered nonoperable
(clinical T3, Nx, or greater) could be rendered resectable
 Chapter 27 Regionally Advanced Adenocarcinoma of the Prostate (T3-TN + M0) 499
after 3 months of hormonal treatment.50–52 The rate of
positive surgical margins in these studies was significantly
reduced by 40% to 60% in patients receiving the hor-
monal therapy compared with those treated by surgery
alone. This effect on margin status, however, has not
translated into any therapeutic improvement, there being
no difference in biochemical or clinical recurrence rates
in both treatment groups. This lack of therapeutic bene-
fit has been attributed, in part, to insufficient follow-up,
underpowered study design, or inadequate duration of
hormone therapy.
To address the issue of optimal length of androgen
deprivation required before RP, the Canadian Urologic
Oncology Group designed a phase III trial comparing
3-month versus 8-month preoperative treatment with
leuprolide and flutamide in patients with T1b-T2 adeno-
carcinoma of the prostate. Gleave et al.53 recently pre-
sented the 3-year follow-up results of this study.
Prolonged androgen deprivation in these patients was
associated with significant reduction in preoperative PSA
levels (75.1% versus 43.3% with PSA < 0.1 ng/ml,
p < 0.0001), positive surgical margins (12% versus 23%,
p = 0.0106), and incidence of lymph node metastasis
(0.4% versus 3.1%, p = 0.038). The longer duration of
hormone therapy was also associated with significantly
more patients clinically downsized based on DRE or
TRUS evaluation. Prolonged androgen deprivation was
associated with more toxicity, 87% of patients treated for
8 months reporting hot flashes versus 72% of those
treated for 3 months (p < 0.0001). Longer follow-up is
required to assess the effect of duration of preoperative
hormonal therapy on clinical and biochemical outcomes
in these patients.
Prostatectomy and Adjuvant Hormonal Therapy
The role of adjuvant hormonal therapy in patients found
to have positive nodal metastasis after RP with pelvic
lymphadenectomy for T1-2 prostate cancer was prospec-
tively investigated by Messing et al.54 In this study,
patients were randomized to immediate hormonal ther-
apy (goserelin or orchiectomy) versus observation until
disease progression. After a median follow-up of >7
years, the early use of androgen deprivation was associ-
ated with significant improvement in PFS (77% versus
18%, p < 0.001), cause-specific survival (92% versus 69%,
p < 0.01), as well as OS (85% versus 65%, p = 0.02), com-
pared with patients receiving delayed hormonal therapy.
The incidence of side effects, most commonly hot
flashes, gastrointestinal disturbances, and gynecomastia,
were reported in up to 20% to 60% of patients receiving
the adjuvant therapy. One criticism of this trial is that
hormonal therapy alone (without RP) could have pro-
duced similar results but no study would be conducted
today to test such a hypothesis.
Secondary analysis of RTOG 85-31 examined the
effect of immediate versus delayed goserelin therapy in
postprostatectomy patients found to have extra-capsular
extension to the resection margin and/or seminal vesi-
cle invasion before initiation of EBRT.55 In contrast
with Messing’s results, no difference was detected in
rates of local progression, distant relapse, or OS in the
two groups, with only prolonged freedom from bio-
chemical relapse being noted in patients receiving
immediate hormonal therapy at 5-year follow-up.
Duration of androgen deprivation, as well as the addi-
tion of EBRT, may account for the survival difference
noted in these two trials.
TOXICITY
Each of the various treatment modalities for regionally
advanced adenocarcinoma of the prostate has associated
adverse side effects, which need to be taken into account
when managing patients with this disease. Both acute and
late complications associated with the use of EBRT for
locoregionally advanced prostate cancer have been
described; the former includes increased urinary fre-
quency, dysuria, diarrhea, and rectal urgency; and the
latter includes urethral stricture, hematuria, urinary
and fecal incontinence, rectal bleeding, and impo-
tence.56–59 While the incidence of bowel and bladder
complications following EBRT has been reported at or
below 10%, impotence is at least twice this rate by 2
years following treatment, with additional men reporting
loss of potency at longer follow-up intervals. The occur-
rence of adverse side effects from radiation for prostate
adenocarcinoma is not unexpectedly correlated to
total dose of radiation delivered.60,61 New technologic
advances in the delivery of radiation to the prostate, such
as intensity-modulated radiation therapy, are designed to
reduce toxicity to adjacent normal structures. The
reports on the effectiveness of this type of targeted ther-
apy on tumor control and side effect profile are eagerly
anticipated.
The side effects associated with the various hormonal
therapies for prostate adenocarcinoma have previously
been delineated in the section “Androgen Deprivation
Therapy” and are summarized in Table 27-1. The effect
of combination androgen deprivation with EBRT on
adverse treatment sequelae has recently become the focus
of several reports.
Schultheiss et al.60 observed an increased risk of late
gastrointestinal and genitourinary toxicity in patients
treated with NHT as opposed to those receiving EBRT
alone. A study from the Italian National Institute for
Cancer Research also identified adjuvant androgen dep-
rivation as a significant independent predictor of late rec-
tal toxicity at 2 years in patients treated with
three-dimensional conformal radiation therapy.62 This
500 Part V Prostate Gland and Seminal Vesicles

Table 27-1 Mechanism of Action and Major Side Effects of Hormonal Agents
Agent LHRH LH FSH Testosterone Side Effect(s)

Estrogens — ↓ — — Gynecomastia, thrombosis

LHRH agonist (short-term use) ↑ ↑ ↑ ↑ Flare reaction

LHRH agonist (long-term use) ↑ ↓ — ↓ Hot flashes, loss of libido, osteoporosis,

muscle wasting

LHRH agonist+Antiandrogen ↑ ↑ ↑ Inhibited Hot flashes, no flare, GI side effects,

gynecomastia

Antiandrogen (steroidal) ↑ ↓ — Inhibited Hot flashes, GI side effects, gynecomastia

Antiandrogen (nonsteroidal) — — — Inhibited Gynecomastia

GnRH antagonist Inhibited ↓ ↓ ↓ Histamine release

effect appears to be related to duration of hormonal ther-
apy, with treatment in excess of 9 months being associ-
ated with decreased rectal tolerance to radiation.63
The effect of combined modality therapy on sexual
potency was examined in patients enrolled in RTOG 86-
10. Preservation of sexual potency was similar for both
patients receiving EBRT or EBRT with hormonal ther-
apy, with 81% return of sexual potency for the latter
compared to 74% for the men receiving EBRT-only.35
This finding was confirmed by the use of validated self-
administered questionnaires given at baseline and serially
after treatment, with change in sexual function scores and
overall quality of sex life being similar for both groups.64
However, additional studies suggest that the use of long
duration androgen deprivation for periods >6 months
may increase the likelihood of decreased libido secondary
to failure of testosterone level normalization following
combined radiation and hormonal therapy.65
As patients with advanced adenocarcinoma of the
prostate can be expected to demonstrate continued
improvement in OS, with 5-year survival rates currently
being reported at ~70% (Table 27-2), the topic of treat-
ment-related toxicity and effect on quality of life will
become ever more important areas of investigation and
targets for improved treatment design. Based on the evi-
dence, concerns of adverse side effects should not neces-
sarily deter clinicians from recommending to men with
locoregionally advanced prostate cancer combined short
duration (4 to 6 months) NHT and EBRT.
OUTCOMES AND PROGNOSIS
Adenocarcinoma of the prostate is characteristically a
slow growing malignancy with high 10-year survival rates
being reported for early stage disease.66 Analysis of the
survival data of patients with prostate cancer enrolled in
the prospective, randomized clinical trials described in
the earlier sections suggests that even with locoregionally
advanced disease, men can expect to live on average 8
years regardless of treatment modality employed (see
Table 27-2). It is estimated that this number will likely
increase with the widespread institution of PSA screen-
ing both with earlier initial diagnosis and identification of
relapse/disease progression.
Roach et al.67 examined >1500 men treated with radia-
tion therapy alone on RTOG phase III trials 75-06, 77-06,
85-31, and 86-10; and they identified factors associated with
poorer overall and disease-specific survival. These adverse
prognostic factors include high Gleason score, advanced
clinical stage, and positive nodal status, and of these,
Gleason score was found to be the single most important
predictor of death in these patients. In a more recent analy-
sis by this group (specifically addressing the impact of race
on survival), patients treated with EBRT, both with and
without hormonal therapy, were included, and Gleason
score, clinical T stage, and lymph node status again demon-
strated prognostic value with respect to overall and disease-
specific survivals.69 In addition, low pretreatment PSA levels
and addition of hormonal therapy were found to be associ-
ated with improved outcomes in these patients.
Currently, the use of PSA testing is commonly
employed in the follow-up of patients diagnosed with
adenocarcinoma of the prostate. Biologic control and
relapse based on PSA values have been reported in recent
studies.38,39,41,42 To date, however, no clear correlation
between biologic failure and decreased survival has been
established (perhaps due to the long natural history of
this disease), and the significance of this biomarker rela-
tive to patient outcome needs to be further elucidated.
FUTURE DIRECTIONS
The randomized trials investigating therapeutic options
for patients with locoregionally advanced adenocarcinoma
 Chapter 27 Regionally Advanced Adenocarcinoma of the Prostate (T3-TN + M0) 501

Table 27-2 Survival Data from Trials of Hormonal Therapy for Prostate Cancer
5-year 8-year Median Survival
Study References Arm OS (%) OS (%) p Value (year)

RTOG 86-10 35 RT 68 44 NS <8

NHT+RT 72 53 ~8

RTOG 85-31 38–39 RT+early HT 75 49 NS 8

RT+late HT 71 47 8

EORTC 40–41 RT 62 NA 0.0002 NA

RT+HT 78 NA NA

RTOG 92-02 42 NHT+RT 78 NA NS NA

NHT+RT+HT 79 NA NA

Swedish 43 RT ~70 NA NS ~8

RT+orchiect ~80 NA not met

MRC 44 Early HT n.a. 38* NS

Delayed HT n.a. 29* not reported

RTOG 94-13 46 NHT+WPRT 88 NA NS NA

NHT+PRT 83 NA NA

WPRT+HT 81 NA NA

PRT+HT 82 NA NA

Messing 55 RP? HT 85 85† 0.02 NA

RP? observe 70 65† NA

NA, not available; NS, not significant ( p > 0.05); NHT, neoadjuvant hormonal therapy; WPRT, whole pelvis RT; PRT, prostate-only RT.
*10-year OS.
†7-year OS.

of the prostate conducted over the past two decades have
not significantly changed the practice of urologists or
radiation oncologists. The reason for this is due in large
part to flawed protocol design (e.g., non-PSA based strat-
ification schemas) and evaluation of treatment modalities
(such as perineal prostatectomy or DES use) already out-
dated by the time the trials were reported. The effects of
the various treatments on local symptom control and on
quality of life were also frequently overlooked. The goal
of future clinical trials examining the efficacy and pat-
terns of failure in regionally advanced prostate cancer is
to ensure better study design by taking into account
patient selection, tumor characteristics, prognostic fac-
tors and staging methods and by including quality of life
and cost-benefit issues in addition to survival, locore-
gional control, and distant, clinical or biochemical failure
as study endpoints.
There are several prospective randomized studies cur-
rently underway designed to address the timing and
duration of hormonal therapy (either alone or in con-
junction with other treatment modalities), as well as the
benefit of hormonal therapy in low-risk patients versus
intermediate-risk patients with prostate cancer. These
are briefly discussed in the next paragraph.
The National Cancer Institute of Canada has a phase
III trial investigating hormonal therapy (pharmaceutical
or surgical) with or without EBRT for patients with stage
III/stage IV disease. A phase III study being conducted
by the EORTC (22961) was designed to address the
question of duration of androgen blockade (observation
versus continued 2.5-year treatment) following initial 6
months of hormonal therapy with EBRT for patients with
T1c-2b, N1-2 or T2c-4, N0-2 prostate cancer. The length
of total androgen suppression is also being investigated
502 Part V Prostate Gland and Seminal Vesicles
by the RTOG in a phase III study (99-10), which is ran-
domizing intermediate risk patients to 8 versus 28 weeks
of hormonal therapy prior to concurrent androgen dep-
rivation and EBRT. The RTOG is additionally looking at
the role of radiation therapy with or without androgen
deprivation both in low-risk (T1b-2b, Nx-0, PSA < 20
ng/ml) patients (RTOG 94-08) and in postoperative
(pT3N0M0 or pT2N0M0 with positive margins)
patients (RTOG 96-01 and RTOG 00-11). The results
of these and other prospective randomized trials are
expected to provide important information regarding the
future care and management of patients with regionally
advanced adenocarcinoma of the prostate.
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4 years. Urology 1998; 51:389–396.
31. Pilepich MV, Krall JM, Sause W T, et al: Prognostic
factors in carcinoma of the prostate-analysis of
RTOG study 75-06. Int J Radiat Oncol Biol Phys 1987;
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32. Pilepich MV, Krall JM, John MJ, et al: Hormonal
cytoreduction in locally advanced carcinoma of the
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33. Pilepich MV, John MJ, Krall JM, et al: Phase II
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radiotherapy. Am J Clin Oncol 1990; 13:461.
34. Pilepich MV, Buzydlowski JW, John MJ, et al: Phase II trial
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Radiation Therapy Oncology Group (RTOG) trial 86-10
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36. Laverdiere J, Gomez JL, Cusan L, et al: Beneficial effect
of combination therapy administered prior and following
external beam radiation therapy in localized prostate
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37. Zagars GK, Johnson DE, von Eschenbach AC, et al:
Adjuvant estrogen following radiation therapy for stage C
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38. Pilepich MV, Caplan R, Byhardt RW, et al: Phase III trial
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39. Lawton CA, Winter K, Murray K, et al: Updated results
of the phase III radiation therapy oncology group
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therapy for unfavorable prognosis carcinoma of the
prostate. Int J Radiat Oncol Biol Phys 2001; 49:937–946.
40. Bolla M, Gonzalez D, Warde P, et al: Improved survival in
patients with locally advanced prostate cancer treated with
radiotherapy and goserelin. N Engl J Med 1997;
337:295–300.
41. Bolla M, Collette L, Blank L, et al: Long-term results
with immediate androgen suppression and external
irradiation in patients with locally advanced prostate
cancer (an EORTC study): a phase III randomized trial.
Lancet 2002; 360:103–106.
42. Hanks G, Lu J, Machtay M, et al: RTOG protocol 92-02:
a phase III trial of the use of long term androgen
suppression following neoadjuvant hormonal
cytoreduction and radiotherapy in locally advanced
carcinoma of prostate. ASCO Abstr 1284, 2000.
43. Granfors T, Modig H, Jan-Erik D, et al: Combined
orchiectomy and external radiotherapy versus
radiotherapy alone for nonmetastatic prostate cancer with
or without pelvic lymph node involvement: a prospective
randomized study. J Urol 1998; 159: 2030–2034.
44. Medical Research Council Prostate Cancer Working
Party Investigators Group: Immediate versus deferred
treatment for advanced prostate cancer: initial results of
the Medical Research Council Trial. Br J Urol 1997;
79:235–246.
45. Roach M III, DeSilvio M, Lawton C, et al: Neoadjuvant
hormonal therapy (NHT) with whole-pelvis (WP)
radiotherapy (RT) improves progression-free survival
(PFS): RTOG (Radiation Therapy Oncology Group)
9413, a phase III randomized trial. ASCO Abstr 711,
2002.
46. D’Amico AV, Whittington R, Malkowicz SB, et al:
A multivariate analysis of clinical and pathological factors
that predict for prostate specific antigen failure after
radical prostatectomy for prostate cancer. J Urol 1995;
154:131.
47. Gerber GS, Thisted RA, Scardino PT, et al: Results of
radical prostatectomy in men with clinically localized
prostate cancer. JAMA 1996; 276:44.
48. Kattan MW, Stapleton AM, Wheeler TM, et al:
Evaluation of a nomogram used to predict the pathologic
stage of clinically localized prostate carcinoma. Cancer
1997; 79:528.
49. Partin AW, Kattan MW, Subong EN, et al: Combination
of prostate-specific antigen, clinical stage, and Gleason
score to predict pathological stage of localized prostate
cancer: a multi-institutional update. JAMA 1997;
277:1445–1451.
50. Soloway MS, Sharifi R, Wajsman Z, et al: Randomized
prospective study comparing radical prostatectomy alone
versus radical prostatectomy preceded by androgen
blockade in clinical stage B2 (T2bNxM0) prostate cancer.
J Urol 1995; 154:424.
51. Goldenberg SL, Klotz LH, Srigley J, et al: Randomized,
prospective, controlled study comparing radical
prostatectomy alone and neoadjuvant androgen
withdrawal in the treatment of localized prostate cancer.
J Urol 1996; 156:873.
52. Fair WR, Cookson MS, Stroumbakis N, et al: The
indications, rationale, and results of neoadjuvant androgen
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Sloan-Kettering Cancer Center results. Urology 1997;
49:46.
53. Gleave ME, Goldenberg SL, Chin JL, et al: Randomized
comparative study of 3 versus 8-month neoadjuvant
hormonal therapy before radical prostatectomy:
biochemical and pathological effects. J Urol 2001;
166:500–507.
54. Messing EM, Manola J, Sarosdy M, et al: Immediate
hormonal treatment compared with observation after
radical prostatectomy and pelvic lymphadenectomy in
men with node-positive prostate cancer. New Engl J Med
1999; 341:1781–1788.
55. Corn BW, Winter K, Pilepich MV: Does androgen
suppression enhance the efficacy of postoperative
irradiation: a secondary analysis of RTOG 85-31. Urology
1999; 54:495–502.
56. Dearnaley DP, Khoo VS, Norman AR, et al: Comparison
of radiation side-effects of conformal and conventional
radiotherapy in prostate cancer: a randomized trial.
Lancet 1999; 353:267–272.
57. Schultheiss TE, Hanks GE, Hunt MA, et al: Incidence
of and factors related to late complications in conformal
and conventional radiation and treatment of cancer of the
prostate. Int J Radiat Oncol Biol Phys 1995; 32:643–649.
58. Roach M III, Chinn DM, Holland GP, et al: A pilot
survey of sexual function and quality of life following 3D
conformal radiotherapy for clinically localized prostate
cancer. Int J Radiat Oncol Biol Phys 1996; 35:869–874.
59. Litwin M: Measuring health related quality of life in men
with prostate cancer. J Urol 1994; 152:1882–1887.
60. Schultheiss TE, Lee WR, Hunt MA, et al: Late GI and
GU complications in the treatment of prostate cancer. Int
J Radiat Oncol Biol Phys 1997; 37:3–11.
61. Hanks GE, Schultheiss TE, Hanlon AL, et al:
Optimization of conformal radiation treatment of prostate
cancer: report of a dose escalation study. Int J Radiat
Oncol Biol Phys 1997; 37:543–550.
62. Sanguineti G, Agostinelli S, Foppiano F, et al: Adjuvant
androgen deprivation impacts late rectal toxicity after
conformal radiotherapy of prostate carcinoma.
Br J Cancer 2002; 86:1843–1847.
63. Vavassori V, Cozzarini C, Bianchi C, et al: Androgen
deprivation and prostate gland shrinkage during
conformal radiotherapy. Int J Radiat Oncol Biol Phys
2002; 51:18–19.
64. Chen CT, Valicenti RK, Lu JD, et al: Does hormonal
therapy influence sexual function in men receiving 3D
conformal radiation therapy for prostate cancer? Int
J Radiat Oncol Biol Phys 2001; 50:591–595.
65. Padula GD, Zelefsky MJ, Venkatraman ES, et al:
Normalization of serum testosterone levels in patients
treated with neoadjuvant hormonal therapy and three-
dimensional radiotherapy for prostate cancer. Int J Radiat
Oncol Biol Phys 2002; 52:439–443.
66. Johansson JE, Adami HO, Andersen SO, et al: High
10-year survival rate in patients with early, untreated
prostatic cancer. JAMA 1992; 267:2191–2196.
67. Roach M III, Lu J, Pilepich MV, et al: Long-term survival
after radiotherapy alone: radiation therapy oncology
group prostate cancer trials. J Urol 1999; 161:864–868.
68. Roach M III, Lu J, Pilepich MV, et al: Race and survival
of men treated for prostate cancer on radiation therapy
oncology group phase III randomized trials. J Urol 2003;
169:245–250.
C H A P T E R
28Metastatic Adenocarcinoma
of the Prostate
Miah-Hiang Tay, MBBS, MRCP, and William K. Oh, MD
The clinical profile of newly diagnosed prostate cancer has
changed considerably over the past decade. A so-called
“stage shift” has occurred, coinciding with the widespread
use of serum prostate-specific antigen (PSA) testing for
prostate cancer screening. As a result, fewer patients are
diagnosed initially with metastatic disease. Between 1986
and 1992, 12% of patients presented with metastatic
prostate cancer, but by 1998, only 6% of patients with prostate
cancer had metastases at presentation.1 Important advances
in the treatment of metastatic prostate cancer have been
made since Huggins and Hodges2 first showed that pallia-
tion of metastatic disease could be achieved by androgen
deprivation therapy (ADT). Despite progress, however,
prostate cancer remains a significant problem in the United
States. With an estimated 28,900 deaths in 2003, it is the
second leading cause of cancer death among men.
HORMONE-SENSITIVE METASTATIC PROSTATE
CANCER
There has been little change in the primary concept that
guides the initial treatment of metastatic prostate cancer.
Indeed it was over 60 years ago that prostate cancer was
first shown to be androgen dependent. Since that time,
there has been an increase in the number of therapeutic
options, as well as controversies regarding the optimal
form and timing of ADT. In particular, issues, such as the
role of combination androgen blockade (CAB) versus
luteinizing hormone releasing hormone (LHRH) agonist
monotherapy, the duration of treatment and the proper
timing of therapy have been debated recently.
Androgen Deprivation Therapy: Standards of Care
The standard of care today for a man diagnosed with
metastatic prostatic cancer is the initiation of ADT. The
original method used to achieve ADT was bilateral sur-
gical orchiectomy.3,4 Castration by orchiectomy is per-
manent and is the treatment modality to which other
forms of ADT have been compared.5 ADT can be
achieved medically by treatments, such as estrogens and
LHRH agonists.
Seidenfeld et al.6 performed a systematic review of
various forms of ADT, analyzing 24 randomized trials
with over 6600 patients with metastatic disease. No sur-
vival difference was noted between surgical and medical
castration using LHRH agonists. Trials comparing the
estrogen, diethylstilbestrol (DES), with orchiectomy or
LHRH agonists also revealed no significant difference in
survival. However, DES had a higher risk of throm-
boembolism, which has limited its use as a primary
modality for ADT in the United States.
LHRH agonists have become the most commonly
used method of ADT in the United States. This prefer-
ence is partly explained by the negative psychologic
effects patients associate with surgical castration. In a
survey of 159 men with newly diagnosed prostate cancer
given a choice of either bilateral orchiectomy or LHRH
agonist therapy, only 22% chose orchiectomy.7 Despite
these findings, orchiectomy does offer several advan-
tages, including lack of the tumor flare response associ-
ated with initiation of LHRH agonists and a significantly
lower overall cost.8
Leuprolide acetate and goserelin acetate are com-
monly used LHRH agonists and are available in 1-, 3-,
and 4-month depot formulations. Both agents have com-
parable efficacy, with the primary difference being the
route of delivery. Leuprolide acetate is administered
intramuscularly, while goserelin acetate is deposited sub-
cutaneously as a pellet. Newer systems of delivery for
leuprolide are available, which employ a tiny osmotic
pump that allows for once yearly dosing. As these drugs
505
506 Part V Prostate Gland and Seminal Vesicles
are LHRH agonists, an initial LH surge is seen with
resultant increase in testosterone in the initial 1 to 2
weeks following administration. Though this effect
diminishes over a month, there is a risk that such a testos-
terone flare may cause an acute growth of cancer, leading
to such complications as spinal cord compression and
bladder outlet obstruction in some patients.9,10 Hence,
antiandrogen therapy is typically administered for at least
1 month and should be started several days to 2 weeks
prior to the initiation of LHRH agonist, if possible.11
LHRH pure antagonists, such as abarelix, are being
investigated as an alternative to LHRH agonists. Studies
comparing abarelix and LHRH agonists have suggested
that these agents are comparable in efficacy, though there
is no associated testosterone flare.12,13
Estrogenic drugs were used for many years as the pri-
mary means of medical castration in men with metastatic
prostate cancer. In the 1960s and 1970s, the VA
Cooperative Urological Research Group (VACURG)
performed a series of randomized trials designed to eval-
uate estrogenic therapies for prostate cancer.14 Their
conclusions were: (1) DES at 5 mg/day leads to excess
cardiovascular deaths, though there were fewer prostate
cancer-related deaths; (2) estrogen and orchiectomy were
equivalent and the two together were no better than
either alone; (3) DES at 1 mg/day was as effective as 5
mg/day without excess cardiovascular toxicity. Thus
doses of DES between 1 and 3 mg/day became the stan-
dard medical therapy for metastatic prostate cancer in the
United States. However, because of the toxicity of DES,
other forms of nonsurgical hormonal ablation have been
sought over the years. Natural estrogens, such as ethinyl
estradiol, and other synthetic estrogens, such as
polyestradiol phosphate (PEP), have been investigated;
and indeed these drugs have been extensively evaluated
and continue to be used outside of the United States.
Combined Androgen Blockade
Though the testicles produce up to 95% of circulating
androgens, the adrenal glands produce a small but poten-
tially significant amount. After medical or surgical cas-
tration, the adrenal glands become an important source
of androgen.5 Despite the dramatic response to ADT,
prostate cancer eventually becomes hormone refractory
with a median progression-free survival of 18 to 24
months and a median survival of 24 to 30 months. Based
on the concept that prostate cancer in a “castrate” envi-
ronment may be sustained by androgen from the adrenal
glands, many randomized trials have been performed to
determine whether combined androgen blockade (CAB)
using either medical or surgical castration together with
an antiandrogen is superior to castration alone. Many of
these trials were underpowered and used different meth-
ods of castration and/or antiandrogens, which may have
led to contradictory results. For example, an influential
Intergroup study (INT-0036) compared leuprolide
acetate with or without flutamide in 603 men with metasta-
tic prostate cancer.15 Both progression-free (16.5 months
versus 13.9 months) and overall survivals (35.6 months ver-
sus 28.3 months) were significantly longer in patients
treated with CAB than those treated with leuprolide
alone. In addition, a subgroup analysis found that the
greatest benefits were seen in patients with good per-
formance status and minimal disease. Two other studies,
EORTC 00853 and the Anandron International Study,
also showed that CAB favored an improved median sur-
vival compared to orchiectomy alone.16,17 On the other
hand, some clinical trials have failed to demonstrate a
benefit to CAB.18–22 The largest and most important of
these was also an Intergroup trial (INT-0105). One thou-
sand three hundred and seventy eight patients were ran-
domized to surgical orchiectomy plus flutamide versus
orchiectomy alone. Although a 10% survival benefit for
the combination arm was seen, it was not statistically sig-
nificant. This result was different from INT-0036, which
showed a 7-month absolute survival advantage in favor of
the CAB compared with leuprolide monotherapy. In
addition, INT-0105 failed to show a survival advantage
for patients with minimal disease. Two reasons could
explain these discrepant findings. The primary difference
between these trials was the use of surgical castration in
INT-0105, in which case tumor flares cannot occur. It is
possible that the primary value of antiandrogen therapy
is in suppression of a tumor flare in patients with
metastatic disease. Furthermore, INT-0105 allowed the
use of salvage antiandrogen therapy in patients who pro-
gressed on leuprolide acetate. Since this was not allowed
for patients on INT-0036, any added benefit to up-front
CAB may have been abrogated by the use of delayed
CAB in INT-0105.
Several meta-analyses have been performed to deter-
mine the overall impact of CAB. The largest meta-
analysis is from the Prostate Cancer Trialists’ Collaborative
Group, which analyzed 27 clinical trials with over 8000
men, the majority with metastatic disease.23 This analysis
indicated that the addition of antiandrogen to androgen
suppression therapy improved 5-year survival by approx-
imately 2% or 3% depending on whether the analysis
included or excluded cyproterone acetate, respectively.
Whether this additional small benefit should alter the
standard of care of single modality LHRH agonists or
orchiectomy as first line treatment for patients with
metastatic prostate cancer is controversial, especially
when the additional cost and side effects of antiandrogen
therapy are considered.
In summary, though it is a controversial area, no com-
pelling evidence exists for routine CAB use in patients
with hormone sensitive metastatic prostate cancer. Both
LHRH agonists and surgical orchiectomy have equivalent
 Chapter 28 Metastatic Adenocarcinoma of the Prostate 507
clinical efficacy and can be considered as primary means
of ADT, though an antiandrogen should be used for at
least 1 month to block a tumor flare response associated
with LHRH agonists. Nonsteroidal antiandrogens can be
subsequently added upon disease progression after pri-
mary ADT. Estrogen therapy is also a choice for primary
ADT, but toxicity has generally made estrogen use rare in
the United States, though it is more popular in Europe.
Timing of Hormonal Therapy
In the VACURG trials, overall survival in patients with
asymptomatic metastatic disease was not significantly
improved by early use of DES compared to placebo.14
However, conclusions from this study may not justify
delaying the use of hormonal therapy in a patient with
metastatic prostate cancer in the modern era. Since the
1970s, newer and safer androgen ablation therapies have
been developed that abrogate the significant cardiovascu-
lar risks of DES. Furthermore, there are now three stud-
ies that support the earlier use of ADT for metastatic
prostate cancer, though some of these data remain indi-
rect. In an EORTC study, Bolla et al.24 studied the role
of long term adjuvant hormonal therapy following defin-
itive radiotherapy for high-risk patients, including those
with lymph node disease. In this randomized placebo-
controlled study of 415 patients, actuarial 5-year survival
for the radiotherapy plus goserelin arm was significantly
higher than the radiotherapy-alone arm (79% versus
62%, respectively; p = 0.001). In another trial by Medical
Research Council (MRC) in the United Kingdom, the
authors reported that immediate hormonal therapy with
orchiectomy or an LHRH agonist for men with locally
advanced or asymptomatic metastatic prostate cancer sig-
nificantly reduced the need for transurethral resection
for local progression, rates of pathologic fracture, spinal
cord compression, ureteral obstruction, and incidence of
bone metastasis as compared to men randomized to
deferred therapy.25 In addition, deaths attributable to
prostate cancer occurred more frequently in men whose
treatment was deferred (257 versus 203; p = 0.001).
Unfortunately, this study was criticized for the potential
bias created by different follow-up schedules between the
two arms, resulting in a number of patients not receiving
hormonal therapy in the deferred arm (54% of whom
died from prostate cancer). A third study that supports
earlier ADT use is a study by Messing et al.,26 in which
98 men with pelvic lymph node involvement were ran-
domized to early ADT or observation following radical
prostatectomy. At 7 years of follow-up, 7 of 47 (15%)
men in the immediate therapy arm had died, compared
to 18 of 51 (35%) men in the delayed arm (p = 0.02).
In summary, there is growing evidence that earlier
ADT may confer a survival benefit compared with signif-
icantly delayed therapy, although the optimal timing of
ADT is poorly defined. This is especially true in the PSA
era, when evidence of recurrence by PSA generally pre-
dates metastatic disease by many years.27 Contemporary
guidelines for when to initiate hormonal therapy incor-
porate factors such as PSA doubling time, patient con-
cerns over libido, and quality of life, and disease
characteristics, such as Gleason score. Little justification
can be made for withholding ADT in the presence of
metastatic disease, whether symptomatic or not. Further
study is needed to determine the optimal timing of ADT.
ALTERNATIVE APPROACHES TO HORMONAL
THERAPY
ADTs, such as LHRH agonists and orchiectomy, are
associated with a growing list of previously underappre-
ciated toxicities. ADT induces castrate levels of testos-
terone, causing side effects, such as hot flashes, loss of
libido, and osteoporosis. As a result, patients are seeking
alternative hormonal treatments, including intermittent
therapy and antiandrogen monotherapy. Antiandrogens
may have less toxicity than ADT, for instance, with libido
and physical capacity. However, randomized trials sug-
gest that antiandrogen monotherapy is inferior to stan-
dard ADT in controlling metastatic disease, though the
difference is not marked.
Intermittent Androgen Deprivation
Prostate cancer progresses from a hormone sensitive to
hormone refractory state by several possible mechanisms.
First, there is preferential expansion of androgen-
independent clones that are present within the tumor at
the time ADT is started. Second, there is an upregulation
of growth factors as a result of adaptation of cancer cells
to the androgen-depleted environment, as well as activa-
tion of alternative pathways in androgen receptor signal-
ing. Finally alternate paracrine and autocrine pathways
appear to develop that sustain tumor growth.28 By inter-
mittently depriving prostate cancer cells of androgen
stimulation, the aim is to delay the time to androgen
independence and preserve the sensitivity of the cancer
cells to further ADT in the future. Another potential
advantage of intermittent androgen deprivation is an
improvement in quality of life with improvements in
libido, erectile function, energy level, and bone density
during the period when ADT is suspended.
Intermittent androgen deprivation is usually achieved
with LHRH agonists until the serum PSA falls to unde-
tectable levels (or at least a nadir <4 ng/ml), at which time
therapy is held. During the first cycle of treatment, ADT
typically continues for at least 6 to 9 months after the
nadir has been achieved. Androgen deprivation is
resumed once the PSA climbs to an arbitrary fixed level,
for instance, 50% of the initial pretreatment value, an
508 Part V Prostate Gland and Seminal Vesicles
absolute PSA level >5 to 10 ng/ml or (rarely) clinical evi-
dence of disease. Current data for intermittent ADT indi-
cate that about half of patients have resolution of the side
effects from treatment during the rest period.29–32 More
importantly, the disease tends to remain responsive to
subsequent androgen suppression therapy, although the
treatment-free intervals shorten with each subsequent
cycle. Nonetheless, there are several important unre-
solved questions, such as its potential impact on survival
in comparison with continuous ADT. Randomized trials
comparing these two forms of treatment are currently in
progress. Until the results of these trials are known, inter-
mittent androgen deprivation remains investigational.
Peripheral Androgen Blockade
Antiandrogen monotherapy has been extensively evaluated
in phases II and III trials as initial hormonal therapy for
advanced prostate cancer.6,13,33 Flutamide is active when
used as a single agent but inferior to both DES and
orchiectomy in randomized trials. High-dose bicalutamide
has been compared to CAB in at least two large random-
ized studies in men with locally advanced or metastatic
prostate cancer. Though both studies suggested that high-
dose bicalutamide was equivalent to CAB for nonmetasta-
tic disease, one of these trials demonstrated a survival
benefit in metastatic disease for CAB. There was also evi-
dence that bicalutamide monotherapy was better toler-
ated, with improved libido and physical capacity. The use
of antiandrogens as single agents is accompanied by an
increase in gonadotropins due to competition in the hypo-
thalamus of the antiandrogen with circulating androgens.
Sustained gonadotropin increase results in enhanced
testosterone secretion, which may override the antiandro-
gen effect. The inability to demonstrate a role for antian-
drogens alone, their cost, and their toxicity spectrum have
prevented wide acceptance of antiandrogen monotherapy
as the initial therapy for advanced prostate cancer.
The 5-alpha-reductase inhibitor finasteride has mini-
mal activity as monotherapy for prostate cancer.
However, finasteride lowers dihydrotestosterone levels
and, when added to the antiandrogens flutamide or bica-
lutamide, demonstrates additional PSA suppression. This
combination may also spare libido and erectile function,
as testosterone is not depleted. Phase II studies of finas-
teride plus flutamide show significant activity in hor-
mone sensitive prostate cancer with 72% to 95%
achieving a complete PSA response.34–36 However, in the
absence of randomized data, combined flutamide and
finasteride therapy remains investigational.
SECONDARY HORMONAL THERAPY
Despite a response rate of over 80% to 90% with primary
ADT, nearly all men with metastatic disease progress
after an average of 18 to 24 months. The mechanism by
which prostate cancer becomes hormone refractory is
poorly understood. A small number of patients who
relapse may in fact have noncastrate levels of testosterone
and, in this situation, surgical orchiectomy should be
considered. The majority of patients who progress after
primary ADT in fact do have castrate testosterone levels.
Despite disease progression, many investigators advocate
continuing ADT. There is evidence of a persistent popu-
lation of hormone sensitive cells, which may regrow if
testosterone is allowed to return to normal levels. One
retrospective analysis showed that continuing ADT was
associated with a survival benefit of 2 to 6 months com-
pared with discontinuation in the hormone-refractory
setting.37
Secondary hormonal maneuvers may benefit some
patients after failing primary androgen ablation. In these
patients, responses may be elicited through the following
pathways: (1) enhanced blocking of residual serum
androgens to the androgen receptor; (2) reduction
in adrenal androgen production; (3) binding of agents
to other nuclear receptors in the prostate cancer cells
(Table 28-1).
About 20% to 30% of patients will experience a sig-
nificant PSA decline after antiandrogen withdrawal, last-
ing from 3 to 5 months, although individual responses
can last for over 2 years. Flutamide paradoxically can
activate specific mutant androgen receptors cloned from
prostate cancers, which may provide a mechanism to
explain the antiandrogen withdrawal syndrome.38 The
blockade of residual serum androgens may be achieved
using antiandrogens. In one of the first large series of 209
men, Labrie et al.39 reported an overall response of
34.5% with addition of flutamide after failing initial hor-
monal therapy with orchiectomy, DES, or an LHRH
agonist. The mean duration of response was 24 months.
After antiandrogen withdrawal, another antiandrogen
may be considered, as antiandrogens do not appear to
have complete cross-resistance in their mechanism of
action. The use of a second antiandrogen is predicated on
the possibility that despite their functional similarities,
antiandrogens interact differently with the androgen
receptor. There is evidence, for example, that in the
LNCaP cell line, flutamide acts as a partial agonist (and
not an inhibitor), whereas bicalutamide maintains an
inhibitory function.40 Bicalutamide at dose of 150 to 200
mg have been used in clinical trials in patients who pro-
gressed after primary hormonal manipulation. Expected
response rates from this second line treatment range
from 15% to 40%. Unfortunately, the response is typi-
cally short-lived, with progression-free survival of about
4 months.41,42
The adrenal gland is the main source of androgens
following effective castration. Suppressing adrenal
androgens has been demonstrated with ketoconazole and
 Chapter 28 Metastatic Adenocarcinoma of the Prostate 509
Table 28-1 Secondary Hormonal Therapy
Therapy Number
Antiandrogen withdrawal 153
Second antiandrogen
Bicalutamide 134
Nilutamide 14
Adrenal androgen inhibitors
Aminoglutethimide 583
Ketoconazole 204
Low-dose steroids 241
Estrogens
DES 405
PC-SPES 114
NR, not reported.
aminoglutethimide. Ketoconazole is effective in sup-
pressing testicular and adrenal androgen production. In
vitro experiments also suggest a possible direct cytotoxic
effect of ketoconazole on prostate cancer cells. Older
studies in androgen-independent prostate cancer using
high-dose ketoconazole plus replacement steroids
showed measurable responses in approximately 15%.
Three recent trials of high-dose ketoconazole demon-
strate much higher response rates using PSA endpoints.
Small et al.43 treated 48 patients with 400 mg tid in a
phase II trial and found PSA declines of 50% or greater
in 63%. In another trial of 45 patients treated with high-
dose ketoconazole, Millikan et al.44 showed a 40% PSA
response rate using a similar dose. In CALGB 9583, con-
current antiandrogen withdrawal and high-dose keto-
conazole demonstrated a 27% PSA response rate and a
13% measurable response rate.45 Increased gastric pH
decreases drug absorption, so ketoconazole should be
taken on an empty stomach and, if possible, in the
absence of H2 blockers or antacids. Though toxicity is
generally mild or moderate, including nausea, diarrhea,
fatigue, and skin changes, some patients require discon-
tinuation of the drug because of toxicity. A recent phase
II study suggests that similar response rates may be
obtained with half the traditional dose (i.e., 200 mg tid),
with fewer apparent side effects.46 In a review of 13 clin-
ical trials of aminoglutethimide plus hydrocortisone,
there was an overall partial response rate of 9%.
Aminoglutethimide toxicity includes fatigue, nausea, skin
rash, orthostatic hypotension, and ataxia.
>50% PSA Measurable
Decline (%) Response (%)
15–33 13
23–24 0
50 NR
NR 9
78–80 16
18–22 NR
21–86 NR
45–81 NR
Estrogens and their analogs also have some activity in
patients with hormone-refractory disease. Using 1 mg
DES in 21 men who failed with ADT, Smith et al.47
demonstrated a response rate of 43% based on more than
50% decrease in PSA level. Its utility in prostate cancer
has been unfortunately limited by the risk of throm-
boembolic complications but nevertheless is a potentially
useful drug in this setting. DES is no longer marketed in
the United States but is available through compounding
pharmacies. PC-SPES was supplement consisting of 8
different herbs and showed estrogenic activity. Its effi-
cacy in both androgen sensitive and androgen insensitive
prostate cancer was demonstrated in several trials.48–50
Despite of its potential, PC-SPES has been taken off the
market when it was recently found to contain synthetic
agents, such as warfarin and DES.
CHEMOTHERAPY
In the traditional view of chemotherapy in hormone-
refractory prostate cancer (HRPC), there is either no or
little impact in the history of the disease. Two reviews
from 1985 suggested that the response with chemother-
apy is poor.51,52 In the first review of 17 randomized clin-
ical trials by Eisenberger et al.,53 total response rate was
4.5%, while a second review of 26 trials performed in the
late 1980s showed an overall response rate of only 8.7%.
However, recent studies with new drugs and combina-
tions have shown that prostate cancer is in fact
chemosensitive. At the same time, new endpoints of
510 Part V Prostate Gland and Seminal Vesicles
treatment, such as PSA response and parameters of qual-
ity of life, as well as better supportive measures and
improvement in the management of comorbid condi-
tions, have allowed a resurgence of interest in the use of
chemotherapy to palliate advance disease.54
Two randomized trials reestablished the promise of
chemotherapy in HRPC, both analyzing mitoxantrone
and a corticosteroid.55,56 In the first study with 161 symp-
tomatic patients, Tannock et al.55 showed that mitox-
antrone plus prednisone significantly improved pain
control compared to prednisone alone (29% versus 12%;
p = 0.01). The duration of palliation in the chemotherapy
arm also was significantly longer (43 weeks versus 18
weeks; p < 0.0001). In a second study by Kantoff et al.56
242 patients with HRPC were randomized to receive
either mitoxantrone and hydrocortisone or hydrocorti-
sone alone. Although there was no significant difference
in survival, a trend towards longer time-to-progression
and time-to-treatment-failure in the combination arm
was evident (3.7 months versus 2.3 months; p = 0.25).
Furthermore, there was a higher percentage of patients
in the combination arm who achieved a >50% maxi-
mum reduction in PSA (38% versus 22%; p = 0.008), as
well as a trend for improved pain control. Despite a lack
of survival benefit, mitoxantrone was approved for pal-
liative use in HRPC patients and has become the stan-
dard of care to which future agents will be compared
(Table 28-2).
Taxanes combinations are among the most active reg-
imens tested to date in phase II trials. As single agents,
Table 28-2 Chemotherapy
Regimen Number
Paclitaxel 41
Paclitaxel/estramustine 62
Paclitaxel/estramustine/VP-16 40
Paclitaxel/estramustine/carboplatin 88
Docetaxel 113
Docetaxel/estramustine 131
Docetaxel/estramustine/carboplatin 38
Mitoxantrone/steroid 199
Vinorelbine 77
Vinorelbine/estramustine 25
Vinorelbine/estramustine/VP-16 25
NR, not reported.
paclitaxel and docetaxel have moderate activities.57,58
Estramustine, by itself, also has modest activity.59 The
activity of this drug is not due to the estrogen moiety as
first thought to be but rather due to its ability to disrupt
mitotic activity through the binding of the microtubule
assembly proteins.60 Although estramustine has been
studied in combination with other chemotherapeutic
agents, it is the synergism with other antimicrotubule
agents (paclitaxel and docetaxel) that have generated
enthusiasm. PSA response rates ranging from 50% to
65% and from 39% to 82% for estramustine plus pacli-
taxel or docetaxel, respectively, have been reported in
several clinical studies. In spite of the high activity of the
combination therapy, the optimal dose and schedule in
HRPC are yet to be defined. In fact, the added value of
estramustine in these combinations is counterbalanced by
significant toxicity. Several groups have tested the efficacy
of single agent docetaxel chemotherapy with reported
PSA response ranging from 41% to 47% and less toxic-
ity.58,61 The Southwest Oncology Group has completed a
phase III study with over 600 patients randomized either
to estramustine and docetaxel or mitoxantrone and pred-
nisone. Overall survival is the primary endpoint and
results are pending.
Many other chemotherapeutic drugs have also been
tested, including etoposide, vinblastine, and cyclophos-
phamide. In general, these have modest single agent
activity in HRPC. On the other hand, results of triple
drug combination have also been published. One such
regimen consists of weekly paclitaxel, estramustine, and
>50% PSA Measurable
Decline (%) Response (%)
33–60 22–33
53–61 38–44
45 65
67–100 17–45
41–47 28–33
63–82 17–57
71 47
38 NR
17–36 13–66
24–65 NR
56 32
 Chapter 28 Metastatic Adenocarcinoma of the Prostate 511
carboplatin. In 56 patients treated, 50% or greater PSA
declines were seen in 67% and median survival was 20
months.62 Unfortunately, the trial was complicated by
thromboembolic event in 25% of the patients. Current
estramustine-based clinical trials now also include low-
dose warfarin to decrease the risk of thromboembolism.
Following hormonal therapy failure, chemotherapy
may control disease progression, as well as to palliate
symptoms. Although mitoxantrone chemotherapy is the
first to be approved for treatment of hormone-refractory
disease, the most active therapies are probably taxane-
based. As chemotherapy continues to make inroads into
management of prostate cancer, patients should be
encouraged to participate in clinical trials.
BONE-DIRECTED THERAPIES
Skeletal complications are a major cause of morbidity for
men with advanced prostate cancer. Over 80% of men
with metastatic prostate cancer have radiologic evidence
of bone involvement. Palliative external beam radiother-
apy has been used for decades for relief of bone pain, but
recently, bisphosphonates and radiopharmaceutical
agents have been approved for use in HRPC.
There are three potential uses of bisphosphonates in
advanced prostate cancer: (1) to prevent osteopenia that
commonly accompanies the use of ADT; (2) to prevent
or delay skeletal complications in men with bone metas-
tasis; (3) to relieve pain from bony disease as well. In the
United States, zoledronic acid is a bisphosphonate
approved for use in HRPC. The landmark randomized,
placebo-controlled trial of zoledronic acid in patients
with HRPC with bone metastasis was reported by Saad et
al.63 In this trial, there were significantly more skeletal-
related events in men receiving placebo compared to
zoledronic acid (44.2% versus 33.2%; p = 0.021).
Skeletal-related events were defined as bone fractures,
spinal cord compression, surgery to bone, radiotherapy
to bone, or a change in antineoplastic agents. The time
to first skeletal event was also significantly longer in the
arm receiving zoledronic acid (363 days versus 321 days;
p = 0.021). In another study, using high-dose clodronate
as adjuvant therapy, the time to development of sympto-
matic bone metastasis in 311 men with prostate cancer
was 23.6 months in those receiving clodronate compared
with 19.3 months in placebo arm (p = 0.08).64 However,
significantly more dose reductions were required in
clodronate arm due to adverse events (93 versus 108,
hazard ratio, 0.75).
Strontium-89 (89St) chloride, samarium-153
(153Sm), and 32-phosphorus (32-P) are approved radio-
pharmaceutical agents for treatment of symptomatic
bone metastases. There have been no comparative stud-
ies between the different radioisotopes although the pain
response rates and the patterns of pain relief with differ-
ent radioisotopes appear similar. However, the main tox-
icity of these radiopharmaceutical agents is potentially
severe and prolonged myelosuppression, which may ren-
der a patient not suitable to participate in any potential
clinical trials with chemotherapy in future.
SUMMARY
There is no doubt that significant progress has been
made in treatment of metastatic prostate cancer. ADT
remains the mainstay of treatment; LHRH agonists,
orchiectomy, and estrogen therapy are all standard meth-
ods of achieving ADT. Alternative methods of hormonal
treatment include intermittent ADT and peripheral
androgen blockade. After progression on initial ADT,
secondary hormonal therapies and chemotherapy have
growing promise in both palliating patients and poten-
tially controlling disease, though randomized trials are
ongoing. Current research is focused on several areas
with promise of better therapeutics against prostate can-
cer in the future. Promising therapeutic approaches
include antisense oligonucleotides, vaccines, angiogene-
sis inhibitors, and signal transduction inhibitors.65–69
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C H A P T E R
29 Anatomic Nerve-Sparing Radical
Retropubic Prostatectomy
Misop Han, MD, and William J. Catalona, MD
The management of clinically localized prostate cancer
has undergone substantial changes over the past two
decades. Widespread screening with serum prostate-
specific antigen (PSA) testing and digital rectal examina-
tion has allowed much earlier detection of prostate cancer
during this era.1,2 In addition, the modification of surgical
technique by Walsh has allowed better hemostasis,
improved visualization during dissection, and preserva-
tion of neurovascular bundles supplying corpora caver-
nosa.3 As a result, a skilled surgeon can perform radical
prostatectomy with a high cure rate, while preserving uri-
nary continence and erectile potency in the majority of
patients. Thus, since 1990, radical prostatectomy has
been the most commonly performed treatment for clini-
cally localized prostate cancer.4 In a landmark study,
Holmberg et al.5 recently reported on the first prospec-
tive, randomized trial showing that radical prostatectomy
reduces the rates of metastases and death from prostate
cancer. Consequently, the rationale for treating clinically
localized prostate cancer surgically is convincing.
In this chapter, we discuss patient selection, surgical
technique, outcomes, and complications of anatomic rad-
ical retropubic prostatectomy using the senior author’s
surgical series of more than 3500 anatomic radical
prostatectomies as an example. The outcomes are similar
to those of other previously reported, large radical
prostatectomy series in the PSA era.6,7 It is not only rep-
resentative of large modern prostatectomy series but also
includes all men who underwent surgery in the analysis,
even those with known adverse prognostic features.
PATIENT SELECTION
An ideal candidate for radical prostatectomy should have
a life expectancy of at least 10 years, a completely
resectable and biologically significant tumor, and no
514
comorbidity that might make the operation unacceptably
risky. Actuarial life tables can project the life expectancy
of U.S. men,8 and with appropriate adjustment for
comorbidities, life expectancy can be estimated for the
individual patient.
After confirming the likelihood of a sufficiently long
life expectancy, the next step in patient selection is to
identify those with potentially curable disease. Radical
prostatectomy provides the best chance for cure for men
whose tumor is confined to the prostate gland. As a
result of widespread screening for prostate cancer and
more restrictive preoperative patient selection, the pro-
portion of men with organ-confined or specimen-
confined disease has increased in recent years.9
However, the lack of accuracy of conventional radi-
ographic imaging studies in staging prostate cancer has
been disappointing. Therefore, nomograms predicting
the pathologic stage based on preoperative clinical and
pathologic parameters have been widely used to identify
patients who are likely to benefit from the surgical resec-
tion and those who are not.10,11 Alternatively, nomo-
grams predicting postsurgical or postradiation therapy
recurrence-free survival probabilities also are sometimes
useful for patients.12–14 For patients with a low probabil-
ity of resectable disease or a short life expectancy due to
age or comorbidity, an alternative treatment to surgery
should be recommended.
For the patient to have realistic expectations concern-
ing postoperative potency and continence outcomes, the
surgeon should provide the patient with relevant infor-
mation on the nerve-sparing aspect of radical prostatec-
tomy during the preoperative consultation. Anatomic
nerve-sparing radical retropubic prostatectomy is a safe
choice without compromising cancer control in appropri-
ately selected patients. Nerve-sparing radical prostatec-
tomy is inappropriate in men with locally advanced
 Chapter 29 Anatomic Nerve-Sparing Radical Retropubic Prostatectomy 515
disease, especially if the primary goal of the surgery is
cancer control. The feasibility of the nerve-sparing sur-
gery is questionable when a patient has extensive involve-
ment by cancer of prostate biopsies, palpable evidence on
digital rectal examination of possible extraprostatic exten-
sion, a serum PSA level >10 ng/ml, a biopsy Gleason score
>7, poor quality erections preoperatively, a lack of interest
and/or willingness of a partner in restoring potency, or
the presence of other medical conditions that may
adversely affect potency, such as diabetes mellitus, hyper-
tension, psychologic or psychiatric diseases, neurologic
diseases, and medications. Therefore, it is important to
review the clinicopathologic features of the tumor and the
patient’s medical history and erectile function status
before embarking on a nerve-sparing operation.
After discussing the prospects for preservation of
potency, information on the treatment of erectile dys-
function should be imparted. This should include pro-
viding information on phosphodiesterase inhibitors,
intraurethral and intracorporal vasodilators, vacuum
erection devices, venous flow constrictors, and artificial
penile prostheses. The discussion should include the
anticipated postoperative erectile rehabilitation program
to be used and the timing of the return of erections that
usually begins 3 to 6 months postoperatively and lasts for
up to 36 months. If erectile function is of paramount
importance to the patient, he can be reassured that erec-
tions can be almost always restored, regardless of
whether or not nerve-sparing surgery can be successfully
performed.
Finally, the surgeon should discuss possible need for
and potential side effects of adjuvant radiation therapy or
hormonal therapy if the final pathology report reveals
adverse prognostic features. At the end of the preopera-
tive counseling session, if nerve-sparing radical retropu-
bic prostatectomy is appropriate, the patient and his
spouse or partner should sign an informed consent form
authorizing a surgeon to perform the procedure.
SURGICAL TECHNIQUE
Before the operation, a first-generation cephalosporin
antibiotic is given intravenously. After a general endotra-
cheal or regional anesthesia is administered, thigh-high
elastic hose are placed on the patient. Sequential com-
pression devices are used only in patients with increased
risk for thromboembolic complications. The patient is
positioned with his legs on spreader bars, and the operat-
ing table is dorsiflexed with the break just above the
patient’s anterosuperior iliac spine (Figure 29-1). The
abdomen and genitalia are appropriately prepped and
draped.
There are eight key steps in performing anatomic
nerve-sparing radical prostatectomy: (1) a limited pelvic
lymphadenectomy; (2) incision of the endopelvic fascia
and the puboprostatic ligaments; (3) ligation, proximal
and distal suture ligation, and transection of the dorsal
venous complex; (4) dissection of the prostate from the
neurovascular bundles; (5) vascular control and transec-
tion of the prostatic pedicles; (6) transection and recon-
struction of the bladder neck; (7) dissection of the
seminal vesicles and ampullary portions of the vasa def-
erentia; and (8) performance of the vesicourethral anas-
tomosis. These steps are described in detail here with
corresponding illustrations.
1. Limited Pelvic Lymphadenectomy
A superficial midline (or transverse) lower abdominal
incision is made with a scalpel. The linea alba is incised
and the space of Retzius is entered. Taking care to avoid
disrupting the lymphatic tissue lateral to the external iliac
vein and to avoid compression of the vein itself, a Balfour
retractor is placed. A modified pelvic lymphadenectomy
is performed, removing only the lymph nodes medial to
the external iliac vein. Care is taken during the lym-
phadenectomy to preserve any accessory arterial
branches to the corpora cavernosa that arise from the dis-
tal external iliac or obturator arteries. The obturator
nerve is identified and preserved. In most incidences, the
patient elects to have the prostate gland removed, even if
there are pelvic lymph node metastases; otherwise, the
excised lymph node packet is sent for frozen-section
examination. If the frozen section examination reveals
metastatic cancer, it is unlikely that the patient will be
cured by radical prostatectomy, and the operation is ter-
minated. Lymphadenectomy is optional in patients who
are at low risk for pelvic lymph node metastases by virtue
of a low Gleason grade, low PSA, and low biopsy tumor
volume.
After completing the lymphadenectomy, the adipose
and areolar tissues are swept gently from the anterior
surface of the prostate and the endopelvic fascia to expose
the puboprostatic ligaments. Care is taken to avoid injury
to the perforating branches of Santorini’s plexus that
pierce the endopelvic fascia between the puboprostatic
ligaments and pass cephalad on the anterior surface of
the prostate gland and bladder.
2. Incision of the Endopelvic Fascia and the
Puboprostatic Ligaments
The endopelvic fascia is incised in the groove between
the levator ani muscles and the lateral border of the
prostate (Figure 29-2). Inside the endopelvic fascia, the
lateral surface of the prostate is covered by a smooth,
glistening membrane overlying the lateral portion of
Santorini’s plexus. Strands of the levator ani muscles are
gently dissected off the prostate to the level of the uro-
genital diaphragm. Often, venous tributaries pass from
516 Part V Prostate Gland and Seminal Vesicles
Figure 29-1 Positioning of the patient. A,Legs are separated on spreader bars. B, The
operating table is flexed with the break just above the patient’s anterosuperior iliac spine.
the levator ani muscles to the prostate just lateral to the
puboprostatic ligaments. These vessels are either cauter-
ized, secured with hemostatic clips, or ligated laterally,
and then clamped medially with a delicate snub-nose
right-angle clamp. After the vein is transected sharply, its
medial portion is ligated. When the endopelvic fascia has
been opened from the base to the apex of the prostate, the
superficial branch of Santorini’s plexus is gently retracted
medially, and the puboprostatic ligaments are placed on
stretch and divided close to the pubic symphysis (Figure
29-3). Care is taken not to divide the puboprostatic liga-
ments too medially or too far under the pubic symphysis
to avoid injuring the dorsal venous complex.
3. Suture Ligation and Transection of the Dorsal
Venous Complex
After the puboprostatic ligaments have been divided, the
lateral surfaces of the urethra are palpated. The groove
between the anterior surface of the urethra and the dor-
sal venous complex is developed with a pinching motion
of the left index finger and thumb. The plane between
the urethra and the dorsal venous complex is then devel-
oped gently, first with a large right-angle clamp. This
facilitates tight ligation of the dorsal venous complex.
After the dorsal venous complex has been ligated, it is
also suture ligated in a slightly more caudal site with a 2-0
chromic catgut suture on a CT-1 needle (Figure 29-4). A
suture ligature is also placed in the anterior surface of the
prostate to reduce the back-bleeding from Santorini’s
plexus (Figure 29-5).
The right-angle clamp is then passed behind the dor-
sal venous complex and the jaws of the clamp are spread.
The dorsal venous complex is transected with electro-
cautery or a scalpel (Figure 29-6). Back-bleeding from
the dorsal venous complex is controlled with figure-of-
eight 3-0 sutures. It is important to obtain good hemo-
stasis so that the apical dissection of the prostate may be
 Chapter 29 Anatomic Nerve-Sparing Radical Retropubic Prostatectomy 517

Figure 29-2 The endopelvic fascia is incised in the groove between the levator ani muscles
and the lateral border of the prostate.

Figure 29-3 The puboprostatic ligaments are placed on stretch and incised.
518 Part V Prostate Gland and Seminal Vesicles

Figure 29-4 The dorsal venous complex is suture ligated with a 2-0 chromic catgut suture
on a CT-1 needle.

Figure 29-5 To reduce back-bleeding from Santorini’s plexus, the cephalad aspect of the
dorsal venous complex is suture ligated.
 Chapter 29 Anatomic Nerve-Sparing Radical Retropubic Prostatectomy 519
Figure 29-6 The dorsal venous complex is transected with a right-angle clamp jaws spread
behind the complex.
performed in a relatively bloodless field. If the dorsal
venous complex ligature slips off, the complex is over-
sewn using a 3-0 chromic catgut suture on a 5/8-circle
needle. The goal in oversewing the complex is to pass the
suture just through the lateral borders of the complex
itself in its anterior, middle, and posterior aspects,
respectively. Wide, imprecisely placed sutures may dam-
age the neurovascular bundles.
The anterior surface of the urethra is palpated
between the neurovascular bundles. The circumurethral
sphincter muscle and the anterior wall of the urethra are
incised with a scalpel just distal to the apex of the prostate
without dissecting around the lateral or posterior sur-
faces of the urethra (Figures 29-7 and 29-8). The incision
should not be carried too far lateral, where it may injure
the neurovascular bundles. The urethral catheter is
exposed and carefully hooked with a delicate right-angle
clamp. Gentle traction on the clamp in a cephalad direc-
tion exposes the posterior urethral wall. The catheter is
divided and placed on cephalad traction, the posterior
urethral wall is sharply transected. Fibromuscular bands
tethering the apex of the prostate to the pelvic floor are
incised using sharp dissection (Figure 29-9). The rec-
tourethralis muscle is incised, exposing the prerectal fat.
4. Separation of the Prostate from the
Neurovascular Bundles
The lateral pelvic fascia is incised from the apex of the
prostate to the base. A delicate right-angle clamp may be
used to elevate the lateral pelvic fascia from the underly-
ing veins on the surface of the prostate. Small perforating
vessels are secured with hemoclips, ties, or ligatures to
ensure adequate hemostasis. The posterolateral groove
between the prostate and the neurovascular bundles is
developed using sharp and blunt dissection, allowing the
prostate to assume a more anterior position in the pelvis.
The lateral aspect of the prostate is then dissected
from the neurovascular bundles, allowing the bundles to
retract laterally. In a case of extensive fibrosis, the dissec-
tion is performed sharply. The dissection is carried
cephalad until the portion of Denonvilliers’ fascia cover-
ing the ampullary portions of the vasa deferentia and the
seminal vesicles is exposed (Figure 29-10). Denonvilliers’
fascia is incised with the cautery. The Metzenbaum scis-
sors are then used to develop the proper plane of dissec-
tion for the prostatic vascular pedicles. If there is
continued bleeding from the periurethral tissues and api-
cal pedicles of the prostate, hemostatic sutures should be
placed at this juncture to avoid continued blood loss dur-
ing the remainder of the procedure.
5. Vascular Control and Transection of Prostatic
Pedicles
The prostatic pedicles are divided by inserting the right-
angle clamp medial to them, with the tip of the clamp
directed almost parallel to the lateral surface of the
prostate. The prostatic pedicle is ligated or hemoclipped
laterally, taking care to place the tie or clip medial to the
520 Part V Prostate Gland and Seminal Vesicles

Figure 29-7 The circumurethral external sphincter muscle fibers are incised to expose the
urethra.

Figure 29-8 The anterior wall of the urethra is incised with a scalpel without dissecting
around the lateral or posterior surfaces of the urethra.
 Chapter 29 Anatomic Nerve-Sparing Radical Retropubic Prostatectomy 521

Figure 29-9 The apical pedicles of the prostate may require suture ligation. Fibromuscular
bands tethering the apex of the prostate to the pelvic floor are incised using sharp
dissection. The prostate gland is dissected from neurovascular bundles.

Figure 29-10 The dissection is carried cephalad until the portion of Denonvilliers’ fascia
covering the ampullary portions of the vasa deferentia and the seminal vesicles is exposed.
Denonvilliers’ fascia is incised with the cautery. Denonvilliers’ fascia is incised to expose
vascular pedicles at prostate base.
522 Part V Prostate Gland and Seminal Vesicles
neurovascular bundle (Figure 29-11). The pedicle is
divided close to the prostate. This dissection is per-
formed on both sides to a point just cephalad to the sem-
inal vesicles. Care is taken when dissecting near the
seminal vesicles to avoid injuring the neurovascular bun-
dles that are situated just lateral to the seminal vesicles.
The seminal vesicles are freed from the bladder base
using sharp and blunt dissection, and a large right-angle
clamp is used to further develop this plane. Two hemo-
static sutures of 3-0 chromic catgut are placed in the lat-
eral bladder pedicles cephalad to the seminal vesicles, one
just lateral to the prostate and another just medial to the
neurovascular bundles. The lateral bladder neck fibers
are then partially incised with the cautery but are not
incised through their entire thickness.
6. Transection and Reconstruction of the Bladder
Neck
The anterior bladder neck is transected with electro-
cautery in the natural groove between the bladder and
the prostate. The bladder neck opening is enlarged with
scissors, and the catheter is pulled through and used as a
tractor on the prostate (Figure 29-12). The posterior
bladder neck is incised with the cautery. The muscular
attachments between the bladder and prostate are
divided using electrocautery and/or hemostatic clips for
hemostasis.
Figure 29-11 Prostate base pedicle is ligated or hemoclipped laterally, taking care to place
the tie medial to the neurovascular bundle.
7. Dissection of Seminal Vesicles and Ampullary
Portions of the Vasa Deferentia
The seminal vesicles are dissected first along their lateral
edges, carrying the plane of dissection medially. Many
small perforating arteries enter the lateral and terminal
portions of the seminal vesicles. These are secured with
small hemoclips. The ampullae are freed, using sharp and
blunt dissection, and then are clipped and transected.
After the seminal vesicles have been dissected to their tips
and the hemoclips placed, the surgical specimen is
removed. At this point, the pelvis is carefully inspected
for hemostasis. Small bleeders on the neurovascular bun-
dles may require 4-0 absorbable suture ligatures. It is
important not to use the cautery for hemostasis on the
neurovascular bundles, to avoid cautery injury to the cav-
ernosal nerves. Suture ligatures of 3-0 or 4-0 absorbable
material are placed in the “pockets” of the seminal vesi-
cle pedicles on the medial aspects of the neurovascular
bundles to ensure good hemostasis in this difficult-to-
visualize region.
8. Vesico-Urethral Anastomosis
Reconstruction of the bladder neck begins by placing a
continuous running everting suture of 3-0 chromic
catgut that encompass bladder mucosa and underlying
muscle for a distance of nearly the entire anastomotic
 Chapter 29 Anatomic Nerve-Sparing Radical Retropubic Prostatectomy 523
Figure 29-12 The anterior bladder neck is transected in the natural groove between the
bladder and the prostate. The bladder neck opening is enlarged with scissors. The ureteral
orifices are identified.
circumference (Figure 29-13). The bladder neck is then
reconstructed in a tennis racket fashion, with the handle
of the racket directed posteriorly. The bladder neck clo-
sure is accomplished in two layers with a continuous 3-0
chromic catgut suture on the first layer and a continuous
2-0 chromic catgut suture on the second layer. Care
should be taken to avoid compromising the ureteral ori-
fices. The bladder neck is closed to a size of approxi-
mately 22Fr to 24Fr.
An 18Fr catheter with a 30-ml balloon is passed
through the urethra. While an assistant exerts pressure
on the perineum with a sponge forceps to better expose
the cut end of the urethra (Figure 29-14), double-armed
2-0 chromic catgut sutures are used for the vesi-
courethral anastomosis (Figure 29-15). A 5/8-circle nee-
dle is used to place the sutures in the urethra from inside
to outside, avoiding placing the suture into the neurovas-
cular bundles. The tip of the catheter is grasped and
brought out of the wound to expose the posterior lip of
the cut end of the urethra. The posterior sutures are sim-
ilarly placed. The anterior sutures are placed at the 10
o’clock and 2 o’clock positions and the posterior sutures
are placed at the 5 o’clock and 7 o’clock positions. The
other ends of the sutures containing an SH 3/8-circle
needle are placed in the corresponding positions of the
bladder neck from inside to outside. These sutures
encompass mucosa and muscle and exit at the edge of the
mucosa. The catheter tip is placed in the bladder, and
the bladder neck is guided gently toward the cut end of
the urethra. The anastomotic sutures are tied carefully
under direct vision. The bladder is then irrigated free of
clots, a single suction drain is placed in the pelvis and
brought out the lower end of the wound. The incision is
closed with #1 loop Maxon running sutures on the fascia,
2-0 chromic catgut suture on the subcutaneous tissue,
and a 4-0 polyglycolic acid subcuticular suture on the
skin. The skin incision is covered with Steri-Strips.
Postoperative Care
Patients are ambulated with assistance once the night of
surgery, 5 times on the first postoperative day and 7 times
on the second postoperative day. A clear liquid diet is
given on the night of surgery, advancing to a regular diet
as tolerated on the following days. A suction drain and
dressing are removed on the second postoperative day.
Intravenous antibiotics are discontinued after the suction
drain is removed. For analgesia, Ketorolac (30 to 60 mg)
is given intravenously every 6 hours for the first 48 hours.
It may be supplemented sparingly with morphine, as
needed. Antibiotic ointment is applied to the urethral
meatus around the catheter 4 to 6 times a day until the
catheter removal. Most patients are discharged from the
hospital on the second or third postoperative day.
The catheter may be removed on either the seventh,
10th, or 14th postoperative day, depending on the perceived
524 Part V Prostate Gland and Seminal Vesicles

Figure 29-13 A continuous running mucosa-everting suture of 3-0 chromic catgut is placed
for a distance of nearly the entire anastomotic circumference.

Figure 29-14 Perineal pressure is applied with a sponge forceps to better expose the cut
end of the urethra.
 Chapter 29 Anatomic Nerve-Sparing Radical Retropubic Prostatectomy 525
Figure 29-15 Double-armed 2-0 chromic catgut sutures are used for the vesicourethral
anastomosis.
amount of tension on the vesicourethral anastomosis. A
cystogram is not performed before removing the catheter
unless an anastomotic leak is suspected. The catheter
should not be removed before 7 days, as 10% to 15% of
men may experience urinary retention from edema and
require recatheterization.15,16 Oral fluoroquinolone is
given 1 day before and 1 week following the catheter
removal. Daily Kegel exercises are performed in four sets
of 10, before the surgery and following the catheter
removal until continence returns. A protective pad or
diaper is used until a complete urinary control is
achieved. The first postoperative serum PSA level is
measured 2 weeks or more after the operation.
CANCER CONTROL OUTCOME
The most important objective of radical prostatectomy is
cancer control. To cure prostate cancer with radical
prostatectomy, the patient must have a resectable tumor
and the surgery must completely encompass the tumor.9
A rising serum PSA level is usually the earliest evidence
of recurrence or progression following surgery.17 Follow-
up data are still not sufficiently mature to effectively eval-
uate cancer-specific survival trends. For example, in large
contemporary radical retropubic prostatectomy series,
including the current series, actuarial 10-year cancer-
specific survival ranged between 96% and 98%.6,7,18
Therefore, biochemical recurrence (detectable serum
PSA)-free survival has been used frequently as a surro-
gate in evaluating the treatment efficacy in radical
retropubic prostatectomy series.
An analysis of the senior author’s series, including
more than 3170 men who underwent anatomic radical
retropubic prostatectomy between 1983 and 2002,
including those with adverse prognostic features, has
been presented.18,19 Cancer progression was defined as
detectable serum PSA (>0.2 ng/ml), local recurrence, or
distant metastases. With a median follow-up of 4.5 years
(mean 5.3, range 0 to 18), cancer progression occurred in
19% of the men following radical prostatectomy.
Actuarial 10-year cancer progression-free survival proba-
bility was 67%.
Cancer progression following radical prostatectomy
was strongly associated with many clinical and pathologic
parameters, including Gleason grade, clinical, and patho-
logic tumor stage, era of treatment, and patient age. For
example, preoperative serum PSA level was inversely
associated with both the rate of organ-confined disease
and the 10-year progression-free survival rate. Patient
selection and the duration and frequency of follow-up
monitoring are critical in determining outcomes as well.
Therefore, factors other than treatment effectiveness can
influence treatment outcomes. Accordingly, caution is
indicated in comparing the results of contemporary rad-
ical prostatectomy series using different patient selection
criteria and follow-up protocols.
URINARY CONTINENCE OUTCOME
The overall urinary continence outcome following
nerve-sparing radical retropubic prostatectomy was
excellent in the current series. More than 93% of men
526 Part V Prostate Gland and Seminal Vesicles
achieved complete urinary continence, defined as requir-
ing no protection for daily activities.19 The return of uri-
nary continence was strongly associated with the age of
the patient. For example, more than 95% of men
younger than age 50 were continent following surgery. In
contrast, 85% of men above age 70 were continent post-
operatively. There was no significant difference in conti-
nence rate according to the era. Only 4 men (0.2%)
eventually required an artificial urinary sphincter place-
ment for stress urinary incontinence.
POTENCY OUTCOME
There are several possible goals of the nerve-sparing
aspect of radical retropubic prostatectomy. Patients with
intact libido and erectile potency want to maintain cur-
rent quality of erections or erections sufficient for pene-
tration with the help of oral medication, such as
phosphodiesterase inhibitors. Others with poor quality
erections preoperatively might accept erections that at
least offer some rigidity to provide sensory satisfaction
for both sexual partners. The erectile potency in the cur-
rent series was defined as an ability to maintain erections
strong enough for penetration with or without the help
of oral phosphodiesterase inhibitor.
The return of erectile potency following radical
retropubic prostatectomy was strongly associated with
the age of the patient, preoperative potency status, nerve-
sparing status (bilateral sparing versus partial sparing),
and the era of surgery (1980s versus 1990s).19 More than
75% of men younger than age 60 regained potency fol-
lowing bilateral nerve-sparing radical retropubic prosta-
tectomy. For men below age 50, more than 95%
recovered potency following surgery, in the modern era.
Between 62% and 72% of men in their 60s became
potent following bilateral nerve-sparing surgery. Finally,
there was a significant improvement in recovery of
potency in men treated in the 1990s compared to those
treated in the 1980s, even after correcting for the age and
nerve-sparing status.
COMPLICATIONS
The hospital cancer registry survey performed by the
American College of Surgeons reported a perioperative
(within 30 days of surgery) mortality rate of 0.4% fol-
lowing radical prostatectomy.20 There was no intraoper-
ative or immediate postoperative mortality in the current
series. With a careful selection of patients and perform-
ance of necessary cardiovascular evaluation, perioperative
mortality can be largely avoided.
The overall complication rate of radical prostatectomy
was 8% in the current series. Initially, the complications
occurred more commonly in older men, but the overall
complication rate gradually decreased with the surgeon’s
experience. The most common complications of
anatomic nerve-sparing radical retropubic prostatectomy
included anastomotic stricture/bladder neck contracture,
thromboembolic complications (deep vein thrombosis
and pulmonary embolism), and postoperative inguinal
hernia occurrence. In the current series, the rate of anas-
tomotic stricture/bladder neck contracture decreased
from 8% in the 1980s to <1% in the 1990s. Similarly, a
drastic decrease in thromboembolic events was observed
with the rate decreasing from 3% to 1% during the past
20 years. Other less frequent complications (<1%) asso-
ciated with radical prostatectomy included infection,
lymphocele formation, neurologic deficit, and cardiovas-
cular events.
Anastomotic stricture can be initially managed with a
gentle, serial dilation. Alternatively, a careful internal
urethrotomy can be performed. For a long and persistent
stricture, a transurethral resection of the scar tissue above
the external sphincter may be necessary. After resection,
triamcinolone can be injected via cystourethroscopic
approach to prevent inflammatory response and subse-
quent, recurrent scar formation.
Inadvertent injury to the obturator nerve can occur
during the pelvic lymphadenectomy. One management
option is to treat it conservatively with physical therapy
since some patients usually do not exhibit significant
thigh adductor deficit following the injury.21 Otherwise,
a primary nerve repair can be attempted. When a ten-
sion-free primary nerve repair is not feasible, a nerve
grafting can be performed utilizing either the sural nerve
or the lateral antebrachial cutaneous nerve.22
An injury to the ureter can occur inadvertently during
the transection of bladder neck or the dissection of the
lateral prostate pedicles. When recognized, a simple
mobilization of the ureter and ureteroneocystostomy
should be performed. The reimplanted ureter can be
cannulated using a 5Fr or 8Fr pediatric-feeding tube to
prevent an edema at the reimplantation site.
Usually, a rectal injury can be repaired primarily using
a multiple layer closure.23 However, a diverting
colostomy should be strongly considered in men with a
large rectal defect or a history of pelvic radiation therapy.
A diverting colostomy should also be considered in those
on a long-term preoperative steroid therapy.
A vesicorectal fistula can develop following anatomic
radical retropubic prostatectomy. This uncommon,
iatrogenic fistula can be repaired using a transrectal,
transsphincteric (York-Mason) approach with excellent
results.24–26
SUMMARY
Anatomic nerve-sparing radical retropubic prostatec-
tomy provides excellent cancer control with an accept-
able rate of complications in appropriately selected
 Chapter 29 Anatomic Nerve-Sparing Radical Retropubic Prostatectomy 527
patients. Many clinical and pathologic parameters are
associated with cancer control and return of urinary con-
tinence and potency following surgery. Over the past
2 decades, widespread screening for prostate cancer and
better patient selection have resulted in a favorable shift
of these parameters and improved surgical outcomes.
The treatment outcomes following radical prostatectomy
will most likely continue to improve as active screening
for prostate cancer is expanded in the future.
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26. Wood TW, Middleton RG: Single-stage transrectal
transsphincteric (modified York-Mason) repair of
rectourinary fistulas. Urology 1990; 35:27–30.
C H A P T E R
30Radical Perineal Prostatectomy
Philipp Dahm, MD, Johannes Vieweg, MD,
and David F. Paulson, MD
Modern radical perineal prostatectomy (RPP) traces its
origins back to 1904, when Dr. Hugh Hampton Young
performed the first prostatectomy to treat prostate can-
cer using the perineal approach. Today, RPP remains an
attractive modality to treat localized prostate cancer, hav-
ing retained its distinct advantage over alternative surgi-
cal approaches: It provides the most direct access to the
prostate gland. This characteristic is reflected in the low
perioperative morbidity of this approach, which has led
some to perform RPP as outpatient surgery.1 Meanwhile,
its long-term efficacy in treating clinically organ-confined
disease has been established in large patients series with
extended follow-up of over 20 years.2–5 Compared to
radical retropubic prostatectomy (RRP), RPP allows pro-
static dissection in a relatively avascular surgical field,
providing good exposure for reconstruction of the ure-
throvesical anastomosis and allowing dependent postop-
erative drainage of the prostatic fossa. Modifications of
the classic RPP allow sparing of the neurovascular bundles
to preserve potency with equal efficacy as in RRP.6,7 If
capsular invasion is suspected, wide field dissection of
the prostate permits the removal of the prostate with the
same margin of extracapsular tissue as RRP.8,9 While the
inability to perform a simultaneous staging pelvic
node dissection was previously considered a major disad-
vantage of the perineal approach, the recent trend
towards detection of prostate cancer at earlier stages
combined with the availability of accurate staging nomo-
grams have made staging lymph node dissections unnec-
essary in most patients.10–12 These features make modern
RPP an attractive treatment choice for patients with
organ-confined prostate cancer that should be offered to
patients as part of an individualized, rational approach to
the surgical management of localized disease. Since the
resurgence of the perineal approach will likely continue,
it appears prudent for contemporary urologists to famil-
iarize themselves with this procedure.
528
PATIENT SELECTION
The main indication for RPP is the primary treatment of
localized adenocarcinoma of the prostate, and many con-
temporary patients of the prostate-specific antigen (PSA)
era with newly diagnosed prostate cancer are excellent RPP
candidates. Modern staging algorithms, based on clinical
stage, serum PSA level, and Gleason score, allow an accu-
rate prediction of local extent and the likelihood of regional
lymph node spread, thereby obviating the need for a staging
node dissection in most patients. A bilateral pelvic lymph
node dissection (BPLND) is recommended in patients with
poorly differentiated disease Gleason scores of 8 to 10. In
addition, patients with a PSA ≥ 20 ng/ml should undergo a
BPLND. According to patients’ and surgeons’ preferences,
BPLND may be performed through an open minilaparo-
tomy or by laparoscopic technique. Either approach may be
performed as a separate procedure, yet more commonly
BPLND is completed immediately before RPP under the
same anesthesia and frozen sections of the sampled nodes
are analyzed during the time of repositioning.
The perineal approach has few contraindications, the
most important being the inability of the patients to
assume an exaggerated lithotomy position due to condi-
tions, such as spinal stenosis, hip ankylosis, or a history of
vertebral fractures. If vertebral mobility is in question,
the position may be readily simulated at the time of the
preoperative office visit. While obese patients may bene-
fit from a perineal approach by avoiding the dissection of
deep layers of abdominal adipose tissue, a subset of mas-
sively obese patients with a “large barrel abdomen” may
not be suitable candidates because of the high ventilatory
pressures (in excess of 40 mm Hg) required during gen-
eral anesthesia. These patients should be counseled about
the possibility that RPP cannot be performed for the
above reasons and alternative treatment forms should be
discussed beforehand.

While a large prostate (greater than 80 or 100 g) has
been cited as a relative contraindication for the perineal
approach, it is the relative size of the prostate to the dis-
tance between the ischial tuberosities that determines the
width of the surgical field. A digital rectal examination
(DRE) in the office prior to surgery provides a good
estimate of the spatial proportions and the feasibility
of RPP in very large prostates but it requires some clini-
cal experience for making this judgment. Transrectal
ultrasound examinations have not been helpful in our
experience.
SURGICAL TECHNIQUE
Patient Preparation and Positioning
RPP is routinely performed after same day admission.
Due to the proximity of the anus and rectum to the inci-
sion line and plane of dissection, particular emphasis is
placed on a thorough mechanical and antibiotic bowel
preparation at home. The patient is placed in an exag-
gerated lithotomy position taking care to pad all extrem-
ities well and avoid overextension. The perineum is
correctly positioned by bringing the sacrum downwards
on the table until the buttocks reach approximately
15 cm beyond the edge. A bolster is placed below the
sacrum to further elevate the pelvis. Correct positioning
places the perineum parallel to the floor to provide opti-
mal exposure. Following a routine preparation of a wide
surgical field, the patient is draped in such a way that a
DRE is possible at the beginning of the case to reorient
the surgeon to the individual anatomy and confirm cor-
rect placement of the prostate retractor. The anus is then
covered by an impermeable drape and excluded from the
sterile surgical field for the remainder of the case.
Access to the Prostate
Skin incision is made approximately 1.5 cm above the
anal verge and extended posterolaterally on either side,
medial to the ischial tuberosities. The central tendon is
identified and divided. An anterior retractor is then
placed and the rectourethralis muscle identified as a
fibromuscular band in the midline, which is partially
swept to the side and partially divided. At this point, the
prostate is separated from the posterior surface of the
rectum in the midline by gentle, blunt dissection. A moist
gauze is placed over the rectum to protect it from inad-
vertent injury and displacement is maintained by a
retractor blade.
Dissection of the Prostate
Classic perineal prostatectomy proceeds with a transverse
incision of Denonvilliers’ fascia followed by exposure of
the apex of the prostate using a combination of sharp and
Chapter 30 Radical Perineal Prostatectomy 529
blunt dissection. The dorsal venous complex is not
encountered and the urethra may be divided with preci-
sion in a relatively avascular field. A Young retractor or
straight Lowsley prostatic retractor aids in further dis-
section of the posterior and the lateral aspects of the
prostate. It is important to adequately dissect free the
anterior bladder neck so that a tension-free vesi-
courethral anastomosis can later be achieved. The
prostatovesical junction is identified and the prostate is
sharply cut away from the bladder. After sharp entry into
the bladder between 10 o’clock and 2 o’clock, the Young
retractor is withdrawn and a Foley catheter is passed
through between the prostate and the bladder neck to
serve as a retractor device. Intravenous indigo-carmine
may be administered to aid in visualization of the ureteral
orifices as the prostate is dissected away from the circular
detrusor fibers. Finally, the posterolateral pedicles, vas
deferens, and seminal vesicles are isolated, clipped, and
transected. Complete excision of the seminal vesicles is
readily achieved 13 in most patients; however, is felt to
rarely benefit the patient from an oncologic perspective.
Bladder Neck Reconstruction and Urethrovesical
Anastomosis
Once hemostasis is established, the bladder neck is
reconstructed. The bladder mucosa is averted to mini-
mize the risk of stricture formation, and the bladder neck
is approximated in a racket-handle fashion. Two of the
racket-handle sutures and two additional sutures tied to
the bladder neck at 10 o’clock and 2 o’clock position
serve as Vest sutures to align the urethrovesical anasto-
mosis and are later brought out through the perineal
body and tied. Four anastomotic sutures are routinely
used that are placed and tied under direct vision over an
18 French urinary catheter to establish a watertight anas-
tomosis. The operating field is copiously irrigated and a
DRE is performed to rule out rectal injury. A soft drain
is placed and the fibers of the rectourethralis, levator ani,
and central tendon are approximated thereby obliterating
any dead space and restoring the anatomy, followed by
closure of the skin.
Postoperative Care
From the operating room the patient is taken to the
recovery room, where he is typically monitored for
approximately 2 hours to ensure appropriate recovery
from general anesthesia, adequate urinary drainage, and
good pain control. Since the average blood-loss in RPP is
low and averages at <500 cc, postoperative transfusions
are a rare event. Oral analgesics are started in the recov-
ery room. Patients will routinely tolerate a clear liquid
diet the evening of surgery and advance to their regular
preoperative diet on the morning of postoperative day 1.
530 Part V Prostate Gland and Seminal Vesicles
The drain is left in place until postoperative day 2 or the
time of the patient’s first bowel movement. At that time
the patient is instructed to either take an antiseptic sitz
bath or alternatively to clean himself using a hand-held
shower. Criteria for patient discharge are the ability to
tolerate a regular diet, ambulate without assistance, as
well as good pain control with oral analgesics. These cri-
teria are normally met towards the end of postoperative
day 1 and patients are typically discharged home by the
morning of postoperative day 2.
MODIFICATIONS OF CLASSIC RPP
Nerve-Sparing Radical Perineal Prostatectomy
Preservation of the neurovascular bundles is as feasible in
RPP as in RRP, yet requires an intimate understanding of
the course of the neurovascular bundles as viewed from
the perineum to prevent unintended injury. The proce-
dure differs in that initially a vertical instead of a trans-
verse incision of the posterior layer of Denonvilliers’
fascia is made. Reflection of this layer over the apex of
the prostate gland and laterally, allows establishing a
plane between the prostate and the neurovascular bun-
dles. Posterolateral dissection of the prostate is kept close
to the prostatic substance and small clips rather than
electrocautery are used to achieve hemostasis. Finally,
care is taken not to inadvertently injure the neurovascu-
lar bundles, which course in close proximity, when dis-
secting out the tips of the seminal vesicles.
Wide-Field Dissection Radical Perineal
Prostatectomy
Patients at high risk for extracapsular extension may be
considered for a wide-field dissection of the prostate,
which encompasses the lateral pelvic fascia and sacrifices
both neurovascular bundles. The prostate is exposed as
described. However, after the rectum is displaced poste-
riorly, a surgical plane is developed between the posterior
layers of Denonvilliers’ fascia, the anterior rectal surface
posteriorly and the levator musculature anteriorly. The
prostate remains surrounded by the periprostatic lateral
pelvic fascia. All fibrovascular pedicles are divided as far
away from the prostate as possible. The seminal vesicles
are dissected as described but clipped and dissected at
such a level to include the neurovascular bundle.
Additionally, wider margins of the bladder neck may be
taken to achieve negative margins followed by recon-
struction as described.
COMPLICATIONS OF RPP
Ureteral Injury
Problems in reconstruction of the bladder neck may
occur if the posterior margin of the incision has been
carried so close to the ureteral orifices, either for onco-
logic reasons or inadvertently. In this case, the ureteral
orifices can be stented using open-ended ureteral
catheters followed by bladder neck closure from 6 o’
clock to 12 o’clock of the detrusor musculature only, not
incorporating the bladder mucosa. The stents are
brought out separately, secured and typically left in place
for 5 to 7 days. Alternatively, the ureteral orifice may be
reimplanted through the perineal incision. The limited
exposure, however, makes this maneuver technically
challenging. Should primary ureteral reimplantation not
be feasible, patients may alternatively be managed by
placing a percutaneous nephrostomy tube on postopera-
tive day 1. This delay will allow for some degree of dilata-
tion of the collecting system to occur which facilitates
tube placement. Ureteral reimplantation may then be
performed in a delayed fashion using an abdominal
approach, ideally at 6 to 12 weeks postoperatively.
Rectal Injury
Rectal injury is a well-recognized risk of radical prostate
surgery. It is a potentially concerning, but rare complica-
tion of the perineal approach, with an incidence of 1% to
3% in the hands of experienced surgeons.9 The risk of
rectal injury in RPP relates to the intimate relationship of
the plane of initial dissection to the rectum and most
commonly occurs either at the time of dissection of the
rectourethralis muscle or during placement of the poste-
rior weighted retractor. With strict adherence to the cor-
rect surgical technique and careful placement of the
retractors, however, injury appears avoidable in most
cases. If rectal injury does occur, prompt recognition and
appropriate management may minimize subsequent mor-
bidity to the patient. This should consist in copious irri-
gation of the surgical field followed by primary closure of
the defect in several layers using an absorbable monofil-
ament. A diverting colostomy is rarely necessary, unless
gross fecal soiling is present, which is not encountered
if the patient has been adequately prepared using both
mechanical and antibiotic bowel preparations. Post-
operative management includes the use of broad-spectrum
antibiotics and maintaining patients on a clear liquid diet
for 3 days. Placement of a rectal tube is unnecessary. The
outlined management usually results in uncomplicated
healing of the rectal injury with no adverse consequences
to the patient.
Lower Extremity Neuropraxia
Lower extremity neuropraxia is a unique problem associ-
ated with the exaggerated lithotomy position. While it
is relatively common in the immediate postoperative
setting occurring in up to 25% of patients, symptoms are
usually transient and consist of sensory deficits below the

knee only.14 These symptoms invariably resolve, in most
cases prior to the patients discharge from the hospital on
postoperative day 2. The etiology of these injuries is
mostly attributable to a stretch injury to the sciatic or
common peroneal nerve, less often due to direct com-
pression injury to the sensory nerves of ankle of foot.
The recognition of the mechanisms of injury, often
resulting from a lack of awareness by inexperienced oper-
ating room personnel has resulted in a significant reduc-
tion of this problem at our institution. In addition, a
recent study from our institution suggests that the
likelihood of postoperative lower extremity neuropraxia
correlates with surgery time; patients with a surgery
time of greater than 2 hours were twice as likely to
report symptoms than patients who’s procedure was
completed in less time. Based on these findings it appears
critical to minimize the amount of time patients spend in
the exaggerated lithotomy position. If neuropraxia does
occur, management is expectant and conservative.
Further diagnostic work-up is usually not indicated
unless neurologic symptoms are progressive, suggesting a
different etiology, such as spinal stenosis or a herniated
disk.
DISEASE CONTROL
RPP has been demonstrated to achieve long-term disease
control in patients with clinically organ-confined
10
.9
.8
Probability of cancer-associated survival
.7
.6
.5
.4
.3
.2
.1
0.0
0 2
2006
Figure 30-1 Kaplan-Meier analysis of cancer-associated survival of patients following RPP
(n = 2006) grouped by tumor extent, applying the categories organ-confined (OC),
specimen-confined (SC), and margin-positive (MP).
Chapter 30 Radical Perineal Prostatectomy 531
prostate cancer. The Duke Radical Perineal Prostatectomy
Database represents one of the largest series of radical
prostatectomy patients from a single institution and is
based solely on RPP patients. A large cohort of patients
who underwent RPP at our institution have been fol-
lowed for clinical, biochemical, and radiographic evi-
dences of recurrent disease for an extended period of
time of up to 20 years, offering the unique opportunity
to study the long-term outcome of patients that chose
this approach as treatment for clinically localized prostate
cancer. Outcome is best described as time to cancer-asso-
ciated death, which is used for any death associated with
recurrent disease irrespective of treatment as docu-
mented by a rising PSA level of ≥0.5. In addition, patho-
logic staging using the categories “organ-confined”
(OC), “specimen-confined” (SC), and “margin positive”
(MP) provides a robust classification system that has
withstood the many changes of the TNM system over
the last 2 decades, yet carries important prognostic
implications.
The overall 10- and 15-year cancer-associated survival
rates for all RPP candidates in this series (n = 2006) are
84.5 ± 1.4% and 71.7 ± 2.3%, respectively. Figure 30-1
illustrates the strong prognostic impact of local extent;
15-year cancer-associated survival rates for patients
with organ-confined, specimen and margin positive dis-
ease are 86.6 ± 2.5, 70.7 ± 6.5, and 49.8 ± 4.4, respec-
tively. In addition, the Gleason score of the prostatectomy
OC (n = 1179)
SC (n = 399)
p = 0.001
MP (n = 428)
4 6 8 10 12 14 16 18 20 Follow-up (years)
1222 884 249 106 35 Patients at risk
532 Part V Prostate Gland and Seminal Vesicles
specimen, as a marker for the biologic aggressiveness
of the tumor, has consistently demonstrated an impact
on long-term survival15 as illustrated in Figure 30-2.
Fifteen-year cancer-associated survival rates for
patients with Gleason score 5 to 6, 7, and 8 to 10 are
81.1 ± 3.4%, 67.3 ± 4.6%, and 49.2 ± 6.1%, respectively.
When combining both prognostic variables one finds
that patients with the most unfavorable combination
of margin positive, high Gleason score disease of 8 to
10 (n = 146) experience extended survival periods with
10- and 15-year cancer-associated survival rates of
43.1 ± 6.8% and 31.3 ± 8.2%, respectively. These find-
ings emphasize the need for long follow-up periods
when studying prostate cancer and suggest that many
current series of alternative curative therapies lack
follow-up of sufficient duration to permit comparison
with the results of radical surgery. While the use of dif-
ferent staging systems and endpoints of outcome cloud a
direct comparison between RPP and RRP, the disease
control achieved by RPP and RRP may be considered
equivalent.16,17
URINARY CONTINENCE
Urinary continence is one of the most significant out-
come parameters of radical surgery for prostate cancer
and perineal prostatectomy achieves excellent urinary
continence rates, ranging between 92% and 96%,
10
.9
.8
Probability of cancer-associated survival
.7
.6
.5
.4
.3
.2
.1
0.0
0 2
1969
Figure 30-2 Kaplan-Meier analysis of cancer-associated survival of patients following RPP
(n = 1969) grouped by Gleason score (GS), applying the GS categories 2 to 4, 5 to 6, 7,
and 8 to 10.
depending on the type of definition used.5,18 Urinary
continence is typically achieved early in the postoperative
course; Weldon et al.18 reported a return of continence
(defined as “no routine pad use”) in 23% of patients at 1
month, 56% by 3 months, and 90% by 6 months. It has
furthermore been suggested that patients may seek to
minimize adverse outcomes when discussing them with
their surgeon, and physician and patient assessment of uri-
nary symptoms following radical prostatectomy may differ
significantly.19,20 Thus, more recent investigations have
utilized validated instruments that are self-administered
to more comprehensively characterize urinary function
and minimize potential bias.21,22 In a prospective study at
our institution of 78 RPP candidates that underwent
RPP in a standardized technique and applying a defini-
tion of urinary incontinence of greater than “occasional
dribbling” we found a proportion of patients self-
reporting urinary incontinence of 35.9%, 15.4%, 5.1%,
and 3.7% after 3, 6, 9, and 12 months, respectively.
Meanwhile, 5.6% of patients had some degree of preex-
isting urinary incontinence when questioned prior to sur-
gery and applying the same definition. These results may
be regarded as preliminary, based on a small cohort of
patients. Nevertheless, they compare favorably with the
reported self-assessed urinary incontinence rates
reported in a series of RRP patients reported by Wei et al.22
and document the early and consistent return of urinary
continence following RPP in a majority of patients.
GS 2−4 (n = 85)
GS 5−6 (n = 888)
p = 0.001
GS 7 (n = 704)
GS 8−10 (n = 292)
4 6 8 10 12 14 16 18 20 Follow-up (years)
1222 884 249 106 35 Patients at risk

POTENCY
The nerve-sparing modification of RPP may be regarded
as equally effective as the retropubic approach6,7,23 and is
offered to select patients with favorable preoperative
staging characteristics. These include patients with clini-
cally organ-confined disease, a serum PSA ≤ 10 ng/ml
and a Gleason score ≤ 6. It has been our personal prac-
tice to offer the bilateral nerve-sparing approach only to
those patients with a single positive biopsy core.
Therefore, most patients undergo a unilateral nerve-
sparing RPP with deliberate sacrifice of the neurovascu-
lar bundle on the side where biopsies are positive,
suggesting the location of the bulk of the tumor. When
reviewing the potency rates following RPP at our institu-
tion, Frazier et al.6 found 77% of patients to be potent 1-
year after nerve-sparing RPP. Weldon et al.18
additionally analyzed the time course to recovery of
potency and found that potency returned in 50% of
patients after 1 year and in 70% after 2 years. An addi-
tional, important observation was the strong inverse
correlation of the rate of successful potency sparing and
increasing age. Potency returned in all patients <50 years
of age but only 29% of older patients. It appears impor-
tant to emphasize these two aspects pertaining to the
recovery of potency—the extended time interval neces-
sary and the decreased potential for functional recovery
with increasing age—with the patient prior to surgery to
generate realistic expectations with regard to the level of
postoperative sexual functioning that may be anticipated.
FECAL INCONTINENCE
A recent study suggested that RPP is associated with a
high risk of postoperative fecal incontinence.24 These
findings were based on a retrospective study of two
groups of patients—from the authors’ institution and
from a nationwide database. Patients in either group
denied any preexisting preoperative fecal incontinence,
yet reported fecal incontinence rates of 18% and 15%,
respectively, at least 1 year following RPP. A particular
concerning observation of this study was that a majority
of patients did not seek medical assistance for the prob-
lem of involuntary stool leakage despite detrimental
effects to their quality of life. The suggestion that fecal
incontinence may be common after RPP, yet under-
appreciated because it is not routinely addressed during
follow-up, prompted us to design a study to evaluate the
incidence of bowel-related symptoms and complaints,
and fecal incontinence in particular, following RPP.
Using a validated patient self-assessment tool we per-
formed a longitudinal assessment of bowel function and
bowel-related bother of 78 consecutive patients undergo-
ing RPP, while accounting for preoperatively determined
baseline characteristics for comparison. We found an
Chapter 30 Radical Perineal Prostatectomy 533
unexpected high prevalence of occasional fecal inconti-
nence symptoms in 11.5% of patients (9/78) prior to sur-
gery. Of these 9 patients, 3 suffered from involuntary
stool leakage once a week or less frequently, yet 6 patients
experienced this symptom at least once daily. Meanwhile,
only 2 patients (2.6%) identified fecal incontinence as
greater than a “very small problem.” All bowel-related
symptoms, including involuntary stool leakage, were
transiently increased 1 month following RPP yet
returned to baseline levels within 3 to 6 months postop-
eratively. Compared to their individual baseline, 15.4%,
7.7%, 5.1%, and 3.9% of patients reported worsened
symptoms of fecal incontinence after 3, 6, 9, and 12
months, respectively (Figure 30-3). When analyzing the
rate of fecal incontinence in patients who denied preop-
erative problems (n = 69) the incidence after 12 months
was only 2.9%, which is considerably lower than the
range of 15% to 18% previously reported by Bishoff et
al.24 Potential explanations for this discrepancy include
differences in the patient populations, as well as a recall
bias in the previous study, resulting in the inadvertent
inclusion of patients with some degree of preexisting fecal
incontinence that was not accounted for retrospectively.
Finally, the patients in the study reported by Bishoff et
al.,24 underwent surgery at least 1 year prior to the time
they were questioned. While our results give us no indi-
cation that fecal incontinence initially improves and then
subsequently deteriorates, information about the long-
term outcome of the patients remains pending. Longer
follow-up of our cohort of patients may allow us to char-
acterize the incidence of fecal incontinence further.
QUALITY OF LIFE FOLLOWING RPP
Quality of life is being increasingly recognized as an
important complementary endpoint, when considering
treatment options for prostate cancer. A small number of
well-designed studies addressing this issue have been
reported that provide longitudinal rather than cross-sec-
tional observations and include a measurement of quality
of life before initiation of therapy, allowing each patient
to serve as his own control. Litwin et al.25 investigated
the recovery of general and prostate-specific quality of
life in 247 men following RRP. The authors found that
21% of patients reached their individual baseline level of
HRQOL in the urinary domain within 3 months follow-
ing surgery, and 56% by 12 months. In the bowel
domain, over two-thirds of patients recovered their base-
line scores by 3 months, and >90% recovered by 12
months. Meanwhile, sexual function and bother took
longer to return, and was recovered by 33% and 51% of
patients within 1 year, respectively.
To our knowledge, no dedicated investigation of the
recovery of HRQOL in RPP patients has been pub-
lished, yet preliminary data from a cohort of 78 patients
534 Part V Prostate Gland and Seminal Vesicles

10

.9

.8

.7
Probability of stool leakage
.6

.5

.4

.3

.2

.1

0.0
0 1 2 3 4 5 6 7 8 9 10 11 12
Time after RPP (months)

Figure 30-3 Kaplan-Meier analysis of the probability of patients (n = 78) to experience

worsening symptoms of involuntary stool leakage compared to their individual preoperative
status, based on responses to a validated patient self-assessment instrument, the EPIC,
completed by patients prior to surgery, at 4 weeks, 3, 6, 9, and 12 months following RPP.

who underwent RPP at our institution with a minimum
follow-up of 6 months have recently become available.
The patients have been studied longitudinally prior to
surgery, after 1 month and subsequently at 3-month
intervals following RPP using a validated patient self-
assessment tool, the Expanded Prostate Cancer Index
Composite (EPIC).21 The mean age was 60.3 years
(range 43 to 78) and the majority (78.2%) of patients
were treated using a non nerve-sparing approach. Of
these patients, 47.1% and 81.7% recovered their individ-
ual urinary and bowel-related HRQOL within 3 months
following RPP (Table 30-1). While based on a small
number of patients, these results compare favorably with
the available RRP data, particularly with respect to the
urinary domain.
SUMMARY
Modern RPP constitutes an excellent treatment modality
for select patients with clinically organ-confined prostate
cancer. Features of this approach include documented
long-term disease control, favorable functional results,
low morbidity, and fast patient recovery. These charac-
teristics make RPP an attractive treatment choice that

Table 30-1 Longitudinal Assessment of the Recovery of Health-related Quality of Life (HRQOL) Scores
in the Domains Urinary, Bowel, and Sexual within 12 Months Following RPP
1 Month (n = 78) 3 Months (n = 71) 6 Months (n = 78) 9 Months (n = 66) 12 Months (n = 64)

Urinary (%) 19.5 47.1 71.8 78.8 82.8

Bowel (%) 35.1 81.7 92.3 90.9 90.6

Sexual (%) 19.4 20.6 20.3 24.6 23.3

Patients were assessed prior to surgery, after 4 weeks, and subsequently at 3 months intervals using the EPIC, a validated patient self-assessment
tool. HRQOL scores of each patient were calculated on a scale of 0 to 100 for every domain. Patients were considered to have recovered their
individual level of HRQOL if they reached a score within ±10 points of their baseline value.
 Chapter 30 Radical Perineal Prostatectomy 535

should be offered to patients as part of an individualized, 13. Vordos D, Delmas V, Hermieu JF, et al: Can a precise
rational approach to the surgical management of local- vesiculectomy be performed during radical prostatectomy?
ized disease. Prog Urol 2001; 11:1259.
14. Price DT, Vieweg J, Roland F, et al: Transient lower
extremity neurapraxia associated with radical perineal
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18. Weldon VE, Tavel FR, Neuwirth H: Continence, potency
Radical prostatectomy in stage A prostatic
and morbidity after radical perineal prostatectomy. J Urol
adenocarcinoma. J Urol 1988; 140:535.
1997; 158:1470.
5. Gibbons RP: Total prostatectomy for clinically localized
19. Gray M, Petroni GR, Theodorescu D: Urinary function
prostate cancer: long-term surgical results and current
after radical prostatectomy: a comparison of the
morbidity. NCI Monographs 1988; 123.
retropubic and perineal approaches. Urology 1999;
6. Frazier HA, Robertson JE, Paulson DF: Radical
53:881.
prostatectomy: the pros and cons of the perineal versus
20. Wei JT, Montie JE: Comparison of patients and
retropubic approach. J Urol 1992; 147:888.
physicians rating of urinary incontinence following radical
7. Weldon VE, Tavel FR: Potency-sparing radical perineal
prostatectomy. Semin Urol Oncol 2000; 18:76.
prostatectomy: anatomy, surgical technique and initial
21. Wei JT, Dunn RL, Litwin MS, Sandler HM, Sanda MG:
results. J Urol 1988; 140:559.
Development and validation of the expanded prostate
8. Korman HJ, Leu PB, Huang RR, Goldstein NS:
cancer index composite (EPIC) for comprehensive
A centralized comparison of radical perineal and
assessment of health-related quality of life in men with
retropubic prostatectomy specimens: is there a difference
prostate cancer. Urology 2000; 56:899.
according to the surgical approach? J Urol 2002; 168:991.
22. Wei JT, Dunn RL, Marcovich R, Montie JE, Sanda MG:
9. Thrasher JB, Paulson DF: Reappraisal of radical perineal
Prospective assessment of patient reported urinary
prostatectomy. Eur Urol 1992; 22:1.
continence after radical prostatectomy. J Urol 2000;
10. Gingrich JR, Paulson DF: The impact of PSA on prostate
164:744.
cancer management. Can we abandon routine staging
23. Weldon VE: Technique of modern radical perineal
pelvic lymphadenectomy? Surg Oncol Clin N Am 1995;
prostatectomy. Urology 2002; 60:689.
4:335.
24. Bishoff JT, Motley G, Optenberg SA, et al: Incidence of
11. Partin AW, Mangold LA, Lamm DM, et al:
fecal and urinary incontinence following radical perineal
Contemporary update of prostate cancer staging
and retropubic prostatectomy in a national population.
nomograms (Partin tables) for the new millennium.
J Urol 1998; 160:454.
Urology 2001; 58: 843.
25. Litwin MS, Melmed GY, Nakazon T: Life after radical
12. Parra RO, Isorna S, Garcia PM, Cummings JM, Boullier JA:
prostatectomy: a longitudinal study. J Urol 2001; 166:587.
Radical perineal prostatectomy without pelvic
lymphadenectomy: selection criteria and early results.
J Urol 1996; 155:612.
C H A P T E R
31Laparoscopic Radical Prostatectomy
Guy Vallancien, MD, and Xavier Cathelineau, MD
HISTORY
Laparoscopic surgery, which was developed in gynecol-
ogy during the 1940s, was used in gastrointestinal
surgery from 1986 onward, especially following develop-
ment of the technique by Philippe Mouret in Lyon and
François Dubois in Paris. It was not, however, immedi-
ately extended to the field of urology. The first laparo-
scopic nephrectomy was performed in 1990 by Ralph
Clayman in St. Louis, but the urologic community
remained reticent for a long time about the value of these
time-consuming techniques, which had only limited indi-
cations. From 1995 onward, the development of intra-
corporeal suture, allowing repair of anomalies of the
ureteropelvic junction and nephrectomies for cancer, led
to a renewed interest in laparoscopy.
In 1992, the first attempt to perform laparoscopic
prostatectomy in two cases was published by Schuessler
et al.1 in an abstract presented to the American Urology
Association Congress. In 1997, the same team published
9 cases of laparoscopic radical prostatectomy and reached
the conclusion that this technique did not provide any
advantages over open surgery due to the duration and
difficulty of the operation, especially when performing
the vesicourethral anastomosis.
In the same year, Raboy et al.2 published a case of
extraperitoneal radical prostatectomy. In December
1997, Richard Gaston (Bordeaux, France), in a personal
communication, indicated that he had performed a
transperitoneal radical prostatectomy in less than 6
hours. Six weeks later, Guillonneau and Vallancien3,4
started to perform their first radical prostatectomies. Five
months later, Abbou,5 in Créteil, also started to perform
this new surgical technique.
Laparoscopy requires appropriate instruments, an
intellectual investment (long training) and a physical
investment (this surgery is more tiresome than open sur-
gery). Most importantly, surgeons must be assisted by
536
motivated teams, composed of instrument nurses, scrub
nurses, anesthetists, and the hospital administration. It
would be impossible to perform laparoscopic surgery
without such an environment.
INDICATIONS AND CONTRAINDICATIONS
Indications
The indications of laparoscopic radical prostatectomy are
exactly the same as the open radical prostatectomy. The
development of the laparoscopic procedure has not
changed the indications and the selection of the patient
candidates to a surgical treatment.
The best indication is probably the young patient,
whose PSA is <15 ng/ml, with less than 50% of positive
biopsies and Gleason score <8.
Laparoscopic radical prostatectomy is feasible for
some selected T3N0M0, with condition not preserving
the neurovascular bundles and informing the patient of
possible complementary treatment.
Salvage laparoscopic radical prostatectomy is also fea-
sible after radiation therapy or brachytherapy, but the
patient has to be informed of the risk of temporary
colostomy.
Contraindications
Anesthetic Contraindications
There are no specific anesthetic contraindications for
laparoscopic radical prostatectomy. Contraindications
for this procedure are the same as those for all laparo-
scopic procedures.
The main absolute contraindication for laparoscopic
approach is high-intracranial pressure whatever its origin
(primary or secondary to intracranial process).
The relative anesthetic contraindications are: severe
emphysema, severe cardiac injury, chronic respiratory

disease, and glaucoma. Those contraindications have
to be underlined specifically for extraperitoneal
approach. Effectively, there is an increased partial
pressure of carbon dioxide (pCO2) during all the
extraperitoneal procedure, which requires increased
minute ventilation, in order to maintain a p CO 2
between 30 and 35 mm Hg.
Anatomic Contraindications
There are no anatomic contraindications for laparo-
scopic radical prostatectomy.
Obviously, some cases are more difficult, and especially
at the beginning of the experience, the surgeon has to take
care of those difficulties and probably select the best cases.
Difficult Cases
Different factors can increase the difficulty of the proce-
dure, especially:
● Previous hormonotherapy
● Previous TURP or prostatectomy
● Prostatitis
All of these factors can modify the prostatic and
periprostatic tissues and make the surgery really difficult.
Moreover, very big prostate (more than 100 g)
increase the difficulty of the dissection. According to his
experience, the surgeon has probably to avoid those cases
at the beginning of his learning curve.
In any case, conversion is not a shame but a sign of
wisdom.
OPERATIVE TECHNIQUE
Transperitoneal Approach: the Montsouris
Technique6
Medical Preparation
Prophylactic antibiotics are not given to the patient; they
do not decrease the risk of infection but can induce selec-
tion of bacteria, especially enterococci.
Thromboembolic complications are prevented by
injection of low molecular weight heparin on the day
before the operation, which is continued for at least 7
days postoperatively, associated with varicose veins stock-
ing during hospitalization.
No gastrointestinal or skin preparation is required.
Installation of the Patient
The operation is performed under general anesthesia.
The patient is placed in the dorsal supine position,
with the lower limbs in abduction allowing intraoperative
access to the rectum.
Chapter 31 Laparoscopic Radical Prostatectomy 537
An exaggerated Trendelenburg position is essential, at
least for the initial posterior phase of the operation.
The upper limbs are positioned alongside the body to
avoid the risk of stretch injuries to the brachial plexus.
An adhesive elastic bandage is placed in cross fashion
over the thorax, which ensures better comfort for the
patient than shoulder rests.
The surgeon stands to the left of the patient and the
assistant stands to the right. The camera is attached to a
voice-controlled robotic arm.
Material
There is no specific instrument for laparoscopic radical
prostatectomy. As for all the others laparoscopic proce-
dures adapted material is primordial. All the instruments
had to be checked before the procedure, especially bipo-
lar forceps and scissors, in order to detect a leak, which
could induce a burning of intraabdominal organ.
Main Steps of the Operation
Insufflation is performed with a Veress needle in the
umbilicus or left hypochondrium.
The 10-mm trocar for the scope is placed in the
umbilicus. Four other trocars are used for the surgeon
and the assistant, arranged according to the surgeon’s
usual practice; either in a triangular pattern (the operator
uses a left pararectal trocar and a right pararectal trocar,
and the assistant uses a trocar in the right iliac fossa and
an interumbilico-pubic trocar) or in a parallel pattern
(the operator uses a trocar in the left iliac fossa and a left
pararectal trocar, and the assistant uses two symmetrical
trocars on the right side).
Pelvic lymph node dissection with frozen section
examination is performed according to the preoperative
findings.
The operation comprises seven successive steps:
1. Posterior phase. The posterior peritoneum is
incised over the vasa deferentes, which are
sectioned, and the seminal vesicles are completely
dissected. The median part of Denonvilliers’ fascia
is incised.
2. Anterior phase. The anterior parietal peritoneum is
incised from one umbilical artery to the other
providing access to the retropubic space after section
of the urachus.
The pelvic fascia is incised as far as the
puboprostatic ligaments, which are sectioned. The
prostatic apex is completely dissected. Santorini’s
venous plexus and the preprostatic venous drainage
are then ligated with 2/0 Vicryl (this stitch can also
be placed after the dissection of prostatic vascular
pedicles, just before cutting the uretra).
538 Part V Prostate Gland and Seminal Vesicles
3. Vesicoprostatic dissection is performed by preserving, as
far as possible, the fibers of the bladder neck.
Dissection of the posterior surface of the bladder
neck provides access to the plane of the seminal
vesicles and vasa deferentes.
4. Dissection of prostatic pedicles and neurovascular bundles.
The prostatic vascular pedicles are selectively
coagulated with bipolar forceps. Neurovascular
bundles are preserved depending on anatomical and
oncological conditions.
5. Section of the urethra. The urethra is sectioned away
from the prostatic apex. The rectourethralis muscle is
also sectioned and the prostate is then completely
released (a bougie in the rectum can be useful to
identify the rectum in the case of difficult posterior
dissection).
6. Vesicourethral anastomosis. It is performed by
interrupted 3/0 Vicryl sutures. An 18 F Foley
catheter is inserted. The absence of anastomotic leak
is verified intraoperatively.
7. Extraction of the operative specimen. The prostate is
placed in a laparoscopic bag and removed by enlarging
the umbilical incision. A Redon drain is inserted in
the retropubic space or the pouch of Douglas. The
5-mm trocar orifices are closed in one layer and the
10-mm trocar orifices are closed in two layers.
Postoperative Management
The bladder catheter is left in place for 3 to 7 days
depending on the quality of the suture (cystography is
not performed).
Analgesia is limited to paracetamol (8 g by intravenous
injection) during the first 24 hours, followed, on D1, by
oral paracetamol/dextropropoxyphene pro re nata (p.r.n.)
Major analgesics are not administered routinely but are
prescribed p.r.n.
The IV infusion is stopped on D1.
Oral fluids are started on D1 and a normal diet can
generally be resumed on D2.
Variants of the Transperitoneal Approach
Transperitoneal Approach With Initial Anterior
Approach
Rassweiler et al.7,8 reported their experience with a mod-
ified version of the Montsouris technique. They perform
an initial anterior approach providing access to the
retropubic space. The pelvic fascia is incised, the pubo-
prostatic ligaments are sectioned, and Santorini’s venous
plexus is ligated. The urethra is then sectioned, and when
the neurovascular bundles are preserved, they are dis-
sected in an ascending direction.
The vesicoprostatic dissection is then performed,
prior to dissection of the seminal vesicles and section of
the vasa deferentes. The anastomosis is then performed
with interrupted sutures.
Overall, this technical modification is designed to
reproduce the various steps of retropubic prostatectomy.
Number of Trocars
Most teams6,9,10 performing laparoscopic radical prosta-
tectomy use 5 trocars, which may be arranged in differ-
ent ways according to the surgeon’s usual practice.
Rassweiler et al.7,8 add a sixth 5-mm trocar at Mac
Burney’s point, which is designed to improve exposure,
especially during seminal vesicle dissection.
Use of an Arm for the Scope
The use of an arm for the scope provides valuable assis-
tance when performing a laparoscopic procedure, such as
radical prostatectomy, as it ensures a fixed image and
frees one of the assistant’s hands, allowing more active
participation in the operative procedure.
Many teams6–10 use a voice-controlled robotic arm
(AESOP), but other types of arms are also available, espe-
cially less expensive, manually guided, compressed air arms.
Modalities of Dissection of Neurovascular
Bundles
Preservation of the neurovascular bundles precludes the
use of mechanical staplers for section of the superior pro-
static pedicles. Control and section of these pedicles and
preservation of neurovascular bundles require precise
dissection, ideally performed by selective bipolar coagu-
lation6,9,11 or even the use of clips.10 The choice between
these two approaches is a matter of personal preference,
as neither technique has been shown to be superior.
Technical Modalities of Vesicourethral
Anastomosis
The vesicourethral anastomosis can be performed with
interrupted sutures or a running suture. Whatever the
choice, the rules are the same and especially the necessity
of using both hands with forehand and backhand.
The running suture has the advantage of being less
time-consuming, but it requires constant, good quality
traction to ensure a perfectly leak proof suture. In every
case, the operator’s experience and that of his team
appear to be essential for both the rapidity and the qual-
ity of the procedure.
Extraperitoneal Approach
In 1997, Raboy et al.2 described, for the first time, their
experience of extraperitoneal laparoscopic radical

prostatectomy. In 2001, Bollens et al.12 reported their
experience of 46 cases performed according to this
technique.
The scope is introduced via a 10-mm trocar placed at
the inferior margin of the umbilicus. Four trocars are
used: two 10-mm trocars placed in the left iliac fossa and
right iliac fossa; a 5-mm trocar is introduced about 5 cm
above the pubic symphysis; and the last 5-mm trocar is
placed in the right flank.
The first phase of the procedure consists of creation of
a prevesical working space. Bladder neck dissection is
performed prior to seminal vesicle dissection. The pelvic
fascia is then incised and Santorini’s venous plexus is lig-
ated. The neurovascular bundles are then dissected
before coagulation and section of the superior prostatic
pedicles. Denonvilliers’ fascia is then incised, releasing
the posterior surface of the prostate. The apex is then
dissected and the urethra is sectioned. The anastomosis is
performed by interrupted sutures.
Overall, the advantages of the extraperitoneal
approach, according to its supporters, would be a reduc-
tion of the risk of damage to intraperitoneal organs and a
similar surgical approach to that of open retropubic
prostatectomy. Its disadvantages would be a limited
working space and the difficulty of the anastomosis due
to the more limited mobilization of the bladder.
We reviewed 200 consecutive procedures performed
in Montsouris Institute by two surgeons; 100 transperi-
toneal procedures were compared to the first 100
extraperitoneal cases. This study showed equivalent
results in term of operative, postoperative, and patholog-
ical data.
PERIOPERATIVE COMPLICATIONS
Improvement of the surgical technique has allowed a
reduction of the morbidity of radical prostatectomy.
Comparative studies of the complications according to
the surgical technique are often difficult and must always
take into account not only the operator’s level of experi-
ence with the technique but also the patient characteris-
tics and finally the modalities of evaluation of
complications, especially functional complications.
The morbidity is related not only to the technique
itself but also to the patient’s comorbidities, particularly
the ASA3 score13 and blood loss.
The mortality rate is currently close to 0%, regardless
of the technique used (retropubic, perineal or laparo-
scopic)14–17 (Tables 31-1 and 31-2).
Considering the different phase of the laparoscopic
procedure, the complications can be divided according
each step:
● Patient positioning
● Insufflation and placement of trocars
Chapter 31 Laparoscopic Radical Prostatectomy 539
● Dissection
● Extraction of surgical specimen and removal of
trocars
● Early postoperative phase
● Late postoperative phase
Complications of Patient Positioning
The main complications at this step are:
● Compartment syndrome
● Peripheral neuropathy
● Scapular pain
The risk is related to protections used for the posi-
tioning and also, obviously, to the length time of the pro-
cedure. So, the surgeon has always to check by himself
the protections of the patients and to take care of the
length time of the operation (conversion is sometimes
the best solution).
Those complications are exceptional (<0.1%), and
their risk decrease significantly with experience of the
surgeon and his team.
Complications of Insufflation and Trocar
Placement
The main risk is vascular or bowel injuries with the first
trocar. There is no rule to use or not open laparoscopic
procedure and the choice depends on the usefulness and
the experience of each team.
Small vessels injury can also occur during the place-
ment of other trocars, especially epigastric artery (0.3%).
Intraoperative Complications
Blood Loss
Median intraoperative bleeding reported by experienced
teams performing retropubic prostatectomy varies
between 1000 and 1500 ml.14,19 Dillioglugil19 reported a
transfusion rate of 29% for all the series and 15% for the
last 135 patients among a total of 472. For Catalona,14
using the technique of hemodilution, most of the patients
received autologous transfusion during or after surgery
and 9% need also heterologous postoperative transfu-
sion. In the same series, the rate of hematoma was 0.05%.
The median blood loss during laparoscopic prostatec-
tomy varies from 370 ml20 to 1230 ml11 for patient series
with a comparable experience.11,20 The transfusion rates
for these two series were 7% and 30%, respectively, at
the beginning of their experience.
Guillonneau et al.17 reported, for the last 100
patients, a mean estimated blood loss of 290 ml and a
transfusion rate of 3.5%. The rate of hematoma in this
series was 1%.
540 Part V Prostate Gland and Seminal Vesicles

Table 31-1 Complications of Radical Prostatectomy

Catalona *Guillonneau *Rassweiler
Study Lepor et al.39 et al.14 (14) et al.17 et al.11

Number of patients 150 1000 1870 567 180

Rectal injury 6/0.6 3/2 5/0.5 1/0.05 8/1.4 1.1

Ileocolic injury nc nc nc nc 4/0.7 nc

Ileus nc nc 4/0.4 nc 6/1.1 2.8

Bladder injury nc nc nc nc 9/1.6 nc

Ureteral injury nc 7/4.7 1/0.1 1/0.05 3/0.5 0

Deep venous thrombosis 13/1.3 4/2.7 2/0.2 39/2 2/0.4 0

Pulmonary embolism 7/0.7 nc 4/0.4 nc 0 0

Anastomotic leakage nc 15/10 2/0.2 nc 46/8.1 2.2

Lymphocele 1/0.1 3/2 1/0.1 11/0.6 1/0.2 0

Hydronephrosis nc nc nc nc nc 2.8

Acute renal failure Nc 2/1.3 nc nc 1/0.2 nc

Pelvic hematomas 1/0.1 nc nc nc 5/0.9 8.9

Wound /0.9 nc 9/0.9 15/0.8 7/1.2 0.6

Nerve injury nc nc 1 5/0.3 3/0.5 0

Myocardiac infarction 7/0.7 0 5/0.5 2/0.1 0 nc

Cerebral vascular accident nc nc nc 0 0 nc

Death nc 1/0.7 1/0.1 0 0 nc

Anastomotic stricture nc nc 10/1 71/3.8 nc 2.8

Total complications 35/3.5 143/8 95/16.7 nc

*Laparoscopic approach.

Table 31-2 Evolution of the Complication Rate with Experience in Laparoscopy (Montsouris Experience)
Patients 1–200 Patients 200–400 Patients 400–567

Lymphadenectomy (%) 25 19 14

Mean operative time (minutes ) 234 190 180

Mean estimated blood loss (ml) 372 398 350

Transfusions (%) 7.5 5 3.8

Conversions (%) 3.5 0 0

Number rectal injuries 3 1 4

Reinterventions (%) 6 7 9

Digestive Injuries
Digestive injuris are rare and directly related to the oper-
ator’s experience and to the patient’s history (especially
previous radiation therapy).
The rate of rectal injuries is similar regardless of the
technique (retropubic or laparoscopic), ranging from
0.5% to 2%.11,19–21
In laparoscopic procedure, using a rectal bougie can
help to identify the rectal wall but cannot ensure risk-free
surgery.
Ureteric Injuries
Ureteric injuries are also rare, occurring in 0.05% to
0.3% of cases, regardless of the technique.
Complications of Specimen Extraction
and Trocar Removal
The complications that can occur are: bleeding from ori-
fice of 10 mm trocar and ileum injury (with the endobag
or during the opening for extraction of the specimen).
These complications are exceptional.
Early Postoperative Complications
Thromboembolic Complications
Thromboembolic complications constitute the main cause
of postoperative mortality in open procedure.1,22
Dillioglugil19 reported 2% of thromboembolic accidents,
while Rassweiler11 and Guillonneau17 reported <0.5% of
thromboembolic accidents.
Prophylactic anticoagulation and early mobilization
(especially after laparoscopic procedure) decrease the fre-
quency of these complications.
Anastomotic Leaks
Anastomotic leaks are often missed when minimal and
correctly drained, and their incidence is therefore often
underestimated.
Length time of bladder catheter has to be directly
related to the quality of the anastomosis.
Lymphoceles
Lymphoceles are now less frequent, whatever the way
laparoscopic or open, due to better selection of patients
requiring pelvic lymph node dissection.
Late Postoperative Complications
Urinary incontinence and impotence are the two most
frequent and most disabling functional sequelae. Stenosis
of the vesicourethral anastomosis is observed more rarely.
Chapter 31 Laparoscopic Radical Prostatectomy 541
Urinary Incontinence
The quality of continence after radical prostatectomy is
difficult to assess (Table 31-3), as reflected by the marked
variability of incontinence rates reported in the litera-
ture. This variability is related to three main factors: def-
inition of incontinence, modalities of evaluation, and
follow-up.
The definition of incontinence varies considerably
from one study to another; total absence of protection
or use of a maximum of one protection. Geary et al.23
reported that 80.1% of patients did not require any
protection, while Eastham et al., 32 considering
patients who required a maximum of one protection to
be continent, reported that 91% of patients were
continent.
No consensus has therefore been reached concerning
the definition of incontinence. In Table 31-2, continence
is defined as complete absence of either occasional or
permanent protection.
The modalities of evaluation also vary from one author
to another: clinical interview by the surgeon, clinical
interview by another doctor, self-administered question-
naire. The method of data collection is essential to obtain
perfectly objective information. Development of a vali-
dated questionnaire, based on a standardized definition,
would facilitate comparison of the various results
reported in the literature.27,30
The follow-up also frequently differs from one
series to another. Although about one-half of patients
are “dry” between 1 and 3 months, and most are dry
at 1 year, some patients can still recover for up to 2
years. A follow-up of at least 12 months is therefore
essential. 23,28,32,33
Furthermore, the main predisposing factor for post-
operative incontinence appears to be age >70
years.14,16,24,32,34 The respective roles of preoperative
continence, stage of the disease, and development of
anastomotic stenosis are also discussed.14,15,23,29,32
Finally, some authors consider that certain technical
modifications appear to facilitate preservation of conti-
nence: quality of apical dissection,15 neurovascular bun-
dle preservation,25 preservation of the bladder neck, and
preservation of puboprostatic ligaments. In any case,
experience of the surgeon is an essential factor to
improve the recovery of continence.
Impotence
As for continence, objective evaluation of sexual potency
encounters a number of difficulties: absence of a consen-
sual definition of sexual potency, various methods of eval-
uation, and variable follow-up (Table 31-4).
The definition of sexual potency varies according to the
criteria adopted: erection with or without sexual inter-
course and erection allowing sexual intercourse.
542 Part V Prostate Gland and Seminal Vesicles

Table 31-3 Continency

Number Follow-Up
Study of Points (months) Evaluation Mean Age =1 Pad/Day (%)

Catalona et al.14 1325 50 Physician 63(38-79) 8

Geary et al.23 458 >18 Physician 64.1±0.3 19.90

Leandri et al.24 620 12 Physician 68 (46–84) 5

Steiner25 593 12 Physician ? (34–76) 5.50

*Turk et al.9 125 9 Physician 60 (37–72) 8

*Bollens et al.12 50 6 Physician 63 (47–71) 15

Igel et al.22 692 Physician 21

*Rassweiler et al.7 100 6 Questionnaire 68 (55–74) 22

Fontaine et al.26 116 51.6 Patient quest 65.2 (48–76) 19.80

McCammon et al.27 203 40.3 Patient quest 63.7 (43–73) 23.70

Jonler et al.28 86 22.5 Patient quest 64 (49–75) 47

Bates et al.29 83 22 Patient quest 65 (49–73) 24

Walsh et al.15 64 18 Patient quest 57 (36–67) 7

Wei and Montie30 145 12 Patient quest 62.3 (40–80) 13

Talcott et al.31 94 12 Patient quest 61.5 39

*Guillonneau et al.17 567 12 Patient quest 63 (49–77) 21

*Hoznek et al.10 29 12 Patient quest 64.8 (47–77) 13.80

*Laparoscopic approach.

The methods of evaluation of sexual potency are also
very heterogeneous, as shown in Table 31-4: clinical
interview by the surgeon, clinical interview by another
doctor, self-administered questionnaire. The possible use
of a treatment for erectile dysfunction, not systematically
reported, also makes it difficult to compare various series.
Follow-up also constitutes an important parameter in
this evaluation. While a large number of series have
demonstrated the possibility of late recovery, most stud-
ies are limited to a relatively short follow-up. The assess-
ment of recovery of sexual function requires a follow-up
of at least 18 months.15,36
Other elements must also be taken into account: qual-
ity of erections before surgery, patient’s age, and type of
surgery (preservation of one or two neurovascular bun-
dles). Moreover, the surgeon’s experience is essential for
preserving the neurovascular bundles. Finally, the selec-
tion of patients eligible for preservation of neurovascu-
lar bundles is an important factor, rarely mentioned in
the literature.14
Anastomotic Stenosis
Stenosis of the vesicourethral anastomosis occurs in
0.5% to 4% of cases.14
ONCOLOGIC RESULTS
The aim of laparoscopic procedure that is to increase the
quality of the dissection and to reduce the morbidity is
only acceptable if the oncologic efficacy is demon-
strated. For patients with organ-confined disease, at
3 years, Catalona et al.14 had a recurrence-free survival of
93%. Similar results are observed by the Johns Hopkins
group where their 5-year recurrence-free was 97% for
organ-confined cancer. In retropubic approach, the rate
of positive margins range between 15% and 40%
depending on the experience of the team and the preser-
vation or not of the neurovascular bundles. In their expe-
rience of laparoscopy, after 3 years, Guillonneau et al.37
observed that 92% of the pT2a and pT2b had a PSA
< 0.1 ng/ml. Among the patients with a PSA < 10 ng/ml
 Chapter 31 Laparoscopic Radical Prostatectomy 543

Table 31-4 Potency

Number Mean Follow-up Impotence
Study of Points Age Months Evaluation (%) Definition

Leandri et al.24 620 68 12 Physician 29 Intercourse

Igel et al.22 692 Physician 97.5 Erection

*Turk et al.9 44 60 ? Physician 41 Intercourse with sildenafil

*Bilatéral 5 nc

*Unilatéral 39 nc

*Rassweiler et al.11 100 68 ? Physician Intercourse

*Unilatéral 10 6/10 Intercourse with sildenafil

or PGE1

Geary et al.23 459 64.1 18 Questionnaire 44.4 Intercourse

Bilatéral 69 68.1

Unilatéral 203 86.7

Catalona et al.14 858 63 18 Questionnaire 33.5 Intercourse

Bilatéral 798 32

Unilatéral 60 53

Fowler et al.35 739 ? 24 Patient quest + 79 Erection

questionnaire

Walsh et al.15 64 57 18 Patient quest 14 Intercourse 1/3 with

sildenafil

Stanford et al.34 1291 62.9 18 Patient quest + 59 Intercourse

questionnaire

Bilatéral 44

Unilatéral 46.6

No preservation 34.4

Talcott et al.31 94 61.5 12 Patient quest

Bilatéral 19 4/19 Incomplete erection

*Bollens et al.12 50 63 6 Patient quest

*Bilateral 6 1/6 Intercourse with sildenafil

or PGE1

*Hoznek et al. 25 64.8 12 Patient quest 11/25 Erection (intercourse?)

*Laparoscopic approach.
544 Part V Prostate Gland and Seminal Vesicles
and a Gleason score < 7, 95.5% had a PSA < 0.2 ng/ml.
The overall rate of positive margin was 17%. No port
seeding was observed.
REMOTE-CONTROLLED ASSISTED RADICAL
PROSTATECTOMY
Laparoscopy is probably a transitional technique
between open surgery and remote-controlled surgery. As
it is no longer necessary to open the abdomen to operate
and almost all of the necessary instruments can be intro-
duced via trocars, it is only logical to develop remote-
controlled surgery for the following reasons; the
laparoscopy position is not very ergonomic. The surgeon
stands to the side of the patient and has to operate by
crossing his hands over the midline, especially for
sutures. This position can cause scapular pain. The vesi-
courethral suture at the bottom of the lesser pelvis is also
a difficult procedure, requiring an experienced operator
to ensure a good quality anastomosis.
Many papers have been written on experimental
remote-controlled surgery in animals, but very few have
yet been published in man. A first series of 10 cases of
remote-controlled assisted radical prostatectomy has been
published.38 The operating time was 9 hours. It should be
noted that this team started to perform remote-controlled
assisted radical prostatectomy without any previous expe-
rience of laparoscopic surgery. Abbou et al.39 published 1
case and, more recently, Guglielmo et al.40 and Pasticier
et al.41 also published their cases. In the United States,
Tewari et al.42 in Detroit, after 1 year of training in pelvic
laparoscopy, have acquired a certain experience with
remote-controlled laparoscopic surgery (70 cases).
The Institut Montsouris experience, based on 30 cases,
together with the cases operated in Detroit, illustrates
the following advantages of remote-controlled surgery:
good ergonomy for the surgeon, whose forearms are
supported to allow precise manipulation of the joysticks.
A possible reduction of the amplitude of displacement of
the remote-controlled robotic arms and especially 6
degrees of freedom, allowing rotation of the remote-
controlled needle holders in all directions, makes sutur-
ing much easier. The 3D vision provided by a dual scope
is extremely precise, but it is not specific to remote-
controlled surgery.
The disadvantages of remote-controlled surgery, at the
present time, are the absence of practical bipolar coagula-
tion to ensure reliable hemostasis and intraoperative
bleeding is slightly greater than with that of laparoscopy.
As good quality bipolar coagulation is essential to ensure
an optimal laparoscopic procedure, engineers are cur-
rently working to rapidly develop this instrument.
The future of surgery is clearly remote-controlled sur-
gery, as it is less tiring for the surgeon and ensures more
precise sutures.
Teaching could be ensured by virtual reconstitution of
prostatectomies from operative videos. The trainee sur-
geon would be able to practice on the operating console
in the same position as when performing remote-
controlled laparoscopic surgery.
Finally, a senior surgeon would be able to control two
or three operating rooms, each equipped with a remote-
controlled system and console operated by a junior surgeon.
The senior surgeon would be in a separate room, super-
vising the external and endoscopic screens of each room
under his direction. His console could be connected in a
fraction of a second to the other operating consoles in the
event of difficulties. Such “industrialization of surgery”
will probably considerably change our everyday practice.
Performing surgery at distant sites would appear to be
more difficult; a surgeon would still need to be present
on site to insert the trocars and to treat any complica-
tions. The transmitted image could be used to help
another surgeon seeking advice, but there is no future for
remote-controlled surgery of the entire procedure.
In conclusion, remote-controlled surgery does not
currently provide any significant benefit for the patient.
Bleeding is higher than with laparoscopic surgery, but the
development of a hemostasis system, such as good qual-
ity bipolar forceps, should reduce bleeding. Suture is eas-
ier, but a surgeon experienced in laparoscopy can achieve
similar results. For the operator, the operation is less tir-
ing and the various procedures are facilitated. Virtual
teaching systems must be developed to allow young oper-
ators to learn the basic techniques of remote-controlled
surgery.
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16. Zincke H, Bergstralh EJ, Blute ML, et al: Radical
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Perioperative complications of laparoscopic radical
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20. Guillonneau B, Rozet F, Barret E, Cathelineau X,
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21. Guillonneau B, Gupta R, El Fettouh H, et al:
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22. Igel TC, Barrett DM, Segura JW, Benson RC Jr, Rife
CC: Perioperative and postoperative complications from
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23. Geary ES, Dendinger TE, Freiha FS, Stamey TA:
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retropubic prostatectomy: morbidity and quality of life.
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26. Fontaine E, Izadifar V, Barthelemy Y, Desgrippes A,
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27. McCammon KA, Kolm P, Main B, Schellhammer PF:
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28. Jonler M, Madsen FA, Rhodes PR, et al: A prospective
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of life in patients undergoing radical retropubic
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29. Bates TS, Wright MP, Gillatt DA: Prevalence and impact
of incontinence and impotence following total
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30. Wei JT, Montie JE: Comparison of patients’ and
physicians’ rating of urinary incontinence following radical
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31. Talcott JA, Rieker P, Propert KJ, et al: Patient-reported
impotence and incontinence after nerve-sparing radical
prostatectomy. J Natl Cancer Inst 1997;
89(15):1117–1123.
32. Eastham JA, Kattan MW, Rogers E, et al: Risk factors for
urinary incontinence after radical prostatectomy. J Urol
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33. Donnellan SM, Duncan HJ, MacGregor RJ, Russell JM:
Prospective assessment of incontinence after radical
retropubic prostatectomy: objective and subjective
analysis. Urology 1997; 49(2):225–230.
34. Stanford JL, Feng Z, Hamilton AS, et al: Urinary and
sexual function after radical prostatectomy for clinically
localized prostate cancer: the prostate cancer outcomes
study. JAMA 2000; 283(3):354–360.
35. Fowler FJ Jr, Barry MJ, Lu-Yao G, et al: Patient-reported
complications and follow-up treatment after radical
prostatectomy. The National Medicare experience:
1988–1990 (updated June 1993). Urology 1993;
42(6):622–629.
36. Kim ED, Nath R, Slawin KM, et al: Bilateral
nerve grafting during radical retropubic
prostatectomy: extended follow-up. Urology 2001;
58(6):983–987.
37. Guillonneau B, Gerard C, El Fettouh H, et al: Mid-term
oncological follow-up of laparoscopic radical
prostatectomy: mono-institutional experience based on
800 consecutive patients. In 97th Annual Meeting, AUA,
Orlando, May 2002.
38. Binder J, Kramer W: Robotically assisted laparoscopic
radical prostatectomy. BJU Int 2001; 87:408–410.
39. Abbou CC, Hoznek A, Salomon L, et al: Laparoscopic
radical prostatectomy with a remote controlled robot.
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546 Part V Prostate Gland and Seminal Vesicles
40. Guglielmo B, Nakada SY, Rassweiler JJ: Future
developments and perspectives in laparoscopy. Eur Urol
2001: 40:84–91.
41. Pasticier G, Rietbergen JBW, Guillonneau B, et al:
Robotically assisted laparoscopic radical prostatectomy:
feasibility study in men. Eur Urol 2001; 40:70–74.
42. Tewari A, Desari R, Hemal A, et al: A prospective
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C H A P T E R
32Complications of Surgical Treatment
for Localized Prostate Cancer
Glen W. Barrisford, MD,
and Michael P. O’Leary, MD, MPH
In developed countries prostate cancer represents the
most commonly detected malignancy and the second
leading cause of cancer death in men over 50. In the year
2000, over 180,000 American men were newly diag-
nosed.1 Despite the 30% lifetime risk of developing
prostate malignancy, the protracted course of this disease
only results in a comparatively low 3% risk of death.2
The number of prostate cancer deaths has been esti-
mated to rise in accordance with an aging worldwide
population. However, the emphasis on screening and
early detection, through digital rectal examination
(DRE) and prostate-specific antigen (PSA) testing, has
resulted in a downward trend in the United States.
Accordingly, 77% of newly detected cancers will be lim-
ited to the prostate (T1 to T2).3
The objective of treatment for localized prostate
malignancy is cure. Historically, prostatectomy has been
treatment of choice. Originally described in 1894 by
Fuller,4 prostatectomy was performed via the suprapubic
approach. However, this method was a blind 15-minute
procedure that required digital enucleation of the gland.
In 1900, Freyer5,6 completed a series of 1600 cases that
carried a 5% mortality. This mortality was considered
diminutive in the absence of antimicrobials and blood
product replacement. In 1947, Millin7 introduced the
retropubic prostatectomy, which was summarily
embraced as the new method of choice. Several modifi-
cations and new techniques followed, but radical change
did not again take place until 1979. At this time, a more
complete description of the surgical anatomy resulted in
an innovative and meticulous surgical approach to the
dissection of the prostate and with preservation of the
neurovascular bundles.8,9 The anatomic prostatectomy
described by Walsh10 offered several advantages, includ-
ing preservation of the cavernous nerves, improved
hemostasis, superior exposure, and a very defined apical
dissection. These improvements, coupled with improve-
ments in anesthesia and surgical care, have lead to a
steady decline in morbidity and mortality over the last
20 years.11
Despite the great success of surgical treatment for
localized prostate disease, the complications remain sig-
nificant. Persistent imperfections of surgical therapy have
encouraged clinicians to seek other, less morbid nonsur-
gical treatment modalities. Alternatives to surgical ther-
apy have included watchful waiting,12,13 transperineal
prostate brachytherapy,14,15 external and conformal beam
radiation therapy, cryotherapy, and laser ablation.
However, these alternative modalities offer an equally
complex combination of risks and benefits. Ultimate
choice of treatment is therefore a comprehensive deci-
sion based on a number of factors, including patient pref-
erence and physician bias.
This chapter addresses several central topics. First, the
discussion will focus on the surgical complications.
Second, the methods designed to reduce risks will be con-
sidered. Third, the treatment options for the presented
complications will be evaluated. To conclude, there will
be consideration of quality-of-life evaluation and treat-
ment satisfaction in the setting of common complications.
SURGICAL APPROACHES
The anatomic prostatectomy (radical retropubic prosta-
tectomy) described by Walsh remains the mainstay of
current surgical technique. Many variations and modifi-
cations are utilized, but the critical elements are near uni-
versal. The dissection can be completed in a retrograde
547
548 Part V Prostate Gland and Seminal Vesicles
or anterograde fashion with judicious preservation of the
circular fibers of the bladder neck and neurovascular
bundles.16 In comparison to the 5% mortality described
by Freyer, contemporary series utilizing the anatomic
retropubic prostatectomy carry a morbidity and mortal-
ity in the range of 0% to 1.7%.10
Perineal prostatectomy remains as an alternative to
radical retropubic prostatectomy. The main advantages
include an avascular field, improved exposure for vesi-
courethral anastomosis, and dependent postoperative
drainage.10 However, there are several disadvantages.
First, there exists a requirement for two incisions to com-
plete the pelvic lymph node dissection. Second, this
method presents a more difficult anatomic approach for
the task of preserving the neurovascular bundles.
Additionally, the perineal approach is contraindicated in
individuals who have undergone prior open prostate sur-
gery, in those who are obese patients, and in patients with
musculoskeletal conditions that would prohibit exagger-
ated lithotomy positioning.
Laparoscopic prostatectomy has recently gained wide-
spread recognition following its initial description in
1999.17–19 However, there exists ongoing debate regard-
ing the benefits. For the individual surgeon, it is a techni-
cally demanding procedure with a relatively steep
learning curve. Initial cases often require extended opera-
tive time and result in increased urinary leakage and rectal
injuries.20 These differences eventually become statisti-
cally insignificant once the preliminary obstacles have
been overcome. In experienced hands, the laparoscopic
approach offers a reduction in lymphoceles, wound infec-
tion, pulmonary embolism, pneumonia, and anastomotic
stricture.20 Laparoscopic prostatectomy offers potential
new alternatives for reducing surgical morbidity and
improving the results of radical prostate surgery.
PATIENT SELECTION
Preoperative evaluation and appropriate patient selection
is the critical first step in complication reduction. At our
institution, the preoperative evaluation begins in the uro-
logic clinic with a complete history, physical examina-
tion, and appropriate screening. Criteria for selection of
the surgical candidate includes: biopsy proven histologic
presence of prostate malignancy; clinically established
localized disease (T1 to T2); a life expectancy of >10 years;
absence of surgical contraindications (comorbid condi-
tions); and informed consent of the patient. Under the
guidance of the anesthesia team, the assessment contin-
ues in the preadmission testing center. The American
Society of Anesthesiology (ASA) scoring system is utilized
to estimate the risks associated with various existing comor-
bidities. Additional evaluation is tailored to the individual
patient. In the absence of further preoperative assess-
ment, the patient returns on the morning of surgery.
Several general guidelines are followed when prepar-
ing for operative therapy. Radical prostatectomy should
be delayed 4 to 8 weeks following transrectal ultrasound
guided biopsy10,21 and 3 to 4 months following
transurethral resection of the prostate.21 The purpose of
this delay is to afford resolution of the postprocedure
inflammatory response, resulting in a more precise intra-
operative dissection.
At our institution, bowel preparation and autologous
blood donation are offered but are not routinely under-
taken. Transfusion rates approximate 20%. Perioperative
pain control is established with intravenous narcotic
boluses and 48 hours of standing dose ketorolac.
Transition to oral narcotics routinely occurs by postoper-
ative day 1. The expected length of hospital stay is 2 days.
The average cost of hospitalization (in the absence of
physician reimbursement) is approximately $25,500.
OPERATIVE COMPLICATIONS
Hemorrhage predominates as the most common intraop-
erative complication associated with prostatectomy.
Venous hemorrhage may occur during pelvic lym-
phadenectomy and originates from branches of the
hypogastric vein. Additionally, venous backbleeding from
the Doral vein complex can occur during several stages of
the procedure, including incision of the endopelvic fas-
cia, division of the puboprostatic ligaments, and during
exposure of the prostatic apex. Expected blood loss is
typically 1 liter,22 and is routinely greater during nerve-
sparing approaches. Persistent hemorrhage characteristi-
cally resolves once the dorsal vein complex is divided and
ligated.
Rectal injury is a rare complication of radical prostate
surgery (0% to 5.3%),22–26 typically occurring during the
apical dissection while developing a plane between the
rectum and Denonvilliers’ fascia. In the event of injury,
the rectum should be repaired in 2 layers with an inter-
posed pedicle of omentum. This method has been asso-
ciated with a low incidence of rectourethral fistula and
abscess formation.23,24 Rectal injuries that are not identi-
fied intraoperatively carry the highest probability of fis-
tula formation. Intestinal diversion can usually be
avoided, with the exception of patients who have received
previous pelvic irradiation. In these cases, diversion
should be the standard of care.
Ureteral injury is another rare complication that
occurs on the order of 1%.25 This injury classically occurs
during extended pelvic lymph node dissection at the iliac
bifurcation or while dissecting the posterior aspect of the
bladder neck. Injuries are more commonly associated with
advanced stages of disease and are repaired with uretero-
neocystostomy if identified intraoperatively.
Nerve injury is another rare complication associated
with pelvic lymph node dissection. These injuries often
 Chapter 32 Complications of Surgical Treatment for Localized Prostate Cancer 549
occur from sharp dissection or as a result of retractor
positioning. The two most commonly injured nerves are
the obturator and the femoral. Obturator nerve injury
may result in a thigh abduction deficit, whereas femoral
nerve injury may lead to distressing weakness of the
quadriceps, combined with anteromedial thigh paresthe-
sia. Intraoperative identification of these injuries indi-
cates primary repair with fine absorbable sutures. Injury
that is not identified intraoperatively is managed conser-
vatively with physical therapy. The majority of patients
will eventually fully recover from these injuries.
POSTOPERATIVE COMPLICATIONS
Early Complications
In the immediate postoperative, period the most com-
mon and potentially devastating complications include
thromboembolism, pulmonary embolism, and myocar-
dial infarction. Subcutaneous heparin, sequential com-
pression devices, and early ambulation have all been
successfully utilized postoperatively to minimize risks.
Recent series have demonstrated a 0.8% to 2.7% throm-
boembolic complication rate.21 Prophylactic low dose
heparin has not been associated with increased risks of
postoperative bleeding. Additionally, intraoperative
Trendelenburg positioning has been thought to enhance
passive venous drainage of the lower extremities.
Myocardial infarction remains an uncommon, though
grave, complication, requiring special efforts to minimize
risks. Specific preoperative evaluation and perioperative
management recommendations are addressed in high-
risk patients during the preoperative assessment. The
coordination of the surgical, anesthesia, and cardiology
teams is crucial in order to implement optimum cardio-
vascular medical management. Likewise early recogni-
tion of symptoms and intervention are essential in
appropriately managing this complication.
Wound infection/dehiscence, seroma, lymphocele
formation, and delayed hemorrhage are all uncommon
early postoperative complications. Sterile technique and
perioperative gram-positive prophylactic antibiotic cov-
erage is utilized to reduce the risk of wound infection.
Appropriate fascial closure, hemostasis, and lymphostasis
reduce risks for dehiscence, hemorrhage, and lympho-
cele, respectively. Hematoma or lymphocele formation
may require computed tomography (CT)-guided
drainage in order to prevent the development of a pelvic
abscess.
Anastomotic disruption commonly occurs in the early
postoperative period when the Foley catheter is uninten-
tionally dislodged. Intraoperative testing of the balloon
establishes catheter integrity. Further methods to prevent
dislodgment include secure catheter anchorage via intra-
operative cystotomy and attachment of the catheter to an
abdominal wall button. In the event that the catheter is
unintentionally removed, a single attempt at replacement
can be initiated with a smaller caliber coude tip catheter.
If the catheter does not easily pass on the first attempt,
placement should be undertaken under direct vision with
cystoscopy. If catheter removal occurs after postoperative
day 5, the patient can be safely monitored without
catheter reinsertion.21
Anastomotic leakage is another rare early complica-
tion of radical prostate surgery. Typically the vesi-
courethral anastomosis consists of 4 to 6 precisely placed
sutures. Leakage can occur when the anastomotic
integrity is incomplete or compromised. The observation
of high serous output from the surgical drains suggests
urinary leakage. To verify suspected urinary leakage, a
creatinine level can be measured in the drain output.
Drain output creatinine that mirrors urinary creatinine is
diagnostic of an anastomotic leak. The majority of small
anastomotic leaks resolve spontaneously or with
extended Foley catheter drainage. In the setting of a large
leak, urinoma formation can occur and may require CT-
guided drainage.
Late Complications
Bladder Neck Contracture
Bladder neck contracture is a late complication of prosta-
tectomy. It is known to occur weeks to months postoper-
atively and typically presents with urinary incontinence
and/or a weak urinary stream. Generally, bladder neck
contracture is thought to be an uncommon complication.
However, it has been reported in 3% to 12% of cases.10
It is suspected to be a consequence of poor vesicourethral
anastomotic quality. The construction of a dependable
anastomosis requires adequate vascularity and an imper-
meable seal. Meticulous surgical technique, hemostasis,
eversion of the bladder neck, superior mucosal apposi-
tion, and the use of 4 to 6 fine absorbable sutures pro-
motes a proper anastomosis. Intraoperative bleeding can
lead to pelvic hematoma and the formation of an anasto-
motic disruption. Poor surgical technique can lead to uri-
nary extravasation and subsequent periurethral scarring.
This scarring can lead to urinary stricture and inconti-
nence.
Bladder neck contracture is a difficult diagnosis to
establish when overflow incontinence is the only pre-
senting complaint. Evaluation includes measurement of
postvoid residual urine volumes and identification using
urethroscopy. Once the diagnosis is established it can be
treated with dilation. Typically, 1 to 2 dilation procedures
will resolve the contracture. Rarely dilation can result in
a perforation into the rectum and result in a rectourethral
fistula. This can become a very challenging problem.
Failure of dilation can be resolved with incisions made in
the bladder neck at the 12 o’clock, 3 o’clock, and
9 o’clock positions.
550 Part V Prostate Gland and Seminal Vesicles
Urinary Incontinence
Urinary incontinence has been considered by many to be
the most distressing and disabling complication of
prostate surgery. Prior to the description of the anatomic
prostatectomy, total urinary incontinence was observed
in 10% of men.27 Fortunately, complete urinary inconti-
nence is now an uncommon occurrence. However, lesser
degrees of incontinence exist and represent one of the
most important quality-of-life measures in radical prosta-
tectomy patients.
Historically assessing the complication rate has been a
challenge. In extensive academic series, incontinence
rates have been reported in 0.3% to 12.5% of
patients.28–30 However, some degree of urinary leakage
was reported in 30% of men according to the National
Medicare Experience.31 The wide range of reported
incontinence could be attributed to varied definitions
applied by both physicians and patients. As a conse-
quence, studies reported in the literature have been diffi-
cult to interpret. Several questionnaires have been
developed in order to standardize the definition of incon-
tinence, in turn allowing for greater comparison among
studies.
Normal urinary continence is achieved when a stable
compliant detrusor is coupled with a competent bladder
outlet (sphincter mechanism). The sphincter mechanism
is considered as two functionally distinct units, the proxi-
mal and distal urethral sphincters. The proximal sphinc-
ter mechanism consists of the bladder neck, prostate, and
prostatic urethra to the level of the verumontanum. The
distal urethral sphincter is comprised of mucosal infold-
ing, longitudinal smooth muscle, striated muscle, and the
intrinsic periurethral rhabdosphincter distal to the veru-
montanum. Passive continence is maintained by the stri-
ated urethral sphincter. It consists of slow twitch fibers
that are capable of maintaining tone over prolonged peri-
ods of time. This is in comparison to, periurethral leva-
tor ani muscle fibers, which are fast twitch and are
associated with rapid forceful muscle contraction. This
mechanism is designed to maintain continence during
events that raise intra-abdominal pressure. Failure of
the sphincter mechanism leads to urinary incontinence.
The proximal sphincter mechanism is removed during
radical prostatectomy and the distal sphincter mechanism
is then solely responsible for the maintenance of urinary
continence.
A number of risk factors have been thought to be asso-
ciated with increased risk of urinary incontinence follow-
ing radical prostatectomy. Patient age at surgery,
preoperative continence status, previous transurethral
resection of the prostate, anastomotic stricture, stage of
disease, surgical technique, and experience of the sur-
geon have been evaluated to determine significance with
respect to postoperative continence. Greater inconti-
nence rates are observed with advancing age. This has
been attributed to rhabdosphincter atrophy32 and neural
degeneration.33,34 Preoperative urinary incontinence can
persist postoperatively. More advanced stages of disease
are likely to be associated with greater dissection and lead
to increased rates of incontinence. Surgical technique
and surgeon’s experience have also been determined to be
significant factors in predicting postoperative continence
rates.35
Evaluation of postoperative incontinence begins with a
complete history and physical examination. Type and
severity of incontinence, precipitating factors, number of
daily episodes, and degree of protection (pads, penile
clamp, etc.) required should be established. A history con-
sistent with stress incontinence has been associated with
the existence of sphincter dysfunction.36 Initial blood tests
may incorporate blood urea nitrogen, creatinine, and PSA
(to detect cancer recurrence). Measurement of postvoid
residual urine volume and noninvasive uroflow are
included in the initial evaluation. However, urodynamic
testing remains the most valuable method available to
accurately diagnose the cause of urinary incontinence.
Cystourethroscopy can also be utilized to evaluate the
mucosal surfaces, vesicourethral anastomosis, and bladder
wall, but it is particularly useful for direct visualization if
surgical intervention is considered.
The problem of postoperative urinary incontinence
can be dealt with effectively at many levels. Therapy
should be tailored to maximize patient’s quality of life
and minimize additional risks and complications. Many
patients will meet the criteria for urinary incontinence
but do not consider it to negatively impact quality of life.
It is vital to identify patient bother and expectations of
treatment. Once the diagnosis has been established, the
problem can be addressed in a stepwise fashion.
Fluid restriction, behavioral modification, anticholin-
ergic/tricyclic antidepressant medication and pelvic floor
exercises have been utilized to address postoperative uri-
nary incontinence attributed to bladder dysfunction. For
patients with significant urinary complaints who fail
these methods, augmentation cystoplasty,37 or neuro-
modulation (not yet studied in postprostatectomy
patients) can be considered.
Sphincter dysfunction can be addressed similarly with
biofeedback and pelvic floor exercises. In cases of sphinc-
ter dysfunction, these methods have met with mixed
results with respect to restoration of continence.
However, they have been effective in reducing the
postoperative interval required to regain continence.38
Alpha agonists (ephedrine, phenylpropanolamine) and
imipramine have been used in females with sphincteric
(stress) urinary incontinence but have not been evaluated
in prostatectomy patients. These agents are unlikely to
offer substantial results and will likely be of limited use.39
Bulking agents injected beneath the urethral mucosa
 Chapter 32 Complications of Surgical Treatment for Localized Prostate Cancer 551
(glutaraldehyde cross-linked bovine collagen, silicone
macroparticles) have offered short-term efficacy. The
difficult identification of anatomic landmarks and scar-
ring has resulted in low rates of total dryness. Sling pro-
cedures have been used in limited cases as prophylaxis
during radical prostate surgery. A rectus muscle fascial
sling has effectively resulted in earlier and more complete
return of urinary continence.40 The most efficacious pro-
cedure available to address urinary incontinence is the
artificial urinary sphincter. It has been widely used for
treating urinary incontinence of various etiologies.41–44
Of those receiving an artificial urinary sphincter 77%
have been satisfied and have reported a significant reduc-
tion in the number of pads used for protection.45 In cases
refractory to all forms of therapy urinary diversion has
been employed to relieve intolerable incontinence.
A better understanding of the pelvic floor anatomy has
resulted in improved continence rates. Despite the vari-
ous modalities used to treat urinary incontinence it
remains a difficult problem. A number of intraoperative
techniques have been utilized to preserve urinary conti-
nence. Bladder neck preservation,46 intussusception,27
and tubularization (preservation of functional urethral
length)47,48 have provided efficacy in reducing postoper-
ative time to continence. Unfortunately, these techniques
have not offered an improvement in overall continence.
A longer functional urethral length has been associated
with greater continence.31,35 Consequently, preoperative
evaluation of the functional urethral length via endorec-
tal magnetic resonance imaging may offer predictive
information regarding postoperative continence rates.49
Such information could influence patient choice of ther-
apy. Sparing of the puboprostatic46 ligament and mainte-
nance of the urethral mucosal vascularity have not been
shown to affect,30 postoperative continence rates.50
Erectile Dysfunction
When Young described radical perineal prostatectomy in
1903, the procedure had been associated with a 60%
mortality.51 Following Young’s anatomic description
mortality was reduced to 16.6% (incontinence 13%).52
At that time preservation of potency had not been
deemed a priority. Consequently, over 60% of patients
were left with erectile dysfunction. Despite the reduction
of mortality over time, emphasis had not shifted toward
preservation of potency until the nerve-sparing approach
was described by Walsh and Donker.9 Subsequent to the
development of the anatomic prostatectomy, preserva-
tion of potency soon became a reasonable objective.
Potency has been defined as the ability to establish and
maintain an erection that is suitable for intercourse. In a
large series, 503 patients were deemed preoperatively
potent. Postoperatively 68% were found to have retained
erectile function. Age, stage of disease, and extent of
nerve sparing (unilateral or bilateral) were substantial
factors affecting potency.53,54 Younger age, less advanced
disease and preservation of both neurovascular bundles
were all found to be associated with greater postoperative
erectile function.
Postoperatively patients often may experience a wide
variety of emotions related to a change in body image,
the possibility of cancer recurrence, incontinence, erec-
tile dysfunction, and a change in relationship dynamics.
During the months following surgery erectile dysfunc-
tion may be partially attributed to psychogenic factors.
However, preoperative and postoperative libido meas-
urements by O’Leary et al.55 brief sexual function inven-
tory was not found to be significantly different from age
matched controls. Despite the numerous reasons to have
psychogenic erectile dysfunction, the majority of patients
have been found to have an organic origin as determined
by nocturnal penile tumescence or Rigiscan studies.56
The origin of the erectile dysfunction is likely multifac-
torial but largely a result of neurovascular damage and
preexisting disease.
Treatment for postprostatectomy erectile function has
been addressed at several levels of invasiveness. Patient
desire to regain potency should dictate the vigor of the
treatment regimen. An initial wait and see approach has
been advocated to allow spontaneous recovery of erectile
function. Resolution of surgical inflammation, tissue
healing, and resolution of neuropraxia can take 1 to 2
years. After that time it is reasonable to assume that
greater improvement is unlikely.
Vacuum erection devices offer a mildly effective non-
invasive therapy. However, the ring used to maintain
tumescence may serve to prolong natural revitalization.57
Intraurethral prostaglandin therapy (MUSE) became
widely popular in 1997. Initial reports boasted a 57% to
70% success, with a disproportionate 20% satisfaction
rate.58 However, intraurethral therapy offered a less inva-
sive option for men than the more invasive intracaver-
nosal injection therapy (Caverject/PGE1/trimix). Since
1983, intracavernosal therapy has been highly effective,
once men overcome the fear of self-injection. It has been
associated with pain (14%), penile fibrosis (2% to 15%),
cumbersome mixtures, and relative expense.59 Sildenafil,
a selective phosphodiesterase-5 inhibitor, gained wide
popularity in 1998 as the first oral therapy for erectile
dysfunction. Initial trials reported a 43%60 response rate,
while subsequent trials report satisfaction rates from
15% to 80%.61–63 Despite the mixed response rates it
became the best selling medication of all time and soon
became the first line of therapy for erectile dysfunction.
Penile prosthesis has remained the most invasive and last
line of therapy. In the event of treatment failure at all lev-
els a prosthetic device can be placed with great efficacy.
Since 1973, these devices have successfully restored
potency. Infrequent infections can occur and may require
552 Part V Prostate Gland and Seminal Vesicles
explanation of the device. Fortunately, those cases are the
rare exception.
Erectile dysfunction has historically been a low profile
problem of great magnitude. Over the last 2 decades
research has focused on improving the quality of life in
postprostatectomy patients. Treatment efficacy continues
to rise while delivery methods become less invasive. The
future for therapy in erectile dysfunction will likely rely
on more selective and mechanistically varied oral agents,
and neurogenic and vascular growth factors aimed at the
restoration/preservation of function.
Quality of Life
Quality of life has become a central theme to consider
when counseling patients with localized prostate disease.
Over the last decade several nonsurgical therapies have
arisen that may offer less objectionable side effects while
providing a comparable rate of survival. Patients are less
likely to seek a therapy that will provide a lower quality
of life. In order to evaluate patient satisfaction with radi-
cal prostatectomy a number of questionnaires have been
created, validated, and administered.64,65 These patient
surveys report that the primary concern remains survival,
and than a strong concern for urinary incontinence and
erectile dysfunction. Difficulty with continence and
potency are most associated with a decrease in a patient’s
perception of his own well-being.21 However, as surgical
techniques have improved in treating prostate cancer and
as our ability to manage complications has also improved,
more men have and will continue to be effectively treated
for this very common cancer.
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53. Quinlan DM, Epstein JI, Carter BS, et al: Sexual function
following radical prostatectomy: influence of preservation
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54. Rabbani F, et al: Factors predicting recovery of erections
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55. O’Leary MP, Fowler FL, Lendrking WR, et al: A brief
male sexual function inventory for urology. Urology 1995;
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56. Sohn MH, Seeger U, Sikora R, et al: Criteria for
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57. Montorsi F, Guazzoni G, Strambi L, et al: Recovery of
spontaneous erectile function after nerve sparing radical
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intracavernous injections of alprostadil. J Urol 1997;
158:1408–1410.
58. Costabile RA, Spevak M, Fishman IJ, et al: Efficacy and
safety of transurethral alprostadil in patients with erectile
dysfunction following radical prostatectomy. J Urol 1998;
160:1325–1328.
59. Evans C: Complications of intracavernosal therapy for
impotence. In Carson C, Kirby R, Goldstein I (eds):
Textbook of Erectile Dysfunction, pp 365–370. Oxford,
Isis Medical Media, 1999.
60. Pfizer data on file. New York, Pfizer, 1998.
61. Marks LS, Duda C, Dorey FJ, et al: Treatment of erectile
dysfunction with sildenafil. Urology 1999; 53:19–24.
62. Zippe CD, Jhaveri FM, Klein EA, et al: Role of Viagra
after radical prostatectomy. Urology 2000; 55:241–245.
63. Zagaja GP, et al: Sildenafil in the treatment of erectile
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554 Part V Prostate Gland and Seminal Vesicles

64. Sebesta M, et al.: Questionnaire-based outcomes of 65. Penson DF, Litwin MS, Aaronson NK: Health related
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2002; 60(6):1055–1058.
C H A P T E R
33 Seminal Vesicles: Diagnosis, Staging,
Surgery, and Management
Nelson N. Stone, MD, Richard G. Stock, MD,
and Pamela Unger, MD
Malignant tumors of the seminal vesicles are uncommon.
The most frequent etiology results from secondary exten-
sion from prostate cancer. The diagnosis of prostate can-
cer within the vesicles requires pathologic assessment of
seminal vesicle tissue. Unlike with prostate cancer, where
an elevated prostate-specific antigen (PSA) or an indurated
nodule motivates the urologist to perform a biopsy, there
are few indications for sampling seminal vesicle tissue.
Generally, there are no presenting signs or symptoms
that would indicate tumor of the seminal vesicles.
However, pain, a sensation of prostate congestion, irrita-
tive bladder symptoms, hematospermia or hematuria
may suggest to the clinician that a digital rectal and
prostate exam is indicated.1–6 A palpable mass, involving
the base of the prostate in association with an elevated
PSA, usually indicates the presence of prostate cancer.
However, a normal PSA, in association with a lesion that
seems to occupy just the seminal vesicles may indicate a
primary process. If this is the case, further investigation
is warranted. More common benign lesions, such as sem-
inal vesicle cysts, as well as uncommon lesions, such as
papillary adenomas, cystadenomas, fibromas, myomas,
and schwannomas have been reported.1–6 Primary
tumors of the vesicles include adenocarcinoma, rhab-
domyosarcoma, squamous cell carcinoma, myosarcoma,
hemangiosarcoma, cystadenocarcinoma phyllodes, and
seminoma.7
DIAGNOSIS AND EVALUATION
Biopsy is warranted when a suspicious lesion of the vesi-
cles is encountered and can be most easily accomplished
by the transrectal ultrasound-guided route. Additional
evaluation will depend on the pathology, with asympto-
matic benign lesions requiring no further testing.
Primary malignancies should undergo extensive radio-
logic evaluation to help ascertain the feasibility of surgi-
cal or radiotherapeutic intervention.
Transrectal ultrasound-guided biopsy of the vesicles is
easy to perform and for the most part is done the same
way as prostate biopsy.8–16 The only differences is that
the spring-loaded needle should be positioned just poste-
rior to the wall of the seminal vesicle so the core will
include both posterior and anterior walls and not punc-
ture the base of the bladder (Figure 33-1). The cores of
tissue are similar to prostate cores and, when normal,
should not be difficult for the pathologist to interpret.
The decision to perform a seminal vesicle biopsy when
evaluating patients with a diagnosis of prostate cancer is
controversial. Several studies have determined the accu-
racy of performing such biopsies, although the number of
biopsies (ranging from 1 to 6 cores) and where to take
them has not been standardized. Wymenga et al.15 per-
formed 2 biopsies at the junction of the seminal vesicles
prior to radical prostatectomy. Eighty-three out of 138
had positive biopsies and the accuracy was 91%. PSA,
clinical stage, and Gleason score were all predictive of SV
involvement. Okihara et al.16 performed SV staging
biopsies in 244 men with prostate cancer and found 31%
positive. The number of cores taken varied with their
clinical indication for the biopsies. Ninety underwent RP
and no false positive biopsies were encountered. Stone
described a technique where 6 seminal vesicle biopsies
were taken, 3 from each side at a separate setting.13 With
this technique, 15% of patients were found to have vesi-
cle involvement. Linzer and associates7 compared the 6
biopsy method (n = 222) to a cohort of 187 men who had
radical prostatectomy and developed indications for vesicle
biopsy (Table 33-1). Univariate and multivariate analyses
demonstrated a PSA > 10 ng/ml, Gleason score ≥ 7,
555
556 Part V Prostate Gland and Seminal Vesicles
and clinical stage T2b (1992 AJCC) independently
predicted for involvement of the vesicles.7 Based on these
data, the following indications for seminal vesicle biopsy
were developed: PSA > 10 ng/ml or stage T2b or greater
or Gleason score ≥ 7. In contrast, Fowler found no
advantage in performing a seminal vesicle biopsy in con-
junction with the prostate biopsy.17 He performed only
one biopsy that was taken at the time of the initial
prostate biopsy. These data suggest that if seminal vesicle
staging is to be performed, at least 4 biopsies should be
taken and they should not be performed at the time of
the primary prostate biopsy.
Tables or nomograms have also been used to predict
extraprostatic disease.18–20 Penson et al.19 used the Partin
tables to assess the probability of extraprostatic extension
in 1162 men from the CapSure database. The calculated
receiver operating characteristics curve area was 0.726
Figure 33-1 Transrectal ultrasound guided biopsy of the
seminal vesicles.
Table 33-1 Likelihood of Encountering Prostate Cancer Involving the Seminal Vesicles either by Trus-Guided
Seminal Vesical Biopsy (SVB, n = 222) Prior to Radiation Therapy or Following Radical Prostatectomy
(RP, n = 187)
Clinical Positive SVB in
Characteristics Radiation Patients
PSA 10–20 ng/ml 11/63 (17%)
PSA > 20 ng/ml 17/53 (32%)
T2b 19/96 (20%)
T2c 11/37 (30%)
Gleason score 7–10 23/62 (37%)
From Linzer DG, Stock RG, Stone NN, et al: Urology 1996; 48:757–761.
for predicting seminal vesicle involvement. While nomo-
grams are predictive of seminal vesicle involvement, they
are not a substitute for biopsy. In planning a patient’s
treatment, the confirmed presence of vesicle involvement
will influence further diagnostic evaluation and the even-
tual treatment decision.
Endorectal coil magnetic resonance imaging (MRI)
has also been used to detect extracapsular extension and
seminal vesicle invasion.20 The MRI has a high specificity
when it detects SV involvement, but a sensitivity of <50%
is suggesting that it often misses smaller tumors.21
Pathologic confirmation, by biopsy will most likely be
required if the MRI is suggestive of vesicle involvement.
If the urologist aggressively stages the high-risk
prostate cancer patient using the seminal vesicle biopsy,
then a diagnosis of extraprostatic extension can be made
in advance of definitive therapy. Advance knowledge of
seminal vesicle involvement may preclude recommenda-
tions for standard radical prostatectomy, external beam
irradiation, or brachytherapy. In addition, patients with
seminal vesicle involvement are at increased risk for
pelvic lymph node metastases.12,13 One-third of men with
biopsy detected seminal vesicle involvement will have
metastases to the pelvic lymph nodes. These patients
should probably undergo pelvic lymph node dissection
prior to considering definitive therapy.12,13,16
TREATMENT OPTIONS FOR PATIENTS WITH
SEMINAL VESICLE INVOLVEMENT
The treatment of patients with seminal vesicle involve-
ment from prostate cancer will depend on whether it was
discovered following prostatectomy or if it was identified
by biopsy prior to definitive therapy. The literature seems
to indicate that the former is the more common scenario.
The options for treating patients following prostatectomy
include observation, adjuvant radiation therapy, or hor-
SV Involvement
in RP Patients p-Value
6/39 (15%) 0.78
22/165 (13%) 0.98
14/66 (21%) 0.82
2/13 (15%) 0.31
8/40 (20%) 0.06
 Chapter 33 Seminal Vesicles: Diagnosis, Staging, Surgery, and Management 557
monal therapy. The argument for treatment is the high
recurrence rate, while the argument for observation and
deferred therapy is the lack of randomized studies indi-
cating an advantage of one over the other.
The choice to administer some forms of adjuvant
therapy results form the high relapse rate. Sofer et al.22
assessed the outcomes of 812 men of whom 106 (13%)
were found to have seminal vesicle involvement follow-
ing radical prostatectomy. At an average follow-up of 48
months follow-up, 53% of the entire cohort were free of
disease (PSA < 0.4 ng/ml). In an analysis of prognostic
variables only patients with a PSA > 10 ng/ml showed a
higher recurrence rate (70% versus 30%, p < 0.001). The
5-year likelihood of being disease free with seminal vesi-
cle involvement was 35%.
Van den Ouden et al.23 performed radical prostatec-
tomy on a group of 83 men with T3 prostate cancer. Of
these patients, 64 (77%) were found with extracapsular
extension and/or growth into the seminal vesicles. At a
median follow-up of 52 months, 19% demonstrated local
recurrence and 57% PSA relapse. Actuarial biochemical
progression at 5 years for the pT3G1-2 patients was 61%
and for the pT3G3 group 100%. Van Poppel et al.24
described 110 men who had radical prostatectomy for T3
prostate cancer. Five-year PSA-free survival for the
entire group was 40%. Lerner et al.25 reported on 812
patients with clinical T3 treated at the Mayo Clinic. Of
the 812 patients, 290 (35.7%) had pT3c (seminal vesicle
involvement) disease. PSA-free survival (>0.2 ng/ml) at 5
years for the entire cohort was 41% and at 10 years was
30%. Ten-year cause specific for the pT3c group was
60%. Several other reports of men who underwent radi-
cal prostatectomy with seminal vesicle involvement
demonstrate similar results26–30 (Table 33-2).
Adjuvant radiation therapy has been used in the set-
ting of positive margins and seminal vesicle involvement
Table 33-2 Comparison of Current Series of Patients with Seminal Vesicle Implant to Biochemical Freedom
from PSA Failure Following Radical Prostatectomy with Vesicle Involvement
Study Number Definition
Catalona and Bigg26 86 >0.6
D’Amico et al.27 39 >0.2
Kupelian et al.28 60 >0.2
Sofer et al.22 66 >0.4
Trapasso et al.29 93 >0.4
Zeitman et al.30 12 >0.2
Van den Ouden et al.23 83 2 increases above 0.1
Current 32 ASTRO
with mixed results. The lack of randomized data compar-
ing adjuvant versus no treatment have hampered decision-
making. Choo et al.31 analyzed 125 patients with a
positive resection margin or pT3 disease of whom 73
were treated with adjuvant radiation therapy and 52 were
followed expectantly. Radiation therapy was delivered a
median of 3.4 months post-RP with a 4-field technique
to a dose of 60 to 66 Gy. The clinical target volume
(CTV) was limited to the prostate bed, and if the seminal
vesicles were pathologically involved, they were also
included in the CTV. The treatment volume included a
1-cm margin around the CTV. A Cox proportional haz-
ards model of relapse-free probability versus time
demonstrated adjuvant radiation therapy (0.22, p = 0.0008),
PSA preprostatectomy (1.022, p = 0.029) and seminal
vesicle involvement (2.03, p = 0.09) as important vari-
ables. Unfortunately, there was no independent seminal
vesicle analysis.
Patients with seminal vesicle involvement are at risk
for local and systemic recurrence. The exact incidence of
each and whether local failure presages systemic relapse
has never been fully defined. Gibbons et al.32 reported a
44% local failure rate following radical prostatectomy in
patients with seminal vesicle involvement. In a 15-year
follow-up study, up to 83% of patients have been
reported with local recurrence if the radical prostatec-
tomy specimen contained pT3 disease.33 In looking for
local recurrence, Medini et al.34 analyzed 40 men who
were found to have elevated PSA 9 to 96 months post-
prostatectomy. Of the 40 patients, 25 had a positive sur-
gical margin and 6 had involvement of the seminal
vesicles. Twenty-eight were found to have recurrent local
disease as determined by transrectal biopsy.
Zeitman et al.35 performed a review of residual disease
after radical surgery or radiation therapy in patients with
prostate cancer. He noted a 12% to 68% risk of local
Rate (%) Years
32 5
5 2
20 6
35 5
56 5
4 4
29 5
74 7
558 Part V Prostate Gland and Seminal Vesicles

Figure 33-2 A, Axial image showing two implant needles at “C1” and “c1” positions within
the seminal vesicles. The bladder with Foley balloon can be seen just above. Arrow points to
anterior rectal wall. B, Longitudinal image of implant needle in anterior seminal vesicle wall.
The bladder is above and to the left. The arrow points to the posterior wall of the SV. A Mick
applicator will be used to deposit two seeds, one proximal and one just above prostate base.

recurrence, which was associated with a poorer prognosis.
In a review of patients with T2 to T3 disease receiving
radiation therapy, between 27% and 100% were found
to have positive biopsies, including 27% treated with
EBRT plus AU-198 seeds and 28% with EBRT plus
I-125 seeds.36,37
Planning a radiation treatment field that adequately
boosts dose to encompass disease that has extended into
the seminal vesicles has not been addressed. While dose
escalation trials have been performed on high-risk
prostate cancer patients and have demonstrated an
advantage to doses in excess of 75 Gy, no studies have
specifically addressed these higher doses in the seminal
vesicles.38,39 The problem in adequately targeting the
seminal vesicles with the higher doses and sparing the
rectum, bladder base, and ureters has probably prevented
an adequate treatment to this region. Centers that choose
to treat high-risk prostate cancer with a combination of
brachytherapy and beam irradiation risk under treatment
if the disease has extended into the seminal vesicles.
Stock et al.40 have shown that the implant provides very
little radiation dose to the seminal vesicles if the implant
is limited to the prostate. The most proximal 20% of
seminal vesicle tissue (SV1) received a median of 35% of
the prostate dose while the next cephalad 20% (SV2)
received just 3%. With external radiation dose of 45 Gy
in this situation, adequate treatment of the seminal vesi-
cle extension would be inadequate. In the same study,
Stock et al.40 demonstrated in a small cohort of 5 patients
with seminal vesicle tumor how to boost the SV dose
with an implant technique developed for this purpose
(Figure 33-2A and B). The postimplant prostate D90/SV1
D90 ranged from 63% to 97% (median 80%) and the
prostate D90/SV2 D90 ranged from 19% to 88%
(median 52%).
A multimodality treatment program has been devel-
oped to address these high-risk prostate cancer patients
with biopsy proven SV involvement.41,42 The protocol
consists of three parts: neoadjuvant and concomitant
hormonal therapy, partial palladium-103 implant (plan-
ning dose 83 to 90 Gy) with seeds placed in the prostate
and seminal vesicles followed 2 months later with 45 Gy
of conformal EBRT, which includes a 1.5-cm margin
around the prostate and seminal vesicles (Figure 33-3).
High-risk patients undergo routine evaluation, which
includes bone and CT scanning. Seminal vesicle biopsies
identify those patients with vesicle involvement (Figure
33-4A,B). Laparoscopy can exclude the 25% to 35%,
who may harbor micrometastatic disease in the pelvic
lymph nodes. Treatment is begun with 3 months of com-
plete androgen blockade. Preimplant prostate volume is
determined with an extra 10 cc added to account for the
seminal vesicles. The real-time method of seed implanta-
tion where total activity is identified by nomogram and
planning done in the operating room is used.43–45 The
patient is brought to the OR and placed in the lithotomy
position. The probe is advanced to the base of the bladder
until the tips of the seminal vesicles are no longer visible.
The probe is then retracted until the seminal vesicles
appear under the bladder base. The seminal vesicles are
contoured at 5-mm intervals, which is continued when
the prostate is reached to encompass both the prostate
base and seminal vesicles. The contouring is continued to
the prostate apex. The physicist can then match these
structures, as well as urethra and rectum, in order to per-
form the intraoperative planning (Figure 33-5A,B).
 Chapter 33 Seminal Vesicles: Diagnosis, Staging, Surgery, and Management 559

Stage T3c prostate cancer

Laparoscopic pelvic lymph node dissection

Node negative Node positive

3 months LHRHa plus antiandrogen Hormonal therapy

partial Pd-103 implant to prostate and seminal vesicles

Dose 100 Gy (NIST 99)

2 month break
continue HT

45 Gy conformal EBRT to prostate and SV

continue HT till end of radiation

Figure 33-3 Flow chart of treatment protocol for high-risk prostate cancer patients with
biopsy proven seminal vesicle involvement.

Figure 33-4 A, Pretreatment biopsy: seminal vesicle with lamina propria extensively
infiltrated with prostatic adenocarcinoma (Gleason’s pattern 4 + 4, total score 8). The
seminal vesicle epithelium shows mild nuclear pleomorphism and atypia, which is a normal
degenerative finding (arrow) (H/E, 200×). B, Posttreatment biopsy: seminal vesicle that is
negative for prostatic adenocarcinoma. Focally, the seminal vesicle glands contain
intraluminal secretions (arrow). Endothelium in a small vessel shows nuclear atypia
consistent radiation effect (arrowhead) (H/E, 200×).

Once the intraoperative planning is complete, the sources. With the use of intraoperative planning software
peripheral needles are placed. The implant is performed (VariSeed 7.0, Varian, Palo Alto, CA) in an interactive
in two phases, with placement of the peripheral needles fashion, the plan continually evolves as each seed is
and sources first, followed by the interior needles and placed. The Mick Applicator (Mick Radionuclear
560 Part V Prostate Gland and Seminal Vesicles

Figure 33-5 A, Axial image from planning computer (VariSeed, Varian, Palo Alto, CA)
demonstrating intended needle and seen positions in seminal vesicles with isodose
contours superimposed. Center isodose contour represents 100% of prescription (100 Gy
palladium-103). B, 3D representation of completed implant showing the prescription dose
cloud covering the prostate and proximal seminal vesicles.
 Chapter 33 Seminal Vesicles: Diagnosis, Staging, Surgery, and Management 561

Figure 33-6 A, Postimplant CT image of seminal vesicle seed implant with bladder above
rectum below. The 80% and 100% isodose contours encompass the vesicles with very little
dose distributed to bladder or rectum. B, Coverage of SV at base of prostate.

Instruments, Mount Vernon, NY) permits each seed to
be placed individually, maximizing the ability to conform
the radiation dose cloud to the prostate and seminal vesi-
cles (see Figure 33-5B).
Postimplant dosimetry is performed 1 month after the
implant is used in part to confirm prostate and seminal
vesicle doses and to aid in the external beam planning
(Figure 33-6A,B). Two months postimplant 45 Gy of
conformal external beam is given, limited to the prostate
and seminal vesicles with a margin of 1.5 cm. The hor-
monal therapy is continued till the end of the external
beam (total length of time 9 months). Routine prostate
562 Part V Prostate Gland and Seminal Vesicles
100
Percent free from PSA failure
Survival Function
Censored
0
0 3 5 8
Years
Figure 33-7 Kaplan-Meier estimates of PSA freedom from
failure defined as being free from 3 consecutive PSA rises
above a nadir (ASTRO). Of the 32 patients treated, 8 have
failed. The 7-year freedom from failure is 74%. The median
PSA for these 24 is <0.1 ng/ml.
and seminal vesicle biopsies were performed 2 years after
completion of treatment (see Figure 33-4A,B). Biopsies
were repeated in the case of rising PSA. To date, no
patients have demonstrated evidence of local recurrence.
The results of this multimodality approach have been
highly effective and safe.41,42 An update of previously
published data continues to demonstrate the efficacy of
this approach in 32 men with biopsy confirmed seminal
vesicle involvement followed a minimum of 3 years.
Initial PSA ranged from 4 to 88 ng/ml (mean 22.2,
median 16.3), Gleason score was 4 to 6 in 9 (28.1%), 7 in
13 (40.6%), and 8 to 9 in 10 (31.3%). Clinical stage was
T1c to T2a in 3 (9.4%), T2b in 3 (9.4%), T2c in 18
(56.2%), and T3 in 8 (25%). Follow-up was a mean of 5
years (2.5 to 8). PSA failure was defined as three consec-
utive rises above the nadir (ASTRO). Eight patients have
met the criteria for failure yielding a 7-year actuarial
freedom from biochemical failure of 74% (Figure 33-7).
Neither presenting PSA nor stage predicted for bio-
chemical outcome. There was a trend for higher Gleason
score and worse outcome (Figure 33-8).
Overall morbidity with this regimen has been accept-
able. No patients have experienced a grade 3 or grade 4 rec-
tal injury. One patient (3%) with a history of prior TURP
has minor stress incontinence. Testosterone levels have
returned to above 200 ng/dl in the majority of patients.
The data from the multimodality approach suggest
that there may be an advantage with this approach over
radical prostatectomy (see Table 33-2). There are several
possible explanations for these favorable results. The
implant patients were treated with 9 months of hormonal
therapy and the current PSA readings might result from
100
90
Percent free from PSA failure
80
70
60
50
Gleason 8−10
40
30 Gleason −7
20
10 p = 0.128 Gleason 4−6
0
0 3 5 8
Years
Figure 33-8 PSA freedom from failure for Gleason score 4 to
6 (100%), 7 (67%), and 8 to 10 (60%). Although the
differences were not significant, there does appear to be
worse outcome for patients with Gleason score 8 to 10 in the
seminal vesicles.
a continued state of androgen deprivation. Only one
patient still had a testosterone level below 50 ng/dl while
the rest had values above 200. Therefore, it is not likely
that these favorable results are a reflection of persistent
hormonal therapy effects. It is likely that the short-
term hormonal therapy benefits these patients, probably
from a combination of cytoreduction during the neoad-
juvant phase and additive effects during the treatment
phase. There is both animal model and clinical data to
support this concept.46–49 There may be no benefit in
continuing the hormone therapy beyond the end of radi-
ation if all of the local tumor can be eradicated with the
shorter-term treatment and high radiation doses.
Testosterone production will recover in most men
treated with luteinizing hormone releasing hormone
agonists if given for less than a year.49 In contrast, longer-
term administration of these agents is likely to result in
permanent hypogonadism. The improvement in results
with the multimodality approach cannot be explained on
the basis of prolonged hormonal therapy usage noted in
trials where androgen deprivation has been administered
for a prolonged period.49 In fact, almost all of the patients
had a return in serum testosterone levels, suggesting that
persistent androgen deprivation does not explain these
favorable results. It is likely that this regimen eradicates
all of the local disease, which was evident by the negative
biopsies, especially in those patients with PSA progres-
sion. In contrast, when seminal vesicle involvement was
found in the prostatectomy specimen, local relapse was
quite common.22–29 The difference in PSA-free relapse
between these data and the prostatectomy data implies
that difference may be accounted for by the persistence
 Chapter 33 Seminal Vesicles: Diagnosis, Staging, Surgery, and Management 563
of residual adenocarcinoma following an inadequate
prostate resection. It is not unreasonable to believe that
residual disease would remain following prostatectomy in
patients with seminal vesicles involvement.
SUMMARY
Primary tumors of the seminal vesicles are uncommon.
Extension of prostate cancer into the vesicles should be
identified prior to consideration for definitive therapy. A
monotherapy approach to management of this disease
will most likely fail. A combined therapeutic approach
either with radiation or surgery should be considered for
this difficult disease.
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2. Iqbal N, Zins J, Klienman GW: Schwannoma of the
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and associated anomalies. BJU Int 2002; 90:265–271.
4. Berger AP, Bartsch G, Horninger W: Primary
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5. Yanagisawa N, Saegusa M, Yoshida T, Okayasu I:
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6. Tabata K, Irie A, Ishii D, et al: Primary squamous
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biopsy: accuracy and implications for staging of prostate
cancer. Urology 1996; 48:757–761.
8. Peabody JO, Korman HJ, Amin MB: Miscellaneous
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18. Roach M, Chen A, Song J, et al: Pretreatment
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the risk of extracapsular extension and the risk of
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localized prostate cancer. Semin Urol Oncol 2000;
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19. Penson DF, Grossfeld GD, Li YP, et al: How well does
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Critical analysis of the ability of the endorectal coil
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in patients with clinically organ confined prostate cancer.
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spread of clinically localized prostate cancer: factors
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imaging examination results. Radiology 2002;
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22. Sofer M, Savoie M, Kim SS, et al: Biochemical and
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adenocarcinoma with seminal vesicle invasion. J Urol
2003; 169:153–156.
23. Van den Ouden D, Hop WCJ, Schroder FH: Progression
and survival of patients with locally advanced prostate
caner (T3) treated with radical prostatectomy as
monotherapy. J Urol 1998; 160:1392–1397.
24. Van Poppel H, Goethuys H, Callewaert P, et al:
Radical prostatectomy can provide a cure for well
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25. Lerner SE, Blute MI, Zinke H: Extended experience with
radical prostatectomy for clinical stage T3 prostate
cancer: outcome and contemporary morbidity. J Urol
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26. Catalona WJ, Bigg SW: Nerve-sparing radical
prostatectomy: evaluation of results after 250 patients.
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27. D’Amico A, Whittington R, Malkowicz S: A multivariate
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prostate specific antigen failure after radical prostatectomy
for prostate cancer. J Urol 1995; 154:538–548.
28. Kupelian P, Kathcher J, Levin H, et al: Correlation of
clinical and pathologic factors with rising prostate-specific
antigen profiles after radical prostatectomy alone for
clinically localized prostate cancer. Urology 1996;
48:249–260.
29. Trapasso JG, deKernion JG, Smith RB, et al: The
incidence and significance of detectable levels of serum
PSA after radical prostatectomy. J Urol 1994;
152:1816–1825.
30. Zeitman AL, Edelstein RA, Coen JJ, et al: Radical
prostatectomy for adenocarcinoma of the prostate: the
influence of preoperative and pathologic findings on
biochemical disease free outcomes. Urology 1994;
43:828–833.
31. Choo R, Hruby G, Hong J, et al: Positive resection
margin and/or pathologic T3 adenocarcinoma of
prostate with undetectable postoperative prostate-
specific antigen after radical prostatectomy: to
irradiate or not? Int J Radiat Oncol Biol Phys 2003; 52:
674–680.
32. Gibbons RP, Cole BS, Richardson G, et al: Adjuvant
radiotherapy following radical prostatectomy: results and
complications. J Urol 1986; 135: 65–68.
33. Jewett HJ, Eggleston JC, Yawn DH: Radical
prostatectomy in the management of carcinoma of the
prostate: probable causes of some therapeutic failures.
J Urol 1972; 107:1034–1040.
34. Medini E, Medini I, Reddy PK, Levitt SH:
Delayed/salvage radiation therapy in patients with
elevated prostate specific antigen levels after radical
prostatectomy. Cancer 1996; 78:1254–1259.
35. Zeitman AL, Shipley WU, Willett CG: Residual disease
after radical surgery or radiation therapy for prostate
cancer. Cancer 1993; 71:959–969.
36. Scardino PT, Wheeler TM: Local control of
prostate cancer with radiotherapy: frequency and
prognostic significance of positive results of
postirradiation prostate biopsy. Monogr Natl Cancer
Inst 1988; 7:95–103.
37. Schellhammer PF, El-Mahdi AM, Higgins AM, et al:
Prostate biopsy after definitive treatment by interstitial
125 iodine implant or external beam radiation therapy.
J Urol 1987; 137:897–901.
38. Pollack A, Zagers GK, Starkschall G: Prostate cancer
radiation dose response: results of the M.D. Anderson
phase II randomized trial. Int J Radiat Oncol Biol Phys
2002; 53:1097–1105.
39. Hanks GE, Hanlon AL, Epstein B, et al: Dose response in
prostate cancer with 8–12 years follow-up. Int J Radiat
Oncol Biol Phys 2002; 54:427–435.
40. Stock RG, Lo YC, Gaildon MS, Stone NN: Does
prostate brachytherapy treat the seminal vesicles? A dose-
response histogram analysis of seminal vesicles in patients
undergoing combined Pd-103 prostate implantation and
external beam irradiation. Int J Radiat Oncol Biol Phys
1999; 45:385–389.
41. Stone NN, Stock RG: Prostate brachytherapy: treatment
strategies. J Urol 1999; 162:421–426.
42. Stock RG, Stone NN: Preliminary toxicity and prostate-
specific antigen response to a phase I/II trial of
neoadjuvant hormonal therapy, Pd-103 brachytherapy,
and 3D conformal external beam irradiation in the
treatment of locally advanced prostate cancer.
Brachytherapy 2002; 1:2–10.
43. Stone NN, Hong S, Lo YC, et al: Comparison of
intraoperative dosimetric implant representation to
post-implant dosimetry in patients receiving prostate
brachytherapy. Brachytherapy 2003; 2:17–25.
44. Stone NN, Stock RG: Brachytherapy for prostate cancer:
Real time three dimensional interactive seed implantation.
Tech Urol 1995; 1:72–80.
45. Stock RG, Stone NN, Lo YC, et al: Post-implant
dosimetry for I-125 prostate implants: definitions and
factors affecting outcome. Int J Radiat Oncol Biol Phys
2000; 48: 899–906.
46. Cahlon O, Stock RG, Kollmeier M, Stone NN:
Hormonal therapy, brachytherapy and external beam
irradiation in the treatment of high risk prostate cancer,
post-treatment and PSA outcomes. Bracytherapy 2003;
2:P-72.
47. Zeitman AL, Nakfoor BM, Prince EA, et al: The effect of
androgen deprivation and radiation therapy on an
androgen-sensitive murine tumor: an in vitro and in vivo
study. Cancer J Sci Am 1997; 3:31–36.
48. Pilepich MV, Winter K, John MJ, et al: Phase III
radiation therapy oncology group (RTOG) trial 86-10 of
androgen deprivation adjuvant to definitive radiotherapy
in locally advanced carcinoma of the prostate. Int J Radiat
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49. Bolla M, Collette L, Blank L, et al: Long-term results
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Lancet 2002; 360:103–106.
C H A P T E R
34 Testis Tumors: Diagnosis
and Staging
Avrum Jacobson, MDCM, and Paul H. Lange, MD
DIAGNOSIS
Introduction
Testicular germ cell tumors (GCTs) typically strike men
in the prime of their lives. It is the most common malig-
nancy in men aged 20 to 35, and the second most com-
mon malignancy in men aged 35 to 39.1 On a positive
note, however, GCTs have become a paradigm of the
potential of translational cancer research. Advancements
in imaging, tumor markers, surgical techniques, and most
importantly, the introduction of cisplatin-based
chemotherapy have drastically impacted morbidity and
mortality, improving overall survival from 10% in the
1970s to 90% today.2 Despite these advances, 20% of
patients who present with metastasis still succumb to
their disease.3
Delay in diagnosis continues to be a major concern.
Bosl et al.4 reported a median delay from onset of symp-
toms to pathologic diagnosis of 85 days. In 285 cases ini-
tially seen by primary care physicians, only 56% were
suspected of malignancy, despite testicular signs being
noted in 92%. A British study reported even more
abysmal results with a mean delay in presentation to
medical care of 5.5 months.5 In both studies, delay was
associated with higher stage, and in the later study, mor-
tality doubled from 8% to 16% if delay was greater than
6 months.4,5 In our own institution, we continue to see
rare young men referred by outside physicians who have
been diagnosed by retroperitoneal mass biopsy without
ever having had a testicular examination. Clearly, there is
a great need for educational programs. The general pub-
lic should be indoctrinated in the need for regular self-
examination of the testis, as well as periodic physical
examination performed by a physician. The physicians
must be aware that any mass within the testicle should be
considered malignant until proven otherwise, and that in
such cases urgent referral to a specialist is crucial. In
addition, physicians must understand that GCTs are high
among the differential diagnoses for a retroperitoneal
mass of unknown primary in a young man. All such men
should, at the very least, undergo a thorough genital
examination and have testicular serum markers drawn.
Presentation
The most common presentation of GCTs is that of a
painless testicular mass. However, although only 10%
present with an acute painful scrotum,6 some pain has
been reported in up to 32%.7 Neither pain nor testicular
tenderness should not dissuade one from making the
diagnosis of malignancy. A history of trauma should also
not decrease the index of suspicion, as 4% of GCT
patients give such a history.7 It is possible that either the
trauma draws their attention to their testicular abnor-
mality, or that the tumor increases the sensitivity of the
testis to a degree of trauma that would otherwise not
have brought the patient to medical attention.
Occasionally, pain prevents a proper assessment of the
testis. If, in such cases, epididymitis or orchitis is diag-
nosed, the patient should be treated and followed very
closely for reexamination. If malignancy can still not be
ruled out, an ultrasound should be obtained. In the vast
majority of cases, however, the key to diagnosis is a well-
executed genital examination.
The physical examination of the testes is best per-
formed with the patient standing and the physician
seated facing him. The testis is palpated between the
thumb and the first 2 fingers. The normal testis should
be examined first to establish a baseline. The normal
testis should be homogeneous, freely mobile, and distinct
from the epididymis and other cord structures. Any area
567
568 Part VI Testis
within the testis itself, which appears fixed, firm, or
nodular, should be considered highly suspicious.
Seventy percent of GCTs are discovered by self-exam-
ination and an additional 15% are discovered by physi-
cian examination.7 Patients may also seek attention for
symptoms of disseminated disease. At diagnosis, 50% are
found to have metastasis; signs and symptoms of these,
however, are found in approximately 10%.4 Patients may
complain of generalized weakness, fatigue, and weight
loss. Abdominal pain, back pain, GI disturbances, or
lower extremity edema can arise secondary to retroperi-
toneal adenopathy, and pulmonary metastasis may mani-
fest as dyspnea, cough, or hemoptysis. Manifestations of
other sites of metastasis include headaches, seizures, or
other palpable masses, most commonly in the left supra-
clavicular area. Other presenting symptoms include
infertility and a 3% incidence of gynecomastia,7 which is
believed to be secondary to an estrogen/testosterone
imbalance caused by the effect of human chorionic
gonadotropin (hCG) on Leydig cells.
Serum Tumor Markers
Tumor markers can be considered to be biologic attrib-
utes of malignant cells that help to distinguish them from
normal cells. These may be uniquely identified with cer-
tain neoplasms or may be normal constituents, which, in
the face of a tumor, are expressed in abnormal locations
and/or quantities, or display abnormal functions. In
GCTs, perhaps more than any other tumor, the serum
tumor markers, including α-fetoprotein (AFP), hCG,
and lactate dehydrogenase (LDH), play a key role in all
aspects of clinical management. Their role in diagnosis is
perhaps best illustrated in the 5% to 7% of GCTs that
present with extragonadal primaries.8 These lesions often
present as poorly differentiated carcinomas of unknown
origin; positive immunohistochemical staining for AFP
or hCG, or elevated serum levels, can confirm the diag-
nosis. In testicular primaries, serum markers retain a crit-
ical diagnostic role. Nonseminomatous GCTs (NSGCT)
present with elevated AFP or hCG in 85% of cases (AFP
alone in 40%, hCG alone in 50% to 60%).9 Seminoma,
on the other hand, by definition, never presents with ele-
vated AFP, but detectable hCG is present in 10% to 25%
of cases.10 In the context of a testicular mass, elevated
markers are practically pathognomonic, and can, to a
degree, predict histology.
AFP is the dominant serum protein of the early
embryo and although detectable at birth, levels fall by
age 1 to the minimal level seen in adults (<10 mg/dl).
Trophoblastic cells, which are present in embryonal car-
cinoma, teratocarcinoma, and yolk sac tumor, are respon-
sible for its production. These elements are never present
in pure choriocarcinoma or seminoma.11 This has impor-
tant ramifications, as in the presence of a positive AFP,
even when histology demonstrates only pure seminoma,
the patient should be treated according to NSGCT pro-
tocols. AFP elevation has been associated with other
malignant and benign processes. These include pancre-
atic, gastric, and lung cancer,12 as well as liver disease,
pregnancy, ataxia telangiectasia, and tyrosenemia.12,13
However, in the clinical context of GCTs, these other
diagnosis are rarely a source of confusion.
HCG is a biologically active hormone, secreted by the
placental syncytiotrophoblasts, which is responsible for
maintaining the corpus luteum. Elevated serum concen-
trations have been reported in hepatic, pancreatic, gas-
tric, pulmonary, breast, renal, and bladder tumors, as well
as multiple myeloma.12 Levels >10,000 IU/l, however,
are seen almost exclusively in pregnancy, gestational dis-
orders, or GCTs.14 Forty percent to 60% of patients with
GCTs will have an elevated hCG. This includes essen-
tially all patients with choriocarcinoma, 80% of those
with embryonal carcinoma, and 10% to 25% of those
with seminoma.10
LDH is elevated in a wide spectrum of illnesses and,
thus in GCTs, LDH has not been shown to have a strong
predilection for certain histologies. Its usefulness in diag-
nosis is therefore somewhat limited. Nonetheless, LDH
has been shown to reflect tumor burden15 and be an
important indictor of prognosis.16,17 Routine LDH levels
are therefore recommended in all GCT patients.18,19
Other markers, which have been proposed for GCTs,
include placental alkaline phosphatase (PLAP) and
neuron-specific enolase (NSE). PLAP, although widely
accepted as a reliable histologic marker for seminoma,
has largely been abandoned as a serum marker. Although
elevated in 50% to 72% of seminoma,20–22 specificity is
poor. Elevated levels can be detected in smokers and in
other malignancies, including lung, ovary, breast, and
gastrointestinal.23,24 Even among nonsmokers, positive
predictive value has been shown to be less than 50%.24
NSE, which has been found to be a useful marker in neu-
roendocrine tumors, initially showed promise as a marker
in GCTs, especially seminoma. Further investigation,
however, failed to demonstrate clinical utility25, and
investigational interest has waned.
Imaging
Scrotal ultrasound (U/S) is the current standard for testis
imaging. It is essential for suspicious (as opposed to def-
inite) testicular masses found on physical examination
and also for those patients in whom physical examination
is limited either by pain or by a hydrocele. In addition, in
patients who present with extragonadal GCTs, U/S may
reveal an occult testis primary. U/S is generally easy to
obtain, noninvasive, inexpensive, and accurate. Newer
high frequency transducers (5 to 10 MHz) can detect
lesions as small as 1 to 2 mm. U/S can also distinguish

cystic from solid masses with 100% accuracy and
intratubular from extratubular testicular with 99% accu-
racy.26 Cyst can be seen within the tunica albuginea but
are uncommon, especially among younger men, within
the testis itself. In men older than 60, testicular cysts can
be seen in 8% to 10%; these occur near the mediastinum
at the superior/lateral aspect of the testis and must fulfill
all criteria of simple cyst.26 Solid lesions within the testes,
that are malignant, cannot be distinguished absolutely
from those that are benign for reasons that we will now
discuss.
The normal testis is uniformly heterogeneous on U/S.
Seminomas typically appear as well-defined hypoechoic
masses within the substance of the testis, without calcifi-
cation or cystic components. NSGCTs, on the other
hand, are typically inhomogeneous hypoechoic, normoe-
choic, or hyperechoic masses, with a higher incident of
cystic components and echogenic foci.27–29 U/S cannot
distinguish histology among NSGCT but has been shown
to distinguish correctly seminoma from nonseminoma in
70% of cases.29 In addition, U/S does not provide accu-
rate local staging information. The tunica albuginea is
poorly seen and even in seminoma where more precise
borders are present, only 44% of patients are staged accu-
rately. In NSGCT, this figure drops to 8%.29
Parenchymal changes may occur in infection,
inflammation, vascular insult, or trauma, which may
mimic a tumor on ultrasound. Infective changes, on
appropriate therapy, should improve within 2 weeks.
However, severe orchitis with microabscesses may not
resolve and may appear identical to necrosis and hem-
orrhage. Small infarcts and intratesticular hematomas
may also mimic tumor and be slow to resolve.26 In
these settings, one must use clinical judgment and
explore surgically if any doubt remains; keeping in
mind that excision of a diseased benign testis is cer-
tainly preferable than retaining tumor.
The testis can also be well visualized with MRI. The
normal testis displays homogeneous signal intensity on
both T1 and T2 weighted images. The hallmark of a
tumor is loss of high signal intensity on T2. On T1, in
contrast, tumors can be difficult to distinguish from nor-
mal parenchyma. After gadolinium, however, brisk het-
erogeneous enhancement may be seen, providing clear
visualization of the lesion.30 NSGCT are markedly het-
erogeneous and can be differentiated from seminoma in
almost all cases. Differentiating NSGCT from
hematoma, and seminoma from benign lesions, however
can be difficult or even impossible. Also, despite good
visualization of the tunica albuginea, local staging
remains poor. Partial volume averaging and similar
intensities between the tumor and tunica albuginea
makes assessment of invasion difficult. Finally, the medi-
astinum testis can be difficult to see, and local tumor
extension into this structure is therefore inaccurate.30
Chapter 34 Testis Tumors: Diagnosis and Staging 569
Thus, in general, MRI provides good imaging of testicu-
lar neoplasms but has not been shown to have any advan-
tage over the cheaper and more easily accessible scrotal
ultrasound, an exception to this is possibly cryptorchid
(especially intraabdominal) testes.
STAGING
Introduction
Prior to 1997, there was no consensus on staging of tes-
ticular GCTs. Most staging systems were based on the
model introduced by Boden and Gibb31 in 1951, which
divided the disease into 3 stages: I, limited to the testis,
II, spread to the retroperitoneum, and III, spread beyond
the retroperitoneum. Other systems generally kept this
basic format, subdividing stage II based on the size of the
retroperitoneal adenopathy. As well, different systems
were intended for seminoma and nonseminoma, and for
clinical staging and pathologic staging.12,32–35 The
plethora of systems, each with its own subtleties led to
confusion and difficulty in comparing data from various
institutions. In 1997, the American Joint Committee on
Cancer (AJCC) introduced an internationally accepted
consensus classification.36 This system, which will be dis-
cussed in detail later, provided much needed uniformity.
Staging Modalities
Testis tumors generally spread initially through lym-
phatic channels, which follow the embryologic origin of
the testis to the retroperitoneum. The primary landing
site of right testicular tumors is intraaortocaval, at the
level of the second lumbar vertebra, and the primary
landing site of left tumors is paraaortic (i.e., to the left
side of the aorta), just below the renal hilum.37
Hematologic dissemination can also occur, and is mani-
fested most often as lung metastasis; however, more
advanced disease can present with involvement of the
liver, bone, or brain. The AJCC recommends radi-
ographic assessment of the chest, abdomen, and pelvis.36
Routine bone scan and brain imaging are generally
unnecessary unless clinically indicated, as these locations
are extremely rarely the sole metastatic site, and their
presence is often accompanied by symptoms. The cur-
rent standard for imaging the chest, abdomen, and pelvis
is CT scan of the abdomen and pelvis, and plain CXR.
CT chest should be performed if the CXR is abnormal or
if CT abdomen reveals metastasis.
Although CT scan has become the imaging modality
of choice for the retroperitoneum, the ideal lymph node
size criterion has not been firmly established. Using the
conventional, but arbitrary, cutoff of 1 cm, 22% to 44%
of metastasis can be missed.38 As expected, as smaller
sizes are applied, sensitivity improves and specificity
worsens. Stomper et al.39 evaluated various size criteria;
570 Part VI Testis
at 5, 10, and 15 mm, sensitivity was found to be 88%,
73%, and 58% respectively, and specificity was found to
be 44%, 60%, and 76% respectively. A study out of Indiana
University examined transaxial lymph node diameter as a
continuous variable between 0 and 25 mm. They found
that the highest overall accuracy was reached at a diame-
ter of 8 mm. At that level, sensitivity was 66.7% and
specificity was 94.4%. Separate analysis revealed that
enlarged nodes within the expected landing zone were
more likely to represent true metastasis. Using a cutoff of
10 mm outside the predicted landing zone and 3 mm
within, a sensitivity and specificity of 90.7% and 53.3%,
respectively, were attained.40
Other modalities, which have been utilized to evaluate
the retroperitoneum, include ultrasound, MRI, lym-
phography, positron emission tomography (PET) scan,
and laparoscopic lymph node dissection. Ultrasound
examination of the retroperitoneum is often limited
either by bowel gas or by patient obesity. Even in cases
where a good quality examination can be obtained, ultra-
sound is markedly inferior to CT scan. Subtle lymph
node metastases are generally impossible to diagnose,
and even nodes between 2 and 2.5 cm are accurately
found in only 60%.26 Ultrasound is generally uninforma-
tive unless bulky lymphadenopathy is present, and even
then, CT is preferable for more precise anatomic infor-
mation and for follow-up comparison. MR, on the other
hand, provides excellent imaging of the retroperitoneum
with overall accuracy of approximately 80%. Studies,
however, have shown no additional benefit over CT.41,42
One clear advantage is the ability of MR to distinguish
lymph node from vessel in the absence of contrast. In
patients in whom intravenous contrast is ill advised, MR
is a sound alternative.
Bipedal lymphangiogram has largely been replaced
with CT scan. Although imaging of retroperitoneal
nodes is fair, with a positive predictive value of 83% and
negative predictive value of 69%,43 lymphography is
invasive and, as such, has inherent morbidity.
Complications include fever, local pain, wound infection,
lymphadenitis, and pulmonary dysfunction. As well, reac-
tive changes can increase difficulty of future surgery, and
imaging above L2 is poor, as at that level many lymphatic
vessels coalesce into the thoracic duct. The only advan-
tage of lymphography over other imaging is that abnor-
mal architecture can be detected in the absence of
enlargement. Normally the lymphatic sinusoids pick up
contrast well, while follicles pick up very little. This pro-
duces a characteristic appearance of homogeneously dis-
tributed droplets. Replacement of a node by tumor can
produce a filling defect, or compression of sinusoidal sys-
tem can produce an inhomogeneous contrast scattered
throughout the node, termed “foamy.” In addition, typi-
cal meandering collaterals often accompany obstruction
of the lymphatic system.44 Although it has been sug-
gested that patients with stage I GCTs undergo lym-
phangiogram prior to initiating watchful waiting,43 in
174 patients with a negative work up (including negative
CT and tumor markers), lymphangiogram found only
4% unsuspected metastases and another 2% had false
positive findings.45 Today, there is little role for lym-
phography in the management of testicular GCTs.
PET scan demonstrates uptake of the glucose analog
18-fluoro-2 deoxyglucose, and relies on the fact that
many tumors have a high rate of glycolysis. In GCTs,
however, PET scan has not been widely investigated. In
a German study, PET slightly out performed CT scan in
50 GCT patients staged at initial diagnosis. Sensitivity
was 87% versus 73%, with equal specificity of 94%. CT
scanners in that study, however, were not standardized,
and pick up on PET scan of small positive lymph nodes
was still poor.46 In another European study, PET scan
upstaged 3 of 31 patients, although management
remained unchanged.47 At present, PET scanning for
initial staging remains mainly investigational, but clearly
further study is warranted. Parenthetically, in assessing
postchemotherapy residual masses, PET still holds some
promise for differentiating viable tumor, teratoma, and
necrosis.
The gold standard for staging of the retroperitoneum
is a formal retroperitoneal lymph node dissection.
Despite all available modalities, 23% to 30% of clinical
stage I patients are found to harbor retroperitoneal dis-
ease.48–51 In high risk patients, this number increases to
approximately 50%.50,51 Recently, specialized centers
have attempted to lessen operative morbidity by per-
forming the dissection laparoscopically. As a staging pro-
cedure, outcomes have been excellent, with, to our
knowledge, no retroperitoneal recurrences.52,53 However,
although it is clear that open RPLND is therapeutic in
addition to diagnostic, the therapeutic benefit of laparo-
scopic RPLND remains unproven. This question arises
because the laparoscopic groups have treated their stage
IIA patients with 2 cycles of chemotherapy, a practice
that is not common after RPLND, as after surgery alone
these patients have been shown to have recurrence rates
of only 8% to 20%.54 In our institution, we are convinced
that the laparoscopic dissection can exactly mimic the
open technique. Therefore, we do not routinely adminis-
ter adjuvant therapy for our stage IIA group but remain
watchful to our results and other groups in that.
Finally, what staging modality is best for chest imag-
ing? Although CT is obviously more sensitive than CXR,
this does not always equate with being a superior test.
The issue with CT of the chest is that there is a high inci-
dence in the general population of small lesions seen on

CT, which are entirely benign. The morbidity of finding
such lesions can, at times, be considerable; either requiring
excision for pathologic diagnosis or leading to incorrect
staging and treatment. One study found that in
42 patients, with a negative abdominal CT, only 4.4%
had chest involvement. All were diagnosed on both CXR
and CT scan, while CT scan picked up 3 additional
lesions were found to be benign. In patients with positive
abdominal CT scan, on the other hand, the rate of pul-
monary metastasis was considerably higher at 40%. In
this group, CT chest picked up an additional 12.5% of
patients missed on CXR alone. In addition, 3 cases of
extrapulmonary metastasis were identified as well.55
1997 American Joint Committee On Cancer Staging
System
The 1997 AJCC staging of testis tumors depends on the
determination of T (tumor), N (node), M (metastases),
and S (serum tumor markers), categories. Although the
TNM classification is commonly used among various
malignancies, the S category is unique to testis tumor and
is a reflection of the importance of serum markers in the
management of this disease.
Primary Tumor
Histologic evaluation of the radical orchiectomy speci-
men is required for the T classification. The tumor
should be sampled extensively, including all grossly
diverse areas, as well as the junction of tumor and the
nonneoplastic testis, and at least one section remote from
the tumor. Whenever possible, sections should include
overlying tunica albuginea.
New to this system, is the introduction of lymphvas-
cular invasion into staging (Table 34-1). This modifica-
tion assists the clinician to better differentiate stage I
patients at high risk of harboring undetected retroperi-
toneal metastasis (stage IB) from those at lower risk
(stage IA) (Table 34-2); if lymphvascular invasion is pres-
ent, 50% are found on RPLND to be understaged stage
II, while if lymphvascular invasion is absent, this drops to
only 18% to 23%.49,56 Another factor also commonly
used in the same fashion is the percent embryonal carci-
noma in the specimen; however, pathologic tumor type is
inherently not a staging factor, and indeed, is not
included in the TNMS system.
Regional Lymph Nodes
Interaortocaval, paraaortic, paracaval, preaortic, precaval,
retroaortic, and retrocaval lymph nodes, as well as nodes
along the spermatic vein, are considered regional.
Chapter 34 Testis Tumors: Diagnosis and Staging 571
Intrapelvic, external iliac, and inguinal nodes are consid-
ered regional only after scrotal or inguinal surgery prior
to presentation with a testicular tumor. All other nodes
are considered distant and are staged within the M clas-
sification. For pathologic staging, it is critical that the
pathologist carefully examines and liberally samples the
specimen, including cystic, fibrotic, hemorrhagic,
necrotic, and solid areas. The number of lymph nodes
involved with tumor should be recorded, as should any
evidence of extranodal involvement.
Distant Metastasis
The International Germ Cell Cancer Collaborative
Group (IGCCCG), a panel of leading experts from
around the world, retrospectively studied prognostic fac-
tors in 5662 patients with metastatic testicular GCT, all
of whom received cisplatin (or carboplatin) containing
chemotherapy regiments. Based on this work, such
patients could be categorized into good, intermediate, or
poor prognostic groups. The presence of liver, bone,
brain, or other nonpulmonary visceral metastasis, was
shown, in NSGCT, to be a poor prognostic factor with a
5-year survival rate of 47%. In seminoma, although no
poor risk group was found, the most important prognostic
factor was again the presence of nonpulmonary visceral
metastases, placing patients in the intermediate prognosis
group with a 5-year survival of 72% (Table 34-3).57 This
information was integrated into the staging system by
subdividing the M1 category into M1a and M1b (see
Table 34-1).
Serum Tumor Markers
For staging purposes, AFP, hCG, and LDH should be
performed immediately after orchiectomy and, if ele-
vated, repeated serially after orchiectomy to assess for
persistent elevation. In the absence of disease, markers
should decline according to their half-lives: <7 days for
AFP and <3 days for hCG. The subdivisions of the S
category (see Table 34-1) were adapted from the
IGCCCG,57 and play an extremely important role, not
only in prognosis, but also in the management of testic-
ular GCTS. Patients with no other evidence of metastatic
disease with persistent marker elevation after orchiec-
tomy are labeled stage 1S (see Table 34-2). These
patients are almost always found to have disseminated
disease and are better treated with chemotherapy than
surgery.58 Patients with S2 or S3 marker levels with evi-
dence of only regional nodal disease are upstaged to
stage III, and again are better treated with chemother-
apy, and, in the case of S3, perhaps even with more
aggressive regiments.
572 Part VI Testis

Table 34-1 2002 AJCC TNMS Staging Classification

Primary Tumor (pT) Pathologic

Clinical pNX Regional lymph nodes cannot be assessed

Tumor stage is generally determined after
orchiectomy at which time a pathologic stage is
assigned
Pathologic
pTX Primary tumor cannot be assessed (if no radical
orchiectomy has been performed, TX is used)
pT0 No evidence of primary tumor (e.g., histologic
scar in testis)
pTis Intratubular germ cell neoplasia (carcinoma in
situ)
pT1 Tumor limited to testis and epididymis without
vascular/lymphatic invasion; tumor may invade
into tunica albuginea but not into tunica
vaginalis
pN0 No regional lymph node metastasis
pN1 Metastasis with a lymph node mass 2 cm or less
in greatest dimension and less than or equal to 5
nodes positive, none more than 2 cm in greatest
dimension
pN2 Metastasis with a lymph node mass more than
2 cm but not more than 5 cm in greatest
dimension; or more than 5 nodes positive, none
more than 5 cm; or evidence of extranodal
extension of tumor
pN3 Metastasis with a lymph node mass more than
5 cm in greatest dimension
Distant Metastasis (M)
MX Distant metastasis cannot be assessed

pT2 Tumor limited to the testis and epididymis with M0 No distant metastasis
vascular/lymphatic invasion, or tumor extending
through the tunica albuginea with involvement M1 Distant metastasis
of the tunica vaginalis
M1a Nonregional nodal or pulmonary metastasis
pT3 Tumor invades the spermatic cord with or
without vascular/lymphatic invasion M1b Distant metastasis other than to nonregional
lymph nodes and lungs
pT4 Tumor invades the scrotum with or without
vascular/lymphatic invasion Serum Tumor Markers (S)

Regional Lymph Nodes (N) SX Markers studies not available or not performed

Clinical S0 Marker study levels within normal limits

NX Regional lymph nodes cannot be assessed S1 LDH < 1.5 × N and

N0 No regional lymph node metastasis hCG (mIU/ml) < 5000 and

N1 Metastasis within a lymph node mass 2 cm or AFP (ng/ml) < 1000

less in greatest dimension; or multiple lymph
S2 LDH 1.5 − 10 × N or
nodes, none more than 2 cm in greatest
dimension HCG (mIU/ml) 5000 − 50,000 or
N2 Metastasis with a lymph node mass more than AFP (ng/ml) 1000 − 10,000
2 cm but not more than 5 cm in greatest
dimension; or multiple lymph nodes, any one S3 LDH > 10 × N or
mass greater than 2 cm but not more than 5 cm
in greatest dimension HCG (mIU/ml) > 50,000 or

N3 Metastasis with a lymph node mass more than AFP (ng/ml) > 10,000
5 cm in greatest dimension
 Chapter 34 Testis Tumors: Diagnosis and Staging 573

Table 34-2 Staging Classification (Stage Groups)

Stage grouping

Stage 0 pTis N0 M0 S0

Stage I pT1-4 N0 M0 SX

Stage IA pT1 N0 M0 S0

Stage IB pT2-4 N0 M0 S0

Stage IS Any pT/Tx N0 M0 S1-3

Stage II Any pT/Tx N1-3 M0 SX

Stage IIA Any pT/Tx N1 M0 S0-1

Stage IIB Any pT/Tx N2 M0 S0-1

Stage IIC Any pT/Tx N3 M0 S0-1

Stage III Any pT/Tx Any N M1 SX

Stage IIIA Any pT/Tx Any N M1a S0-1

Stage IIIB Any pT/Tx N1-3 M0 S2

Stage IIIB Any pT/Tx Any N M1a S2

Stage IIIC Any pT/Tx N1-3 M0 S3

Stage IIIC Any pT/Tx Any N M1a S3

Stage IIIC Any pT/Tx Any N M1b Any S

Table 34-3 International Germ Cell Consensus Classification

Nonseminoma Seminoma

Good prognosis
Testis/retroperitoneal primary Any primary site

And And
No nonpulmonary visceral metastasis No nonpulmonary visceral metastasis

And And
Good markers Nomal AFP, any HCG, any LDH

AFP < 1000 ng/ml and

HCG < 5000 IU/l (1000 ng/ml) and

LDH < 1.5 upper limit of normal

5-year PFS 89% 5-year PFS 82%

5-year survival 92% 5-year survival 86%

Continued
574 Part VI Testis

Table 34-3—cont’d
Nonseminoma Seminoma

Intermediate prognosis

Testis/retroperitoneal primary Any primary site

And And
No nonpulmonary visceral metastasis Nonpulmonary visceral metastasis

And And
Intermediate markers Nomal AFP, any HCG, any LDH

AFP > 1000 ng/ml and <10,000 ng/ml or

HCG > 5000 IU/l and <50,000 IU/l or

LDH > 1.5 × N and <10 × N

5-year PFS 75% 5-year PFS 67%

5-year survival 80% 5-year survival 72%

Poor prognosis

Mediastinal primary

Or
Nonpulmonary visceral metastasis

Or
Poor markers

AFP > 10,000 ng/ml or

HCG > 50,000 IU/l or

LDH > 10 × upper limit of normal

5-year PFS 41%

5-year survival 48%

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In American Joint Committee on Cancer (AJCC) Cancer
Staging Manual, 5th edition. Philadelphia, PA,
Lippincott-Raven, 1997.
37. Donohue JP, Zachary JM, Maynard BR: Distribution of
nodal metastasis in nonseminomatous testis cancer. J Urol
1982; 128:315–320.
38. Hilton S, Herr HW, Teitcher JB, et al: CT detection of
retroperitoneal lymph node metastasis in patients with
clinical stage I testicular nonseminomatous germ cell
cancer: assessment of size and distribution criteria. AJR
1997; 169(2):521–525.
39. Stomper PC, Fung CY, Socincki MA, et al: Detection of
retroperitoneal metastasis in early stage nonseminomatous
testicular cancer: analysis of different CT criteria. AJR
1987; 149:1187–1190.
40. Leibovitch I, Foster RS, Kopecky KK, et al: Improved
accuracy of computerized tomography based clinical
staging in low stage nonseminomatous germ cell cancer
using size criteria of retroperitoneal lymph nodes. J Urol
1995; 154:1759–1763.
41. Ellis JH, Bies JR, Kopecky KK, et al: Comparison of
NMR and CT imaging in the evaluation of metastatic
retroperitoneal lymphadenopathy from testicular
carcinoma. J Comput Assist Tomogr 1984; 8(4):709–719.
42. Hogeboom WR, Hoekstra HJ, Mooyaart EL, et al:
Magnetic resonance imaging of retroperitoneal lymph
node metastases of nonseminomatous germ cell tumours
of the testis. J Surg Oncol 1993; 19:429–437.
43. Bussar-Maatz R, Weissbach L: Retroperitoneal lymph
node staging of testicular tumours. BJU 1993;
72:234–240.
44. Casellino RA: Lymphography. In Pollack HM,
McClennan BL (eds): Pollack Clinical Urography, 2nd
edition. Philadelphia, PA, WB Saunders, 2000.
45. Wishnow KI, Johnson DE, Tenney D: Are
lymphangiograms necessary before placing patients with
nonseminomatous testicular tumors on surveillance?
J Urol 1989; 141:1133–1135.
46. Cremerius U, Wildberger JE Borchers H, et al: Does
positron emission tomography using 18-fluoro-2-
deoxyglucose improve clinical staging of testicular cancer?
Results of a study of 50 patients. Urology 1999;
54:900–904.
47. Hain SF, O’Doherty MJ, Timothy AR, et al:
Fluorodeoxyglucose PET in the initial staging of germ
cell tumours. Eur J Nucl Med 2000; 27(5):590–594.
48. Donohue JP, Thornhill JA, Foster RS: Retroperitoneal
lymphadenectomy for clinical stage A testis cancer
(1965–1989): modifications of technique and impact on
ejaculation. J Urol 1993; 149:237–243.
576 Part VI Testis
49. Klepp O, Olsson AM, Henrikson H, et al: Prognostic
factors in clinical stage I nonseminomatous germ cell
tumors of the testis: multivariate analysis of a
prospective multicenter study. Swedish-Norwegian
testicular cancer group. J Clin Oncol 1990;
8:509–518.
50. Albers P, Siener R, Kliesch S, et al: Risk factors for relapse
in clinical stage I nonseminomatous testicular germ cell
tumors: results of the German testicular cancer study
group trial. J Clin Oncol 2003; 21:1505–1512.
51. Hermans BP, Sweeney CJ, Foster RS, et al: Risk of
systemic metastases in clinical stage I nonseminomatous
germ cell testis tumor managed by retroperitoneal lymph
node dissection. J Urol 2000; 163:1721–1724.
52. Janetschek G, Hobisch A, Peschel R, et al: Laparoscopic
retroperitoneal lymph node dissection. Urology 2000;
55:136–140.
53. Nelson JB, Chen RN, Bishoff JT, et al: Laparoscopic
retroperitoneal lymph node dissection for clinical stage I
nonseminomatous germ cell testicular tumors. Urology
1999; 54:1064–1067.
54. Richie JP, Kantoff PW: Is adjuvant chemotherapy
necessary for patients with stage B1 testicular cancer?
J Clin Oncol 1991; 9:1393–1396.
55. See WA, Hoxie L: Chest staging in testis cancer patients:
imaging modality selection based upon risk assessment as
determined by abdominal computerized tomography scan
results. J Urol 1993; 150:874–878.
56. Hoskin P, Dilly S, Easton D, et al: Prognostic factors in
stage I nonseminomatous germ cell testicular tumors
managed by orchiectomy and surveillance: implications for
adjuvant chemotherapy. J Clin Oncol 1986; 4:1031–1036.
57. The International Germ Cell Collaborative Group:
International germ cell consensus classification: a
prognostic factor-based staging system for metastatic
germ cell cancers. J Clin Oncol 1997; 15(2):594–603.
58. Davis BE, Herr HW, Fair WR, et al: The management of
patients with nonseminomatous germ-cell tumors of the
testis with serologic disease only after orchiectomy. J Urol
1994; 152:111–114.
C H A P T E R
35Seminoma: Management
and Prognosis
Michael A. S. Jewett, MD, FRCSC, FACS,
Rishikesh Pandya, MCh, DNB, MS, and
Padraig Warde, MB, BCh, BAO
Testicular cancer is uncommon and accounts for only 1%
to 2% of all cancers in North America, but it is the most
common solid malignancy in men 20 to 35 years of age.1
The vast majority (98%) are primary germ cell tumors
(GCTs). Of GCTs, approximately 60% are seminomas
and most usually present as an asymptomatic testicular
mass.1,2 The identification of prognostic factors in
patients with both early and advanced disease has helped
to refine management strategies for these patients. The
management of patients with testicular tumors is signifi-
cantly affected by histology and disease extent.
Treatment results with seminoma have been good for
many years because of the relatively low metastatic rate
and high radiosensitivity. More recent advances in
chemotherapy (CT) have improved the cure rate to
>95% overall. The postorchidectomy management of the
stage I group seminoma patients is focused on reducing
the side effects of therapy. Treatment options include
surveillance, adjuvant radiation therapy (RT), retroperi-
toneal lymphadenectomy, and adjuvant CT. Adjuvant
retroperitoneal RT remains the treatment of choice in
most centers. The success of surveillance in stage I non-
seminomatous germ cell testis tumors, the establishment
of curative CT for advanced disease, and the improve-
ments in computed tomography for staging have led to
reexamination of the standard treatment approach in
some centers. Also, while the acute morbidity of the rel-
atively low-dose RT used in this setting is minimal, there
are reports of impaired spermatogenesis, increased rates
of gastrointestinal symptoms and peptic ulceration on
long-term follow-up, and increasing concern regarding
the possible induction of second malignancies by RT.
However, the low relapse rates following radiation, the
lack of apparent serious morbidity with adjuvant RT, the
lack of long-term follow-up in surveillance studies, and
the increased cost of surveillance have all dissuaded most
clinicians from abandoning the traditional treatment
approach.3 Stage II group patients with small bulk
retroperitoneal lymphadenopathy have a high probability
of long-term disease control with RT.4 Stage II group
patients with large masses and stage III group patients
are managed by CT.
EPIDEMIOLOGY
The age distribution of testicular cancer is similar in all
Caucasian populations. There is a small peak in early
childhood around 2 years of age, with rates then remain-
ing low until 15 years of age.5 There is a second peak in
young adults around 25 to 40 years of age and the rate
then declines with a small peak again between 65 and 75
years of age. Testicular cancers occurring in childhood
and in the young adult years are usually GCTs, while
those occurring after age 65 are principally nongerm cell
malignancies, mainly lymphomas. Nonseminomatous
tumors are more common in childhood and in the 15-to-30
age group, while seminomas are seen more frequently in
slightly older (25 to 45 years) patients. In 2003, it is esti-
mated that there will be approximately 7500 new cases
and probably 300 deaths due to testicular cancer in the
U.S.6 The current incidence of testicular cancer in the
white U.S. population is 6:100000 males per year and in
Canada it is 4:100000.7,8 The cumulative lifetime risk of
developing a GCT is 0.2%.5 The incidence of testicular
tumors is rising but the reasons are not well understood.
The incidence rate has doubled in the past 30 years, and
577
578 Part VI Testis
while most patients present with early-stage curable dis-
ease, the continued rising incidence of these tumors pres-
ents a challenge. Weir et al.2 reported that the incidence
of testicular GCT (TGCT) has risen in Ontario by 60%
between 1964 and 1996. Seminomas have increased by
72% and nonseminomas by 45%. From SEER data, the
overall incidence of TGCT rose over 44% from 3.35 to
4.84 per 100,000 men between 1973 to 1978 and 1994 to
1998. Among white men, the incidence rose 52% from
3.69 in 1973 to 1978 to 5.62 per 100,000 men in 1994 to
1998. Among black men, the overall incidence of TGCT
rose 25% from 0.83 in 1973 to 1978 to 1.04 per 100,000
men in 1994 to 1998.1. The incidence in England and
Wales was 5.4 in 1997 compared with 2.9 per 100,000
person-years in 1971.9 Similar increases in incidence
have been reported in other populations with European
ancestry, including Australia, New Zealand, and Europe
itself.10 Geographically, the highest incidence of testicu-
lar cancers is seen in Denmark (8.4 per 100,000 men per
year) and Switzerland (8.8 per 100,000 per year).5 It is
known that the incidence is lower in nonwhites com-
pared to whites. Low incidence rates are seen in other
ethnic groups, such as Americans of Chinese and
Japanese descent. However, a high incidence of testicular
cancer is seen in some nonwhite populations, such as the
Maoris in New Zealand and Native Americans.
ETIOLOGY
Cryptorchidism affects 0.7% of men and is the only con-
dition that has been definitely associated with an
increased risk of testicular cancer.7,11 The mechanisms are
unknown. Pure seminoma is the most common tumor
histology observed in cryptorchid testes.11 Impalpable
cryptorchid testes may be detected with 91% and 95%
accuracy by ultrasound and CT, respectively. The pattern
of nodal metastasis may be different from that of scrotal
primary tumors with a much higher incidence of pelvic
nodal involvement.12 There is ongoing research to define
the genetics of susceptibility to testicular cancer. An
international consortium has been established to collect
pedigrees of patients and their families who are thought
to have increased susceptibility. A gene on the X chromo-
some (Xp27) has been identified. Patients with a family
history of testis cancer, undescended testes, and bilateral
testicular cancers are being studied to identify further sus-
ceptibility genes.13 There may be a relation between
estrogenic exposure in utero and testicular cancer, and
there is evidence that environmental pollutants with
estrogenic or antiandrogenic activity result in hormonal
disruption and are responsible for the steadily increasing
incidence of testicular cancer.14,15
The increased incidence of germ cell cancers among
men with testicular atrophy, testicular dysgenesis, cryp-
torchidism, and infertility suggests a common etiologic
relation between germ cell cancers and these genital
abnormalities.
SYMPTOMS
The commonest mode of presentation is a painless
swelling of the testis but a few patients complain of pain
or heaviness in the affected side. A hard, nontender testis
mass that cannot be transilluminated is diagnostic of a
testicular cancer until proven otherwise. Occasionally,
presentation with loss of libido or infertility leads to
detection of a testicular mass. Acute presentations with
symptoms resembling torsion, hematospermia, varico-
cele, or thrombosis of the pampiniform plexus are rare.
Nipple tenderness or breast swelling is noted in approxi-
mately 5% of patients. Back pain as a result of metastatic
lesion is a very rare presentation.
Any history of cryptorchidism, orchiopexy, or any
other inguinal or scrotal surgeries should be elicited, as
these may be relevant to etiology or pattern of metasta-
sis. When RT is being considered, the presence of
inflammatory bowel disease (IBD), previous abdominal
or pelvic surgeries, or any other intraabdominal diseases
should be ruled out.
PRIMARY SURGERY AND STAGING
Radical inguinal orchiectomy is usually the initial treat-
ment that is both diagnostic of the tumor type and ther-
apeutic. It is curative in approximately 75% of patients
with clinical stage I disease. An intraoperative excisional
biopsy of the testicular mass for frozen-section evalua-
tion after delivery of the testis from the scrotum may pre-
vent unnecessary orchiectomy in the small proportion of
patients who are ultimately found to have benign testic-
ular masses, but it is not routinely performed if the mass
is large or clinically malignant in appearance.
Measurement of the serum tumor markers alpha-
fetoprotein (AFP), the beta subunit of human chorionic
gonadotropin (β-hCG), and lactate dehydrogenase
(LDH) play an important role in the diagnosis, treat-
ment, and establishment of prognosis. A detectable AFP
is an indication of nonseminomatous elements, which
mandates treatment as a nonseminoma. Up to 40% of
patients with pure seminomas have low but detectable
levels of (β−hCG) and >200 ng/ml of (β−hCG) suggests
metastatic disease or nonseminomatous elements.16
LDH is a useful marker in cases of advanced seminoma
and therapy can be monitored by serial measure-
ments.17,18 Placental alkaline phosphatase is nonspecific
and has not generally been found useful in the manage-
ment of seminoma.18
The half-lives of AFP and β-hCG are 5 days and 24
hours, respectively. The tumor markers are measured
serially, immediately before or at the time of radical

orchidectomy. If elevated, measurements should be
repeated until the level(s) normalize or plateau (the later
indicates residual metastatic disease).
Staging investigations should include a chest x-ray and
a CT scan of the abdomen and pelvis. Patients with
retroperitoneal lymphadenopathy should also have a CT
scan of the chest and a bone scan.
Clinical staging of testis tumors is now generally
done according to the 2002 UICC TNM staging system
(see staging chart as Table 35-1). Seminoma is clinically
confined to the testis at diagnosis (T1–4, N0, M0, or
stage I group) in approximately 75% of men. The dis-
ease is characterized by an orderly, predictable spread
pattern from the testis to paraaortic lymph nodes at or
below the renal hilar and then to distant sites, including
mediastinal and supraclavicular lymph nodes, lung, and
bone. Approximately 20% of patients have involvement
of regional lymph nodes at presentation (any T, N1-3,
M0, or stage II group), most commonly paraaortic
nodes. Distant metastases are evident at diagnosis
(any T, Any N, M1, or stage III group) in only 5% of
patients.
Nonstandard surgical approaches (scrotal violations),
including scrotal orchiectomy, open testicular biopsy, and
fine needle aspiration, have historically been condemned
as potentially complicating further treatment and com-
promising patient prognosis.19 Capelouto et al.20 showed
that although statistically significant differences were
found in the local recurrence rate among the scrotal vio-
lation and inguinal group studies, the overall local recur-
rence rates were small (2.9% versus 0.4%, respectively)
and did not occur in stage I group seminoma patients.
There were no statistical differences in distant recur-
rences or survival rates in all groups analyzed. Patients
with scrotal violation who did not receive prophylactic
local therapy fared as well as those who did. Patients with
stage I disease and scrotal violation should not necessar-
ily be disqualified from surveillance protocols or sub-
jected to adjuvant local therapy.
PATHOLOGY
Testicular Intraepithelial Neoplasia
Testicular intraepithelial neoplasia (TIN), previously
referred to as carcinoma-in-situ (CIS), is the precursor
to all TGCTs except spermatocytic seminoma.21
Furthermore, virtually all cases of TIN in postpubertal
men will progress to invasive cancer if given sufficient
time.22 The incidence of TIN in the contralateral testis
of men with a unilateral GST is approximately 5%,
which approximates the incidence of second contralateral
testicular tumors.23–26
There are three histologic subtypes of seminoma: clas-
sical (70% to 85%), anaplastic (10% to 30%), and sper-
matocytic (2% to 12%).
Chapter 35 Seminoma: Management and Prognosis 579
Classical seminoma is usually seen in the fourth decade
of life. The typical histologic picture is sheets of rela-
tively large cells with clear cytoplasm and densely
staining nuclei with 10% to 15% of them showing syn-
cytiotrophoblastic elements and 20% showing lympho-
cytic infiltration. β-hCG levels are proportionate to the
extent of syncytiotrophoblastic cells.
Anaplastic seminoma also occurs in the fourth decade.
This histologic subtype may indicate a poorer prognosis
but this is not supported by the results with surveil-
lance.27 Increased mitotic activity, microinvasion, nuclear
pleomorphism, and cellular anaplasia are its typical fea-
tures. β-hCG levels are elevated in 36%, 25% present
with higher stage disease, and almost half of these
patients have extragonadal extension of the primary
tumor.
Spermatocytic seminoma is a histologic variant that
occurs in the elderly, around the sixth decade. They are
large multinodular fleshy gelatinous and hemorrhagic
tumors. Under the microscope they have solid sheets of
cells interrupted by pseudoglandular patterns. Nests of
cells in edematous stroma with occasional lymphocytic
infiltrates can be seen. Spermatocytic seminomas do
not metastasize, so radical orchiectomy is an adequate
treatment.
Warde et al.28 showed that on univariate analysis,
tumor size (relapse-free rate or RFR: = 4 cm 87% ver-
sus >4 cm 76%; p = 0.003), rete testis invasion (RFR:
86% when absent versus 77% when present, p =
0.003), and the presence of SVI (small vessel invasion)
(RFR: 86% when absent versus 77% when present, p =
0.038) were predictive of relapse.28 On multivariate
analysis, tumor size (= 4 cm) and invasion of the rete
testis remained important predictors for relapse.
Thus, the size of the primary tumor and rete testis
invasion are important prognostic factors for relapse
in patients with stage I seminoma when managed with
surveillance.
PATTERNS OF SPREAD
The N staging of the testicular tumor depends on the
number and size of involved retroperitoneal lymph
nodes. Spread is primarily lymphatic and is predictable.
Surgical mapping studies by Donohue et al.,29 Weissbach
and Boedefeld,30 and other workers have defined the pat-
terns of metastasis in terms of its landing sites or stations.
For right-sided tumors, the first station is the interaorto-
caval nodes, then the precaval and preaortic; for left-
sided, first station is paraaortic and preaortic and then the
interaortocaval nodes. The presence of more caudal
metastatic nodes is generally seen in high volume disease
or with aberrant lymphatic drainage. Contralateral
spread is more common from right-sided tumors than
left, especially in high volume disease.
580 Part VI Testis

Table 35-1 Staging (UICC 2002)

DEFINITIONS

Pathologic Primary Tumor (T)(1)

■ pTX Primary tumor cannot be assessed (if no radical orchiectomy has been Notes
performed, TX is used) 1. Except for pTis and pT4,
extent of primary tumor is
■ pT0 No evidence of primary tumor (e.g., histologic scar in testis) classified as radical orchiectomy.
TX may be used for other
■ pTis Intratubular germ cell neoplasia (carcinoma in situ) categories in the absence of
radical mechiactomy.
■ PT1 Tumor limited to the testis and epididymis without vascular/
lymphatic invasion; tumor may invade into the tunica albuginea
but not the tunica vaginalis

■ pT2 Tumor limited to the testis and epididymis with vascular/

lymphatic invasion, or tumor extending through the tunica
albuginea with involvement of the tunica vaginalis

■ PT3 Tumor invades the spermatic cord with or without vascular/lymphatic

invasion

■ pT4 Tumor invades the scrotum with or without vascular/lymphatic invasion

Clinical Primary Tumor (T)

■ Tumor stage is generally determined after orchiectomy at which time a pathologic stage is assigned.

Pathologic Regional Lymph Nodes (N)
■ pNX Regional lymph nodes cannot be assessed
■ pN0 No regional lymph node metastasis
■ pN1 Metastasis with a lymph node mass 2 cm or
less in greatest dimension and less than or equal
to 5 nodes positive, none more than
2 cm in greatest dimension
■ pN2 Metastasis with a lymph node mass more than 2 cm
but not more than 5 cm in greatest dimension; or
more than 5 nodes positive, none more than 5 cm;
or evidence of extranodal extension of tumor
■ pN3 Metastasis with a lymph node mass more
than 5 cm in greatest dimension
Clinical Pathologic Distant Metastasis (M)
Clinical Regional Lymph Nodes (N)
■ NX Regional lymph nodes cannot be
assessed
■ N0 No regional lymph node metastasis
■ N1 Metastasis with a lymph node mass 2 cm
or less in greatest dimension; or
multiple lymph nodes, none more
than 2 cm in greatest dimension
■ N2 Metastasis with a lymph node mass
more than 2 cm but not more than
5 cm in greatest dimension; or multiple
lymph nodes, any one mass greater
than 2 cm but not more than 5 cm
in greatest dimension
■ N3 Metastasis with a lymph node mass
more than 5 cm in greatest dimension

■ ■ MX Distant metastasis cannot be assessed

■ ■ M0 No distant metastasis

■ ■ M1 Distant metastasis

■ ■ M1a Non-regional nodal or pulmonary metastasis

■ ■ M1b Distant metastasis other than to non-regional lymph nodes and lungs

Biopsy of metastatic site performed ■ Y ■ N

Source of pathologic metastatic specimen_____

 Chapter 35 Seminoma: Management and Prognosis 581

Table 35-1 Staging—cont’d

Serum Tumor Murder (S) (N indicates the upper limit of normal for the LDH assay)

■ ■ SX Marker studies not available or not performed

■ ■ S0 Marker study levels within normal limits

■ ■ S1 LDH < 1.5 × N AND

hCG (mIu/ml) < 5000 AND

AFP (ng/ml) < 1000

■ ■ S2 LDH 1.5–10 × N OR

hCG (mIu/ml) 5000–50,000 OR

AFP (ng/ml) 1000–10,000

■ ■ S3 LDH > 10 × N OR

hCG (mIu/ml) > 50,000 OR

AFP (ng/ml) > 10,000

Clinical Pathologic Stage Grouping Notes

Additional Descriptiors
■ ■ 0 pTis N0 M0 S0 Lymphatic Vessel Invasion (L)

■ ■ I pT1-4 N0 M0 SX LX Lymphatic vessel invasion cannot

be asscesed
■ ■ IA pT1 N0 M0 S0
L0 No lymphatic vessel invasion
■ ■ IB pT2 N0 M0 S0
L1 Lymphatic vessel invasion
pT3 N0 M0 S0
Venous Invasion (V)
pT4 N0 M0 S0
VX Venous invasion cannot be assumed
■ ■ IS Any pT/Tx N0 M0 S1–3
V0 No venous invasion
■ ■ II Any pT/Tx N1–3 M0 SX
V1 Microscoic venous invasion
■ ■ IIA Any pT/Tx N1 M0 S0
V2 Macroscopic venous invasion
Any pT/Tx N1 M0 S1

■ ■ IIB Any pT/Tx N2 M0 S0

Any pT/Tx N2 M0 S1

■ ■ IIC Any pT/Tx N3 M0 S0

Any pT/Tx N3 M0 S0

■ ■ III Any pT/Tx Any N M1 SX

■ ■ IIIA Any pT/Tx Any N M1a S0

Any pT/Tx Any N M1a S1

■ ■ IIIB Any pT/Tx N1–3 M0 S2

Any pT/Tx Any N M1a S2

Continued
582 Part VI Testis

Table 35-1 Staging—cont’d

■ ■ IIIC Any pT/Tx N1-3 M0 S3

Any pT/Tx Any N M1a S3

Any pT/Tx Any N M1b Any S

Residual Tumor (R)
■ RX Presence of residual tumor cannot be assessed
■ R0 No residual tumor
■ R1 Microscopic residual tumor
■ R2 Macroscopic residual tumor

Additional Descriptors

For identification of special cases of TNM or pTNM

classifications, the “m” suffix and “y,” “r,” and “a”
prefixes are used. Although they do not affect the stage
grouping, they indicate cases needing separate analysis.

■ m suffix indicates the presence of multiple primary

tumors in a single site and is recorded in parentheses:
pT(m)NM.

■ y prefix indicates those cases in which classification is

performed during or following initial multimodality
therapy. The cTNM or pTNM category is identified by
a “y” prefix. The ycTNM or ypTNM categories the extent
of tumor actually present at the time of that examination.
The “y” categorization is not an estimate of tumor prior to
multimodality therapy.

■ r prefix indicates a recurrent tumor when staged after a

disease-free interval, and is identified by the “r”
prefix rTNM.

■ a prefix designates the stage determined at autopsy:

aTNM. Indicate on diagram primary tumor and regional
nodes involved.
Prognostic Indicators (if applicable)

Involvement of inguinal, pelvic, and iliac lymph nodes

is uncommon except in cases of (i) prior pelvic or abdom-
inal surgery where the normal lymphatic drainage may be
disturbed, (ii) seminomas arising in a cryptorchid testis,
(iii) congenital anomalies of the genitourinary tract, (iv)
bulky paraaortic lymphadenopathy, and (v) possibly post-
scrotal orchiectomy with incision of the tunica albuginea
and with tumor invasion of tunica vaginalis or the lower
third of the epididymis.31–33
PREVENTION AND EARLY DETECTION
The identification of TIN as a precursor of TGCT has
raised the possibility that the development of invasive
testicular cancer can be prevented by treating TIN. The
incidence of TIN in the general population is low at
0.7%; however, the diagnosis should be considered in
high-risk patients, including those with a history of cryp-
torchidism, presumed extragonadal GCT, androgen

insensitivity syndrome, with intersex syndromes or
gonadal dysgenesis, and in patients with contralateral
GCTs.34,35 It has been suggested that men with a uni-
lateral tumor should undergo biopsy of the contralateral
testis, preferably at the time of ipsilateral orchiectomy
with the aim of identifying and treating TIN before
progression to invasive disease.36 Those with a small,
soft contralateral testis and severe oligospermia or
aspermia are at a higher risk that appears to justify
biopsy if treatment is going to be recommended. Men
with a normal testicular biopsy can be reassured that
their risk of a contralateral tumor is <1%.23 Those with
a positive biopsy should be considered for testicular RT
using a fractionated dose of 20 Gy that has been
reported to eradicate TIN and prevent the development
of invasive cancer.22 Leydig cell function with andro-
gen production appears to be preserved in most
patients.35,37
Testicular self-examination has been advocated by
many for the early detection of invasive tumors but its
usefulness is unproven. There is no evidence to indi-
cate that a screening program would be of benefit;
however, there is a need for education about the early
signs and symptoms of testicular cancer to reduce delay
at presentation. Patients with unilateral TGCTs and
cryptorchidism should practice transmissible spongi-
form encephalopathy (TSE). An ultrasound can be
done for early detection and intervention if a tumor is
suspected.
Testicular microlithiasis has been considered a pre-
cursor of testicular cancer. The term testicular
microlithiasis refers to the high intensity signals that are
recorded on ultrasound, where microcalcifications are
within the tubules. 38–40 Patients with testicular
microlithiasis found on ultrasound along with associ-
ated risk factors, such as infertility or cryptorchidism,
may require close follow-up considering its association
with testicular neoplasia.39
MANAGEMENT OF CLINICAL STAGE I (T1–4,
N0, M0) GROUP
Stage I seminoma represents the most common presen-
tation of the disease, representing 70% to 80% of all new
cases.3,41 For the past 20 years, clinical experience with
surveillance has demonstrated that, after orchiectomy,
survival is equivalent to the outcome with adjuvant RT,
which remains the standard of care. With surveillance,
many patients can avoid unnecessary therapy but require
close follow-up, and a proportion will progress and
require further treatment. For this latter reason, it is
important to identify potential prognostic factors for
occult metastatic disease so that patients at high risk of
relapse can be treated with adjuvant treatment after sur-
Chapter 35 Seminoma: Management and Prognosis 583
gery. The optimal follow-up program for surveillance has
not been determined and has evolved over time.
Abdominal radiation to the paraaortic lymph nodes is
highly effective with rare in-field relapse.42 Acute side
effects are modest although long-term follow-up has
revealed a slight increase in secondary malignancy.43,44
Primary chemotherapy for high-risk patients is not
widely practiced in North America, in part because
strong prognostic factors have not been defined.45
Role of Surveillance
Surveillance is feasible in patients with seminoma
because of the predictable recurrence pattern, the avail-
ability of high quality abdominal imaging, which allows
recurrences to be detected at an early stage, and the
effectiveness of chemotherapy at curing even patients
with advanced disease. Surveillance is a safe alternative to
adjuvant RT in stage I seminoma. It avoids unnecessary
treatment and treatment-induced morbidity in the
majority of patients and does not compromise cure.
Newly diagnosed patients at Princess Margaret Hospital
(PMH) are usually offered both surveillance and imme-
diately RT, and most opt for surveillance. Nevertheless,
surveillance is not yet an accepted alternative to RT in
many centers for several reasons. It requires a commit-
ment by both patient and physician to long-term inten-
sive monitoring with regular physical examination, chest
x-ray, CT imaging of the abdomen and pelvis, and meas-
urement of serum LDH, AFP and β-hCG. A number of
prospective nonrandomized studies of surveillance have
been conducted over the past 15 years. The largest
reported series are the PMH and Danish Testicular
Carcinoma Study Group’s (DATECA) trials.46 In the
PMH study of 241 patients, 5-year actuarial relapse-free
survival was 86% with a median follow-up of 7.3 years.3
In the DATECA study, 19% of patients had failed with a
median follow-up of 48 months.41 Other studies with
greater than 36-month follow-up have reported similar
relapse rates. Site of relapse was similar in all surveillance
studies with the vast majority recurring in the paraaortic
and interaortocaval nodes, 33 of 37 (89%) and 41 of 49
(82%) in the PMH and DATECA studies, respectively.
While the median time to relapse ranged from 12 to 18
months, recurrences have been reported as late as 9 years
from diagnosis.47,48 This implies the need for ongoing
follow-up over an extended period. Patients who choose
surveillance but are poorly compliant with follow-up may
compromise their outcome by delaying the diagnosis of
recurrence until a late stage when more intensive therapy
is necessary or cure is not possible. Hao et al.49 described
two deaths among poorly compliant patients with non-
seminomatous testicular cancers on surveillance, but
none among patients who attended regularly for follow-up.
584 Part VI Testis

Finally, at least one economic analysis has suggested that
surveillance may be more costly to the health care budget
than immediate RT, although the costs of managing treat-
ment-induced second malignancies and the psychologic
and social costs to patients were not considered.50
Prognostic factors for relapse have been identified.51 A
list of studies comparing these prognostic factors is pro-
vided in Table 35-2. In the PMH series, only age (≤34
years) and tumor size (>6 cm) were associated with
relapse.48 Among 57 patients who had no adverse prog-
nostic factors (age > 34, tumor size < 6 cm, and no lym-
phvascular invasion), tumor relapse was 6% at 5 years. In
the DATECA study, primary tumor size was the only risk
factor. Risk of relapse at 4 years was 6%, 18%, and 36%
among patients with tumors <3 cm, 3 to 6 cm, and >6 cm,
respectively.46 In a series published by the group at Royal
Marsden, only the presence of lymph vascular space
involvement was associated with relapse (9% versus 17%).52

Table 35-2 Prognostic Factors for Relapse in Stage I Seminoma Patients on Surveillance
Series Relapse (%) Factor Strata Relapse (%)

Horwich, 1992, n = 103 18 SVI* No 10

Yes 20

von der Masse, 1993, n = 261 20 Size <3 cm 6

3–5.9 cm 18

>6 cm 36

Histology Spermatocytic 0

Classical 16

Anaplastic 33

Necrosis No 14

Yes 23

Rete testis No 14

Yes 23

Warde, 1997, n = 201 15 Size <6 cm 12

>6 cm 33

Age <34 9

>34 21

SVI No 14

Yes 31

18 Size <4 cm 13

Worde et al. 1999, n = 638 >4 cm 24

Rete testis No 14

Yes 24

SVI No 14

Yes 23

*SVI, Small vessel invasion by tumor.


Effective surveillance for seminoma implies effica-
cious therapy for patients who relapse. In the DATECA
and PMH series, most patients were treated with
retroperitoneal RT. Second relapse post-RT was 19% in
the PMH series and 11% in the DATECA series.
Although this relapse rate is higher than de novo treated
patients, it is important to recognize that this represents
a subset of patients who have already failed surveillance.
Overall failure for the entire cohort is similar to upfront
RT, and almost 100% of patients are cured regardless of
choice of therapy postorchiectomy.
An additional concern about surveillance is the ability
to detect retroperitoneal disease at a small volume
(<5 cm) such that recurrence can be managed with RT
without the need for cytotoxic chemotherapy. In the
PMH experience, a similar number of patients managed
with surveillance (13 of 241) and adjuvant RT (10 of 254)
ultimately required chemotherapy as part of their treat-
ment regimen. It is difficult to determine the incidence of
this phenomenon from the reported literature, as in many
centers chemotherapy is routinely used at relapse; also in
many isolated cases, patients had known contraindications.
Role of Adjuvant Radiation Therapy for Dose
Reduction
The traditional management of patients with stage I
seminoma following radical orchiectomy is with RT
directed to the paraaortic lymph nodes below the
diaphragm and the ipsilateral common and external iliac
lymph nodes to the level of the mid-obturator foramen.
The inguinal lymph nodes may or may not be included
depending on the estimated risk of inguinal involvement.
The radiation dose is typically 25 to 30 Gy in 15 to 20
daily fractions. Patients experience fatigue and mild gas-
trointestinal upset during therapy that is usually readily
controlled with 5-hydroxytryptamine antagonists for
nausea and antimotility agents for cramping and diar-
rhea. These side effects typically resolve within a few
weeks of completing RT, although fatigue may occasion-
ally persist longer. Numerous reports have documented
long-term disease control rates of approximately 95%
following radiation.27,53,54 Recurrences within the irradi-
ated volume are extremely rare if treatment is planned
and delivered appropriately, and follow-up imaging of
the abdomen and pelvis is therefore not required. The
few recurrences that do arise typically involve the medi-
astinal or supraclavicular lymph nodes or the lung
parenchyma and can usually be detected with a combina-
tion of regular physical examination and chest x-ray. The
majority of these patients are salvaged with chemother-
apy administered at the time of relapse, and overall cure
rates approach 100%.
While the acute side effects of radiation that develop
during treatment are usually self-limiting and of minimal
Chapter 35 Seminoma: Management and Prognosis 585
consequence, the side effects that arise months or years
after the treatment is finished may have long-term con-
sequences. Chronic gastrointestinal symptoms may
develop, and an increased incidence of peptic ulceration
particularly after abdominal radiation doses in the range
of 30 to 45 Gy has been reported.55,56 The germinal
epithelium of the testis is one of the most sensitive tis-
sues in the body to ionizing radiation, and doses as low
as 20 cGy (<1% of the dose that is usually used to
treat seminoma) are sufficient to transiently elevate
gonadotropins and reduce sperm counts.57,58 Even with
shielding of the remaining testis, the scatter radiation
dose results in a significant risk of infertility in previously
fertile men.59 However, the most dire consequence of
radiation for seminoma may be the increased risk of sec-
ond malignant tumors within the irradiated volume many
years after treatment. Radiation-induced tumors must be
distinguished from the development of a second GCT,
which occurs in about 5% of patients with seminoma and
reflects an underlying predisposition.25,26 The largest
study of second malignant non-GCTs in patients with
testicular cancer was a cooperative effort involving over
28,000 patients from 16 population-based cancer reg-
istries.44 The actuarial excessive risk of developing a sec-
ond malignancy increased progressively with time from
diagnosis of testicular cancer, and was 18% at 25 years.
The risk was the same for seminoma and nonseminoma-
tous tumors. RT was associated with a 2- to 6-fold
increased risk of leukemia, as well as an increased risk of
solid tumors of the gastrointestinal and genitourinary
tracts. Chemotherapy that included alkylating agents was
associated with a 7- to 10-fold excessive risk of leukemia.
Role of Modified Adjuvant Radiation Therapy
Given these concerns about abandoning adjuvant RT
entirely in patients with clinical stage I seminoma in
favor of surveillance, alternate management strategies
have emerged that aim to reduce the toxicity of RT by
reducing either the radiation dose or the volume that is
treated. A radiation dose of 25 Gy in 20 daily fractions
controls microscopic seminoma in paraaortic lymph
nodes with a probability approaching 100%. The dose-
response relationship for seminoma below this level is
unknown, although there are isolated reports of in-field
recurrences after fractionated doses of 15 and 21 Gy.60,61
There is experience in the United Kingdom using a radi-
ation dose of 20 Gy in 8 daily fractions. The treatment
was well tolerated, and there was only one in-field recur-
rence among 263 patients. It is difficult to compare these
results to more conventional dose-fractionation schemes
because of differences in daily fraction size (2.5 Gy ver-
sus 1.25 to 2 Gy, respectively). Total dose and fraction
size both influence the biologic effectiveness of a course
of RT. The Medical Research Council of the United
586 Part VI Testis
Kingdom (MRC, UK) has conducted a phase III ran-
domized study comparing high- and low-dose radiation
schedules with equal fraction size (30 Gy in 15 fractions
versus 20 Gy in 10 fractions). The results of this study,
which are not yet available, should better define the low-
est dose that is necessary to reliably control microscopic
deposits of seminoma. However, small to modest reduc-
tions in dose of this magnitude may not necessarily trans-
late into a reduced risk of infertility or second
malignancy, especially if treatment is administered in an
otherwise conventional fashion to encompass the
paraaortic and ipsilateral pelvic lymph nodes.
Paraaortic relapse accounts for 85% of recurrences in
seminoma patients on surveillance, whereas recurrence
in the ipsilateral iliac lymph nodes is seen in <10% of
patients.46,48,52 In addition, surgicopathologic series of
patients with clinical stage I nonseminomatous testicular
cancer have demonstrated ipsilateral common iliac nodal
involvement in only about 10% of cases.29 One of the
most important factors determining the radiation dose to
the remaining contralateral testis, and therefore the risk
of infertility, is the distance from the inferior edge of the
radiation field to the scrotum.59 With this knowledge,
several investigators have proposed limiting the radiation
fields to treat only the paraaortic nodes.42,62–64 An MRC,
UK, randomized phase III study comparing conventional
paraaortic and ipsilateral pelvic radiation to paraaortic
RT alone in 478 patients was recently reported, and
showed no difference in disease-free survival between the
two arms.42 There were four iliac lymph node recur-
rences in patients who received paraaortic irradiation
alone, and none in patients treated with paraaortic and
ipsilateral pelvic radiation. Sperm counts after treatment
were significantly higher in the paraaortic group.
This study is likely to significantly influence the stan-
dard of RT practice for patients with stage I seminoma,
in that a greater proportion will receive paraaortic radia-
tion alone. However, the small risk of iliac lymph node
recurrence remains problematic. The other usual sites of
recurrence after paraaortic RT alone are the inguinal,
mediastinal, and supraclavicular lymph nodes and the
lung parenchyma.42,63 These areas are easily followed by
physical examination and chest x-ray, but regular CT
imaging may be necessary to detect pelvic recurrence at
an early stage. The advantage of paraaortic RT alone is
therefore diminished, particularly in comparison to sur-
veillance. A compromise may be to irradiate the paraaor-
tic and ipsilateral common iliac lymph nodes by
positioning the inferior border of the radiation fields at
the lower aspect of the sacroiliac joints.65 This encom-
passes the lymph nodes that are typically removed at
lymphadenectomy in patients with nonseminomatous
tumors.66 The external iliac and inguinal nodes are not
treated but are unlikely to harbor occult metastases. This
approach has the potential to reduce the scatter dose to
the remaining testis and preserve fertility without the
requirement for ongoing pelvic surveillance.67
Role of Primary Chemotherapy
The effectiveness of multiagent cisplatin-containing
chemotherapy in advanced seminoma has lead to at least
4 studies of adjuvant chemotherapy with one or two
courses of single-agent carboplatin in patients with stage I
disease as an alternative to RT or surveillance.68–70
Median follow-up was 24 to 74 months. Only 2 of the
160 patients developed a recurrence. Treatment was well
tolerated without significant acute morbidity. There was
minimal disruption of normal lifestyle and fertility did
not appear to be compromised.68,71,72 However, notwith-
standing these promising results, the use of chemother-
apy in this setting must be approached cautiously. The
experience is small, and the follow-up remains short.
Late recurrences may yet arise and the long-term toxic-
ity of this treatment, particularly with respect to the
induction of leukemia, is not known.44 The MRC, UK is
presently comparing a single cycle of carboplatin to adju-
vant RT in a randomized study that should help to clar-
ify the relative efficacy and toxicity of these treatments.
Several studies have reported that adjuvant chemother-
apy yields higher cure rates in relapsed surveillance
patients compared with those who underwent adjuvant
RT , reinforcing the value of adjuvant chemotherapy for
stage I seminoma.
MANAGEMENT OF CLINICAL STAGE II (ANY
T, ANY N, M0) GROUP
Only about 20% of patients have clinically evident
involvement of paraaortic lymph nodes at diagnosis and
are classified as having stage II disease. The number of
patients is too small to mount phase III clinical trials of
management, and treatment decisions are generally
based on reports from single institutions where patients
have been treated in a uniform fashion.54,73–76
The most important prognostic factor in stage II
seminoma is the bulk of the retroperitoneal tumor, meas-
ured as the axial diameter of the largest lymph node or
lymph node mass visible on CT scan. Patients who are
staged according to the 2002 UICC TNM classification
are stratified into 3 groups reflecting nodal masses of <2
cm (stage IIA), 2 to 5 cm (stage IIB), and >5 cm (stage
IIC). Approximately 70% of stage II patients have small
bulk retroperitoneal disease at presentation with lymph
nodes that are <5 cm.76
Lymph node size was the only factor that predicted
recurrence in 80 patients with stage II seminoma treated
with RT at PMH.76 The 5-year RFR in patients with
nodal disease of <5 cm was 89%, compared to 44% in
patients with bulkier disease. In total, 16 of 80 patients

treated with radiation developed recurrence, most com-
monly in mediastinal or supraclavicular lymph nodes,
lung, or bone. Thirteen patients were treated with
chemotherapy at relapse, and 9 were free of disease at
last follow-up. The other 4 patients plus 2 additional
patients who did not receive salvage chemotherapy died
of progressive seminoma. In contrast, no recurrences or
deaths were seen in the 19 patients who received initial
chemotherapy, even though 14 had nodal masses >5 cm
in size. These results support the continued use of pri-
mary RT in stage II patients with small bulk lym-
phadenopathy. However, the high failure rate following
RT in patients with bulky retroperitoneal disease, the
fact that not all patients with recurrence were salvaged,
and the apparently better outcome of similar patients
who were treated with chemotherapy at diagnosis man-
dates primary chemotherapy instead of radiation in this
population.
Tumor bulk should not be the only parameter used to
decide on treatment of retroperitoneal disease in patients
with stage II seminoma. Other patient and tumor-related
factors should also be considered. Lymph node masses
that are situated laterally may necessitate irradiating a
large volume of one or both kidneys or the liver in order
to adequately encompass the tumor. The same situation
may arise in cases of abnormal anatomy, such as with
horseshoe or pelvic kidney. These patients are better
treated with chemotherapy because of an unacceptably
high risk of radiation toxicity. Patients in whom RT and
chemotherapy are contraindicated or the diagnosis is
uncertain should be considered for retroperitoneal
lymph node dissection.77
RT offers a high probability of controlling metasta-
tic seminoma in lymph nodes <5 cm in size. The treat-
ment volume includes the gross tumor, as well as the
paraaortic and ipsilateral common and external iliac
lymph nodes. The radiation dose is typically 25 Gy in
20 daily fractions plus a boost of a further 10 Gy in 5 to
8 fractions to the gross lymphadenopathy. A CT scan
with the patient in the treatment position is used to
ensure that the gross tumor is adequately encompassed
by the radiation fields and that the minimal possible
volume of kidney and liver is irradiated. The contralat-
eral iliac lymph nodes may also be treated in cases
where lymphadenopathy in the low paraaortic area is
deemed to increase the risk of these nodes being
involved by tumor. However, this is probably of most
concern in patients with bulky retroperitoneal lym-
phadenopathy, who are better treated with primary
chemotherapy as discussed previously.33 Adjuvant radi-
ation of supraclavicular lymph nodes in patients with
stage II disease has been recommended by some,
although it is not justified on a routine basis in view of
the low risk of isolated supraclavicular recurrence (5%
of patients with retroperitoneal nodal masses >5 cm in
Chapter 35 Seminoma: Management and Prognosis 587
the PMH series), the ease with which supraclavicular
lymph nodes can be followed clinically, the availability
of effective salvage chemotherapy, the possibility of
compromising bone marrow reserve for subsequent
chemotherapy should it be necessary, and the potential
for radiation-induced cardiac toxicity.54,78,79
Patients with gross retroperitoneal lymphadenopa-
thy require follow-up imaging of the abdomen after
treatment until complete regression of disease has
occurred. Residual retroperitoneal masses are fre-
quently seen that may either regress slowly over time
or remain stable. A stable persistent mass often repre-
sents fibrosis or necrosis and only the minority contain
active tumor.80–82 However, the possibility of a non-
seminomatous component to explain the persistence
needs to be kept in mind even in patients whose pri-
mary tumors show pure seminoma.76 The Memorial
Sloan-Kettering Cancer Center (MSKCC) has the
largest reported experience with the management of
residual retroperitoneal masses in seminoma.82
The most common sites of recurrence following RT
in stage II patients with small bulk lymph node metas-
tases are mediastinal or supraclavicular nodes, lung, and
bone.76 Most relapsing patients are cured with
chemotherapy, which underscores the importance of reg-
ular follow-up with clinical examination and chest x-ray
after radiation. CT imaging of the abdomen and pelvis is
not necessary after complete resolution of abdominal dis-
ease. In the PMH series, 4 of the 16 patients who
recurred had bone metastases, and 3 of these 4 presented
with spinal cord compression as the first sign of recur-
rence.76,83 Therefore, all patients with unexplained back
pain require a bone scan to exclude metastases, and those
with new onset neurologic deficits require urgent imag-
ing of the spine with magnetic resonance imaging or
myelography.
MANAGEMENT OF CLINICAL STAGE III (ANY
T, ANY N, ANY M) GROUP
Approximately 20% of testicular seminoma patients have
metastatic disease; 15% in the regional lymph nodes and
5% in distant organ metastasis (stage III).84 Multiagent
cisplatin-based chemotherapy is effective treatment for
patients with distant metastases at diagnosis (stage III),
and even those with very advanced disease are frequently
cured.85 The most important factor predicting survival of
patients with stage III seminoma is the presence or
absence of nonpulmonary visceral metastases. The
International Germ Cell Consensus Group reported that
stage III patients with nonpulmonary visceral metastases
had a 67% 5-year disease-free survival, compared to 82%
in patients with only lung or lymph node involvement.83
Liver or brain metastases, which are rarely seen in patients
with seminoma, carried a particularly poor prognosis
588 Part VI Testis
with reported disease-free survivals of 50% and 57%,
respectively.
The evolution of chemotherapy for metastatic semi-
noma has paralleled the evolution of chemotherapy for
nonseminomatous GCTs. Cisplatin and carboplatin are
the most active single agents and are responsible for the
high cure rates, particularly when combined with other
drugs. Historically, the most commonly used regimens
consisted of cisplatin plus vinblastine, cyclophosphamide,
actinomycin-D and bleomycin (VAB-6), or cisplatin plus
vinblastine and bleomycin (PVB).81,86 The vinblastine in
the PVB regimen was replaced by etoposide (BEP) with
no difference in outcome but a significant reduction in
neuromuscular toxicity.87 Investigators at the MSKCC
later showed that 4 cycles of cisplatin and etoposide (EP)
produced equivalent long-term disease-free survival to
bleomycin-containing regimens without the risk of pul-
monary toxicity associated with bleomycin.88 EP is now
the most widely used regimen for initial treatment of
metastatic seminoma. Salvage treatment for patients who
develop progressive disease after first-line chemotherapy
most often consists of combinations of cisplatin, ifos-
famide, and vinblastine.89 High-dose chemotherapy with
autologous bone marrow transplantation should be con-
sidered for patients who fail more conventional therapy.
There is no role for routine surgery or RT in the man-
agement of stage III seminoma, although there may be
specific indications in individual patients. Surgery should
be considered for residual clinical or radiographic abnor-
malities in the retroperitoneum or at other sites follow-
ing chemotherapy, extrapolating from the experience
with nonseminomatous tumors.90 Surgery and RT may
be useful in achieving rapid tumor debulking in situations
where normal tissue function is compromised, such as
with brain metastases or spinal cord compression.91,92
EFFECTS OF TREATMENT
Acute
With the low doses of RT used in seminoma, acute compli-
cations are minor in most patients. Mild nausea and vomit-
ing are common. A small proportion of patients require
regular antiemetics and are unable to complete daily tasks
while receiving RT. Diarrhea develops in a minority of
patients. An increased incidence of peptic ulceration in
patients treated with 30 to 45 Gy has been reported.
Chronic
Late Gonadal Toxicity
Germinal epithelium is highly radiosensitive and
although the contralateral testis is not directly located in
the field, scatter dose can be significant and profoundly
diminish spermatogenesis. A radiation dose between 20
and 50 cGy may produce temporary aspermia, and doses
>50 cGy may preclude recovery of spermatogenesis.93
Scrotal shielding does limit this somewhat but cannot
assure protection in all patients. In men who recover
spermatogenesis after RT for seminoma, there is no evi-
dence of an increased incidence of genetic anomalies
among their offspring.93 Limiting the RT field to
paraaortic and common iliac has reduced the concern
regarding post-RT infertility. Elevated LH values with
normal testosterone values have been observed after
infradiaphragmatic irradiation.94
Second Malignancy
Patients with seminoma are at higher risk of later sec-
ondary cancers in addition to an increased risk of con-
tralateral GCTs; they are at risk for other neoplasms,
some of which may be related to treatment and others
related to genetic/environmental exposures unrelated to
treatment.44,95–97 Cancers that may arise secondary to
treatment are an important consideration for possible
surveillance versus radiation for stage I seminoma. Travis
et al.44 reported on the risk of second cancers among
28,843 long-term survivors of testicular cancer, of which
15,000 had seminoma. Overall, seminoma patients had a
42% increased rate of second cancers. Risks were signif-
icantly elevated among patients treated initially by RT
but not chemotherapy although the absolute number in
the chemotherapy cohort was relatively small (n = 560).
Subsequent reanalysis of these data also suggests that
chemotherapy also elevated the risk of leukemia.43
Specific cancers that were detected at higher than
expected rates included leukemia, colon, renal, gastric,
pancreatic, and bladder. Overall risk of second non–germ
cell malignancy was 18.2% at 25 years. Ruther et al.98
assessed second malignancies among 839 patients with 4-
year follow-up. Among this cohort, of whom the vast
majority had RT , an excess number of renal cancers were
noted. Although it is difficult to determine to what
degree these incidence rates would drop by active sur-
veillance, most investigators believe that a significant
proportion of these cases are iatrogenic in nature.
Psychologic Toxicity
The vast majority of men with seminoma suffer no psy-
chologic sequelae from their illness.99 Some studies sug-
gest that these patients have an improved outlook on life
compared to their state prior to the detection of testicu-
lar cancer and to that of age-matched controls. Isolated
patients, however, suffer severe psychologic symptoms in
the domains of sexuality, parenthood, distress, and social
upheaval. Data of the psychologic distress of surveillance
versus up-front active therapy are few. One study suggests
that men on surveillance have fewer sexual problems than
men on active treatment.100

Loss of one or both testes may cause psychologic dis-
tress related to the feeling of decreased masculinity and
changed body image. Testicular prostheses are helpful in
many cases, especially bilateral tumors; however, many
unilaterally orchiectomized patients frequently regard
them as not necessary. In spite of residual treatment and
disease-related morbidity (Raynaud’s phenomena, periph-
eral sensory neuropathy, dry ejaculate, and hypogonadism)
in one-third of patients, most patients cope satisfactorily
with the long-term posttreatment distress and do not
report a major reduction of health-related quality of life.
Fertility
In testicular cancer patients, the overall paternity rates
are probably reduced by 15% to 30% compared with the
normal population. After standard RT or standard
chemotherapy most patients are oligo or azoospermic for
6 to 12 months, but sperm production recovers within
the following 2 years.101 The risk adapted treatment of tes-
ticular cancer preserves fertility in many patients, such as
the use of paraaortic fields instead of RT to paraaortic and
iliac region, increased use of surveillance protocols, the
development of nerve-sparing retroperitoneal lym-
phadenectomies, which are now being practiced laparo-
scopically, reduction of number of chemotherapy cycles
and the use of spermatogenesis saving cytostatics.
Infertility and subfertility are major issues in the health-
related quality of life in the young testicular cancer sur-
vivor. Pretreatment cryopreservation of the semen
technique should be used to offer an option for parent-
hood to these patients. Assisted reproductive technique
can be offered in pretreatment or posttreatment cases hav-
ing low sperm count.102 Rectal probe electroejaculation or
sperm aspiration techniques can be used in patients with
emission problems of the ejaculate posttreatment.103
MANAGEMENT OF RESIDUAL MASSES
Residual retroperitoneal masses remain in 20% to 80%
of cases after chemotherapy and the management
remains controversial. Different approaches have been
reported, including surgery, RT, and surveillance.
Surgery is technically more difficult in seminomas com-
pared to nonseminomas after chemotherapy because of
extensive fibrosis. Complete excision is often difficult and
only biopsies are performed. The percent of viable semi-
noma is low at 10% to 20% and viable disease only seems
to present in well-delineated residual masses 3 cm or
greater. RT has been proposed for postchemotherapy
residual masses, although it may increase the risk of a sec-
ond solid tumor and decrease hematologic tolerance to
salvage chemotherapy in cases of relapse. Surveillance is
an option based on the spontaneous regression of resid-
ual masses.
Chapter 35 Seminoma: Management and Prognosis 589
The largest reported series is from the MSKCC with
55 cases; 32 (58%) underwent complete resection and 23
had multiple biopsies only. In 27 patients the mass was >3
cm in diameter and 8 of these had residual tumor.82 Of
the 8 with positive histologic findings 6 were seminomas,
complete resection was possible in 6, 4 seminomas, and 2
teratomas. By CT scan characteristics well-defined lesions
were more likely to be completely resected (78%) than
poorly defined masses (44%). Unfortunately, the inter-
vals from the completion of chemotherapy to surgery and
the pretreatment sizes were not reported. Ravi et al.104
reported similar findings in 107 patients, in whom 43 had
residual tumor. Nineteen underwent surgery and in 11
patients who had well-defined masses >3 cm in diameter,
6 had positive histology. Flechon et al.105 reported that
viable tumor cells were noted only in residual masses 3 cm
or greater (13%) and 50% of residual masses disappeared
during surveillance.
A recent report has suggested that the routine use of
RT in this setting is of little value, in part reflecting the
low incidence of active tumor in residual masses and the
possibility of nonseminomatous elements that are less
radio-responsive.106 While it appears that surgery should
be reserved for postchemotherapy residual masses >3 cm
in diameter and those <3 cm should be observed, it is also
evident that surgery may be complicated due to excessive
fibrosis following the chemotherapy and that there is a risk
of perioperative mortality. Laparoscopic technique is
being used at many centers for nonseminomas in an
attempt to reduce the morbidity of the open retroperi-
toneal lymph node dissection. The advantages of
decreased pain, shorter hospital stay and convalescence,
and superior cosmesis make laparoscopic retroperitoneal
lymph node dissection a promising procedure for
choice.107 Further studies are needed as it may be safer to
follow masses, even >3 cm, to determine if they will
decrease in size. The natural history of residual masses in
seminoma is not well defined. It may be one of gradual
shrinkage unless nonseminomatous elements or a second
primary are present.
OTHER ISSUES AND MANAGEMENT
OF UNUSUAL CASES
Patients With High hCG
β-hCG > 200 ng/ml are suggestive of metastatic disease
and/or there may be nonseminomatous elements as the
cause.16 Thus, the higher levels of β-hCG normally
should arouse a suspicion for nonseminomatous tumors.
Weissbach and Busser-Maatz108 (in a large prospective
study of seminomas) found 31% of patients with β-hCG
secreting tumors were more likely to have metastases in
retroperitoneal lymph nodes. In seminoma, β-hCG is an
indicator of tumor burden rather than a sign of tumor
aggressiveness. A high hCG with negative imaging
590 Part VI Testis
studies is suggestive of retroperitoneal or distant occult
metastatic disease.
Bilateral Tumors
The reported incidence of bilateral synchronous or
metachronous testicular germ cell tumors is 0.5% to 7%.
Approximately 5% are bilateral.25,26,109 Several studies
have reported an increasing incidence possibly due to
increased overall survival and earlier age of onset.109,110
Frequent examination of the remaining testis after treat-
ment of a unilateral tumor, including self-examination by
patients, is important to detect a second GCT early when
small and confined to the testis. Bilateral inguinal
orchiectomy has been the standard management in this
situation. However, patients then require life-long
androgen replacement therapy, which may be associated
with sexual dysfunction, mood swings, and a general
impairment of quality of life. Partial orchidectomy with
preservation of some normal testicular tissue and andro-
gen production has been proposed as an alternative to
orchiectomy.111–113 Heidenreich and coworkers reported
52 metachronous and 17 synchronous bilateral testicular
germ cell tumor patients who underwent an organ-spar-
ing approach. As expected, approximately 60% had semi-
noma, 20% embryonal carcinoma, 15% mature
teratoma, and 8% mixed GCT. The mean tumor diame-
ter was 15 mm. Eighty-two percent of patients had asso-
ciated TIN and the residual testis was treated with 18 Gy
of local radiation. On mean follow-up of 91 months (3 to
191 months) 98.6% patients had no evidence of disease
and only 1 had died of disease. There was no local relapse
in 46 patients who received local radiation. Testosterone
levels were normal in 85% of patients, and clinical
hypogonadism occurred in about 10%. For tumors of 20
mm and less, tumor enucleation may be a reasonable
alternative to bilateral orchiectomy.
Horseshoe or Ectopic Kidney
Horseshoe kidney occurs in approximately 1 in 400 of
the general population. There is an association between
renal fusion abnormalities and cryptorchidism, which in
turn is associated with an increased incidence of testicu-
lar neoplasms.114 There are two main problems in the
management of GCTs associated with horseshoe or
pelvic kidney. The first is related to the technical prob-
lem of delivery of RT in patients with seminoma. In a
number of cases of horseshoe kidney, a large part of the
renal parenchyma lies within the standard radiation vol-
ume and directly overlies the regional lymph nodes. The
delivery of a standard radiation dose would be associated
with an unacceptable risk of radiation nephritis. The sec-
ond problem is related to the possible abnormalities in
lymphatic drainage of the testis and therefore the possi-
bility of relapse when the standard radiation fields are
used. Unusual patterns of relapse have been observed in
patients managed by surveillance, confirming concerns
regarding abnormal lymphatic pathways.115 For these
reasons, postorchiectomy surveillance in stage I and
chemotherapy in stage II have usually been recom-
mended. Retroperitoneal lymphadenectomy is another
option for patients unwilling to follow the surveillance
program. This approach has been reported to be both
safe and effective in selected cases where it was per-
formed although surgeons must be aware of the potential
for anomalous vasculature.116,117
Inflammatory Bowel Disease
Preexisting morbid conditions like IBD have to be taken
into consideration when RT is planned. Radiation leads
to increased gastrointestinal bleeding, peptic ulceration,
and long-term incidence of stenosis.
SEMINOMA IN PATIENTS WITH
IMMUNOSUPPRESSION AND HUMAN
IMMUNODEFICIENCY VIRUS INFECTION
Testicular neoplasms appear to be 20 to 50 times more
prevalent among patients on immunosuppression com-
pared to the general population and in patients who are
seropositive for human immunodeficiency virus
(HIV).118,119 The interpretation of staging investiga-
tions for seminoma can be difficult in the later patients
because of the benign lymphadenopathy that is fre-
quently associated with HIV infection. A compilation of
the reported experience with testicular tumors in HIV-
positive patients showed a higher than expected fre-
quency of stage II disease (58% versus 20%).119 This
may be attributable at least in part to the false assign-
ment of patients with HIV to stage II because of benign
paraaortic lymphadenopathy. However, it is also possi-
ble that seminoma may have a more aggressive clinical
course in HIV-positive patients. The majority of
patients described in the literature have received stan-
dard treatment. RT and chemotherapy appear to be well
tolerated except in patients with very advanced
immunosuppression. 119 Most patients are cured.
Overall survival is usually determined by the severity of
immunosuppression and the complications of the
acquired immunodeficiency syndrome (AIDS) rather
than by seminoma.119,120
Following renal transplant there are cases reported of
seminomas.49,121,122 In such patients stages I and II have
usually been treated with postoperative RT, but the con-
cerns regarding potential damage to the transplanted
kidney may dictate surveillance. Short-term follow-up of
these patients does not suggest a higher risk of relapse,
but the available data are limited.

THE NONCOMPLIANT PATIENT
As the cure rate for patients with stages I and II semino-
mas approaches 100%, problems with patient compli-
ance with treatment or follow-up recommendations may
affect the outcome more than choice of therapy. Every
large cancer center has experience with patients refusing
conventional therapy or failing to attend for follow-up
with eventual death due to disease. Although Hao et al.49
reported that compliance with clinical evaluations in
patients with nonseminomas was 61.5% in year 1 and
35.5% in year 2, compliance with CT was only 25% and
11.8% in years 1 and 2, respectively. The compliance
with this surveillance program was poor but this study
was too small to demonstrate whether poor compliance
adversely affects overall survival; other studies show no
relation to survival. Patient education regarding the diag-
nosis, available treatment options and outcome in testis
tumors, and need for regular evaluation should be given
high priority.
MANAGEMENT OF SEMINOMA IN CRYPTORCHID
TESTES
The management of seminoma presenting in cryptorchid
testis depends on the location of the primary tumor and
the extent of the disease. The awareness of orchiopexy
early in childhood appears to have led to a significant
drop in the incidence of patients presenting with tumors
in uncorrected cryptorchids. Giving similar doses of radi-
ation and adjusting the size of the paraaortic and pelvic
radiation fields to cover the known extent of disease can
achieve comparable survival.123
EXTRAGONADAL GERM CELL TUMORS
Extragonadal germ cell tumors (EGCTs) have a similar
histology to testicular GCTs but are found in other parts
of the body, in the absence of a testicular mass. They
account for 1% to 5% of all GCTs and, like testicular
GCTs, tend to occur in young men, although the median
age of presentation is 5 to 10 years older than with testic-
ular GCTs.124 Ten percent of adult EGCTs occur in
women, usually as ovarian dysgerminomas. In infants,
EGCTs are more common than testicular primary tumors
(usually sacrococcygeal teratomas).125,126 An increased
incidence of EGCTs is seen with Klinefelter’s syndrome.126
Overall, patients with extragonadal GCTs (especially
NSGCTs) have a worse prognosis than patients with tes-
ticular primaries. In a recent review of published results of
chemotherapy for mediastinal tumors, 28 of 37 (76%)
patients with seminomatous histology were disease free in
comparison to 90 of 204 patients (44%) with nonsemino-
matous tumors.127 The use of aggressive regimens for
patients with nonseminomatous tumors has been recom-
Chapter 35 Seminoma: Management and Prognosis 591
mended, and a 5-year survival of 73% has been reported
with the use of cisplatin + vincristine + methotrexate +
bleomycin + actinomycin D + cyclophosphamide +etopo-
side (POMB/ACE) chemotherapy.128
SUMMARY
Testicular seminoma is highly curable with currently
available treatments. There is good evidence that
patients with stage I disease can be managed equally well
after radical orchiectomy with either adjuvant RT or sur-
veillance. Current areas of investigation in stage I
patients include optimization of the RT treatment tech-
nique to minimize toxicity and the use of 1 or 2 cycles of
single-agent carboplatin instead of RT or surveillance.
Patients with small bulk stage II disease are treated effec-
tively with RT. Patients with bulky stage II or stage III
disease should receive 4 cycles of etoposide and cisplatin
(EP) or equivalent chemotherapy. Overall, more than
95% of patients with seminoma are cured with this strat-
egy. The current challenge for clinicians is to maintain
high cure rates while minimizing toxicity and individual-
izing therapy to the specific social, emotional, and eco-
nomic circumstances of each patient. It is important to
continue to study the long-term consequences of current
treatment strategies, particularly with respect to serious
late side effects that might ultimately compromise the
longevity of patients with seminoma diagnosed and
treated decades earlier. The treatment objectives not only
include long-term survival but should include a near nor-
mal quality of life. It is important that modifications in
surgery, radiation, and chemotherapy, as well as advanced
care to improve the quality of life in terms of sexual func-
tion, fertility, and problems of hormone replacement be
integrated into current management strategies as they
become available, and that the doctrine established as a
result of years of successful treatment not present an
insurmountable barrier to changes that may enhance the
therapeutic ratio and improve overall patient outcome.
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Chapter 35 Seminoma: Management and Prognosis 595
123. Sham JS, Choy P, Chan KW et al: Seminoma of
normally-descended and cryptorchid testis. Eur J Surg
Oncol 1990; 16(1):33–36.
124. Shirdasani RA: Extragonadal germ-cell tumours. In
Scher H, Raghavan D, Leibel S, Lange P (eds):
Principles and Practice of Genitourinary Oncology,
p 751. Philadelphia, Lippincott-Raven Publishers,
1997.
125. Mann JR, Pearson D, Barrett A, et al: Results of the
United Kingdom Children’s Cancer Study Group’s
malignant germ cell tumor studies. Cancer 1989;
63(9):1657–1667.
126. Nichols CR, Heereina NA, Palma C, et al: Klinefelter’s
syndrome associated with mediastinal germ cell
neoplasms. J Clin Oncol 1987; 5(8):1290–1294.
127. Droz JP, Horwich A: Extragonadal germ cell tumours. In
Vogelzang NJ, Scardino P (eds): Comprehensive
Textbook of Genitourinary Oncology. Baltimore,
Williams & Wilkins, 1995.
128. Bower M, Brock C, Holden L, et al: POMB/ACE
chemotherapy for mediastinal germ cell tumours. Eur
J Cancer 1997; 33(6):838–842.
129. Worde P, Specht L, von der Masse H, et al: Prognostic
factors for relapse in Stage I seminoma managed by
surveillance (abstract). J Urol 1999; 161:158.
C H A P T E R
36 Nonseminomatous Germ Cell Testis
Tumors: Management and Prognosis
Randall G. Rowland, MD, PhD
The survival rates for patients with testis cancer have
improved dramatically over the last 30 years. This has
been especially true for nonseminomatous germ cell testis
tumors (NSGCTT). There are several factors involved
in this improvement in survival: improved diagnostic
tools, such as serum markers; better imaging studies;
improved surgical techniques; effective chemotherapeu-
tic agents; multimodal therapy when appropriate; and
increased public awareness.
The high rate of cure of NSGCTT has allowed us
to concentrate on reducing the morbidity and mortal-
ity of the treatments, while maintaining the high rate of
efficacy. Fertility can even be preserved in the majority
of patients using modified templates and nerve-sparing
techniques during radical retroperitoneal lymph node
dissection (RPLND).
This chapter will focus on the diagnoses, staging,
treatments, and outcomes of NSGCTT.
DIAGNOSIS
Germ cell testis tumors (GCTT) are the most common
solid tumors in males from the age of 20 to 35 years.1
GCTTs have been reported in patients from infants to
age 89 years. NSGCTTs account for approximately 60%
of all GCTTs.2
Any mass in the testicle has to be considered a poten-
tial GCTT until proven otherwise. GCTTs must also
be considered as a possibility in patients with scrotal
pain and/or swelling, the presence of a hydrocele, or
a hematocele after relatively minor scrotal trauma.
Production of human chorionic gonadotropin (HCG)
by some tumors causes patients to present with gyneco-
mastia or breast tenderness. Metastases of GCTT have
made some patients present with hemoptysis from pul-
596
monary lesion or back pain from large retroperitoneal
adenopathy.
Physical examination of the testicle still plays a major
role in the evaluation of the patient. It is important to dif-
ferentiate a mass in the testicle versus the epididymis or
cord structures.
Scrotal ultrasound is perhaps the best and most read-
ily available imaging study for suspected GCTTs.
Ultrasound scans facilitate the location of scrotal masses,
as well as giving us information on the homogeneity or
heterogeneity of the mass.
Scrotal ultrasounds may give some insight regarding
the cell type(s) in a mass. Pure seminomas tend to be very
homogeneous masses (Figure 36-1), while mixed GCTTs
may have a heterogeneous echo pattern (Figure 36-2).
The finding of cystic structures in a mass suggests the
presence of teratoma (Figure 36-3).
Serum markers are also helpful in making the
diagnosis of testis cancer. Overall approximately
70% of patients with testis cancer will have elevated
alpha-fetoprotein (AFP) and/or HCG levels in their
blood. The clinical test for HCG is a radioim-
munoassay that measures the beta chain of the HCG
and is designated B-HCG. Yolk sac cell tumors pro-
duce AFP with rare exception. HCG is made by
syncytio-trophoblasts, which are present in all cases of
choriocarcinoma and in about 10% of cases of pure
seminoma.
Lactate dehydrogenase (LDH) is sometimes used as a
measure of tumor bulk; however, the author does not
find this text useful in clinical practice. Placental alkaline
phosphatase (PLAP) is present in up to 84% of patients
with seminoma. PLAP is falsely elevated in a high per-
centage of smokers, which could negate the value of the
marker.3
 Chapter 36 Nonseminomatous Germ Cell Tests Tumors: Management and Prognosis 597
Figure 36-1 Sagittal ultrasound of testis with a central mass, which was a seminoma. Note
the homogeneity of the mass.
RADICAL ORCHIECTOMY VERSUS PARTIAL
ORCHIECTOMY
The standard approach for making the definitive diag-
nosis of testicular cancer has been the radical orchiec-
tomy performed by removing the testicle using an
inguinal approach. This approach helps prevent cross-
contamination of the testicular lymphatics to the
inguinal lymphatics. The vas deferens and the gonadal
vessels are ligated and divided at the level of the internal
inguinal ring.
An organ-sparing approach has been advocated by
some authors.4,5 In this approach, the testicle is still
delivered through an inguinal incision, except the mass in
the testicle is excised. The testis is reconstructed and
returned to the scrotum. This technique is a benefit in
patients with a solitary testis or an intratesticular lesion
that is questionable with respect to its being a testicular
tumor. The down-side of a local excision is the potential
for leaving a finger of a lesion or a satellite lesion behind.
Transscrotal needle biopsy of testicular masses is dis-
couraged for two reasons. First, there can easily be a sam-
pling error that would not give a true representation of
the pathology present. Second, there is a possibility for
cross-contamination for the testicle lymphatics with the
scrotal/inguinal lymphatics.
PATHOLOGY
Histologic study of the orchiectomy specimen should
include documenting the cell type(s) present in the tumor
and the T stage of the tumor. Extensive sampling of the
testis should be performed to allow a careful and thor-
ough determination of the cell types that are present.
T stage can be accurately assessed by careful observation
and extensive histologic sampling.
Tumors can be intratubular (CIS) or invasive. The cell
types of germ cell tumors that occur are shown in Table
36-1. Approximately 40% of patients present with pure
598 Part VI Testis
Figure 36-2 Sagittal ultrasound of testis with a mass, which was a mixed germ cell tumor.
Note the more heterogeneous character of the mass.
seminoma and 60% present with nonseminomatous cell
elements either as a pure cell type or more commonly as
mixed cell type tumors.2 The determination of cell types
present in a testicular tumor is very important in terms of
treatment. Pure seminomas, including spermatocytic
seminomas, are treated with a different approach than
tumors with nonseminomatous elements.
Table 36-2 shows the American Joint Commission on
Cancer’s (AJCC) definitions of the pathologic T stages of
testicular tumors.6
CLINICAL STAGING
Once the histologic diagnosis of testicular cancer is docu-
mented, the patient should have clinical staging performed
to allow the formulation of a treatment plan to best fit the
patient’s needs. Clinical staging involves assessment of the
patient using tumor markers before and after orchiectomy,
radiologic imaging studies of the chest, abdomen and
pelvis, and physical examination to document any
adenopathy or abdominal masses. Care should also be
taken to evaluate the contralateral testis since bilateral syn-
chronous or metachronous testicular tumors do occur.
Serum Markers
AFP and HCG should be rechecked after orchiectomy in
all patients, but especially in those patients with elevated
serum markers prior to orchiectomy. If the tumor was
localized in the testis only, orchiectomy should cause
the markers to return to normal. If tumor remains, the
markers may not return to normal.
When following the serum marker level, the time after
orchiectomy and the serum half-life of each marker must
be considered. The serum half-life of AFP is approxi-
mately 5 days and that of HCG is about 1 day. Markers
that either fall at a lower than expected rate or rising are
indicative of persistent disease.
When LDH is used as a marker, it is usually consid-
ered in terms of its percentage or number of times the
normal value. LDH has a half-life of approximately
3 days.
 Chapter 36 Nonseminomatous Germ Cell Tests Tumors: Management and Prognosis 599

Figure 36-3 Sagittal ultrasound of testis with two adjacent masses. Note the hypoechoic
areas, which correspond to cystic areas of teratoma.

Table 36-1 Germ Cell Testicular Tumors Table 36-2 Pathologic Stage of The Primary Tumor (T)
Precursor lesions Intratubular germ cell neoplasia (CIS) pTX Primary tumor cannot be assessed

Tumors of one Seminoma pT0 No evidence of primary tumor (e.g., histologic

histologic type Spermatocytic seminoma scar in testis)
Embryonal carcinoma
Yolk sac tumor (endodermal pTis Intratubular germ cell neoplasia (carcinoma in situ)
sinus tumor)
Choriocarcinoma PT1 Tumor limited to the testis and epididymis without
Teratoma vascular/lymphatic invasion; tumor may invade into
Mature the tunica albuginea but not the tunica vaginalis
Immature
pT2 Tumor limited to the testis and epididymis with
With malignant component(s)
vascular/lymphatic invasion, or tumor extending
Monodermal variants
through the tunica albuginea with involvement
Carcinoid tumor
of the tunica vaginalis
Primitive neuroectodermal
tumor PT3 Tumor invades the spermatic cord with or without
vascular/lymphatic invasion
Tumors of more Mixed germ cell tumors
than one (specifically individual types) pT4 Tumor invades the scrotum with or without
histologic type vascular/lymphatic invasion

These T stages are based on the pathologic findings from

orchiectomy specimens.
600 Part VI Testis
Imaging Studies
The goal of imaging studies is to detect any nodal or vis-
ceral tumor involvement. Based on the known patterns of
spread of testicular tumors by lymphatics and rarely by
vasculature, the studies need to cover the chest, both pul-
monary parenchyma and the mediastinum, the abdomen,
again the viscera and the retroperitoneal lymph nodes,
and the pelvis.
The chest was initially evaluated by standard chest
x-rays and whole lung tomograms. With the advent of
computed axial tomography (CT) and subsequent
improvement in CT techniques, CT scans have become
the most frequent modality for doing initial clinical stag-
ing of the chest. Chest involvement more frequently
occurs as peripheral pulmonary nodules in cases of low
volume metastases and with the addition of mediastinal
adenopathy in more advanced cases. It is important to
examine the lung fields using both soft tissue settings and
bone window settings. This allows parenchymal lesions
to be evaluated for the presence of calcification, which
leads to a finding of pulmonary granuloma rather than
metastasis. Figures 36-4 and 36-5 show CT scans of a
patient with metastatic pulmonary lesions. Notice that
the lesions visible in Figure 36-4 do not appear in Figure
36-5, which indicates a lack of calcification.
The abdomen and retroperitoneum were originally
evaluated by intravenous pyelograms (IVPs) to look for
evidence of displacement of the kidneys or ureters by
retroperitoneal masses. The CT scan made it possible
to much more accurately evaluate the abdominal viscera
and retroperitoneum. There has been some debate
related to the size threshold of retroperitoneal lymph
nodes that is considered abnormal and likely to repre-
sent metastases. Many authors have picked a 1-cm
threshold in evaluating retroperitoneal lymph nodes.
Using this criterion, the sensitivity has been reported at
approximately 70%. The specificity has been approxi-
mately 94%.7 Liebovitch and his associates at Indiana
reported setting their size threshold at 3 mm for lymph
nodes that are in the areas most likely to have nodal metas-
tases and kept the 1-cm threshold for any other adenopa-
thy. This increased the sensitivity to 91% but decreased
the specificity to 52%.8 Using CT techniques, the sensi-
tivity will most likely not rise about 75% because approx-
imately 25% of patients who have normal imaging studies
and still undergo surgical staging will have microscopic or
small volume macroscopic retroperitoneal metastases.9
Figure 36-6 shows typical CT findings in a patient with
low volume retroperitoneal lymphadenopathy, while
Figure 36-7 shows higher volume retroperitoneal disease.
MRI scan and PET scan have been tried in evaluation
of patients with testicular cancer.7,10 As of this time,
neither of these techniques offer significant advantages
over CT scans in terms of initial staging of patients.
Physical Examination
Patients should be carefully examined for adenopathy
(inguinal, axillary, or cervical). The physician needs to
check for neck, abdominal, or scrotal masses. The con-
tralateral testis should be examined with great care for
any possible intratesticular masses. Scrotal ultrasound
is again very helpful in evaluating the contralateral
testis.
Clinical Stage Designations
Assigning a clinical stage requires consideration of
the pathologic T stage (see Table 36-2), the clinical
N stage (Table 36-3), the clinical M stage (Table 36-4),
and the S stage (Table 36-5).6 The T stage is based on the
pathologic findings from the orchiectomy specimen. The
clinical regional node stage (N) is based on imaging stud-
ies of the abdomen and pelvis. The distant metastases
stage (M) is assigned based on evidence from imaging
studies as well. The serum marker stage (S) is determined
by the preorchiectomy marker determinations for the
initial clinical staging.6
The pT, N, M, and S data are used to assign the
patient to a clinical stage group as shown in Table 36-6.
These clinical stage groups are used as a basis for treatment
recommendations and outcomes analysis.
TOOLS OF TREATMENT
The various treatment modalities for testis cancer,
including observation, are presented in the following
prior to specific treatment recommendation for the
clinical stage groups.
Observation
In patients with a low risk for nodal or metastatic disease,
observation may be appropriate. The criteria for observing
patients who present with localized testicular cancer are
shown in Table 36-7. Primary tumor stage and cell types
present along with the cell type proportions are used
along with imaging study findings and marker levels to
determine eligibility for observation.
Table 36-8 presents the tests and examinations recom-
mended for use in patients who will have observation as
their primary treatment modality. The frequency recom-
mended for tests and examinations decreases with time
since the risk of recurrence diminishes with time.
Primary Retroperitoneal Lymph Node Dissection:
Surgical Staging and Treatment
RPLND techniques have undergone significant evolu-
tion over the last 40 years. In the 1960s the concept of
 Chapter 36 Nonseminomatous Germ Cell Tests Tumors: Management and Prognosis 601

Figure 36-4 Chest x-ray of a patient who presented with hemoptysis from metastatic
testicular cancer.

“more is better” prevailed and the limits of RPLND were
extended. Figure 36-8 illustrates the limits of dissection
that were established.11 The dissection was performed in
an en bloc style from the diaphragm to the level of the
bifurcation of the common iliac arteries and laterally
from ureter to ureter. The ipsilateral gonadal vessels
were removed completely. Although this dissection was
performed safely with low morbidity and mortality rates,
virtually all patients lost their ability to have ejaculatory
fluid emission secondary to the removal of the postgan-
glionic sympathetic nerve fibers that traversed the field of
dissection.
In the 1980s efforts were made to preserve emission in
patients first by modifying the templates of dissection based
on the knowledge of the distribution of positive lymph
nodes in patients with low volume metastatic disease.12,13
Figures 36-9 and 36-10 show the limits of dissection gen-
erally adopted for low-stage (stage I or stages IIA and IIB)
602 Part VI Testis
Figure 36-5 CT scan of chest of patient with metastases to the lungs (arrows) from a
primary testicular cancer.
disease with right- and left-sided primary tumors, respec-
tively. The dissections within the limited templates were
still performed with the en bloc technique. This offered
preservation of the contralateral sympathetic systems. The
success rates at preserving emission were greater on right-
sided dissection than on the left-sided dissection.
Later in the 1980s and early 1990s a prospective
nerve-sparing technique was developed and adopted
using the modified templates. A better understanding of
the anatomy of the lumbar sympathetic nerves allowed
this technique to be applied very successfully in terms of
preservation and maintenance of the efficacy of the dis-
section as measured by continued low tumor relapse
rates.14,15 Figure 36-11 shows a diagram of the lumbar
sympathetics and the postganglionic branches as would
be seen in a right-sided modified template dissection.
The postganglionic fibers are best identified as they
emerge under the medial edge of the vena cava in the
interaortocaval zone. Figure 36-12 shows the typical
arrangements of the left lumbar sympathetic fibers as
they travel anteriorly and caudally onto the aorta. These
nerves are best identified by dissecting along the poste-
rior body wall from lateral to medial until the lumbar
sympathetic chain is identified. The use of these prospec-
tive nerve-sparing techniques has resulted in preservation
of emission in almost all patients.16
A laparoscopic approach to RPLND (LRPLND) for
low-stage disease was first performed in 1992 by two
European groups.17,18 These series reported favorable
initial results for conversion to open procedures, 1/34
and 2/125, respectively.17,18 After the learning curve had
been overcome, the mean operating times were 248 min-
utes in Rossweiler’s series, 219 minutes for clinical stage I
patients in Jauetschek’s series for clinical stage I patients,
and 226 minutes for clinical stage IIB patients. In both
series together there was only one retroperitoneal recur-
rence.
Ogan et al.19 compared the cost of LRPLND versus
open RPLND. Open RPLND was less costly at $7162
than LRPLND at $7804 for operative costs. LRPLND
showed a cost advantage for hospital stay costs. If an
LRPLND patient’s surgery took under 5 hours and his
 Chapter 36 Nonseminomatous Germ Cell Tests Tumors: Management and Prognosis 603

Figure 36-6 Abdominal CT scan of a patient with a prominent small interaortocaval lymph
node consistent with metastatic testicular cancer.

hospital stay was less than 2.2 days, the overall cost of
LRPLND was less than open surgery.
With the increase in the number of surgeons per-
forming laparoscopic surgery, more patients will have the
opportunity to be treated laparoscopically. It should be
noted, however, that LRPLND is an advanced laparo-
scopic procedure that should only be performed by
advanced laparoscopists.
The AJCC has defined classifications for pathologic
nodal status that are valuable for planning the treatment
for patients and assessing results of these treatments.
Table 36-9 shows these definitions.
Postchemotherapy RPLND
Generally, patients with bulky retroperitoneal disease
(stage IIc) or disseminated disease (stages IIIA to IIIC)
are treated initially with systemic chemotherapy. Surgical
resection is usually used in those patients who do not
achieve a complete response to chemotherapy to resect
any residual disease apparent on physical examination or
imaging studies.
Once gross nodal involvement occurs, retrograde lym-
phatic flow can occur with the subsequent spread of tumor
to nodes that would not ordinarily be involved. As a result
the limits of dissection are usually those of the full bilateral
template (see Figure 36-8). Depending on the location of
nodal involvement noted on imaging studies, the nerve-
sparing technique may be used in zones where no obvious
nodal involvement has occurred. When a contralateral
zone can be dissected with a nerve-sparing technique, up
to 89% of the patients can have preservation of emission.20
Laparoscopic postchemotherapy RPLND (LPCR-
PLND) has been reported by Palese et al.21 Five of
7 patients had successful completion of laparoscopic pro-
cedures. Two required conversion to open surgery. There
were 3 cases with major complications and 1 with minor
complications. The authors concluded that LPCRPLND
should be attempted only in selected patients with small
volume radical masses.
604 Part VI Testis

Figure 36-7 Abdominal CT scan of a patient with bulky retroperitoneal metastases (stage
IIC), which compresses the vena cava.

Table 36-3 Clinical Regional Node Stage (N)

NX Regional lymph nodes cannot be assessed

N0 No regional lymph node metastasis

N1 Metastasis with a lymph node mass 2 cm or less in

greatest dimension; or multiple lymph nodes, Table 36-4 Distant Metastases (M)
none more than 2 cm in greatest dimension MX Distant metastasis cannot be assessed
N2 Metastasis with a lymph node mass more than 2 cm M0 No distant metastasis
but not more than 5 cm in greatest dimension; or
multiple lymph nodes, any one mass greater than M1 Distant metastasis
2 cm but not more than 5 cm in greatest
dimension M1a Nonregional nodal or pulmonary metastasis

N3 Metastasis with a lymph node mass more than 5 cm M1b Distant metastasis other than to nonregional
in greatest dimension lymph nodes and lungs

These nodal stages are based on imaging studies. Evidence of metastases is based on imaging studies.
 Chapter 36 Nonseminomatous Germ Cell Tests Tumors: Management and Prognosis 605

Table 36-5 Serum Marker Status (S) Table 36-7 Criteria for Primary Observation
SX Marker studies not available or not performed Primary tumor: pT1

S0 Marker study levels within normal limits AFP, B-hCG: normal or return to normal after or
orchiectomy
S1 LDH < 1.5 × N* AND
hCG (mIU/ml) < 5000 AND Embryonal carcinoma component ≤ 40%
AFP (ng/ml) < 1000
No teratomatous elements
S2 LDH 1.5 – 10 × N OR
hCG (mIU/ml) 5000–50,000 OR No choriocarcinoma
AFP (ng/ml) 1000-10,000
No nodal or metastatic masses by imaging studies
S3 LDH > 10 × N OR (N0, M0)
HCG (mIU/ml) > 50,000 OR
AFP (ng/ml) > 10,000

*N indicates the upper limit of normal for the LDH assay. Chemotherapy
Primary Short Course or Adjuvant Chemotherapy
for Low-Stage Disease (Stages I, IIA and IIB)
Primary chemotherapy has been a treatment option for
patients with clinical stages I, IIA, or IIIB. Since 1985,
two cycles of bleomycin, etoposide, and cisplatin (BEP)
have been the standard therapy in this setting.22-24
Table 36-6 Clinical Stage Groups Schefer et al.25 reported a trial of a single course of BEP
Stage 0 pTis N0 M0 S0 for high-risk stage I NSGCTT.
In the adjuvant setting, the Indiana group has reported
Stage 1 PT1–4 N0 M0 SX on 86 patients receiving 2 courses of BEP after RPLND
for pN1 disease or pN2 disease.22 Kondagunta and
Stage IA pT1 N0 M0 S0
Motzer26 published the Memorial Sloan-Kettering
Stage IB pT2 N0 M0 S0 Cancer Center experience using cisplatin and etoposide
pT3 N0 M0 S0 (EP) as adjuvant treatment for pN2 patients.
pT4 N0 M0 S0

Stage IS Any pT/Tx N0 M0 S1–3 Primary Chemotherapy for High-Stage Disease

Stage II Any pT/Tx N1–3 M0 SX

The addition of cisplatin to Velban and bleomycin (PVB)
revolutionized the treatment of metastatic testicular can-
Stage IIA Any pT/Tx N1 M0 S0 cer in 1974.27 The standard treatment of metastatic tes-
Any pT/Tx N1 M0 S1 ticular cancer changed to cisplatin, etoposide, and
bleomycin (BEP) in 1984 after a randomized trial showed
Stage IIB Any pT/Tx N2 M0 S0 that the BEP treatment was more effective and had a
Any pT/Tx N2 M0 S1
lower rate of toxicity.28
Stage IIC Any pT/Tx N3 M0 S0 The next area to be studied was trying to reduce the
Any pT/Tx N3 M0 S1 intensity of chemotherapy to reduce toxicity while main-
taining efficacy. In order to be able to do this effectively,
Stage III Any pT/Tx Any N M1 SX a system for stratification of the risk level of patients with
high-stage tumors was needed. Several attempts were
Stage IIIA Any pT/Tx Any N M1a S0
Any pT/Tx Any N M1a S1
made to define the risk categories. Starting in 1991 an
international group, the International Germ Cell Cancer
Stage IIIB Any pT/Tx N1–3 M0 S2 Cooperative Group (IGCCCG), was started. In 1997 this
Any pT/Tx Any N M1a S2 group published its validated definitions of good progno-
sis, intermediate prognosis, and poor prognosis groups.29
Stage IIIC Any pT/Tx N1–3 M0 S3 The definitions of the groups for NSGCTs are shown in
Any pT/Tx Any N M1a S3
Table 36-10. These groups are often equated to minimal
Any pT/Tx Any N M1b Any S risk, moderate risk, and high risk for the patients.
Treatment choices are frequently made on the basis of
606 Part VI Testis

Figure 36-8 Drawing of the margins of dissection for a full bilateral RPLND. The hatched
areas represent the right and left suprahilar zones, which are removed en bloc with the
interaortocaval zone and left periaortic zone, respectively.

minimal-to-moderate risk categories versus high-risk
categories.
Second-Line or Salvage Chemotherapy
For patients who did not achieve a complete response with
primary chemotherapy and still had positive markers, sal-
vage or second-line chemotherapy was tried. EP was tried
starting in 1978 at Indiana for salvage treatment.30 From
1984 to 1989, vinblastine, ifosfamide, and cisplatin were
used at Indiana for second-line therapy.31 Motzer et al.32
reported the use of 4 courses of paclitaxel, ifosfamide, and
cisplatin (TIP) for second-line chemotherapy.32 Hinton
et al.33 have reported a phase II Eastern Cooperative
Oncology Group (ECOG) trial of paclitaxel and gemc-
itabine in refractory germ cell tumors.
High-dose chemotherapy with antologous bone mar-
row transplantation was tried at Indiana University
 Chapter 36 Nonseminomatous Germ Cell Tests Tumors: Management and Prognosis 607

Figure 36-9 Modified template for an en bloc or prospective nerve-sparing RPLND for a
patient with a right-sided tumor.

between 1986 and 1989. Broun et al.34 reported the use
of high-dose carboplatin and etoposide with bone mar-
row transplant rescue.34 A more recent report using the
same approach was made from the University of
Michigan by Ayash et al.35 The use of paclitaxel in sal-
vage regimens along with cisplatin and/or ifosfamide has
been reported by Kollmannsberger et al.36 from
Germany.36 Another new approach for salvage therapy
was reported by Rick et al.37 from Berlin. They used 3
cycles of TIP followed by 1 cycle of high-dose carbo-
platin, etoposide, and thiotepa (CET).37 The patients
had rescue with antologous stem-cell transplantation.
There are several additional trials still in progress.
TREATMENT BY STAGE
This section will present treatment alternatives by clini-
cal stage. The tools of treatment and general follow-up
routines have been presented in the previous section.
When results are available from several series and are
608 Part VI Testis
Figure 36-10 Modified template for an en bloc or prospective nerve-spring RPLND for a
patient with a left-sided tumor.
similar, the percentages after various treatments or peri-
ods of observation will be given on the treatment option
algorithms shown in Figures 36-13 to 36-15.
Clinical Stage I
For patients with clinical stage IA, there are three possible
choices: observation, primary RPLND, or short course
primary chemotherapy (see Figure 36-13). The criteria for
observation are given in Table 36-7. The suggested follow-
up testing for observation is shown in Table 36-8. Overall
approximately 70% of patients observed for clinical stage
IA disease will remain disease free. Approximately 30%
will relapse over a 4-year period. Most relapses will occur
within the first year and nearly 90% within 2 years.
Patients on observation who relapse are treated based
on their stage at relapse. Those who relapse with stage
IIA disease or stage IIB disease are treated as shown in
Figure 36-14, while those with stage IIC disease or stage
III disease are treated as shown in Figure 36-15.
Stage IA patients may also be treated by RPLND
(modified template-nerve-sparing technique if fertility is
 Chapter 36 Nonseminomatous Germ Cell Tests Tumors: Management and Prognosis 609

Figure 36-11 A view of the interaortocaval zone with the patient’s head to the right. Note
the right-sided postganglionic sympathetic nerve branches emerge from under the vena
cava obliquely in a caudal-anterior direction onto the anterior surface of the aorta. The
branches usually are located just cephalad to the lumber (suture around one).

Figure 36-12 A view of the right and left lumbar sympathetic trunks and the postganglionic
branches with the patient’s head to the right. Branches from each side join at the hypogastric
plexus around the origin of the inferior mesenteric artery. Branches from the hypogastric
plexus cross the area of the bifurcation of the aorta and travel caudally to the pelvic plexus.
610 Part VI Testis

Table 36-8 Primary Observation Schema

Year 1 Year 2 Years 3–4 Years = 5

Serum markers Monthly Bimonthly Biannually Annually

Chest x-ray Monthly Bimonthly Biannually Annually

CT scans (chest, abdomen, and pelvis) Quarterly Semiannually Annually —

Physical examination Bimonthly Every 4 months Biannually Annually

Table 36-9 Pathologic Nodal Stage (PN)
pNX Regional lymph nodes cannot be assessed
pN0 No regional lymph node metastasis
pN1 Metastasis with a lymph node mass 2 cm or less in
greatest dimension and less than or equal to 5
nodes positive, none more than 2 cm in greatest
dimension
pN2 Metastasis with a lymph node mass more than
2 cm but not more than 5 cm in greatest
dimension; or more than 5 nodes positive, none
more than 5 cm; or evidence of extranodal
extension of tumor
pN3 Metastasis with a lymph node mass more than
5 cm in greatest dimension
Nodal status is determined from RPLND specimens.
Table 36-10 IGCCCG NSGCT Definitions
Good prognosis Testis/retroperitoneal primary and
No nonpulmonary visceral metastases and
AFP < 1000 ng/ml and
HCG < 5000 IU/1 and
LDH < 1.5 × N*
Intermediate Testis/retroperitoneal primary and
prognosis No nonpulmonary visceral metastases
and
AFP = 1000 and = 10,000 ng/ml and/or
HCG = 5000 and = 50,000 IU/1 and/or
LDH = 1.5 × N and = 10 × N
Poor prognosis Mediastinal primary
or
Nonpulmonary visceral metastases
or
AFP = 10,000 ng/ml and/or
HCG = 50,000 IU/1 and/or
LDH = 10 × N
*N = upper limit of normal.
an issue) or primary short course chemotherapy. RPLND
has been performed more in the United States, while
chemotherapy has been used more frequently in Europe.
For clinical stage IB patients, RPLND has been the
more prevalent treatment and chemotherapy has been
used less frequently in the U.S. In clinical stage IB,
patients who have T4 disease, a hemiscrotectomy is also
usually performed if it was not already completed as part
of the radical orchiectomy.
RPLNDs in clinical stages IA and IB patients yield neg-
ative lymph nodes in approximately 70% of the patients,
while the remaining 30% have positive lymph nodes (pN1
or pN2) despite negative markers and imaging studies.
Patients with clinical stage is used to be treated rou-
tinely with RPLND. Davis et al.38 recommended the use
of primary chemotherapy instead of RPLND because of
the high relapse rate after RPLND. In the last several
years, the Indiana group has recommended primary
chemotherapy in these patients.39
Primary chemotherapy for stages IA, IB, or S has low
relapse and death rates (1% to 2% and <1%, respectively)
for an overall progression-free long-term survival rate
of about 97%.40 Most series involved 2 courses of BEP
and several have used 3 courses of BEP. In an attempt to
reduce toxicity, a single course of BEP has been, and is
being, tried by several groups. A series by Corti et al.41 in
1997 reported no relapses in 18 stage I NSGCTT
patients with 1 course of cisplatin-based chemotherapy
with a median follow-up of 46.9 months. Studies by the
German Testicular Cancer Study Group are on-going.
The overall survival rates for patients with stage I
NSGCTT is between 97% and 99% for observation
series or primary chemotherapy and 98% to 100% in
patients treated with primary RPLND. Long-term mor-
bidity, mortality, and treatment-induced infertility are
very low. Good results are, of course, predicated on
reliable patients and compulsive medical caregivers.
Clinical Stages IIA and IIB
Clinical Stages IIA and IIB accounts for approximately
40% of NSGCTT patients at presentation. An algorithm
for treatment of these patients is shown in Figure 36-14.
 Treatment of clinical stages I NSGCIT (40%)

Stage IA Stage IB Stage IS

pT1 pT 2−4 pT 1−4

OR
OR OR

Primary RPLND
Primary short
with
Observation hemiscrotectomy
course
chemotherapy
for pT4 only

Partial
Complete
No relapse relapse Nodes (−) Nodes (+) remission or
remission
(70%) (30%) (70%) (30%) progression
(97%)
(2-3%)

OR

Adjuvant
PC-RPLND
Observation chemotherapy Observation
(see Figure 36−15
(see Table 36-11) (see Figure 36-14 (see Table 36-11)
PC-RPLND arm
RPLND arm)

Continued
observation IIA,B IIC,III
(see Table 36-8) (see figure 14) (see figure 15)

Figure 36-13 Schematic drawing of the treatment options and stratifications based on
tumor or marker parameters for clinical stage I NSGCTT.

Treatment of clinical stages II A and B (40%)

Chemotherapy OR
RPLND
(2−4 courses)

Partial remission,
Complete
no response, or Nodes (−)
remission Nodes (+)
progression markers (−)
(67%)
(33%)

PC-RPLND
Observation Observation Post-Op Post-Op
(see Figure 36-15
(see Table 36-11) (see Table 36-15) markers (+) markers (−)
PC-RPLND arm)

OR

Adjuvant Adjuvant
chemotherapy Observation chemotherapy
(3-4 courses) (2 courses)

Figure 36-14 Schematic drawing of treatment options and stratifications based on tumor
and marker parameters for patients with stages IIA and IIB NSGCTT.
612 Part VI Testis

Treatment of clinical stages II C and III (20%)

Primary
chemotherapy

CR PR
(70%) (30%)

Observation Markers (+)

Markers (−)

Relapse
Localized disease Diffuse disease
(10%)

Post-chemo, OR
RPLND
Surgical
resection Bone marrow
Salvage chemo
(RPLND +/− transplant (BMT)
thoracotomy)

Scar Teratoma Cancer

(44%) (44%) (12%)

Complete Incomplete
resection resection

Observations
(see Table 12)
OR

Salvage
Observation BMT
chemotherapy

PR CR

BMT Observation

Figure 36-15 Schematic drawing of treatment options and stratifications based on tumor
and marker parameters for patients with stage IIC/stage III NSGCTT.
 Chapter 36 Nonseminomatous Germ Cell Tests Tumors: Management and Prognosis 613

There are two main treatment pathways or options:
primary chemotherapy and primary RPLND. As in clin-
ical stage I, primary chemotherapy is favored more in
Europe, while primary RPLND is favored in the U.S.
Primary chemotherapy usually consists of 2 to 4
courses of cisplatin-based multiagent treatment.
Horwich et al.42 reported 122 patients with stage IIA or
stage IIB NSGCTT treated with 4 courses of cisplatin-
based combination chemotherapy. Overall 97% of the
patients were disease free with a median follow-up of 5.5
years. In stage IIA patients, 17% required a PC-RPLND,
while 39% of stage IIB patients required this surgery. In
a randomized trial by the German Testicular Cancer
Study Group, 87 patients received primary chemother-
apy with 3 courses of BEP or carboplatin, etoposide and
bleomycin (CEB). Two-thirds achieved complete remis-
sion (CR) with chemotherapy alone, while one-third
required PC-RPLND. With a 3-year follow-up, 11%
total in this arm relapsed.43
The patients treated with primary chemotherapy for
stage IIA disease or stage IIB disease that achieve a CR
can be followed using the same schedule as primary
RPLND follow-up as shown in Table 36-11. Those
patients requiring PC-RPLND are treated as shown on
the PC-RPLND arm of Figure 36-15 and follow as
shown in Table 36-12.
Primary RPLND has been the predominant treat-
ment of stages IIA and IIB NSGCTT in the U.S. for the
last 4 decades. The templates for dissection and the dis-
section techniques have evolved over this time period as
presented in the section “Tools of Treatment.” In those
patients with a desire to remain fertile, the modified
template, prospective nerve-sparing technique is the
usual treatment. Sometimes the dissection is extended to
a bilateral template in the presence of medium volume
nodal disease (2 to 5 cm).
Emission is preserved in nearly all patients in whom
the nerve-sparing technique is employed. Operative
complication rates run in the range of 8% to 12%, the
reoperation rate is about 1% and the operative and post-
operative mortality rate is approximately 0.25%.
In those patients with pathologically negative nodes
(pN0), observation is appropriate with a follow-up sched-
ule as shown in Table 36-11. The overall relapse rate in
pN0 patients is in the range of 7% to 12% with
retroperitoneal recurrences within the field of dissection
being about 1%.
For patients who have pathologically positive lymph
nodes (pN+), there are two options: observation or adju-
vant chemotherapy. Relapse in patients with pathologi-
cally positive nodes is related to nodal tumor volume. In
those patients with pN1 tumors, the relapse rate is in the
range of 15% to 20%. For patients with pN2 tumors, the
relapse rate runs between 30% and 50%, while it is 50%
to 90% in patients with pN3 tumors.
Most centers that treat testicular cancer tailor the rec-
ommendations for adjuvant chemotherapy based on the
risk of recurrence, which is related to the pN stage as

Table 36-11 Follow-Up After Primary RPLND

Year 1 Year 2 Years 3–4 Years = 5

Serum markers Monthly Bimonthly Semiannually Annually

Chest x-ray Monthly Bimonthly Semiannually Annually

CT scans (chest, abdomen, and pelvis) None* None* None* None*

Physical examination Bimonthly Every 4 months Semiannually Annually

*CTs are needed for patients with teratoma in the nodes or with cancer in the nodes and normal serum markers using the same schedule as shown
in Table 36-8.

Table 36-12 Follow-Up After Postchemotherapy RPLND Pathology—Necrosis Only

Year 1 Year 2 Years 3–4 Years = 5

Serum markers Bimonthly Every 4 months Biannually Annually

Chest x-ray Bimonthly Every 4 months Biannually Annually

CT scans (chest, abdomen, and pelvis) None None None None

Physical examination Every 4 months Biannually Biannually Annually

Pathology—teratoma or cancer without serum marker elevation—as earlier and add CT scans as in Table 36-8.
614 Part VI Testis
shown earlier. When adjuvant therapy is used, it usually
consists of 2 courses of BEP or EP.26,44 Subsequent
relapse rates are around 1%. Overall treatment mortality
rates are less than 1%.
If patients had pathologically positive lymph nodes
pN+ and positive postoperative markers, full course
chemotherapy is given. The same applies for pN0
patients who relapse after observation.
The overall cure rate for stages IIA and IIB patients
using the treatment scheme shown in Figure 36-14 is
97% to 99%.
Clinical Stage IIC and/or Stage III
Based on the very high recurrence rate for patients with
stage IIC/stage III NSGCTT after RPLND, these
patients have been treated with primary chemotherapy
first since combination cisplatin-based treatment became
available in the mid-1970s to late 1970s. Figure 36-15
shows how these patients are usually treated.
Approximately 70% of patients with stage IIC/stage
III disease will achieve a CR after 3 or 4 courses of BEP
or similar combination. Fortunately, 90% of these CR
patients will enjoy a durable response, while 10% will
relapse. About 30% of the patients with stage IIC/stage
III disease will only achieve a partial response (PR). This
group of patients and the patients who relapse after a
primary chemotherapy CR are stratified for further treat-
ment by marker status. If the serum markers are negative,
the patients have a PC-RPLND without/with addi-
tional surgical procedures to clear the retroperitoneum
using the full bilateral template as shown in Figure 36-8
and remove any other metastases in the chest or neck.
The majority of these patients will only require the
PC-RPLND.
Patients who have a PC-RPLND for a PR after pri-
mary chemotherapy have a 44% incidence of necrosis
only, a 44% incidence of teratoma, and a 12% chance of
active cancer in the tissue removed. Patients those have
necrosis only and/or teratoma can be observed as per
Table 36-12.
If active cancer is found in the tissue removed at
PC-RPLND, patients are stratified by complete or
incomplete surgical resections. For those patients in
whom complete resection was possible, observation
as shown on Table 36-11 is used. If tumor resection
was incomplete, patients are treated by salvage
chemotherapy (often VIP) or high-dose chemotherapy
with autologous bone marrow transplantation based
on the good-to-moderate or poor prognosis status
as defined by the IGCCCG classification shown in
Table 36-10.
For patients who were treated with primary chemo-
therapy and had a PR with persistently positive markers,
treatment is determined by the imaging studies. If a
patient has a well-localized disease and all abnormal areas
are respectable, a surgical approach is taken. This may
require procedures in addition to the PC-RPLND, such
as a thoracotomy or cervical lymph node dissection.
Depending on the extent of disease, the procedures may
need to be performed in more than one sitting.
In these same circumstances, the patients with positive
markers after a PR from primary chemotherapy are
treated with either salvage chemotherapy or high-dose
chemotherapy with autologous bone marrow transplan-
tation. The choice of treatment approach is again usu-
ally determined based on the IGCCCG prognosis
classifications as discussed earlier.
Fortunately, the patients who present with stage
IIC/stage III account for only 20% of all patients with
NSGCTT. A high percentage of patients enjoy a durable
CR with primary chemotherapy [70% CR minus 10% of
these with relapse (7%) = 63%]. Approximately 75%
of patients who are treated with PC-RPLND after PR or
relapse after chemotherapy will have a long-term survival
without or with salvage or high-dose chemotherapy and
autologous bone marrow transplantation. This yields a
long-term survival or “cure” rate for stage IIC/stage III
of approximately 90%, which is a dramatic improvement
before the era of cisplatin-based chemotherapy.
SUMMARY
The treatment of NSGCTT has changed markedly over
the last 4 decades. The morbidity and mortality from
treatment have decreased in this same period, while sur-
vival rates have increased for all stages of disease. There
are ongoing efforts to further reduce the amount and
severity of treatment used for this disease. The preserva-
tion of fertility for these patients through modifications in
surgical techniques and the intensity of chemotherapy has
been a major area of progress. Careful reporting of results,
complications, late recurrences, and the development of
secondary malignancies will be important in guiding
future modifications of treatment schemes for this disease.
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21. Palese MA, Su LM, Kavoussi LR: Laparoscopic
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35. Ayash LJ, Clarke M, Silver SM, et al: Double dose-
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carboplatin, etoposide, and thiotepa followed by
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or refractory germ cell cancer. J Clin Oncol 2001;
19:81–88.
38. Davis BE, Heu HW, Fair WR, Bosl GJ: The management
of patients with nonseminomatous germ cell tumors of
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J Urol 1994; 152:111–113.
39. Saxman SB, Nichols CR, Foster RS, et al: The
management of patients with clinical stage I
nonseminomatous testicular tumors and persistently
elevated serologic markers. J Urol 1996; 155(2):593–594.
40. Albers P, Perabo FGE, Melchior D, Siener R: Adjuvant
chemotherapy in stage I and stage II testicular cancer.
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41. Corti OD, Foneron BA, Troncoso SL: Treatment of stage
I nonseminomatous testicular cancer with one cycle of
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42. Horwich A, Norman A, Fischer C, et al: Primary
chemotherapy for stage II nonseminomatous germ cell
tumors of the testis. J Urol 1994; 151(1):72–77.
43. Weissbach L, Bussar-Maatz R, Flechtner H, et al:
RPLND or primary chemotherapy in clinical stage IIA/B
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prospective multicenter trial including quality of life
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44. Williams SD, Stablein DM, Einhorn LH, et al:
Immediate adjuvant chemotherapy versus observation
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C H A P T E R
37Nongerm Cell Tumors of the Testis
Aaron J. Milbank, MD, Howard S. Levin, MD,
and Eric A. Klein, MD
Nongerm cell tumors of the testis comprise a heteroge-
neous group of benign and malignant neoplasms, which
may be primary or metastatic. As a group they account
for only 5% to 6% of all testicular neoplasms, the
remaining testicular tumors being of germ cell origin
(Figure 37-1). The most commonly occurring primary
tumors of nongerm cell origin are classified as sex
cord/stromal tumors or tumors of specialized gonadal
stroma. These tumors may be associated with somatic or
constitutional chromosomal syndromes. Other less com-
monly encountered primary tumors include mesenchy-
mal tumors from nonspecialized stroma, such as blood
vessels or smooth muscle, tumors arising from hematopoi-
etic cells, and a multitude of other benign tumors, which
mimic malignant lesions. In addition, a number of malig-
nancies from other sites may rarely present initially in the
testis or as a late sign of more diffuse disease. Certain
populations are at higher risk for the development of
germ cell and nongerm cell testis tumors; multiple cases
of malignant lymphoma (ML) and malignant germ cell
tumors in patients with the acquired immune deficiency
syndrome and other forms of immunosuppression have
been reported.1,2 A useful practical classification of
nongerm cell testicular tumors is presented in Table 37-1.
Most primary tumors of nongerm cell origin are bio-
logically benign. The clinical presentation of these
tumors is similar to, and often indistinguishable from,
those of germ cell origin. Common presenting symptoms
include testicular pain and enlargement, which may be of
prolonged duration. Breast tenderness or enlargement
may also be present. Physical examination typically con-
firms the presence of testicular swelling or intratesticu-
lar mass. Most primary nongerm cell tumors appear
as discrete hypoechoic lesions on ultrasonography, while
leukemic or lymphomatous infiltration demonstrate
enlargement with multiple focal or diffuse areas of
decreased echogenicity. The presence of diffuse unilat-
eral or bilateral testicular enlargement, rather than a dis-
crete mass on physical examination or scrotal ultra-
sonography, suggests a secondary rather than primary
neoplasm. Peripheral lymphadenopathy is rare with pri-
mary nongerm cell tumors and should prompt a search to
exclude a primary tumor from another site, notably lym-
phoma. Gynecomastia, loss of libido or other signs of
feminization may be present with some tumors (notably
Leydig or Sertoli cell tumors) due to active secretion
of estrogens, alterations in serum estrogen/testosterone
ratios or peripheral aromatization of testosterone.3
Serum levels of human chorionic gonadotropin hCG and
alpha fetoprotein (AFP) will be normal. All of these clinical
features may also be present with primary germ cell
tumors, and histologic examination of the affected testicle
is the sine qua non for distinguishing these tumor types and
determining the need for further evaluation and treatment.
In adults with a palpably normal opposite testis,
inguinal orchiectomy without frozen section is consid-
ered standard therapy. Occasionally a nongerm cell
tumor or other benign process may be strongly suspected
based on presenting signs and symptoms and/or the
ultrasonographic appearance of the lesion. In these cases
and in patients with a solitary testis or atrophic con-
tralateral testis, inguinal exploration and excisional
biopsy with the intent of sparing the uninvolved ipsilat-
eral testis should be considered. In such instances, frozen
section examination (FSE) of the excised tumor is neces-
sary to exclude the presence of malignancy. Elert et al.4
recently retrospectively reviewed their experience with
354 patients who underwent inguinal exploration, isola-
tion of the testicle, and biopsy with FSE. With respect to
malignant versus benign, FSE correctly categorized all
lesions. Within the malignant category, 9% of the tumors
were incorrectly identified (nonseminoma versus semi-
noma or vice versa), a finding which did not affect the
intraoperative management. In all such cases, the
617
618 Part VI Testis

Figure 37-1 Embryologic origin of testis tumors.

Table 37-1 Classification of Nongerm Cell Testicular Tumors

Tumors of Specialized Tumors of Generalized Hematologic
Stroma Stroma Tumors Miscellaneous Tumors

LCT Vascular tumors Lymphoma Carcinoid

Sertoli cell tumor Smooth and skeletal muscle Leukemia Epidermoid cyst
tumors

Granulosa cell tumor Plasmacytoma Adenocarcinoma of the rete testis

Mixed tumor Adenomatoid tumor Metastatic tumors

Incompletely differentiated Mesothelioma Ovarian surface epithelial—type

tumors tumors

PRIMARY TUMORS OF SEX CORD/STROMAL

clinical aspects and topography of the mass should be
shared with the pathologist. In cases with equivocal find-
ings on frozen section, inguinal orchiectomy should be
performed in patients with a normal contralateral testis.
Frozen section is also useful in identifying MLs so that
fresh tissue can be used for tumor phenotyping. A descrip-
tion of individual tumor types with characteristic clini-
cal and pathologic features and recommendations for
management follows.
ORIGIN
Leydig Cell Tumors
Clinical Presentation
Leydig cell tumors (LCTs) comprise approximately 1%
to 3% of testicular tumors. They occur in males of all
ages with predominance in children older than 4 and
adults in the third to sixth decade. In prepubertal boys
they produce isosexual precocity with penile enlarge-
 Chapter 37 Nongerm Cell Tumors of the Testis 619

ment, sexual hair growth, increased bone growth, deep-
ened voice, and aggressive behavior as a consequence of
increased testosterone production by the neoplasm.
Clinical signs and symptoms are usually manifest before
the discovery of the neoplasm, which may be impalpable
and difficult to detect with ultrasonography.5 In postpu-
bertal males, LCTs usually present with a unilateral pain-
less testicular mass or incidentally as a mass discovered
during physical examination. Only 30% have signs of
increased hormonal function, and in contrast to the pre-
pubertal group affected adults exhibit feminization, with
unilateral or bilateral gynecomastia, impotence, and hair
loss.3 LCTs have been reported in cryptorchid testes
before and after orchidopexy, in the contralateral testis
of a 40-year old, 7 years after orchiectomy for a mixed
malignant germ cell tumor, in association with Klinefelter’s
syndrome and tuberous sclerosis, in the descended testicle
of a man with contralateral cryptorchidism, and in multi-
ple asymptomatic men presenting for evaluation of infer-
tility.6–11 There is some evidence from animal studies that
lack of regulation of steroid production/conversion may
be etiologically associated with LCTs. Overexpression of
aromatase has been shown to induce LCTs in transgenic
mice.12 Activating mutations of the gene encoding the
luteinizing hormone receptor have been described.13
10 cm in diameter (Figure 37-2). They may be bilateral.14
The microscopic appearance is variable with a spectrum
of cell shapes extending from polygonal to spindled.
Leydig cell nuclei are generally round with a small single
nucleolus but binucleate, multinucleate, and giant cells
with giant nuclei may be present (Figure 37-3). Mitotic
figures are generally sparse. Cell cytoplasm is usually
eosinophilic and sometimes ground glass in appearance
but may be vacuolated depending on the amount of intra-
cytoplasmic lipid. Approximately 40% of LCTs contain
intracytoplasmic Reinke’s crystals. Lipochrome pig-
ment may also be present in varying amounts. The tumor
cells may grow in sheets, cords, and tubular formations.
Capillaries are abundant between aggregates of epithelial
cells. The stroma may be loose or dense and hyaline. The

Pathologic Characteristics
The gross appearance of LCTs is characteristically
mahogany or yellow-brown in color, rubbery, discrete,
nonencapsulated, and nonnecrotic. LCTs vary consider-
ably in size ranging from nonpalpable to more than
Figure 37-2 Benign LCT. Discrete nonencapsulated soft tan
2.2 cm mass in bivalved testis in 29-year-old man with left
testicular mass and bilateral gynecomastia.

Figure 37-3 LCT. Twenty-year-old with enlarged testis. The testicular parenchyma was
substantially replaced by a yellow-brown mass. The Leydig cells contain round uniform
nuclei and eosinophilic granular cytoplasm (H&E × 31.2).
620 Part VI Testis

ultrastructural appearance resembles that of other steroid

hormone-producing cells. LCTs stain positively for lipid.
In tumors of prepubertal males seminiferous tubules
adjacent to the neoplasm have shown response to local
androgen manifested as proliferative activity of germinal
epithelium with development to the spermatid stage.15
Seminiferous tubules in the contralateral testis and dis-
tant from the tumor in the ipsilateral testis typically
retain prepubertal morphology. Conversely, in postpu-
bertal men seminiferous tubules adjacent to feminizing
LCTs show reduced spermatogenesis and thickening of
the tunica propria.
Approximately 10% of LCTs are malignant and over
30 such cases have been reported. Malignant LCTs are
Figure 37-4 Malignant LCT. Sixty-three-year-old man noted
larger than benign LCTS have no clinical endocrine
enlargement and soreness of the testis for 4 to 5 weeks. The
hyperfunction and have a shorter clinical duration prior testis measured 6 × 7 × 7 cm and was almost totally
to orchiectomy.16 The absolute criterion for malignancy replaced by a bulging light tan to dark brown variegated
of an LCT is metastasis, but other morphologic features mass with multiple apparent septae. (Photograph courtesy of
that strongly suggest malignancy include large tumors, California Tumor Tissue Registry.)
marked cellular anaplasia, frequent or atypical mitoses,
infiltrating margin and necrosis16 (Figure 37-4). Invasion
of lymphatics and/or blood vessels are also suggestive of tumors not associated with metastasis. Metastases usually
malignancy (Figure 37-5). Cheville et al.17 retro- occur within months to years after the original diagnosis
spectively reviewed their experience with 30 LCTs, 23 but initial metastasis has been recorded as late as 17 years
without metastasis, and 7 with metastasis to identify after orchiectomy.18 In this latter case, the retroperi-
predictors of malignancy. They found that the follow- toneal metastasis exhibited sarcomatoid differentiation.
ing features were significantly associated with metastatic Initial metastasis is usually to retroperitoneal lymph nodes,
behavior: presence of cytologic atypia, necrosis, angi- but subsequent metastases involve remote lymph
olymphatic invasion, increased mitotic activity, atypical nodes and possibly viscera. Benign LCTs generally have
mitotic figures, infiltrative margins, extension beyond the diploid DNA content whereas malignant LCTs generally
testicular parenchyma, DNA aneuploidy, and increased have aneuploid DNA by flow cytometry.19,20
MIB-1 activity. Tumors associated with metastasis tended Ulbright et al.21 recently reported 19 cases of LCTs
to be larger (mean 4.7 cm versus 2.6 cm) and occur in with unusual features—adipose metaplasia, calcification
older patients (mean age 62 years versus 48 years) than (sometimes with ossification), and spindle cell growth.

Figure 37-5 Malignant LCT, same case as in Figure 37-4. Neoplastic Leydig cells are
present within a vein. The tumor thrombus shows central necrosis (H&E × 15.6).
 Chapter 37 Nongerm Cell Tumors of the Testis 621

Follow-up was reported for 6 of 8 cases exhibiting spin-

dle cell growth. Two patients developed metastases and
both had malignant features apart from spindle cells.
The other 4 did not have malignant features and were
free of disease from 2.3 to 6 years after orchiectomy.
Recognizing that adipose tissue may be present in LCTs
may prevent the misdiagnosis of extratesticular growth or
LCT associated with congenital adrenal hyperplasia (see
later). Similarly, the recognition that spindle cells may be
identified with LCTs may limit misclassification of such
tumors as sarcomas.

Tumors in Males with Congenital Adrenal
Hyperplasia
An important distinction must be made between LCTs
and the testicular masses in the salt-wasting form of con-
genital adrenal hyperplasia (CAH). In CAH males from
the neonatal period to adulthood may develop bilateral
testicular or peritesticular masses, which are histologi-
cally similar to LCTs (Figures 37-6 and 37-7).22,23 One
recent study identified testicular tumors ranging in size
from 0.2 to 4 cm in 16 of 17 adolescents and adults with
CAH (both salt-wasting and not salt-wasting).24 The
cells of these masses do not contain Reinke’s crystals but
do contain abundant lipochrome pigment that gives the
gross tumors a brown or black appearance. These masses
resemble those in patients with Nelson’s syndrome. The
fact that the masses often disappear after corticosteroid
therapy and are sensitive to ACTH stimulation suggests
they are of adrenocortical origin. Davis et al.25 described
one instance of a malignant LCT in a patient with CAH.
Figure 37-6 Probable congenital adrenal hyperplasia.
Twenty-nine-year-old man had right testicular enlargement for
2 years. Left testis was removed 4 years earlier and
demonstrated a similar mass. Bivalved testis demonstrates a
dark mahogany colored bilobed 6.8 cm mass replacing
testicular parenchyma.
In order to avoid inappropriate orchiectomy in patients
with CAH, and because of their response to corticos-
teroid therapy and the risk of adrenal insufficiency if
these patients are not treated with corticosteroids after
orchiectomy, it is important to distinguish true LCT
from CAH with testicular masses.
Evaluation and Management
In children presenting with precocious puberty, bio-
chemical evaluation is necessary to distinguish primary
LCT from Leydig cell hyperplasia secondary to CAH.
The presence of a unilateral tumor with normal serum or

Figure 37-7 Probable congenital adrenal hyperplasia mimicking LCT. Same case as in
Figure 37-6. Uniform cells contain similar-appearing round nuclei and granular cytoplasm
containing fine brown pigment (H&E × 128).
622 Part VI Testis
urinary levels of DHEA, androstenedione, and 17-
hydroxyprogesterone strongly favors the diagnosis of pri-
mary LCT, while bilateral testicular and/or peritesticular
masses or those associated with abnormalities of steroid
biosynthesis favor CAH. In either instance serum testos-
terone levels may be elevated. ACTH stimulation and
dexamethasone suppression tests are occasionally neces-
sary to establish tumor origin. Gabrilove et al.3 reviewed
37 cases of feminizing LCTs of the testis, 5 of which were
in prepubertal boys. In 20 patients where estrogens were
measured, 13 had high urinary titers. Serum estrogen
levels may also be elevated with a concomitant reduction
in serum testosterone. Gonadotropin levels will vary with
associated levels of serum androgens and estrogens.
The treatment of LCT is surgical excision. In cases
where the diagnosis of LCT is not suspected preopera-
tively, inguinal orchiectomy is the procedure of choice.
In children and adults, in whom the diagnosis is sus-
pected, a testis-sparing enucleation or excisional biopsy is
acceptable provided that histologic confirmation of the
lesion is obtained by frozen section. Following tumor
excision the endocrinologic manifestations of the tumor
typically disappear in adults. In children with symptoms
of short duration the signs of masculinization generally
abate and puberty will proceed normally. However, in
some children with long-standing symptoms the signs of
precocious puberty will persist.
The management of Leydig cell hyperplasia associ-
ated with CAH begins with the hormonal evaluation
described earlier. Some authors have advocated needle
biopsies of such lesions to ascertain the presence or
absence of Reinke’s crystals.23,26 If the crystals are not
identified, treatment with corticosteroid may be initiated
and orchiectomy may be deferred. These lesions often
diminish in size. Unfortunately, the probability of
demonstrating Reinke’s crystals on needle biopsy is low.
Virtually all LCTs in children and 90% of LCTs in
adults are benign, have a good prognosis, and require no
therapy other than excision. Patients with malignant
tumors have a poor prognosis and usually die within
2 years after the discovery of metastatic disease. Patients
in whom a malignant tumor is suspected on histopathol-
ogy should undergo a metastatic evaluation, including
chest x-ray, abdominal and pelvic CT scan, and bio-
chemical evaluation in the hopes of identifying a usable
tumor marker. The optimum management of patients
with malignant LCT following excision of the primary
lesion is unknown. There are no available data to evalu-
ate the benefit of prophylactic retroperitoneal lym-
phadenectomy versus observation in patients with disease
clinically localized to the testis. In a review of the man-
agement of 32 patients with established metastatic LCT,
Bertram et al.27 reported no objective responses to radia-
tion therapy, minimal or no benefit to various com-
binations of chemotherapy (including platinum-based
regimens), and only isolated reports of benefit from
resection of low-volume or solitary metastatic deposits.
Complete responses to mitotane have been reported but
the patients ultimately relapsed and died of progressive
disease.28
Sertoli Cell Tumor
Clinical Presentation
A variety of Sertoli cell tumors (SCTs) have been
described, which together comprise only 1% of testicular
tumors. The principal cell types are classic Sertoli cell
tumor (CSCT), sclerosing Sertoli cell tumor (SSCT),
large cell calcifying Sertoli cell tumor (LCCSCT), and
Sertoli cell adenoma (SCA) associated with androgen
insensitivity syndrome (AIS). All but the last of these
variants typically present with painless testicular enlarge-
ment and occur in males of any age. SCA in AIS occurs
in phenotypic females. Gynecomastia is present in about
20% of cases of SCA and is a typical feature of malignant
SCTs. SCTs are to be distinguished from microscopic or
barely grossly visible masses of persistent immature
tubules that have been termed Pick’s adenomas or
androblastomas, which are often seen in cryptorchid
testes and have no malignant potential.
Pathologic Characteristics
Classic sertoli cell tumor. On gross inspection CSCTs
are generally circumscribed and yellow, tan or white, and
may be hemorrhagic (Figure 37-8). Microscopically, they
grow in tubules, cords, sheets, aggregates and occasional
retiform configurations separated by fibrovascular septae
(Figure 37-9). Nuclei are round to ovoid and may contain
nucleoli. Tumor cell cytoplasm may be pale or
eosinophilic and may contain lipid vacuoles. The latter
finding in a tumor with a diffuse growth pattern may be
confused with the appearance of an LCT. The stroma of
Figure 37-8 Sertoli cell tumor. The tumor is a discrete 8 mm,
nonencapsulated, nonnecrotic, firm mass in a 44-year-old
man.

Figure 37-9 Sertoli cell tumor. The tumor contains solid uniform tubular structures with
round to oval nuclei and prominent nucleoli. The tubules are surrounded by basement
membrane. Elsewhere, similar-appearing cells lack lumens and grow in more solid
configurations (H&E × 62.2).
a CSCT may be scant or abundant and hyalinized. Most
CSCTs behave in a benign fashion, but up to 30% of
CSCTs may be malignant as evidenced by the presence of
local invasion and metastases.
Young et al.29 reviewed 60 cases of CSCT. Age at pres-
entation ranged from 15 to 80 years (mean 45 years) and
the size of the tumors ranged from 0.3 to 15 cm (mean
3.6 cm). Long-term follow-up (>5 years) was available for
16 patients; 9 patients were alive with no evidence of dis-
ease, 4 were alive with recurrent disease and 3 were dead
with the cause of death attributed to recurrent SCT. The
following pathologic features were correlated with a
malignant course: tumor diameter greater than 5 cm,
necrosis, moderate to severe nuclear atypia, vascular
invasion, and >5 mitoses per 10 high power fields. Only
1 of 9 benign cases exhibited more than 1 of these fea-
tures; 5 of 7 of the malignant cases exhibited 3 or more.
Sclerosing sertoli cell tumor. SSCT is a recently
described entity. Zukerberg et al.30 described 10 patients
aged 18 to 80 years (median 30) with SSCT. The tumors
generally presented as a painless mass, with one arising in
a cryptorchid testis and another in a testis that had
undergone orchiopexy. All tumors were unilateral and
ranged from 0.4 to 4.0 cm in diameter. Eight of 10
tumors were l.5 cm or less. The tumors were well demar-
cated, hard, and yellow-white to tan. Microscopically 9 of
10 tumors were discrete. The 10th tumor invaded the rete
testis, epididymis, and blood vessels. The tumors con-
tained simple and anastomosing tubules, large cellular
Chapter 37 Nongerm Cell Tumors of the Testis 623
aggregates, and cords of epithelial cells. The cells were
medium sized with rounded vesicular to dark nuclei. The
epithelial elements proliferated in a dense hyaline stroma
within which were entrapped nonneoplastic seminiferous
tubules lined by immature Sertoli cells. No patient showed
evidence of malignant behavior, including the 80-year old
man with histologic evidence of invasion. Several cases
have been reported subsequent to the report by Zukerberg
et al.31 bringing the total number of cases reported to 12.
Large cell calcifying sertoli cell tumor. Proppe and
Scully,32 in 1980 characterized unusual and distinctive
tumors of the testis in 10 patients as LCCSCTs. Since
then, at least 35 additional LCCSCTs have been
reported.33–35 Age at presentation ranges from 5 to 48
years with the majority less than age 20. As of 1995, only
2 reported cases were deemed malignant.36 There have
been subsequent reports of malignant cases.37 The tumor
has been associated with a variety of somatic syndromes,
including Carney’s syndrome (cardiac myxomas, spotty
skin pigmentation, endocrine abnormalities, and schwan-
nomas), Peutz-Jeghers syndrome (gastrointestinal poly-
posis and mucocutaneous pigmentation), adrenal cortical
hyperplasia, primary pigmented adrenal cortical disease,
LCTs of the testis, acromegaly, pituitary gigantism,
Cushing’s syndrome, acidophilic adenoma of the pitu-
itary gland, gynecomastia, isosexual precocity, and
AIS.33,34,38 A recent review of Carney’s syndrome identi-
fied 26 reported cases of testicular tumors in patients
with Carney’s syndrome, most of proven LCCSCT
624 Part VI Testis
pathology.39 The neoplasms may involve the entire testis
but in general are 4 cm or less in maximum dimension.
They are frequently multifocal, bilateral in approxi-
mately 40%, and are well circumscribed. On cross-sec-
tion the masses are yellow-tan sometimes with calcific
foci. Microscopically, the tumor grows both within sem-
iniferous tubules and within the interstitium. Within
tubules the neoplastic cells are large with abundant pink
cytoplasm and expand the tubules. Some tubules have a
markedly thickened tunica propria, which extends into
tubular lumens as eosinophilic spherules. The interstitial
tumor is composed of cords, nests, and trabeculae. The
tumor cells range from 12 to 25 μm in diameter and have
ground glass or finely granular cytoplasm. Transitions
between intratubular and interstitial growth may be seen.
Calcific rounded nodules, plaques, and masses may be
present as intratubular and extratubular aggregates.
Of the first 35 reported cases of LCCSCT, metastasis
was observed in 2 cases.35 However, in 1997, Kratzer
et al.35 reported 6 malignant and 6 benign LCCSCTs.
Malignant tumors were more likely to be unilateral (all 8
cases to date), solitary, occurred in older patients (mean
age 39 versus 17 for benign cases), and occurred in the
absence of a genetic syndrome. Pathologic features that
were more frequently identified in the malignant cases
included the following: size >4 cm, extratesticular growth,
necrosis, high-grade cytologic atypia, vascular space inva-
sion, and more than 3 mitoses per 10 high power fields.
All malignant cases exhibited at least 2 of these features;
all benign cases exhibited none of these features.
Sertoli cell adenoma associated with androgen insen-
sitivity syndrome. AIS is caused by defective or absent
cellular androgen receptors. As a result, patients with
complete AIS are phenotypic females with a shallow
vagina and absent Wolffian duct derivatives. The patients
have 46 XY karyotypes, and bilateral intraabdominal
testes that frequently contain nodular masses comprised
of multiple tubules lined almost exclusively by Sertoli
cells (Figure 37-10). Hamartomas contain small tubules
lined by immature Sertoli cells and may have hyperplas-
tic Leydig cells and ovarian type stroma. Young and
Scully40 and Rutgers and Scully41 distinguish between
hamartomas and pure SCA, which is comprised exclu-
sively of tubules lined by Sertoli cells (Figure 37-11).
Although the SCA may be a monomorphic manifestation
of a hamartoma, some SCAs achieve sizes up to 25 cm in
diameter. SCAs and hamartomas are completely benign.
Rarely, other types of sex cord-stromal tumors have been
reported in AIS, including a few malignant tumors.42
While the SCAs and hamartomas are benign, it is well to
remember that these masses are occurring in cryptorchid
testes, and malignant germ cell tumors, principally
malignant intratubular germ cell neoplasia and semino-
mas may develop concomitantly. Approximately 30% of
Figure 37-10 Sertoli cell adenoma of right testis in patient
with AIS. The patient was a 17-year-old virilized phenotypic
female. In the right orchiectomy specimen is a firm 1.6-cm
nonencapsulated tan nodule. The white firm areas at the
bottom of the photographs of the testes are smooth muscle
masses at the medial portion of the testes and are of
probable müllerian duct origin.
patients with complete AIS will develop malignant germ
cell tumors by age 50.40
Evaluation and Management
Most SCTs are not suspected preoperatively and are
diagnosed only at the time of orchiectomy performed for
a testicular mass. In the context of a known associated
syndrome, the presence of the LCCSCT variant may be
suspected preoperatively by the presence of testicular
calcifications on scrotal ultrasound, but this finding is not
specific to LCCSCT. When suspected, a testis-sparing
surgical approach as described for LCT may be consid-
ered remembering that rare LCCSCTs may be malignant
and that some may be multifocal. Histologically, benign
tumors require no further therapy, although long-term
follow-up may be indicated, as the occurrence of
metastatic disease has been reported as long as 15 years
after initial diagnosis. For metastatic lesions, involvement
of the retroperitoneal nodes is frequent and there are sev-
eral case reports of long-term complete remission fol-
lowing retroperitoneal lymphadenectomy. Experience
with chemotherapy for malignant SCTs is limited and
the response rate is undefined. There are reported cases
of complete responses to multiagent chemotherapy.43
Granulosa Cell Tumors
Clinical Presentation
Two forms of granulosa cell tumors have been described
in males, adult and juvenile. Nineteen cases of adult
granulosa cell tumor (AGCT) of the testis have been
reported in the literature, although additional sex cord-
 Chapter 37 Nongerm Cell Tumors of the Testis 625

Figure 37-11 Sertoli cell adenoma. Same patient as in Figure 37-10. The SCA is on the right
and is comprised of discrete uniform tubules lined by Sertoli cells. The larger tubules on the left
are of the nonadenomatous testis and are separated by prominent Leydig cells (H&E × 31.2).

stromal tumors with granulosa cell differentiation have

been reported.44–46 The majority have presented as
scrotal masses with testicular enlargement ranging from
2 months to 15 years in the described cases. The patient
with a mass of 15 years duration had delayed testicular
descent and 2 other patients had been cryptorchid. Five
tumors have had associated estrogenic clinical manifes-
tations (gynecomastia). Four of these patients had
lymph node or visceral metastases and 2 patients died of
their disease. One patient developed metastases 121
months after diagnosis and died of disease 13 months
later.
Juvenile granulosa cell tumors (JGCT) rarely arise in
infants over 6 months old and in all probability arise in
utero. A total of 48 cases have been reported.47 Fifty per-
cent of cases were diagnosed in newborns and 90% by 6
months of age (mean 1 month, range 0 to 11 months). Figure 37-12 Juvenile granulosa cell tumor. One-month-old
They have been associated with 45XO/46XY and boy with left testicular mass. The testis measured 3 × 2.5 ×
45XO/46XY iso(Yq) karyotypes and numerous other 1.5 cm. The surface was smooth and red-tan. On cut
forms of mosaicism.48 The tumors are generally found in sections, there was a variegated red to yellow lobulated
descended testes although they have been discovered parenchyma with cystic areas up to 5 mm in diameter.
in undescended and torsed testes. The tumor is not (Photograph and case courtesy of California Tumor Tissue
associated with isosexual precocity. The testis harbor- Registry.)
ing this tumor is usually enlarged, solid, and/or cystic
(Figure 37-12). and either solid or cystic. Two patients with metastases
had hemorrhagic or friable and necrotic foci in their
tumors. Their microscopic appearance has resembled
Pathologic Characteristics that of ovarian granulosa cell tumor with solid, cystic,
The reported AGCTs ranged in size from 4 microscopic insular, gyriform, and trabecular patterns. Individual
lobules to 13 cm and were well circumscribed.44 They granulosa cells have been described as fairly uniform with
have been described as brownish, white, yellow, and pink scanty cytoplasm, indistinct cell borders, and longitudi-
626 Part VI Testis
nal nuclear grooves in elongate cells. Jimenez-Quintero
et al.44 recorded up to 26 mitotic figures in 50 high power
microscopic fields. Tumor cells have been described as
positive for vimentin and negative for keratin or epithe-
lial membrane antigen.
JGCT are grossly multicystic and contain follicular
structures of varying size lined by one to multiple layers
of cells and contain pale eosinophilic or basophilic intra-
luminal material (Figures 37-12 and 37-13). The stroma
is fibrous and may contain groups of cells that resemble
theca cells and granulosa cells, which do not resemble the
cells of AGCT. Lawrence et al.48 found only a few
grooved cells in a minority of tumors. In the JGCTs the
granulosa cells have round to oval nuclei and pale to
eosinophilic cytoplasm. Tumor granulosa cells stain pos-
itively for vimentin and some cells stain positively for ker-
atin and S100 protein with immunoperoxidase stains.49
The cells that resemble theca cells have been demonstrated
to stain positively for muscle-specific actin, vimentin, and
focally for desmin with immunoperoxidase stains. Mitoses
may be numerous. Tumor cells may be present in relation-
ship to seminiferous tubules and have even been described
within a seminiferous tubule. The differential diagnosis of
JGCT of the testis consists of those tumors developing in
the neonatal period. Probably most congenital testicular
tumors and those discovered in the first 4 months of life are
JGCTs rather than yolk sac tumors. Yolk sac tumors may be
solid and/or cystic and may have macrocystic or microcys-
tic areas. However, definitive areas diagnostic for yolk sac
tumor, including Schiller-Duval bodies and immunoperox-
idase staining for AFP, are absent in JGCT. Levels of serum
Figure 37-13 Juvenile granulosa cell tumor. Same patient as in Figure 37-2. Multiple small
cysts and areas of solid polyhedral to rounded cells comprise the tumor. Elsewhere, larger
follicles were present (H&E × 31.2).
AFP are normally elevated in the neonate relative to adult
values, so serum AFP levels are of no value in the diagnosis
of this tumor.
Evaluation and Management
The diagnosis of AGCT is not usually established until
the time of orchiectomy and surgical excision may be cur-
ative. There is insufficient experience with malignant
forms of this tumor to comment on therapy. JGCT can be
suspected on the basis of patient age and karyotype. They
are invariably benign and are cured by excision. Although
follow-up in many cases is still limited, none of the 48
reported cases have been associated with recurrence.47
MIXED SEX CORD/GONADAL STROMAL TUMORS
AND INCOMPLETELY DIFFERENTIATED TUMORS
Tumors of mixed histology occasionally occur and may
consist of some areas with recognizable elements mixed
with incompletely differentiated cells resembling ovarian
stroma (Figure 37-14). A recently described transgenic
mouse model suggests that at least some of these neo-
plasms may arise from tumors, that begin as SCTs.50 Like
pure forms, tumors of mixed histology and incompletely
differentiated tumors present as an isolated testicular mass
usually without endocrinologic signs or symptoms and
are diagnosed at the time of orchiectomy (Figure 37-15).
Most are biologically benign but some metastatic tumors
have been described.51,52 Treatment is by inguinal
orchiectomy. Retroperitoneal lymph node dissection may

Figure 37-14 Incompletely differentiated gonadal stromal tumor. Testicular mass in 46-year-
old. Interlacing fascicles of basophilic spindled cells with large uniform nuclei resemble cells
of ovarian stroma (H&E × 62.2).
Figure 37-15 Incompletely differentiated gonadal stromal
tumor; 2.2-cm tan nonencapsulated, subcapsular tan firm
mass. Same patient as in Figure 37-14.
have value in some cases with metastasis.53 Good
responses to platinum-based chemotherapy have been
described for metastatic disease.54
Miscellaneous Tumors
Epidermoid Cysts
Epidermoid cysts are benign lesions, which typically
present as a painless testicular mass and are frequently
noted incidentally on physical examination. They occur
Chapter 37 Nongerm Cell Tumors of the Testis 627
Figure 37-16 Epidermoid cyst. Eighteen-year-old with 3-
month history of nontender mass of left testis. The testis
contains a well-circumscribed 2-cm cyst with a 1-mm thick
gray wall filled with yellow-white friable cheesy material.
slightly more commonly on the right side and rarely are
much larger than 2 to 3 cm. Grossly they appear as a usu-
ally solitary cyst containing laminated keratinous mate-
rial (Figure 37-16). Histologically they are composed of
a squamous lining and filled with keratin.55 Treatment
has historically been by orchiectomy, but there are sev-
eral reports in the literature describing a characteristic
appearance of this lesion on ultrasound, which may allow
diagnosis preoperatively.56 The ultrasonographic
appearance of a markedly heterogeneous intratesticular
628 Part VI Testis

mass with or without alternating hypoechoic and hyper-
echoic layers surrounded by a hypoechoic or echogenic
rim and absence of blood flow on color Doppler sonog-
raphy suggest the diagnosis of a testicular epidermoid
cyst. Although these criteria are not diagnostic, they may
strengthen the indication for excisional biopsy. In such
cases, inguinal exploration and excisional biopsy seem
reasonable, especially in children or patients with a soli-
tary testicle or bilateral lesions.57,58 Epidermoid cysts
have rarely been reported in a patient with Klinefelter’s
syndrome, and we have seen another such patient (Figure
37-17).59
Rete Testis Carcinoma
Clinical presentation. Orozco and Murphy60 reported
one case and reviewed 43 cases of rete testis carcinoma
(RTC) that have been recorded in the literature through
1992. The patients have ranged in age from 17 to 91 years
of age with a mean of 50 years. The clinical onset may or
may not be associated with pain. Testicular enlargement
averaged about 2 years in duration but had been present
for 5 years in four instances. Serum tumor markers were
not elevated. All patients were treated by orchiectomy and
some were also treated with radiotherapy, chemotherapy,
and retroperitoneal lymphadenectomy. Of the reviewed
patients, 33% died of RTC, 75% within a year of diagno-
sis. Twenty patients were alive at the time of the report,
80% free of disease at a maximum 2-year follow-up.
Pathologic characteristics. RTCs are poorly circum-
scribed gray nodules at the hilus of the testis. Most
tumors are single, but multiple masses have been
reported. Reported tumors have ranged in size from 1 to
15 cm. Histologically, RTCs are adenocarcinomas. The
predominant growth pattern is papillary with solid, spin-
dled, and cystic areas less common (Figures 37-18 and
37-19). Tumor cells are columnar to cuboidal with aci-
dophilic to amphophilic cytoplasm. Nuclei are enlarged,
pleomorphic and round to oval with coarsely granular
chromatin and sometimes prominent nucleoli. Mitoses
may be frequent. The tumors stain negative for mucin,
occasionally positive for CEA, and positive for vimentin,
epithelial membrane antigen, and keratin with
immunoperoxidase stains. Immunoperoxidase stains are
negative for AFP, hCG, and PSA. The diagnosis of RTC
should be made in cases where the tumor is present in the
hilus of the testis, where there is a transition from histo-
logically normal rete testis to RTC, where primary tes-
ticular tumors of germ cell and nongerm cell origin and
mesothelioma can be excluded, and where extratesticular
origin can be reasonably excluded on a histologic and
clinical basis. The histologic distinction between an RTC
and adenoma or hyperplasia of the rete testis should not
be difficult.
Evaluation and management. RTCs are usually found
incidentally by palpation or at the time of orchiectomy
for a testicular mass. They may be suspected on preoper-
ative examination or ultrasound by a hilar location

Figure 37-17 Epidermoid cyst. Sixteen-year-old with cystic testicular mass. The cyst is lined
by flattened squamous epithelium. Laminated keratin is present in the left upper corner.
Mostly flattened seminiferous tubules lined by Sertoli cells are present beneath the cyst.
Leydig cells are prominent. The patient was subsequently found to have Klinefelter’s
syndrome (H&E × 31.2).
 Chapter 37 Nongerm Cell Tumors of the Testis 629

Figure 37-18 RTC. Forty-seven-year-old with recurrent hydrocele and firm nontender mass
at the superior pole of the right testis. Orchiectomy specimen contained numerous irregular
firm 1- to 4-cm nodules with involvement of epididymis. Papillary and solid neoplasm
involves the rete testis, surrounding and projecting into rete testis lumens (H&E × 31.2).

Figure 37-19 RTC. Same case as in Figure 37-18. Glandular spaces are lined by epithelial
cells with round to oval, pleomorphic, enlarged nuclei with prominent nucleoli. Glands are
infiltrating connective tissue (H&E × 62.2).

or involvement of the epididymis. Initial therapy is

orchiectomy followed by a staging evaluation for distant
disease.61 One long-term complete remission has been
reported following retroperitoneal lymphadenectomy for
micrometastatic disease. Chemotherapy for disseminated
disease has generally been unsuccessful.61
Malignant Mesothelioma of the Tunica Vaginalis
Clinical presentation. Malignant mesothelioma (MM)
is a rare lesion. The literature consists of 81 cases with
the largest series reported by Jones et al. in 1995.62,63
The age range is 7 to 80 years with a mean of 53.5 years.
630 Part VI Testis
Two-thirds of patients were over 50 years at the time of
diagnosis. Most patients presented with a benign appear-
ing hydrocele with or without an inguinal or scrotal mass.
Of those patients who were asked about asbestos expo-
sure, 41% had some degree of occupational exposure.
The large majority of patients had a hydrocele sac stud-
ded with papillary excrescences from several millimeters
to several centimeters (Figure 37-20). In some cases, a
mass involved the spermatic cord, other paratesticular
structures, or rarely, the testis proper. MM that extended
beyond the confines of the hydrocele invaded local struc-
tures, including spermatic cord, epididymis, testis, and
penile, scrotal and lower abdominal wall skin. Jones’
series includes follow-up on 52 patients (6 months to 15
years, mean 2.8 years). Twenty-five patients developed
distant metastases. The principle sites of metastasis were
retroperitoneal and inguinal lymph nodes, other lymph
nodes and lung. Retroperitoneal and inguinal lymph
node involvement was present at the time of diagnosis in
9 and 4 cases, respectively. Of the 52 patients with fol-
low-up data, 44% died of disease, 17% were alive with
disease, and 38% had no evidence of disease. The latter
figure should be considered with caution since late recur-
rence of well-differentiated epithelial MM has been
observed. Forty-six percent of patients who presented
with tumor confined to the hydrocele sac were free of
disease at 2 years compared with 5.3% of patients who
presented with local invasion of the spermatic cord, skin,
testis, or with distant metastasis. In a review of 74 cases
of MM of the tunica vaginalis, Plas et al.64 found a
median survival time of 23 months.
Figure 37-20 Papillary mesothelioma. Fifty-three-year-old man with recurrent left hydrocele.
The tunica vaginalis is studded with yellow-tan excrescences from 0.2 to 1.0 cm in
maximum dimension.
Pathologic characteristics. Seventy-five percent of the
tumors described by Jones et al.62 were epithelial and
25% were biphasic. Epithelial tumors grew in a tubular
and/or papillary growth pattern (Figure 37-21). Cellular
anaplasia was variable with some tumors comprised of
bland cells without mitotic activity growing in a papillary
pattern on fibrous stalks with others containing large
eosinophilic cells with hyperchromatic irregular nuclei,
prominent nucleoli, and frequent mitoses growing in an
infiltrating tubular pattern. Tumor stroma was usually
dense. Psammoma bodies were occasionally present. The
majority of tumors, even the best differentiated, showed
some degree of stromal invasion. MMs with a biphasic
pattern had a sarcomatous component with spindled cells
of variable differentiation, sometimes containing numer-
ous mitotic figures.
MM must be distinguished from a number of benign
and malignant lesions. Mesothelial cell hyperplasia,
although prominent in a hernia sac, is rarely present in a
hydrocele and does not contain the fibrous stalks charac-
teristic of the papillary MM. Adenomatoid tumor is a
benign tumor derived from mesothelial cells but has a
characteristic gland-like architecture and cytology that
distinguishes it from MM. It is far more difficult to dis-
tinguish MM from metastatic adenocarcinoma, RTC,
and serous borderline tumors of müllerian origin (ovar-
ian surface epithelial type) that resemble ovarian tumors
of borderline malignancy, which may involve the testis or
paratesticular tissue.65 Borderline serous tumors gener-
ally have broad papillae with stratified epithelial cells
having a more columnar appearance, some of which are

Figure 37-21 Papillary mesothelioma. Same case as in Figure 37-20. The tumor is
multifocal and comprised of a complex papillary growth lined by a single layer of mesothelial
cells with oval, prominently nucleolated nuclei growing on fibrous stalks. The patient is free
of MM 5 years after orchiectomy (H&E × 3 1.2).
ciliated. Immunohistochemical stains may be useful in
distinguishing between these two tumors since serous
tumors are frequently positive for Leu-M1, B72.3, CEA,
and CA125, whereas MMs are negative for these anti-
gens.65 MMs are usually positive for CK 5/6 and calretinin.
RTC may be associated with a hydrocele and focally may
have a histologic resemblance to MM, but if the criteria
of diagnosis enumerated earlier are adhered to, there
should be no problem distinguishing the two entities.
Electron microscopy may also help distinguish the enti-
ties since mesothelial cells have long thin, bushy
microvilli, and epithelial cells of rete testis origin do not.
As in the pleura and peritoneum, there may rarely be a
problem distinguishing MM from metastatic adenocarci-
noma. The same immunohistochemical stains used to
distinguish müllerian papillary serous tumors are useful
in distinguishing metastatic adenocarcinomas from MM.
Adenocarcinomas, that may be of gastrointestinal origin
should stain positively for Leu-Ml, B72.3, and CEA and
may contain intracytoplasmic mucin.
Evaluation and management. MM is usually not sus-
pected preoperatively; 97.3% are encountered inciden-
tally during hydrocelectomy.64 When the initial
presentation is a scrotal mass, inguinal orchiectomy
should be performed with en bloc excision of involved
adjacent structures. If the tumor is incidentally discov-
ered during a transscrotal procedure, frozen section
should be performed and inguinal orchiectomy com-
pleted at the same sitting or soon thereafter after consul-
Chapter 37 Nongerm Cell Tumors of the Testis 631
tation with the patient. Orchiectomy is associated with a
lower local recurrence rate compared with hydrocelec-
tomy (11% versus 36%, respectively) although no differ-
ence in overall survival has been demonstrated.64 A
metastatic evaluation is appropriate but there is little
experience in the literature to address the issues of sur-
veillance, adjuvant chemotherapy, or prophylactic
retroperitoneal or inguinal lymphadenectomy.
Metastatic Tumors
Symptomatic metastatic nonhematologic tumors of the
testis occur only rarely. Price and Mostofi66 identified
only 38 metastatic carcinomas involving the testis suit-
able for study at a time when the AFIP had 1600 primary
testicular tumors. Four of the patients had bilateral
tumors. Only 6 tumors were clinically symptomatic, gen-
erally due to testicular enlargement. The majority of
tumors in their report were discovered at autopsy. Of the
38 tumors, 14 were from the lung and 12 were from the
prostate gland. Tiltman67 found metastases in 6 of 248
autopsies in males with metastatic carcinoma. Testicular
metastases occurred in 2 of 12 cases of prostate carci-
noma, 2 of 9 cases of malignant melanoma, 1 of 4 cases of
malignant pleural mesothelioma, and 1 of 89 cases of car-
cinoma of the lung. Haupt et al.68 reviewed the literature
through 1982 and found the most common tumors
metastasizing to the testes were (in descending order)
carcinomas of the prostate and lung, malignant
melanoma, and carcinomas of the kidney, stomach, and
632 Part VI Testis

pancreas. These findings emphasize the relative rarity of

metastases to the testis and the fact that in most patients
testicular involvement will be discovered incidentally
despite a known history of cancer. Only 24 cases of tes-
ticular enlargement as the primary manifestation of a
tumor metastasis have been reported. These included
primary tumors of the prostate, kidney, and GI tract,
some of which were initially thought to represent pri-
mary testicular tumors even after histologic examination.
Grossly metastatic tumors are generally multinodular
(Figure 37-22). Microscopically, the tumor grows in the
interstitium and may be within endothelial-lined spaces.
The morphology of the tumor may be characteristic of
the primary tumor (Figure 37-23). Treatment for tumors
metastatic to the testis is directed at the underlying Figure 37-22 Metastatic undifferentiated carcinoma, small
malignancy. cell type, of lung. Seventy-six-year-old man with left testicular
mass and previous history of undifferentiated small cell
Carcinoid Tumors carcinoma of lung. Metastatic confluent nodules of neoplasm
are present in the lower left portion of the testis.
Carcinoid tumor (CT) involving the testis and testicular
adnexa represents a special problem inasmuch as both reported through 1992 were metastatic. The largest of
primary and metastatic tumors may have similar mor- the metastatic CTs on which data were recorded was 2.5
phology. The nests of tumor grow in an insular pattern cm, and 3 patients had symptoms of the carcinoid syn-
with groups of uniform centrally nucleated cells having drome. Most patients with metastatic CTs died within a
fine nuclear chromatin and granular eosinophilic cyto- year although one patient survived for 12 years. Factors
plasm (Figure 37-24). The majority of CTs stain posi- that favor a metastatic origin for a CT are bilaterality,
tively with argentaffin and argyrophil stains and for involvement of peritesticular structures, absence of a ter-
chromogranin, neuron-specific enolase, and other atomatous component, and the presence of carcinoid
polypeptides with immunoperoxidase stains. Zavala- syndrome symptomatology. Most primary testicular car-
Pompa et al.69 indicated that 9 of 62 testicular CTs cinoids are cured with inguinal orchiectomy. However,

Figure 37-23 Metastatic prostatic adenocarcinoma. Fifty-eight-year-old man with bilateral

orchiectomy for prostate cancer. One testis contained a firm tan irregular mass. Solid
aggregates of tumor and neoplastic glands expand the interstitium adjacent to a
seminiferous tubule (H&E × 31.2).
 Chapter 37 Nongerm Cell Tumors of the Testis 633

Figure 37-24 Carcinoid tumor. Forty-two-year-old male with enlarged right testis and
epididymis containing a 3.5-cm yellow to red, firm to fibrous mass. The tumor is comprised
of solid nests and cysts growing in an insular pattern. Tumor cells contain uniform, centrally
nucleated cells with fine nuclear chromatin and granular eosinophilic cytoplasm (H&E × 3
1.2). (Case courtesy of California Tumor Tissue Registry.)

all patients should have a metastatic evaluation and malignant testicular tumors and, in the case of malako-
retroperitoneal lymphadenectomy should be considered plakia and granulomatous orchitis, from ML.
in those tumors associated with teratoma.

Hematologic Tumors
Other Miscellaneous Tumors
Malignant Lymphoma
A variety of other uncommon and usually benign lesions Clinical presentation. While MLs comprise only a
may mimic more aggressive testicular tumors. Simple small percentage of testicular tumors, they account for
cysts have been described in 17 patients of all ages and more than 50% of testicular tumors in men over age 65.
ranging in size from 1 to several centimeters in diameter About 80% of testicular MLs occur in men over age 50.
but are probably more common.70 Histologically, they The neoplasm generally presents as a unilateral, painless,
are lined by flat or cuboidal epithelium and have a benign
appearance. Cysts may be suspected preoperatively by a
smooth-walled, anechoic appearance on ultrasound.
Adenomatoid tumors are benign mesenchymal prolifera-
tions that usually arise from the epididymis but may also
arise from the tunica albuginea and may infiltrate testic-
ular parenchyma. Two reports of true intratesticular ade-
nomatoid tumors have been published.71,72 These tumors
present as painless enlargement and are firm or hard to
palpation (Figures 37-25 and 37-26). Fibromas and
fibrous pseudotumors of the testicular tunics presenting
as hard painful or incidentally discovered masses have
also been reported. Granulomatous orchitis and malako-
plakia are benign inflammatory conditions usually diag-
nosed following orchiectomy. They have characteristic
histologic appearances, which are pathognomonic. All of Figure 37-25 Adenomatoid tumor of epididymis. The
these lesions are cured by orchiectomy or simple excision epididymal specimen consists of a discrete white uniform
and are important mostly to be differentiated from rubbery 0.9-cm nodule in a 44-year-old man.
634 Part VI Testis
Figure 37-26 Adenomatoid tumor of epididymis. Same patient as in Figure 37-25. Gland-
like structures lined by flattened cells infiltrate collagenous tissue. Numerous intraluminal and
intracytoplasmic vacuoles of varying size are present, creating a spider-web appearance in
some areas (H&E × 31.2).
intrascrotal mass. About 5% of men present with bilat-
eral synchronous involvement, and approximately 20%
with a unilateral presentation will develop lymphomatous
involvement of the opposite testis. Bilateral disease may
occur in the absence of any other systemic disease.73
Generally, the diagnosis of ML is first made at the time
of orchiectomy. Only a small percentage of patients have
a history of antecedent lymphoma. Of 127 men with ML
of the testis, Gowing74 reported only 8 with antecedent
ML and 13 with active lymphoma elsewhere at the time
of orchiectomy.
Pathologic characteristics. The neoplasm mainly
involves the testis but often extends into the epididymis
or spermatic cord. The testis is enlarged, sometimes mas-
sively, and on cut section is partially or extensively
replaced by an ill-defined tan-grey mass. The tumor
merges imperceptibly with testicular parenchyma.
Tumor consistency is more rubbery than hard, and
necrosis may be present. The large majority of testicular
lymphomas are diffuse non-Hodgkin’s type. Gowing74
indicated that 41% of the British Testicular Tumor Panel
cases were poorly differentiated lymphocytic lymphomas
and 59% were large cell lymphomas (undifferentiated
“stem cell reticulum cell type”). They had no cases of
Hodgkin’s disease among their 127 cases. Virtually all
types of ML other than Hodgkin’s disease occur in the
testis. Ferry et al.75 in 1994 reported 64 ML, which pre-
sented primarily in the testis. Of these, 53 were diffuse
large cell lymphoma of which 27 were of noncleaved type
in the working formulation, 10 immunoblastic, 6 small
noncleaved, and 6 were NOS. Of those tumors that were
immunophenotype 33 were of B-cell lineage, one was of
T lineage, and 5 were of indeterminate lineage.
Irrespective of cell type, the pattern of infiltration is sim-
ilar. Tumor cells proliferate in the interstitium separating
seminiferous tubules, infiltrating the tunica propria and
blood vessel walls, eventually obliterating many tubules
and vessels (Figure 37-27). Sections may contain no rec-
ognizable testicular parenchyma. Tumor cells may extend
into the rete testis, epididymis, tunica albuginea, or
peritesticular soft tissue.
Evaluation and management. The prognosis of men
with ML of the testis has been poor. Gowing74 indicated
62% of their patients died of disseminated ML. Only 12
of 124 patients (10%) survived 5 years after orchiectomy.
In a more recent study, Ferry et al.75 found 20 of 55
patients (36%) to be free of disease a median of 49
months after orchiectomy, 6 (11%) were alive with dis-
ease and 29 (53%) died of ML. With careful staging of
ML it is apparent that prognosis is related to the stage of
the disease at the time of orchiectomy. Turner et al.76
reported 60% disease-free survival in stage I ML con-
trasted with a 17% disease-free survival for stages II, III,
and IV. Turner et al.’s cases were classified according to
the Rappaport system and the working classification of
non-Hodgkin’s lymphomas. In the latter classification,
the large cell noncleaved, large cell cleaved, and diffuse
mixed lymphomas were designated intermediate grade
 Chapter 37 Nongerm Cell Tumors of the Testis 635

Figure 37-27 ML, diffuse large cell type. A 225-g 9.5 cm in maximum dimension testis was
subtotally replaced by a dark tan, focally hemorrhagic, focally necrotic, ill-defined mass. An
extensive cellular infiltrate greatly expands the interstitium and compresses seminiferous
tubules. The individual cells contain large, variably shaped, prominently nucleolated nuclei
with sparse cytoplasm (H&E × 62.2).

lymphomas, and immunoblastic lymphoma, Burkitt’s
lymphoma and diffuse undifferentiated lymphomas were
designated as high-grade lymphomas. Eight of 17 men
with intermediate grade ML were alive and well with an
average follow-up of 24 months. There were no survivors
among 6 men in the high-grade group whose average
survival was 13 months. Thus, grade appears to be
another prognostic variable. Stage I disease, unilateral
right-sided ML, and microscopic sclerosis were also asso-
ciated with an improved prognosis in Ferry et al.’s
study.75
In 2001, Lagrange et al.77 reviewed their experience
with 84 cases of primary testicular lymphoma. The
median age at presentation was 67 (range 17 to 85).
Forty-two patients presented with stage I disease, 19 with
stage II, and 23 with stage III/IV. Using the REAL clas-
sification, 75% of the patients exhibited diffuse large B-
cell histology. Treatment was generally multimodal and
involved orchiectomy and chemotherapy ± radiation. A
complete response was obtained in 72.6% of patients
(100%, 68%, and 33% for stages I, II, and III/IV, respec-
tively). However, median survival was 32 months (52, 32,
and 12 months for stages I, II, and III/IV, respectively).
Zucca et al.,78 in 2003, examined their experience with
373 patients with primary testicular diffuse large B-cell
lymphoma. The median age at diagnosis was 66 years.
Anthracycline-based chemotherapy was used in 68%,
prophylactic intrathecal chemotherapy in 18%, and pro-
phylactic scrotal radiotherapy in 36%. Median survival
was 4.8 years, but the survival curves showed no clear evi-
dence of a substantial portion of cured patients. There
was a 52% relapse rate at a median follow-up of 7.6 years.
Relapses occurred in the CNS in 15% of the patients,
occasionally as late as 10 years postorchiectomy. The
authors identified a continuous risk of contralateral tes-
ticular recurrence in those patients not receiving scrotal
radiotherapy. On multivariate analysis, lack of B-
symptoms, use of anthracyclines, and scrotal radiotherapy
were associated with longer survival.
Evidence is accumulating that primary testicular lym-
phoma in children has a very different natural his-
tory.79–81 Most lymphomas involving the testicle are
secondary lesions in patients with diffuse extrascrotal
lymphoma. Only 10 cases of primary testicular lym-
phoma in children have been reported. All have shared
similar histology (follicular large cell lymphoma) and,
despite the aggressive histologic appearance, a good
prognosis. Most patients have been treated with orchiec-
tomy and multiagent chemotherapy. The 10 reported
cases include children ranging in age from 3 to 11 years.
None of the tumors has demonstrated the presence of
bcl-2 protein. The size of the tumors ranged from 2 to 4
cm. All 10 patients are reported to be free of disease with
follow-up ranging from 7 to 59 months.
It is clear that some cases of ML originate in the testis.
Although rare survivals have been reported following
orchiectomy alone, this is certainly insufficient therapy since
the large majority of men ultimately develop extratesticular
636 Part VI Testis
ML. Extratesticular involvement tends to occur in sev-
eral areas, including Waldeyer’s ring and the central
nervous system. Turner et al.’s76 series also suggests that
MLs at these sites may have been present at the time of
orchiectomy. Ferry et al.’s75 data indicate that MLs that
relapsed in the testis tended to be extranodal, and that
ML presenting in the testis tended to have lymphoma in
extranodal sites, notably bone, CNS, skin, orbit,
paranasal sinuses, stomach, nose, thyroid, and larynx.75
Treatment should be based on stage and histologic type
of lymphoma.
Plasmacytoma
Plasma cell neoplasms involving the testis are rare and
have the same implications as ML. The tumors are bilat-
eral and sequential in about 20% of men. Tumors gener-
ally manifest as painless enlargement and are part of a
systemic process sometimes identified prior to orchiec-
tomy. Tumors may be associated with hydroceles and, on
at least two occasions, the diagnosis was made on the basis
of cytologic analysis of hydrocele fluid.82 All patients with
sufficient follow-up reviewed by Levin and Mostofi83 and
all 7 in the literature until that time succumbed to sys-
temic disease. The mean age at the time of diagnosis was
55 years with only 8 patients under 50 and the youngest
aged 26. There have been 42 reported cases of testicular
plasmacytoma, only 10 of which had no documented sys-
temic myeloma.82,84,85 The gross and microscopic appear-
ances of plasmacytoma are similar to those of ML, the
only difference being the cell type, which is a neoplastic
plasma cell of variable morphology (Figure 37-28).
Leukemia
Leukemic involvement of the testis is common. In an
autopsy study, Givler86 found 63% of 140 males with
Figure 37-28 Plasmacytoma. Massive enlargement and
complete replacement of testicular parenchyma by a
lobulated gray-yellow 11-cm mass in a 42-year-old man.
acute leukemia (AL) and 22% of 76 males with chronic
leukemia (CL) had testicular involvement. All varieties of
AL were represented. It is recognized that children with
acute lymphoblastic leukemia (ALL) in bone marrow
remission may have recurrence first demonstrated in the
testis. In Givler’s study, 8 children with ALL developed
testicular masses while receiving chemotherapy. Five of
the children were in hematologic remission and the tes-
ticular masses were either the sole evidence of leukemia
or associated with other extramedullary leukemic masses.
Hematologic relapse followed in all cases. In 5 of 8 cases,
testicular involvement was bilateral. In cases of ALL fol-
lowing completion of chemotherapy, biopsy of the testes
to rule out occult leukemic involvement is part of some
current protocols. Neither palpation nor radiographic
studies, such as ultrasound or MRI, are sufficiently sensi-
tive to the presence of leukemic infiltrates to obviate the
need for biopsy. Buchanan et al.87 reported that one-third
of patients with overt testicular recurrence of ALL
treated with an intense protocol exhibited prolonged sec-
ond remissions with the potential for cure. Only a small
percentage of patients will develop testicular recurrence
following a negative biopsy. The interstitial pattern of
testicular involvement in ALL is similar to that of ML.
Occasionally ALL involvement of the testis produces a
massive enlargement (Figure 37-29).
Tumors of Generalized Stroma
Tumors of generalized stroma (blood vessels, smooth
muscle, and other supporting stroma), also known as
mesenchymal tumors, rarely occur in the testis.
Petersen70 reported a total of 26 such tumors described
in the literature, most of which (62%) were malignant.
The histologies of the benign tumors included 5 heman-
giomas, 3 hemangioendotheliomas, 1 leiomyoma, and 1
Figure 37-29 Acute lymphocytic leukemia. Massive
replacement of right testis by a cream-colored, focally
hemorrhagic, ill-defined mass in a 10-year-old with an 8-year
history of treated ALL.

myxoid neurofibroma. The malignancies included 14
rhabdomyosarcomas, 1 osteosarcoma, and 1 leiomyosar-
coma. The microscopic appearance of these tumors is
similar to those that occur at more typical sites. Most
of these patients presented with testicular enlargement
and underwent inguinal orchiectomy with the diagnosis
of a mesenchymal tumor made only after surgical exci-
sion of the testis. Benign tumors found in this manner do
not require further evaluation or treatment.
Rhabdomyosarcomas of the testis proper occur less fre-
quently than in paratesticular locations but should be
similarly treated with retroperitoneal lymphadenectomy,
chemotherapy, and radiation, depending on stage.
Testis Tumors in Acquired Immunodeficiency
Syndrome
Patients infected with HIV or with full-blown AIDS
appear to be at a 20- to 50-times higher risk of develop-
ing primary or secondary testis tumors.88 Testis tumors
are the third most common HIV-associated/AIDS-asso-
ciated malignancy.88 The first 2 cases of germ cell tumors
of the testis in AIDS patients were reported in 1985.89
Wilson et al.89 reported 5 of 3015 HIV positive men pre-
senting with testicular tumors over a 5-year period, an
incidence of 0.2%, more than 50 times the incidence of
testis tumors in the general population. There have been
additional cases of testis tumors described in the AIDS
population in the urologic literature, including semi-
noma and mixed nonseminomatous germ cell tumors,
Kaposi’s sarcoma, MLs, and plasmacytomas.90 Some of
these cases presented with testicular swelling as the initial
and primary manifestation of HIV infection,91 and some
of these patients presented with symptoms of acute pro-
statitis or epididymo-orchitis and were initially treated
with antibiotics before returning with complaints of pro-
gressive testicular enlargement. Reported cases were ulti-
mately managed by inguinal orchiectomy and additional
therapy based on tumor histology and status of the patient’s
immune system. These reports highlight the need for a
high index of suspicion for testicular tumors in men at
risk for HIV who present with testicular enlargement.
Testicular and Paratesticular Tumors of Ovarian
Surface Epithelial Type
Prior to 1995, 17 cases had been reported of testicular
and paratesticular tumors of ovarian surface epithelial
type, when Jones et al. reported an additional 5 cases of
paratesticular serous carcinoma.92,93 These occurred in
an age range of 11 to 68 years with a median of 47 years
in Young et al.’s series of testicular and paratesticular
tumors and in a range of 16 to 42 years with a mean of 31
years in Jones et al.’s series of paratesticular serous carci-
noma. The majority of tumors of ovarian surface epithe-
Chapter 37 Nongerm Cell Tumors of the Testis 637
lial origin are paratesticular, but at least 7 principally
involved testicular parenchyma. Other areas of involve-
ment included the tunica vaginalis and the testicular-
epididymal groove at the upper pole of the testis. The
majority of cases have been of serous borderline type, but
serous papillary carcinoma, mucinous cystadenoma, and
cystadenocarcinoma, endometrioid adenoacanthoma,
clear cell carcinoma, and Brenner tumors have been
reported.92,93 These tumors may be derived from müller-
ian duct remnants, the tunica vaginalis, or both. Most
borderline serous tumors behave in a benign fashion if
completely excised, but the clear cell adenocarcinoma
and two cases of papillary serous carcinoma behaved in a
malignant fashion, one causing metastasis and death and
another having extensive abdominal recurrence.93 A third
patient without demonstrable recurrence has persistent
elevation of serum CA125.93 It is important to recognize
the müllerian nature of these neoplasms and to accurately
distinguish between borderline and frankly malignant
variants.
The differential diagnosis of müllerian surface epithe-
lial tumors includes germ cell tumors, rete testis adenocar-
cinoma, mesothelioma of the tunica vaginalis, and
metastatic adenocarcinoma. Germ cell tumors, because
they are the most frequent tumor in this region, must be
considered in the differential diagnosis, but only teratomas
with mucinous glandular differentiation or transitional cell
foci might remotely be considered in the differential diag-
nosis of mucinous or Brenner variants of müllerian
tumors. As described earlier, rete testis adenocarcinomas
have a combination of diagnostic features that must be rec-
ognized for a correct diagnosis. Paratesticular and tunica
vaginalis MM may closely resemble paratesticular and
tunica vaginalis borderline serous müllerian tumors. MMs
are about three times more frequent. Müllerian tumors
stain positively for keratin and frequently for CEA, B72.3,
BER-EP4, EMA, Leu-M1, S-100 protein, and PLAP,
whereas MMs stain positively for cytokeratins, including
CK 5/6 and calretinin.65 Although borderline serous
tumors and epithelial MMs may have papillary configura-
tions, borderline serous tumors generally have stratified
nuclei and may be ciliated, whereas MMs are lined by a
single cell layer. Metastatic carcinomas to the testis, tunica
vaginalis and paratesticular tissues are rare but should be
considered in the differential diagnosis.
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53. Gohji K, Higuchi A, Fujii A, Kizaki T: Malignant gonadal
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C H A P T E R
38 Radical Orchiectomy and
Retroperitoneal Lymph Node Dissection
Richard S. Foster, MD, Ashraf Mosharafa, MD,
and Richard Bihrle, MD
RADICAL ORCHIECTOMY
General Considerations
Approximately 95% of primary intratesticular tumors are
of germ cell origin. The other 5% of tumors consist of a
variety of benign and malignant lesions. These include
Leydig cell and Sertoli cell tumors, adrenal cortical rests,
and other benign lesions.1 Similarly, secondary tumors of
the testis may occur rarely and mainly are hematopoietic
in origin. Hence, patients presenting with a tumor that is
intratesticular are usually found histologically to have a
germ cell tumor.
Most patients present with a palpable intratesticular
mass. Typically, the mass is firm and definitely different
from the consistency of normal testicular tissue. If such a
lesion is discovered, immediate determination of serum
alpha fetoprotein and beta-HCG is necessary and the
elevation of either of these markers confirms the diagno-
sis of a germ cell tumor. If the tumor is palpable, testicu-
lar ultrasound is not necessary and the patient may be
taken immediately to radical inguinal orchiectomy.
Alternatively, if there is doubt as to the diagnosis, transs-
crotal ultrasound is useful and the finding of an intrates-
ticular abnormality on testicular ultrasound in a patient
in the appropriate age range for germ cell tumors may
confirm the diagnosis. Magnetic resonance imaging has
been studied in the diagnosis of testicular tumors but is
rarely needed clinically.2
Historically, radical inguinal orchiectomy meant
removal of the testis and cord but sometimes also
included an extension of the incision and palpation of the
retroperitoneum.3 With modern imaging and staging
techniques this extension of the incision to palpate the
retroperitoneum is not necessary. Currently, radical
inguinal orchiectomy includes an inguinal approach to
high ligation of the spermatic cord at the internal ring
and the subsequent removal of the testis. It is typically
performed as an outpatient procedure.
The technique is relatively straightforward; an
inguinal incision is made parallel to the inguinal ligament
and the dissection is carried through the subcutaneous
tissues to the aponeurosis of the external oblique. The
external ring is identified, and the aponeurosis of the exter-
nal oblique is split from the external ring to the internal
ring. Cremasteric fibers are divided and the ilioinguinal
nerve is identified and dissected from the cord structures.
Next, the cord is dissected from the inguinal floor and
circumferential control is attained at the internal ring. If
the decision has been made to perform inguinal orchiec-
tomy, the cord is divided into 2 segments with a large
clamp, after which the segments are ligated with perma-
nent sutures and/or suture ligatures. Sometimes it is nec-
essary to dissect the peritoneum away from the medial
aspect of the cord prior to performing ligation. Typically,
after ligating the cord the cord stump retracts into the
abdomen through the internal ring. This facilitates
removal of the cord stump at subsequent retroperitoneal
lymph node dissection (RPLND). After ligation of the
cord the dissection is carried distally with subsequent
mobilization of the testis through the upper part of the
scrotum and division of the gubernacular fibers. If
the testis tumor is so large that it cannot be easily deliv-
ered through the opening in the scrotum, the incision is
extended on to the scrotum in order to remove the testis
intact. After hemostasis is obtained the aponeurosis
of the external oblique and Scarpa’s fascia are subse-
quently closed. Typically, the skin is closed using a
running subcuticular suture.
641
642 Part VI Testis
If the diagnosis is unclear at the time of exploration
and a frozen section is necessary, the same steps are per-
formed with the exception of early division of the cord.
Typically, if a frozen section is to be obtained, a tourni-
quet is applied to the cord at the internal ring after which
the testis is mobilized up into the incision. Drapes are
placed over the incision and the frozen section is done
away from the incision itself so as to not spill tumor into
the incision. Subsequently, if a frozen section diagnosis
confirms a germ cell tumor, the radical orchiectomy is
completed.
The reasoning behind an inguinal approach to a germ
cell tumor of the testis is to avoid spilling tumor into the
wound. Typically, germ cell tumor implants and if tumor
is spilled into the inguinal area, potentially another area
of lymphatic drainage (inguinal nodes) is contaminated.
Historically, if a scrotal approach to a testis tumor was
carried out, a subsequent recommendation was made to
perform hemi-scrotectomy so as to avoid contamination
of the inguinal lymphatics. With the advent of systemic
chemotherapy this procedure now is rarely necessary
although the inguinal approach to radical orchiectomy
continues to be the standard of care and should be appro-
priate management for any patient presenting with a
germ cell tumor of the testis.4
Approximately 1% to 2% of all patients who present
with a testicular germ cell tumor will develop a subse-
quent tumor on the contralateral side.5 Historically, rad-
ical inguinal orchiectomy was performed for the second
tumor and the patient was placed on testosterone supple-
mentation so as to maintain libido and sexuality. It is now
clear that small secondary tumors at the polar aspects of
the testis can be managed by partial orchiectomy with
good long-term results. Most series of partial orchiec-
tomy have recommended postoperative radiation therapy
to the testis, which prevents local recurrence and eradi-
cates carcinoma in situ in the remaining testicular tissue.6
The benefit of this approach is that over the long term
these patients are able to sustain production of androgens
from the remaining Leydig cells and therefore do not
need supplementation. However, the postoperative radi-
ation therapy effectively eliminates fertility, and therefore
the benefit of partial orchiectomy is to maintain adequate
androgen serum levels.
RETROPERITONEAL LYMPH NODE DISSECTION
The germ cell tumors of the testis are not only chemo-
sensitive but also “surgery sensitive.” Even after lym-
phatic metastasis has occurred, the surgical removal of
involved lymph nodes may be curative from 50% to 75%
of the time, dependent on the volume of metastatic dis-
ease.7,8 Most other cancers (breast, colon, lung, etc.) are
not surgically curable if lymphatic metastasis occurs;
germ cell testis tumors are surgically curable in the face
of lymphatic metastasis. From a urologic point of view,
this is perhaps the most unique aspect of the surgical
treatment of germ cell tumors.
Hence, since surgery may be curative in many patients
with metastatic germ cell tumor, urologic oncologists
necessarily need to understand and be proficient in tech-
niques of removal of lymph nodes in the retroperi-
toneum. RPLND is essentially two different operations;
one operation for low-stage disease in patients who have
not received chemotherapy and a completely different
operation for those patients who require an RPLND for a
residual mass after chemotherapy. These two techniques
are discussed separately.
RETROPERITONEAL LYMPH NODE
DISSECTION FOR LOW-STAGE DISEASE
Low-stage seminoma is not managed surgically and the
discussion here relates only to low-stage nonseminoma.
Clinical stage I disease is defined as no evidence of metas-
tasis on radiologic imaging. Typically, this involves CT
scanning of the abdomen and chest. Some prefer only a
chest x-ray as opposed to a CT of the chest. Additionally,
serum alpha fetoprotein and beta-hCG should have nor-
malized after radical orchiectomy or alternatively should
be decaying based on normal half-lives of approximately
5 days for alpha fetoprotein and 11⁄2 days for beta-hCG.9
If the patient has no evidence of metastasis on radiologic
imaging but these markers are not normalizing according
to half-life, the patient should be treated with
chemotherapy because of the high probability of having
occult systemic disease.10,11
Several alternatives for management exist in clinical
stage I that in the short term yield roughly the equivalent
chance for survival. These alternatives include RPLND
(with nerve sparing), surveillance with chemotherapy at
relapse, or primary chemotherapy. Pro and con argu-
ments exist for each of these approaches depending on
long-term side effects, psychologic issues, access to
health care, etc. As opposed to surveillance, the benefits
of RPLND include the immediate determination of
pathologic stage, the avoidance of chemotherapy (since
many of these patients are cured with surgery alone), and
the elimination of the necessity of using CT scans of the
abdomen in follow-up. Conversely, the follow-up period
after RPLND is only 2 years, whereas patients managed
on surveillance have to be followed for a longer period of
time.12 Similarly, the main benefit of surveillance is that
patients who have no metastasis receive no treatment and
only patients documented to have metastatic disease are
subject to any sort of therapy.
Approximately 30% of clinical stage I patients are sub-
sequently found to have metastatic disease.13 Generally,
metastatic tumor is found in retroperitoneal lymphatics.
Rarely, the retroperitoneum is normal and metastasis is
 Chapter 38 Radical Orchiectomy and Retroperitioneal Lymph Node Dissection 643

hematogenous only. Hence, the high probability of

retroperitoneal metastasis is the rationale for performing
RPLND. Risk factors identified in the orchiectomy spec-
imen may increase the probability of metastasis to 50%,
but prediction of metastasis at a higher level than 50% is
not possible.14 Therefore, clinical stage I patients will
have a 50% to 70% chance of having normal lymph
nodes removed.
Since some patients who undergo RPLND for clinical
stage I disease have no metastasis, it is important and per-
tinent to limit the morbidity of the procedure. Currently,
RPLND for low-stage disease has an acceptably very low
morbidity, which consists of about a 1% chance of devel-
oping a subsequent small bowel obstruction and a 3% to
5% chance of an abdominal incisional hernia.15 The
operative procedure is approximately 2 to 2 hours in
length. Transfusions are not required and the average
hospitalization is about 3.3 days. Return to full physical
activity occurs in three to 6 weeks depending on age of
the patient and body habitus.

TECHNIQUE FOR LOW-STAGE DISEASE

In low-stage nonseminoma mapping studies have shown
that metastatic spread is unilateral.16 Hence, for a patient
presenting with a right-sided primary, the involved lym-
phatics are usually interaortocaval, precaval, and right
paracaval (Figure 38-1). Similarly, for a left-sided pri-
mary, the involved lymphatics are typically left paraaortic
and preaortic (Figure 38-2). Though historically full
bilateral RPLND was performed (Figure 38-3), these
mapping studies illuminated the fact that a unilateral
template could be used. This was important since a uni-
lateral template dissection preserved contralateral sym-
pathetics important for emission and ejaculation. These
so-called modified templates preserved ejaculation at the
30% to 90% level, depending on individual technique.7,8
In order to further minimize morbidity, it was neces-
sary to improve the technique to maintain emission and
ejaculation at a higher level. These modifications were
termed nerve sparing since nerve-sparing RPLND
involves the prospective dissection of efferent sympathetic
fibers followed by removal of lymphatics based on a uni-
lateral template (Figure 38-4).17,18 Thus, nerve-sparing
RPLND preserves sympathetic nerves bilaterally
whereas a template dissection preserves only contralat-
eral nerves. The prospective dissection and preservation
of efferent sympathetic fibers maintains emission and
ejaculation at the 99% level.
Right Nerve-Sparing RPLND
A midline incision is made and a self-retaining retractor
is used. A general palpation and inspection of the
abdomen is performed and in the rare circumstance of
Figure 38-1 The template of dissection for a patient
presenting for a right-sided primary is displayed.
discovery of higher-volume metastasis than was predicted
by preoperative scans, a full bilateral dissection may be
required. Currently, CT scans are high resolution and
the intraoperative discovery of unsuspected high-volume
metastasis is rare.
After palpation and inspection an incision is made in
the posterior peritoneum from the cecum to the area
of the ligament of Treitz. The root of the small bowel
and the right colon are reflected to the patient’s right and
held in place with self-retaining retractors. The template
of dissection includes the interaortocaval, precaval, and
right paracaval lymph nodes. The so-called “split and roll”
maneuver is employed. This is essentially a vascular iso-
lation technique whereby lymphatic tissue is split at the
12 o’clock position over vessels and rolled laterally away
from those vessels. RPLND is a vascular procedure.
First, the split maneuver is performed over the left renal
vein and tissue is rolled inferiorly. The anterior aspect of
the aorta is identified posterior to the left renal vein and
the split maneuver is carried out on the 12 o’clock posi-
tion of the aorta from the crossing of the left renal vein
644 Part VI Testis
Figure 38-2 The template of dissection for a left-sided
primary is displayed.
distally to the origin of the inferior mesenteric artery.
Tissue is rolled medially into the interaortocaval zone in
order to determine whether or not a lower pole right-
sided precaval renal artery is present. Attention is then
turned to the vena cava. The split maneuver is performed
at the 12 o’clock position on the vena cava (Figure 38-5).
The origin of the right gonadal vein is identified and
divided between silk ties. It is subsequently dissected
to the internal ring at which point the cord stump from
the radical orchiectomy is identified, mobilized from the
internal ring, and the specimen is removed as right
gonadal vein. The roll maneuver is then performed on
the vena cava after which all lumbar veins passing poste-
riorly from the cava to the posterior body wall are iden-
tified and divided between silk ties (Figure 38-6).
Typically, the efferent sympathetic fibers from the right
sympathetic chain pass cephalad to these lumbar veins.
Care must be taken to not injure the nerves in the course
of dividing the veins. The nerves are then dissected away
from lymphatic tissue and placed in vessel loops.
Typically, the right-sided nerves coalesce in the interaor-
Figure 38-3 Full bilateral RPLND includes the removal of
right paracaval, interaortocaval, left peri-aortic, and interiliac
nodal packages.
tocaval area and then pass distally into the interiliac area
at the bifurcation of the aorta. Attention is then turned
back to the aorta at which point the split maneuver is
continued along the distal aorta and right common iliac
artery. The nerves have been previously dissected and
therefore are avoided in the process of this split maneu-
ver. Tissue is rolled medially into the interaortocaval area
and the right-sided lumbar arteries are divided between
ties. The renal artery is typically seen passing over the
crus of the diaphragm and lymphatic tissue, is dissected
away from it. Finally, the right ureter is dissected laterally
away from lymphatic tissue after which the right para-
caval and interaortocaval nodal packages are dissected
from the posterior body wall (Figure 38-7). Clips are
used as necessary to secure lymphatics or to gain hemo-
stasis from the lumbars as they penetrate the posterior
body wall. Cautery is also helpful in this regard. After
irrigation the posterior peritoneum is closed. Closure of
the abdominal incision is performed using a looped
absorbable suture.
 Chapter 38 Radical Orchiectomy and Retroperitioneal Lymph Node Dissection 645

Figure 38-5 Viewed from the patient’s left side, the split
maneuver on the superior portion of the aorta and the vena
cava as performed for a right modified nerve-sparing RPLND
is displayed.

Technique for Left-Sided Nerve-Sparing RPLND

Figure 38-4 The anatomy of retroperitoneal sympathetic
nerves in relationship to the vascular structures is shown.
For a left-sided dissection, after palpation and inspection
has been performed, an incision is made in the posterior
peritoneum lateral to the left colon. The left colon is
mobilized medially and held in place with self-retaining
retractors. The first step in a left-sided dissection is to
identify the efferent sympathetic fibers. Typically, these
can be seen coursing anterior to the left common iliac
artery and can be dissected away from lymphatic tissue
and placed in vessel loops (Figure 38-8). If these fibers
are not easily seen at this level an alternative approach is
to mobilize the left ureter laterally and roll lymphatic tis-
sue off the psoas muscle to expose the sympathetic chain.
The efferent fibers can then be seen passing from the
sympathetic chain to the interiliac area. After the nerve

Figure 38-6 Mobilization of the vena cava is performed by rolling lymphatic tissue away
from the vena cava, identifying the lumbar veins and subsequently dividing them. The three
lumbar veins passing to the posterior body wall are shown in the figure prior to division.
646 Part VI Testis

Figure 38-7 In a completed right modified nerve-sparing
RPLND all lymphatic tissue is removed in the interaortocaval
and right para-caval packages. Shown in the figure are the
mobilized vena cava, the sympathetic chain, and the efferent
sympathetic fibers in vessel loops.
Figure 38-9 The lymphatic tissue has been rolled away from
the left side of the aorta. Two lumbar arteries passing
posteriorly are seen. A silk tie has been passed around one in
preparation for subsequent ligation distally and division of the
lumbar artery.

fibers are identified they are dissected slightly proximally.
In a left-sided dissection, the lymphatics intermingle
with the efferent fibers and the dissection is technically
slightly more difficult because of this. The split maneu-
ver is performed over the left renal vein and tissue is
rolled inferiorly. The origin of the left gonadal vein is
identified, dissected, and divided between silk ties. The
left gonadal vein is then dissected to the internal ring at
which point the cord stump is mobilized from the inter-
nal ring and the left gonadal vein specimen is removed.
Next, the split maneuver is performed on the aorta from
the crossing of the left renal vein distally to the bifurca-
tion of the left common iliac artery. The bifurcation of
the left common iliac represents the lower boundary
of the dissection. Tissue is rolled into the left paraaor-
tic area and the left-sided lumbar arteries are identi-
fied, dissected, and divided between silk ties (Figure
38-9). Care must be taken to determine whether or not
lower pole renal arteries exist and these should be pre-
served if possible. The ureter is dissected laterally away

Figure 38-8 In this figure the anatomy of left-sided sympathetic efferent fibers is shown.
Note the confluence of the fibers anterior to the left common iliac artery. Right-sided fibers
join the left-sided fibers in the inter-iliac area.
 Chapter 38 Radical Orchiectomy and Retroperitioneal Lymph Node Dissection 647
from the lymphatic tissue and this represents the lateral
boundary of the dissection. Finally, lymphatic tissue is
dissected off the posterior body wall as one package
taking care to avoid the sympathetic chain and the
efferent sympathetic fibers passing into the interiliac
area. At the renal hilum lymphatic tissue is dissected
away from the renal artery and clips are applied at the
crus of the diaphragm. The left colon is then placed
back in the anatomic position and the abdomen
is closed as noted earlier with a running, looped
absorbable suture.
POSTOPERATIVE MANAGEMENT
Historically, nasogastric tubes were used because of the
suspicion of the postoperative paralytic ileus. Currently,
no postoperative nasogastric decompression is necessary.
Patients are given liquids the day after the procedure and
subsequently are advanced to full diet. The average hos-
pitalization for this procedure is around 3 days and return
to full physical activity is three to 6 weeks. Patients are
followed postoperatively with chest x-rays, physical
examination, and determination of serum alpha-fetopro-
tein and beta-hCG. This monitoring typically is per-
formed for 2 years. The frequency of these examinations
is contingent on the pathologic stage. CT scans of the
abdomen are not necessary postoperatively.
Figure 38-10 CT scan performed after chemotherapy in a patient with normal alpha
fetoprotein and beta-hCG. Pathologically the resected tumor proved to be teratoma.
POSTCHEMOTHERAPY RETROPERITONEAL
LYMPH NODE DISSECTION
Indications
Patients who present with high volume distant metastatic
germ cell cancer are typically managed with systemic
chemotherapy. After the administration of systemic
chemotherapy, if serum alpha-fetoprotein and beta-hCG
have normalized and no evidence of metastatic tumor
remains on radiographic imaging, patients are observed.
The probability of relapse in this clinical situation is low
and hence observation is reasonable. Some centers advo-
cate postchemotherapy RPLND in the absence of per-
sistent radiographic tumor if the transverse diameter of
disease in the retroperitoneum before chemotherapy was
>3 cm.19 However, the practice at Indiana University is to
observe patients with a complete clinical remission.20
If patients normalize serum markers and have persist-
ent tumor on radiographic imaging in the retroperi-
toneum, postchemotherapy RPLND is advised (Figure
38-10). Histologically, remaining tumor consists of ter-
atoma in 40% to 60% of cases, fibrosis and necrosis in
approximately 40% of cases, and persistent germ cell
cancer (or nongerm cell cancer arising in a teratoma) in
5% to 10% of cases. The surgical removal of teratoma or
cancer is therapeutic and hence the rationale for RPLND
in these clinical situations is solid. However, the surgical
648 Part VI Testis
removal of necrosis confers no survival advantage on the
patient and it would be desirable to select such patients
preoperatively so as to avoid postchemotherapy
RPLND. It is very difficult to clinically select for patients
who have only necrosis and therefore RPLND is advised
for any persistent mass. Exceptions to this rule include
those patients with pure seminoma managed with sys-
temic chemotherapy and some highly selected patients
with no teratoma in the orchiectomy specimen who
experience a dramatic response to systemic chemother-
apy. However, controversy exists in the management of
the postchemotherapy mass in pure seminoma patients.
Some advocate resection of the mass if it is >3 cm in
transverse diameter; at Indiana University these patients
are observed because of the high probability of the mass
containing fibrosis only.21,22
Rarely, postchemotherapy RPLND is recommended
in patients who have not experienced a normalization of
serum AFP or HCG. These are very highly selected
patients who have failed all systemic chemotherapy but
have a persistent retroperitoneal mass. Since beta-HCG
and/or alpha fetoprotein are elevated, germ cell cancer
remains within the mass. Postchemotherapy RPLND in
this situation is termed “desperation RPLND” but is
capable of curing such patients around 30% of the time.23
It is truly remarkable that in this situation of chemo
refractory metastatic disease surgery remains a therapeu-
tic option. Testis cancer is a unique and interesting
disease.
TECHNIQUE OF POSTCHEMOTHERAPY RPLND
Generally, postchemotherapy RPLND is a full bilateral
dissection, which includes the resection of tumor and
lymphatics from the crus of the diaphragm to the bifur-
cation of the common iliac arteries, from ureter to ureter.
The reasoning behind performing a full bilateral dissec-
tion is that mapping studies showed that the higher vol-
ume of metastasis, the greater the likelihood of bilateral
retroperitoneal disease. It is clear, however, that highly
selected patients do not require full bilateral RPLND
and that the likelihood of bilateral disease in some
patients is very low. Typically, these are patients who have
been administered so-called good risk chemotherapy and
initially presented with relatively low volume metastatic
disease to the retroperitoneum. However, generally, full
bilateral RPLND is recommended.
The type incision is contingent on the position and
size of the tumor. Depending on the individual patient,
a midline, chevron, supra 11th extra pleural approach,
or thoracoabdominal approach may be used. The same
techniques employed in low-stage disease are used in
postchemotherapy RPLND. These techniques include
the split and roll technique and in highly selected patients,
nerve sparing. However, in postchemotherapy RPLND
there is commonly a fibrotic and desmoplastic reaction in
the retroperitoneum that makes tumor and lymphatics
quite adherent to surrounding structures, such as the
aorta, the vena cava, and the renal arteries and veins.
Dissection along the great vessels should be in an extra
adventitial plane so as to not weaken these vessels, which
can lead to significant vascular problems. Surgeons who
undertake postchemotherapy RPLND should be well
versed in techniques of vascular control and repair, as this
essentially is a vascular procedure.
The “subtraction” technique was initially described by
Donohue. This technique employs the prospective dis-
section of the vessels away from tumor followed by resec-
tion of tumor and lymphatics from the posterior body
wall (Figure 38-11). Hence, after the incision is made,
the retroperitoneum is exposed by incising in the poste-
rior peritoneum from the foramen of Winslow distally
around the cecum up to the area of the inferior mesen-
teric vein. The inferior mesenteric vein is divided and the
right colon and root of the small bowel is dissected off
the retroperitoneum and retracted onto the patient’s
chest with a self-retaining retractor. Typically, tumor
does not invade the mesentery but sometimes may invade
the duodenum, which requires resection of duodenum
and subsequent repair. Fortunately, invasion of the duo-
denum is relatively rare and typically the bowel is easily
dissected onto the patient’s chest. The split maneuver is
then performed on the left renal vein and tissue is rolled
inferiorly. The anterior aspect of the aorta is identified
and the split maneuver is performed on the aorta at the
12 o’clock position from the crossing of the left renal
vein distally to the origin in the inferior mesenteric
artery. For full bilateral dissection the inferior mesen-
teric artery is typically dissected and divided between silk
Figure 38-11 The subtraction concept involves the
mobilization of great vessels away from retroperitoneal tumor
and lymphatics with a subsequent resection of tumor and
lymphatics from the posterior body wall. In this figure the
aorta is being mobilized from tumor and lymphatics.
 Chapter 38 Radical Orchiectomy and Retroperitioneal Lymph Node Dissection 649

ties. This allows the left mesocolon to be retracted later-

ally. Because testis cancer is typically a disease of young
men, the vascularity of the left colon is maintained
through collaterals and colon ischemic has not occurred
in these postchemotherapy patients. The dissection is
then carried distally along the aorta and along both com-
mon iliac arteries. The split maneuver is continued and
subsequently tissue is rolled medially and laterally off the
aorta and the common iliac arteries. Lumbar arteries are
subsequently identified and divided. Typically, three lum-
bar arteries exist on each side of the aorta and their posi-
tion is fairly predictable. Superiorly, the left gonadal vein
is divided from the left renal vein, and the left renal vein
and left renal artery are dissected from lymphatics and
tumorous tissue. Attention is then turned to the vena
cava. A similar split maneuver at the 12 o’clock position
is performed on the vena cava. The origin of the right
gonadal vein is divided and subsequently tissue, tumor,
and lymphatics are rolled medially and laterally from the
vena cava. The lumbar veins are identified, dissected, and
divided between ties. The position and size of the lumbar
veins is not as predictable as arterial lumbar anatomy.
Lymphatics and tumor are dissected from the right renal
artery as it passes over the lower portion of the crus of
the diaphragm. Similarly, the ureters are dissected later-
ally away from the lymphatics and tumorous tissue. The
gonadal vein is removed along with the cord stump,
depending on the laterality of the primary. Finally, as the
vessels and ureters have been dissected away from the
tumor and lymphatics, these lymphatic packages are dis-
sected from the posterior body wall. Typically, in full
bilateral RPLND there will be four packages: the right
paracaval, interaortocaval, left para-aortic, and interiliac.
The bowel is then placed back in anatomic position and
secured in anatomic position with running absorbable
sutures. The bowel is run to make sure there is no evi-
dence of any retractor injury, after which closure of the
abdomen is performed.
SPECIAL CONSIDERATIONS
Preoperatively, postchemotherapy RPLND patients are
given informed consent indicating that intraoperative
decisions may be necessary. The decision to resect adja-
cent organs, such as bowel or kidneys, requires intra-
operative judgment.24 A decision to resect an adjacent
organ depends on the amount of adherence to the tumor
and also the clinical situation. For instance, the thresh-
old for resecting an adjacent organ is much lower in
desperation RPLND as opposed to straightforward
RPLND performed for a patient with low volume tumor
and normal markers. However, a partial removal of
tumor is not therapeutic and surgeons performing
RPLND should have the mind set to remove all palpable
and visual tumor.
Figure 38-12 Postchemotherapy, full bilateral RPLND with
bilateral nerve sparing. Such patients maintain emission and
ejaculation and if recovery from chemotherapy is complete
may maintain fertility.
Nerve sparing is possible in some patients who
undergo postchemotherapy RPLND.25 Indeed, some of
these patients may recover fertility after recovery from
the effects of chemotherapy. Again, the decision to per-
form nerve sparing is dependent on the clinical situation
and intraoperative findings (Figure 38-12).
The complications of postchemotherapy RPLND
are generally more significant and frequent compared
to primary RPLND.26 The major source of posto-
perative morbidity relates to the lungs, as many of
these patients have received bleomycin as a part of the
chemotherapeutic regimen. Typically, an effort is made
to restrict fluids perioperatively so that if bleomycin-
induced ARDS occurs the patient is not volume over-
loaded. Other complications of postchemotherapy
RPLND include ileus, lymphatic or chylous ascites, and
other complications associated with a major surgical
procedure. Nasogastric tubes are used variably and the
hospitalization is typically more lengthy compared to
primary RPLND.
SUMMARY
Germ cell tumors of the testis are not only chemo sensi-
tive but also surgery sensitive. For optimal care of a
patient with germ cell cancer chemotherapeutic therapies
and surgical techniques are complimentary. Surgeons
who perform these procedures should be well versed in
techniques of vascular mobilization and control. Finally,
though some of these procedures may be time consum-
ing and arduous providing, excellent long-term outcomes
are possible after complete surgical removal of metastatic
tumor.
650 Part VI Testis
REFERENCES
1. Ulbright TM, Amin MB, Young RH: Tumors of the
Testis, Adnexa, Spermatic Cord, and Scrotum.
Washington, Armed Forces Institute of Pathology, 1999.
2. Thurnher S, Hricak H, Carroll PR, et al: Imaging the
testis: comparison between MR staging and us. Radiology
1988; 167:633.
3. Hinman F: The operative treatment of tumors of the
testicle with the report of thirty cases treated by
orchiectomy. JAMA 1914; 63:2009.
4. Our scrotal violation paper.
5. Kristianslund S, Fossa SD, Kjellevold K: Bilateral
malignant testicular germ cell cancer. Br J Urol 1986;
58:60.
6. Heidenreich A, Weissbach L, Holtl W, et al: Organ
sparing surgery for malignant germ cell tumor of the
testis. J Urol 2001; 166:2161.
7. Richie JP: Clinical stage I testicular cancer: the role of
modified retroperitoneal lymphadenectomy. J Urol 1990;
144:1160.
8. Donohue JP, Thornhill JA, Foster RS, et al:
Retroperitoneal lymphadenectomy for clinical stage A
testis cancer (1965 to 1989): modifications of technique
and impact on ejaculation. J Urol 1993; 149:237.
9. Nichols CR, Timmerman R, Foster RS, et al: Neoplasms
of the testis in cancer medicine. Baltimore, Williams &
Wilkins, 1997
10. Davis BE, Herr HW, Fair WR, et al: The management of
the patients with nonseminomatous germ cell tumors
of the testis with serologic disease only after orchiectomy.
J Urol 1994; 152:111.
11. Saxman SB, Nichols CR, Foster RS, et al: The
management of patients with clinical stage I
nonseminomatous testicular tumors and persistently
elevated serologic markers. J Urol 1996; 155:587.
12. Sharir S, Foster RS, Donohue JP, et al: What is the
appropriate follow-up after treatment? Semin Urol Oncol
1996; 14:45.
13. Roeleveld TA, Horenblas S, Meinhardt W, et al:
Surveillance can be the standard of cave for stage I
nonseminomatous testicular tumors and even high risk
patients. J Urol 2001; 166:2166.
14. Read G, Stenning SP, Cullen MH, et al: Medical research
council prospective study of surveillance for stage I
testicular teratoma. J Clin Oncol 1992; 10:1762.
15. Baniel J, Foster RS, Rowland RG, et al: Complications of
primary retroperitoneal lymph node dissection. J Urol
1994; 152:424.
16. Donohue JP, Zachary J, Maynard B. Distribution of nodal
metastases in nonseminomatous testis cancer. J Urol 1982;
128:315.
17. Jeweh MA, Kong YS, Goldberg SD, et al: Retroperitoneal
lymphadenectomy for testis tumor with nerve sparing for
ejaculation. J Urol 1988; 139:1220.
18. Donohue JP, Foster RS, Rowland RG, et al: Nerve-
sparing retroperitoneal lymphadenectomy with
preservation of ejaculation. J Urol 1990; 144:287.
19. Toner GC, Panicek DM, Heelan RT, et al: Adjunctive
surgery after chemotherapy for nonseminomatous germ
cell tumors: recommendations for patient selection. J Clin
Oncol 1990; 8:1683.
20. Debono DJ, Heilman DK, Einhorn LH, et al: Decision
analysis for avoiding post chemotherapy surgery in
patients with disseminated nonseminomatous germ cell
tumors. J Clin Oncol 1997; 15:1455.
21. Motzer R, Bosl G, Heelan R, et al: Residual mass: an
indication for further therapy in patients with advanced
seminoma following systemic chemotherapy. J Clin Oncol
1987; 5:1064.
22. Schutlz SM, Einhorn LH, Conces DJ, et al: Management
of post chemotherapy residual mass in patients with
advanced seminoma: Indiana University experience. J Clin
Oncol 1989; 7:1497.
23. Donohue JP, Leibovitch I, Foster RS, et al: Integration of
surgery and systemic therapy: results and principles of
integration. Semin Urol Oncol 1998; 16:65.
24. Our nephrectomy paper.
25. Wahle, GR, Foster RS, Bihrle R, et al: Nerve-sparing
retroperitoneal lymphadenectomy after primary
chemotherapy for metastatic testicular carcinoma. J Urol
1994; 152:428.
26. Baniel J, Foster RS, Rowland RG, et al: Complications of
postchemotherapy retroperitoneal lymph node dissection.
J Urol 1994; 152:424.
C H A P T E R
39 Retroperitoneal Tumors: Diagnosis,
Staging, Surgery, Management, and
Prognosis
S. Bruce Malkowicz, MD, and Victor Ferlise, MD
Retroperitoneal tumors are uncommon lesions that are
important to the urologist because they occur in our sur-
gical domain and often involve urologic organs. These
lesions often present as very large lesions, which have
been relatively indolent. Because of their rarity (0.5% to
1.0% of adult malignancies) it is important to be aware of
the systematized approach to the treatment of these
tumors. Beyond the attempt to attain complete surgical
resection, it is difficult to outline the optimal treatment
scheme for these lesions since there are few large cohorts
of patients treated in a similar fashion. Additionally,
many clinical reports have a combination of extremity, as
well as retroperitoneal lesions mixed together in the
results.
The clinical assessment of these lesions and the surgi-
cal approach to therapy is fairly well outlined and
remains the foundation of treatment. Radiation therapy
and chemotherapy for these lesions continue to evolve,
although their overall efficacy in retroperitoneal lesions
is unclear.
Primary sarcomas of the genitourinary organs are
even rarer than primary retroperitoneal sarcomas. When
radical extirpation is possible, it is usually the appropriate
option, although in some instances, such as bladder
lesions, other choices do exist. The evaluation of adju-
vant and salvage therapies for these lesions is limited. But
overall frequently with these lesions it is required to reor-
ganize and appropriately treat these lesions.
PRIMARY RETROPERITONEAL SARCOMA
Incidence and Etiology
Retroperitoneal sarcomas are rare tumors that account
for only 0.1% to 0.2% of all malignant tumors and
approximately 10% to 20% of all soft tissue sarcomas.1
Less than one-half of all retroperitoneal tumors are
retroperitoneal sarcomas. Generally, 15% to 20% of
retroperitoneal tumors are benign (e.g., lipoma). The
remainders comprise lymphomas or primary urologic
tumors.2 Approximately 500 to 1000 new cases of
retroperitoneal sarcoma are diagnosed each year.
Incidence figures on specific genitourinary sarcomas are
difficult to establish due to the rarity of such lesions.2,3
Retroperitoneal sarcomas arise most commonly in the
5th and 6th decade of life, but age incidence may span
from the 2nd to 8th decades.3,4
There is a slight male predominance but no distinct
ethnic or racial distribution. While any histologic pat-
tern may be seen at any age, rhabdomyosarcoma gener-
ally clusters in younger patients, even excluding the
pediatric population, and malignant fibrous histiocy-
toma is usually seen in older age groups. Generally, these
lesions are not associated with other conditions and a
pattern of familial transmission has not been demon-
strated. However, rare patients with neurofibromatosis
may develop malignant schwannomas at an anatomic
site.5
There is little known of the etiology of retroperitoneal
sarcomas. Radiation injury, prior trauma, and environ-
mental exposure to agents, such as dioxin and asbestos,
have been implicated.6,7 Radiation may predispose
patients to the development of sarcomas. Approximately
0.1% of patients treated with radiation therapy who sur-
vive >5 years may develop a sarcoma at that site.8 To
qualify as a postradiation sarcoma a lesion must meet spe-
cific established criteria.6 In these cases, the sarcoma has
to develop within the radiated field and prior documen-
tation stating that the area was normal must be estab-
lished. Additionally, histologic confirmation of the
diagnosis is necessary, and a latency of at least 3 years is
651
652 Part VI Testis
required. There appears to be no difference in the inci-
dence of postradiation-induced disease between those
patients treated with orthovoltage and megavoltage. The
most common postradiation tumor is the malignant
fibrous histiocytomas (MFHs) followed by osteosarcoma
and fibrosarcoma. Most of these postradiation-induced
lesions appear to be of high grade and generally have
poorer survival.8
Earlier epidemiologic studies reported that exposure
to herbicides, such as dioxin and wood preservatives, may
contribute to the development of retroperitoneal sarco-
mas.9 More recent data are mixed in its findings and may
be affected by the particular herbicide used and the
degree of dioxin contamination.10 In studies of Vietnam
era soldiers exposed to Agent Orange, no significant
association was found between the development of sarco-
mas and exposure in case control studies.11 In some
industrial studies, an association was noted between
dioxin exposure and the development of sarcomas if the
exposure was prolonged (>1 year) and the period signifi-
cant (over 20 years).12 No distinct viral or immunologic
etiologies have been proposed for the development of
retroperitoneal sarcomas.
PATHOLOGY
Retroperitoneal sarcomas arise primarily from soft tis-
sues of fibrous and adipose origin, as well as muscle,
nerve, and lymphatic tissues. These tissues are derived
from primitive mesenchyme from the mesoderm with
some contribution from neuroectoderm.13 Their loca-
tion allows for a rather long indolent preclinical course at
that time the tumor can grow to significant proportions.
This growth may result in local areas of necrosis or liq-
uefaction as the tumor outstrips its vascular supply.
In classic reviews of these lesions the common tissue
distribution in descending order is liposarcoma,
leiomyosarcoma, and fibrosarcoma followed by other
histologies.4,14–26 MFH figures much more prominently
in contemporary series; however, owing to intensive
pathologic interest in defining this disorder, many
tumors previously described as variants of fibrosarcoma
or liposarcoma have been reclassified as MFH.27,28
Therefore, fibrosarcoma has been replaced in frequency
order by this condition.
Although a well-developed understanding of the funda-
mental pathology of these lesions has not yet emerged,
evaluation of the cytogenetic alterations in many sarcomas
is beginning to suggest some molecular themes. Several of
these tumors display specific chromosomal translocations.
Although the translocations appear unique for specific
tumors [t(12;16)(q13;p11) in myxoid liposarcoma] nearly
all of these translocations result in the production of novel,
tumor-specific, chimeric, transcription factors. These fac-
tors interact with the upstream regulatory component of a
gene and can significantly affect the expression of that
gene at the messenger RNA level. The nucleic acid bind-
ing domain of the chimeric transcription factor confers
target specificity within the tissue genome, while the tran-
scription factor portion of this novel protein determines
the transactivation potential and expression level of the
target gene.29–31
Additionally, the development of extra abnormal chro-
mosomes (ring chromosomes and giant rods) involving
chromosome 12 can result in the amplification of certain
gene products, such as MDM2 and SAS. MDM2 can be
involved in p53 inactivation that can contribute to car-
cinogenesis32,33 Additionally, alterations in cell cycle reg-
ulating elements, such as CDK4, have been
demonstrated.34 Novel these insights into sarcoma
pathology may provide approaches for future therapeutic
strategies directed at these lesions.
Benign Lesions
Lipomas
Lipomas consist almost entirely of mature fat and are
uncommonly found in the retroperitoneum (Table 39-1).
They are probably the most common soft tissue tumor in
man. Most of these lesions occur superficially but they
may occur in other areas, such as the retroperitoneum.
Deep lipomas within the retroperitoneum are usually not
as well circumscribed as their superficial counterparts
and can conform to irregular spaces in this body
space.35,36 The adipocytes are normal or slightly larger in
appearance and have a well-developed vascular network.
There is very little in the way of nuclear irregularity.
Differing levels of fibrous connective tissue can be found
in these lesions. The rim of the lipocyte is reactive for S-
100 protein. While the majority of these masses are idio-
pathic in nature, they can occasionally be a manifestation
of steroid lipomatosis.
Pelvic lipomatosis while not a distinct tumor per se was
first described in 1959 as an overgrowth of fat in the
perivesical and perirectal area. It is a hyperplastic rather
Table 39-1 Benign Lesions of the Retroperitoneum
Lipoma
Pelvic lipomatosis
Myelolipoma
Leiomyoma
Ganglioneuroma
Hemangiopericytoma
Schwannoma
 Chapter 39 Retroperitoneal Tumors 653

neoplastic entity which can create a space occupying
lesion. Approximately two-thirds of patients are African-
American and women are rarely affected.37 The growth is
diffused rather than nodular and often it is difficult to dis-
tinguish it from normal adipose tissue. The condition may
be associated with cystitis glandularis.38 The general clini-
cal course is slowly progressive and may result in the need
for urinary diversion.39 Occasionally fat necrosis in these
lesions can be mistaken for sarcomatous degeneration.40
Myelolipoma
rate of metastasis depends on the degree of tumor differ-
entiation, with nearly 90% of poorly differentiated
tumors metastasizing.46–48
Significant advances in cytogenetics has allowed the
reclassification of these lesions on a molecular basis
(Table 39-2). Well-differentiated and dedifferentiated
Table 39-2 Malignant Lesions of the Retroperitoneum
and Histologic Subclassifications
Liposarcoma

This is a tumor-like growth of mature fat and bone mar- Myxoid liposarcoma
row elements. Although it usually occurs in the adrenal
gland, it can be seen as an isolated pelvic lesion.41,42 It is Well differentiated
distinct from extra-medullary hematopoietic tumors Lipoma-like
which are usually multiple and generally associated with
mild proliferative diseases and skeletal disorders. These Inflammatory
generally occur in patients older than 40 years of age and
are rarely >5 cm in size.43 They are usually found as inci- Sclerosing
dental imaging findings. The adrenal gland can create Differentiated
inferior renal displacement due to radiolucent mass.
Pathologically, it may display the features of a lipoma or Round cell
have a darker appearance if myeloid elements predomi-
nate. Adrenal myelolipoma development may be second- Pleomorphic
ary to prolonged stress and excessive stimulation with Leiomyosarcoma
adrenocorticotropic hormones.
Malignant fibrous histiocytoma (MFH)
Leiomyoma Storiform-pleomorphic
These, generally rare lesions, are seen in a distribution Myxoid MFH
that represents smooth muscle tissue in the body. They
are overwhelmingly found in the female genital tract but MFH-giant cell type
have also been reported in the urinary bladder. There are
occasional reports of these tumors in the retroperi- Inflammatory MFH
toneum, where they can grow asymptomatically to a con- Fibrosarcoma
siderable size. Leiomyomas stain positive for desmin,
which separates them from their malignant counterpart. Rhabdomyosarcoma
Extension of these lesions from the uterus into the vas-
cular system can create tumor thrombi not unlike those Embryonal
seen with renal lesions.44 Botryoid

Alveolar
Malignant Lesions
Liposarcoma Pleomorphic
Liposarcomas are among the most common of primary Spindle cell
retroperitoneal tumors that are often distinguished by
their large dimensions and range of subtypes. These Malignant hemangiopericytoma
lesions are found with their peak incidence between ages
40 and 60.45 They account for 10% to 15% of sarcomas Malignant peripheral nerve sheath tumors (malignant
and approximately 20% of these lesions arise in the schwannoma)
retroperitoneum. One unfortunate clinical feature of Synovial sarcoma
these lesions is their great tendency to recur often within
the first 6 months after surgery. The principal tissue type Angio sarcoma
is usually recapitulated at the time of recurrence. The
654 Part VI Testis
lesions are a continuum of lesions based on the genetic
abnormality of giant and ring chromosomes usually
involving chromosome 12. Gene amplification, particu-
larly MDM2 drives their pathology.49,50 Myxoid and
round cell, cell lesions (poorly differentiated myxoid) are
another continuum, which have fusion transcripts caused
by translocations in chromosomes 16 and 12 as their
principle pathologic feature. Pleomorphic liposarcomas
are rare and poorly understood.51
Unlike benign lipomas, liposarcomas may bear little
resemblance to classic fat filled structures. The gross
lesion is usually described as having a “fish flesh” appear-
ance, and while generally encapsulated, it can often
display invasive characteristics. Besides the retroperi-
toneum, these lesions arise in the deep soft tissues of the
proximal extremities. They generally present as very
large lesions when originating from the retroperi-
toneum.
Myxoid liposarcoma is the most common liposarcoma
usually occurring in the lower extremity. It accounts for
50% of sarcomas and represents a large proportion of
retroperitoneal lesions. Its peak presentation is in the
fifth decade. They display a background of stellate mes-
enchymal cells, and a prominent capillary pattern often
described as a “chicken wire” (Figure 39-1). The distinct
cell is the lipoblast that is similar to the fetal adipocyte.
These cells are noted by a lipid vacuole that scallops the
nucleus. This creates the lipoma-like appearance of these
Figure 39-1 Myxoid liposarcoma displaying myxoid vascular pattern and minimal lipoblasts
(H&E × 250).
lesions (Figure 39-2). These lesions have as their com-
mon pathology fusion proteins as mentioned previously.
Higher-grade lesions tend to demonstrate a higher num-
ber of p53 mutations.52 The round cell subtype is also
referred to as a lipoblastic variant and is distinguished by
sheets of round cells with lipoblastic differentiation.
These lesions are considered the most aggressive part of
the spectrum of myxoid lesions.
Well-differentiated liposarcomas mostly resemble
lipomas and are usually designated as low grade. They
are a common sarcoma of later life. Subvariants include
the lipoma like, inflammatory, sclerosing, and differenti-
ated. The first 3 variants are often confused with benign
processes, such as scarring or inflammation, while the
differentiated subtype is often noted in long-standing
retroperitoneal lesions and considered higher grade.
Generally, these lesions are now considered as a group
with dedifferentiated lesions since they share genetic
similarities.
Pleomorphic liposarcoma comprises 10% to 15% of
liposarcomas and are defined as a high-grade malignant
variant with very bizarre nuclei and huge lipoblasts.
Leiomyosarcoma
This tumor accounts for <10% of all soft tissue sarcomas,
yet it is a significant percentage of retroperitoneal sarco-
mas since almost half of them appear in this region. They

Figure 39-2 Myxoid liposarcoma displaying lipoblasts and myxoid matrix (250 ×).
have a 2:1 female to male presentation and generally
occur in middle age (mean age 60). The molecular
pathology of these lesions is not understood. They are
usually categorized by site of origin (soft tissue, vascular,
or superficial) although many of the soft tissue lesions are
felt to originate from smaller blood vessels. On imaging
examinations, however, they appear to have moderate to
low vascularization.
Grossly, low-grade leiomyosarcoma can be difficult to
distinguish from leiomyomas, but higher-grade lesions
display a more infiltrative flesh-like appearance.53 Low-
grade lesions are often distinguished from leiomyomas by
their chromatin pattern and the number of mitoses (>5
mitoses per high power field) present in the specimen.
Again, a continuum exists in the pathologic progression of
these smooth muscle lesions; therefore, the cut point
between benign, moderate and high grade may sometimes
be arbitrary. There is little evidence of sarcomatous degen-
eration from benign leiomyomas. The characteristic
pathologic finding of a leiomyosarcoma is malignant spin-
dle cells with “cigar”-shaped nuclei. The muscle fascicles
interweave. These tumors immunohistochemically stain
for smooth muscle myosin, vimentin, actin, and less often
for desmin. They stain negative for S-100. Ultrastructural
features include bundles of thin cyto-filaments that can
help distinguish leiomyosarcomas from other lesions.
The rare retroperitoneal variants of these tumors are
leiomyosarcomas, which originate from the great vessels.54
These occur predominantly in women. Tumors of the iliac
Chapter 39 Retroperitoneal Tumors 655
vessels usually present with lower extremity edema, while
those of the inferior vena cava can display findings consis-
tent with Budd-Chiari syndrome.55 Resection of these
lesions is recommended when anatomically feasible.
Survival, however, is usually <2 years and many inferior
vena caval tumors are unresectable because of the intra-
hepatic location of many of these lesions.
Malignant Fibrous Histiocytoma
MFH was originally described in 1963 and has come to
be the predominant histologic diagnosis for contem-
porarily reported soft tissue sarcomas.56 It was defined as
a sarcoma of primary histocytic origin, yet it is now felt
that it is a lesion derived from fibroblast differentiation.
Many pleomorphic variants of fibrosarcoma, liposar-
coma, and rhabdomyosarcoma have been reclassified
into this category. With the thorough evaluation of a
tumor specimen, distinct regions of leiomyosarcoma,
liposarcoma, and other soft tissue sarcomas may be iden-
tified. In such cases, the tumor may be defined by those
findings and the mention of associated MFH pattern.57
These lesions are most often seen on the extremities and
are less common in the retroperitoneum. Their molecu-
lar pathology is unclear. An analysis of these lesions in
the retroperitoneum suggests that many of these could
be reclassified as a dedifferentiated liposarcoma.58
Several subtypes of MFH that may coexist in a particular
lesion: storiform-pleomorphic, myxoid, giant cell, and
656 Part VI Testis
inflammatory. The angiomatoid variant is seen almost
exclusively in the extremities and trunk.59
Storiform-pleomorphic variant has a distinct but not
pathognomonic pinwheel pattern caused by the collagen
pattern of curling fascicles of cells (Figure 39-3). It is the
most common variant, usually comprising 40% to 60%
of most series. While this pattern may predominate, it
may not be present throughout the lesion in question.
Areas of collagen or foamy cells may also be encountered.
The nuclei tend to be irregular and large with discernible
mitosis. The constellation of tissue histology and nuclear
irregularities in addition to the inflammatory compo-
nents differentiate this lesion from benign entities.
Myxoid MFH make 25% of this overall tumor type. It is
often difficult to distinguish it from liposarcoma, yet the
myxoid MFH has little neutral fat but is rich in
mucopolysaccharide residing in intracytoplasmic vacuoles.
MFH giant cell type is distinguished by large benign
appearing osteoclasts. Multinucleated giant cells and the
stoma comprise the malignant components of this lesion.
If cartilage or osteoid is detected, these lesions are classi-
fied as a soft tissue osteosarcoma, which usually has a
poorer prognosis than MFH.
Inflammatory malignant fibrous histiosarcoma is rare
and often difficult to distinguish from benign processes,
such as nodular fascitis, when the presentation is truncal
or extremity. A neutrophilic infiltrate is generally noted
Figure 39-3 Storiform pattern of malignant fibrous histiocytoma (250 ×).
with matrix of reticular cells. Often an exact diagnosis is
not made until a recurrence is biopsied.
Fibrosarcoma
Fibrosarcomas are malignant tumors of fibroblast origin.
They have a range of gradation and grossly display a clas-
sic “fish flesh” pattern with hemorrhage and necrosis.
Low-grade lesions can display a herringbone—spindle-
shape histologic pattern. On retrospective review, these
lesions are often reclassified as MFH or as a desmoid
lesion (aggressive fibromatosis). Therefore, these lesions
represent a smaller proportion of primary retroperitoneal
tumors than previously reported. There is a greater inci-
dence of blood bone metastases with this tumor to the
lung and bones.60
Rhabdomyosarcoma
Rhabdomyosarcoma comprises a minor percentage of
reported retroperitoneal sarcomas, yet it is a significant
lesion in pediatric oncology, as well as pediatric tumors
associated with the genitourinary system. This topic is dealt
with extensively in Chapter 49. These lesions are generally
classified as embryonal, botryoid, alveolar, or pleomorphic,
with spindle cell more recently described as a subtype of
the embryonal form.61,62 The pathology of these lesions is

associated with chromosomal abnormalities and the fusion
transcripts associated with these translocations.
Embryonal rhabdomyosarcoma comprises more than
half of all rhabdomyosarcomas and has a large array of
anatomic locations, including the genitourinary tract
and retroperitoneum. It can range from very well-
differentiated lesions to poorly differentiated lesions and
express the multiple stages of muscle development.
Botryoid lesions are an anatomic variant of the embry-
onal type and are generally seen in hollow viscera. The
spindle cell subtype is noted for its favorable clinical
behavior.
Alveolar rhabdomyosarcoma accounts for approxi-
mately 20% of rhabdomyosarcomas and tend to occur
more frequently in the extremities. The tumor is
arranged in aggregates of round or oval cells that create
irregular spaces reminiscent of alveoli. These tissues may
be surrounded by fibrous septae, and areas of necrosis are
not uncommon.
Pleomorphic rhabdomyosarcoma comprise 5% of adult
rhabdomyosarcomas and generally occur in older patients.
It generally occurs in the extremities and is similar to
MFH in appearance. The absence of cross-striations
makes diagnosis difficult. With all rhabdomyosarcomas,
immunostaining for desmin, myoglobin, and muscle-
specific actin is useful.
Malignant Hemangiopericytoma
These rare lesions originate from pericytes, which are
unique cells that arborize about small vessels and capillar-
ies. Their contractile properties allow them to control
microvascular flow and permeability. Less than 200 of
these lesions have been described, yet 25% of them have
occurred in the retroperitoneum or pelvis. They are usu-
ally well circumscribed, and if possible complete surgical
excision is warranted. Hemangiopericytomas display a rich
vascular pattern and stain positive for factor VIIIa. They
are negative for desmin and actin. The clinical behavior of
these lesions is difficult to predict, but metastases may
develop in 20% to 50% of cases. Those lesions with >4
mitoses per 10 HPF have a worse prognosis.64,65
DIAGNOSIS
Because of their slow growth and anatomic location,
retroperitoneal tumors (usually sarcomas) tend to grow to
a large size before they are detected. In a recent series of
MFHs, the average size at diagnosis for extremity lesions
was 5 cm, while retroperitoneal lesions were 16.5 cm in
size,27 thus such lesions can often be enormous by usual
pathologic standards. While the age at presentation is dis-
tributed across a large spectrum, the majority of patients
are diagnosed with retroperitoneal tumors in the sixth
decade of life. Since the progression of symptoms is slow,
Chapter 39 Retroperitoneal Tumors 657
there is usually a lag time of 5 months from initial symp-
toms to diagnosis. The principle clinical finding is abdom-
inal mass and abdominal pain (60% to 80%).1 Many
patients also experience nausea and vomiting and weight
loss (20% to 30%). Neurologic findings are noted in 30%
of patients.66 Lower extremity edema is seen in 17% to
20% of patients, while urinary symptoms are surprisingly
rare, seen in 3% to 5% of patients in most series.
Physical examination will generally demonstrate a
protuberant abdomen that may be accompanied by an
appearance of extremity wasting. Peripheral or inguinal
adenopathy may be present although lymphadenopathy
is not usually associated with these tumors (<5%).65
Lower extremity edema and or increased abdominal wall
venous markings suggest the presence of vena caval com-
pression or obstruction.
Diagnostic imaging is imperative to delineate the
anatomic limits of the lesion and assess the integrity and
function of adjacent organs. This is most appropriately
demonstrated with cross-sectional imaging68,69 (Figure
39-4). Important issues to address with this modality are
bilateral renal function, the presence or absence of vis-
ceral metastases, and lymphadenopathy. Attention should
also be given to the axial skeleton. Tumor involvement of
neural foramina suggest unresectability of the lesion.
Germ cell tumors, which should be suspected in young
men and diagnosed through a thorough physical exami-
nation and testicular ultrasound, are usually distin-
guished on computed tomography (CT) scan from other
primary retroperitoneal lesions. This is also generally
true for lymphomas. The CT scan, however, is not
Figure 39-4 CT image demonstrates massive right-sided
liposarcoma with suggestion of internal fibrous bands
displacing the liver and right-sided retroperitoneal structures.
658 Part VI Testis
particularly diagnostic for the multiple tumor histologies
of primary retroperitoneal tumors besides a liposarcoma
with high fat content.
Earlier literature attests to the value of intravenous
urography, upper and lower gastrointestinal (GI) series,
and angiography in defining displacement and delineat-
ing function. Advances in cross-sectional imaging have
largely supplanted this multistudy approach, and the
application of magnetic resonance arteriography allows
for the delineation of vascular involvement by these
uncommon lesions. From a practical standpoint, CT and
magnetic resonance imaging (MRI) are complimentary
rather than redundant and should be employed as
needed.70 In some cases, imaging will not provide a rea-
sonable diagnosis; in that case, a biopsy prior to definitive
resection may need to be performed. Classic references
suggest that percutaneous needle biopsies of these
retroperitoneal masses are generally unsatisfactory even
when aided with imaging techniques, such as ultrasound
or CT.21 More recent sources indicate that diagnosis may
be a function of experience with these lesions and that
percutaneous biopsy or even needle aspiration may be
quite satisfactory.71,72 Due to the uncommon nature of
these lesions at most centers, it would seem appropriate
to obtain a correct tissue diagnosis with a reasonable tis-
sue sample when the diagnosis is in question.
In specific cases, an intraoperative biopsy may be indi-
cated to diagnose the lesion or differentiate it from a lym-
phoma or germ cell tumor. In those instances, care must
be taken to obtain the sample from a solid part of the
lesion and employ meticulous technique to avoid any
tumor spillage. This is accomplished through appropriate
draping of the operative field, excellent hemostasis, and
meticulous closure with covering of the wound.21
Laparoscopic sampling, while possible, would probably
not be feasible in most of these patients. Tumor specimens
should be sent for frozen section and touch preparations
prepared to establish a diagnosis. In the appropriate
patient, the serum tumor markers (beta-HCG and alpha
fetoprotein) for germ cell tumors should be obtained pre-
operatively. There are no specific serum tumor markers
for primary retroperitoneal sarcomas, yet vanillylmandelic
acid (VMA) may be elevated in the rare case of gan-
glioneuroma or extra adrenal pheochromocytoma.
STAGING
The primary determinant of staging for primary
retroperitoneal tumors is the tumor grade. The grading
is based on a G1 to G3 or G4 scale, and stage grouping
is done through the TNM system. Because of the impact
of tumor grade this is often referred to as a GTMN sys-
tem (Table 39-3).72
Tumor grading is determined by several factors,
including atypical mitosis, cytoplasmic and nuclear pleo-
morphism, and necrosis.73,74 Grade 1 lesions are denoted
by few mitoses, acellularity, minimal alterations of the
nucleus, few or absence of nucleoli. Scoring often takes
into consideration other factors, such as tumor size and
patient age. Grade 2 lesions display small to moderate
size nucleoli, moderate nuclear pleomorphism, irregular
chromatin distribution, and a moderate amount mitosis.
Areas of necrosis may be noted in the microscopic field.
Grade 3 lesions are characterized by numerous mitoses,
gross chromatin clumping, moderate or considerable
necrosis, and variation in nuclear morphology. The dis-
tinction between T1 and T2 lesions is made at 5 cm.
Clinical staging beyond physical examination should
also include a bone scan and a dedicated chest CT, as well
as an abdominal/retroperitoneal CT scan with attention to
the liver. Bilateral renal function must be determined pre-
operatively. In experienced hands, cross-sectional scanning
alone may provide enough local staging information. Since
these lesions are rare, however, any question regarding the
extent of contiguous organ involvement should be
answered by the appropriate confirmatory imaging test
(e.g., upper GI series). Laboratory tests may provide some
diagnostic discrimination, yet generally add little to a stag-
ing evaluation. Detailed evaluation of sarcomas can be
found in the NCCN sarcoma practice guidelines.75
SURGERY
Extirpative surgery is the principle and most effective
form of therapy for primary retroperitoneal tumors.
Preoperative planing to assess the extent of the disease is
essential since successful surgery is defined by complete
excision of the mass with adequate margins of normal tis-
sue. A complete resection rate between 38% and 78%
(average 55%) is reported in many large series14–26,75,76
(Table 39-4). In several large series of retroperitoneal
sarcomas, univariate and multivariate analyses of inde-
pendent treatment variables have been performed. In
over 280 patients, a complete resection was the single
most important positive predictive feature.77
Intermediate or high tumor grade is a strong negative
feature.20,78–80 In most reported series, intermediate and
high-grade lesions comprise 55% to 70% of the tumors
described. Tumor histology, tumor size, or patient age
were not significant factors in survival in multivariable
analysis.81,82 Therefore, carefully planned and skillfully
executed surgical therapy is critical for any chance at
long-term success.83,84
Operative Technique
The classic approach for surgery on these lesions is
described through long midline incisions or chevron
incisions. The tumors are usually right-sided or left-
sided; however, few actually rising from the midline. A
full flank position, such as that employed for renal stone
surgery, is discouraged since it can limit exposure to the
 Chapter 39 Retroperitoneal Tumors 659

full retroperitoneum or abdomen.1,21 Since these lesions
are not compartmentalized by the retroperitoneum, they
can cross many anatomic boundaries. It is important,
therefore, to determine the potential for resectability,
beyond that presupposed through imaging. This is first
accomplished by developing a subadventitial plane along
the lateral borders of the great vessels extending dorsally
between the spine and psoas and quadratus muscles
(Figure 39-5). In this manner one can determine if the
tumor has spread along a spinal nerve route and into the
spinal foramina or even further into the spinal cord. If
this is the case, the tumor is generally considered unre-

Table 39-3 American Joint Commission on Cancer

GTNM Classification and Stage Grouping of Soft
Tissue Sarcomas
Tumor grade

G1 Well differentiated

G2 Moderately differentiated

G3 Poorly differentiated

G4 Undifferentiated

Primary tumor

T1 Tumor ≤ 5 cm in greatest diameter

T1a Superficial tumor

T1b Deep tumor

T2 Tumor > 5 cm in greatest diameter

T2a Superficial tumor

T2b Deep tumor

Regional lymph node involvement

N0 No known metastasis

N1 Verified metastases to lymph nodes

Distant metastasis

M0 No known distant metastasis

M1 Known distant metastasis

Stage grouping

Stage 1A Low grade, small (G1-2, T1a or b, N0, M0)

Stage 1B Low grade, large, superficial (G1-2, T2a, N0, M0)

Stage IIA Low grade, large, deep (G1-2, T2b, N0, M0)

Stage IIB High grade, small (G3-4, T1b.N0, M0)

Stage IIC High grade, large, superficial G3-4, T2a, N0, M0

Stage III High grade, large, deep G3-4, T2b, N0, M0

Stage IV Nodal or distant metastases Any G, any T, N1, M0 or any G, any T, any N, M1

Continued
660 Part VI Testis

Table 39-3—cont’d
DEFINITIONS
Clinical Pathologic Primary Tumor (T)
Notes
■ ■ TX Primary tumor cannot be assessed 1. Superficial tumor is located
exclusively above the superficial fascia
■ ■ T0 No evidence of primary tumor without invasion of the fascia; deep
tumor is located either exclusively
■ ■ T1 Tumor 5 cm or less in greatest dimension beneath the superficial fascia, superficial
to the fascia with invasion of or through
■ ■ T1a superficial tumor(1) the fascia, or both superficial yet beneath
the fascia. Retroperitoneal, mediastinal,
■ ■ T1b deep tumor and pelvic sarcomas are classified as deep
tumors.
■ ■ T2 Tumor more than 5 cm in greatest dimension 2. Ewing’s sarcoma is classified as G4.

■ ■ T2a superficial tumor(1)

■ ■ T2b deep tumor

Regional lymph nodes (N)

■ ■ NX Regional lymph nodes cannot be assessed

■ ■ N0 No regional lymph node metastasis

■ ■ N1 Regional lymph node metastasis

Distant metastasis (M)

■ ■ MX Distant metastasis cannot be assessed

■ ■ M0 No distant metastasis

■ ■ M1 Distant metastasis

Biopsy of metastatic site performed ■ Y ■ N

Source of pathologic metastatic specimen __________________

Stage Grouping

■ ■ I T1a N0 M0 G1-2 G1 Low

T1b N0 M0 G1-2 G1 Low

T2a N0 M0 G1-2 G1 Low

T2b N0 M0 G1-2 G1 Low

■ ■ II T1a N0 M0 G3-4 G2-3 High

T1b N0 M0 G3-4 G2-3 High

T2a N0 M0 G3-4 G2-3 High

■ ■ III T2b N0 M0 G3-4 G2-3 High

■ ■ IV Any T N1 M0 Any G Any G High or low

Any T N0 M1 Any G Any G High or low

 Chapter 39 Retroperitoneal Tumors 661

Table 39-3—cont’d
Histologic Grade (G) Notes

■ GX Grade cannot be assessed Additional Descriptors

Lymphatic vessel invasion (L)

■ G1 Well differentiated
LX Lymphatic vessel invasion cannot be assessed
■ G2 Moderately differentiated L0 No lymphatic vessel invasion
L1 Lymphatic vessel invasion
■ G3 Poorly differentiated
Venous Invasion (V)
■ G4 Poorly differentiated or
undifferentiated (four-tiered VX Venous invasion cannot be assessed
systems only)(2) V0 No venous invasion
V1 Microscopic venous invasion
V2 Macroscopic venous invasion
Residual Tumor (R)

■ RX Presence of residual tumor cannot be

assessed

■ R0 No residual tumor

■ R1 Microscopic residual tumor

■ R2 Macroscopic residual tumor

Table 39-4 Pooled Data on Complete Versus Partial Resection

No. of Resection (No. %) Mean Survival (Months) Complete Resection

Series Patients Complete Partial Complete Partial 5–Yr Survival (%)

Dalton et al.19 116 63/54 25/21 72 13 54

Jacques et al.20 86 43/50 34/39.5 65 28 74

McGrath et al.18 47 18/38 18/38 120 24 70

Glenn et al.22 50 37/74 8/16 40 — 38

Karakouis et al.24 68 27/40 7/10 84 48 64

Kilkeny et al.26 63 49/78 10/16 41 9 48

Zornig et al.23 51 30/59 21/41 60 — 35

TOTAL 481 267/55.5 123/25.6 70.3 24.4 54.7

sectable. It has also been suggested that the lateral inci-
sion of the peritoneum into the deep body wall is impor-
tant to explore on a level posterior to the spinous
processes (see Figure 39-5). If the operator’s fingers can
be bi-manually palpated, this sarcoma is considered
resectable.
It is imperative in the preoperative period that both
the patient and the surgeon realize the potential need for
en bloc resection of affected organs. This can include
vascular structures, as well as the kidney, portion of the
diaphragm, liver, stomach, gall bladder, spleen, pancreas,
and gut. In review of several series, up to 68% of opera-
tions required resection of an adjacent organ to insure
adequate negative margins. The most frequently resected
organs are listed in decreasing order in (Table 39-5). A
recent review reported that 20% of patients undergoing
surgery for a retroperitoneal sarcoma required nephrec-
tomy. The majority of them (72%) underwent this dur-
ing their initial resection. The usual reason for
nephrectomy was total encasement of the organ, fol-
lowed by dense adherence to the kidney, and less often
direct invasion of the renal unit.85 While a Dacron graft
can be employed to replace a portion of resected aorta,
there is debate among surgeons with regard to the need
for venous reconstruction. Many feel that the venous col-
laterals that develop secondary to vena caval compression
662 Part VI Testis
Determination of resectability
Operative maneuvers
1 acceptable. An operative mortality of 2% to 7% with
2 morbidity rates of 6% to 25% is the norm. Hemorrhage,
IVC A
o
2
Psoas major muscle
Quadratus lumbarum muscle
Vertebra Spinal cord
Figure 39-5 Transabdominal approach to determine
resectability of a primary retroperitoneal sarcoma. Pertinent
maneuvers consist of intraabdominal assessment of visceral
and vascular contents and retroperitoneal assessment of
attachment to musculoskeletal and spinous structures.
Table 39-5 Organs Sacrificed During Complete
Resection of Sarcoma
Organ Frequency of Resection (%)
Kidney 32–46
Colon 25
Adrenal gland 18
Pancreas 15
Spleen 10
are adequate to allow for appropriate drainage from oth-
erwise vascularly compromised organs. When bowel via-
bility is questionable, it should be resected if possible.
Although many visceral organs can be resected, unre-
sectability is usually denoted by sarcomatosis, nerve root
involvement, pelvic sidewall involvement, malignant
ascites, or the presence of distant metastasis.1,21
When defining the operative field it is often necessary
to release multiple intraabdominal adhesions. This must
be performed meticulously since an enterotomy and sub-
sequent fistula formation can cause major morbidity.
Tactile, as well as visual perceptions, aids in avoiding vio-
lation of the bowel. In addition, the use of sharp curved
Mayo scissors rather than Metzenbaum scissors may aid
in avoiding this complication. During the dissection of a
large tumor mass, it is often necessary to shift the loca-
tion of the dissection when one particular area becomes
difficult due to concerns of a clear margin or the poten-
tial for vascular damage. A centripetal dissection allows
one to dissect those areas that are amenable to dissection,
and which in turn may free up a previously more con-
strained area of the operative field.86 Morbidity and mor-
tality rates for contemporary surgical series are
intra-abdominal abscess, and enterocutaneous fistula are
the most commonly described complications.
Another surgical technique is the modified thoracoab-
dominal approach, which has been developed and popu-
larized by Skinner. Those familiar with the technique feel
that it allows maximum exposure to the posterior
retroperitoneum, which is often a difficult area to assess
through a midline incision. Additionally, it provides
access and control to the ipsilateral great vessels above
the diaphragm. Whether a left- or right-sided procedure
is performed, excellent exposure can be developed in the
contralateral retroperitoneal region without difficulty. A
technique described here is a summary of Skinner’s
approach.87
With the thoracoabdominal approach, patient posi-
tioning is critical. The patient is not placed in a “pure
flank” position, similar to that used in stone surgery.
Rather, a modified flank position is employed. The con-
tralateral leg is flexed 90 degrees, and the hip is flexed
approximately 30 degrees. The ipsilateral shoulder and
chest is placed 20 degrees off the horizontal with the arm
brought across the chest and placed in an adjustable
armrest. The pelvis is at most rotated 10 degrees off the
horizontal, and this position is maintained with a role
sheet. The table is fully hyperextended with the break
located above the iliac crest. The patient is secured with
wide adhesive tape, and the ipsilateral leg is supported on
a pillow.
A mid-axillary incision is carried in the mid-axillary
line from the 8th, 9th, or 10th rib. The height of this
incision is based on the size of the primary lesion. It
extends over the rib and costochondral junction into the
epigastrium and then proceeds inferiorly as a midline
incision into the pelvis. The rib is resected subpe-
riosteally and the costochondral junction is divided. The
rectus muscle is divided and retracted laterally. In most
instances, the peritoneum will be opened, and the bowel
contents mobilized superiorly. This mobilization is based
on the superior mesenteric artery pedicle. It is important
that this artery be identified initially, and care is taken not
to traumatize it. In many instances, the inferior mesen-
teric artery may have to be resected. Most care should be
taken to maintain the marginal artery. In most instances,
a large bowel section will be avoided, yet if there is a
question of viability at the end of the case, any suspect
area of bowel should be resected. Vena cava obstruction
may be associated with any right-sided lesions, and if this
is the case, it is usually best to resect the vena cava en bloc
with removal of the tumor. Often, a right nephrectomy

may also be required. If this maneuver is performed, it is
best to maintain vascular connection between the vena
cava and left renal vein to decrease the possibility of acute
or long-term renal insufficiency.
In general, the aorta can be dissected free of large
retroperitoneal tumors but rarely may require replace-
ment with a Dacron graft. During dissection or mobi-
lization of the great vessels, care must be taken to control
the lumbar vessels with ligation and division to avoid
problematic bleeding. While the distal vessels may be
controlled with hemoclips, it is appropriate to ligate the
lumbar vessel at its origin on its great vessel. In the case
of significant bleeding, the vessel tear can be controlled
with the use of a Judd or Allis clamp. While the possibil-
ity of spinal devascularization exists, it is very uncommon
due to the significant collateral blood supply to the spine
from the artery of the Adamkiewicz. In younger patients,
the potential for ejaculatory dysfunction is significant.
SURGICAL OUTCOME
The classic overall survival for patients presenting with
retroperitoneal sarcomas is poor. In a multiinstitutional
review, the 2-, 5-, and 10-year mean survivals for patients
with this disease were 56%, 34%, and 18%, respec-
tively.21 Recent series suggest 2-year survivals of over
70% and 5-year survivals of 50% to 60% in patients
without metastases.88,89 The effective surgical manage-
ment of retroperitoneal tumors has been limited by their
size at presentation that often results in secondary organ
involvement. This has a poor impact on the ability to
achieve negative surgical margins even with the resection
of adjacent organs. Historically, a complete surgical
resection with negative margins was achieved in 50% to
60% of patients. The more recent series demonstrate
complete resection rates in the 60% to 80% range, which
may be due to improvements in imaging, preoperative
planning, and surgical technique.
Those patients who achieve a complete resection dis-
play superior survival to those patients with incomplete
resection of their tumors (see Table 39-4). This is also
supported in laboratory models.90 In an analysis of
microscopic margins, however, positive margins at this
level of pathologic resolution had little impact on recur-
rence-free survival.91
On the average, the 5-year survival of patients with
completely resected tumors is 54% compared to 17% for
incomplete resections at 10 years, this difference is 45%
to 17%. Thus, a nearly 40% survival advantage is seen at
5 to 10 years in those patients with complete surgical
resection of their lesion (Figure 39-6). Tumor recurrence
after complete surgical resection, however, is significant.
There is a 72% chance of local recurrence at 5 years and
a 90% chance of recurrence at 10 years in most series.
These data imply fairly poor survival at 15 years.21
Chapter 39 Retroperitoneal Tumors 663
Proportion Surviving
1.0
81
0.8
0.6
54
45
0.4 34
0.2
17
8
0.0
0 2 5 10
Years
Complete Resection Incomplete Resection
Figure 39-6 Patient survival as a function of completeness of
the surgical resection. The data represent x complete
resections and y incomplete resections from collected series.
Reoperative surgery for the treatment of recurrent
retroperitoneal sarcoma can be of value. Over 60% of
patients may be experienced a complete resection.88 In
one series, 30 patients with a previous complete resection
of the primary lesion experienced local tumor recurrence
at a mean interval of 23 months. Sixty percent of these
patients were rendered free of disease after reoperative
surgery. To accomplish this, 33% of these patients
required the resection of adjacent viscera. Those patients
who achieved a complete resection with a second opera-
tion had a 33-month median survival compared to a 14-
month median survival in those patients who did not
experience a second complete resection.92
The role of subtotal resection has never been clearly
established, yet some data suggest that this may have
some positive value compared to palliative or debulking
surgery. The argument for the possible value of incom-
plete resection has been made the management of
liposarcomas. In a series of 55 patients, 75% received
symptom relief from their surgery and partial resection
compared with biopsy or exploration alone had a signifi-
cant impact on increased survival (26 months versus 4
months).93 In another report, 22 patients with complete
resection of tumor displayed a similar median survival to
15 patients with subtotal resection (median survival >120
months) compared to those only having a partial pallia-
tive resection or exploration (12 to 20 months).94 An
aggressive surgical approach in cases where near com-
plete resection can be obtained has also been advocated
by others.24
There is no set protocol for the postoperative monitor-
ing of patients with primary retroperitoneal sarcoma, but
recommendations can be made given the rapidity of recur-
rence, the advantage of reresection, and the lethality of
this condition. It would be appropriate to perform an
abdominal CT scan, chest x-ray, and biochemistry profile
with complete blood count (CBC) every 6 months. A
664 Part VI Testis
Proportion Surviving
1.0
83
0.8 74
0.6
54 42
0.4
0.2 24
11
0.0
0 2 5 10
Years
G 2,3 Tumors G 1 Tumors
Figure 39-7 Patients’ survival as a function of tumor grade in
cases of primary retroperitoneal sarcoma. The data represent
50 low-grade and 80 high-grade tumors from collected
series.
lengthening of this follow-up interval should be consid-
ered only after 5 years. Data support the concept that close
follow-up allows for early detection less bulky recurrences
that allow for more successful salvage surgery.95
The effect of tumor grade on patient survival cannot
be underestimated. Low-grade lesions display a 50% sur-
vival advantage over intermediate- and high-grade
lesions at 5 years (74% to 24%) and a 30% survival at 10
years (42% to 11%) (Figure 39-7). This is demonstrated
even in the face of total surgical resection. While aggres-
sive surgical resection of retroperitoneal sarcoma serves
as the foundation of therapy for this condition, the high
local recurrence rate and eventual mortality from this
disease has prompted the exploration of adjuvant thera-
peutic modalities.
RADIATION THERAPY
The role of radiation therapy in the treatment of soft
tissue sarcomas has been established by the advances in
extremity lesions. Unfortunately, the radiosensitivity of
adjacent soft visceral organs in the retroperitoneum has
limited the direct transfer of such techniques to lesions
in this region.96,97 While extremity tumors are treated
in the dose range of 60 to 64 Gy, most series of
retroperitoneal lesions are treated in the 40- to 55-Gy
range.
In general, one sees a decrease in local recurrences
compared to historic controls at the cost of increased gas-
trointestinal complications (nausea, vomiting, and enteri-
tis). It is difficult to demonstrate a significant
improvement in survival, and on multivariable analysis
the completeness of the surgical resection and the grade
of the tumor have the most significant bearing on out-
comes.98–100 Intraoperative radiation therapy (IORT) has
been employed as a surgical adjuvant in several small
series. It is associated with a lower rate of local recur-
rences and fewer GI complications, yet peripheral neu-
ropathies are more frequent, and it is difficult to
demonstrate a survival advantage with its use.100–104
Combined modality therapy with external beam and
radiation with surgery and IORT (15 Gy) is being
explored. It appears that such intensive regimens are tol-
erable up to 50.4 Gy of EBRT.105 Additionally, the use of
brachytherapy postoperatively in primary or recurrent
disease has been explored using different techniques up
to 32 Gy.106,107 These techniques are feasible yet signifi-
cant side effects can be encountered when they are
applied to the upper abdomen. Newer radiation delivery
techniques, such as intensity modulated radiation therapy
(IMRT), are being explored for the treatment of these
lesions.108,109
CHEMOTHERAPY
Multimodal therapy for extremity sarcoma has provided
an inference for the role of chemotherapy in retroperi-
toneal lesions. The majority of large-scale chemotherapy
trials, however, comprise patients with extremity disease,
so these findings may not be directly applicable. Overall,
the argument for adjuvant therapy seems reasonable
since the potential for distant recurrence is significant
with retroperitoneal lesions. The data in this regard have
been somewhat contradictory, yet a metaanalysis of these
studies suggests a slight advantage for the use of adjuvant
doxorubicin therapy to decrease the risk of death and
recurrence in patients with high-grade extremity
lesions.99 Such therapy is associated with toxicity, how-
ever, and has not gained considerable acceptance for
retroperitoneal lesions.110
Metastatic Disease
Approximately 20% of patients with soft tissue retroperi-
toneal sarcoma will present with metastatic disease.
Those patients who recur after treatment for localized
disease generally do so by 60 months.111,112 Those
patients who recur demonstrate disease at multiple sites
(47%) or display a local recurrence (30%). Isolated pul-
monary lesions occur in approximately 20% of patients.
Three-year survival in patients undergoing complete
excision of lung-only lesions is 38%.113
Doxorubicin is the foundation for chemotherapy in
advanced sarcoma.114,115 The general response rate is
20% to 25%, but sustained complete responses are
uncommon. Other classic agents demonstrating activity
include dacarbazine, ifosfamide, methotrexate, and
cyclophosphamide. In several phase III studies, however,
combination treatments were not superior to single-
agent doxorubicin.116–118 Other phase III studies have
not demonstrated superior response, yet they do show
 Chapter 39 Retroperitoneal Tumors 665

significant increased toxicity (myelosuppression and car- Table 39-6 Common Genitourinary Sarcomas in
diac) with the addition of other agents.119 Another com- Decreasing Order of Frequency
bination regimen of mesna, adriamycin (doxorubicin), Renal
ifosfamide, and dacarbazine (MAID) has been successful
in neoadjuvant programs for extremity sarcomas com- Leiomyosarcoma
pared to historic controls, yet less data are available with
regard to other soft tissue sites.120,121 In general, salvage Liposarcoma
therapy for patients has been associated with poor Malignant fibrous histiocytoma
responses and little in the way of quality of life advan-
tages.121 Hemangiopericytoma
More recently, gemcitabine has been investigated as
an initial agent in advanced disease and for salvage ther- Rhabdomyosarcoma
apy. As a single agent the results have been disappointing Osteogenic sarcoma
with response rates below 5% in either setting.122–124
The combination of gemcitabine and docetaxel in Bladder
patients with unresectable leiomyosarcoma, however,
demonstrated a 10% complete response and an overall Leiomyosarcoma
response of 53%. It was felt to be a tolerable and active
Rhabdomyosarcoma
combination in treated and untreated patients.125
Disseminated intraperitoneal spread of disease is very Osteogenic sarcoma
difficult to treat. A novel approach is the application of
photodynamic therapy.126 In a preliminary report, Liposarcoma
patients underwent surgical debulking and were treated
Malignant fibrous histiocytoma
with photofrin and laser light. Of initial 11 patients, 5
demonstrated no evidence of disease over a range of 2 to Fibrosarcoma
17 months. The advancement of such technologies and
the implementation of small molecule therapy may pro- Prostate
vide improved outcomes for such patients in the future.
Leiomyosarcoma

ADULT URINARY TRACT SARCOMA Rhabdomyosarcoma

Primary sarcomas arising from the genitourinary system Fibrosarcoma

are extremely rare lesions overall and comprise only 1%
Spindle cell sarcoma
to 2% of urologic tumors in adults. Only 800 to 1000 such
tumors have been described from multiple genitourinary Spermatic cord, testis, paratestis
sites. Although many small clusters go unreported, prac-
tice principles in the diagnosis and treatment of these Leiomyosarcoma
tumors must therefore be derived from anecdotal pooled
Rhabdomyosarcoma
data.127,128 General treatment principles are also extrapo-
lated and applied from the clinical experience with pri- Liposarcoma
mary retroperitoneal sarcomas. These lesions behave
differently from pediatric genitourinary sarcomas, Fibrosarcoma
notably pediatric rhabdomyosarcoma, which is discussed
Malignant fibrous histiocytoma
separately in Chapter 49. Thus, treatment strategies,
especially for advanced disease, tend to be empiric.
Despite their rarity, the collective data regarding sar-
RENAL SARCOMA
comas of the genitourinary tract provide significant data
with regard to clinical presentation and clinical outcome Approximately 1% to 2% of kidney tumors are true renal
that provide rough guidelines for treatment when these sarcomas. This excludes the sarcomatoid variant of renal
uncommon lesions are encountered. The most common cell carcinoma (RCC) that demonstrates spindle cells or
sarcomatous lesions of the urinary system originate in the giant cells and a rapidly progressive clinical course. The
spermatic cord and paratesticular structures, which are most frequent histologic subtypes of sarcoma encoun-
not strictly speaking retroperitoneal. In decreasing inci- tered in the kidney are listed in Table 39-6.
dence, sarcomas of the kidney, the bladder, and the Leiomyosarcoma is the most common renal sarcoma,
prostate are encountered (Table 39-6). comprising 30% to 40% of most reported series.
666 Part VI Testis
Liposarcoma and MFH are then encountered in near
equal frequency. Other histologies include rhabdosar-
coma, osteosarcoma, and hemangiopericytoma.129–132
Renal sarcoma usually presents at a slightly younger age
than the average patient with RCC with pain and flank
mass as the common symptoms. Hematuria is seen less
frequently with classic RCC. They have no distinguish-
ing imaging characteristics but tend to be hypervascular.
When small, they are hard to distinguish from RCC, but
hypovascularity combined with contiguous tumor spread
may suggest sarcoma.
Treatment for renal sarcoma is similar to RCC,
namely, wide surgical excision. The principles for a stan-
dard radical nephrectomy conform to those for sarcoma
surgery, and the modified thoracoabdominal approach is
particularly suited to large lesions. As is the case in all soft
tissue sarcomas, tumor size reflected in complete
resectability, and grades are the major determinants of
clinical outcome. There are no data to support
chemotherapy or radiation in the adjuvant setting, and it
is unlikely that these modalities will confer a survival
benefit for patients with advanced disease. The overall 5-
year survival for these patients is approximately 30%.
Those individuals with liposarcoma or hemangiopericy-
toma perform much better than patients with
leiomyosarcoma. The survival rate at 5 years is in the
80% to 90% range for liposarcoma yet <50% for
leiomyosarcoma. This more than likely a reflection of
tumor grade at presentation.127,128,131
Patients with renal sarcoma should adhere to close
postoperative follow-up, including more frequent evalu-
ation of the renal bed, since local recurrence is the rule
rather than the exception with sarcomas. Therapy for
advanced disease usually consists of single agent doxoru-
bicin-based chemotherapy or multiagent doxorubicin-
based chemotherapy. While responses may be seen,
sustained complete responses are not reported.
URINARY BLADDER
In the adult, primary urinary bladder sarcomas are very
rare with roughly 200 cases reported in the medical liter-
ature.127,128 They comprise approximately 0.1% to 0.2%
of all primary bladder tumors, yet present in a manner
similar to typical bladder tumors. Most patients display
hematuria, dysuria, or urinary frequency as the present-
ing signs and symptoms of their lesions. On imaging
studies they can display upper urinary tract obstruction
or filling defects of the bladder.131–135 The diagnosis can
usually be made by transurethral resection of the bladder
tumor. Pelvic and abdominal imaging with CT or MRI is
useful in perioperative staging. The most common tumor
histology in adult bladder sarcoma is leiomyosarcoma,
followed by rhabdomyosarcoma. These lesions of muscle
origin comprise 70% to 80% of all adult bladder sarco-
mas. Liposarcoma, MFH, and osteosarcoma account for
<5% each of bladder sarcoma.136,137 A recent report also
collected a cohort of 10 angiosarcomas the majority of
which responded poorly to therapy (Engel). The devel-
opment of some bladder sarcomas has been attributed to
the secondary effects of radiation therapy or chemother-
apy exposure.138,139
The treatment of bladder sarcoma results in excep-
tionally good outcomes for a tumor type generally
expected to perform poorly. Cystectomy and diversion in
combination with other treatment modalities can result
in 5-year disease-free survivals of 62%.140 Smaller,
selected cystectomy series have demonstrated similar
findings.136 Significant long-term disease-free survival
rates have also been achieved with less aggressive surgery.
In an earlier series from Memorial Sloan Kettering
Cancer Center, 14 of 15 patients with resectable bladder
tumors displayed no evidence of disease 1 to 9 years after
surgery, this included 4 patients who underwent partial
cystectomy.127 In a more recent series from the same
institution, 7 of 10 patients with bladder sarcoma are
alive without evidence of disease with over 5 years of fol-
low-up, including 2 patients treated only with
transurethral resection of 2 cm leiomyosarcomas of the
bladder.131 Other series have demonstrated that low-
grade lesions can respond reasonably well to organ-spar-
ing therapy.141 These data suggest that bladder
preservation is a reasonable option in the treatment of
this disease especially in the case of leiomyosarcoma.
Partial cystectomy is a reasonable option if wide (3 to 4
cm) margins can be obtained. Involvement of the trigone
or more distal structures, however, would suggest total
cystectomy and continent reconstruction as an appropri-
ate option. Although the data are anecdotal, the use of
chemotherapy and external beam radiation may be
appropriate in patients with bladder sarcoma at high risk
for local or distant recurrence. Overall 5-year survival for
patients with bladder sarcomas is 60%. Those patients
with adult rhabdomyosarcoma of the bladder have a
poorer prognosis than their pediatric counterparts and
adults with leiomyosarcoma. The 5-year survival for
patients with adult rhabdomyosarcoma is approximately
30%. Angio sarcoma is a very rare bladder lesion (10
reported cases) that is highly progressive. It responds best
to multimodal oncologic therapy.142
PROSTATE
Approximately 150 reported cases of primary sarcoma of
the prostate have been reported.127,128,135,143,144 Given the
estimated yearly incidence of prostate cancer at over
220,000 cases, these lesions comprise <0.1% of primary
prostate tumors. The majority of prostate sarcomas is
either leiomyosarcoma (50%) or rhabdomyosarcoma
(30%). The remainders of tumors are distributed over

multiple tissue types. In general, patients with prostate sar-
coma tend to present somewhat younger than the typical
patient with adenocarcinoma of the prostate. The most
common presenting symptom is bladder outlet obstruc-
tion and dysuria. A combination of symptoms and a palpa-
ble mass (often smooth) on physical examination lead to
endoscopic evaluation and needle biopsy diagnosis. The
majority of patients present with regional or local disease,
while 10% to 20% of patients may have metastases.
Cystoprostatectomy has generally been the treatment
of choice for these tumors since most are large at the time
of diagnosis, also because usually defined tissue planes
may be obliterated by these tumors. In the case of exten-
sive retroperitoneal disease it may be preferable to per-
form a total pelvic exenteration to achieve complete local
control. Since the potential for total continent recon-
struction of both the urinary and lower GI tract exists,
this aggressive approach is a more favorable option than
double ostomies or palliative therapy.145 As in the case of
bladder sarcoma, a pelvic lymph node dissection should
accompany the exenterative procedure since nodal
involvement, especially in rhabdomyosarcoma, can exist.
In general, patients with prostate sarcoma have an
unfavorable outcome. The average 5-year survival is
approximately 25%. Patients with leiomyosarcoma have
a 40% 5-year survival, while those with rhabdomyosar-
coma have a 0% to 10% 5-year survival. A recent series
of these lesions demonstrated a 3- and 5-year survival of
43% and 38%. The factors most associated with a good
outcome were the absence of metastatic disease at pres-
entation and the finding of negative surgical margins.146
It is difficult to assess the value of combined adjuvant
therapy, but in the case of high-grade or extensive dis-
ease, a doxorubicin-based protocol and the addition of
external beam radiation would be appropriate.
PARATESTICULAR TUMORS
The most common primary genitourinary sarcomas are
those of the paratestis, spermatic cord, and testis
proper.127,128,131,147,148 Almost 300 cases of such lesions
have been reported. The majority of these lesions from
muscle origin and are either rhabdomyosarcoma or
leiomyosarcoma (50% of tumors). Liposarcomas and
fibrosarcomas are commonly seen, along with a distribu-
tion of other rare lesions. The most common benign
tumor of the spermatic cord, however, is a lipoma, while
the most common benign lesion of the paratesticular
region is an adenomatoid tumor.
These lesions segregate into an adolescent-early
adult and older age group (over 50) with the majority of
rhabdomyosarcomas concentrated in the younger
patients. Rhabdomyosarcomas also have a greater
predilection for occurring in an intrascrotal area.
Liposarcoma and leiomyosarcoma generally occur in
Chapter 39 Retroperitoneal Tumors 667
older age groups and can occur anywhere along the
inguinal to paratesticular region and are often found in
the inguinal region. It is unusual to have a sarcoma in
the testicular parenchyma.
Patients with paratesticular sarcomas have a firm pal-
pable mass in the scrotum or the spermatic cord. Any
lesions of the scrotal contents should be evaluated with
ultrasound and all solid lesions should be classically
treated with inguinal exploration biopsy and radical
orchiectomy if indicated. Transscrotal exploration should
not be performed. Further therapy for these is dictated
by tissue histology. Postoperative radiation therapy can
be administered especially if it appears that one has not
achieved negative margins after the initial surgery.149
Rhabdomyosarcoma and leiomyosarcoma generally
perform poorly. It is necessary to assess these patients for
the presence of metastatic disease, particularly retroperi-
toneal lymph node involvement. In the absence of gross
disease, a retroperitoneal lymph node dissection is appro-
priate, especially in the case of rhabdomyosarcoma where
the incidence of positive retroperitoneal nodes may be
>50%.149–151 It has also been advocated for MFH and
fibrosarcomas of the cord. If gross nodal or distant metasta-
tic disease is detected, doxorubicin-based chemotherapy is
the classic treatment for advanced disease and is generally
employed in the presence of microscopic metastasis. Those
patients with liposarcoma generally show nearly complete
cure through local excision.151 Ninety percent of patients
may be treated in this fashion, but local recurrence have
been reported and can result in fatalities.
True primary sarcoma of the testis is exceedingly rare
with only 16 cases reported in the literature the mean
patient age was 32 with a range from 3 to 86. The major-
ity of lesions were leiomyosarcomas, and spindle cell sar-
comas were the next most frequent histology.85
Carcinosarcoma is a very rare lesion. It is a malignant
mixed tumor with sarcomatous and carcinomatous com-
ponents. There are <100 reported cases, and the majority
of these affect the urinary bladder.152,153 It appears that
these lesions have a clonal origin similar to bladder
tumors but that additional unique changes lead to this
aggressive phenotype.154 This has been reported in the
prostate and kidney. Patient outcomes are uniformly
poor, and treatment for this disease beyond radical sur-
gery is anecdotal.
SUMMARY
Genitourinary sarcomas are exceedingly rare lesions,
which are not amenable to controlled clinical trials.
Precise standards for clinical care are therefore difficult
to establish. While the management of renal sarcomas
differs little from the classic management of renal
tumors, it is interesting to note that bladder sarcoma is a
very treatable disease, in which cure may be obtained in
668 Part VI Testis
many cases without the loss of function. Prostate sarco-
mas are best treated with very aggressive surgery, and the
outcome of paratesticular sarcomas is very much affected
by primary histology. In urologic sarcomas, there appears
to be a role for lymph node dissections in conjunction
with primary therapy, which is different than the clinical
recommendations for primary retroperitoneal sarcomas.
Adult rhabdomyosarcoma generally responds less well
than its pediatric counterpart even when successful pedi-
atric, therapeutic protocols are employed. In all instances
of genitourinary sarcoma, the overall lack of sustained
responses to doxorubicin-based therapy suggests that
patients with advanced disease should be enrolled in
novel protocols.
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Chapter 39 Retroperitoneal Tumors 669
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C H A P T E R
40 Urethral Cancer
Robert C. Flanigan, MD
Urethral cancer is a rare disorder in both men and
women. Because of the differences in etiology, presenta-
tion, cell type, and treatment between the two sexes, this
chapter will address male and female urethral cancer
separately.
MALE URETHRAL CANCER
Cancer of the male urethra typically occurs in the 5th
decade of life but cases have been described from ages 13
to 90.1 The etiologies that have been shown to be related
include chronic infection or inflammation, urethral stric-
ture, sexually transmitted disease, and human papillo-
mavirus 16 (HPV 16).2 The incidence of urethral stricture
in men who develop urethral cancer ranges from 24% to
76% and most often involves the bulbomembranous ure-
thra. Because the development of cancer in a chronic stric-
ture patient is often insidious, the urologist should have a
high index of suspicion and a low threshold to biopsy a
urethral stricture in this setting, especially when the stric-
ture is rapidly recurrent or does not otherwise respond
well to treatment. It is estimated that nearly one-quarter of
patients with urethral cancer have a history of sexually
transmitted disease and that over 90% of these patients are
symptomatic at presentation.3 The most common present-
ing clinical signs of urethral cancer are bleeding, perineal
pain, decreased force of stream due to stricture or obstruc-
tion, urinary frequency or dysuria, or urinary fistula.
Location and histologic type are the keys to catego-
rization of male urethral strictures.4 The frequency of
cancer by site is bulbomembranous urethra (60%), penile
urethra (30%), and prostatic urethra (10%). Eighty per-
cent are squamous cancers, 15% transitional cell, and 5%
adenocarcinomas or undifferentiated tumors. The histo-
logic subtypes, as expected, vary with anatomic site,
based largely on the typical lying cells of that area (Figure
40-1). Thus, carcinomas of the prostatic urethra are typ-
ically transitional cell (90%), while cancers of the penile
urethra and bulbomembranous urethra are squamous cell
cancers in 90% and 80% of cases, respectively.5 An
understanding of the normal and abnormal urethral
urothelium is, therefore, important to the understanding
of cancer development, local invasion, and metastases.
PATHOLOGY
Normal Urothelium
Normal transitional urothelium is composed of 3 to 7
layers of transitional cells with large umbrella cells over-
lapping the cells of the intermediate cell layers that in
turn rest on a basal cell layer. Below the epithelium lies
the lamina propria and submucosal layer. The submu-
cosal layer contains the muscularis mucosa and multiple
vascular spaces. Below the submucosal layer lies the ure-
thral muscle. The diminished barrier to tumor extension
presented by the thin muscular layer explains the ready
access of tumor to the paraurethral space.6
Abnormalities of the Urothelial Layer
Abnormalities of the urothelial layer can range from
hyperplasia to carcinoma. Hyperplasia may be further
subdivided into epithelial hyperplasia, inverted papil-
loma, von Brunn’s nests, and cystitis cystica.
Metaplasia
Metaplastic lesions of the urothelium include cystitis
glandularis (believed to be a precursor of urothelium ade-
nocarcinoma), nephrogenic adenoma, and squamous
metaplasia.
Dysplasia
Dysplasia of the urethra may take the form of atypical
hyperplasia, mild atypia, moderate atypia, or severe
675
676 Part VII Urethra and Penis
Figure 40-1 Anatomic regions of the male urethra and
corresponding histology and histopathology.
atypia. In addition, leukoplakia of the urethra may occur.
Dysplastic urothelium exhibits histologic changes that
are intermediate between normal urothelium and carci-
noma in situ. It is generally felt that lesions on the severe
end of this spectrum are neoplastic rather than dysplastic.
Superficial Carcinomas
Superficial carcinomas of the urethral urothelium include
carcinoma in situ and cancers involving the epithelium
and submucosal layers. Histologically, these cancers are
either transitional cell, squamous, or adenocarcinomas.
Carcinoma In Situ
Histologically, carcinoma in situ is characterized by a
poorly differentiated cancer involving only the urothe-
lium. A loss of cellular cohesiveness, widening of the
intracellular spaces, separation of cells from the basement
membrane, and a loss of the superficial umbrella cell
layer is characteristic. Carcinoma in situ may occur
focally or diffusely within the urothelium. It is often
associated with high-grade and high-stage transitional
cell cancers. Although carcinoma in situ of the transi-
tional cell epithelium may occur in the absence of visible
bladder tumor, its association with either a concurrent or
prior bladder tumor significantly increases the risk of
progression to invasion.
The cystoscopic appearance of carcinoma in situ is
often misleading in that a normal-appearing epithelium
is the most common finding. A reddened or velvety patch
of erythematous mucosa should, however, suggest the
possibility of carcinoma in situ. Carcinoma in situ, like
papillary urothelial cancer, is more common in men than
in women. Because carcinoma in situ frequently presents
with irritative voiding symptoms, the patient is often
misdiagnosed as suffering from prostatism, urinary
tract infection, or neuropathic bladder dysfunction.
Cytopathologic studies of voided urine are positive in
85% to 90% of patients with carcinoma in situ.
The natural history of carcinoma in situ is unpre-
dictable. Early in its evolution, carcinoma in situ may
produce no symptoms, and, in fact, patients with focal
asymptomatic carcinoma in situ have been reported to
generally display a protracted clinical course with low
likelihood of development of invasive cancer. In contrast,
patients with more diffuse or symptomatic carcinoma in
situ, especially in association with a history of bladder
cancer, often display a poor prognosis despite definitive
therapy.
Papillary Transitional Cell Carcinoma
TCC is generally graded on a scale of 1 to 3 (some sys-
tems grade from 1 to 4). Grade 1 TCCs differ from nor-
mal epithelium by having an increased number of
epithelial cell layers. With increasing grade, abnormali-
ties of nuclear morphology, loss of cellular polarity,
abnormalities of the normal cellular maturation from
the basal to superficial layers, nuclear crowding, and
increased nuclear-to-cytoplasmic ratio are seen. In
addition, prominent nucleoli with clumping of the
chromatin and an increased number of mitoses may be
appreciated.
Squamous Cell Carcinoma and Adenocarcinoma
In the United States, squamous cell carcinomas account
for approximately 80% of urethral cancers. These tumors
are commonly associated with a chronic inflammatory
process involving the urothelium, including the presence
of a chronic foreign body (e.g., an indwelling catheter,
urinary tract calculi, or recurrent urinary tract infec-
tions). Generally, a greater proportion of patients with
squamous cell carcinoma, as compared with TCC, pres-
ent with advanced disease at the time of diagnosis.
Adenocarcinoma of the urethra is an uncommon
lesion accounting for very small percentage of urethral
cancers.
 Chapter 40 Urethral Cancer 677

NATURAL HISTORY extent of involvement of the surrounding tissues and can

vary from transurethral excision or local resection to par-
Numerous chromosomal abnormalities have been
tial or total penile amputation. The treatment of urethral
found to be associated with the development of TCC,
cancer can also be divided into three areas of urethral
including chromosome 9 loss, c-myc amplification, Y
involvement: the penile urethra and fossa navicularis, the
chromosome loss, and p53, p21, and erb-B-2 abnormal-
bulbomembranous urethra, and the prostatic urethra.
ities. Of these, chromosome 9 loss and p53 abnormali-
The prognosis of urethra cancers is dependent on the
ties may be the most important. Loss of heterozygosity
type of cancer, site of the lesion (distal better than proxi-
of chromosome 9 seems to be an early event associated
mal), the depth of invasion, and the ability to achieve
with the formation of papillary tumors, whereas p53
complete local control.9 A summary of prognosis by site
gene deletion seems to be associated with the formation
of involvement is given in Table 40-2.
of dysplasia and carcinoma in situ. By the time a TCC
invades the lamina propria, both of these genetic events
have typically occurred. Chromosome 9 deletion is felt Penile Urethra and Fossa Navicularis Cancers
to result in a homozygous deletion of the MTS-1 gene
When distal urethral cancer is superficial, papillary, or in
(a tumor-suppressor gene), and it is a frequent event in
situ, transurethral resection and fulguration may be
TCC but not a driving force in tumor progression. P53
employed. When the cancer invades the corpus spongio-
is a tumor-suppressor gene located at 17p13.1, which
sum, more aggressive therapy is indicated and may
codes for a DNA-binding protein involved in the regu-
include urethrectomy with sparing of the corpora caver-
lation of transcription. Deletion of this gene results in
nosa (penile-sparing), partial penectomy with an ade-
an overexpression of the p53 (missense mutation), lead-
quate margin (2 cm), and total penectomy. Partial
ing to an extension of the half-life of the protein. p53
penectomy is most useful in cancers that involve the dis-
and another transcription-mediating gene, p21, are
tal half of the penis. In any case, the advantages of tissue-
associated with progression of TCC.
conserving approaches must be balanced against the
The natural history and molecular biology of squa-
probability of local recurrence and death from metastatic
mous cell and adenocarcinomas of the urothelium are
disease.10 Ilioinguinal lymphadenectomy is indicated in
less well understood than that of TCC. Squamous cell
the presence of palpable nodes but the value of prophy-
carcinoma is an invasive lesion with a nodular infiltrative
lactic node dissection has not been demonstrated in this
growth pattern. It is postulated that nitrosamines pro-
disease.
duced by bacteria in infected urine act as carcinogens and
tumor promoters. A recent study of cytogenetics in squa-
mous cell urethra cancer has demonstrated involvement Bulbomembranous Cancers
of chromosomes Y, 2, 3, 4, 6, 7, 8, 11, and 20 but of inter-
Superficial lesions of the bulbomembranous urethra are
est, not chromosomes 9 and 17, which are widely involved
quite rare but have been successfully managed by
in transitional cell cancer.7
transurethral resection and local excision with end-to-
end urethral reanastomosis. In general, radical excision
Evaluation and Staging seems to be the best approach, employing radical cysto-
The TNM staging system is based on the depth of invasion of prostatectomy combined with total penectomy and bilat-
the primary tumor, the presence of regional lymph node eral pelvic lymphadenectomy. In severe cases, extending
involvement, and the presence of distant metastases (Table 40-1). the en bloc excision to include the pubic rami and uro-
The diagnosis and staging of urethral cancer begins with phys- genital diaphragm has been recommended.11,12
ical examination of the external genitalia, urethra, rectum, and
perineum. Cystoscopy and bimanual examination-under- Prostatic Urethral Cancers
anesthesia are often useful. Transurethral or percutaneous
needle biopsy of the lesion is performed. Cytologic studies of Primary carcinoma of the prostatic urethra is rare. In this
first voided urine may be helpful. Local involvement, includ- setting, transitional cell and adenocarcinomas are the
ing involvement of regional lymphatics and contiguous struc- most common histologies. It is imperative to rule out
tures, as well as estimation of the extent of local disease, is best extension of these cancers from the bladder, as this pres-
determined by MR or CT imaging. MR is particularly help- entation is far more common than tumor arising in the
ful in determining invasion of the corporal bodies.8 prostatic urethra. Patients typically present with hema-
turia or obstructive symptoms and rarely with prostatic
induration on digital rectal exam (a sign of advanced dis-
Treatment
ease). Diagnosis may require both transurethral biopsy
Surgical excision remains the primary therapy for male and transrectal ultrasound-guided needle biopsy.
urethral cancers. The extent of resection depends on the Superficial papillary or in situ cancers may be managed
678 Part VII Urethra and Penis

Table 40-1 Urethral Cancer TNM Staging System

Primary tumor (T) (male and female)

Tx Primary tumor cannot be assessed

T0 No evidence of primary tumor

Ta Noninvasive papillary, polypoid, or verrucous carcinoma

Tis Carcinoma in situ

T1 Tumor invades subepithelial connective tissue

T2 Tumor invades any of the following: corpus spongiosum, prostate, periurethral muscle

T3 Tumor invades any of the following: corpus cavernosum, beyond prostatic capsule, anterior vagina, bladder neck

T4 Tumor invades other adjacent organs

Transitional cell carcinoma of the prostate

Tis-pu Carcinoma in situ, involvement of the prostatic urethra

Tis-pd Carcinoma in situ, involvement of the prostatic ducts

T1 Tumor invades subepithelial connective tissue

T2 Tumor invades any of the following: prostatic stroma, corpus spongiosum, periurethral muscle

T3 Tumor invades any of the following: corpus cavernosum, beyond prostatic capsule, bladder neck (extra prostatic exten-
sion)

T4 Tumor invades other adjacent organs (invasion of the bladder)

Regional lymph nodes (N)

Nx Regional lymph nodes cannot be assessed

N0 No regional lymph node metastasis

N1 Metastasis in a single lymph node, 2 cm or less in greatest dimension

N2 Metastasis in a single lymph node, more than 2 cm but <5 cm in greatest dimension; or in multiple nodes, none >5 cm

N3 Metastasis in a lymph node >5 cm in greatest dimension

Distant metastasis (M)

Mx Presence of distant metastasis cannot be assessed

M0 No distant metastasis

M1 Distant metastasis

OPERATIVE TECHNIQUES FOR MALE URETHRA

successfully by transurethral resection in select
patients.13 In the great majority of cases, however, the
cancer involves the prostatic stroma and is typically
treated by cystoprostatectomy with total urethrectomy
and bilateral pelvic lymphadenectomy. The outlook in
this setting is poor, with reported 5-year survival ranging
from 6% to 26%.14
CANCERS
Partial and Total Urethrectomy in the Male Patient
with Primary Urethral Carcinoma
Distal urethral carcinoma in the male includes all tumors
distal to the bulbous urethra.15 These tumors may be
managed by transurethral resection, partial penectomy,

Table 40-2 Treatment Survival for Urethral Cancer
Site Treatment
Fossa navicularis Partial penectomy
Penile Partial or total penectomy
Bulbomembranous Total penectomy, urethrectomy,
cystoprostatectomy
Prostatic superficial Transurethral resection
Invasive Cystoprostatectomy, urethrectomy
Figure 40-2 A, Patient position for radical
cystoprostatectomy. Umbilicus is placed over break of table,
and table is fully flexed and tilted into Trendelenburg’s
position, until legs are parallel to floor. B, Patient position for
urethrectomy. Leg braces are elevated until hips are flexed 60
degrees and knees are fully extended.
or partial penectomy with perineal urethrostomy. Standard
positioning techniques are pictured in Figure 40-2.
For patients with posterior urethral cancers, total ure-
threctomy with cystoprostatectomy is typically under-
taken. The patient is placed in the lithotomy position
with special attention to abduction of the legs. After rad-
ical cystectomy and lymphadenectomy is completed, the
membranous urethra is dissected from the urogenital
diaphragm using finger dissection. Attention is then
directed to the perineum. A midline or inverted Y inci-
sion is made in the anterior perineum overlying the cen-
tral tendon (Figure 40-3). The superficial and deep fascia
Chapter 40 Urethral Cancer 679
No. Patients Survival
12 11 (92%)
100 34 (34%)
64 10 (16%)
45 39 (87%)
78 29 (37%)
are incised and the bulbocavernosus muscle divided in
the midline and reflected laterally to expose the bulbous
urethra. A perineal ring retractor (e.g., Turner-Warwick
or Omni) provides good exposure. After a segment of
the urethra is isolated by incising Buck’s fascia overlying
the inferior lateral grooves between the corpus spongio-
sum and the corpus cavernosum and dividing its supero-
medial attachments, a Penrose drain is advanced through
the defect and used to create countertraction on the cor-
pus spongiosum during the remaining distal dissection
(Figure 40-3B). The plane between corpus spongiosum
and corpus cavernosus is remarkably easy to develop in
most cases, although inadvertent laceration of the tunica
albuginea of the corpora cavernosa may produce consid-
erable hemorrhage, which is most readily controlled
with continuous 3-0 chromic or polyglycolic acid (PGA)
sutures.
During distal dissection, the penis becomes inverted
and the plane between the corpus spongiosum and cor-
pora cavernosa is lost. A decision must be made whether
or not to preserve the fossa navicularis at this point.
Preservation of the fossa navicularis may be helpful in
allowing for more adequate placement and seating of the
tips of a penile prosthesis at a later date. If the fossa nav-
icularis is to be resected, the penile meatus is circum-
scribed using a tear-shaped incision and the fossa
navicularis is mobilized from the glans penis and pulled
into the perineal incision (Figure 40-5). Defects in the
glans penis are closed with interrupted 2-0 chromic or
PGA sutures. Isolation of the proximal urethra at the bul-
bomembranous junction is the most difficult aspect of
the procedure. Dissection is carried in a posterior and
lateral direction with special care to identify and secure
branches of the pudendal arteries entering at the
4 o’clock and 8 o’clock positions (Figure 40-4). Small
hemoclips or 3-0 chromic/PGA sutures are particularly
useful for this maneuver. The urethrectomy is completed
by mobilizing the most proximal bulbous urethral spon-
giosum and by dissecting the remaining membranous
urethra from the urogenital diaphragm. At this point, the
appropriate plane of dissection may be best appreciated
680 Part VII Urethra and Penis

Figure 40-3 Total urethrectomy with cystoprostatectomy.

 Chapter 40 Urethral Cancer 681

Figure 40-4 Control of the bulbar arteries fudging urethrectomy.

Figure 40-5 Inverted T-incision on glans penis and dissection

of glanular urethra.

by combined perineal and abdominal palpation and

inspection.
The perineal wound is carefully irrigated and a suc-
tion or Penrose drain is positioned in the bed of the
bulbous urethra and brought out through a separate
stab wound (Figure 40-6). Reapproximation of the bul-
bocavernosus muscle is undertaken in the midline using
2-0 chromic or PGA sutures. The subcutaneous tissue
is closed with interrupted 3-0 chromic or PGA sutures
and the skin is closed with interrupted 3-0 nylon
sutures. The shaft of the penis is wrapped loosely with
gauze or is covered with a self-adhering dressing of Figure 40-6 Closure of the perineal incision and placement
some variation. Exposure of the tip of the glans penis in of the Jackson-Pratt drain.
682 Part VII Urethra and Penis
order to permit prompt identification of postoperative
ischemia is important.
Total Urethrectomy in the Male Patient in
Association with Cystectomy
The procedure for concomitant urethrectomy at the time
of cystoprostatectomy is very similar to that described
previously for the treatment of primary urethral cancer.
The bulbomembranous and prostatic urethral segments
are those most often involved by extension of the primary
bladder cancers; thus careful dissection of these areas is
essential. This part of the dissection can be considerably
more difficult when urethrectomy follows cystoprostate-
ctomy by more than several weeks.16 In such cases, a
Foley catheter must be placed to the proximal end of the
urethra and secured in place by suturing to the meatus,
and dissection carried to the proximal extent of the
catheter. Dissection of the proximal urethra should be
done carefully and methodically because extensive trac-
tion on the urethra may avulse the proximal portion as a
result of extensive fibrosis in this area. Drainage of the
proximal urethral bed using a Jackson-Pratt or Penrose
drain is suggested.
Radiation Therapy and Multimodal Therapy
Radiation therapy alone may be adequate to control
small lesions in the distal urethra.17 Radiation may be
delivered using brachytherapy or intracavitary tech-
niques. Chemotherapy using MVAC or paclitaxel and
ifosfamide have recently been reported to successfully
treat transitional cell cancers of the urethra.18
Figure 40-7 Anatomic regions of the female urethra and
corresponding histology and histopathology.
FEMALE URETHRAL CANCERS
Urethral cancer is more common in women than men
(ratio 4:1). Risk factors include race (Caucasian more
common), age (>50 years most common), a history of
chronic inflammation or irritation, urinary tract infec-
tions, or proliferative lesions, including caruncles,
papillomas, adenomas, and leukoplakia. Most women
present with urethral bleeding, urinary symptoms, and a
palpable mass or induration. Tumors may be papillary,
fungating, or ulcerating and may cause induration of the
anterior vaginal wall. Odor producing necrosis and dis-
charge may occur. Local extension is not uncommon
and may involve the bladder neck, vagina, or vulva.
Metastases to regional lymphatics are common, occur-
ring in up to one-third of patients at presentation.
Anterior urethral cancers drain into the superficial and
deep inguinal nodes whereas posterior urethral tumors
drain into the external iliac, hypogastric, and obturator
nodes. Female urethral cancer often produces systemic
metastases without regional node involvement. Generally,
therefore, groin dissection is reserved for those patients
who have palpable lymphadenopathy without distant
spread of cancer.19
Pathology
As with male urethral cancer, the urethral cancer cell type
in women is related to the site of urethra involved and
may be squamous, transitional cell, or adenocarcinomas
(Figure 40-7). Carcinomas of the proximal or posterior
urethral are typically locally advanced and high grade,
whereas distal cancers are, in general, low grade and less
extensive. Overall, squamous cell cancers are most common

(60%), followed by transitional cell (20%), adenocarci-
noma (10%), undifferentiated or sarcomatous (8%), and
melanoma (2%).
Evaluation and Staging
Pelvic examination combined with cystoscopy and biopsy
is the cornerstones of diagnosis. The TNM staging sys-
tem is similar to that of male urethral cancer and is
shown in Table 40-1. Prognosis has been reported in var-
ious studies to be dependent on tumor size, location in
the urethra (posterior versus anterior), histology, and
extent of disease (early versus advanced) (Table 40-3).20
In one series of 76 patients, 5-year disease-specific sur-
vival was 89% for low-stage tumors compared to 33% for
high-stage tumors.21
Treatment
Although local excision may suffice for low grade, low-
stage tumors, single modality therapy often fails to ade-
quately control advanced cancer and is associated with a
20% 5-year survival and a local recurrence rate exceeding
65%.22 As with male urethral cancer, treatment options
vary considerably with site of urethral involvement: distal
or proximal.
Distal Urethral Cancer
Distal cancers, as stated above, are more often superficial
and well localized with infrequent lymph node metas-
tases. Local excision is often sufficient and is accom-
plished by circumferential excision of the involved
urethra with adjacent portions of the anterior vagina.
Spatulation of the remaining urethra with approxima-
tion to the adjacent vagina and labia is associated with
preservation of continence in most cases.
Proximal Urethral Cancer
Proximal urethral cancers are most often aggressive and
invasive and require extensive resection, including ante-
Table 40-3 Prognosis for Early and Advanced Tumors
Stage Treatment
Early Radiation therapy
Surgery
Radiation therapy plus surgery
Advanced Radiation therapy
Radiation therapy plus surgery
Chapter 40 Urethral Cancer 683
rior exenteration with wide resection of the vagina in
most cases. Partial and total urethrectomy can be useful
in selected cases of female urethral cancer.
OPERATIVE TECHNIQUES FOR PARTIAL AND
TOTAL URETHRECTOMY IN THE FEMALE
Partial and Total Urethrectomy in the Female
Patient with Primary Urethral Cancer
The female patient with primary urethral cancer is pre-
pared for anterior exenteration with mechanical and
antibiotic bowel preparation, systemic antibiotics, and
intravenous hydration. In those patients presenting with
tumors of the distal third of the urethra that are con-
fined to the mucosa, submucosa, or periurethral muscu-
lature, a distal urethrectomy may be appropriate. Distal
urethrectomy is performed with the patient in the litho-
tomy position after full vaginal and abdominal prepara-
tion. A weighted speculum is used to improve
visualization of the urethral orifice. A traction suture
ligature of 0 or 2-0 silk is passed through the urethral
meatus or the surrounding periurethral tissue. An encir-
cling incision is then made around the meatus (Figure
40-8). After sharp dissection of the urethral meatus, a
longitudinal incision is made on the vaginal mucosa
overlying the epithelium to approximately 2 cm beyond
the point of palpable induration. Sharp dissection then
circumscribes the urethra, which is transected at the
previously determined proximal extent of dissection.
Frozen sections of the proximal urethral margin should
be evaluated to document the absence of microscopic
involvement of the urethra at that point. Mucosal edges
of the remaining urethra may then be approximated to
the vaginal mucosa using 3-0 chromic or PGA sutures.
A 16 to 18 French Foley catheter is inserted into the
bladder to provide urinary drainage. Vaginal repair is
then completed using an interrupted or running 2-0 or
3-0 chromic or PGA suture. Povidone-iodine soaked
vaginal packing is left within the vaginal vault and is
removed on postoperative day 1.
In those patients in whom tumor extends microscopi-
cally beyond the point of palpable induration, and/or
No. Patients Survival
140 94 (67%)
24 20 (83%)
5 4 (80%)
157 54 (34%)
39 21 (54%)
684 Part VII Urethra and Penis
Figure 40-8 Technique for resection of the distal third of the
female urethra.
those patients with proximal urethral cancers in whom
proximal urethral involvement of the tumor is established
preoperatively, total urethrectomy, vulvectomy, clitorec-
tomy, and anterior exenteration may be required to
remove the tumor with an adequate margin.23 In selected
cases, resection of the pubic rami may also be necessary.24
The female candidate for total urethrectomy is prepared
in a fashion similar to that described for partial urethrec-
tomy. The operation is generally begun abdominally,
where radical cystectomy and pelvic lymph node dissec-
tions are performed in the standard fashion. In addition,
salpingo-oophorectomy and hysterectomy are also per-
formed in most cases. Resection of the anterior urethra
en bloc with the abdominal structures proceeds along the
lines described previously. Complete excision of the ante-
rior compartment of the perineum may require a gracilis
flap to provide for adequate pelvic floor support (Figure
40-9).25 Resection of the pubic rami is undertaken only in
very extensive tumors because it may be associated with
significant complications, including sacroiliac joint dis-
ruption and perineal hernia formation.26 It is important
to preserve vulvar skin whenever possible and to remove
the specimen en bloc so as to avoid contamination of the
operative field by tumor spillage. After completion of the
extirpative aspects of the procedure, urinary diversion is
completed.
Multimodal Therapy
Because of the dismal results with single modality ther-
apies in female urethral cancers, attempts to provide a
multimodal approach have been undertaken. In a recent
Figure 40-9 In extensive pelvic/perineal exenteration, the
urethra and external genitalia in continuity with the pelvic
structures are removed. The pubic rami are identified and
prepared for excision by freeing the overlying subcutaneous
tissue, the suspensory ligament of the penis, and the various
muscular attachments. The outlines of exenteration of the
bone are indicated by the dotted lines.
report, 6 women were managed with high-dose rate
brachytherapy, anterior exenteration, and external beam
radiation therapy with 4 patients receiving adjuvant plat-
inum-based chemotherapy. Despite this approach, 3 of 6
patients had distant metastases at a mean follow-up of 21
months.27 In another series, surgery was combined with
either neoadjuvant or adjuvant radiation therapy in 12
patients, resulting in a 44% 5-year cause-specific sur-
vival.20 A single case of squamous cell cancer successfully
managed with external beam radiation therapy and cis-
platin, and 5-fluorouracil has been reported.28
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papillomavirus type 16 is associated with squamous cell
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2. Cupp MR, Reza MS, Goellner JR, et al: Detection of
human papillomavirus DNA in primary squamous cell
carcinoma of the male urethra. Urology 1996;
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3. Dalbagni G, Zhang ZF, Lacombe L, Herr HW: Male
urethral carcinoma: analysis of treatment outcome.
Urology 1999; 53:1126–1132.
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5. Grigsby PW, Herr HW: Urethral tumors. In
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7. Fadl-Elmula I, Gorunova L, Mandahl N, Elfving P, Heim
S: Chromosome abnormalities in squamous cell carcinoma
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of carcinoma of the male urethra. Urol Clin North Am
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10. Davis JW, Schellhammer PF, Schlossberg SM:
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rami resection with en bloc radical excision for invasive
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J Urol 1989; 141:853–856.
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the prostate. Eur Urol Update Series 1998; 7:1–7.
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edition, pp 2774–2781. Philadelphia, WB Saunders, 1992.
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C H A P T E R
41 Urethrectomy
Sanjaya Kumar, MD
INDICATIONS
Over the years, the indications for urethrectomy have
changed. The trend has shifted towards preservation of the
urethra. The indications for preserving the urethra have
been liberalized for several reasons. These include the
widespread utilization of orthotopic neobladders in both
men and women, better understanding of the anatomy of
the female urethra, and importantly the reduced risk of
urethral recurrence following orthotopic urinary diver-
sion.1 Currently, the absolute indication to remove the
urethra includes the involvement of the urethra by carci-
noma. The single most important predictor of recurrent
disease in the male urethra is transitional cell carcinoma
(TCC) involvement of the prostatic urethra, specially the
stroma.2–4 The single most important predictor of recur-
rent disease in the female urethra is involvement of tumor
at the bladder neck.5,6 However, the absolute indication
for a prophylactic urethrectomy includes the histologic
evidence of cancer at the urethral margin at the time of
cystectomy in both men and women.
A urethrectomy may be performed simultaneously dur-
ing a cystoprostatectomy for transitional cell cancer, if the
prostatic urethra is involved by tumor at the time of the
cystectomy, or at a later time, should there be a recurrence
of tumor in the urethra. Ideally, a complete urethrectomy
is performed, both in males and females. However, in
males, under certain circumstances, such as when there is a
superficial isolated solitary recurrence, following an ortho-
topic neobladder, a partial or segmental urethrectomy may
be performed, provided it is surgically feasible.
OPERATIVE TECHNIQUE
Urethrectomy in the Male
Simultaneous Urethrectomy with
Cystoprostatectomy
Pelvic dissection. A simultaneous urethrectomy with
cystoprostatectomy is performed for TCC of the bladder
686
involving the urethra. The prostatic urethra is usually
involved and this determination is made from prior stag-
ing resection and biopsy. A frozen section analysis of the
membranous urethra is always undertaken at the time of
cystoprostatectomy. Positive findings will necessitate
abandoning the orthotopic neobladder and performing a
complete urethrectomy. If the patient is not able to tol-
erate the simultaneous procedure, the urethrectomy can
be performed at a later date.
For a concomitant radical cystoprostatectomy, the
patient is positioned in a lithotomy position to allow
access to the abdomen, pelvis, and the perineum.
Modified stirrups or boots are usually used that allow the
position of the patient to be modified in a sterile fashion
during the urethrectomy (Figure 41-1). All pressure
points must be carefully padded and protected. A two-
team approach may be more expeditious. Once the dis-
section for the cystoprostatectomy is complete, attention
is directed towards performing an en bloc urethrectomy.
At this point the dorsal venous complex and other attach-
ments have been divided and the bladder and prostate are
in continuity with the membranous urethra. The mem-
branous urethra is dissected from the urogenital sinus
using blunt and sharp dissection. An umbilical tape is
passed under the urethra, below the apex of the prostate.
Gentle traction on the tape facilitates dissection in a plane
between the urethral smooth muscle and the striated mus-
cle of the urogenital diaphragm. The dissection is per-
formed carefully to visualize the bleeders and preserve the
neurovascular bundles located posterolateral to the ure-
thra (Figure 41-2). The use of electrocautery should be
minimized if a nerve-sparing technique is being adopted.7
Once the membranous urethra has been completely
mobilized from the urogenital diaphragm, attention is
directed towards dissecting the anterior urethra.
Secondary urethrectomy is difficult at this location
due to scarring from previous cystoprostatectomy.
The procedure can result in shredding of the urethra,

Figure 41-1 A, Patient position for radical
cystoprostatectomy. Umbilicus is placed over break of table,
and table is fully flexed and tilted into Trendelenburg’s
position, until legs are parallel to floor. B, Patient position for
urethrectomy. Leg braces are elevated until hips are flexed 60
degrees and knees are fully extended. (From Brendler CB,
Schlegel PN, Walsh PC: J Urol 1990; 144:270–273.)
incomplete resection, and risk injury to bowel. It is there-
fore important at this time to dissect the urethra as far
distally as is safely possible. Attention is now directed
towards the perineum. However, if a frozen section spec-
imen of the urethra is necessary, the urethra should be
tied before transaction to prevent tumor spillage. The
urethra may be deliberately divided here if the patient is
unable to withstand anesthesia for the additional time
necessary to perform the anterior urethrectomy. The
urethrectomy can then be performed as a secondary pro-
cedure several weeks later.
Perineal dissection. The lithotomy position can now
be exaggerated by tilting the boots up. An inverted Y-
shaped incision is made in the skin of the perineum
between the scrotum and the anal verge (Figure 41-3).
The subcutaneous tissue is divided to expose the bulbo-
cavernous muscle. The bulbocavernous muscle is divided
in the midline (Figure 41-4). Two Richardson retractors
or ring retractors are used to keep the wound open.
The corpus spongiosum is now dissected. The urethra
can be palpated through the urethral catheter. In a sec-
ondary urethrectomy, a metal sound (Van Buren) can be
used instead of a catheter. Pinch the catheter surrounded
by the urethra by the fingers and using a Metzenbaum
scissors expose the dorsal aspect of the urethra. Create
adequate space between the urethra and corpus caver-
Chapter 41 Urethrectomy 687
nosum to pass a quarter inch Penrose drain around the
urethra (Figure 41-5). The dorsum of the urethra is usu-
ally adherent to the corpus cavernosum. Traction on the
Penrose and sharp dissection in this plane allows separa-
tion of the urethra from the corpus cavernosum. The
pointed tip electrocautery on a low setting works well in
this midline plane (Figure 41-6). Cavernosal bleeding
and minor rents can be closed with 2-0 Vicryl/monofila-
ment absorbable sutures. Distal dissection and traction
on the urethra eventually results in inversion of the penis
into the wound (Figure 41-7A,B). Once the dissection
reaches the urethral tip, the fossa navicularis and the
meatus are cored out. Alternatively, the penis is straight-
ened, and either a wedge or a T-shaped incision made of
the ventral aspect of the glans penis. The fossa navicularis
and the meatus can now be dissected (Figure 41-8). Strict
hemostasis is ensured. The glans penis is reconstructed
with 3-0 chromic catgut or monofilament absorbable
sutures. For cosmetic reasons, under certain circum-
stances, the fossa navicularis can be preserved.
Once the distal urethra is completely mobilized and
disconnected from the glans penis, the proximal urethra
is freed from the perineal investments. The bulbar ure-
thral arteries are posterolateral to the bulb. These are
carefully secured (Figure 41-9). Anteriorly, the urethra
is dissected under the pubic symphysis (Figure 41-10).
Eventually, dissections around the urethra, from the
pelvis above and the perineum below, meet up in a com-
mon plane (when combined with cystoprostatectomy),
through the urethra genital diaphragm. It is important
to dissect close to the urethra to avoid injury to the
erector nerves. The urethra is now completely mobi-
lized. It can either be removed separately or pulled from
the abdominal side and removed en bloc with the cys-
tectomy specimen. In a secondary urethrectomy, the
very last proximal end of the urethra is surrounded by
scar tissue and is carefully dissected. The operator must
safeguard against urethral avulsion, at the pelvis, by
avoiding undue traction on the urethra. The urethra
must be removed in its entirety (Figure 41-11A,B) while
the surgeon is cognizant of potential injury to underly-
ing bowel.
The wound is irrigated with antibiotic solution, strict
hemostasis ensured and closed in layers. The bulbocav-
ernous muscles and the urogenital diaphragm are reap-
proximated with 2-0/3-0 absorbable sutures. A number 7
french Jackson-Pratt drain is left indwelling for 24 to 48
hours in the urethral bed and brought out through a sep-
arate stab incision (Figure 41-12). The subcutaneous
tissue is closed with 3-0 absorbable sutures. Additional
layers may need to be reapproximated in the pelvic area
to close all dead space. The skin is closed with 4-0
Monocryl. Either Steri-Strips or Dermabond can be used
for additional support. A gentle compressive dressing
with Kerlex sponges is then applied.
688 Part VII Urethra and Penis

Figure 41-2 A, Urethra is ligated with 1-0 silk suture to prevent spillage of urine
around catheter (NVB, neurovascular bundle; Pros, prostate). B, Mobilization of
membranous urethra from urogenital diaphragm with Kitner dissector. C, Further
mobilization of membranous urethra. D, Lateral view shows membranous urethra (Ur)
fully mobilized with neurovascular bundles displaced posterolaterally. E, Urethra is
transected, and catheter is drawn cephalad into wound. Neurovascular bundles are
seen intact, lateral to the urethra. (From Brendler CB, Schlegel PN, Walsh PC: J Urol
1990; 144:270–273.)

dure are similar to those mentioned in the section on

Total Anterior Urethrectomy in the Male
Complete anterior urethrectomy may be performed as a
secondary procedure for TCC or as a primary procedure
for nontransitional cell cancers of the anterior urethra.
This procedure is performed for transitional cell cancer
of the prostatic urethra, as a staged procedure, if a cysto-
prostatectomy with concomitant urethrectomy cannot be
completed in a primary setting. Total anterior urethrec-
tomy is also performed for recurrent transitional cell
cancer of the anterior urethra. The details of the proce-
perineal dissection.
The extent of urethral resection for nontransitional cell
cancer of the urethra depends on the pathology and stage
of the cancer. Most of the distal urethral tumors are low
stage and proximal urethral tumors are high stage.8 Thus,
surgery for tumors in the anterior urethra may vary from
transurethral resection, segmental resection, and partial
penectomy to total penectomy with perineal urethros-
tomy. Tumors of the bulbomembranous and prostatic ure-
thra are generally advanced at the time of presentation and
 Chapter 41 Urethrectomy 689

Figure 41-5 Mobilization of urethra off corpus cavernosa

facilitated using a Penrose drain. (From Graham SD Jr (ed):
Glenn’s Urologic Surgery, 5th edition, pp 461–466.
Philadelphia, Lippincott, Williams and Wilkins, 1998.)

Figure 41-3 Perineal skin incision for urethrectomy. (From

Hinman F, et al: Atlas of Urologic Surgery, 2nd edition.
Amsterdam, Elsevier Science, 1998.)

Figure 41-6 Use of electrocautery to dissect the urethra from

Figure 41-4 Division of bulbocavernous muscle and the corpus cavernosum. (From Hinman F, et al: Atlas of
exposure of urethra. (From Graham SD Jr (ed): Glenn’s Urologic Surgery, 2nd edition. Amsterdam, Elsevier Science,
Urologic Surgery, 5th edition, pp 461–466. Philadelphia, 1998.)
Lippincott, Williams and Wilkins, 1998.)
690 Part VII Urethra and Penis
Figure 41-7 Distal dissection of the urethra resulting in inversion of the penis. (A from Hinman F, et al: Atlas of Urologic
Surgery, 2nd edition. Amsterdam, Elsevier Science, 1998; B courtesy Sanjaya Kumar, M.D.)
are treated with total penectomy and urethrectomy,
prostatectomy and continent cutaneous urinary diver-
sion. It has recently been proposed that locally advanced
male anterior urethral carcinoma be treated with multi-
modal treatment, including chemoradiation and extirpa-
tive surgery.9
Urethrectomy in the Female
Primary urethral cancer in women is rare. Although
women have a lower incidence of transitional cell cancer
than men, urethral cancer per se is 4 times more common
in women than men. The common urethral cancers
include squamous cell (60%), transitional cell (20%), and
adenocarcinoma (15%). Primary transitional cell cancer
of the urethra is very rare. In patients with transitional
cell cancer of the bladder a total urethrectomy is usually
performed at the time of the cystectomy, unless the
patient is a candidate for an orthotopic neobladder.
Distal urethrectomy is performed in patients with tumors
of the distal one-third of the urethra, preferably for
tumors close to the meatus.
Urethrectomy for Small Distal Tumors
The patient is placed in a lithotomy position.
Trendelenburg position helps better visualization of the
anterior vaginal wall. A Foley catheter is inserted in the
urethra and a weighted speculum is placed in the vagina.
The labia are retracted with silk sutures (Figure 41-13).
The urethral meatus is circumscribed with a purse
string sutures. A circumferential incision is made
around the urethra (Figure 41-14). Palpation of the
Foley catheter allows the urethra to be dissected out in
a plane between the full thickness of the urethra and the
surrounding tissues. The anterior vaginal wall may be
incorporated en bloc in the posterior dissection to
obtain negative margin. Proximal dissection of the ure-
thra is complete if a reasonable margin (5 mm) proximal
to the tumor is achieved. The urethra is tied with a silk
suture to prevent tumor spillage and the distal urethra
transected (Figure 41-15). Negative margins are con-
firmed by frozen section. The proximal cut edge of the
urethra is now approximated with 3-0 absorbable
sutures to the vaginal mucosa to create a neoorifice

Figure 41-8 A, Incision used for dissection of the urethral
meatus and the glandular urethra (B). Note that the penis has
been placed in its normal anatomic position.
Figure 41-9 Anatomy and ligation of bulbar urethral arteries.
A, B, Ligation of bulbar urethral arteries with hemoclips. C,
Lateral view shows relationship between internal pudendal
and bulbar arteries, and ischium and inferior ramus of pubis.
The bulbar arteries should not be fulgurated to prevent injury
to internal pudendal arteries from which they arise and which
provide arterial supply to corpora cavernosa. (From Brendler
CB, Schlegel PN, Walsh PC: J Urol 1990; 144:270–273.)
Chapter 41 Urethrectomy 691
Figure 41-10 Dissection of the proximal urethra at the
urogenital diaphragm. (From Brendler CB, Schlegel PN,
Walsh PC: J Urol 1990; 144:270–273.)
(Figure 41-16). The anterior vaginal wall is also closed
with absorbable sutures. The proximal urethra and the
vaginal mucosa may need to be mobilized to achieve
a tension-free anastomosis. A Foley catheter is left
indwelling for 7 days and a vaginal pack for about 24 hours.
Treatment of Larger Distal or Proximal Urethral
Tumors
Extensive dissection of the mid to proximal urethra can
result in incontinence. If the tumor is not involving the
bladder neck, then a distal urethrectomy is performed,
including a cuff of the bladder neck. The bladder is pre-
served, augmented, and a continent cutaneous urinary
diversion performed. The patient will need to catheterize
the augmented continent bladder. This approach is
employed for squamous cell carcinoma and adeno carci-
noma of the urethra. Bladder preserving techniques can-
not be performed for transitional cell cancer, as they are
a field defect change mandating a cystectomy.
The patient is positioned in a lithotomy position.
There are 3 steps to the operation. The first step includes
an abdominal part where the bladder neck and proximal
urethra are dissected. However, if there is involvement of
the bladder neck by tumor, a radical cystectomy may be
necessary. Rarely, resection of the pubic ramus, vulva,
692 Part VII Urethra and Penis

Figure 41-11 A, Completed proximal urethrectomy. Dissection of bulbar urethra is completed without difficulty, because the
membranous urethra has previously been mobilized through the pelvis. B, Specimen: total anterior urethra, including fossa
navicularis. (A from Brendler CB, Schlegel PN, Walsh PC: J Urol 1990; 144:270–273; B courtesy Sanjaya Kumar, M.D.)

Figure 41-12 Closure of the perineal incision and placement Figure 41-13 Exposure of urethra and vagina.
of the Jackson-Pratt drain. [From Walsh PC (ed): Campbell’s
Urology, 6th edition. Philadelphia, WB Saunders, 1992.]
 Chapter 41 Urethrectomy 693

Figure 41-14 Placement of suture around urethral meatus Figure 41-15 Transection of distal urethra.
and incision of urethra and anterior vaginal wall.

and pelvic tissues may be necessary. In the face of lymph

node involvement or extensive tumor, given the poor
prognosis, only palliative procedures should be per-
formed. The perineal dissection is next. It is similar but
more extensive than that for distal urethrectomy.
Sometimes, a more extensive dissection of the anterior
vaginal wall is necessary to achieve complete tumor
resection. If the anterior vaginal tissue cannot be suffi-
ciently mobilized to close the defect, gracilis flaps can be
raised to close the defect. The third stage is closure of the
bladder neck, bladder augmentation, and creation of a
continent reservoir. Details of these procedures have
been described elsewhere in this book.

SUMMARY
Urethrectomy is well tolerated in both males and Figure 41-16 Creation of neourethral orifice and closure of
females. Postoperative edema and ecchymosis is common anterior vaginal wall.
but obtaining meticulous hemostasis and anatomic clo-
sure can minimize postoperative hematomas and infec-
tion. Overall cosmetic results are excellent. Urethral REFERENCES
stenosis in females can be easily managed with dilations.
Cancer control depends on the histology, stage, and 1. Naitoh J, Aronson WJ, DeKernion JB: Urethral cancer in
grade of the tumor. In general, urethrectomy alone women. In Graham SD Jr (ed): Glenn’s Urologic Surgery,
results in excellent cure rates for low stage and low-grade 5th edition, pp 461–466. Philadelphia, Lippincott,
tumors. The cure rate for more advanced tumors is lim- Williams and Wilkins, 1998.
ited despite extensive surgery.
694 Part VII Urethra and Penis
2. Kakizoe T, Tobisu K: Transitional cell cancer of the
urethra in men and women associated with bladder
cancer. Jpn J Clin Oncol 1998; 28(6):357–359.
3. Hardeman SW, Soloway MS: Urethral recurrence
following radical cystectomy. J Urol 1990; 144:666–669.
4. Levinson KA, Douglas EJ, Wishnow KI: Indications for
urethrectomy in an era of continent urinary diversion.
J Urol 1990; 144:73–75.
5. Stenzl A, Draxl H, Posch B, et al: The risk of urethral
tumors in female bladder cancer: can the urethra be used
for orthotopic reconstruction of the urinary tract? J Urol
1995; 153:950–955.
6. Freeman JA, Tarter TA, Esrig D, et al: Urethral
recurrence in patients with orthotopic ileal neobladders. J
Urol 1996; 156:1615–1619.
7. Brendler CB, Schlegel PN, Walsh PC: Urethrectomy
with preservation of potency. J Urol 1990; 144:270–273.
8. Gheiler EL, Tfilli MV, Tiguert R, et al: Management of
primary urethral cancer. Urology 1998; 52(3):488–493.
9. Dalbagni G, Zhang ZF, Lacombe L, Herr HW: Male
urethral carcinoma: analysis of treatment outcome.
Urology 1999; 53(6):1126–1132.
10. Aronson WJ, Naitoh J, DeKernion JB: Carcinoma of the
male urethra. In Graham SD Jr (ed): Glenn’s Urologic
Surgery, 5th edition, pp 467–474. Philadelphia,
Lippincott, Williams and Wilkins, 1998.
C H A P T E R
42Squamous Cell Carcinoma of the
Penis: Diagnosis and Staging
Kevin R. Loughlin, MD, MBA
INCIDENCE
The incidence of squamous cell carcinoma of the penis
varies widely according to geographic distribution. In the
United Sates and most industrialized countries, squa-
mous cell carcinoma of the penis is a rare malignancy,
accounting for <1% of all male cancers.1,2 The incidence
in the United States has been estimated to be 1 to 2 cases
per 100,000 males per year.2,3 However, in societies that
are more agrarian and where circumcision is less com-
mon, the incidence of squamous cell cancer of the penis
is much higher. Reddy et al.4 have reported that penile
cancer comprises 16.7% of all cancer in parts of India,
and Dodge and Linsell5 have reported that penile cancer
accounts for 12.2% of all cancers diagnosed in Uganda.
EPIDEMIOLOGY
Squamous cell carcinoma of the penis is virtually
unknown in populations where neonatal circumcision is
routinely practiced. Maden et al.6 have reported that the
risk for penile cancer was 3.2 times greater in men who
were never circumcised and 3.0 times greater in men who
underwent circumcision after the neonatal period. These
authors also identified a 2.8-times-increased risk for
penile cancer among current smokers compared to men
who never smoked.6
Penile squamous cell carcinoma most typically occurs
in men in the sixth and seventh decades of life; however,
it can occur in men below the age of 40.3 Racial predilec-
tion has not been clearly proven, and any observed racial
differences are more likely due to socioeconomic or envi-
ronmental factors.7
There appears to be an infectious component to the
etiology of squamous penile cancer. Maden et al.6 have
reported a strong correlation between a history of geni-
tal warts and subsequent development of penile cancer.
These authors reported that the risk of penile cancer
among men who reported a history of genital warts was
5.9 times that of men who reported no such history.6
Beyond the link between a history of condylomata and
subsequent penile cancer, there is strong molecular bio-
logic evidence demonstrating an association between
human papillomavirus (HPV) infection and subsequent
penile cancer. Iwasawa et al.8 examined 111 untreated
penile carcinomas retrospectively and found 70 to be
positive for HPV DNA by polymerase chain reaction. In
situ hybridization analysis found the HPV to be localized
in the nuclei of the malignant cells.
Similar findings have been published by Scinicariello
et al.9 They demonstrated that HPV 16 DNA was incor-
porated into the host’s genome in a primary squamous
cell carcinoma and its lymph node metastases using
Southern blot analysis and two-dimensional gel elec-
trophoresis. These findings suggest a causal relationship
between HPV and penile squamous cell carcinoma.
Other reports have shown a similar relationship between
HPV 16 and cervical cancer.10 Such relationships raise
the question of whether penile and cervical carcinomas
may, in some instances, be considered venereal disease.11
DIFFERENTIAL DIAGNOSIS
The clinician must be aware of several pathologic condi-
tions of the penis that may mimic squamous cell carci-
noma. Buschke-Löwenstein tumors may grossly be
indistinguishable from squamous cell carcinoma.
Buschke-Löwenstein tumors also resemble condyloma
acuminatum and have been referred to as “giant condy-
loma.” However, they differ in that Buschke-Löwenstein
tumors can invade and penetrate tissue, whereas condy-
loma acuminatum cannot. Despite the ability to invade
locally, Buschke-Löwenstein tumors rarely metastasize.
695
696 Part VII Urethra and Penis
However, as with condylomata acuminatum and squa-
mous cell carcinoma, the etiology of some Buschke-
Löwenstein tumors appears to be viral. HPV types 6 and
11 have been identified in some of these lesions.12
Erythroplasia of Queyrat and Bowen’s disease are both
considered carcinoma in situ of the penis. Erythroplasia
was first described by Queyrat13 as a red, velvety lesion
found on the glans penis or prepuce. The lesion may be
ulcerative or painful. Histologically, the mucosa appears
to be replaced by atypical, hyperplastic cells with hyper-
chromatic nuclei and mitotic figures.
Bowen’s disease refers to an intraepithelial neoplasm
of the skin associated with a high occurrence of subse-
quent internal malignancy. 14 However, the terms
“Bowen’s disease of the penis” and “erythroplasia of
Queyrat” are used interchangeably. Visceral disease is
not associated with carcinoma in situ of the penis. HPV
has also been identified in carcinoma in situ of the
penis.15
PRESENTATION
Squamous cell carcinoma of the penis occurs almost
exclusively in uncircumcised men. The cancer typically
begins as a small lesion on the glans. The primary lesion
may be either exophytic or flat and ulcerative. The local
lesion can grow to invade the entire glans, shaft, and cor-
pora. The only reliable means of diagnosis is biopsy and
histologic examination. No definite therapy, surgical or
medical, should be instituted prior to histologic diagno-
sis. It is not unusual for many of these patients to delay
seeking medical attention, and it has been reported that
15% to 50% of patients have the penile lesion for >1 year
prior to diagnosis.16,17 Pain is usually not a presenting
complaint, although weakness, weight loss, and fatigue
can be present as a result of chronic suppuration.
The physical examination should note the size and
extent of the local lesion. In addition, there should be
careful palpation of the inguinal areas to determine if
adenopathy is present.
LABORATORY STUDIES AND STAGING
There are no tumor markers for penile carcinoma.
However, several investigators have reported an associa-
tion between penile carcinoma and hypercalcemia.18,19
Sklaroff and Yagoda19 reported that 17 of 81 patients
with penile carcinoma treated at Memorial Sloan-
Kettering were hypercalcemic. Hypercalcemia seemed to
be related to the bulk of the disease and may resolve with
surgical excision of inguinal metastases.20 Parathormone-
like substances can be produced by the primary tumor or
metastases.21
The most common sites of metastatic spread of penile
cancer are the inguinal lymph nodes, the pelvic lymph
nodes, lung, and bone. Cavernosography, lymphangiog-
raphy, computed tomography (CT), ultrasonography,
and magnetic resonance imaging (MRI) have all been uti-
lized to stage the local lesion and metastatic extent of
penile cancer. Despite reports of its accuracy, caver-
nosography is normally not performed because of the
invasive nature of the technique.22
Horenblas et al.23 examined the role of lymphangiog-
raphy, CT, and fine-needle aspiration in penile cancer
staging. In 98 patients with penile cancer, they found that
CT scan provided accurate local staging in 74% of the
patients. Lymphangiography was utilized in 19 patients
to assess regional (inguinal and pelvic) lymph node status.
All 6 patients with pathologically proven negative nodes
had negative lymphangiograms; however, of the 13
patients with pathologically proven positive nodal
involvement, 9 had negative lymphangiograms and 4
were positive, for a sensitivity of 31% and a specificity of
100%. Fine-needle aspiration was used to evaluate the
inguinal nodes only in 18 patients. In this cohort, aspira-
tion cytology had a sensitivity of 71% and a specificity of
100%.
The use of ultrasound in the staging of primary penile
cancer was first reported in 2 patients in 1989.24 A larger
experience was reported by Horenblas et al.25 In their
group of 16 patients, accurate assessment of the depth
and extent of the primary lesion was only achieved in 7
patients (44%). Ultrasound was most limited in differen-
tiating invasion of subepithelial tissue from corpus spon-
giosum in the glans. However, determination of invasion
into the corpus cavernosum was clearly demonstrated in
all cases where it was present.
MRI has also been used to stage penile carcinoma.
deKervilier et al.26 reported their preliminary experience
with MRI and staging penile cancer. They found that
MRI correctly staged local tumors in 7 of 9 cases. T2-
weighted sequences were most useful, and they recom-
mended that spin-echo T2-weighted sequences should
be used in evaluating such patients.
Aspiration of nodes under either fluoroscopic or com-
puted tomographic guidance has been reported as an
additional staging technique. However, like other biopsy
techniques, false negatives can occur.27
In addition to radiographic staging of penile cancer,
Cabanas28 introduced the concept of “sentinel node
biopsy.” This concept was based on the belief that penile
cancer first spreads to a group of nodes located supero-
medial to the junction of the saphenous and femoral
veins in the area of the superficial epigastric vein.
However, subsequent reports29–31 have failed to confirm
the efficacy of the sentinel node biopsy and such a stag-
ing procedure is no longer recommended. Finally, in
addition to staging the local lesion and regional lymph
nodes, all patients with penile cancer should have a base-
line chest x-ray and bone scan.
 Chapter 42 Squamous Cell Carcinoma of the Penis 697

A more recent staging system that incorporates the

STAGING SYSTEMS
Two major staging systems have been commonly
employed to stage penile cancer. The Jackson system,
introduced in 1966,32 is the oldest system used (Table
42-1). A newer system, the TNM classification, is widely
accepted and is now more commonly used than the
Jackson system (Table 42-2).
histologic degree of differentiation and the extent of local
invasion of the primary tumor has been recently pro-
posed by Heyns et al.33 Their staging system appears in
Table 42-3. It provides a predictive distinction between
T1 and T2-4 tumors and indicates that lymphadenec-
tomy can be avoided in T1 tumors but should be per-
formed in all patients with T2 to T4 tumors.

Table 42-1 Classification for Carcinoma of the Penis Table 42-3 Heyns Classification of Penile
Stage I (A) Tumors confined to glans, prepuce, or both Carcinoma-Primary Lesion
T1 Grade 1–2 with invasion through dermis
Stage II (B) Tumors extending onto shaft of penis
T2 Any grade with invasion through the corpus
Stage III (C) Tumors with inguinal metastasis that spongiosum or cavernosum
are operable
T3 Any grade with invasion of the urethra
Stage IV (D) Tumors involving adjacent structures;
tumors associated with inoperable inguinal T4 Grade 3, regardless of invasion
metastasis or distant metastasis

Table 42-2 TNM Classification of Penile Carcinoma SUMMARY

Primary tumor (T) Penile cancer is a rare malignancy in regions where cir-
cumcision is routinely practiced. A careful physical exam-
Tx Primary tumor cannot be assessed
ination and radiographic imaging are necessary to stage
T0 No evidence of primary tumor local and distant involvement of the tumor. A biopsy and
pathologic confirmation of the diagnosis must be
Tis Carcinoma in situ obtained prior to initiating treatment.
Ta Noninvasive verrucous carcinoma

T1 Tumor invades subepithelial connective tissue REFERENCES

T2 Tumor invades corpus spongiosum or cavernosum
1. Grabstald H: Cancer of the penis. J Cont Ed Urol 1979;
T3 Tumor invades urethra or prostate 18:15.
2. Sufrin G, Huben R: Benigh and malignant lesions of the
T4 Tumor invades other adjacent structures penis. In Gillenwater JY, Grayback JT, Howard SS,
Duckett JW (eds): Adult and Pediatric Urology, 2nd
Regional lymph nodes (N) edition, pp 1643–1681. St. Louis, Mosby, Year Book, 1991.
3. Schellhammer PF, Jordon GH, Schlossberg SM:
Nx Regional lymph nodes cannot be assessed Tumors of the penis. In Walsh PC, Retik AB, Stamey TA,
Vaughan ED Jr (eds): Campbell’s Urology, 6th edition,
N0 No regional lymph node metastasis
pp 1264–1298. Philadelphia, WB Saunders Co, 1992.
N1 Metastasis in a single superficial, inguinal lymph node 4. Reddy CRRM, Raghavaigah NV, Mouli KC: Prevalence
of carcinoma of the penis with special reference to India.
N2 Metastases in multiple or bilateral superficial Int Surg 1978; 60:470.
inguinal lymph nodes 5. Dodge OG, Linsell CA: Carcinoma of the penis in
Uganda and Kenya Africa. Cancer 1963; 16:1255.
N3 Metastasis in deep inguinal or pelvic lymph node(s) 6. Maden C, Sherman KJ, Beckmann AM, et al: History of
unilateral or bilateral circumcision, medical conditions, sexual activity and risk
of penile cancer. J Natl Cancer Inst 1993; 85:19.
Distant metastases (M) 7. Hall NEL, Schottenfeld D: Penis. In Shottenfeld D,
Fraumens JF Jr (eds): Cancer Epidemiology and
Mx Distant metastasis cannot be assessed Prevention, p 964. Philadelphia, WB Saunders, 1982.
8. Iwasawa A, Kumanoto Y, Fujnaga K: Detection of human
M0 No distant metastases
papilloma virus deoxyribonucleic acid in penile carcinoma
M1 Distant metastases by polymerase chain reaction and in situ hybridization.
J Urol 1993; 149:59.
698 Part VII Urethra and Penis
9. Scinicariello F, Rudy P, Saltzstein D, et al: Human
papilloma virus 16 exhibits a similar integration pattern in
primary squamous cell carcinoma of the penis and its
metastasis. Cancer 1992; 70:2143.
10. Rohan T, Mann V, McLaughlin J, et al: PCR detected
genital papilloma virus infection: prevalence and
association with risk factors for cervical cancer. Int J
Cancer 1991; 49:856.
11. Loughlin KR: Penile cancer. Curr Opin Urol 1993; 3:415.
12. Boshart M, Zor Hausen H: Human papilloma virus (HPV)
in Buschke-Löwenstein tumors: physical state of the DNA
and identification of a tandem duplication in the non-
coding region of a HPV 6 subtype. J Virol 1986; 58:963.
13. Queyrat L: Erythroplasia du gland. Sec Franc Dermatol
Syphilol 1911; 22:378.
14. Bowen J: Precancerous dermatoses: a review of two cases
of chronic atypical epithelial proliferation. J Cutan Dis
1912; 30:241.
15. Pfister H, Haneke E: Demonstration of human papilloma
virus type 2 DNA in Bowen’s disease. Arch Dermatol Res
1984; 276:123.
16. Hardner J, Bhanalaph T, Murphy GP, et al: Carcinoma of
the penis: analysis of therapy in 100 consecutive cases.
J Urol 1972; 108:428.
17. Gursel EO, Georgourtzos C, Uson AC, et al: Penile
cancer. Urology 1973; 1:569.
18. Rudd FV, Rott RK, Skoglund RW, Ansell JS: Tumor
induced hypercalcemia. J Urol 1972; 107:986.
19. Sklaroff RB, Yagoda A: Penile cancer: natural history and
therapy. In Chemotherapy and Urological Malignancy, pp
98–105. New York, Springer, 1982.
20. Block NL, Rosen P, Whitmore WF: Hemipelvectomy for
advanced penile cancer. J Urol 1973; 110:703.
21. Malakoff AF, Schmidt JD: Metastatic carcinoma of penis
complicated by hypercalcemia. Urology 1975; 5:519.
22. Raghavaiah NV: Corpus cavernosogram in the evaluation
of carcinoma of the penis. J Urol 1978; 120:423.
23. Horenblas S, Van Tinteren H, Delemarre JF, et al:
Squamous cell carcinoma of the penis: accuracy of tumor,
nodes and metastasis classification system and role of
lymphangiography, computerized tomography scan and
fine needle aspiration cytology. J Urol 1991; 146:1279.
24. Yamashita T, Ogawa A: Ultrasound in penile cancer. Urol
Radiol 1989; 11:174.
25. Horenblas S, Kroger R, Gallee MPW, et al: Ultrasound in
squamous cell carcinoma of the penis: a useful addition to
clinical staging. Urology 1994; 43:702.
26. deKervilier E, Ollier P, Desgrandchamps F, et al:
Magnetic resonance imaging in patients with penile
carcinoma. Br J Radiol 1995; 68:704.
27. Scappini P, Piscioli F, Pusiol T, et al: Penile cancer
aspiration biopsy cytology for staging. Cancer 1986;
58:1526–1533.
28. Cabanas R: An approach to the treatment of penile
carcinoma. Cancer 1977; 39:456.
29. Catalona WJ: Role of lymphadenectomy in carcinomas of
the penis. Urol Clin North Am 1980; 7:785.
30. Perinetti EP, Crane DC, Catalona WJ: Unreliability of
sentinel lymph node biopsy for staging penile carcinoma.
J Urol 1980; 124:734.
31. Wespes E, Simon J, Schulmann CC: Cabanas’ approach:
Is sentinel node biopsy reliable for staging of penile
carcinoma? Urology 1986; 28:278.
32. Jackson SM: The treatment of carcinoma of the penis.
Br J Surg 1966; 53:33.
33. Heyns CF, VanVollenhaven P, Steenkamp JW, Allen FJ,
Van Velden DJ: Carcinoma of the penis – appraisal of a
modified tumor-staging system. Br J Urol 1997;
80:307–312.
C H A P T E R
43 Superficial Carcinoma of the Penis:
Management and Prognosis
Jay S. Belani, MD, and Gerald L. Andriole, MD
Penile cancer is a rare entity in developed nations. In the
United States only 0.3% of all cancers diagnosed are
malignancies of the penis.1 The annual incidence rate in
the U.S. and Europe is about 0.5 to 1 per 100,000 men,1
which has remained constant over the past 5 decades.2 In
other countries the incidence varies based on hygienic
standards and culture. The incidence is much higher in
developing countries, such as Mexico, China, India, and
many African countries. In addition, as socioeconomic
conditions improve in developing countries, the rates of
cancer have declined.
Cancer of the penis usually occurs in elderly men. The
rate of cancer abruptly increases at about age 60 and
peaks at 80 years old.1,3 This trend seems to be evident
worldwide; however, those countries with a higher inci-
dence of the disease seem to have an earlier age of onset.
In the U.S., blacks are more commonly diagnosed than
whites by about 2:1.1 However, decreased rates of cir-
cumcision and a lower socioeconomic status may be con-
founding factors in the statistics.1,2
The most common malignancy of the penis is squa-
mous cell carcinoma (SCC), accounting for about 95% of
cases.3,4 Other rare neoplasms include malignant
melanoma, basal cell carcinoma, sarcoma, Paget’s disease,
lymphoreticular malignancy, and metastasis from other
sources. In addition, transitional cell carcinoma (TCC) of
the urethra can involve the penis by local spread.
ANATOMY
Knowledge of penile anatomy is essential in compre-
hending the pathophysiology, staging, and management
options of penile cancer. The penis is made up of two
corpora cavernosa dorsally and the corpus spongiosum
ventrally. Buck’s fascia provides a dense layer of covering
around the corpora. Superficial to Buck’s fascia lie the
superficial penile fascia and skin.
The arterial supply of the penis is derived from
branches of the penile artery, which arises from the
pudendal artery. The penile artery divides into the bul-
bourethral artery, deep artery (AKA: cavernosal artery),
and dorsal penile artery.5 Three venous systems drain the
penis: the superficial, intermediate, and deep.6 The
superficial system drains the skin of the dorsal penis and
prepuce. The intermediate system is made up of the deep
dorsal veins and circumflex veins, which drain into
Santorini’s plexus along the prostate. The deep system
consists of the cavernosal and crural veins, which are the
main drainage system of the corpora cavernosa and drain
into the internal pudendal vein.
Penile lymph vessels drain into one of two inguinal
nodal groups: superficial or deep. In general, most lym-
phatic channels from the body of the penis and prepuce
travel to the superficial inguinal nodes. The glans may
drain into the superficial or deep inguinal nodes.5
More proximal lymphatic drainage generally occurs in
a stepwise fashion. The superficial nodes drain into the
deep inguinal nodes, which, in turn, drain into the pelvic
lymph nodes. Lymphatic drainage is not uniform and sig-
nificant cross-communication occurs. Hence, tumors
may spread to ipsilateral, contralateral, or bilateral lymph
node chains (Figures 43-1 and 43-2).7
SQUAMOUS CELL CARCINOMA
Presentation, Signs and Symptoms
Carcinoma of the penis may present as an area of ery-
thema, induration, ulceration, or nonhealing sore. Some
699
700 Part VII Urethra and Penis
Superficial dorsal vein
Deep dorsal vein Dorsal artery
Buck’s fascia
Cavernosal artery
Urethra Corpus cavernosum
Corpus sponglosum
Figure 43-1 Cross-sectional diagram of penile shaft.
Figure 43-2 Diagram of penile lymphatic drainage.
patients experience persistent bleeding or eventual
sloughing and self-amputaion.10 About 47% present with
a mass or nodule, 35% with an ulcer, and 17% with an
inflammatory lesion or bleeding.11 Only 0.7% of cases
are diagnosed incidentally on a circumcision specimen.
The site of origin is more commonly distal, with 48%
occurring on the glans, 21% on the prepuce, 9% in both
locations, and 6% along the coronal sulcus.11 Direct
extension of the distal tumor to the shaft occurs in 14%
of cases.11
A delay in diagnosis between the initial finding of a
penile lesion and presentation to the physician is typically
between 3 and 26 months, with an average of 10 months
and 60% of lesions are larger than 2 cm at diagnosis.
About 50% of patients will present with inguinal lym-
phadenopathy.11
Physical examination is important in the diagnosis of
penile cancer. Size, location, fixation, and extent of cor-
poral body involvement must be evaluated. Both inguinal
regions should be palpated for lymphadenopathy and the
penile base and scrotum should be inspected.10
Rarely, the primary tumor may be concealed by the
prepuce, and a patient may present with inguinal suppu-
ration, ulceration, or hemorrhage as a result of lymph
node metastasis. Other rare presentations are urinary fis-
tula, urinary retention, and destruction or self-amputa-
tion of the phallus.
Penile carcinoma exhibits two growth patterns: fun-
gating and exophytic, or ulcerative and infiltrative.12,13
Fungating tumors usually present as a papillary verrucous
lesion on the glans or prepuce. Ulcerating tumors pres-
ent as a small, erythematous ulcer, usually on the glans.
As ulcerating lesions grow they infiltrate into deeper tis-
sues and are more likely to metastasize than fungating
tumors. Lateral destruction occurs as the tumor involves
the deeper tissues.
NATURAL HISTORY
SCC usually begins as a superficial growth along the
glans or prepuce and spreads locally. As it grows, Buck’s
fascia provides a strong barrier for deeper infiltration;
however, if left untreated, the tumor will erode into the
corpus cavernosum. Hematogenous spread usually does
not occur despite the extensive vascular network within
the corpus cavernosa. Fistula formation may result with
urethral involvement. Metastasis to the superficial
inguinal nodes is more likely to occur if the prepuce is
initially involved, while metastasis to both the superficial
and deep inguinal nodes occurs with glans involvement.
Spread then goes to the pelvic nodes. Bilateral or cross-
inguinal lymph node involvement is possible given the
rich anastomoses between lymphatics in the subcutaneous
tissue that cross the midline.13
At presentation about 50% of patients have inguinal
lymphadenopathy on examination. About 55% of these
patients have inflammatory inguinal lymphadenopathy
from infection of the primary tumor, while 45% have
metastatic tumor.11,13 Less than 2% have visceral spread
of disease at presentation.13
DIAGNOSIS
Lynch and Krush showed that patients with penile cancer
delay seeking medical attention longer than patients with
other cancers.14 Gursel and Hardner each found that
between 15% and 50% of patients delay diagnosis for
greater than 1 year.15,16 Moreover, Hardner showed a
worse prognosis for patients with delayed presentation.15
 Chapter 43 Superficial Carcinoma of the Penis: Management and Prognosis 701
Given the fact that most tumors begin as superficial
lesions, and that many patients delay presentation, it is
vitally important to biopsy all suspicious lesions at time
of presentation, especially if the lesion fails to resolve
after a short course of conservative treatment. The
biopsy is done to confirm the diagnosis of carcinoma and
determine the extent of invasion. If the lesion is small, an
excisional biopsy may be performed. If it is large, an inci-
sional biopsy, taken from the periphery to include normal
epithelium, is adequate.
If the lesion is suspected to be hidden by a phimotic
foreskin, then a preputial slit should be performed. There
have been no reported cases of spread as a result of the
dorsal slit or biopsy.10,17 Lastly, in some cases, circumcision
may be done to obtain an adequate tissue sample.
GRADING AND STAGING
Histology
Histologically, SCC of the penis has been categorized by
extent of malignant transformation, i.e., carcinoma in
situ (CIS) and invasive SCC. CIS represents a full thick-
ness of atypical epithelial squamous cells. Both Bowen’s
disease and erythroplasia of Queryat represent premalig-
nant lesions that have this growth pattern. In addition,
CIS is often found in association with invasive SCC.18
Two classification systems, described by Broder and
Cubilla, for invasive SCC have been proposed. Broder’s
classification of SCC of the skin has been applied to penile
lesions. Table 43-1 summarizes the system. Increasing
grade has been associated with an increased risk of inguinal
metastasis. The chance of spread to inguinal nodes for
Table 43-1 The Broder’s Classification System For
Grading SCC
Grade Histology
I Cells well differentiated with keratinization
Keratin pearls
II–III Increased nuclear atypia and mitotic activity
Fewer keratin pearls
IV Markedly increased nuclear pleomorphism
and mitotic activity
Necrosis
No keratin pearls
Lymphatic and perineural invasion
Deeply invasive
From Broders AC: Ann Surg 1921; 73:141.
grades 1, 2, and 3 tumors is between 0% to 29%, 26% to
65%, and 80% to 100%, respectively.20–23
A second histologic classification system has been pro-
posed by Cubilla et al,24 which divides penile cancers into
four categories: superficial spread, vertical growth, verru-
cous, and multicentric. Table 43-2 describes each type.
Villavicencio et al.20 studied 81 patients and defined
prognostic values with each category. About 70% of the
patients evaluated had a superficial spreading SCC.
About 66% of these patients were found to be disease
free at an average of 61 months after treatment, and 35%
were found to have lymphatic spread. Vertical growth
implies a worse prognosis. About 90% of these tumors
are usually high-grade lesions, and only 30% are disease
free at 5 years. Verrucous growth tumors usually are of
low grade and all cases have been found to be disease free
at 5 years follow-up.
Staging
Staging of penile SCC was introduced by Jackson in
196625 and is shown in Table 43-3. Stage I lesions are
confined to the glans or prepuce. Stage II lesions extend
along the penile shaft. Stage III tumors involve the
Table 43-2 Classification for SCC of the Penis
Category Description
Superficial spreading Centrifugal growth usually
restricted to superficial layers
Vertical growth Spread is vertical with little radial
growth
Verrucous Usually large, exophytic lesions
Multicentric Two or more foci of histologic
spread
From Cubilla AL, Barreto J, Caballero C, et al: Am J Surg Pathol
1993; 17:753.
Table 43-3 Jackson Staging System
Stage Description
I Tumor confined to glans or prepuce
II Invasion into shaft or corpora; no nodal or distant
metastasis
III Tumor confined to penis; operable inguinal nodal
metastasis
IV Tumor involves adjacent structures; distant
metastasis and/or inoperable inguinal nodes
From Jackson SM: Br J Surg 1966; 53:33.
 Chapter 43 Superficial Carcinoma of the Penis: Management and Prognosis 703
spread beyond the foreskin requires a more aggressive
resection. More proximal lesions may require a more
extensive resection and multiple biopsies of the margins
are warranted to rule out residual disease.8 Moreover, in
patients with severe phimosis or chronic balanoposthitis,
Huben recommends 5000 cGy of radiation therapy
over 5 weeks to eradicate any occult disease after
circumcision.34
PARTIAL PENECTOMY
Lesions of the glans penis can be managed with partial
penectomy as long as a 1.5- to 2.0-cm margin is obtained
to limit local recurrence.8,37,38 Simple wedge resection
has a higher recurrence rate. Local excision is associated
with a 40% to 50% recurrence rate and is not adequate
for any T2 or larger lesion.34,38,39
Surgical Technique
The penis is thoroughly scrubbed with Betadine and the
distal penis containing the tumor is covered with a sterile
surgical glove or condom. A tourniquet is applied to the
base of the penis to minimize blood loss.
An incision is made circumferentially 1.5 cm proximal
to the tumor margin at the dorsal aspect and about 2.0 to
2.5 cm proximal to the tumor at the ventral aspect. The
subcutaneous vessels are coagulated and the superficial
dorsal vein is ligated and divided. Buck’s fascia is incised
and the deep dorsal artery and vein are ligated and divided.
The cavernosal bodies are then transected about 1.5 cm
proximal to the tumor margin, and the cavernosal arteries
are ligated. The urethra should be dissected free with a 1-
cm stump left in place distal to the cavernosal bodies.
The specimen is then evaluated by frozen section to
exclude tumor at the margins. If tumor is found, then a
more proximal resection is done. Once resection is com-
plete, the corpora are closed with a horizontal mattress
suture. The tourniquet is loosened and any remaining
bleeding is controlled. The urethra is spatulated and the
excess skin is brought over the exposed cavernosa. The
urethra is anastomosed to a buttonhole in the skin. A
Foley catheter is usually left in place for 5 days while the
anastomosis heals.35,40
Results
Usually patients have excellent control of their urinary
stream and adequate length for intercourse if at least 2 to
3 cm of the shaft is left in place. Jensen41 showed that
45% of patients with a 4- to 6-cm and 25% of patients
with a 2- to 3-cm stump are able to have sexual inter-
course. If too short a phallic stump is left, it may be
engulfed in the suprapubic fat pad and the patient will
have difficulty voiding in the standing position. In these
cases, the patient may be better served by a total penec-
tomy and perineal urethrostomy.34
Studies have shown a local recurrence rate up to 19%
with a 2-cm proximal tumor-free margin.42 McDougal32
showed that 90% of patients with superficial, local dis-
eases will be cured after partial penectomy. Moreover,
Hardner et al.15 illustrated that partial penectomy is as
effective as total penectomy as long as an adequate mar-
gin is obtained.
Complications
Complications of partial penectomy include infection,
hemorrhage, and stenosis of the urethral meatus.
Infection can occur as a result of spread of bacteria from
the perineum or inoculation from the primary tumor
itself. Infection is minimized by perioperative and post-
operative antibiotics covering skin flora. Wound infec-
tions are best managed by open drainage and allowing
the area to heal by secondary intention. Bleeding is best
avoided by attention to hemostasis after the tourniquet is
removed. Meatal stenosis is minimized with a wide spat-
ulation of the urethra. The problem is best managed with
dilation using meatal sounds or meatotomy.40
TOTAL PENECTOMY
Total penectomy is usually reserved for proximal lesions
where an adequate proximal margin would not be
obtained via partial penectomy. It is the most extensive
means of local surgical excision and has the least risk of
local recurrence, amongst all surgical options.
Surgical Technique
Preparation of the penis is similar to that of partial penec-
tomy, and the tumor is covered in a sterile glove or con-
dom. The anus is draped outside the operative field. A
vertical elliptical incision is made around the base of the
penis 2 cm from the tumor margin. Ventrally, Buck’s fascia
is incised and the corpus spongiosum is separated from the
corpus cavernosum. The urethra is isolated and divided.
Dorsally, the suspensory ligament is divided and the deep
dorsal arteries and veins are ligated and divided at the level
of the urogenital sinus. The corpus cavernosa are tran-
sected 2 cm proximal to the tumor margin. The corpora
are then closed in similar fashion as described for partial
penectomy. A 1.5-cm elliptical incision is made in the per-
ineum and the skin and subcutaneous tissue are excised.
The urethra is tunneled through the subcutaneous tissue
to this opening, ensuring that it has not kinked or twisted.
It is then spatulated and anastomosed to the skin with
interrupted absorbable suture. The skin over the penile
defect is closed elevating the scrotum anteriorly and an 18
French silicone catheter is left in place.35,40
704 Part VII Urethra and Penis
Complications
Similar to partial penectomy, complications include
infection, hemorrhage, and perineal urethrostomy stric-
ture. Bleeding and wound infection are less common
than with partial penectomy.34 Strictures of the perineal
urethrostomy are usually more difficult to manage, and
conservative management with intermittent catheteriza-
tion may fail. Surgical revision may be required. Lastly,
delayed, extended lymphatic drainage has been
described, and is usually managed with conservative
management.34
IMPACT OF TOTAL AND PARTIAL PENECTOMY
Opjordsmoen and Fossa43 showed that men with radia-
tion therapy had improved sexual function than those
who had undergone partial penectomy. About 83% of
patients had normal or slightly reduced sexual function
after radiation therapy, while 66% of patients had
severely reduced sexual function after partial penectomy.
In addition, the study suggested that those patients who
had local excision with laser therapy had worse sexual
function than those after radiation therapy. None of the
patients studied underwent Mohs’ micrographic surgery.
Despite the impaired sexual function, Opjordsmoen and
Fossa43 showed that 7 out of 25 patients preferred a com-
promise in survival to impaired sexual function, while 17
out of 25 preferred long-term survival to penis-sparing
modalities. Hence, when treating patients with SCC of
the penis, all options should be discussed when choosing
a course of management.
MOHS’ MICROGRAPHIC SURGERY
Mohs’ studies showed that SCC of the skin sends out
thin sheets of tumor cells along the path of least resist-
ance, like nerve sheaths, blood vessel adventitia, or fascial
planes.44 This explains why some tumors recur after exci-
sion with a clearly visualized negative margin. Hence,
Mohs described a technique of maximal tissue sparing
and complete tumor excision—Mohs’ micrographic sur-
gery. Studies have shown cure rates and tissue sparing to
be superior than other tissue-sparing techniques.44–46
Surgical Technique
Two techniques have been described: fresh tissue tech-
nique and fixed tissue technique.
Fresh Tissue Technique
The main tumor mass is debulked. Residual tumor is
then serially excised and evaluated microscopically in
horizontal sectioning. The areas of residual disease are
mapped and the adjacent areas are excised. All tissue is
excised until no tumor is seen microscopically. Using
microscopic mapping, all tumor margins are inspected
and normal tissue is spared.34,44
Fixed Tissue Technique
The technique is similar to the fresh tissue technique; how-
ever, a fixative paste, zinc chloride, is used to mark the sur-
face of the specimen. Excision is then performed and
processed with horizontal sectioning. The technique is
repeated until no neoplastic cells are seen. The difference
is that the patient returns each consecutive day for fixative
application and serial sectioning. The process can take
between 1 to 7 days depending on the extent of the lesion.44
Effectiveness
Five-year cure rate is about 74%, which Mohs suggests is
an improvement given that most tumors he treated were
large and recurrent after other treatment methods.44
Mohs describes an 86% cure rate for stage I tumors, 62%
for stage II, and 0% for stage III disease. These rates are
higher than other local treatment options.45 Because of
the inability to cure stage III disease, Mohs’ micro-
graphic surgery is best reserved for small stages I and II
lesions.
Complications
Risks of Mohs’ surgery are minimal. Infection and bleed-
ing have been described. In addition, delayed healing can
occur, as 80% of lesions are usually left to heal by sec-
ondary intention.46
LASER THERAPY
In 1976, Hofstetter and Frank47 first used laser energy to
treat penile carcinoma and preserve the phallus. Recent
studies have suggested that, if done with attention to
meticulous technique, laser therapy provides as good or
better tumor control compared to partial and total
penectomy without the functional impairment and poor
cosmetic result.48,49
Surgical Technique
The technique of laser excision involves one of two
types of lasers: the Nd:YAG laser or carbon dioxide
laser. The Nd:YAG laser penetrates the tissue and
causes coagulation up to 3 to 4 mm deep. It does not
vaporize much tissue at the surface, and keeps the struc-
tural integrity intact. On the other hand, the carbon
dioxide laser minimally penetrates into deeper layers. It
is a better cutting laser than the Nd:YAG and creates
less of a defect. Hence, studies have suggested that the
 Chapter 43 Superficial Carcinoma of the Penis: Management and Prognosis 705
carbon dioxide laser is better for superficial, noninva-
sive tumors (i.e., CIS), while the Nd:YAG laser is better
suited for more invasive disease (i.e., T1 or possibly T2
disease).50
Prior to treatment the tumor site is biopsied to deter-
mine the depth of penetration and grade of tumor.
Circumcision may be performed if the tumor is on the
foreskin or glans. The extent of the lesion is mapped with
5% acetic acid for 20 minutes. The acid helps demarcate
suspicious areas by staining them white. The laser energy
is then applied to the marked areas with a 3-mm margin
around the perimeter of the tumor site.
Effectiveness
Recurrence rates have ranged between 6% and 26%,
depending on the histologic grade and tumor stage.
Unfortunately, Tietjen and Malek51 suggest that dysplas-
tic tissue may be left behind and up to a 26% of patients
recur. Overall, though, they found an 8.3% local recur-
rence for CIS and a 14.3% local recurrence rate for T1
lesions, compared to a rate as low as 6% and 10% in the
literature, respectively (Table 43-5).
Complications
Complications from laser treatment of penile cancers are
minimal. Pain at the site may persist especially if infec-
tion develops. Preputial lymphedema has also been
described in uncircumcised men.
Frimberger et al.49 showed that all patients treated
with laser coagulation were satisfied with the cosmetic
result. Seventy-five percent of patients had functional
erections for intercourse, no patients developed meatal
strictures, and no patient needed psychologic counseling
as a result of the treatment.
The disadvantages of laser therapy include the lack of
accurate pathologic staging and identification of tumor-
free margins. Instead, a biopsy at the base of excision is
performed to rule out any further extension. Hence, van
Bezooijen et al.50 have argued that laser therapy should
only be used for superficial disease or if the depth is
Table 43-5 Local Recurrence after Laser Ablative Therapy
Follow-Up (months)
Tietjen and Malek51 12–117
Windahl and Hellsten52 8–94
Rothenberger53 13–36
Van Bezooijen et al.50 6–75
Frimberger et al.49 7–168
within 3 mm of the surface. Moreover, Tietjen and
Malek51 have suggested that laser therapy probably leaves
some dysplastic premalignant tissue behind, hence it is
important to follow these patients closely for evidence of
recurrence, and treat any recurrence expeditiously.
RADIATION THERAPY
The effectiveness of radiation therapy for penile cancer
treatment is controversial since there are multiple differ-
ent modalities and no uniform dosage has been used.
Most data come from small, retrospective studies.
Proponents of radiation therapy for penile cancer
advocate that it preserves penile function and eliminates
the distress of possible amputation.54 Surgical excision,
either partial or total penectomy, results in significant
functional and psychologic morbidities.43,54–56 T1 and
T2 penile carcinomas have been cured by radiation ther-
apy; however, significant complications can occur,
depending on the type of radiation given.
Radiation therapy can be used for the primary lesion
via external beam or interstitial therapy. The advantage
of radiation therapy is that it provides local control, and
in cases of failure, salvage surgical control may be per-
formed. Moreover, healing after salvage surgery is usu-
ally not impaired, despite the local radiation.
In treating the primary lesion, some suggest that all
patients undergo circumcision to evaluate the extent of
the primary tumor and possibly provide debulking.
Circumcision minimizes some of the complications, by
decreasing the edema and mucosal irritation and reduc-
ing the risk of secondary infection.57 Ravi et al.58 have
suggested that circumcision is not necessary if the fore-
skin can be retracted easily and kept in that position
while the radiation is given. However, if phimosis is pres-
ent or the lesion cannot be assessed accurately, then cir-
cumcision or a dorsal slit is warranted.
BRACHYTHERAPY
Interstitial brachytherapy is the use of radiation sources
implanted within the site of the tumor. The tumor site is
Tumor Stage (n) Recurrence (%)
Tis (17), T1 (14) 8.3, 14.3
T1 (7), T2 (8) 14, 12
T1(9), T2 (8) 22, 0
Tis (19) 26
Tis (17), T1(10) 5.8, 10
706 Part VII Urethra and Penis
transfixed with needles containing a radioactive sub-
stance. Historically, this has been radon, however, more
recently other radioisotopes, including iridium-192,
cobalt-60, tantalum-111, and gold-190, have been used.
Usually, a dose of 70 Gy is given over 5 to 7 days. The
technique of implantation involves using a Plexiglas tem-
plate with drilled holes to guide the needles into proper
position. This ensures accuracy for a homogenous radia-
tion dose to the entire tumor bed.
Brachytherapy has been most successful in T1 and
T2 diseases. Studies have shown a local recurrence rate
of between 12% and 25%, a penile conservation rate of
67% to 83%, and a disease-free survival rate of 85% to
95% (Table 43-6). 59–63 Most failures occurred in
lesions >4 cm. Kiltie et al.61 reported a local failure rate
of 60% for tumors >4 cm and 14% for tumors <4 cm.
Mazeron et al.64 showed a local failure rate of 11% for
tumors <2 cm, 26% for tumors 2 to 4 cm and 50% for
tumors >4 cm. Hence, brachytherapy is mainly recom-
mended for tumors <4 cm and superficial or moder-
ately infiltrating.64
Complications of brachytherapy include skin necrosis,
urethritis, urethral stricture disease, pigmentation, or
telangiectasias. Sexual potency is usually preserved.65
EXTERNAL BEAM RADIATION
External beam radiation has been used for superficial
invasive carcinoma or CIS. It is used to deliver a low dose
of radiation therapy to a superficial area with a 1- to 2 cm
margin. Gerbaulet and Lambin57 have argued that a low
dose of therapy with a high total dose effectively treats
the lesion and minimizes the risk of fibrosis. For exam-
ple, a 2-Gy fraction can be given per day to a total of 65
to 70 Gy. Problems with external beam radiation include
a prolonged treatment time of 6 to 7 weeks and difficulty
in reproducing the area of radiation.
Table 43-6 Effectiveness of Brachytherapy
% Local Recurrence
Number of Cases (Years Follow-Up)
Crook et al.59 30 15 (2)
24 (5)
Kiltie et al.61 31 25 (5)
Rozan et al.62 184 12 (3)
15 (5)
Soria et al.63 72 25
Delannes et al.60 51 18
Local control rates for external beam radiation ther-
apy ranges from 50% to 90%.65 Sarin et al.66 studied 59
patients who received external beam therapy and found a
5- and 10-year local control rate of 51% and 48%,
respectively. McLean et al.67 found a recurrence rate of
28% (5 of 18) for T1 and T2 tumors. Thirty-three per-
cent of patients required penectomy because of local
recurrence in 5 patients and complications in 1 patient.
Table 43-7 summarizes recent studies and the effective
control rate.
Complications include acute skin irritation and
desquamation and penile soreness or swelling, acutely.
Long-term complications include urethral stricture and
meatal stenosis, which is usually managed with dilation.
Uncommonly, penile necrosis may develop and only a
few patients will have a loss of potency.65,68
MANAGEMENT OF INGUINAL NODES
Inguinal lymph node status provides important prog-
nostic information in managing penile carcinoma.
Overall, those patients without lymph node metasta-
sis have a 5-year survival of about 85%, while those
with metastasis only have a 50% 2-year survival.11 The
dilemma, however, revolves around the inaccuracy of
determining inguinal node spread. About 50% of
patients with palpable inguinal nodes will have metas-
tasis and about 20% of patients without palpably
enlarged nodes will have spread.15,32,56 These data
incorporate both stage I and stage II diseases. Patients
with superficial SCC are unlikely to have inguinal
spread. McDougal et al.32 showed that patients with
stage I disease approach a 100% survival rate free of
tumor after local excision alone. Stage II disease is
more likely to have indolent lymphatic metastasis, and
an inguinal lymphadenectomy may be prudent.32,33,71
Figure 43-3 provides an algorithm for management of
Disease-Free
Survival (%)
Penile Conservation (%) (Years Follow-Up)
83 95 (2)
89 (5)
74.8 85.4 (5)
78 88 (5)
82
67
 Chapter 43 Superficial Carcinoma of the Penis: Management and Prognosis 707

Table 43-7 Effectiveness of External Beam Therapy

Sarin et al.66 McLean et al.67 Sagerman et al.69 Fossa et al.70 Grabstald et al.68

Number of patients 59 18 12 11 10

Local control rate (%) 51 (5) 65 66 73 90 (6–10)

(years follow-up)

48 (10)

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Superficial, well-differentiated tumor*

1. Gloeckler-Ries LAHB, Edwards BK (eds): Cancer

Palpable nodes Nonpalpable nodes
Treat with antibiotics
for 4−6 weeks Observe**
Nonpalpable nodes Palpable nodes
Observe** Lymph node dissection
* Primary tumor is T1 after circumcision, partial or total penectomy.
** Exam every 2 months for 2 years, then every 6 months.
Figure 43-3 Algorithm for management of lymphadenopathy
for superficial penile cancer.
inguinal nodes in patients with low stage SCC of the
penis.
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C H A P T E R
44Invasive Carcinoma of the Penis:
Management and Prognosis
Shahin Tabatabaei, MD, and W. Scott McDougal, MD
EPIDEMIOLOGY
Carcinoma of the penis is an uncommon malignancy in
the United States comprising <1% of all malignancies in
males. This translates into 1 to 2 cases per 100,000 pop-
ulation per annum. The American Cancer Society pre-
dicts that 1400 new cancer cases will occur in 2004. The
peek incidence is in the sixth and seventh decades of life.
In other portions of the world, particularly in Asia,
Africa, and South America, however, it is a more com-
mon disease. There appear to be no racial predilections.
ETIOLOGY
The etiology is somewhat controversial; however, several
facts are quite clear. The presence of a foreskin, phimosis,
chronic inflammatory conditions, treatment with psoralen
and ultraviolet A (PUVA) photochemotherapy, exposure
to human papillomavirus (HPV), and history of smoking
appear to have the most evidence suggesting that they may
play a role in the development of this disease.
Lack of Circumcision/Presence of Foreskin
Circumcision has been established as a prophylactic
measure that reduces the risk of penile cancer.1–4 Penile
squamous cell carcinoma (SCC) is rare among Jews and
Muslims, who practice circumcision during the neonatal
period and childhood, respectively. While penile cancer
is common in Africa, it is rare among the Ibos of Nigeria,
who practice ritual male circumcision soon after birth.5
Indeed it is rare to find cancer of the penis in a patient
who has been circumcised at birth. In a case control
study, neonatal circumcision was associated with a 3-fold
decreased risk, albeit 20% of penile cancer patients had
710
been circumcised neonatally.5,6 It is believed that neona-
tal circumcision has a protective effect, particularly for
invasive carcinoma. Tseng et al.7 discovered that neona-
tal circumcision was inversely associated with invasive
carcinoma (odds ratio [OR] = 0.41; 95% confidence
interval [CI] = 013 to 1.1) but not carcinoma in situ
(CIS).
Phimosis
Almost one-half of individuals with cancer of the penis
have had a history of phimosis. Hellberg et al.8 found a
65-fold relative risk for penile SCC among males with
phimosis in a Swedish case control study. Phimosis is one
of the strongest predictors of invasive carcinoma.6–8 It is
hypothesized that men with phimosis are more likely to
retain smegma. Smegma can cause epithelial hyperplasia
and mild to moderate atypia of the squamous epithelium
of the preputial sac in men with phimosis.9
Chronic Inflammatory Conditions
The association of chronic inflammation and irritation,
burned areas, preexisting scars, and draining sinuses is
well established as predisposing factors for SCC in other
parts of the body. The same observation has been made
for penile cancer.10 Hellberg et al.8 reported that 45% of
patients had at least one episode of balanitis, while 8% of
controls were affected by balanitis.
Lichen sclerosis et atrophicus (LSA) is a chronic
inflammatory skin condition of unknown etiology. The
autoimmune response that is triggered by trauma, injury,
or infection has been suggested as its predisposing

cause.5,11 Nasca et al.12 reported that 5.8% of their 86
patients with LSA developed penile cancer in a 10-year
follow-up study. Bissada et al.13 reported the develop-
ment of SCC in postcircumcision scars in 15 patients.
Smoking
A history of smoking is an independent risk factor for the
development of penile cancer.6–8,14,15 The incidence of
penile cancer among men who had ever smoked ciga-
rettes was 2.4 times that of men who had never smoked.7
Although the exact cause is not known, the accumulation
of nitrosamines in genital secretions has been suggeted.8
Ultraviolet Light Irradiation
Treatment with PUVA photochemotherapy has been
considered as a strong risk factor for penile cancer. In a
12.3-year prospective study of 892 men in a cohort of
patients with psoriasis, who had been treated with oral
methotrexate and PUVA, Stern16 identified 14 patients
(1.6%) with 30 genital neoplasms. Recently Aubin et al.17
questioned the high prevalence of penile cancer in men
treated by PUVA and suggested the carcinogenesis is
probably dose dependent.
Cervical Cancer in the Partner
An association of penile cancer and cervical cancer in
partners of patients with penile cancer has been sug-
gested by several authors.18–21 Hellberg, however, has
clearly showed that these studies had methodologic flaws
and his review of 1064 penile cancer cases in Sweden did
not show any association with cervical cancer in their
partners.22 Other recent studies also found either weak or
no risk elevation of penile cancer in men who had part-
ners with cervical cancer.23–25
Human Papillomavirus Infection
HPV infection is a sexually transmitted disease with a
very high rate of infectivity. The infection is character-
ized by a high rate of spontaneous clearance. At least 75
different types of HPV have been identified and these
types vary not only in their DNA sequences but also in
their clinical manifestations.26,27
Different HPV types have been demonstrated in asso-
ciation with different genital lesions. Clinically, 85% of
grossly visible genital condylomas (condyloma acumi-
nata) or anogenital warts contain HPV type 6 and/or
HPV type 11.26 In contrast, microscopic lesions identi-
fied in the male partners of women with cervical dyspla-
sia were shown to contain HPV types 16 or 18 in 60% to
75% of the cases.26,28 These are the lesions that become
visible only by acetowhitening. The causal role of certain
Chapter 44 Invasive Carcinoma of the Penis 711
types of HPV in the development of intraepithelial neo-
plasia and carcinoma of the female cervix is well sup-
ported by experimental and epidemiologic data. The
relative risk patterns of the 15 most common HPV types
implicated in cervical neoplasm have been assessed and
categorized. These include low-risk group (HPV 6, 11,
42, 43, 44), intermediate-risk group (HPV 31, 33, 35, 51,
52, 58), and high-risk group (HPV 16, 18, 45, 56).
The DNA of high-risk HPV types has been detected
in a substantial subset of penile SCC. Dillner et al.5 noted
up to 40% of penile cancer lesions were positive for HPV
with PCR method in two large series, with the majority
of cases positive only for HPV 16 or 18. So far, a few
seroepidemiologic studies indicate that exposure to HPV
is indeed a major risk factor for penile cancer. We could
not find any study to confirm the causal effect of this
association.
The presence of HPV E6 and E7 oncoproteins may
explain the carcinogenic effect of the viral infection.
E6/E7 genes immortalize human keratinocyte on trans-
fection and directly stimulate cell proliferation.
Furthermore, E6/E7 oncoproteins bind to the tumor
suppressor proteins p53 and Rb (retinoblastoma), respec-
tively. E6 binds to ubiquitin-dependent proteinase,
which promotes the degradation of p53. E7 displaces the
transcription factor E2F from the Rb protein and alters
the cell cycle.27 However, we are not aware of any study
that has investigated the expression of E6 and E7 onco-
proteins in penile cancer specimens.
Chromosomal instability,29 cooperation with activated
oncogenes, methylation of viral and cellular DNA sites,
and telomerase activation are some of the other potential
mechanisms of HPV oncogenicity.30–32
PATHOLOGY
Worldwide reports indicate that 95% of penile cancers
are SCC. Sarcomas account for 4% to 5% of the remain-
ing cancers. Rarely, other cancers, such as melanoma and
basal cell carcinoma, arise in the penis.
Premalignant Lesions
The terminology of premalignant penile lesions is one
of the major areas of confusion in the nomenclature of
penile lesions. Premalignant lesions of the penis may be
categorized into two groups as follows. (1) Lesions that
are sporadically associated with SCC of the penis:
bowenoid papulosis of the penis, balanitis xerotica
obliterans (BXO), cutaneous horn of the penis and
Buschke-Löwenstein tumor (Verrucous carcinoma,
Giant condyloma acuminatum). (2) Lesions that are at
risk of developing into invasive SCC of the penis: CIS
of the penis (erythroplasia of Queyrat and Bowen’s
disease).
712 Part VII Urethra and Penis
Bowenoid Papulosis
Bowenoid papulosis, although histologically similar to
CIS, usually has a benign course.33,34 Patterson et al.33
evaluated 51 patients with bowenoid papulosis and
showed that the lesion usually occurs in young men
(mean age 29.5 years). Lesions occur most commonly on
the penile shaft and are usually multicentric, pigmented
papules ranging from 2 to 30 mm. Smaller lesions may
coalesce into larger ones.33
The etiology of bowenoid papulosis is unknown,
although viral (particularly HPV), chemical, and
immunologic causes have been suggested.33,35
The diagnosis is confirmed by excisional biopsy.
Histologically, bowenoid papulosis is characterized by
varying degrees of hyperkeratosis, parakeratosis, irregu-
lar acanthosis, and papillomatosis. As mentioned previ-
ously, histologically these lesions are similar to CIS, but
bowenoid papulosis shows more maturation of ker-
atinocytes and displays different growth patterns relative
to CIS.33,36–38,39
Treatment includes surgical excision or elimination of
the lesion by electrodesiccation, cryotherapy, laser fulgu-
ration, or topical 5-fluorouracil cream. Spontaneous
regression has been reported.33
Balanitis Xerotica Obliterans
BXO is the term applied to LSA of the glans penis and
prepuce. This disorder most often occurs in uncircum-
cised, middle-aged men and may precede, coexist with,
or progress to the penile SCC.40–43
Although initially asymptomatic, most patients com-
plain of penile discomfort and/or pain, difficult urination
secondary to meatal stricture, and painful erection. On
examination, BXO presents as a well-defined marginated
white patch on the glans penis or prepuce that may
involve the urethral meatus. In chronic cases, the lesion
is firm due to a thick underlying fibrosis.
Diagnosis is made by biopsy. Histologically, active
lesions show pronounced orthokeratotic hyperkeratosis
accompanied by striking atrophy of the epidermis, which
is very distinctive. Rete pegs are usually lost and collagen
on the upper third of the dermis is homogenized.
The treatment of BXO is usually difficult and depend-
ing on the severity consists of surgical excision, topical
steroid cream, and/or laser therapy. Meatal stenosis may
need repeated dilatations or even formal meatoplasty.
Cutaneous Horn
A cutaneous horn is an overgrowth and cornification of
the epithelium that forms a solid protuberance. This is
characterized by severe hyperkeratosis, dyskeratosis, and
acanthosis. Penile horn is a rare form of cutaneous horn,
with only 18 cases reported in North America.44 These
lesions are considered premalignant and one-third of
cases reported have been malignant at presentation.45,46.
Surgical excision with a margin of normal tissue
around the base of the lesion has been very successful in
treating it. Most malignant penile horns are of low grade,
but metastasis has been reported. Therefore, wide local
excision and close follow-up to detect early metastasis is
suggested for malignant forms.46–48
Buschke-Löwenstein Tumor, Verrucous Carcinoma,
Giant Condyloma Acuminatum
Whether the Buschke-Löwenstein tumor or giant condy-
loma and verrucous carcinoma are the same or different
lesions is controversial. Histologically, the tumor is com-
posed of wide, circular rete pegs that usually extend to
the deep tissue. There is no sign of anaplasia in the pegs’
squamous cells. The pegs are surrounded with inflamma-
tory cells. These lesions are locally invasive and may be
quite aggressive. They destroy adjacent structures by
local invasion. They rarely, if ever, metastasize.
Treatment is directed at eradicating the local disease.
This can be achieved by local excision of the tumor and
avoiding extensive excision of normal penile tissue. In
rare cases, total penectomy is indicated for large, infiltra-
tive lesions.
Carcinoma In Situ, Bowen’s Disease, Erythroplasia
of Queyrat
Bowen’s disease and erythroplasia of Queyrat are the
same histologically but occur in different locations.
Erythroplasia of Queyrat is CIS of the penile glans or
prepuce, while Bowen’s disease is CIS of the shaft or
remainder of the genitalia and perineal area. CIS of the
penis is a velvety red, well-circumscribed lesion that
usually involves the glans, or less frequently, the pre-
puce or shaft of the penis. Histologically, they are
described as atypical hyperplastic cells in a disordered
array, with vacuolated cytoplasm and mitotic figures at
all levels. The epithelial rete extends into the submu-
cosa and appears elongated and widened. Increased
microvascular density with surrounding inflammatory
infiltrates, predominantly with plasma cells, present in
the submucosal layer.
Up to one-third of patients with CIS of the penis may
also have invasive carcinoma of the penis.49
Diagnosis is based on adequate biopsies of the lesion
with sufficient depth to rule out invasion. These lesions
respond well to limited local excision with minimal inter-
ference with penile anatomy. Circumcision is usually an
adequate treatment for CIS of the prepuce. It seems that
local fulguration with electrocautery is not able to ade-
quately eradicate the tumor. Radiation therapy has been
successfully used for this tumor.50

Topical use of 5-fluorouracil at 5% concentration has
shown excellent results.51,52 Successful use of CO2 or
Nd:YAG laser and liquid nitrogen have also been
reported with excellent cosmetic results.53–56
Invasive Carcinoma of the Penis
Ninety-five percent of cancers of the penis are SCC.
Histologically, the lesion contains heavy keratinization,
epithelial pearl formation, increased mitotic activity, and
hyperchromatic, enlarged nuclei. Various histologic pat-
terns, such as classic, basaloid, verrucous, sarcomatoid
and adenomatoid, may be present.
SCC may be divided histologically into well differen-
tiated, moderately differentiated and poorly differenti-
ated grades according to the classification of Broders.57
This classification was recently confirmed by Maiche et
al.,58 who proposed four grades but with similar prog-
nostic significance. Several authors have also studied the
type of spread. Cubilla et al.59 studied a whole-organ-sec-
tion of 66 patients with SCC of the penis and identified
four types of growth: superficially spreading squamous
carcinoma (42%), vertical invasive carcinoma (32%), ver-
rucous carcinoma (18%), and multicentric carcinoma
(8%). They found that 82% of patients with vertical
growth versus 42% of patients with superficially spread-
ing growth have inguinal lymph node metastasis.
The distinction as to degree of differentiation is par-
ticularly important as a potential predictor for metastatic
disease to the groin.60–62 It is even more powerful when
combined with tumor depth of invasion.60
The remaining 5% of malignancies involving the
penis include the sarcomas (angiosarcoma, fibrosar-
coma, myelosarcoma, Kopasi’s sarcoma), 63–66
melanoma,67,68 basal cell carcinoma,69,70 and lym-
phoma. Other tumors, which have been reported on
very rare occasions, include rhabdomyosarcoma, 71
epithelial sarcoma, malignant schwannoma, myxosar-
coma, and neurofibrosarcoma.
Approximately 50% of SCCs are well differentiated,
30% are moderately differentiated, and 20% are poorly
differentiated.60 Nine percent of lesions are found on the
glans and prepuce, 21% on the prepuce, 48% on the
glans, and 14% on the prepuce, glans, and shaft. Thus,
92% of SCCs of the penis involve the glans and/or pre-
puce. Approximately 6% involve the coronal sulcus and
only 2% of SCCs are found on the shaft with no lesions
elsewhere.
NATURAL HISTORY
Carcinoma of the penis usually presents as a small papil-
lary, exophytic, or flat ulcerative lesion that does not
resolve spontaneously. This ulcer extends gradually and
may ultimately involve the entire glans or penis. It seems
Chapter 44 Invasive Carcinoma of the Penis 713
that flat, ulcerative tumors are usually less differentiated
and are overall associated with earlier nodal metastases.
SCC of the penis is considered a locoregional malig-
nancy. The lymphatic system is the primary route for
metastases. The disease first spreads to the superficial
and deep inguinal nodes, followed by the pelvic nodes,
long before distant metastases occur. Enlarged inguinal
lymph nodes occur in 30% to 60% of patients at presen-
tation.72–75 Half of these patients actually harbor cancer
in the regional nodes. Lymph node involvement with the
cancer may also be present in 20% of patients with neg-
ative palpable nodes.76–78 Up to 60% of the patients may
have tumor metastasis to the contralateral inguinal
nodes.79
The presence and extent of inguinal lymph node
metastases are the most important prognostic factors in
men with SCC of the penis.72,80–83 Lymph node metasta-
sis causes chronic infection and skin necrosis. Untreated,
the majority of patients die within 1 year of diagnosis
from sepsis, hemorrhage secondary to tumor erosion into
the femoral vessels, and/or inanition.84 Distant metas-
tases to the lung, liver, bone, or brain are uncom-
mon.76,78,85
PRESENTATION
The presence of penile lesion is the first presentation.
This could range from a subtle small papule or pustule
that does not heal to a large exophytic, fungating lesion.
Sometimes it presents as superficial, erythematous ero-
sion. These lesions occur most commonly on the glans
and prepuce and less commonly on the coronal sulcus
and penile shaft.
If the primary lesions were ignored due to their loca-
tion under a phimotic foreskin, the patient may present
with a mass in the inguinal area. This could be due to the
lymph node enlargement secondary to inflammatory
response, or metastases. This mass may become ulcera-
tive, suppurative, or hemorrhagic.
These lesions are usually painless. In the late stage of
the disease the patient may experience weakness, weight
loss, loss of appetite, fever, and malaise.
DIAGNOSIS
Unfortunately, there is often a significant delay in diag-
nosis due to patient and/or physician factors. The
patient’s delay is usually due to embarrassment, guilt,
fear, or ignorance. Delay in seeking medical care may be
as long as 1 year and may include up to 50% of the
patients.86
Physician’s delay in diagnosis and treatment is usually
due to prolongation of a conservative approach (long
course of antibiotics, antifungal, or topical steroid ther-
apy), or misdiagnosis.
714 Part VII Urethra and Penis
PHYSICAL EXAMINATION
A thorough physical examination is crucial for the diag-
nosis and accurate staging. The penile lesion should be
evaluated with regard to location, appearance, size, and
depth of involvement. Fixation of the lesion to the adja-
cent structures, such as corporal bodies, needs to be doc-
umented. The scrotum, base of the penis, and perineum
should be examined for any possible tumor extension.
Rectal examination complements the examination and
rules out gross involvement of the perineal body or the
presence of a pelvic mass.
The inguinal area needs to be inspected and palpated
thoroughly for any possible lymph node enlargement.
This is a crucial part of physical examination and we can-
not overemphasize its importance.
Biopsy
Histologic confirmation of penile cancer should be
obtained by a biopsy from the penile lesion. The biopsy
is important to evaluate the depth of invasion, tumor dif-
ferentiation (grade), and the presence of vascular inva-
sion. This information is very helpful to accurately stage
the tumor and allows the surgeon to discuss the thera-
peutic options with the patient. Although it is possible to
perform the biopsy (with frozen section diagnosis) and
partial or total penectomy in one session, we do not
advocate this approach due primarily to psychologic rea-
sons. Loss of the phallus is psychologically devastating to
the patient and most patients need some time to cope
with the diagnosis. The interval between the biopsy and
the definitive radical surgery will allow the patient and
his physician to establish their relationship and address
the psychologic aspects of the treatment to decrease the
enormous tension and stress that ensues following the
ablative surgery.
Imaging
Knowledge of the extent and depth of the primary
tumor and the involvement of inguinal lymph nodes
prior to any surgical intervention is crucial in patients
with penile cancer. In practice, this decision is usually
based on findings from a physical examination. Various
imaging modalities have been used for this purpose,
including ultrasonography, computed tomography
(CT) scan, and magnetic resonance imaging (MRI)
scan.
Due to the poor soft tissue resolution of CT scan,
ultrasound and MRI are clearly superior to CT scan in
the evaluation of primary tumor extension.
Ultrasound cannot precisely detect tumor extension in
the glans penis area. Ultrasound, however, has shown
adequate resolution to detect corpus cavernosum inva-
sion, owing to the thick tunica albuginea that is readily
visible with 7.5 MHz linear array small parts trans-
ducer.87–90 In extensive infiltrating tumors, ultrasound’s
ability to delineate corporal invasion is compromised sig-
nificantly.91
MRI has been tested in several studies and it appears
that it is the most sensitive method for determining cor-
pus cavernosal infiltration but at the cost of lower speci-
ficity.91–95 Lont et al.91 have recently compared the
accuracy of physical examination to MRI or ultrasound in
the evaluation of primary tumor extension and concluded
that physical examination alone is a reliable method for
predicting corporal involvement. MRI and ultrasound
may be reserved only to examine tumors in which the
physical examination is equivocal in determining tumor
extension.
CT scan relies on lymph node size for detecting
metastasis. MRI evaluates the lymph node size and its
signal intensity. Unfortunately, neither of these image
modalities is able to differentiate benign versus malig-
nant lymph node enlargement. Furthermore, their sensi-
tivity and specificity drop remarkably in normal-sized
lymph nodes. Presently, CT scan and MRI scan do not
add additional information over thorough physical exam-
ination, especially in patients with no palpable inguinal
lymph nodes.
Recently, we reported the use of lymphotropic super-
paramagnetic nanoparticles, as an MRI contrast agent, in
evaluating lymph node metastasis in prostate cancer
patients.96 Our early experience of applying this nonin-
vasive technique in a few penile cancer patients is encour-
aging. More studies are required to establish the role of
this technique in patients with penile cancer.
STAGING
An ideal staging system allows accurate prognosis and
assists in determining an optimal treatment.
Unfortunately, the staging system of carcinoma of the
penis is not universally accepted and each system car-
ries its own flaws. Considering that penile cancer is a
locoregional disease, accurate evaluation of the
regional lymph nodes plays a major role in staging. The
original Jackson system (Table 44-1) is not particularly
helpful clinically in selecting who is most likely to have
groin disease.97 The tumor-nodes-metastasis (TNM)
system is a bit better (Table 44-2) but again suffers
from inability to predict the incidence of positive
regional lymph nodes. With the TNM system it is dif-
ficult to assign nodal status before definitive therapy.
Combining the TNM system with tumor differentia-
tion (grade) improves the prognostic ability for
regional nodal involvement60 (Table 44-3). Considering
the low incidence of penile cancer, multicenter
prospective studies are needed to validate and improve
the staging system.
 Chapter 44 Invasive Carcinoma of the Penis 715

TREATMENT superficial lesions and is generally not particularly appli-

Local Treatment of the Primary Lesion
For lesions that are small and involve only the dermis (<1
cm in diameter), Mohs’ micrographic surgery may be
appropriate.98–100 This involves serial local excision of
the primary tumor in thin layers, with thorough micro-
scopic examination of each layer. This technique has the
advantage of preserving the part but is limited to very
Table 44-1 Jackson Staging System
Stage I Tumor confined to glans or prepuce
Stage II Tumor invasive into the shaft or corpora.
No palpable adenopathy
Stage III Palpable metastases to the groin, which are
resectable
Stage IV Inoperable groin nodes or distant metastases
cable for most cancers of the penis.
Advocates of cryotherapy101 and laser therapy suggest
that the local lesions can be destroyed with preservation
of the part. For lesions involving only the dermis, they
may be extremely successful. For lesions involving the
subcutaneous tissue and/or corpora, successful eradica-
tion is less likely and the local recurrence rate is signifi-
cant. Laser therapy as a minimally invasive treatment has
the following outcomes: When the Nd:YAG is used as
primary therapy for patients with CIS, the local recur-
rence rate is 6%; for lesions that invade the subcutaneous
tissue, the recurrence rate is between 10% and 20%; for
lesions that invade the corpora, the recurrence rate
ranges between 50% and 100%.102
External beam radiation therapy carries with it a 61%
recurrence rate103 with an unacceptably high stricture
rate. Local lesions may be treated with brachytherapy
with considerable success, particularly in patients with
T1 to T2 penile cancer, who insist on preserving the

Table 44-2 American Joint Committee on Cancer (AJCC) Staging System for Penile Cancer
Primary tumor (T)

Tx Primary tumor cannot be assessed

To No evidence of primary tumor

TIS CIS

Ta Noninvasive verrucous carcinoma

T-1 Tumor invades subepithelial connective tissue

T-2 Tumor invades corpus spongiosum or cavernosum

T-3 Tumor invades urethra or prostate

T-4 Tumor invades other adjacent structures

Regional Lymph nodes (N)

Nx Regional lymph nodes cannot be assessed

N0 No regional node metastasis

N1 Metastasis in a single superficial, inguinal lymph node

N2 Metastasis in multiple or bilateral superficial inguinal lymph nodes

N3 Metastasis in deep inguinal or pelvic lymph node(s), unilateral or bilateral

Distant metastasis (M)

Mx Distant metastasis cannot be assessed

M0 No distant metastasis

M1 Distant metastasis
716 Part VII Urethra and Penis
Table 44-3 Depth of Invasive/Grade Staging System
Stage I The tumor is superficial with no extension into the subcutaneous tissue
Stage IIA Locally invasive tumor without involvement of the corpora, well or moderately differentiated T1, NO
Stage IIB The tumor invades the corpora or it is poorly differentiated
Stage III Persistent palpable inguinal nodes
Stage IV Bulky groin nodes with invasion extending outside the node, pelvic node involvement,
distant metastases
part.104,105 Crook et al.105 showed that 76% of patients
with T1 to T2 diseases were free of tumor locally for
5 years.
Still, the most effective local therapy is surgical exci-
sion, although the cosmetic defects can be major. If the
lesion is located on the foreskin only, circumcision is
appropriate. However, this approach is associated with a
30% local recurrence rate. Partial penectomy is the most
effective method of dealing with the disorder provided
one can establish a 2-cm proximal margin. This carries
with it a 6% recurrence rate. Total penectomy has the
least risk of local recurrence and is only employed when
the tumor replaces the entire penis or when it is located
at the base of the shaft. It results in a significant cosmetic
defect and many patients have considerable psychologic
issues during the postoperative period.81,106–109
Treatment of the Inguinal Lymph Nodes
The status of the inguinal lymph nodes is the most
important prognostic factor in men with invasive SCC of
the penis.72,80–83 SCC of the penis tends to spread locally
to regional lymph nodes and distant metastasis is rare.
Therefore, even in patients with local lymph node metas-
tases, regional lymphadenectomy alone can be curative
and should be performed.76,81,110,111 Studies suggest that
inguinal lymphadenectomy offers 30% to 60% cure rate
to patients with inguinal node metastases. If the tumor
extends to the pelvic lymph nodes the success rate drops
to <10%. Unfortunately, there is currently no effective
chemotherapeutic and/or radiation therapeutic option
available for patients with disease extending beyond the
inguinal lymph nodes. Most of these patients will suc-
cumb to disease within 1 to 2 years.78,112
The lymphatic drainage of the penis is as follows:
● The prepuce drains with the shaft skin to the
superficial inguinal nodes.
● The glans drains with the corporal bodies to the
deep inguinal nodes.
● The deep inguinal nodes drain to the pelvic nodes.
T Stage
To, TIS, Ta, NO
T1, T2, NO
N-1, N-2
N-3, N-4
● Rarely, deeply invasive tumors, particularly those at
the base of the penis, may bypass the groin and drain
directly to the pelvic nodes.
There are multiple cross-communications so those
lesions on one side of the penis may in fact metastasize to
the contralateral groin. On physical examination approx-
imately 50% of patients have palpable nodes. Often these
nodes are inflammatory due to infection of the primary
lesion. Therefore, a patient should be restaged after the
primary lesion has been eradicated, the wound has been
closed, and the patient is infection free. This generally
requires 6 weeks of antibiotics following closure of the
penile wound. If patients are reevaluated, those with pal-
pably negative groin nodes will have a 20% incidence of
metastatic disease if all patients are subjected to a groin
dissection.
Tumor grade and depth of invasion (stage) have sig-
nificant prognostic value in predicting lymph node
involvement.60,81,111,113 While almost 30% of patients
with grade I penile SCC have inguinal lymph node
involvement, about 80% of grade III tumors have posi-
tive inguinal lymph nodes.60,114 In patients whose pri-
mary lesion involves the corpora (T2) and the tumor is
poorly differentiated, approximately 80% of such
patients will in fact have positive groin nodes.60,111 If
there are discrete palpable lymph nodes, approximately
86% of patients with high-grade tumors will have patho-
logically positive nodes on dissection.
The issue of controversy involves whether preemptive
lymphadenectomy should be performed. Because lym-
phadenectomy carries with it some morbidity and
because there is a defined number of patients who would
undergo lymphadenectomy needlessly if all patients were
subjected to regional groin dissection, a watch-and-wait
approach has been adopted over the years.
Unfortunately, this relegates patients with nonpalpable
microscopic disease to a much worse survival. Patients
who have groin dissections and have nonpalpable micro-
scopic disease have a markedly improved survival over
those in whom the microscopic disease is allowed to

develop into palpable disease at which point a groin dis-
section performed.60,78,80,81,115
It has been suggested that a sentinel lymph node
biopsy would be predictive of the status of the groin so
that an unnecessary groin dissection could be
avoided.116–118 Unfortunately, the location of the sentinel
node, which is most often located between the superficial
epigastric and the superficial external pudendal vein, is
variable. Therefore, its clinical use has not been found to
be reliable by others.119–122
To overcome the anatomic variability of the sentinel
node and based on the experience with breast and
melanoma cancers,123 intraoperative lymph node map-
ping (IOLM) has been proposed recently. Injection of a
vital blue dye and/or technetium-labeled colloid around
the primary lesion allows the surgeon to follow its
drainage to a single or a few lymph nodes in the inguinal
region.124–126 Selective biopsies of these nodes assist to
outline the extent of the lymph node dissection. In the
absence of any sentinel node involvement, some would
argue that there is no need for radical inguinal lymph
node dissection (high negative predictive value). In a
recent report by Horenblas et al.,127 55 patients were
scanned and biopsied. One-third were found not to have
surgical findings that correlated with scintigraphy.
Twenty percent had positive nodes and 6% of patients,
who were found to have negative nodes within a 3-year
period, were found to develop evidence of positive groin
nodes. Thus, this methodology does eliminate a number
of patients who would needlessly undergo a groin dissec-
tion at the expense of subjecting all patients to groin sen-
tinel node biopsies. The number of false-negatives is at
least 6% as the follow-up in the current contemporary
series is too short to determine the true false-negative
rate.
New modalities for lymph node imaging, particularly
with lymphotropic contrast agents used with MRI, are
extremely exciting. Based on our early experience with
this technology at Massachusetts General Hospital, MR
lymphangiogram, in all likelihood will have a diagnostic
efficacy sufficient to predict who should and who should
not receive a groin dissection. Unfortunately, at this time
tumor differentiation and stage of tumor combined are as
predictive as the modalities, such as sentinel node biop-
sies either with or without blue dye. Thus, poorly differ-
entiated tumors have a 80% to 100% incidence of
metastatic disease, moderately differentiated tumors a
46% incidence, and well-differentiated tumors a 24%
incidence of groin metastasis. In tumors that have not
invaded into corpora there is only a 5% to 11% incidence
of metastatic disease, whereas if the corpora are invaded,
there is a 61% to 75% incidence of groin metastases.
Thus, we have proposed a modified staging system60 (see
Table 44-3). Stages I and IIA diseases have an extremely
low likelihood of metastatic groin disease (0% to 12%)
Chapter 44 Invasive Carcinoma of the Penis 717
and their survival in our experience is close to 100%.
Patients with IIB disease have a 78% to 88% incidence of
groin metastases. In this group in whom watchful waiting
is employed there is a 17% 5-year survival; in those who
undergo an immediate lymphadenectomy there is a 92%
survival; those who have a delayed lymphadenectomy
when nodes become palpable have a 33% survival.
Patients with stage III disease who undergo an immedi-
ate lymphadenectomy have a 75% survival, whereas if no
lymphadenectomy is performed there is a 33% survival.60
Thus, it is clear that patients who have nonpalpable
microscopic metastases to the groin and have a groin dis-
section have a much better prognosis than do those in
whom the lymphadenectomy is performed when nodal
disease becomes palpable. The problem, of course, is to
determine who is most likely to have microscopic metas-
tases without subjecting a large group of patients to an
unnecessary operation since the morbidity of the opera-
tion on occasion is not inconsequential.112,113,128–130
Inguinal lymphadenectomy is not without significant
complications. Series from the literature report: skin
edge necrosis, 8% to 50%; major flap necrosis, 5%;
wound infection, 10% to 15%; lymphedema, 25% to
50%; seroma formation, 6% to 16%; death, 0% to
1%.128,130–132 A second operation is required in approxi-
mately 15% of patients.132
If the lymph node dissection is performed for micro-
scopic nonpalpable disease, the complication rate is much
less. In our experience the complications are as follows:
small wound seroma, 15%; minor skin edge necrosis
not requiring a secondary procedure, 20%; minor, self-
limited lymphedema, 20%; prolonged lymphedema, 5%.
None have required secondary operations. The group at
MD Anderson has also reported similar results.132
In our opinion, currently, the most predictive method
of determining the probability of microscopic nodal
metastases is grade of primary tumor combined with
depth of invasion. Sentinel node biopsy as employed with
blue dye and technetium may be helpful in selected cases.
For the present, patients who have clinically negative
groins and have a grade III lesion invasive to the corpora
should have bilateral groin dissections. If the groin dis-
section is positive, a pelvic lymphadenectomy should
subsequently be performed on the ipsilateral side. It is
our preference to do the bilateral groin dissection in
patients with any grade III tumor or any tumor whose
primary lesion invades the corpora. Perhaps the sentinel
node biopsy may be useful in these latter patients, as only
about 60% of them will harbor microscopic metastatic
disease. Of course patients with persistently palpable
groin nodes should undergo a groin dissection. In this
group, approximately 86% of patients will have metasta-
tic disease. It is our preference to perform the bilateral
superficial and deep node dissections in one setting.
When the permanent pathology has returned, a pelvic
718 Part VII Urethra and Penis
lymphadenectomy is performed on the positive side. Our
technique is described in Glenn’s Urologic Surgery133
Although some would suggest that a pelvic lym-
phadenectomy is not likely to impact survival, on occa-
sion we have found an isolated positive node in the pelvis
that resulted in long-term survival. Besides, the knowl-
edge of pelvic node status has prognostic significance and
allows us to consider adjuvant chemotherapy in positive
cases.
On occasion a groin dissection must be performed for
palliative reasons. Under these circumstances large tissue
defects may be created in the process of removing all vis-
ible tumor. These defects can be closed with an abdomi-
nal advancement flap as we have previously described.134
Following closure of the wound, radiation therapy may
be given to the pelvis for palliation; however, invariably
these patients will suffer significant external genitalia
lymphedema, which can be quite disabling in the final
stages of life.
The Role of Radiation and Chemotherapy in
Squamous Cell Carcinoma of the Penis
The role of radiation and topical chemotherapy for the
primary lesion has been discussed previously. Several
nonrandomized studies have reviewed the role of radia-
tion therapy for the treatment of metastatic inguinal
nodes.79,135 The results are overall dismal and indicate
the role of radiation therapy, merely as a palliative meas-
ure at the present time.136
Due to the limited number of cases and lack of
prospective studies, an optimal chemotherapy protocol
has not yet been developed. Most of the chemotherapy
regimens are based on the results of chemotherapy tri-
als in SCC of the head and neck. Cisplatin, methotrex-
ate, bleomycin, and vincristine have been used alone or
in combination. It appears that adjuvant or neoadjuvant
use of chemotherapy agents may be beneficial and
result in partial response in many cases.137–140 The
optimal chemotherapy regimen remains to be deter-
mined.
FUTURE CHALLENGE
In the future, the optimum treatment of penile cancer
needs to be developed. This requires more knowledge of
the tumor biology. Furthermore, a staging system needs
to be revised to allow more accurate prediction of tumor
extension prior to surgery. New imaging technologies,
including lymphotropic agents, need to be applied to
improve the staging accuracy. A multidisciplinary
approach incorporating surgical ablation, applying vari-
ous energy modalities (i.e., radiation, laser, cryotherapy,
thermotherapy, high intensity focused ultrasound, etc.)
and chemotherapy protocols, needs to be developed to
optimize disease-free status.
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Chapter 44 Invasive Carcinoma of the Penis 719
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C H A P T E R
45 Penectomy and Ilioinguinal
Lymphadenectomy
Donald F. Lynch, Jr., MD
In North America, cancer of the penis is an uncommon
disease, but it is a substantial health problem in parts of
Africa, South America, and Asia. Squamous cell carci-
noma (SCC), the most common penile cancer, is a malig-
nancy, like testicular cancer, where the behavior of the
tumor is reasonably predictable, and where regional dis-
ease may be curable by timely surgical intervention.
Patients with Buschke-Löwenstein tumors (verrucous
carcinoma of the penis) are usually managed with local
excision but on occasion may require partial or total
penectomy. Similarly, patients with Kaposi’s sarcoma of
the penis may occasionally require surgical excision or
partial penectomy. These tumor types do not metasta-
size, and further management generally involves only
interval follow-up.
Squamous carcinoma is a far more ominous diagnosis;
these tumors have a propensity for metastasis to the
inguinal lymph nodes and beyond. With squamous carci-
noma, the size of the primary tumor, its location on the
penis, the grade of the tumor, and the depth of invasion
determine the extent of surgical treatment that will be
required.1–3 This information comes from biopsy of the
lesion and from careful physical examination.
The goal of surgery for localized carcinoma of the
penis is complete excision of the tumor with adequate tis-
sue margins. Some superficial lesions of the glans or shaft
may be amenable to wide excision or to treatment using
laser surgery or Mohs’ micrographic surgery, while
superficial tumors limited to the prepuce may sometimes
be managed with circumcision.4,5 In the case of large
tumors (>2.0 cm), lesions that are located so that an ade-
quate margin of resection cannot be achieved, or cancers
that invade the tunica albuginea, corpora, or urethra,
limited resection may not be possible, and partial or total
penectomy will be required. Additionally, patients who
develop recurrent tumor following unsuccessful attempts
at wide excision or who recur subsequent to laser therapy
may also require penectomy.
SURGICAL PROCEDURES FOR THE PRIMARY
LESION
Biopsy
Histology of any penile tumor must be confirmed with
an adequate biopsy. Most penile cancers are SCCs, which
spread by local invasion early in their course. Such
tumors metastasize to regional lymph nodes as they
progress in size and depth to involve the highly vascular
structures of the penis. Histologic confirmation of tumor
depth is important in assessing the need for inguinal
lymphadenectomy, as well as in determining whether
adequate margins of resection are possible so as to permit
partial penectomy. Several recent studies suggest that
tumor grade also is an important determinant in progno-
sis and is an important consideration in assessing the risk
of inguinal metastases.2,3 Penile biopsy may be done as a
separate procedure, or may done in conjunction with
frozen-section confirmation as a prelude to definitive
partial or total penile amputation. Full informed consent
must be obtained prior to such a procedure.
Biopsy is performed by excising a 1- to 1.5-cm wedge of
tissue, which includes the margin of the tumor and provides
normal tissue adjacent to the lesion to be examined for
tumor infiltration (Figure 45-1). The incision may be closed
with interrupted 2-0 or 3-0 chromic gut after that a sterile
compressive dressing is applied. There have been no reports
of tumor dissemination from biopsy of penile cancers.6
Partial Penectomy
Partial penectomy is the surgical treatment of choice for
tumors of the glans and distal penile shaft where a margin
723
724 Part VII Urethra and Penis
Figure 45-1 Biopsy of penile tumor, including normal tissue
for comparison.
of at least 2 cm of normal tissue can be achieved. In the
appropriately selected patient, this procedure should
provide a penile stump of sufficient length to allow the
patient to void while standing. If an adequate stump can-
not be assured, total penectomy with creation of a per-
ineal urethrostomy is preferable.
The incidence of recurrent tumor following partial
penectomy has been reported as ranging from 0% to 6%.
Five-year survival rates of 70% to 80% following a prop-
erly performed partial penectomy have been noted when
inguinal nodes are free of metastatic disease.6,7
Figure 45-2 Partial penectomy.
If the patient has not been receiving antibiotic
therapy prior to surgery, intravenous antibiotics
are administered preoperatively. A broad-spectrum
cephalosporin, which can be converted to oral therapy
48 to 72 hours following surgery, is preferred. With the
patient in the supine position, the entire penis and scro-
tum are scrubbed with povidone-iodine solution, and
the lesion is then covered with a sterile glove or sponge
secured with a sterile rubber band. A 7/8-inch Penrose
drain is used as a tourniquet about the base of the penis
(Figure 45-2A).
A transverse incision is made over the dorsum of the
penis 2.0 cm proximal to the most proximal tumor mar-
gin and carried circumferentially around the shaft. The
superficial dorsal vessels are fulgurated, and the corpora
are then sharply divided down to the urethra, taking care
to ligate the deep dorsal vessel complex (Figure 45-2B).
The distal urethra is dissected free approximately 1 cm
proximally and distally, maintaining the 2-cm margin, to
allow for spatulation and creation of a neomeatus. The
amputation is then completed.
The corporal stumps are closed with interrupted
mattress sutures of 2-0 Vicryl (Figure 45-2B and C).
The tourniquet is then removed and further hemostasis
obtained. The urethra is spatulated and sutured to the
skin of the shaft with 3-0 or 4-0 Vicryl or Dexon. The
remaining shaft skin is closed using 3-0 absorbable
suture (Figure 45-2D). An 18Fr Foley catheter is placed
to straight drainage for 24 to 48 hours, and the wound
is dressed.
Alternatively, the penile shaft skin can be excised to
create a flap dorsally. This can be folded ventrally to
cover the stump of the penis, and the urethra spatulated
and brought through a buttonhole in the flap. The flap
edges are sutured with 3-0 Vicryl, and excess flap skin is
then excised as needed.
Additional stump length can sometimes be gained by
dividing the suspensory ligament of the penis, dividing
 Chapter 45 Penectomy and Ilioinguinal Lymphadenectomy 725
the ischiocavernosus muscle, and mobilizing the crura
from the inferior pubis. The scrotum is incised along the
raphe and reconstructed superior to the transposed phal-
lus.8 These maneuvers may provide 1 or 2 cm of addi-
tional length and avoid the need for a total penectomy in
selected cases.
Total Penectomy
Total penectomy is the treatment of choice in patients
where the lesion is located too proximally on the shaft to
permit a partial amputation. The patient is placed in
standard lithotomy position, and the penis, scrotum,
lower abdomen, and perineum prepared with povidone-
iodine solution. The tumor is covered with a glove or
dressing.
An elliptical incision is begun over the pubis and
carried around the base of the penis to the midportion
of the scrotal raphe (Figure 45-3A). The corpus spon-
giosum is exposed ventrally and mobilized to the uro-
genital diaphragm. It is transected distal to the bulb,
taking care to assure a 2-cm margin from the lesion
(Figure 45-3B and C ). Dorsally, the incision is carried
Figure 45-3 Total penectomy. (See text for details.)
down through Buck’s fascia, and the deep dorsal venous
complex is identified and traced to the symphysis pubis
(Figure 45-3D). The dorsal vein complex is clamped,
ligated with 2-0 silk suture and divided at this point.
The suspensory ligament of the penis is divided, and
with downward traction on the penile shaft, the cor-
pora cavernosa are identified and dissected from their
attachments to the inferior pubis. The corpora are
individually ligated with 0 Vicryl suture and divided
behind the pubis.
Following amputation of the penis, a 1-cm ellipse of
skin is excised from the region of the perineal body
midway between the rectum and scrotum. Using blunt
dissection, a tunnel is developed in the perineal subcuta-
neous tissue, and the urethra grasped and directed
through this passage, taking care not to create excessive
angulation. Excess urethra is excised and the urethral
stump spatulated and secured to the perineal skin with 3-
0 chromic or Vicryl sutures (Figure 45-3E). After 3/4-
inch Penrose drains are placed in the subcutaneous space,
the primary incision is sutured with interrupted 3-0
Vicryl transversely, which closes the suprapubic wound
and serves to elevate the scrotum off of the perineum
726 Part VII Urethra and Penis

(Figure 45-3E and F ). The wound is dressed and an 18Fr

Foley catheter is placed to straight drainage for 48 to 72
hours. The patient is maintained on broad-spectrum
antibiotic therapy for 7 to 10 days.

MANAGEMENT OF REGIONAL DISEASE

A thorough understanding of the lymphatic drainage of
the penis is essential to stage the patient, to monitor his
progress following initial surgical intervention, and to
deal with regional disease if it is present at diagnosis or
develops subsequent to primary treatment. While penile
cancer, like testis cancer, remains one of the few malig-
nancies for which regional lymphadenectomy can be cur-
ative, controversy exists regarding the timing and
indications for inguinal and pelvic lymphadenectomy, as
well as the extent of the surgery required.

Anatomic Considerations
For the surgeon performing inguinal lymphadenectomy,
a thorough knowledge of the anatomy of the groin region
is essential. Inguinal anatomy has been meticulously
described by Daseler, who performed a series of 450
inguinal lymphadenectomies for a variety of tumors, and
whose technique has been viewed as the standard for
penile cancer.7 The boundaries of the classical lym-
phadenectomy and their relationship to significant
anatomic landmarks are illustrated in Figure 45-4. Figure 45-4 Limits of dissection for both the classical
(Daseler) lymphadenectomy (solid line) and the modified
(Catalona) lymphadenectomy (dashed line). Relation of the
Fascial Planes
femoral vein, saphenous vein, and sentinel node group to the
The lower abdomen has two superficial fascial compart- dissections is shown.
ments, Scarpa’s and Camper’s fasciae. Camper’s fascia is a
fibrofatty layer that is continuous from the lower
abdomen onto the thigh. At the scrotum, it fuses with the the fascia lata except for the fossa ovalis, an opening
deeper Scarpa’s fascia to form the tunica dartos. Scarpa’s through which the greater saphenous vein passes to empty
fascia is comprised of a distinct fibrous sheath. From the into the femoral vein below. Passing through the femoral
abdomen, it crosses the inguinal ligament and fuses with triangle are the femoral vessels and nerve. The vessels are
the fascia lata of the thigh about 1 cm inferior to invested within the femoral sheath that is formed by
Poupart’s ligament, forming Holden’s line. extensions of the transversalis fascia, which passes below
Within the pelvis, the iliac fascia invests the iliopsoas the inguinal ligament. This sheath is comprised of three
muscle and also covers the femoral nerve. The iliac fascia compartments: the medial containing the lymph nodes
fuses with the transversalis fascia at the inguinal ligament. and lymphatic trunks, the middle the femoral vein, and
The inguinal ligament is formed by the aponeurosis of the the lateral the femoral artery. Lateral to the artery within
external oblique muscle and runs from the anterior supe- the iliac fascia is the femoral nerve (Figure 45-5).
rior iliac spine to the pubic tubercle. The internal oblique
muscle attaches to the lateral half of the inguinal liga-
Veins
ment, and the transversus abdominis to its outer third.
The femoral vein enters the femoral triangle at its apex,
medial to the femoral artery. About 4 cm below Poupart’s
Femoral Triangle (of Scarpa)
ligament, it receives the greater saphenous vein anteri-
The femoral triangle is formed by the inguinal ligament, orly and the profunda femoris vein posteriorly. The
the medial margin of the sartorius muscle, and the medial greater saphenous vein originates at the dorsal venous
border of the adductor longus muscle. It is covered by arch of the foot and ascends medially, passing posterior
 Chapter 45 Penectomy and Ilioinguinal Lymphadenectomy 727
Figure 45-5 Relationship of femoral anatomy—nerve, artery, vein, lymph nodes—at
the level of the fossa ovalis.
to the medial epicondyle at the knee. It ascends in the
superficial fascia of the thigh and empties into the femoral
vein after passing through the fossa ovalis. Just before the
fossa ovalis, it receives the superficial epigastric and exter-
nal pudendal veins medially and the accessory saphenous
Figure 45-6 Superficial inguinal nodes, inguinal ligament, and
major venous structures.
and circumflex iliac veins laterally (Figure 45-6). The
femoral vein passes below the inguinal ligament to
become the external iliac vein, which joins with the inter-
nal iliac (hypogastric) vein at the level of the sacroiliac
joint to form the common iliac vein. The paired common
iliac veins empty into the inferior vena cava at the level of
the fifth lumbar vertebra.
Arteries
The common iliac arteries arise from the terminal aorta
and divide at the level of the sacral promontory into the
internal and external iliac arteries. The internal iliac
passes posteromedially and divides to supply the pelvic
musculature and pelvic organs. The external iliac artery
passes below the inguinal ligament to become the
femoral artery, which supplies the lower limb. Just prior
to passing beneath the inguinal ligament, the external
iliac artery gives off the medial inferior epigastric artery
and the lateral circumflex iliac artery. Just after passing
beneath the inguinal ligament, the femoral artery gives
off the superficial epigastric artery, the superficial cir-
cumflex iliac artery, the superficial and deep external
pudendal arteries, and the profunda femoris artery
(Figure 45-7). The femoral artery continues past the apex
of the femoral triangle and terminates in the lower third
of the adductor magnus, where it becomes the popliteal
artery.
Nerves
The femoral nerve lies beneath the iliac fascia lateral to
the femoral vessels and outside of the femoral sheath. It
is usually not visualized in the inguinal dissection, as the
femoral nodal tissue lies medial to the vessels within the
femoral sheath. Other nerves that may be encountered in
728 Part VII Urethra and Penis
Figure 45-7 Surgical approaches to inguinal and pelvic node dissections.
the groin are the ilioinguinal and lateral cutaneous nerve
of the thigh. The obturator nerve and genitofemoral
nerves are encountered in the course of the pelvic lym-
phadenectomy.
Lymphatics
Lymphatic drainage of the penis is to the superficial and
deep inguinal lymph nodes and to the pelvic nodes. The
superficial inguinal nodes are comprised of from 4 to 25
nodes lying within Camper’s fascia, superficial to the
deep fascia of the thigh, and closely associated with the
saphenous vein (see Figure 45-6). Rouviere’s classic study
of inguinal anatomy divides the superficial inguinal nodes
into five zones with the sentinel nodes lying within zone 2,
just medial to the femoral vein around the superficial epi-
gastric and superficial external pudendal veins.7,8 The deep
inguinal nodes—usually 1 to 3 on a side—lie below the fas-
cia lata medial to the femoral vein (Figure 45-8E and F).
Lymphatic drainage of the prepuce and penile skin
commences in the ventral penile skin, drains superficial
to Buck’s fascia in a dorsolateral direction and then
courses proximally along the dorsum of the penis to the
superficial inguinal nodes. From the glans penis, lym-
phatic drainage coalesces at the frenulum and passes lat-
erally to the dorsal penis, deep to Buck’s fascia paralleling
the deep dorsal vein. One pathway is to the deep femoral
node chain, which includes the femoral node of Cloquet
or Rosenmüller. An additional lymphatic pathway may
course along the inguinal canal to the lateral retro-
femoral node, the most superficial of the external iliac
chain.
The drainage of the corporal bodies also accompanies
the deep dorsal vein of the penis, anastomosing freely
with the presymphyseal lymphatic plexus at the base of
the penis and draining into both superficial and deep
inguinal nodes. Because of this network, metastatic
involvement of both inguinal regions is possible. Further
drainage from the base of the penis occurs via channels
following the femoral canals proximally into the external
iliac and pelvic nodes.7–10
The pelvic nodes include the external iliac group, the
internal iliac or hypogastric nodes, and the common iliac
chain. The external iliac group—usually 8 to 10 nodes—
lies anterior and medial to the external iliac vein. The
hypogastric nodes—4 to 6 in number—are located
 Chapter 45 Penectomy and Ilioinguinal Lymphadenectomy 729

Figure 45-8 Modified (Catalona) technique for inguinal lymphadenectomy. A, Inguinal

incisions. B, Fascia lata exposed. C, Mobilization of lymphatic tissues around saphenous
vein and femoral vessels. D, Superficial inguinal dissection has been completed. Note that
the saphenous vein has been preserved. E, Limits of the modified (solid lines) and full or
classical (Daseler) inguinal lymphadenectomy (dashed line) demonstrating the deep inguinal
nodes and the lower extent of the external iliac nodes (node of Cloquet or Rosenmüller). F,
Dissection of the deep inguinal nodes.
730 Part VII Urethra and Penis
around the hypogastric vein, and the common iliac
chain—4 to 10 nodes—is located medial to or sometimes
posterior to the common iliac vessels. Metastasis to the
pelvic lymph nodes without involvement of the inguinal
nodes is an extremely rare event and appears to be based
on a single report by Schreiner.11 Such metastatic spread
has not been observed in many recent studies.1,12–14
Therefore, in the setting of negative superficial and deep
inguinal node dissections and a negative pelvic computed
tomography (CT) scan, resection of the pelvic nodes is
not required.
Sentinel Node Biopsy
The concept of the sentinel node was proposed by
Cabanas, and postulates that there is a node or group of
nodes—lying between the superficial external pudendal
vein and the superficial epigastric vein—where the earli-
est metastasis from a penile tumor will occur consistently
(see Figure 45-6).10,14 It was postulated that a negative
sentinel node biopsy in the presence of clinically negative
groins indicated that further inguinal dissection was
unnecessary. Five-year survivals of 90% have been
reported in this setting. However, subsequent reports of
the development of metastases following a negative sen-
tinel node biopsy have suggested that sentinel node
biopsy may not be consistently reliable.15–17 Most sur-
geons treating penile cancer no longer use the sentinel
node biopsy technique.18,19 In a patient where the sen-
tinel node biopsy has been performed, the original biopsy
incision should be excised with the lymphadenectomy
specimen.
Considerations in Inguinal and Ilioinguinal
Lymphadenectomy
Because lymph node enlargement and lymphangiitis due
to infection of the primary tumor is common at the time
of diagnosis, all patients with penile cancer should
receive 4 to 6 weeks of antibiotic therapy before under-
going inguinal lymphadenectomy. At the completion of
this course of treatment, the groins are carefully exam-
ined for the presence of abnormal nodes. Thirty percent
to 60% of patients who present with penile cancer have
palpable inguinal nodes, and following antibiotic therapy,
half of these nodes will harbor metastases.19,20 When
metastases are detected clinically in one groin, contralat-
eral metastases will be present in 60% of cases due to the
crossover of lymphatics at the base of the penis.6
Consequently, in this situation contralateral inguinal
lymphadenectomy should be performed.
It is generally accepted that patients with low-grade,
noninvasive tumors and clinically negative inguinal nodes
may safely be managed expectantly if close follow-up
with careful groin examinations every 2 months for at
least 2 years can be assured.1,2,12 Unreliable patients or
others who cannot be provided adequate follow-up are
best served by prompt inguinal lymphadenectomy.
Considerable debate has raged over the years regarding
immediate or delayed lymphadenectomy in patients with
clinically negative groins. There has been support for
expectant management of patients with invasive (T2 to
T4) lesions and no palpable inguinal adenopathy, with
surgical intervention undertaken only when lym-
phadenopathy develops. This avoids the substantial mor-
bidity associated with groin dissection. In those patients
who later develop clinically positive nodes, delayed lym-
phadenectomy can provide cure in 30% to 50%.1,21–23
However, recent series support prophylactic inguinal
lymphadenectomy in these cases, citing ultimate mortal-
ity rates of up to 20% in patients who are followed until
they develop clinically positive nodes before undergoing
inguinal exploration.1,2,6,12,21,23,24,25,26 It would appear
that in these patients, the window of opportunity to pro-
vide a cure has been lost.
In a patient with low-grade, low-stage tumor where
unilateral groin metastases develop some time after surgi-
cal treatment of the primary, inguinal lymphadenectomy
of only the involved groin is required.6 While this would
seem to contradict recommendations outlined above,
bilateral occult metastases present from diagnosis that
become clinically apparent later should manifest them-
selves at about the same time. Consequently, the lack of
clinically detectable nodes on the side contralateral to a
late-developing groin metastasis suggests that the clini-
cally negative nodes were not involved from the outset.
Preoperative staging of the pelvic, common iliac, and
paraaortic nodes with CT or magnetic resonance imag-
ing (MRI) scan and, where indicated, with needle biopsy,
is essential. While survival has followed resection of
tumor limited to the external iliac nodes, no patient with
common iliac or paraaortic metastases has survived.12,27
Fine needle aspiration of suspicious nodes in these areas
may confirm metastatic tumor and thus avoid unneces-
sary surgery. The most important predictor of ultimate
survival continues to be primary tumor stage—the pres-
ence or absence of nodal disease.2,28
Occasionally, palliative groin dissection may be
required, even in the face of extensive regional or distant
metastases. Lymphadenopathy, which threatens to erode
through the inguinal skin or invade into the femoral ves-
sels, may need to be removed to avoid pain, inguinal
infection, or serious hemorrhage.29
Avoiding Complications from Inguinal
Lymphadenectomy
Despite the encouraging prognosis for many patients
with inguinal metastases who undergo inguinal or ilioin-
guinal lymphadenectomy, there has been a long-standing
 Chapter 45 Penectomy and Ilioinguinal Lymphadenectomy 731
reluctance on the part of surgeons to subject patients to
this procedure because of the 30% to 50% incidence of
major morbidity associated with it.22,25,28,30 Complications
include lymphocele, substantial lower limb lymphedema,
skin loss, and infection. Skin flap necrosis can be mini-
mized by selecting the appropriate incision, by careful
tissue handling, by careful attention to skin flap thickness
with excision of ischemic flap margins, and by transposing
the head of the sartorius muscle to cover the defect left over
the femoral vessels. Use of intravenous fluorescein dye and
a Woods’ lamp intraoperatively to assess viability of wound
edges is a useful adjunct.31 Lower limb lymphedema can be
reduced by careful attention to intraoperative ligation of
lymphatics, by immobilization of the limb or limbs in the
postoperative period, and by suction drainage of the lym-
phadenectomy site. Elastic support hose should be used in
the immediate postoperative period and may be required
long term in many patients. Wound infection can be mini-
mized by intensive preoperative antibiotic therapy to
reduce infection and inflammation from the primary and
by the use of prophylactic antibiotics.30,32 Thrombotic
problems may be avoided through the use of subcutaneous
heparin in the perioperative period, particularly when the
full classical inguinal and pelvic dissection is combined with
prolonged bed rest postoperatively.
Technique of Inguinal Lymphadenectomy
Figure 45-7 shows the various incisions described for
inguinal and ilioinguinal lymphadenectomy. Many sur-
geons prefer the oblique incision below and parallel to
the inguinal crease because it maintains the integrity of
the inguinal ligament, and because it preserves the cuta-
neous blood supply that runs parallel to the inguinal lig-
ament (Figures 45-7A and D and 45-8A).
If the patient has impalpable lymph nodes following
antibiotic therapy but has histologically confirmed grade
2 or grade 3 invasive disease, a modified, somewhat lim-
ited inguinal lymphadenectomy as described by
Catalona33 is performed. If bilateral palpable inguinal
nodes persist, a full bilateral ilioinguinal lymphadenec-
tomy, using the classical limits of dissection is under-
taken. In the event one groin normalizes following
antibiotic therapy but the other remains abnormal, a
superficial inguinal dissection is performed on the nor-
mal side with frozen-section evaluation. If this is nega-
tive, a full ilioinguinal dissection is then performed on
the contralateral abnormal side.
Generally, pelvic node dissection is done through a
low midline incision giving access to both right and left
pelvic node groups (see Figure 45-7D). The dissection
technique for this part of the operation is familiar to
urologists, as it is similar to the technique used in blad-
der cancer staging, except that the dissection of the exter-
nal iliac nodes is carried more distally under the inguinal
ligament to include all iliac and deep inguinal nodes
there. If only one groin is involved, a unilateral pelvic
node dissection may be done through an oblique low
abdominal incision (Figure 45-7E) and may provide some
diminished patient morbidity.18
Modified Inguinal Lymphadenectomy
While some patients with clinically negative groins will
have impalpable metastatic disease, many will not. This
coupled with the morbidity associated with the classical
inguinal lymphadenectomies described by Daseler and
Baranofsky has made surgeons reluctant to subject
patients to these procedures, even when tumor charac-
teristics indicate that lymphadenectomy would be advis-
able.7,34 Catalona33 and Puras and Rivera35 have
described modifications of the classical dissection that are
aimed at reducing many of the unpleasant sequelae of the
classical operation.33,35
All patients are treated with 4 to 6 weeks of oral
broad-spectrum antibiotics following excision of the pri-
mary tumor. A clear liquid diet the day prior to surgery is
prescribed, and the patient is given cleansing enemas the
night before surgery. Antiembolism compressive stock-
ings are used.
The patient is placed in a supine position after spinal
anesthesia is first administered. A Foley catheter is placed
to straight drainage. The scrotum and penis are then
retracted out of the field and draped off. The legs are
then abducted and externally rotated to best expose the
anteromedial thigh and groin. A pillow is placed beneath
the knees for support. A 6- to 8-cm incision is then made
3 to 4 cm below the inguinal ligament and parallel to it
(see Figure 45-8A). The incision is carried down to
Scarpa’s fascia. Gentle sponge traction is used to separate
the skin edges (Figure 45-8B). The subcutaneous tissue
in Camper’s layer is carefully preserved, and meticulous
handling of these tissues and the skin edges must be
observed throughout. Stay sutures of 2-0 or 3-0 silk and
skin hooks are helpful to avoid injuring the wound edges.
The saphenous vein and its tributaries are identified,
and the superficial areolar and node-bearing tissue is
gently dissected off the vein downward to the fascia lata
(Figure 45-8C). The venous branches emptying into the
saphenous vein are carefully ligated and divided. The
saphenous vein is preserved (Figure 45-8D). Large lym-
phatics and small venous branches must be carefully and
meticulously ligated or fulgurated. The dissection is car-
ried superiorly to approximately 2 cm above the inguinal
ligament where it is carried down to the fascia of the
external oblique muscle (Figure 45-8E).
The dissection is carried inferiorly to about 4 cm
below the incision. In Catalona’s operation, the lower
limit of dissection is the lower border of the fossa ovalis
(Figure 45-8F ). Other surgeons carry the dissection
732 Part VII Urethra and Penis

slightly lower, although there is not much superficial
nodal tissue in this area. The specimen of superficial
nodal tissue is oriented, labeled, and sent for frozen-
section evaluation.
If the nodes are negative, the wound is thoroughly
irrigated with sterile water and closed in layers, taking
care to eliminate any potential spaces. A closed suction
drainage system is placed (Figures 45-9C and 45-10F )
and remains for 5 to 7 days during that time the patient
is maintained at complete bed rest.
Classic Inguinal Lymphadenectomy (after Daseler)
When known positive nodes are present, or when
metastatic disease is confirmed by frozen section during
a limited inguinal dissection, a classic radical inguinal
lymphadenectomy is performed.9 An incision of 6 to 8
cm is made parallel to the inguinal ligament and about 3
to 4 cm inferior to it. The incision is carried down to
Scarpa’s fascia, and the saphenous vein is identified. This
is ligated with 2-0 silk sutures and divided. The superfi-
cial nodal tissue is systematically mobilized, beginning in
the superomedial quadrant, freeing the tissue towards the
junction of the saphenous vein with the femoral vein at
the fossa ovalis. The sentinel node tissue is identified and
tagged with a suture. Dissection is extended above the
inguinal ligament 2 cm, and the limits of the standard
dissection, as outlined in Figure 45-4, are utilized.
Next, the venous tributaries of the saphenous vein are
meticulously ligated and divided, as well as any large
lymphatics. The saphenous vein is carefully dissected
down to the fossa ovalis and the junction with the
femoral vein is identified, clamped, divided, and ligated.
The fascia lata is opened and excised with all the nodal
tissue superficial to it. This exposes the femoral sheath
and Scarpa’s triangle. The lateral aspect of this dissec-
tion is the medial border of the sartorius, and the medial
border of the adductor longus comprises the medial side.

Figure 45-9 Completed full classical lymphadenectomy. Note that the fascia lata
has been more widely excised and that the saphenous vein has been divided.
The proximal head of the sartorius muscle is transposed to cover the femoral
vessels. Meticulous closure with suction drainage and complete bed rest for 4 or
5 days is essential to avoid wound complications. (See text for details.)
 Chapter 45 Penectomy and Ilioinguinal Lymphadenectomy 733

The femoral sheath is opened from the inguinal liga-
ment to the apex of the femoral triangle. Within the
sheath are the femoral vein, the femoral artery lateral to
it, and fatty areolar tissue containing the deep inguinal
nodes medially (see Figure 45-5). The femoral nerve is
lateral to the artery and is not encountered in the usual
dissection. The vein is gently retracted laterally to allow
dissection of tissue from the lateral and anterolateral
aspect of the vein. Nodal and areolar tissue is then dis-
sected from anterior to the artery and between the artery
and vein (Figure 45-9A). The nodes are dissected to
below the inguinal ligament to the node of Cloquet (or
Rosenmüller), the most proximal of the deep inguinal
chain. One to 5 nodes are usually encountered. About 5
to 8 cm below the inguinal ligament, the profunda
femoris artery arises on the lateral aspect of the femoral
artery. This must be carefully dissected and preserved,
especially if myocutaneous flap coverage may later be
required.
The wound is then irrigated carefully and careful
attention is given to all bleeders and lymphatics. The sar-
torius muscle is separated sharply from its origin on the
anterior superior iliac spine and mobilized medially to
cover the now exposed femoral vessels (Figure 45-9B).34,36

Figure 45-10 Management of the ulcerated groin with vascular involvement. If required, a
Gore-tex vascular graft is placed. Transposition of a myocutaneous flap based on the
gracilis muscle is used to cover the inguinal defect. (See text for details.)
734 Part VII Urethra and Penis
Drainage using a closed suction catheter apparatus is
placed, and the wound is carefully closed in layers.
Several sutures are used to secure Camper’s fascia to the
anterior aspect of the muscles to close potential space and
discourage lymphocele formation (Figure 45-9C).35 The
skin edges are carefully assessed, using intravenous fluo-
rescein and the Woods’ lamp if necessary, and any ques-
tionably viable skin is excised. The wound is then
meticulously closed in layers. The patient is maintained
at complete bed rest with compressive stockings in place
for 5 to 7 days. Subcutaneous heparin is given. The Foley
catheter is discontinued after 24 to 48 hours. Closed suc-
tion is maintained for 5 days.
Management of Enlarged or Ulcerated Nodes and
Femoral Vessel Involvement
SCC is characterized by aggressive local invasion into
surrounding tissues. Large inguinal nodes, particularly
when the patient presents for treatment late or after an
extended period of neglect, will have invaded the overly-
ing skin of the groin and may ulcerate through it in
extreme cases (Figure 45-10A). Induration of the skin is
suggestive of such local invasion. In this setting, the
tumor is excised leaving a 2-cm margin of normal skin
around the indurated or ulcerated area (Figure 45-10B).
A radical ilioinguinal lymphadenectomy is performed,
and all tumor is completely resected.
In some instances, there may be involvement of the
femoral vessels, particularly the vein. Resection of the
anterior wall of the vein with reconstruction using a
saphenous vein graft or Gore-tex patch may be required
(Figure 45-10C and D).36 In some instances of severe
involvement, the vein may be ligated and excised.
Large skin defects may be closed with a tensor fascia
lata or gracilis myocutaneous graft (Figure 45-10E).33,37,38
Such a graft may be based over the hip and swung medi-
ally and superiorly to cover a groin defect (Figure 45-10F).
Again, all postoperative precautions recommended for
the classical radical lymphadenectomy should be
employed for patients undergoing this procedure.
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151:1244.
28. deKernion JB, Tynbery P, Persky L, et al: Carcinoma of
the penis. Cancer 1973; 32:1256.
29. Ferrigni RG, Novicki DE: Complications of
lymphadenectomy in urologic surgery. Atlas Urol Clin
North Am 1995; 3:105.
30. Herr HW: Surgery of penile and urethral cancer. In
Walsh PC, Retik AB, Stamey TA, Vaughan ED Jr (eds):
Campbell’s Urology, 6th edition. Philadelphia, WB
Saunders, 1992.
31. Smith JA, Middleton RG: The use of fluorescein in
radical inguinal lymphadenectomy. J Urol 1979; 122:754.
32. Lynch DF, Schellhammer PF: Partial penectomy, total
penectomy, and radical inguinal lymphadenectomy. In
Krane RJ, Siroky MB, Fitzpatrick JM (eds): Operative
Urology. New York, Churchill Livingstone, 2000.
33. Catalona WJ: Modified inguinal lymphadenectomy for
carcinoma of the penis with preservation of the saphenous
veins: technique and preliminary results. J Urol 1988;
140:306.
34. Spratt JS Jr, Shieber W, Dillard BM: Anatomy and
Surgical Techniques of Groin Dissection. St Louis,
Mosby, 1965.
35. Puras A, Rivera J: Inguinal and pelvic lymphadenectomy
for penile cancer. Atlas Urol Clin North Am 1995; 3:81.
36. Baranofsky ID: Technique of inguinal node dissection.
Surgery 1948; 24:555.
37. Hill HL, Nahai F, Vasconez LO: The tensor fascia lata
myocutaneous free flap. Plast Reconstr Surg 1978; 61:517.
38. Staubitz WJ, Melbourne HL, Oberkircher OJ: Carcinoma
of the penis. Cancer 1955; 8:371.
C H A P T E R
46Neuroblastoma
Michael C. Carr, MD, PhD, and Michael E. Mitchell, MD
Neuroblastoma is the second most common solid tumor
in infants and children. Virchow,1 in 1864, was the first to
speculate that its origin was neural, and he considered it a
glioma. Marchand, in 1891,2 noted the histologic similar-
ities between neuroblastoma and developing sympathetic
ganglia. Following Wright’s use of the term “neuroblas-
toma” in 1910, there has been little debate with regard to
origin of the tumor. Herxheimer3 demonstrated that fib-
rils in neuroblastoma stained with a specific neural silver
stain helping establish the true origin of this tumor. There
was little published in the literature earlier this century,
with Blacklock4 noting only 116 cases in the literature, to
which he added 18 of his own. At that time, neuroblas-
toma was fourth in order of frequency of malignant
tumors in children. The number of cases described
increased to 623 by 1953,5 and today it remains the fourth
most common malignancy in childhood, being less
common than leukemia, brain tumors, and lymphoma.
Cushing and Wolbach6 reported for the first time a
transformation of neuroblastoma into benign gan-
glioneuroma laying the foundation for a greater under-
standing of its biologic variability. Later descriptions
noted that this event generally occurred in infants <6
months of age. Beckwith and Perrin7 noted microscopic
foci of neuroblastoma cells in the adrenal glands in a
number of infants under 3 months of age who died from
other causes. These were termed “neuroblastoma in
situ,” and were estimated to occur approximately 40
times more frequently than the number of neuroblas-
toma cases clinically diagnosed. Recession of these foci
appeared to be complete after 3 months of age.
Biochemical activity associated with neuroblastoma was
initially noted due to elevated levels of urinary pressor
amines.8 It has subsequently been recognized that ele-
vated levels of norepinephrine, its precursors and
metabolites occurs in patients with this tumor.
ETIOLOGY
Neuroblastoma develops from neural crest cells in the
embryo. These cells give rise to sympathetic neuroblasts,
which are found in the adrenal medulla, autonomic gan-
glia, and peripheral nerve sheaths. Other tumors that can
arise from these cells include ganglioneuroma and gan-
glioneuroblastoma. The former may cause considerable
morbidity secondary to spread to contiguous organs but
does not metastasize. The latter is known to metastasize
about 20% of the time and has greater malignant poten-
tial than ganglioneuroma.
Knudson and Strong,9 noting the apparent genetic
influence, suggested that 20% of cases arise in children
predisposed to the tumor by a dominant transmittable
mutation. Later work suggested that familial cases result
from a prezygotic mutation and that nonfamilial cases
result from a postzygotic somatic mutation.
Neuroblastomas are characterized cytogenetically by
deletion of the short arm of chromosome 1, double-
minute chromatin bodies (dmins), and homogeneously
staining regions (HSRs).10,11 The latter two abnormali-
ties reflect gene amplification, whereas the former may
represent deletion of a tumor suppressor gene. No other
specific karyotypic abnormalities have been detected
thus far.
Flow cytometry of DNA content provides a way of
measuring total DNA content, which correlates with
the modal chromosome number. Determination of the
DNA index (DI) of neuroblastomas from infants pro-
vides important information that may be predictive of
response to particular chemotherapeutic regimens, as
well as outcome.12–14 Tumors with “hyperdiploid” DNA
content (DI = 1) are more likely to have lower stages of
disease and to respond to cyclophosphamide and dox-
orubicin, whereas those with a “diploid” DNA content
(DI = 1) are more likely to have advanced stages of
739
740 Part VIII Pediatric Malignancies
disease and do not respond to this combination.15 This
analysis provides no information about specific chromo-
some rearrangements (deletions, translocation, or gene
amplification) but does correlate with biologic behavior.
The discovery of extrachromosomal dmins and chro-
mosomally integrated HSRs is a cytogenetic manifesta-
tion of gene amplification.16,17 The region amplified is
derived from the distal short arm of chromosome 2, con-
taining the proto-oncogene N-myc. Brodeur et al.18 have
demonstrated that N-myc amplification occurs in 25% to
30% of primary neuroblastomas from untreated patients,
and amplification is associated primarily with advanced
stages of disease. Subsequent studies have shown that
N-myc amplification was associated with rapid tumor
progression and a poor prognosis. Amplification was
found in only 5% to 10% of patients with low stage of
disease or stage IV-S but 30% to 40% of advanced dis-
ease patients.19 It is almost always present at the time of
diagnosis and, thus, appears to be an intrinsic biologic
property in a distinct subset with a poor prognosis.20
There is a correlation between N-myc copy number and
expression, and tumors with amplification expressed N-
myc at much higher levels than are seen in tumors with-
out amplification. Finally, there is heterogeneity in the
level of expression among the tumors that have a single-
copy of N-myc, but higher expressing single-copy tumors
do not appear to be a particularly aggressive subset.21,22
Deletions of the short arm of chromosome 1 are found
in 70% to 80% of the near-diploid tumors that have been
karyotyped. This cytogenetic finding is commonly associ-
ated with more advanced stages of disease, whereas tumors
from patients with lower stages are more likely to be
hyperdiploid or triploid with very few structural
rearrangements. The deletions of chromosome 1 are vari-
able but generally map to a region (1p36) that may contain
a suppressor gene important in malignant transformation
or progression. Recent molecular studies have shown a
strong correlation between loss of heterozygosity (LOH)
for chromosome 1p and N-myc amplification, suggesting
that these two events may be related.23 An allelic loss on
the long arm of chromosome 14 also has been noted sug-
gesting that there may be another suppressor gene
involved in the pathogenesis of neuroblastomas.
INCIDENCE
Neuroblastoma accounts for 8% to 10% of all childhood
tumors and is the most common malignant tumor of
infancy. In the United States the incidence is 10.5 per
million per year in white children and 8.8 per million per
year in black children <15 years of age.24,25 Male pre-
dominance is noted but is slight, 1.1 to 1. The incidence
is underestimated because of the occurrence of sponta-
neous regression of neuroblastoma in situ.
Approximately one-third of cases are diagnosed in the
first year of life and another quarter between 1 and 2
years of age. This is a younger age of presentation than
that for Wilms’ tumor. Unlike other childhood tumors, a
low incidence of associated congenital anomalies exists.
However, brain and skull defects have been noted in 2%
of patients with neuroblastoma.26 An association with
neurofibromatosis and Hirschbrung’s disease has been
noted.27
PATHOLOGY
Arising from primitive, pleuripotential sympathetic cells
(sympathogonia) derived from neural crest, neuroblas-
tomas are found in a variety of locations. The adrenal
medulla or cells in the adjacent retroperitoneal tissues on
the posterior abdominal wall account for 50% to 80% of
neoplasms in most reported series. The second most
common location is within the posterior mediastinum
usually in paravertebral sites. The remaining neoplasms
occur in derivatives of the neural crest within the pelvis,
cervical region, lower abdominal sympathetic chain,
rarely within the posterior cranial fossa, or other
locations.
Macroscopically, the growths are lobular, soft in con-
sistency, and weigh between 80 and 150 g. The cut sur-
face is red-gray in color, and areas of hemorrhage and
necrosis may be obvious as the tumor increases in size.
Calcification is not infrequent and this can help in the
radiologic localization (Figure 46-1).
Histologically, the cells are small and dark like lym-
phocytes and frequently are arranged in masses without
any true pattern. It is one of the “small blue round cell”
tumors of childhood (e.g., lymphomas, neuroectodermal
tumor, and rhabdomyosarcoma). In characteristic lesions,
Figure 46-1 Typical adrenal neuroblastoma with areas of
hemorrhage and necrosis. Tumor encircles aorta (straight
arrow) with kidney seen at left (curved arrow). (Courtesy Dr.
Kathleen Patterson, Seattle, WA.)

rosettes are formed when the tumor cells occupy the
periphery and the young nerve fibrils grow into the cen-
ter of each rosette (Figure 46-2).
The fully differentiated, and benign, counterpart of
neuroblastoma is the ganglioneuroma, composed princi-
pally of mature ganglia, neuropil, and schwannian cells.
Ganglioneuroblastoma defines a heterogenous group of
tumors with histopathologic features reflecting the spec-
trum of maturation of neuroblastoma and ganglioneu-
roma. These may be either focal or diffuse, depending on
the pattern seen, but diffuse ganglioneuroblastoma is
associated with less aggressive behavior. Multiple sec-
tions should be examined to categorize these tumors
accurately because viability and histopathologic features
are variable.
Hematoxylin–eosin staining and light microscopy is
often not enough to distinguish these tumors from
other “small round blue cell” tumors of childhood.
Immunohistochemical techniques and electron
microscopy are helpful additions to light microscopy.
Monoclonal antibodies recognizing neural filaments,
synaptophysin, and neuron-specific enolase will stain
neuroblastoma.28 Electron microscopy visualizes the
dense core, membrane-bound neural secretory granules
in addition to microfilaments, and parallel arrays of
microtubules within the neuropil (Figure 46-3).29
A histology-based prognostic classification that has
gained wide-spread acceptance was developed by
Figure 46-2 Histologically, the cells comprising neuroblastoma are small with darkly
staining nuclei and inconspicuous cytoplasm. Rosettes composed of tumor cells
surround neuropil material (arrows). (Courtesy Dr. Kathleen Patterson, Seattle, WA.)
Chapter 46 Neuroblastoma 741
Shimada et al.30 The system is formulated around patient
age and the following histologic features: the presence or
absence of schwannian stroma; the degree of differentia-
tion; the mitosis-karyorrhexis index (MKI). A retrospec-
tive evaluation of the Shimada’s method in 295 patients
treated by the Children’s Cancer Study Group (CCSG)
identified favorable and unfavorable patient subsets. The
histologic patterns were independently predictive of out-
come whereas stage was prognostically less important
than histologic grade.31,32
A simplified system has been devised, which predicts a
favorable outlook based on presence of calcification and a
low mitotic rate (=10 mitoses/10 high power field).33 A
grading system was developed for finding tumors with
both features (grade 1), with the presence of only one of
these features (grade 2), or the absence of both features
(grade 3). When these grades were combined with age (≤1
year or >1 year) and surgicopathologic staging, low- and
high-risk groups emerged, which were clearly correlated
with the Shimada’s favorable and unfavorable groups.
The result of this analysis has led to the formation
of the International Neuroblastoma Pathology Classi-
fication System. A recent study has analyzed the mor-
phologic features of neuroblastoma (schwannian
stroma-poor tumors) in clinically favorable and unfavor-
able groups. This study reaffirmed the prognostic impact
of Shimada’s criteria and demonstrated that additional
morphologic features, such as prominent nucleoli and
742 Part VIII Pediatric Malignancies
Figure 46-3 Electron microscopy showing dense core neural secretory granules
(straight arrows) with microtubules (curved arrow) characteristic of neuroblastoma.
(Courtesy Dr. Kathleen Patterson, Seattle, WA.)
undifferentiated and poorly differentiated neuroblasts,
cellularity and nuclear size provide additional critical rel-
evance partly independent of the patient’s age at diagno-
sis.34 The analysis of these tumors at the cytogenetic and
molecular level revealed ploidy changes, amplification of
the oncogene MYCN, deletions of chromosome 1p,
gains of chromosome arm 17q, and deletions of 11q. It
was demonstrated that in infants, DNA content was sig-
nificantly linked to tumor stage, with advanced stages
seen in diploid tumors. Hyperdiploidy is mainly observed
in low-stage tumors of younger patients with a favorable
clinical outcome, whereas diploid tumors are associated
with advanced tumor growth and significantly reduced
survival probability.35
Approximately 35% of all neuroblastomas have 1p
deletions of variable lengths36 with poor outcomes seen
in patients with large 1p deletions than patients with
short or interstitial deletions.37 Amplified MYCN is one
of the most prominent genomic abnormalities of neurob-
lastoma, being prototypic for the significance of proto-
oncogene amplification and tumor agenesis. Amplified
MYCN correlates with advanced-stage disease; in the
absence of amplified MYCN, overall survival is approxi-
mately 60% over a 5-year period, but only 10% of
patients survived a 1-year period when MYCN was
amplified at more than 10 copies.38
The most frequent genomic alteration in neuroblas-
toma is a gain of 17q, seen in about 50% of tumors. Such
a gain was significantly associated with tumor progres-
sion.39 A recent collaborative study from 6 European
centers identified 17q gain as the most powerful prog-
nostic factor in survival and multivariant analysis with
other clinical and tumor genetic parameters, including 1p
deletion and MYCN amplification.40
PRESENTATION
Neuroblastoma most often presents as an abdominal mass
(65% discovered at the time of routine medical examination
or by the parents). Infants tend to have more thoracic and
cervical primary tumors. The tumor is usually asymmetric
and located in the supraumbilical region, the hypochon-
drium, or the flank often extending beyond the midline.
Tumors which arise from the adrenal or suprarenal sympa-
thetic chain are more lateral whereas the medially located
tumors may arise from the periaortic sympathetic chain.
These tumors may then grow through the intervertebral
foramina and produce spinal cord compression.
Neuroblastomas can arise from anywhere along the
sympathetic chain; about 14% arise in the chest in infants
over 1 year of age, but only 0.5% in the cervical region.
Tumors arising from the cervical sympathetic ganglion
may produce Horner’s syndrome. In about 1% of
patients, a primary tumor cannot be found. The majority
of children with neuroblastoma are diagnosed by the age
of 5 years, and it rarely occurs after age 10.
Metastatic extension of neuroblastoma occurs in two
patterns, lymphatic and hematogenous. Approximately
 Chapter 46 Neuroblastoma 743

70% of all patients will present with metastatic disease at

diagnosis. Regional lymph node metastasis will be noted
in 35% of patients with apparently localized disease.
Tumor spread to lymph nodes outside the cavity of ori-
gin is considered to be disseminated disease. These chil-
dren may have a better prognosis if no other metastatic
disease is found.41 Hematogenous metastasis occurs most
often to bone marrow, bone, liver, and skin. Rarely, dis-
ease may spread to lung and brain parenchyma, usually as
a manifestation of relapsing- or end-stage disease. The
proportion of patients presenting with localized,
regional, or metastatic disease is age dependent. The
incidence for localized tumors, regional lymph node
spread, and disseminated disease is 39%, 18%, and 25%,
respectively, in infants (18% with stage IV-S) compared
to 19%, 13%, and 68%, respectively, in older patients.
Several classical signs and symptoms have been associ-
ated with metastatic neuroblastoma. Proptosis and peri-
orbital ecchymosis are frequent and result from
retrobulbar and orbital infiltration with tumor.
Hutchinson syndrome describes widespread bone mar-
row and bone disease, causing bone pain, limping, and
irritability in the younger child. Skin involvement is seen
exclusively in infants with Evan’s stage IV-S tumors42 and
is characterized by nontender, bluish subcutaneous nod-
ules. Disseminated disease may manifest as failure to
thrive and fever, the latter observed most often in the
presence of bone metastasis. These are usually seen as
lytic lesions on skeletal radiographs. Rarely, patients may
present with the complication of catecholamine secretion
by the neuroblastoma, which may include headache,
hypertension, palpitations, and diaphoresis. The tumor
may also lead to watery diarrhea secondary to vasoactive
intestinal polypeptide.
DIAGNOSTIC EVALUATION
Minimum criteria for establishing the diagnosis of neu-
roblastoma include43: (1) an unequivocal pathologic diag-
nosis is made from tumor tissue by standard methods,
including immunohistology or electron microscopy if
necessary; or (2) bone marrow contains unequivocal
tumor cells (i.e., syncytia) and urine contains increased
urinary catecholamine metabolites (SD > 3 above the
mean, corrected for age). Since neuroblastoma often
secretes catecholamines, urinary levels of vanillylman-
delic acid (VMA) or homovanillic acid (HMA) should be
elevated.44 A 24-hour urine was previously recom-
mended, but normalizing VMA and HMA excretion to
the milligram creatinine in the sample makes a timed col-
lection unnecessary and it avoids false negative results
due to dilution. Table 46-1 outlines the minimum testing
to define the clinical stage of disease.43 The evaluation
often begins with an abnormal ultrasound, which demon-
strates the mass, distinguishing a solid mass from a
hydronephrotic kidney. It can also demonstrate lymph
node enlargement, tumor extension, and liver metastasis,
although the CT or magnetic resonance imaging provide
greater sensitivity (Figures 46-4 to 46-6).
Most centers in the U.S. rely on 99mTc-diphosphonate
scintigraphy for the evaluation of bone disease. Because of
the biochemical activity of neuroblastoma, meta-iodoben-
zylguinidine (MIBG) scintigraphy becomes an attractive
tool.45 The compound is taken up by catecholaminergic
cells, which includes most neuroblastomas. Thus, it
becomes a very specific and sensitive method of assessing
the primary tumor and focal metastatic disease.
There exists great variability in the number of bone
marrow aspirates or biopsies done at different institutions.

Table 46-1 Minimum Recommended Tests for Determining Extent of Disease36

Tumor Site Tests

Primary Three-dimensional measurement of tumor by CT scan or MR or ultrasound

Metastases Bilateral posterior iliac bone marrow aspirates and core biopsies (4 adequate specimens necessary to exclude
tumor)

Bone radiographs and either scintigraphy by 99mTc-diphosphonate or 131I-(or 123I-) meta-iodobenzylguanidine

(MIBG) or both

Abdominal and liver imaging by CT scan or MR or ultrasound

Chest radiograph (AP and lateral) and chest CT scan

Markers Quantitative urinary catecholamine metabolites (VMA and HVA)

Note: For evaluation of bone metastases, 99mTc-diphosphonate scintigraphy is recommended for all patients and is essential if MIBG scintigraphy is
negative in bone. (From Brodeur, GM, Castleberry, RP: Neuroblastoma. In Pizzo PA, Poplack DG (eds): Principles and Practice of Pediatric
Oncology, 2nd edition, p 750. Philadelphia, J.B. Lippincott, 1993.)
744 Part VIII Pediatric Malignancies

Recent data support the increased yield of bone marrow

biopsies versus aspirates. The international conferees on
neuroblastoma staging recommended two bone marrow
aspirates and two biopsies, that is one of each from each
of the posterior iliac crests.43 Core biopsy specimens must
contain at least 1 cm of marrow (excluding cartilage).

STAGING
The current, favored staging system is based on clinical,
radiographic, and surgical evaluation of children with
neuroblastoma. The International Neuroblastoma
Staging System (INSS) allows for uniformity in staging
of patients, facilitating clinical trials, and biologic studies
around the world (Table 46-2).43
The Children’s Oncology Group (COG) risk-based Figure 46-4 CT scan of 4-year old with IV contrast showing
schema is based on three factors: patient age at diagnosis, right adrenal neuroblastoma with diffuse calcification, seen
certain biologic characteristics of the patient’s neuroblas- adjacent to liver. A, aorta; K, left kidney. (Courtesy Dr. Edward
toma tumor, and the stage of the tumor as defined by INSS. Weinberger, Seattle, WA.)

PROGNOSTIC CONSIDERATIONS
The COG is investigating a risk-based neuroblastoma
treatment plan that assigns risk-based on patients’ age,
INSS stage, and tumor biology (Table 46-3).46 The treat-
ment plan is based on the risk group, with low-, intermedi-
ate-, and high-risk groups having an overall survival of
>90%, 70% to 90%, and >30%, respectively, 3 years after
diagnosis. The overall prognosis of patients with stages I,
II, and IV-S is between 75% and 90%, while those with
stage III and IV have only a 10% to 30% 2-year disease-
free survival. Age is a sufficient prognostic variable, with
the outcome of infants under 1 year of age being substan-
tially better than those >1 year. Origin of the tumor is
another important variable, as patients with adrenal pri-
maries have poorer outcomes than those with other origins.
A number of biologic variables have been assessed that
may help predict the ultimate outcome for a patient.
Figure 46-5 CT scan of 1-year old with IV contrast showing
Hyperdiploid tumor DNA is associated with a favorable extensive right adrenal neuroblastoma invading into right
prognosis,47 while N-myc amplification is associated with kidney, encircling aorta (A) and extending beyond the midline.
a poor prognosis regardless of patient age.48–50 A high (Courtesy Dr. Edward Weinberger, Seattle, WA.)
proportion of proliferating tumor cells may independ-
ently predict poor prognosis.51 Expression of the gene
encoding one of the high-affinity neurotrophin receptors
(TRK-A) is associated with good prognosis tumors.52 is also used to make a diagnosis, provide tissue for bio-
Increased levels of telomerase RNA,53 elevated serum logic studies, surgically stage the tumor, and to attempt
ferritin,54 elevated serum lactate dehydrogenase,55 and excision of the tumor. Delayed primary or second-look
the presence of neuroblastoma cells in bone marrow dur- surgery determines the response to therapy.
ing or after chemotherapy are each associated with poor Based on the INSS criteria, the operative protocol
prognosis.55–58 incorporates the following: (1) The resectibility of pri-
mary or metastatic tumor should be determined in light
of tumor location, mobility, relationship to major vessels,
TREATMENT
ability to control blood supply, and overall prognosis of
As with most solid malignant neoplasms, complete surgi- patient. Modern chemotherapy effectively consolidates
cal removal is the most effective form of therapy. Surgery and decreases the size of primary tumors and large lymph
 Chapter 46 Neuroblastoma 745

Figure 46-6 A, Chest x-ray with subtle right paravertebral curvilinear stripe (arrowheads)
raising possibility of right paravertebral mass. B and C, Coronal T1-weighted MRI images.
B represents more posterior view showing large mass between right kidney and vertebral
bodies. C demonstrates multilobulated right paravertebral mass extending through three
contiguous neural foramina into spinal canal with effacement of spinal cord. (Courtesy Dr.
Edward Weinberger, Seattle, WA.)
746 Part VIII Pediatric Malignancies

Table 46-2 International Neuroblastoma Staging System (INSS)

Stage I Localized tumor confined to the area of origin; complete gross excision, with or without microscopic residual
disease; identifiable ipsilateral and contralateral lymph nodes negative microscopically

Stage IIA Unilateral tumor with incomplete gross excision; identifiable ipsilateral and contralateral lymph nodes negative
microscopically

Stage IIB Unilateral tumor with complete or incomplete gross excision; with positive ipsilateral regional lymph nodes;
identifiable contralateral lymph nodes negative microscopically

Stage III Tumor infiltrating across the midline with or without regional lymph node involvement; or, unilateral tumor
with contralateral regional lymph node involvement; or, midline tumor with bilateral lymph node involvement

Stage IV Dissemination of tumor to distant lymph nodes, bone, bone marrow, liver, and/or other organs (except as
defined in stage IV-S)

Stage IV-S Localized primary tumor as defined for stage 1 or stage 2 with dissemination limited to liver, skin, and/or bone
marrow (limited to infants <1 year of age). Marrow involvement should be minimal (<10% of total nucleated
cells identified as malignant by bone biopsy or dry bone marrow aspirate). More extensive bone marrow
involvement would be considered stage 4 disease

node metastasis. Therefore, there is little place for the
less predictable surgical assaults of previous years. (2)
Nonadherent, intracavitary lymph nodes should be sam-
pled. Gross examination during surgery may be inaccu-
rate for detecting or ruling out lymph node metastasis in
up to 25% of cases.59 Lymph nodes adherent to and
removed en bloc with the primary tumor do not alter the
outcome of the patient.60 Ideally, lymph nodes superior
and inferior to the primary tumor should be sought and
sampled, and location documented. Lymph node sam-
pling in patients with high thoracic, low cervical, or large
abdominal primary tumors that are unresectable may be
problematic. Other prognostic factors may be utilized in
these situations, and thus, the value of additional infor-
mation regarding lymph node involvement is question-
able. (3) Routine biopsy of the liver in situations
involving an abdominal neuroblastoma without evidence
of metastatic disease has been advocated. This practice
has come into question, particularly due to the sensitivity
of clinical staging by CT or MR. Until the INSS criteria
for staging are prospectively studied in all age groups,
routine biopsy of liver during initial surgery in patients
with primary abdominal tumors remains appropriate.
The surgical approach to neuroblastoma is best
regarded as a vascular-type procedure. Neuroblastoma
rarely invades the tunica media of large blood vessels but
can involve the tunica adventitia. The appropriate plane
of dissection usually exists beneath the tunica adventitia.
Following partial exposure of the circumference of each
vessel, the tumor is segmentally removed as complete
vessel dissection occurs.60
The approach to an extensive left-sided abdominal
tumor or preaortic tumor is through a long, supraumbil-
ical, transverse incision. The left colon is reflected medi-
ally, followed by mobilizing of spleen, stomach, and pan-
creas. This is best accomplished by maintaining the plane
between the mesocolon and Gerota’s fascia. The viscera
are reflected as far as the midline and placed in an intes-
tinal bag, so that the tumor is exposed.
The first stage of the operation involves exposure of
the arterial wall from below the distal limit of the tumor
to just above the proximal limit of the tumor. The origin
of the main visceral arteries are often noted at this time.
Further dissection focuses on the distal extent of the
tumor, along the external or common iliac artery.
Surgeon and assistant each pick up the adventitia, allow-
ing longitudinal dissection along the middle of the vessel.
The subadventitial plane has been entered, establishing
the plane for the remainder of the operation. Proximal
dissection proceeds to the tumor, incising along the mid-
dle of the vessel down to tunica media. Bipolar cautery is
of considerable benefit.
Sympathetic nerves on the left will be transected, and
an attempt should be made to preserve the nerves on the
right. The aortic bifurcation is encountered and the dis-
section proceeds to the inferior mesenteric artery. If
there is a large bulk of tumor, retrograde dissection may
be helpful. Further dissection cephalad leads to the ori-
gin of the gonadal arteries and left renal vein crossing the
aorta at the same level. Considerable tumor bulk can be
encountered in this area. It is usually possible to identify
the vein before entering the lumen. Dissection of 4 to 5
cm of vein will allow for retraction and adequate dissec-
tion beneath the aorta. Aortic dissection may be difficult
at this level due to tumor adherence and the two gonadal
arteries. Dividing the gonadal arteries and maintenance
of the appropriate plane of dissection allow for safe dis-
section. Cephalad to the vein is the origin of the left renal
 Chapter 46 Neuroblastoma 747

Table 46-3 Children’s Oncology Group Neuroblastoma Risk Group Assignment Schema
INSS Stage Age MYCN Shimada’s Histology DNA Ploidy Risk Group

1 0–21 years Any Any Any Low

2A/2B* <365 days Any Any Any Low

≥365 days to 21 years NonAmp Any — Low

≥365 days to 21 years Amp Fav — Low

≥365 days to 21 years Amp Unfav — High

3† <365 days NonAmp Any Any Intermediate

<365 days Amp Any Any High

≥365 days to 21 years NonAmp Fav — Intermediate

≥365 days to 21 years NonAmp Unfav — High

≥365 days to 21 years Amp Any — High

4† <365 days NonAmp Any Any Intermediate

<365 days Amp Any Any High

≥365 days to 21 years Any Any — High

IV-S‡ <365 days NonAmp Fav >1 Low

<365 days NonAmp Any =1 Intermediate

<365 days NonAmp Unfav Any Intermediate

<365 days Amp Any Any High

Biology defined by MYCN status: amplified (Amp) versus nonamplified (NonAmp)

Shimada’s histopathology: favorable (Fav) versus unfavorable (Unfav)

DNA Ploidy: DI ≥ 1; hypodiploid tumors (with DI <1) will be treated as a tumor with a DI > 1
(DI < 1 [hypodiploid] to be considered favorable ploidy)

*INSS 2A/2B symptomatic patients with spinal cord compression, neurologic deficits or other symptoms will be treated on the LOW RISK NB
Study with immediate chemotherapy for 4 cycles (Course 1).
†INSS 3 or 4 patients with clinical symptoms as above (or in the investigator’s opinion it is in the best interest of the patient) will receive immediate

chemotherapy.
‡INSS IV-S infants with favorable biology and clinical symptoms will be treated on the LOW RISK NB study with immediate chemotherapy until

asymptomatic (2 to 4 cycles). Clinical symptoms defined as: respiratory distress with or without hepatomegaly or cord compression and neurologic
deficit or IVC compression and renal ischemia; or genitourinary obstruction; or gastrointestinal obstruction and vomiting; or coagulopathy with
significant clinical hemorrhage unresponsive to replacement therapy.

artery and just proximal to this is the superior mesenteric
artery (SMA). Thus, at the level of the renal artery, the
plane of dissection should become perpendicular to the
anterolateral wall of the artery rather than directly ante-
riorly. This plane is then maintained as far as the
diaphragm, where normal tissue is usually encountered.
With clearing of the anterior surface of the proximal
aorta, the origins of the celiac artery and SMA are iden-
tified. These vessels are exposed and cleared, with the
SMA usually being the easier vessel to dissect free. Once
this artery is mobilized, the celiac artery and its branches
are given attention. This area can be difficult but by dis-
secting as before and maintaining the subadventitial
plane, success is achieved. Frequently, two diaphragmatic
branches arise from the trunk of the celiac artery or just
proximally from the aorta, and these are divided. The left
gastric artery may also be sacrified without concern.
Once the two main intestinal arteries are immobilized,
748 Part VIII Pediatric Malignancies
the right side of the aorta may be exposed with the right
renal artery next being encountered. The tumor at this
location may be attached posteriorly to the crus of the
hemidiaphragm. Once its main attachments are divided,
the tumor is removed. The tumor that has been attached
between the celiac artery and SMA usually adheres to the
posterior surface of the pancreas as well. In dissecting
this from the pancreas, the termination of the splenic
vein and its junction with superior mesenteric vein are
exposed. It is uncommon to see dense adherence in this
region.60 Following the removal of the preaortic tumor
proximally, the left renal artery should be exposed and
dissected free. This can be fairly tedious but is possible.
When tumor is deep within the renal hilum, nephrec-
tomy may be necessary. Once the renal artery is dis-
played, the primary tumor can be mobilized and excised.
The remaining areas to be cleared lie below the level of
the renal vessels and posterior to the length of the aorta.
These areas do not present any unusual difficulty. As
many as possible of the lumbar arteries should be pre-
served, but no untoward consequences have followed
division of up to 5 arteries.60 Finally, if there is consider-
able tumor bulk posterior to the inferior venae cava,
reflection of the ascending colon may be necessary to
achieve complete tumor clearance.
In general, thoracic procedures become more an exer-
cise of rib clearance rather than a vascular-type opera-
tion. Pelvic tumors may provide some difficulty with
regard to access. An extended Pfannenstiel-type incision,
altered in that the recti are detached from the pubis, pro-
vides optimal exposure, but access may still be difficult.
The anatomy is complicated by the presence of nerves of
the sacral plexus, particularly with formal dissection of
the internal iliac vessels. Once again, formal systematic
and planned exposure of the important structures before
tumor removal is of great value.60
Surgical complication rates in neuroblastoma range
from 5% to 25%.61,62 The incidence increases in
instances of aggressive abdominal resection of tumors at
diagnosis. Reported complications include nephrectomy,
hemorrhage, postoperative intussusception or adhesions,
injury to renal vessels with subsequent renal failure, and
neurologic defects, such as Horner’s syndrome.
Avoidance of surgical risk in infants who have better sur-
vival is recommended. Downstaging of the tumor with
chemotherapy followed by surgical resection is the
favored approach.
Chemotherapy
The mainstay of management in neuroblastoma is
chemotherapy. A number of effective chemotherapeutic
agents have been identified that include cyclophos-
phamide, cisplatin, doxorubicin, vincristine, etoposide,
and teniposide, which alone yield complete response or
partial response rates ranging from 34% to 45%. A com-
bination of agents are used that take advantage of drug
synergism, mechanisms of cytotoxicity, and differences in
side effects. Cyclophosphamide and cisplatin are noncell
cycle-specific agents often used in combination with cell
cycle-dependent drugs (doxorubicin, teniposide). Using
these combinations has resulted in improved response
rates in children with advanced neuroblastoma. The
chemotherapy is given in phases, which include induc-
tion, consolidation, and maintenance phases.
The COG risk stratification schema is currently being
utilized in the treatment of most patients with neuroblas-
toma in North America. This risk-based neuroblastoma
treatment plan assigns each patient to a low-, intermedi-
ate-, or high-risk group. Thus, in patients without
metastatic disease, initial surgery is performed to estab-
lish the diagnosis, to resect as much of the primary tumor
as safely possible, to accurately stage the disease via sam-
pling of regional lymph nodes that are not adherent to
the tumor, and to obtain adequate tissue for biologic
studies.
Treatment of Low Risk Disease
Treatment for patients categorized as low risk (Table 46-3)
consists most commonly of surgery alone but in some
cases surgery combined with 6 to 12 weeks of
chemotherapy. Chemotherapy consists of carboplatin,
cyclophosphamide, doxorubicin, and etoposide. Clearly
the dose of each agent is kept low in order to minimize
permanent injury from the chemotherapy regimen.63
Treatment of Intermediate Risk Disease
Patients categorized as intermediate risk (Table 46-3) are
treated with surgery and 12 to 24 weeks of the same
chemotherapy regimen as described above.64
Treatment of High Risk Disease
In contrast, patients categorized as high risk (Table 46-3)
are generally treated with aggressive multiagent
chemotherapy comprising very high doses of carboplatin,
cyclophosphamide, doxorubicin, etoposide, and ifos-
phamide with high-dose cisplatin. After a response to
chemotherapy, resection of the primary tumor should be
attempted, followed by myeloablative chemotherapy,
sometimes total-body irradiation, and autologous stem
cell transplantation. Irradiation of residual tumor and
original sites of metastasis is often performed before,
during or after myeloablative therapy. After recovery,
patients are treated with oral 13-cis-retinoic acid for 6
months. Both myeloablative therapy and retinoic acid
improve outcome in patients categorized as high risk.65
See Table 46-4 for a summary.

Table 46-4 Disease-Free Survival (2 years) Based on Risk Category and Age
Risk Category Patient Age (years)
All
All
Low <1
<1
Intermediate >1
<1
High >1
*Personal observation, RP Castleberry.
†Difference relates to complete versus partial surgical resection, respectively. Modified from Brodeur, 1993.
Radiation Therapy
Despite the radiosensitive nature of neuroblastoma in
culture models, clinical response has been variable.66
Historically, radiation has been used in the multimodal-
ity management of residual neuroblastoma, bulky unre-
sectable tumors, and disseminated disease. Radiation
therapy is reserved for patients with symptomatic life or
organ threatening tumor that does not respond rapidly
enough to chemotherapy, or for intermediate-risk
patients whose tumor has responded incompletely to
both chemotherapy and attempted resection and also
have unfavorable biologic characteristics. Radiation
therapy to the primary site is recommended for high-risk
patients even in cases of complete resection.
Urgent Chemotherapy
Symptomatic spinal cord compression necessitates
immediate treatment with chemotherapy. Neurologic
recovery is more likely the less the severity of compro-
mise and the shorter the duration of symptoms.
Neurologic outcome appears to be similar whether cord
compression is treated with chemotherapy, radiation
therapy, or surgical laminectomy. However, laminectomy
may result in later scoliosis, and chemotherapy is often
needed whether or not surgery or radiation is used.67,68
The COG neuroblastoma treatment plan recommends
immediate chemotherapy for cord compression in
patients classified as low risk or intermediate risk.
Observation Without Surgery of Localized,
Presumed Adrenal Neuroblastoma in Infants
Studies suggest that selected presumed neuroblastomas
detected in infants by screening may safely be observed
Chapter 46 Neuroblastoma 749
INSS Stage Two-Years Disease-Free Survival (%)
1 >90
2A 85
2B/3 87/89
4S 57–90
2B/3 59
4 75
4 40/15†
without obtaining a definitive histologic diagnosis and
without surgical intervention, thus avoiding potential
complications of surgery in the newborn.69,70 The expe-
rience with tumors detected by mass urinary cate-
cholamine metabolite screening in Japan appears to be
applicable to tumors detected by prenatal or perinatal
ultrasound in the United States. Twenty-six infants with
presumed Evans stages I, II, or IV-S by imaging, urinary
VMA, and HVA levels less than 50 mcg/mg of creatinine,
no tumor involvement of great vessels or invasion into
the spinal canal and tumor size <5 cm were observed with
frequent imaging. Biopsy and tissue diagnosis were not
obtained initially. Progression of tumor size was noted in
one-third of the infants with resection without any
apparent increase in stage being accomplished. All had
favorable biologic features. In the remainder, following
observation for 6 to 73 months, no surgery had been per-
formed, the VMA and HVA had normalized, and in sev-
eral cases the tumors have become undetectable by
imaging.69 The COG is currently investigating system-
atic observation without surgery for infants with pre-
sumed small Evans stage I adrenal neuroblastoma
detected by prenatal or perinatal ultrasound.
FUTURE CONSIDERATIONS
The identification of various prognostic markers of neu-
roblastoma allow for a more precise determination of
biologic potential. A statistically significant association
has been noted with tumors of low histologic grade along
with DI of more than 1 (hyperdiploid), single copy of N-
myc gene per haploid genome, and a serum lactic dehy-
drogenase of <1500 IU/l. High histologic grade was
associated with a DI of 1, amplified N-myc gene, and an
LDH of 1500 or more, factors that are associated with
aggressive behavior.71 The use of these prognostic factors
750 Part VIII Pediatric Malignancies
allow for appropriate risk-specific therapy and the devel-
opment of optimal treatment protocols for childhood
neuroblastoma.
Identification of individuals who are predisposed to
develop the tumor has become increasingly important.
Cytogenetic studies have demonstrated alterations of
chromosome 1p, reaching a frequency of more than
70%.72 Alterations of 1p are also seen in significant fre-
quency in other types of cancers, including colon cancer,
alveolar rhabdomyosarcoma, hepatoblastoma, and ductal
carcinoma of the breast.73 Progress is being made that
should reveal whether specific genetic information is
commonly altered in neuroblastomas and, if so, what its
significance is for tumorigenesis.
Urinary catecholamine metabolites are commonly ele-
vated in neuroblastoma but unfortunately are not as reli-
able tumor markers as alpha fetoprotein or beta-human
chorionic gonadotropin for following germ cell tumors.
With greater understanding of the tumor biology, new
markers, such as telomerase RNA, serum ferritin, and
neurotrophin receptor, may prove useful for following
response to therapy, as well as early relapse.
Treatment strategies continue to evolve as clinical
response improves. The goals now are to maximize the
response and yet minimize the overall morbidity of treat-
ment. Newer modalities currently under investigation
include monoclonal antibody therapy with or without
GM-CSF following chemotherapy,74 targeted radiation
therapy with 131I MIBG,75 tandem myeloablation and
stem cell transplantation,76,77 and inclusion of myelobla-
tive doses of 131I MIBG prior to stem cell transplanta-
tion.78 The knowledge gained from the ongoing biologic
studies will continue to be applied to the clinical arena as
mechanisms of neuroblastoma transformation and pro-
gression are elucidated.
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C H A P T E R
47 Wilms’ Tumor
Michael L. Ritchey, MD, and Max J. Coppes, MD, PhD, MBA
The management of Wilms’ tumor has evolved consider-
ably since its description nearly a century ago by Max
Wilms. Wilms, a German surgeon,1 was the first to pro-
pose that all the various elements of the tumor were
derived from the same cell. His careful pathologic
description of this tumor, also referred to as nephroblas-
toma, led to the association of his name with this tumor.
Initially, surgery held the only hope of cure. The first
attempt at a nephrectomy in a child was probably per-
formed by Hueter in 1876.2 Unfortunately, the patient died
during the surgical procedure. Ten years later, Kocher, in
Bern, Switzerland, performed the first successful nephrec-
tomy in a child. At first the ultimate outcome for patients
with Wilms’ tumor remained poor. By the late 1930s,
improvements in surgical technique provided a survival of
30%. The introduction of radiation therapy as an effective
adjuvant treatment resulted in improved survival,3
although it was not until the introduction of effective
chemotherapy in the 1950s that a dramatic improvement in
survival was achieved.4 First, Farber from Boston reported
the effectiveness of dactinomycin (AMD), then workers at
M.D. Anderson Cancer Center introduced vincristine
(VCR) for the treatment of this disease.5 Due to the rarity
of this tumor it was recognized in the early 1970s that mul-
ticenter collaboration was necessary to conduct the needed
clinical research to improve outcome. The cooperative
group studies conducted by the National Wilms’ Tumor
Study Group (NWTSG) in North America and the
International Society of Paediatric Oncology (SIOP) in
Europe have ultimately provided excellent survival rates for
children with this malignant disorder. This chapter reviews
the major contributions of these clinical trials, some of the
molecular genetic changes associated with this tumor, and
outlines the current treatment strategies.
EPIDEMIOLOGY
Embryonal neoplasms of childhood, named because their
morphologic appearance resembles that observed during
embryogenesis, have provided important information
regarding cancer biology and development. Of particular
interest is Wilms’ tumor, which comprises up to one-
third of pediatric embryonal tumors. In North America,
the annual incidence in children under the age of 15
years is 7 per million.6 Therefore, approximately 450
new cases should be expected each year. The overall
median age at diagnosis is 3.5 years, although for boys it
is 6 months lower than for girls. The disease occurs
nearly equally in girls and boys worldwide.7 The inci-
dence shows some ethnic variation with slightly higher
rates reported for the black populations and a lower inci-
dence in Asian children. Environmental factors are not
that important a role in the etiology of Wilms’ tumor.8
Of greater interest is the genetic epidemiology of
Wilms’ tumor. For many years Wilms’ tumor has been
associated with a number of congenital abnormalities,
including sporadic aniridia, hemihypertrophy, and geni-
tourinary malformations.9,10 A number of recognizable
syndromes are associated with an increased incidence of
Wilms’ tumor (Table 47-1). These may be divided into
syndromes characterized by overgrowth and those lack-
ing overgrowth.
Genitourinary abnormalities, such as hypospadias,
cryptorchidism, and renal fusion anomalies, are seen in
association with Wilms’ tumor in 4.5% of patients with
Wilms’ tumor.11 Of particular interest is the recognition
of the Denys-Drash syndrome12,13 in children presenting
with ambiguous genitalia. The Denys-Drash syndrome is
characterized by ambiguous genitalia and renal mesangial
sclerosis, usually resulting in end-stage renal failure and
Wilms’ tumor.14 Genetic studies indicate that the Denys-
Drash syndrome is associated with specific mutations of
WT1, one of the Wilms’ tumor genes on the short arm
of chromosome 11.15,16 It should be noted that the phe-
notype can vary considerably. Any patient with Wilms’
tumor and renal dysfunction, with or without a geni-
tourinary abnormality, should be evaluated for a WT1
mutation.
753
754 Part VIII Pediatric Malignancies
Table 47-1 Incidence of Congenital Anomalies
Associated with Wilms Tumor Patients Reported to
the National Wilms’ Tumor Study
Anomaly Rate (per 1000)
Aniridia 7.6
BWS 8.4
Hemihypertrophy 33.8
Genitourinary anomalies
Hypospadias 13.4
Cryptorchidism 37.3
Hypospadias and
cryptorchidism 12.0
The incidence of aniridia in patients with Wilms’
tumor is 1.1%, much higher than the incidence in the
general population, which is estimated at 1:50,000 to
1:100,000. Wilms’ tumor will develop in >30% of chil-
dren with the aniridia, genitourinary malformations and
mental retardation (AGR syndrome). In the presence of
Wilms’ tumor, the term WAGR syndrome is used
(Wilms’ tumor and AGR). Most children with the
WAGR syndrome suffer from a constitutional deletion
on band 13 of the short arm of chromosome 11.17
Syndromes with overgrowth features at risk for the
development of Wilms’ tumor include hemihypertrophy,
which may occur alone or as part of the Beckwith-
Wiedemann syndrome (BWS), Perlman, Soto, and the
Simpson-Golabi-Behmel syndromes.11,18,19 BWS is a
rare congenital overgrowth disorder characterized by vis-
ceromegaly (splenomegaly, hepatomegaly), macroglossia,
and hyperinsulinemic hypoglycemia.18,19 Most cases of
BWS are sporadic, but 15% exhibit heritable character-
istics with apparent autosomal dominant inheritance.
Patients with BWS are predisposed for certain cancers, in
particular embryonal neoplasms (adrenocortical neo-
plasms and hepatoblastoma). The incidence of Wilms’
tumor in this patient population is <5%. Children with
BWS found to have nephromegaly (kidneys greater than
or equal to the 95th percentile of age adjusted renal
length) are at the greatest risk for the development of
Wilms’ tumor.20 Children with BWS are also at an
increased risk to develop bilateral tumors.21 A review of
NWTS-3 and NWTS-4 patients found that 21% of the
BWS patients had either synchronous or metachronous
bilateral tumors.
Screening with serial renal ultrasounds has been rec-
ommended in children with aniridia, hemihypertrophy,
and BWS. Review of most studies suggests that 3 to 4
months is the appropriate screening interval. Tumors
detected by screening will generally be a lower stage.22,23
Retrospective reviews have been unable to determine if
early detection had an impact on patient survival.
Children with BWS can also develop nonmalignant renal
lesions.24 Recognition of these benign lesions is impor-
tant to avoid unnecessary nephrectomy when new lesions
are identified on screening ultrasound.
GENETICS
Our knowledge of the genetic alterations involved in the
development of Wilms’ tumor has grown substantially
over the past two decades. Initially, the genetics of
Wilms’ tumor was thought to be very similar to that of
retinoblastoma (a childhood tumor of the retina), since
both tumors can occur bilaterally and/or affect several
members of the same family, although the latter is more
common in retinoblastoma than it is in Wilms’ tumor.
Also, as in retinoblastoma, when Wilms’ tumor occurs
bilaterally, the age at presentation is younger than in
cases where the disease is limited to one kidney, suggest-
ing a constitutional defect that predisposes that child to
tumor formation. The younger age at diagnosis is also
found in children with specific, Wilms’ tumor predispos-
ing, congenital anomalies, such as aniridia.11 However, it
is now clear that the genetic alterations leading to the
development of Wilms’ tumor are more complex than
those of retinoblastoma and in fact involves multiple
genes.25
Analysis of the different median ages at presentation
between groups of patients led Alfred Knudson in the
early 1970s to propose a “two-hit” model for the devel-
opment of retinoblastoma and Wilms’ tumor.26 His
hypothesis predicts that two rate-limiting events are nec-
essary for tumor development. He predicted that chil-
dren with a genetic susceptibility to cancer already have
a constitutional (prezygotic) genetic alteration, either
inherited from one of the parents or resulting from a
spontaneous (de novo) mutation. In these children, only
one additional (postzygotic) genetic alteration would suf-
fice for Wilms’ tumor to develop. By contrast, children
that do not have a constitutional genetic alteration, and
therefore are not susceptible to cancer, require two
postzygotic (or somatic) genetic events for Wilms’ tumor
to develop. Since the probability of one somatic event
occurring is higher than that of two independent ones,
children with a constitutional genetic alteration have a
greatly increased likelihood of developing cancer as com-
pared to children that do not carry a constitutional
genetic defect.
Two genetic regions, both on the short arm of chro-
mosome 11, have been linked to Wilms’ tumor develop-
ment. The first evidence of band 13 of the short arm of
chromosome 11 (11p13) being involved in the development

of Wilms’ tumor was the detection of cytogenetically vis-
ible deletions of this region in patients with the WAGR
syndrome. The deletion in these patients is not restricted
to their Wilms’ tumor cells but is present in all body cells
(i.e., constitutional deletions).27 According to Knudson’s
two-hit hypothesis, the constitutional 11p13 deletion was
proposed to represent the first of two events, the second
event being somatic in these patients. Similarly, the loss
of heterozygosity (LOH) for 11p13 DNA markers
demonstrated in approximately one-third of sporadic
Wilms’ tumors26,28 also suggested that chromosome
11p13 was involved in the development of Wilms’ tumor.
In fact, both observations implied the presence of a
tumor suppressor gene at 11p13, a notion that was con-
firmed in 1990.29–31 Once cloned, alterations of the
Wilms’ tumor suppressor gene WT1 at 11p13 were
shown in tumor DNA obtained from patients with spo-
radic Wilms’ tumors, as well as in the constitutional
DNA of patients with a genetic predisposition to Wilms’
tumor.32 WT1, which is expressed transiently in the
developing kidney and also in specific cells of the gonads,
is required for normal genitourinary development and
specifically of importance for the differentiation of the
renal blastema.33 Constitutional point mutations in the
zinc finger DNA-binding region of WT1 give rise to the
Denys-Drash syndrome, characterized by pseudoher-
maphroditism, early renal failure with diffuse mesangial
sclerosis, and Wilms’ tumor.16
A second Wilms’ tumor locus (already designated
WT2) has been identified on chromosome 11p15.5.34
This same chromosomal region has also been linked to the
BWS.35 Although this region has revealed at least 10
imprinted (expressed preferentially from one of the parent
alleles) genes, for now, it is not known whether a single
gene is responsible for both disorders or adjacent genes
independently for each disease. The presence of imprinted
genes and the observation that in Wilms’ tumors showing
LOH for 11p15 DNA markers, it is invariably the mater-
nal allele that is lost36, suggest that the paternal and mater-
nal genes in this region are functionally unequal. In
keeping with this, some BWS patients have been shown to
have two paternal copies of chromosome 11p in addition
to the maternal copy (trisomy 11p15), while in some
patients with BWS who seem to have grossly normal kary-
otypes (i.e., no trisomy), both copies of chromosome 11
are in fact found to be inherited from the father, a condi-
tion termed uniparental isodisomy.37 Apparently in BWS,
expression is required from two paternal 11p15 alleles,
while in Wilms’ tumor the first of two events almost
always occurs on the paternal 11p15 allele.
Other molecular abnormalities studied in Wilms’
tumor patients seem to be related to outcome rather than
development. Of these, loss of chromosomal material, as
determined by LOH, on the long arm of chromosome
16, demonstrated in ~20% of tumors36,38, and on the
Chapter 47 Wilms’ Tumor 755
short arm of chromosome 1, shown in ~11% of tumors39,
are clinically of greatest importance. In a preliminary
study, tumor-specific loss of either region (16q or 1p) was
correlated with poor outcome, independently from stage
or histology at initial presentation.39 A larger group of
patients has been studied to confirm this observation.
CLINICAL PRESENTATION
The typical presentation of Wilms’ tumor is that of a
large asymptomatic abdominal mass, often found inci-
dentally. Other presentations include acute abdominal
pain mimicking appendicitis or some other intraabdomi-
nal event. This is often the result of tumor rupture with
hemorrhage into the retroperitoneum or the peritoneal
cavity. Hematuria is found in approximately one-fourth
of children at diagnosis, but only gross hematuria war-
rants further evaluation to exclude tumor extension into
the renal pelvis and ureter. Hypertension is also present
in about 25% of cases.40
Vascular tumor extension into the renal vein and infe-
rior vena cava (IVC) can result in atypical presenta-
tions.41,42 For example, a varicocele, particularly one that
persists when the child is supine, may be secondary to
obstruction of the spermatic vein due to tumor throm-
bus. However, varicocele, hepatomegaly due to hepatic
vein obstruction, ascites, or congestive heart failure are
only found in less than 10% of patients with intracaval or
atrial tumor extension.41 Very rarely the tumor can
embolize to the pulmonary artery with catastrophic
consequences.
PREOPERATIVE EVALUATION
Laboratory evaluation should include a complete blood
count, liver function tests, and renal function tests.
Serum calcium should also be checked. Hypercalcemia
should alert the physician for the possible presence of
either congenital mesoblastic nephroma (CMN) or rhab-
doid tumor of the kidney (RTK), rather then Wilms’
tumor.40 A coagulation screen should be obtained to
exclude acquired von Willebrand’s disease. The coagula-
tion defect underlying the acquired von Willebrand’s dis-
ease in patients with Wilms’ tumor can be corrected
preoperatively with the administration of DDAVP.
Modern imaging modalities provide detailed informa-
tion regarding origin and extent of intra-abdominal
tumors. There has been considerable debate regarding
the role of imaging studies in the staging and manage-
ment of children with Wilms’ tumor.43,44 Imaging studies
can often establish the correct diagnosis before surgery
(Figure 47-1). In addition, imaging studies can help the
surgeon to plan for a major surgical procedure. There is
an increased incidence of surgical complications in
Wilms’ tumor patients with an incorrect preoperative
756 Part VIII Pediatric Malignancies
Figure 47-1 CT scan of a large left Wilms’ tumor with a
small rim of functioning renal parenchyma.
diagnosis.45 Preoperative imaging will establish the pres-
ence of a functioning contralateral kidney prior to per-
forming a nephrectomy.
Ultrasonography is the initial investigation performed
in a child with a palpable abdominal mass. This study can
distinguish between solid and cystic lesions, and also
determine if the mass is of intrarenal or extrarenal in ori-
gin. During ultrasonography, the patency of the IVC
should be assessed to exclude extension of tumor throm-
bus into the IVC (Figure 47-2) that occurs in 4% of
Wilms’ tumor patients.41,42 Computed tomography (CT)
may be useful, but visualization of the IVC is often hin-
Figure 47-2 Ultrasound that depicts intracaval thrombus (arrow).
dered by unopacified blood due to an inadequate bolus
injection of contrast. If the ultrasound is inconclusive,
magnetic resonance imaging (MRI) is recommended to
establish IVC patency.42,46,47
One of the unanswered questions regarding imaging is
the role of CT and MRI scans in determining the extent of
disease, i.e., stage.43,44 Since survival is correlated with
stage (and histology), NWTSG investigators keep
stressing the need for accurate staging.48 The current
NWTSG staging system utilizes surgery and pathology
findings only. There have been no studies to compare data
obtained by imaging to those obtained by the surgeon dur-
ing nephrectomy in assessing extrarenal extent.
Occasionally, preoperative CT can suggest extracapsular
tumor extension when there is irregularity of the tumor
margin or evidence of regional adenopathy when lymph
nodes are demonstrated physically separate from the
tumor mass. However, enlarged retroperitoneal lymph
nodes are common in children and often reactive.
Moreover, even intraoperative lymph node evaluation by
the surgeon does not correlate well with histopathologic
findings49 and one would therefore expect similar difficul-
ties when correlating histopathology with imaging studies.
Preoperative imaging can be useful to identify groups
of patients that are best treated with chemotherapy
prior to attempts at surgical excision.50,51 One important
group is children with bilateral Wilms’ tumors (BWTs).
The recommended treatment of these children is preop-
erative chemotherapy to shrink the tumors rather than
upfront surgery. This approach facilitates preservation of
renal parenchyma.50,52 CT and MRI will detect most
bilateral lesions but can miss some lesions <1 cm in
diameter.53 Primary nephrectomy has been shown to be

associated with an increased incidence of surgical com-
plications in patients with either extensive intravascular
tumor involvement or tumors that require en bloc resec-
tion of other organs to achieve complete excision.45 As
noted above, IVC extension can and should be identified
during the preoperative imaging evaluation.
Identifying visceral involvement by CT is much more
difficult. The majority of children identified as having
possible invasion of the liver on CT later prove to be
negative at surgery.54 CT may be able to detect deep
seated liver metastases but is much more predictive for
absence of liver invasion.55
The most common site of distant metastases is within
the lungs, present at diagnosis in 8% of patients. The
majority of these lesions can be identified on routine
chest x-ray films. However, some children are only iden-
tified to have pulmonary metastases by chest CT.56,57
There continues to be some debate regarding the man-
agement of these patients.58,59 Not all small lesions seen
on CT are due to metastatic disease. Some lesions iden-
tified on CT only represent benign lesions, e.g., histo-
plasmosis, granuloma or round atelectasis. An important
question is whether chest x-ray-negative, CT-positive
patients require the same adjuvant treatment as those
with a positive x-ray.59,60 Meisel et al.60 reviewed 53 chil-
dren enrolled in NWTS-3 and NWTS-4 who had a neg-
ative chest roentgenogram but were identified with
metastatic lesions on a chest CT. There was no difference
in survival in those patients treated according to the local
extent of the abdominal disease alone. They did note
fewer pulmonary relapses in patients that did not receive
pulmonary irradiation, but more deaths are attributable
to lung toxicity. Other investigators have also noted an
increased risk of recurrent disease in favorable histology
(FH) patients with pulmonary densities detected on CT
alone when pulmonary irradiation was omitted.56,61
Uncommon sites of metastases can occur in renal
tumors other then Wilms’ tumor. A radionuclide bone
scan and skeletal survey are both recommended if a his-
tologic diagnosis of clear cell sarcoma of the kidney
(CCSK) or renal cell carcinoma (RCC) is confirmed.
Both of these have a propensity to metastasize to the
skeleton.44,48,62,63 RTK and CCSK are associated with
brain metastases, and MRI of the brain should be
obtained in the early postoperative period.
DIFFERENTIAL DIAGNOSIS
RTK, CCSK, and RCC do not have any distinguishing
radiographic features that will allow a preoperative diag-
nosis unless unusual sites of metastases (bone, brain) are
evident.62–67 RTK is more typically seen in infants and
very young children with a mean age of 13 months. RCC
generally presents after the age of 5 years, and it is the
most common renal malignancy in the second decade of
Chapter 47 Wilms’ Tumor 757
life.66,67 Neuroblastoma is the most common solid
abdominal malignancy in childhood but in most cases can
be distinguished by its extrarenal location and excretion
of catecholamines and its metabolites in the urine.
Rarely, neuroblastoma will arise within the kidney mak-
ing the distinction difficult. Renal angiomyolipoma is
only rarely seen in childhood and is associated with
tuberous sclerosis.68,69 Demonstration of fat within a
renal lesion by CT scan preoperatively should alert the
surgeon of the presence of this tumor.
Another tumor commonly seen in infancy is CMN.
This is generally a benign lesion found in approximately
2% of childhood renal tumors. Most patients are under
the age of 6 months at the time of diagnosis.70 In fact
the typical presentation is that of a newborn with an
abdominal mass. A number of cases have been diag-
nosed prenatally (Figure 47-3). However, FH Wilms’
tumor and RTK can also present in the first few months
of life.63,71 Nephrectomy is curative for most patients
with CMN,70 although there have been reports of local
recurrence, more common in those with cellular histol-
ogy and occasionally metastases.72–74 Adequacy of surgi-
cal resection and age at diagnosis in these patients
appear to be more important predictors of relapse than
histology.75
In addition to age at presentation, other clinical
parameters can aid the clinician in narrowing the diag-
nostic possibilities. For example, a renal mass developing
in a child with hemihypertrophy, BWS, or aniridia is
most likely to be a Wilms’ tumor. Bilateral or multicen-
tric renal tumors are also highly suggestive of Wilms’
tumor.
PATHOLOGY
On gross examination, Wilms’ tumor is usually a soft,
lobulated and tan or light gray in color. Hemorrhagic or
necrotic areas are frequently noted. The microscopic fea-
tures of Wilms’ tumor classically consist of three compo-
nents in varying proportions: blastema, stroma, and
epithelium. Tumors that consist predominately of one of
these elements are encountered in 60% of cases and still
considered Wilms’ tumor.76 Blastemal predominant
tumors are important in that they behave more aggres-
sively with early metastatic spread and more advanced
disease at presentation.77 The stromal component can
differentiate into striated muscle, cartilage, or fat. Wilms’
tumors with predominant rhabdomyomatous elements
were once thought to behave less aggressively, but recent
evidence suggests that they are no different from the typ-
ical, triphasic, Wilms’ tumor.76
The most important determinants of outcome are
histopathology and tumor stage. Analysis of early
NWTS patients identified a group of patients with unfa-
vorable histopathologic features, associated with
758 Part VIII Pediatric Malignancies
Figure 47-3 CT scan of a large CMN in a 2-day-old infant that was detected on
antenatal ultrasound.
increased rates of relapse and death.78 These “unfavor-
able histology” tumors are responsible for 50% of tumor
deaths in the NWTSG studies but account for only 10%
of patients.79 Three distinct tumors were originally
included in this unfavorable subgroup: (a) Wilms’ tumor
with extreme nuclear atypia (anaplasia); (b) RTK; (c)
CCSK. The latter two tumor groups have been reclassi-
fied and are now considered to be distinct entities from
Wilms’ tumors. CCSK accounts for 3% of renal tumors
reported to the NWTSG. Its recognition is quite impor-
tant in order that appropriate adjuvant therapy be insti-
tuted. The use of doxorubicin has resulted in an
improved outcome for these children.48,62 RTK is a
highly malignant tumor that accounts for 2% of renal
tumors registered to the NWTSG.48,63 RTK is now con-
sidered a sarcoma of the kidney and not of metanephric
origin.49 The prognosis of RTK remains dismal with
conventional chemotherapeutic regimens and new treat-
ment strategies are being developed for the management
of these children.
Anaplasia is a feature of Wilms’ tumor that is associ-
ated with resistance to chemotherapy. It is therefore not
surprising that the incidence of anaplasia reported by the
NWTSG investigators (5%) is very similar to that
reported in the SIOP studies (5.3%),76 where all tumors
are pretreated with chemotherapy, but the anaplasia per-
sists after treatment.80 Anaplastic features are rare in the
first 2 years of life, but the incidence increases to 13% in
children age 5 years or older.81 Anaplastic Wilms’ tumors
are further stratified into focal and diffuse anaplasia,
based on a topographic principle.82 Focal anaplasia
requires that the anaplastic nuclear changes be confined
to a specified region of the primary tumor and absent
from the surrounding portions of the lesion. Diffuse
anaplasia on the other hand is diagnosed when anaplasia
is present in more than one portion of the tumor or if
found in any extrarenal or metastatic site. Confirming
the notion that anaplasia is more a marker of chemore-
sistance than inherent aggressiveness of the tumor, out-
come is generally excellent only if the tumor is
completely removed, i.e., stage I tumor.83
Precursor Lesions
Lesions apparently representing Wilms’ tumor precur-
sors are found in 30% to 40% of kidneys removed for
Wilms’ tumor.83 Nephrogenic rests are defined as foci of
abnormally persistent nephrogenic cells that can develop
into Wilms’ tumor.84 Two distinct categories of nephro-
genic rests have been identified. The most common is
the perilobar nephrogenic rest (PLNR) that is found in
the periphery of the kidney. There is a higher prevalence
of PLNR in children with Wilms’ tumor and hemihy-
pertrophy or the BWS (Table 47-2). Intralobar nephro-
genic rests (ILNRs) on the other hand can be found
anywhere within the renal lobe (Figure 47-4). Children
with the WAGR syndrome or the Denys-Drash syn-
drome are more likely to have ILNRs. In the presence of
 Chapter 47 Wilms’ Tumor 759

multiple or diffuse nephrogenic rests the term fies patients at risk for the development of contralateral
“nephroblastomatosis” is used. Wilms’ tumor. This is particularly the case for children
The natural history of nephrogenic rests, occasionally younger than 12 months of age who have PLNRs.86
found in kidneys without tumors,85 is not entirely clear. These and other high-risk children need careful follow-
Some undergo spontaneous regression, others hyperplas- up imaging of the contralateral kidney (Table 47-3).
tic changes, producing relatively large tumors. While the
histopathologic differential diagnosis between hyperplas-
Biologic Parameters
tic nephrogenic rests and Wilms’ tumor can be very dif-
ficult (the exact criteria for distinguishing these two As survival of children with FH Wilms’ tumor has con-
lesions remain to be defined), the surgical management tinued to improve, traditional staging factors, e.g., tumor
of both disorders is similar. size, histology, lymph node metastases, are now less able
Multiple rests in one kidney are highly suggestive of to predict risk for tumor progression or relapse in FH
the presence of nephrogenic rests in the other kidney patients. Stratification of FH Wilms’ tumor patients into
since these lesions usually involve both kidneys. low-risk and high-risk groups for relapse, independent of
Consequently, the presence of ILNRs or PLNRs identi- tumor stage, would allow intensification of treatment for
those with an increased risk of relapse. Research has now
Table 47-2 Prevalence of Nephrogenic Rests focused on molecular or biologic factors. The NWTSG
Patient Population ILNR (%) PLNR (%) has established a central tumor bank to maintain biologic
specimens from all patients entered on the study.
As noted previously, LOH for a portion of the long
Infant autopsies 0.01 1 arm of chromosome 16 has been found in 20% of Wilms’
tumor patients.25,38 A prospective study of 232 patients
Renal dysplasia Unknown 3.5
registered on the NWTS found that patients with 16q
Unilateral Wilms’ tumor 15 25 LOH had a statistically significantly poorer 2-year
relapse-free and overall survival than those without LOH
Synchronous bilateral for chromosome 16q.39 In addition, LOH for chromo-
Wilms’ tumor 34–41 74–79 some 1p markers, occurring in approximately 11% of
Wilms’ tumors,39 is also associated with an increased risk
Metachronous bilateral 63–75 42
Wilms’ tumor of relapse, although of borderline statistical significance.
Another potential marker is telomerase; a reverse
Beckwith-Wiedemann, 47–56 70–77 transcriptase that maintains chromosome ends, compen-
hemihypertrophy sating for the loss of DNA that occurs in replication.
High telomerase activity has been found to be an unfa-
Aniridia 84–100 12/20
vorable prognostic feature for several types of cancers. In
Drash syndrome 78 11 a case-cohort study of 78 patients with FH Wilms’
tumor, telomerase enzyme activity, expression of hTR,

Figure 47-4 A, Illustration of renal lobe showing characteristic locations of ILNR (dark gray) and PLNR (black). (From Beckwith
JB: Med Pediatr Oncol 1993; 21:158–168, with permisssion). B, PLNR composed of blastemal cells just beneath the renal
capsule (H&E 40×).
760 Part VIII Pediatric Malignancies

Table 47-3 Recommended Follow-up Imaging Studies for Children with Renal Neoplasms of Proven Histology
and Free of Metastases at Diagnosis
Tumor Type Study Schedule Following Therapy

Favorable histology Wilms’ tumor; Chest films 6 weeks and 3 months postop; then q. 3
Stage I anaplastic Wilms’ tumor q. 6 months × 3, yearly × 2

Irradiated patients only Irradiated bony structures* Yearly to full growth, then q. 5 years indefinitely†

Without NRs, Stages I and II Abdominal ultrasound Yearly × 3

Without NRs, Stage III Abdominal ultrasound As for chest films

With NRs, any stage‡ Abdominal ultrasound q. 3 months × 10, q. 6 months × 5, yearly × 5

Stage II and III anaplastic Chest films As for favorable histology

Abdominal ultrasound q. 3 months × 4; q. 6 months × 4

RCC Chest films Like favorable histology

Skeletal survey and Like CCSK

bone scan

CCSK Brain MRI and/or opacified When CCSK is established; then q. 6 months × 10
CT skeletal survey and
bone scan

Chest films As for favorable histology

Rhabdoid tumor Brain MRI and/or As for CCSK

opacified CT

Chest films As for favorable histology

Mesoblastic nephroma§ Abdominal ultrasound q. 3 months × 6

Modified from D’Angio GJ, Rosenberg H, Sharples K, Kelalis P, Breslow N, Green DM: Med Pediatr Oncol 1993; 21:205–212, with permission.
*To include any irradiated osseous structures.
†To detect second neoplasms, benign (osteochondromas) or malignant.
‡The panelists at the first International Conference on Molecular and Clinical Genetics of Childhood Renal Tumors; Albuquerque, New Mexico,

May 1992, recommended a variation: q. 3 months for 5 years or until age 7, whichever comes first.
§Data from the files of Dr. J.B. Beckwith reveal that 20 of 293 MN patients (7%) relapsed or had metastases at diagnosis; 4 of the 20 in the lungs,

one of the 4 at diagnosis. All but 1 of the 19 relapses occurred within 1 year. Chest films for MN patients may be elected on a schedule, such as
q. 3 months × 4, q. 6 months × 2.

the RNA component of telomerase, and mRNA expres-
sion of high telomerase reverse transcriptase (hTERT),
the gene that encodes the catalytic component of the
enzyme, were measured.87 All had detectable expression
of hTR and 97% had detectable hTERT transcript. The
hTERT mRNA levels correlated with the risk of recur-
rence even after adjustment for tumor stage. A larger
study is underway to determine whether this is an inde-
pendent prognostic indicator.
The proliferative rate of tumor cells can be estimated
by the measurement of DNA content. Several studies
have correlated cell DNA content, measured by flow
cytometry, and prognosis in Wilms’ tumor patients.
Normal somatic cells have a diploid DNA content, cells
in mitosis are tetraploid and tumor cells with gross kary-
otypic abnormalities in number are labeled aneuploid.
Aneuploid DNA histograms are found more commonly
in anaplastic Wilms’ tumors,88 although it is not neces-
sarily associated with poor prognosis.89 While tetraploid
histograms in stage III and stage IV patients are indica-
tive of poor outcome, it remains to be determined
whether DNA ploidy is a more accurate predictor of sur-
vival than histology and stage.90 More recently, investiga-
tors have started using cDNA array technology to
develop tumor-specific molecular profiles in the hope to
distinguish bad from good actors among the low-stage
FH tumors. While a promising approach, solid data have
yet to be published.
The growth of solid tumors is critically dependent on
the induction of neovascularity by angiogenic cytokines.
 Chapter 47 Wilms’ Tumor 761

Table 47-4 Staging System of the National Wilms Tumor Study

Stage I Tumor limited to the kidney and completely excised. The renal capsule is intact and the tumor was not ruptured
prior to removal. There is no residual tumor

Stage II Tumor extends through the perirenal capsule, but is completely excised. There may be local spillage of tumor
confined to the flank or the tumor may have been biopsied. Extrarenal vessels may contain tumor thrombus or be
infiltrated by tumor

Stage III Residual non-hematogenous tumor confined to the abdomen: lymph node involvement, diffuse peritoneal spillage,
peritoneal implants, tumor beyond surgical margin either grossly or microscopically, or tumor not completely
removed

Stage IV Hematogenous metastases to lung, liver, bone, brain, etc.

Stage V Bilateral renal involvement at diagnosis

Vascular endocrine growth factor (VEGF) is an angio-
genic cytokine detected with increased frequency and
quantity in experimental and clinical specimens of
Wilms’ tumor.91 In experimental animals, lung metas-
tases were far more likely to occur in animals with VEGF
positive tumors. The potential of anti-VEGF therapy to
suppress tumor growth has also been assessed.92,93
Tumors were induced in kidneys of nude mice by the
injection of tumor cells. After 1 week, administration of
anti-VEGF antibody resulted in a >95% reduction in
tumor weight and abolished lung metastases.
In Wilms’ tumor there are no biologic markers avail-
able yet that could mimic the function of alpha fetoprotein
in the management of germ cell tumors. Nevertheless,
several biologic markers have been studied, including
serum renin and prorennin, serum erythropoietin, neu-
ron-specific enolase (NSE), and hyaluronic acid (HA), HA
stimulating activity (HASA), and hyaluronidase.40
PROGNOSTIC CONSIDERATIONS
Histopathology and tumor stage are the most important
predictors of survival in Wilms’ tumor patients. The cur-
rent staging system is summarized in Table 47-4. For
NWTS-4, the distribution by stage of FH tumors was
stage I 40%, stage II 27%, stage III 22%, and stage IV
11%.94 Both the surgeon and pathologist have responsi-
bility for determining local tumor stage. Surgical and
pathologic features that are associated with an increased
risk for relapse lead to a higher-stage designation.
Stage I tumors are limited to the kidney and com-
pletely resected. NWTSG pathologists have identified
several pathologic variables predictive of tumor relapse in
patients with stage I FH tumors.95 These are invasion of
the tumor capsule, presence of an inflammatory pseudo-
capsule, renal sinus invasion, and tumor in the intrarenal
vessels. Analysis of these variables found that one or
more of these features were present in 24 stage I FH
patients from NWTS-3 those developed tumor
relapse.95 Tumor extension into the soft tissues of the
sinus or the presence of tumor cells in blood or lymphatic
vessels of the renal sinus is now considered stage II.
Tumors that penetrate the renal capsule or the presence
of tumor cells in the perirenal fat are also classified as
stage II tumors. Tumor spillage during removal of the
tumor increases the stage. Local spills confined to the
renal bed are considered stage II and do lead to an
increased risk of abdominal relapse.96 Diffuse spill into
the peritoneal cavity is considered stage III.
Wilms’ tumor usually metastasizes to regional lymph
nodes, the lungs, and the liver. Patients with lymph node
metastases are classified as stage III and require local radi-
ation therapy following surgery. Since the presence of
lymph node metastases mandates more intensive treatment
and is associated with poorer outcome, it is important for
the surgeon to obtain adequate lymph node sampling dur-
ing nephrectomy in order to allow appropriate staging. In
patients that do not have lymph nodes examined patholog-
ically, there is an increased incidence of abdominal relapse,
most notable for stage I patients.96 Approximately 85% of
hematogenous metastases at presentation are reported in
the lungs, while about 15% present with liver involve-
ment.97 Other sites of metastases, such as bone, medi-
astinum, and spinal cord, are uncommon.
SURGICAL MANAGEMENT
Although most of the improvement in survival of chil-
dren with Wilms’ tumor is attributable to introduction of
effective chemotherapy and radiation therapy, surgery
continues to play a very important role in its successful
treatment. The preoperative evaluation of a child with an
abdominal mass can generally be completed in 48 hours
in most medical centers. Emergent operation is not nec-
essary unless there is evidence of active bleeding. The
surgeon is responsible for safely removing the tumor and
762 Part VIII Pediatric Malignancies
assessing the local tumor stage. This requires a thorough
exploration of the abdominal cavity via a generous
transperitoneal incision. The flank approach should not
be used, as regional staging and examination of the con-
tralateral kidney are not possible. The liver is palpated
and regional lymph nodes are examined for evidence of
tumor spread.
The colon and its mesentery are then reflected off the
tumor and a radical nephrectomy is performed with sam-
pling of regional lymph nodes. Formal lymph node dis-
section is not required.49 Ligation of the renal vessels is
performed prior to mobilization of the tumor, but only if
exposure is adequate. More importantly, the surgeon
should be certain that the contralateral renal vessels,
aorta, iliac, or superior mesenteric arteries have not been
mistakenly ligated.98 Gentle handling of the tumor
throughout the procedure is mandatory to avoid tumor
spillage as these patients have an increased risk for
abdominal relapse.48,96 Additionally, patients with diffuse
tumor spill are considered stage III and require more
intensive therapy with whole abdominal irradiation and
the use of doxorubicin.
Prior to ligation of the renal vein, palpation of the
vein and IVC should be performed to exclude intravas-
cular tumor extension. The majority of patients with
IVC extension will fortunately be identified by imaging
studies obtained prior to surgery.41,42,99 Extension of
tumor into the extrarenal vessels does not adversely
affect prognosis if it is completely excised. For vena caval
involvement below the level of the hepatic veins, the
caval thrombus can be removed via cavotomy after prox-
imal and distal vascular control is obtained. Generally,
the thrombus will be free-floating, but if there is adher-
ence of the thrombus to the caval wall, the thrombus can
often be delivered with the passage of a Fogarty or Foley
balloon catheter. Patients with atrial extension may
require cardiopulmonary bypass for thrombus
removal.100 Certain operative findings may suggest
intravascular extension when it has not been correctly
diagnosed preoperatively. For example, excessive bleed-
ing from dilated superficial and retroperitoneal collater-
als is a clue to obstruction of the vena cava. More
ominous is the finding of sudden unexplained hypoten-
sion, which can result from embolization of the tumor
thrombus.101
Primary surgical resection of inferior vena caval or
atrial tumor extension is associated with increased surgi-
cal morbidity.45 Several reports have demonstrated that
these patients can best be managed by shrinkage of tumor
and thrombus with preoperative chemotherapy.42,51,102
This approach facilitates complete removal of the tumor
with decreased morbidity. While there has been one
report of tumor embolus during chemotherapy,103 this
complication can also occur prior to or during surgical
removal of the tumor.101
Occasionally, patients will present with massive
tumors that are surgically unresectable. Heroic surgery
with radical en bloc resection of the tumor and adjacent
organs is not justified. Such operations are associated
with increased surgical morbidity.45 In addition, the gross
appearance of the tumor at the time of surgery can be
misleading in interpreting tumor extent. These tumors
often compress and adhere to adjacent structures without
frank invasion; and in the majority of cases, tumor inva-
sion is not confirmed after the adjacent visceral organs
are removed.45 The appropriate management of tumors
that are inoperable at presentation is tumor biopsy
followed by chemotherapy. This approach almost
always reduces the bulk of the tumor and renders it
resectable.104,105 Usually, there is adequate size reduction
within 6 weeks. Serial imaging studies are helpful in
assessing response. Patients who fail to respond to
chemotherapy can subsequently be considered for preop-
erative irradiation that may produce enough shrinkage to
facilitate nephrectomy. One disadvantage of using preop-
erative therapy is that there is loss of important staging
information. Patients with unresectable tumors treated
with preoperative chemotherapy with or without addi-
tional radiation therapy should be considered stage III
and treated accordingly.105 Therefore, it is very impor-
tant that tumors are not determined to be unresectable
on the basis of preoperative imaging alone.
The morbidity of the surgical procedure should not be
overlooked in the management of children with Wilms’
tumor. NWTS-4 patients undergoing primary nephrec-
tomy had an 11% incidence of surgical complications.106
The most common complications encountered are hem-
orrhage and small bowel obstruction45,106,107 SIOP
investigators have reported a lower rate of complications
when nephrectomy is performed after preoperative
chemotherapy.108 A prospective study comparing the
incidence of surgical complications between NWTSG
and SIOP is underway.
COOPERATIVE GROUP TRIALS
National Wilms’ Tumor Study Group
Many early accomplishments in the treatment of children
with Wilms’ tumor were made by individuals and large
single institutions, but as survival improved larger num-
bers of patients were needed to conduct prospective ran-
domized trials to answer therapeutic questions. Thus, in
North America, both pediatric cooperative groups, the
Children’s Cancer Group (CCG), and the Pediatric
Oncology Group (POG) initially initiated clinical trials
within their own group but subsequently decided to col-
laborate within the NWTSG. Meanwhile, investigators
in Europe formed the Société International d’Oncologie
Pédiatrique (SIOP) in an attempt to improve the out-
come of children with Wilms’ tumor.

NWTS-1 and NWTS-2
There were many important findings as a result of the
early clinical trials NWTS-1 (1969 to 1973) and NWTS-
2 (1974 to 1978).109,110 For example, postoperative local
irradiation was shown to be unnecessary for group
I patients. Also, combination chemotherapy of vin-
cristine (VCR) and AMD was found to be more effec-
tive than the use of either drug alone. The addition of
doxorubicin (DOX) was shown to improve survival of
higher-stage patients. However, even more important
findings were the identification of unfavorable histo-
logic features of Wilms’ tumor, and of prognostic fac-
tors that allowed refinement of the staging system
stratifying patients into high-risk and low-risk treat-
ment groups.111 After the completion of NWTS-1 and
NWTS-2, it was recognized that the presence of lymph
node metastases had an adverse outcome on survival.
Children with lymph node metastases, as well as those
with diffuse tumor spill, were found to be at increased
risk of abdominal relapse. Therefore, such patients were
considered stage III and given whole abdominal irradi-
ation. These findings were incorporated into the design
of NWTS-3 to try and decrease the intensity of therapy
for the majority of low-risk patients while maintaining
overall survival.
NWTS-3
In NWTS-3, patients with stage I, FH Wilms’ tumor
were treated successfully with a 10-week regimen of
VCR and AMD, considerably decreasing the amount of
chemotherapy administered and, as a consequence, the
total duration of treatment.48 The 4-year relapse-free
survival was 89%, and the overall survival was 95.6%.
Stage II FH patients treated with AMD and VCR with-
out postoperative radiation therapy (XRT) had an equiv-
alent survival, 4-year overall survival of 91.1%, to
patients that received the same treatment plus DOX,
demonstrating the cardiotoxic drug DOX is not neces-
sary for the successful treatment of this group of patients.
The dosage of abdominal irradiation for stage III FH
patients was reduced to 1080 cGy. This was shown to be
as effective as 2000 cGy in preventing abdominal relapse
if DOX was added to VCR and AMD. The 4-year
relapse-free survival for stage III patients was 82% in
NWTS-3, the 4-year overall survival was 90.9%.
Patients with stage IV FH tumors received abdominal
(local) irradiation based on the local tumor stage. In addi-
tion, they all received 1200 cGy to both lungs. In combi-
nation with VCR, AMD, and DOX, the 4-year
relapse-free survival was 79% and the overall survival was
80.9%.112 There was no statistically significant improve-
ment in survival when cyclophosphamide was added to
the three-drug regimen.
Chapter 47 Wilms’ Tumor 763
NWTS-4
The goals of the NWTS-4 (1986 to 1994) were to fur-
ther decrease treatment intensity for patients with favor-
able prognosis, while trying to maintain their excellent
survival. In addition, this was the first clinical pediatric
cancer trial to evaluate the economic impact of two dif-
ferent treatment approaches. Pulse-intensive regimens
utilized simultaneous administration of agents at more
frequent intervals to decrease the number of clinic visits
and hence the cost of cancer treatment. NWTS-4
demonstrated that while the administered drug dose-
intensity was greater on pulse-intensive regimens, these
regimens, which indeed are cost effective, produce less
hematologic toxicity than the standard regimens.113
Patients treated with pulse-intensive regimens achieved
equivalent survival compared to those treated with stan-
dard chemotherapy regimens.94 Treatment durations of
approximately 6 and 15 months were found to be equally
effective in patients with stages II to IV/FH tumors.114
Children with anaplastic Wilms’ tumors were ran-
domized in NWTS-3 and NWTS-4 to receive VCR,
AMD, DOX, or those three drugs with the addition of
cyclophosphamide. There was no difference in outcome
between the regimens for children with focal anaplasia
who had a prognosis similar to that for FH patients.115
For stages II to IV diffuse anaplasia, the addition of
cyclophosphamide to the three-drug regimen improved
the 4-year relapse-free survival (27.2% versus 54.8%).
NWTS-5
The recently closed intergroup study, NWTS-5, was
a single-arm therapeutic trial. Patients were not
randomized for therapy, but instead biologic features of
the tumors were prospectively assessed. The goal of this
study was to verify the preliminary findings that LOH for
chromosomes 16q and 1p are useful in identifying
patients at increased risk for relapse.39 However, many
other biologic factors can be studied with the use of
banked tumor specimens collected on all enrolled
patients.87 This tumor bank is available to all investiga-
tors and will be useful to evaluate new prognostic factors
that may be identified in the future. If molecular genetic
markers are predictive of clinical behavior, they may be
used in subsequent clinical trials to further stratify patients
for therapy. Accrual of patients for the NWTS-5 study was
completed in late 2001. At this time, results from NWTS-
5 have not been published, as data need further matura-
tion. Current recommendations for treatment are outlined
in Table 47-5. These represent the treatment regimens used
in NWTS-5. Treatment for patients with stage I or stage II
FH and stage I anaplastic Wilms’ tumor is the same.
Patients with stage III FH and stage II and stage III
focal anaplasia are treated with AMD, VCR, and DOX
764 Part VIII Pediatric Malignancies
Table 47-5 Treatment Protocol for National Wilms Tumor Study-5
Stage/Histology Radiation Therapy
Stages I and II FH None
Stage I anaplasia
Stages III and IV FH 1080 cGy*
Stages II to IV focal anaplasia
Stages II to IV diffuse anaplasia Yes†
Stages I to IV CCSK
Stages I to IV rhabdoid Yes†
*Stage IV/FH patients are given radiation based on the local tumor stage.
†Radiation therapy is given to all CCSK and RTK patients. Consult protocol for specific treatment.
AMD, dactinomycin; VCR, vincristine; DOX, doxorubicin; CPM, cyclophosphamide; FH, favorable histology.
and 1080 cGy abdominal irradiation. Patients with stage
IV FH tumors receive abdominal irradiation based on
the local tumor stage and 1200 cGy to both lungs.
Children with stages II to IV diffuse anaplasia and stages
I to IV CCSK are treated with a regimen combining
VCR, DOX, cyclophosphamide, and etoposide. Children
with all stages of RTK were treated with carboplatin,
cyclophosphamide, and etoposide. All these patients
receive irradiation to the tumor bed.
One portion of the NWTS-5 study examined the role
of surgery alone for children under 2 years of age with
stage I FH tumors weighing under 550 g has been pub-
lished.116 This study was based on preliminary observa-
tion of favorable outcomes on small numbers of such
patients when postoperative adjuvant therapy had been
omitted.117,118 It was suspended when the number of
tumor relapses exceeded the limit allowed by the design
of the study. Seventy-five patients were enrolled. The
sites of relapse were the lung in 5 children and the renal
bed in 3 patients. The 2-year disease-free survival rate
was 86.5%. The 2-year survival rate of this cohort of
patients with small tumors is 100% with a median follow-
up of 2.84 years,116 and extended follow-up continues.
Observation of untreated children may yield interesting
information on the role of chemotherapy in decreasing
the incidence of contralateral relapse in patients with
NRs. Three of these children (4%) have developed
metachronous contralateral tumors.116
International Society of Pediatric Oncology
The randomized trials conducted by SIOP differ from
those of the NWTSG in that patients receive therapy
prior to surgery. Also, no routine histopathologic diagno-
sis is obtained prior to commencing treatment. The
Chemotherapy
EE-4A; pulse-intensive AMD plus VCR (18 weeks)
DD-4A; pulse-intensive AMD, VCR and DOX (24 weeks)
Regimen I: AMD, VCR, DOX, CPM, and etoposide
Regimen RTK: carboplatin, etoposide, and CPM tumor of the
kidney
rationale for the SIOP approach is that preoperative
chemotherapy will make the tumor less prone to intraop-
erative rupture or spill.119–120 The European investigators
also indicate that preoperative therapy leads to a more
favorable stage distribution at the time of surgery,122 as a
result of which fewer patients will require postoperative
radiation therapy. Preoperative treatment can indeed pro-
duce dramatic reduction in the size of the primary tumor
facilitating surgical excision (Figure 47-5).
The SIOP investigators use tumor extent as found at
the time of delayed (postchemotherapy) surgery to deter-
mine local tumor stage. However, this postchemotherapy
stage may inadequately define the risk of intra-abdominal
recurrence in nonirradiated patients.121 The SIOP stag-
ing system separates stage II into “node-negative” and
“node-positive” groups. In SIOP-6, patients with “post-
chemotherapy stage II” were randomized to receive or
not receive abdominal irradiation. An unacceptable
increase in the number of intra-abdominal recurrences in
nonirradiated patients was noted, although survival rates
for both groups were not significantly different.121 As a
result, stage II node-negative patients are now given an
anthracycline as part of the chemotherapy regimen.
Consequently, a larger percentage of SIOP patients are
now receiving a cardiotoxic drug than do patients regis-
tered to NWTSG studies. The significance of this is dis-
cussed later in the section on late effects. Of interest,
when one compares the numbers of patients receiving
abdominal irradiation, the incidence has decreased for
both groups. The overall survival figures are comparable
between the SIOP and NWTSG.114,123,124
The SIOP group has studied the pathologic changes
in the tumor after preoperative therapy to help guide
treatment decisions. This approach features the impor-
tance of Wilms’ tumor responsiveness as distinguished
 Chapter 47 Wilms’ Tumor 765

Figure 47-5 A, MRI scan of a large inoperable Wilms’ tumor. B, After 6 weeks
of chemotherapy the same tumor has dramatically decreased in size.

from its aggressiveness; the latter is more important in
determining tumor stage at diagnosis. In SIOP-9, patho-
logic review of the resected specimens after chemother-
apy revealed completely necrotic (defined as <1% of
viable tumor) Wilms’ tumor in approximately 10% of
specimens.125 Of these patients, 98% had no evidence
of disease at 5 years (1 nontumor death). These patients
are now considered to be “low-risk tumors” by SIOP.
The other low-risk tumors are CMN, cystic partially dif-
ferentiated nephroblastoma, nephroblastoma with
fibroadenomatous features, and nephroblastoma of
highly differentiated epithelial type. In the latest SIOP
Wilms’ study, stage I low-risk tumors did not receive
chemotherapy after nephrectomy.
Intermediate-risk tumors were defined as mixed
type nephroblastoma, focal anaplasia, regressive type
nephroblastoma, epithelial type nephroblastoma, and
stromal type nephroblastoma.126 High-risk tumors are
diffuse anaplasia and nephroblastoma-blastemal type.
The latter is defined as viable tumor in more than 1/3 of
the mass and 2/3 of the viable tumor consists of blastema.
Although the proportion of patients with blastemal
766 Part VIII Pediatric Malignancies
predominant tumors is decreased after chemotherapy,
these patients had a 31% relapse rate in the SIOP-9
study.125 These patients require more intensive treatment
after nephrectomy.
BILATERAL WILMS’ TUMORS
Synchronous BWT occurs in about 5% of children with
metachronous lesions developing in only 1%.50,52,127
Therapy for patients with BWT is focused on sparing
renal parenchyma to decrease the risk for renal failure
noted in these children.50,52,127,128 Review of NWTSG
patients found that 9.1% of children with synchronous
BWT and 18.8% of metachronous BWT developed
renal failure.129 The most common cause of renal failure
was bilateral nephrectomy for persistent or recurrent
tumor in the remaining kidney after initial nephrectomy.
Therefore, avoiding total nephrectomy at initial surgery
is advised. The NWTSG recommends that all children
with BWT should receive chemotherapy prior to surgi-
cal resection.
At initial surgical exploration, bilateral biopsies should
be obtained for histopathologic confirmation of disease
in both kidneys and definition of the histologic subtype.
Examination for extrarenal spread is performed. If suspi-
cious lymph nodes or other disease is noted, this should
be biopsied and a surgical stage assigned. In NWTS-5,
patients with FH and stage I or stage II disease were
given AMD and VCR, while those with stage III or stage
IV FH also received DOX.
The patient is given 6 weeks of chemotherapy and
then reassessed with imaging studies. Experience from
SIOP has shown that most of the reduction in tumor vol-
ume will occur early. In SIOP-9, the reduction in tumor
volume was 48% after 4 weeks and increased to 62%
after 8 weeks of chemotherapy.123,124 Although this dif-
ference was not of significance for unilateral tumors, fur-
ther shrinkage may facilitate a parenchymal sparing
approach.
It is important to recognize that response of the tumor
by imaging does not always correlate with the histologic
response. A clinically good response (by imaging) is usu-
ally associated with a pathologically good response in
terms of regressive histologic changes.130 The converse is
not always true.
Important data on histology of postchemotherapy
specimens has been collected by SIOP investigators.
Although this information has only been reported for
children with unilateral tumors, the information can be
extrapolated to those with BWT. The distribution of his-
tologic subtypes is different in children treated with pre-
operative chemotherapy compared to those undergoing
primary surgery.83,125,130 Differentiation of the tumor
after chemotherapy has been noted by several investiga-
tors. Stromal predominant tumors were noted in 14%
patients treated with preoperative chemotherapy com-
pared to 1.6% of children undergoing primary nephrec-
tomy in NWTS-4. Epithelial predominant tumors also
were noted with increased frequency. The latter two
types are often associated with a poor clinical response to
therapy as determined by preoperative imaging. There is
a less marked reduction in tumor volume after
chemotherapy but lower rates of relapse.125,130 The prog-
nosis for patients with these tumor types is excellent if
the tumors are completely excised. These tumors do
seem to be more resistant to therapy when seen at higher
stages. Another histologic subtype that often fails to
shrink with chemotherapy is fetal rhabdomyomatous
nephroblastoma.131,132 Some tumors with complete
necrosis and predominantly regressive changes can
increase in size during therapy.
There is a 10% incidence of anaplasia in BWT.50,128
The incidence of anaplasia is higher in girls than
boys.50,128 There can be discordance in the pathology
between the two kidneys. Tumor size or other gross fea-
tures does not correlate with histology, and careful exam-
ination of both specimens is required.
This information demonstrates the importance of
obtaining biopsy specimens in patients those are not
responding to chemotherapy. In some of these children,
further chemotherapy will not lead to tumor shrinkage.
Therefore, if the patient has not responded, reexplo-
ration with biopsy of the tumor should be performed in
12 weeks. At the time of the second look procedure, par-
tial nephrectomy or wedge excision of the tumor is per-
formed whereever possible.
If extensive tumor involvement precluding partial
resection is still present after preoperative therapy,
complete excision of tumor from the least involved kid-
ney is performed. If this leaves a viable kidney, nephrec-
tomy of the other kidney is carried out. Occasionally,
bilateral nephrectomy is indicated. This will result in
the need for dialysis. Indeed the most common cause of
renal failure in NWTS patients is bilateral nephrec-
tomy for persistent tumor.129 If transplantation is later
considered, a waiting period of 2 years is recommended
to ensure that the patient does not develop metastatic
disease.133
TREATMENT OF RELAPSES
Children with relapsed Wilms’ tumor have a variable
prognosis, depending on the initial stage, site of relapse,
time from initial diagnosis to relapse and prior therapy.
Adverse prognostic factors include relapse <12 months
after diagnosis, prior treatment with DOX, and intra-
abdominal relapse in patients who had previously
received abdominal irradiation.134 The risk of tumor
relapse in NWTS-3 at 3 years was 9.6%, 11.8%, 22%,
and 22%, respectively, for stages I to IV. Relapses

occurred in 36% of stages I to III and 45% of stage IV
patients with unfavorable histology.48
LATE EFFECTS OF CANCER TREATMENT
One consequence of the tremendous improvement in
survival of children with malignancies is that there are
many long-term survivors who have been exposed to
both radiation and chemotherapeutic agents. These
children require long-term surveillance, as the sequelae of
this therapy may not be evident for many years. One
of the more serious concerns is the increased risk for
second malignant neoplasms (SMN). Investigators from
the NWTSG have noted a 1.6% cumulative incidence of
SMNs at 15 years posttreatment.135 Prior treatment
for relapse, the amount of abdominal irradiation, and use of
DOX were all associated with an increased incidence
of SMNs.
Another risk associated with DOX is cardiac toxicity.
Congestive heart failure is a well-known acute complica-
tion of treatment with anthracycline and the incidence is
dose related.136 For NWTS-1, NWTS-2, NWTS-3, and
NWTS-4 patients, the cumulative frequency of conges-
tive heart failure was 4.4% at 20 years after diagnosis
among patients treated initially with doxorubicin.137 The
relative risk of congestive heart failure was increased in
females by cumulative doxorubicin dose, lung irradiation,
and left abdominal irradiation.
Numerous other organ systems are subject to the late
sequelae of anticancer therapy. An early report of
NWTSG patients found that musculoskeletal problems,
such as scoliosis, were 7 times more common in children
those were treated with radiation.138 A more recent
review of 2778 NWTSG patients found that reduction in
stature following RT to the pediatric spine is dose
dependent and age dependent. However, average height
deficits observed at maturity for children receiving doses
currently recommended by the NWTSG are clinically
nonsignificant.139
Damage to reproductive systems can lead to problems
with hormonal dysfunction and/or infertility. Female
Wilms’ tumor patients who received abdominal radiation
have a 12% incidence of ovarian failure.140 In addition,
women with prior abdominal radiation have the potential
for adverse pregnancy outcomes.141,142 Perinatal mortal-
ity rates are higher, and infants are more likely to have
low birth weights.143 Gonadal radiation in males can
result in temporary azoospermia and hypogonadism.144
The severity of damage to the testis is dependent on the
dose or radiation.
There has been concern about the late occurrence of
renal dysfunction in children who have undergone
nephrectomy. Patients have been found to develop pro-
teinuria, hypertension, and renal insufficiency secondary
to focal glomerulosclerosis, which has been attributed to
Chapter 47 Wilms’ Tumor 767
hyperfiltration injury.144,145 There is both clinical and
experimental evidences of hyperfiltration damage of
remnant nephrons after a loss of renal mass.146 Most
experimental studies involve a loss of >3/4 of the total
renal mass, but there is only limited data assessing renal
function long term in children following unilateral
nephrectomy.147,148 While several studies have found no
significant alterations in renal function following unilat-
eral nephrectomy for Wilms’ tumor,149–151 other reports
have noted an increased incidence of proteinuria and
decreased glomerular filtration rate (GFR).147,148,152,153
However, clinically important hypertension or renal
insufficiency is rare.
One of the more important risk factors for a decrease in
GFR is the amount of radiation to the remaining kidney.
The correlation of functional impairment with the renal
radiation dose was reported by Mitus et al.154 a review of
100 children treated for Wilms’ tumor. The incidence of
impaired creatinine clearance was significantly greater for
children who received >1200 cGy to the remaining kidney,
and all cases of overt renal failure occurred in patients who
had received more than 2300 cGy.
The concern of renal dysfunction has led some centers
to consider parenchyma-sparing procedures for unilateral
tumors.155,156 Because the majority of tumors are too
large for partial nephrectomy at presentation, the patient
must be given preoperative chemotherapy, after that less
than 10% of patients may then be amenable to partial
nephrectomy. However, in order to scientifically justify
this approach, many children would have to be treated
accordingly to demonstrate its benefits since the inci-
dence of renal failure is quite low for unilateral Wilms’
tumor. A review of the NWTSG database found that
<0.2% of unilateral Wilms’ tumor patients developed
renal failure. Moreover, the majority of these patients suf-
fered from the Denys-Drash syndrome, a disorder
whereby all patients invariably develop end-stage renal
disease irrespective of the cancer therapy.129 A recent
report from the NWTSG did find an increased risk of
renal failure in children with Wilms’ tumor who also had
aniridia or genitourinary abnormalities.157 The cumula-
tive risk of renal failure at 20 years was 38% for the
patients with aniridia.
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147. Argueso LR, Ritchey ML, Boyle ET Jr, et al: Prognosis
of the solitary kidney after unilateral nephrectomy in
childhood. J Urol 1992; 148:747–751.
148. Robitaille P, Mongeau JG, Lortie L, Sinnassamy P:
Long-term follow-up of patients who underwent
nephrectomy in childhood. Lancet 1985; 1:1297–1299.
149. Barrera M, Roy LP, Stevens M: Long-term follow-up
after unilateral nephrectomy and radiotherapy for
Wilms’ tumor. Pediatr Nephrol 1989; 3:430–432.
150. Bhisitkul DM, Morgan ER, Vozar MA, Langman CB:
Renal functional reserve in long-term survivors of
unilateral Wilms’ tumor. J Pediatr 1990; 118:698–702.
151. Bailey S, Roberts A, Brock C, et al: Nephrotoxicity in
survivors of Wilms’ tumour in the North of England.
Br J Cancer 2002; 87:1092–1098.
152. Levitt GA, Yeomans E, Dicks Mireaux C, et al: Renal
size and function after cure of Wilms’ tumor. Br J
Cancer 1992; 66:877–882.
153. Donckerwolcke RM, Coppes MJ: Adaptation of renal
function after unilateral nephrectomy in children with
renal tumors. Pediatr Nephrol 2001; 16:568–574.
154. Mitus A, Tefft M, Feller FX: Long-term follow-up
of renal function of 108 children who underwent
nephrectomy for malignant disease. Pediatrics 1969;
44:912–921.
155. McLorie GA, McKenna PH, Greenberg M, et al:
Reduction in tumor burden allowing partial
nephrectomy following preoperative chemotherapy in
biopsy proved Wilms’ tumor. J Urol 1991; 146:509–513.
156. Moorman-Voestermans C, Aronson D, Staalman CR,
et al: Is partial nephrectomy appropriate treatment for
unilateral Wilms’ tumor? J Pediatr Surg 1998;
33:165–170.
157. Breslow NE, Takashima JR, Ritchey ML, et al: Renal
failure in the Denys-Drash and Wilms’ tumor-aniridia
syndromes. Cancer Res 2000; 60:4030–4032.
C H A P T E R
48 Rhabdomyosarcoma of the Pelvis
and Paratesticular Structures
Hsi-Yang Wu, MD, and Howard M. Snyder III, MD
One of the goals in pediatric oncology is to individualize
therapy for the low-risk patient versus the high-risk
patient. Therefore, the least amount of chemotherapy
and radiation for the low-risk patient, which will achieve
a cure, is desirable, since it decreases long-term morbid-
ity. For the high-risk patient, molecular identification of
poor prognostic factors can suggest that intensified
treatment is necessary. The management of rhab-
domyosarcoma (RMS) remains controversial, because
while a combination of surgery, chemotherapy, and radi-
ation therapy is more successful than any single modal-
ity approach, the optimal timing and dose of each
remains unclear. This is evident when reviewing the dif-
ferent approaches to the disease taken by North
American and European groups. To maintain an overall
perspective in reviewing the literature on RMS, it is use-
ful to remember three key points:
1. Chemotherapy cures microscopic disease.
2. Residual mass does not equal disease.
3. Radiation therapy renders pathology very difficult to
read.
Twenty percent of RMS involves the bladder, prostate,
vagina, or paratesticular area. The incidence peaks
between ages 2 to 4 and 15 to 19. The tumor is nonen-
capsulated, grows rapidly, and spreads to regional lymph
nodes, as well as hematogenously. In the United States,
patients are managed by Intergroup Rhabdomyosarcoma
Study Group (IRSG) protocols. (The IRSG is now the
Children’s Oncology Group Soft Tissue Sarcoma
Committee.) These studies have been ongoing since
1972 to achieve better survival with less morbidity.
Three-year patient survival, which was only 40% to
73% prior to chemotherapy, has improved to 86% in
IRS-IV with vincristine, dactinomycin, and cyclophos-
773
phamide (VAC). Failure-free survival at 3 years is now
77%.1 During the same time, the surgical approach
has changed from exenterative surgery to organ-
preserving surgery following chemotherapy. The func-
tional bladder salvage rate has risen from 25% to 60%
with this change in management. IRS-V was designed to
evaluate new agents, such as topotecan for advanced dis-
ease, while attempting to decrease cyclophosphamide
and XRT dosing for low-risk patients. Unlike neurob-
lastoma, there are no plans for high-dose chemotherapy
followed by bone marrow transplantation in advanced
disease since there are no data showing that this has been
helpful.2,3
PATHOLOGY AND MOLECULAR BIOLOGY
RMS consists of small, blue, round cells (similar to neu-
roblastoma, Ewing’s sarcoma, non-Hodgkin’s lymphoma,
and leukemia) with a microscopic appearance of spindle
cells resembling fetal skeletal muscle. The cells derive
from undifferentiated mesoderm and, therefore, can be
present in tissues, which do not normally express skeletal
muscle. One surgical problem is that although there may
appear to be a pseudocapsule, the tumor will often infil-
trate through the tissue. Multiple biopsies are required to
ensure that the excision is complete. Embryonal pathol-
ogy, which is a favorable factor, accounts for 90% of gen-
itourinary RMS. Sarcoma botryoides (bunch of grapes) is
a polypoid form of embryonal pathology, which occurs in
hollow organs like the bladder. Alveolar pathology, which
tends to occur in extremities, is less favorable. Anaplastic
and undifferentiated pathologies rarely occur in geni-
tourinary tumors (Figure 48-1). Desmin and actin stains
are sometimes useful in determining the diagnosis.
Current lab efforts have found genetic translocations
between chromosomes 1;13 (favorable) and 2;13 (very
774 Part VIII Pediatric Malignancies

Figure 48-1 Histologic subtypes of RMS: A, embryonal; B, spindle cell; C, botryoid; D,

alveolar. (H/E 33X.) (Courtesy Dr. Philip Faught.)

high risk) to be prognostic markers for survival in
patients with alveolar tumors with metastatic disease.4
Unfortunately, there are no good molecular markers for
embryonal tumor behavior that can be followed at the
present time.3
PRESENTATION AND EVALUATION
Bladder and prostate primaries tend to present with uri-
nary retention, a palpable lower abdominal mass, gross
hematuria, and tend to be located at the trigone and blad-
der neck (Figure 48-2). The tumors have a 2.5/1 male
predominance. Sometimes, a child can void a piece of the
tumor per urethra. In females, the sarcoma botryoides
type of tumor can prolapse through the urethra.
Occasionally, the tumor can project posteriorly and cause
constipation. Determining which organ the tumor arose
from can be difficult, but initial treatment does not
depend on this distinction. Computed tomography (CT)
or magnetic resonance imaging (MRI) (T2 weighted) of
the pelvis is the initial study. MRI may give better reso-
lution of tumor invasion.
Vaginal primaries present with vaginal bleeding or an
introital mass and tend to occur on the anterior vaginal

Figure 48-2 Sarcoma botryoides of bladder base showing characteristic polypoid

appearance on cystogram.
 Chapter 48 Rhabdomyosarcoma of the Pelvis and Paratesticular Structures 775

wall. CT or MRI (T2 weighted) of the pelvis is the initial Table 48-1 Preoperative Staging
study. Uterine primaries were formerly considered to be a
T1 Confined to organ of origin, a: ≤5 cm in size,
disease of older females, but more recent studies suggest b: >5 cm in size
that they present at the same age as vaginal primaries and
can be successfully treated with limited excision followed T2 Extension or fixed to surrounding tissue, a:
by chemotherapy. Hysterectomy is rarely carried out.5 ≤5 cm in size, b: >5 cm in size
Vulvar and cervical lesions tend to occur in teenagers.6
N0 Regional nodes clinically negative
Staging for bladder, prostate, and vaginal primaries is
completed by endoscopic examination and biopsy of the N1 Regional nodes clinically positive
lesion. Cold-cup biopsy will give better results than using
a resectoscope loop, since cautery artifact can make inter- Nx Unknown
pretation difficult. If the lesion does not appear to involve
M0 No distant metastasis
the mucosa of the bladder, prostate, or vagina, then a
needle biopsy may be necessary via a percutaneous M1 Metastasis present
(transperineal), transrectal, or laparoscopic approach.
Paratesticular RMS has two peak incidences, in the Stage I Vaginal and paratesticular RMS, any
3- to 4-month-old boy and in the teenager. The bio- T, any N, M0
logic activity of the tumor is different between the
Stage II Bladder/prostate RMS, T1a or T2a, N0
neonate and the teenager (90% versus 63% failure-free or Nx, M0
survival at 3 years).1 The primary tumor presents as a
painless scrotal mass. Scrotal ultrasound, serum β- Stage III Bladder/prostate RMS (T1a or T2a) and N1,
HCG, and AFP should be obtained to confirm that the M0, OR (T1b or T2b), any N, M0
mass is not a testicular primary. Imaging of the
retroperitoneum by CT or MRI is usually carried out Stage IV Any tumor with M1
before surgery. Thirty percent to forty percent will have
microscopic metastases to the retroperitoneum. The
tumor is resected, along with the testis in a radical
Table 48-2 Postoperative Grouping
inguinal orchiectomy. Pathologic staging of retroperi-
toneal lymph nodes is currently recommended for Group 1: Localized disease, completely excised, no microscopic
residual
patients 10 years of age or older, regardless of radiologic
findings, and in patients <10 years of age with retroperi- A Confined to site of origin, completely resected
toneal disease visible on CT or MRI.3
Metastatic workup for all lesions is completed with a B Infiltrating beyond site of origin, completely
chest x-ray (and possibly chest CT), liver function tests, resected
bone scan and bone marrow biopsy.
Group 2: Total gross resection

STAGING A Gross resection with microscopic local residual

The IRS study includes both preoperative staging and
postoperative grouping (Tables 48-1 and 48-2). The IRS-
I to IRS-III studies grouped patients based on complete-
ness of resection, introducing biases (shifting patients
from group 1 to group 3), which are not seen with the use
of the TNM system in IRS-IV and IRS-V. Eighty per-
cent of bladder and prostate primaries are group 3 (gross
residual), whereas 50% of nonbladder/prostate primaries
are group 1 (complete resection), with about 20% in
group 2 (complete gross resection, with microscopic or
nodal tumor) and group 3, respectively.7
GENERAL APPROACH
Chemotherapy/Radiation
In IRS-IV, VAC was shown to be as effective as two other
three drug regimens (VIE/VAE: ifosfamide, etoposide).1
B Regional disease with involved lymph nodes,
completely resected with no microscopic residual
C Microscopic local and/or nodal residual
Group 3: Incomplete resection or biopsy with gross residual
Group 4: Distant metastases
Since cyclophosphamide is cheaper and has less toxicity,
VAC is the current standard chemotherapy. The addition
of doxorubicin or melphalan to VAC has not been bene-
ficial. In IRS-V, low-risk patients are randomized to
receive either VA or VAC, plus or minus XRT.
Intermediate-risk patients receive chemotherapy and
XRT and are randomized to VAC or VAC alternating
with vincristine, topotecan, and cyclophosphamide.
776 Part VIII Pediatric Malignancies
High-risk patients receive CPT-11 (irinotecan), VAC,
and XRT.3
In IRS-IV, hyperfractionated radiation therapy did not
achieve better results than conventional radiation ther-
apy.8 For IRS-V, patients with group 1 embryonal pathol-
ogy will not receive XRT. For other patients, the dose of
radiation to the residual primary will be higher than to
microscopic residual disease, and metastases will be irra-
diated as well.3 Surgery as treatment of gross residual dis-
ease after chemotherapy is still an option. At the
Children’s Hospital of Philadelphia, we have favored this
approach, mainly because of the difficulty of interpreting
the pathology after radiation.
Surgery
The goal of the initial procedure is to obtain adequate
tissue for a definitive diagnosis. If possible, one should
remove the tumor without removing the affected
organ, except in the case of paratesticular tumors. If
excision is not possible, chemotherapy will be given
with a plan for a second look operation. In follow-up
staging, a biopsy is needed during the second look to
confirm whether a residual mass is tumor. The tumor
can involute more rapidly than the supporting stroma,
so gross residual masses may not contain any viable
tumor.
The goal of the definitive operation is a good, radi-
cal, but pelvic organ-sparing operation. If microscopic
residual disease is found, brachytherapy or external
beam radiation therapy can be used. Exenteration is
reserved for patients who have failed previous thera-
pies. In Europe, an alternate approach is to give pri-
mary chemotherapy without any attempt at initial local
control (radiation therapy or surgery), and to offer
local therapy based on the initial chemotherapy
response.9,10
Review of the pathology may reveal persistent rhab-
domyoblasts in a patient who has received as much
chemotherapy as can safely be given. Currently, there
is debate concerning the malignant potential of these
cells, which represent matured rhabdomyoblasts.11,12
Normally, resection of the involved organ is carried out.
However, if this would require destruction of a functional
bladder, observation with frequent radiologic follow-up
may be an option to consider.
Relapse
Five-year survival after relapse is 64% for botryoid
embryonal, 26% for other embryonal, and 5% for alveo-
lar or undifferentiated pathology. Survival after relapse
was also improved in lower-stage embryonal lesions at
the time of diagnosis: 52% stage I, 20% stages II and III,
and 12% stage IV.13
TREATMENT AND OUTCOME
Bladder and Prostate
Chemotherapy and Radiation
IRS-III included intensified chemotherapy (dactino-
mycin, VP-16) and 6 weeks of XRT, increasing the func-
tional bladder salvage rate from 25% to 60%. For
persistent disease, group 2 was treated with 41 Gy and
group 3 was treated with 50 Gy. At 24 weeks, a third
operative evaluation was performed with consideration
for exenteration.14
The difficulty with radiation therapy is that since the
tumors tend to be located at the bladder neck, even the
lowest dose (41 Gy) that the radiation oncologists are
willing to deliver may significantly risk urinary conti-
nence. Current attempts at limiting radiation toxicity to
adjacent organs involve both conformal radiation therapy
and brachytherapy. The long-term risk of radiation vas-
culitis, which is inevitably progressive, as well as possible
bony pelvis deformity in these children, is another issue
to consider. Therefore, one must sometimes weigh
whether preserving a bladder without an outlet is better
than removing the bladder entirely.15,16
Surgery for Bladder Primaries
While a full retroperitoneal lymphadenectomy is not
necessary, any suspicious lymph nodes along the great
vessels between the obturator fossa and the renal veins
should be removed. Multiple frozen-section biopsies of
the bladder are obtained around the tumor. If these are
negative, and the tumor is amenable to partial cystec-
tomy with a 2- to 3-cm margin, then the bladder does not
need to be entirely removed. If the tumor extends down
the urethra, then the symphysis should be split to gain
better access. After completing distal dissection of the
urethra, the symphysis is closed with absorbable suture.
With this improved exposure, it is also possible to per-
form a nerve-sparing dissection. The placement of
brachytherapy catheters for afterloading (to treat micro-
scopic positive margins if needed) should be considered.
For patients who require total cystectomy, we have
often placed Dexon mesh across the abdomen to hold the
intestines out of the pelvis at the level of the sacral
promontory. This is done by attaching it to the sacral
promontory and wrapping it around the sigmoid. This
limits the exposure of the bowel to the radiation field if
postoperative radiation is required. The final surgical
decision is whether to proceed with continent urinary
reconstruction at the same time. We believe that it is not
wise to perform the reconstruction at the same time,
unless the patient is both motivated and able to perform
clean intermittent catheterization to drain a urinary
reservoir. For the younger patients who are not ready to
manage a urinary reservoir, we have either brought up
the remaining bladder plate with ureterovesical junctions
 Chapter 48 Rhabdomyosarcoma of the Pelvis and Paratesticular Structures 777
intact as a vesicostomy, or performed low end-cutaneous
ureterostomies, with the ureters placed side-by-side as a
single stoma on the abdominal wall.
Surgery for Prostate Primaries
The technique is similar to that for localized prostatic
adenocarcinoma. The use of nerve-sparing procedures
may preserve erectile potency in these patients. Splitting
the symphysis is useful as it is essential to remove the ure-
thra to the mid-bulbar level. The placement of
brachytherapy catheters for afterloading (to treat micro-
scopic positive margins if needed) should be considered.
Outcome
In IRS-I and IRS-II, half of the patients survived with
intact bladders, whereas the other half had either total or
partial cystectomy. In those patients with intact bladders,
function (as assessed by questionnaire) was normal in
73%, whereas 8% had incontinence and 9% had fre-
quency and nocturia. Overall renal function as assessed
by serum BUN and creatinine was normal in 95%,
although 29% of the patients had abnormal renal scans,
which was often hydronephrosis in the setting of a uri-
nary diversion.15 In IRS-I to IRS-III, over 25% of
patients treated with partial cystectomy had complica-
tions of gross hematuria, bladder contracture, or inconti-
nence. The risk of complications increased as the XRT
dose raised over 40 Gy.16
More recent outcomes show that 50% of patients were
managed with biopsy, 37% had partial cystectomy, and
13% had prostatectomy. Patients with embryonal pathol-
ogy had an 83% 3-year failure-free survival, compared to
40% in those with alveolar pathology. However, all
patients with group 4 (metastatic) prostate disease died.14
Vagina/Uterus
Chemotherapy and Radiation
Primary treatment with VAC chemotherapy is usually
successful, and a biopsy 8 to 12 weeks after chemother-
apy is recommended. Pelvic lymph node dissection is not
necessary. Vaginectomy or hysterectomy should only be
considered for persistent disease after a complete course
of chemotherapy.17 Rhabdomyoblasts on biopsy are evi-
dence of chemotherapy response, and therefore further
chemotherapy, instead of resection, is the proper treat-
ment. Radiation therapy should only be used for persist-
ent disease or relapse.17,18
Outcome
Surgery and chemotherapy cure most cases of vaginal
RMS. In the overall IRS-I to IRS-IV experience, 42% of
patients were treated with surgery and chemotherapy, 19%
required additional radiation therapy, 21% were treated
with biopsy and chemotherapy alone, and 12% were man-
aged with biopsy, chemotherapy, and radiation therapy.
(There were insufficient data regarding local therapy for
the remaining patients.) Five-year patient survival and fail-
ure-free survival were 82% and 69%.6 In IRS-IV, only 19%
of patients required wide excision of vaginal tumors.18 Age
between 1 and 9 was a favorable factor for survival (94%
versus 76%).6 The experience of the International Society
of Pediatric Oncology (SIOP) in Europe has been similar,
although they prefer intracavitary brachytherapy for local
control rather than hysterectomy.19
Paratestis
Chemotherapy and Radiation
In IRS-I to IRS-III, all patients underwent retroperi-
toneal lymph node dissection (RPLND).1 Based on the
European experience that 17 of 19 patients with clinical
stage I disease were cured with adjuvant chemotherapy
alone20; RPLND was not recommended in IRS-IV for
stage I disease with a normal CT of the abdomen and
pelvis. This led to a significant understaging of disease
based on radiologic evaluation alone and a decrease in
failure-free survival because patients with negative CT
scan did not receive radiation. Thirty percent of those
patients who were clinically stage I and over 10 years of
age required retreatment. Since the outcome for patients
<10 years old with stage I disease was good in IRS-IV,
those patients who are <10 years old have stage I disease,
and negative abdominal/pelvic CT are treated with VA
(vincristine, dactinomycin) only in IRS-V. All patients
with stage I disease who are 10 years or older undergo
RPLND regardless of CT findings. Group 2 tumors
(positive lymph nodes on pathology) are treated with
radiation therapy and VAC.21
Surgery
During inguinal orchiectomy, frozen section of the prox-
imal cord should reveal no tumor. If one makes a scrotal
incision for what turns out to be a solid paratesticular
mass, chemotherapy will often cure residual disease.
However, some cases have required hemiscrotectomy
due to tumor infiltration.
The technique for RPLND is identical to that used
for retroperitoneal involvement by testicular tumors.
Ipsilateral template and nerve-sparing techniques can be
used to maintain ejaculation.22
Outcome
Three-year patient survival and failure-free survival are
92% and 81%, respectively, for group 1 tumors overall.
778 Part VIII Pediatric Malignancies
The failure-free survival was worse than the 95%
achieved in IRS-III, although the patient survival rate is
the essentially the same as the 96% achieved in IRS-III.
Again, this was felt to be due to understaging when the
retroperitoneal lymph nodes were not pathologically
evaluated. Those patients more than 10 years old only
had a 63% survival, leading to the recommendation that
all patients of that age undergo RPPLND.1
COMPLICATIONS
The majority of patients have acute toxicity from the
chemotherapy; 90% developed myelosuppression, 55%
developed significant infections, and renal toxicity was
seen in 2%.1 Most relapses occur within 3 years of initial
diagnosis.13 Late recurrences can occur in patients who
are treated with chemotherapy alone. Out of 883
patients, 10 developed a secondary cancer. Patients with
preexisting renal abnormalities were at a higher risk of
death (5% versus 1%).1 The experience from IRS-I and
IRS-II suggests a 27% long-term urinary complica-
tion rate, with incontinence being the major issue.
Twenty-nine percent required sex hormone replacement
and 11% were shorter than expected.15 If radiation ther-
apy has been used, there is an increased risk of a second-
ary neoplasm, often another sarcoma, in the radiation
field. Complications specific to surgical treatment
include intestinal obstruction, anejaculation, and lower
extremity edema after RPLND. However, this series
evaluated therapy from 1972 to 1984, and current tech-
niques may result in better outcomes.23
SUMMARY
RMS is treated with a combination of surgery, chemother-
apy, and radiation. Bladder, prostate, and vaginal primar-
ies are treated with biopsy followed by chemotherapy,
reresection, and radiation with periodic reevaluations.
Paratesticular primaries receive chemotherapy after
orchiectomy and possibly require a RPLND if spread to
the retroperitoneum is seen or if the boy is >10 years of
age.
REFERENCES
1. Crist WM, Anderson JR, Meza JL, et al: Intergroup
Rhabdomyosarcoma Study-IV: Results for patients with
nonmetastatic disease. J Clin Oncol 2001; 19:3091–3102.
2. Carli M, Colombatti R, Oberlin O, et al: High-dose
melphalan with autologous stem cell rescue in metastatic
rhabdomyosarcoma. J Clin Oncol 1999; 17:2796–2803.
3. Raney RB, Anderson JR, Barr FG, et al:
Rhabdomyosarcoma and undifferentiated sarcoma in the
first two decades of life: a selective review of Intergroup
Rhabdomyosarcoma Study Group experience and
rationale for Intergroup Rhabdomyosarcoma Study
V. J Ped Hem/Oncol 2001; 23:215–220.
4. Sorenson PH, Lynch JC, Qualman SJ, et al: PAX3-FKHR
and PAX7-FKHR gene fusions are prognostic indicators
in alveolar rhabdomyosarcoma: a report from the
Children’s Oncology Group. J Clin Oncol 2002;
20:2672–2679.
5. Corpron C, Andrassy RJ, Hays CM, et al: Conservative
management of uterine rhabdomyosarcoma: a report from
the Intergroup Rhabdomyosarcoma Studies III and IV
Pilot. J Pediatr Surg 1995; 30:942–944.
6. Arndt CAS, Donaldson SS, Anderson JR, et al: What
constitutes optimal therapy for patients with
rhabdomyosarcoma of the female genital tract? Cancer
2001; 91:2454–2468.
7. Barksdale EM, Weiner ES: Rhabdomyosarcoma.
In Pediatric Surgery. Philadelphia, WB Saunders,
2000.
8. Donaldson SS, Neza J, Breneman JC, et al: Results from
the IRS-IV randomized trial of hyperfractionated
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report from the IRSG. Int J Radiat Oncol Biol Phys 2001;
51:718–728.
9. Flamant F, Rodary C, Rey A, et al: Treatment of non-
metastatic rhabdomyosarcoma in childhood and
adolescence. Results of the second study of the
International Society of Pediatric Oncology: MMT84.
Eur J Cancer 1998; 34:1050–1062.
10. Koscielniak E, Harms D, Henze G, et al: Results of
treatment for soft tissue sarcoma in childhood and
adolescence: A final report of the German cooperative soft
tissue sarcoma study CWS-86. J Clin Oncol 1999;
17:3706–3719.
11. Ortega JA, Rowland J, Monforte H, et al: Presence of
well-differentiated rhabdomyoblasts at the end of therapy
for pelvic rhabdomyosarcoma: implications for the
outcome. J Pediatr Hem/Oncol 2000; 22:106–111.
12. Leuschner I, Harms D, Mattke A, et al:
Rhabdomyosarcoma of the urinary bladder and vagina.
Am J Surg Pathol 2001; 25:856–864.
13. Pappo AS, Anderson JR, Crist WM, et al: Survival after
relapse in children and adolescents with
rhabdomyosarcoma: a report from the Intergroup
Rhabdomyosarcoma Study Group. J Clin Oncol 1999;
17:3487–3493.
14. Paidas CN: Results of rhabdomyosarcoma of the bladder
and prostate: Is bladder preservation successful? In
American Academy of Pediatrics Meeting, Chicago, IL,
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15. Raney B, Heyn R, Hays DM, et al: Sequelae of treatment
in 109 patients followed 5 to 15 years after diagnosis of
sarcoma of the bladder and prostate. Cancer 1993;
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16. Hays DM, Raney RB, Wharam MD, et al: Children with
vesical rhabdomyosarcoma (RMS) treated by partial
cystectomy with neoadjuvant or adjuvant chemotherapy,
with or without radiotherapy. J Pediatr Hem/Oncol 1995;
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17. Andrassy RJ, Weiner ES, Raney RB, et al: Progress in the
surgical management of vaginal rhabdomyosarcoma: a
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25-year review from the Intergroup Rhabdomyosarcoma
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18. Andrassy RJ: Modern approach to rhabdomyosarcoma of
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Meeting, Chicago, IL, Section on Surgery, 2000.
19. Martelli H, Oberlin O, Rey A, et al: Conservative
treatment for girls with nonmetastatic rhabdomyosarcoma
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20. Olive D, Flamant F, Zucker JM, et al: Paraaortic
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C H A P T E R
49 Prepubertal Testicular Tumors
Peter D. Metcalfe, MD,
and Darius J. Bägli, MD, CM, FRCSC, FAAP
Pediatric testicular tumors differ significantly from their
adult counterparts in several fundamental aspects. They
are less common, have different histologic distribution,
and they are more likely to be benign. There is also a
much higher incidence of metastases to the pediatric tes-
ticle, primarily of lymphopoietic origin.
The reported incidence of pediatric testicular tumors
is between 0.5 and 2 per 100,000 children, and they
account for 1% of solid tumors in this age group.1–3
Their rarity has prompted collaborative efforts at data
collection, and the development of the Prepubertal
Testicular Tumor Registry by the Section of Urology of
the American Association of Pediatrics (AAP) in 1980.
PRESENTATION
Eighty percent to ninety percent of patients present with
a painless mass.3–5 Trauma and swelling (5%) and hydro-
cele (2%) are the next most common modes of presenta-
tion.3 Leydig cell or granulosa tumors may present with
manifestations of testosterone production.6
Serology is a fundamental part of the initial evalua-
tion. Given the preponderance of yolk sac tumors, alpha
fetoprotein (AFP) is very useful in the evaluation of the
prepubertal testicular mass. However, because it is pro-
duced during normal fetal development, AFP may be ele-
vated beyond adult norms in neonates.7 Because most
yolk sac tumors in this age group are not associated with
mixed germ cell tumors, human chorionic gonadotropin
(HCG) is not elevated.
Scrotal ultrasound is an invaluable adjunct to treat-
ment, as the age of the child or the presence of a large,
tense hydrocele precludes a good physical examination.8
Sensitivity for detecting testicular neoplasia approaches
100%9 and is accurate in distinguishing intratesticular
from extratesticular lesions in up to 90% of cases.10
However, the specificity of the histologic diagnosis
afforded by ultrasound is much lower, and differentiation
780
between benign from malignant masses is not always
demonstrable sonographically.11–14 Color doppler can
demonstrate increased vascularity, increasing the speci-
ficity of a malignant process.12 Teratoma may be sus-
pected by a characteristic solid and cystic appearance,15,16
and epidermoid cysts may have an onionskin or target
appearance17 on ultrasound.
HISTOLOGIC TUMOR TYPES
Yolk Sac Tumors
Previous historic data suggested that yolk sac tumors were
the most commonly diagnosed testis tumor in the pedi-
atric population, and this has been confirmed by AAP reg-
istry data. It comprised 62% to 63% of their tumors.3,18
However, other retrospective, single institution reviews
have incidences of 66%,1 19%,5 and 8%.19 Most diag-
noses occur in boys <2 years of age, with the median age
16 months in data from both the AAP18 and the Hospital
for sick children (HSC) in Toronto, Canada.19
In managing pediatric yolk sac tumors, it is important
to remember the physiologic elevations of AFP in the
neonatal age group. Production from the gastrointestinal
tract or the liver can result in levels as high as 50,000
ng/ml in the neonate.20 Physiologic elevations diminish
quickly after birth but most remain above adult levels for
up to 8 months.7 The prolonged half-life of 33 days dur-
ing months 2 to 4 of life implies an element of neonatal
production.7 AFP binding affinity to concanavalin A may
be useful in the assessing an elevation from a benign ver-
sus a malignant source.21
Staging is according to the Children’s Cancer
Group/Pediatric Oncology Group system. Stage I is
defined as tumor confined to testis; stage II as micro-
scopic disease within the scrotum or spermatic cord and
retroperitoneal adenopathy is < 2 cm; stage III has
retroperitoneal nodes >2 cm, but without visceral
metastases; and stage IV is defined by distant metastases.

Eighty-five percent of patients present with stage I dis-
ease.8
Unlike adults, in this age group, retroperitoneal
lymph node dissection (RPLND) has been associated
with a high rate of complications, including chylous
ascites, bowel obstruction, gastrointestinal bleeding, lig-
ation of the renal artery, and a 10% to 40% incidence of
ejaculatory dysfunction.22 Improved clinical staging with
computed tomography (CT) and AFP combined with
the success of cisplatin, etoposide, and bleomycin
chemotherapy has reduced the role of RPLND for yolk
sac tumors. Contemporary indications are limited to a
persistent retroperitoneal mass, an elevated AFP post-
orchiectomy with no radiographic evidence of metastatic
disease, or an unknown AFP preoperatively.8
Disease-free survival at 5 years is comparable to that
in the adult population, with the results of stages II to IV
reported at >90%.23,24 Liu et al.25 demonstrated a 10%
5-year survival advantage (91% versus 100%) using 2 doses
of cisplatin, vincristine, and bleomycin in stage I disease.
Teratoma
The recently published 2002 AAP registry data listed ter-
atoma as accounting for 23% of testis tumors, a marked
increase from the 14% published in 1993.3,18 Single insti-
tution studies have shown an incidence of up to
60%,1,19,26 where it exceeds the incidence of yolk sac
tumors.20,26 This discrepancy may be accounted for by an
underreporting of benign tumors in the registry data.19,26
Median age at presentation is 13 to 16 months, with a
range of 0 to 146 months.18,19 There are at least two
reports of an antenatal diagnosis of teratomas.19,27
Preoperative findings consistent with a teratoma include
normal serology, as these tumors neither secrete nor stain
for AFP.20,28–30 Scrotal ultrasonography may show charac-
teristic cystic areas with septa and solid stromal ele-
ments,10,31 but the specificity is only 50% to 59%.14,16,31
Mature teratomas in the prepubescent male contrast
sharply with their adult counterparts, as metastasis from
teratoma have never been reported in children.3,18,26,32 The
benign properties of this tumor are likely responsible for
the increasing the popularity of treatment with partial
orchiectomy. The finding of immature elements does not
deter from its benign natural history, provided all other
investigations are in keeping with localized disease.33
Rhabdomyosarcoma
Although a paratesticular tumor, it is included in this dis-
cussion because it is an important consideration in the
differential diagnosis of a pediatric scrotal mass.4 It is the
most frequent tumor of paratesticular origin and, despite
its aggressive behavior, has recently been associated with
a good prognosis.34 The efforts of the Intergroup
Chapter 49 Prepubertal Testicular Tumors 781
Rhabdomyosarcoma Study (IRS) have been credited with
the dramatic improvement in survival from 10% in the
1960s to over 70%.35 Paratesticular rhabdomyosarcomas
are generally considered separate from other genitouri-
nary rhabdomyosarcomas because of the difference in
treatment and prognosis.34
The progenitor cell of the rhabdomyoblast is believed
to be premature striated muscle derived from embryonic
mesenchyme. The most common subtype is embryonal
rhabdomyosarcoma, which also accounts for 97% of
paratesticular cases.36 Microscopically, the cells are pri-
marily spindle shaped with abundant cytoplasm resem-
bling those of a 7- to 10-week fetus.37
Most paratesticular rhabdomyosarcoma patients
(81%) present with a scrotal mass.36 Serum markers are
used to rule out primary testicular processes. Ultrasound
is very sensitive in differentiating testicular masses from
paratesticular masses,5,11,16 and thereby increases the
probability that the scrotal lesion is a rhabdomyosar-
coma. If discrete scrotal lymphatic drainage is violated
during transscrotal surgery for rhabdomyosarcoma in
particular, a hemiscrotectomy is recommended.38
The success of chemotherapy developed during the
IRS studies I to III has resulted in RPLND no longer
being required in all cases.39 This most recent protocol
mandates that patients with localized disease receive vin-
cristine and actinomycin for 1 year, with more advanced
stages requiring actinomycin and cyclophosphamide in
longer, more intense regimes, combined with radiation
therapy. IRS-IV allowed for CT surveillance of the
retroperitoneum, and this demonstrated that children
under the age of 10 years do not require an RPLND, as
their incidence of metastatic nodal disease was signifi-
cantly less. Moreover, successful treatment with
chemotherapy was above 95%.40 However, in those boys
over the age of 10 years, there is a 50% incidence of
retroperitoneal disease, and an ipsilateral RPLND is rec-
ommended.41,42 Positive lymph node metastasis man-
dates radiation therapy, as this is associated with a
significantly worse prognosis.42
Children younger than 10 years of age have been
reported to have up to a 97% 5-year survival, while those
older than 10 years had an 84% 5-year survival.43 Overall
survival using IRS-II and IRS-I is 89% at 3 years, and 93%
for localized disease.44,45 Survivals estimated from IRS-III
and IRS-IV are 96% and 92%, respectively, the difference
not achieving statistical significance (p = 0.30).42 This suc-
cess has resulted in a secondary goal of reducing the mor-
bidity of treatment and identifying biologic characteristics
to allow a more selective treatment regimens.46
Epidermoid Cysts
This universally benign entity accounts for 2% to 10% of
childhood testicular tumors3,18,19,26,27 and are less common
782 Part VIII Pediatric Malignancies
than in the adult population. Histologically, they consist of
a cyst wall filled with keratinizing squamous epithelium,47
and their origin is thought to represent the monodermal
development of a teratoma.48,49 Epidermoid cysts are hor-
monally inactive and usually present as a smooth, firm
intratesticular mass. They have a characteristic ultrasono-
graphic appearance that is consistent with the histology: a
central hypoechoic mass with through transmission, a sur-
rounding echogenic rim, or mixed internal echogenic-
ity.50–52 However, while ultrasound can raise the index of
suspicion it cannot rule out a malignant process.
Testis conserving surgery is accepted by many urolo-
gists as the standard of care for this benign tumor.* There
have never been any reports of metastases nor associa-
tions with intratubular germ cell neoplasia. The benign
nature suggested by physical examination, serology, and
ultrasound, however, requires confirmation by frozen
section before organ sparing can be performed safely.
Gonadal Stromal Tumors
This subgroup of tumors comprises Leydig cell, Sertoli
cell, and juvenile granulosa tumors, and accounts for 8%
to 11% of pediatric testicular tumors.3,18 Although the
majority follows a benign course, reports of metastases
do exist. These tumors are unique as they are often hor-
monally active. Leydig cell tumors account for approxi-
mately 10% of cases of male precocious puberty.6
Both adult Leydig cell and Sertoli cell tumors have a
10% malignancy rate in the adult population. This
appears to be much lower in the pediatric population, but
at least 5 cases of metastatic disease have been
reported.54–56 No reliable histologic characteristics have
been identified, but invasion of the spermatic cord may
be an important prognostic finding.6 Metastatic Sertoli
cell tumor is reported to be responsive to combination
chemotherapy.56
Juvenile granulosa tumors typically present in the
neonatal period. The median age at presentation in the
latest AAP registry was 0.1 months, with a range of 0 to
6 months. The clinical behavior has been universally
benign.18
Other Pediatric Testicular Tumors
Gonadoblastoma may develop from a dysgenetic testis.
This tumor most commonly presents with virilization of a
phenotypic female, often harboring some degree of an XY
karyotype.57 The tumor usually arises from an intraab-
dominal testis and histologically resembles a seminoma.
Spread beyond the testicle has not been reported.1,4,57
Connective tissue tumors arising from the testis that
have been reported include neuroblastoma, hemangiofi-
*References 13, 33, 48, 49, 53.
broma, hamartoma, leiomyoma, and neuroectodermal
tumor. Malignant tumors include leiomyosarcoma,
fibrosarcoma, and reticular cell sarcoma.
Metastases to the Testis
Infiltration of the testis with acute lymphoblastic
leukemia (ALL) is a common cause of a prepubertal tes-
ticular mass and may be bilateral.4,26 Hematologic malig-
nancies accounted for half of testicular biopsy results in a
single institution review.19 Children with bulky ALL at
diagnosis have up to a 20% incidence of experiencing tes-
ticular metastases.58 Synchronous testicular metastases at
the time of initial ALL diagnosis are associated with a
poor prognosis.59 The testicle is the second most com-
mon site of a relapse of an extra-medullary ALL.
Moreover, Askin et al.58 found occult testicular leukemia
in 8.5% of biopsies in patients in clinical remission.
Follicular, Hodgkin’s, and Burkitt’s lymphomas can
also present in the testicle and have a favorable prognosis
if the tumor is completely intraparenchymal.60
TESTIS PRESERVING SURGERY
The high incidence of benign tumors and the ability to
exclude malignancy histologically account for the
increasing use of testis-sparing surgery in the prepuber-
tal population. First advocated by Weissbach in 1984 for
a solitary testicle,61,62 it has been advocated as the surgi-
cal procedure of choice for all potentially benign
tumors.18
The combination of negative serology, an ultrasound
that excludes a paratesticular mass, and the presence of
salvageable testicular tissue in a prepubertal patient
should invite consideration of a testicular preserving
approach. After early control of the spermatic cord, a
frozen section is obtained as a final determinant. Frozen
section is very accurate in differentiating benign from
malignant tumor, and is an essential confirmatory
step.62,63 If the presumptive diagnosis is a teratoma, suf-
ficient normal tissue should be analyzed to rule out
pubertal changes, as the latter would necessitate radical
orchiectomy. A treatment algorithm incorporating the
principal benign pathologies and position for nonradical
surgery is depicted in Figure 49-1.
SUMMARY
Testicular tumors in the prepubertal population are a dis-
tinct entity compared to their adult counterparts. There
is a predisposition towards benign tumors, while mixed
germ cell tumors are very rare. Serum HCG is not help-
ful, while an elevated AFP must be interpreted with cau-
tion in the neonate. Ultrasound is an excellent and
invaluable tool, essential for the determination of a
 Chapter 49 Prepubertal Testicular Tumors 783

History and physical consistent with painless

scrotal mass in prepubertal patient

Testicular
ultrasound

Suggests mature
Confirms or suggests teratoma, epidermoid
malignancy cyst; salvageable
parenchyma

Plan parenchymal
Paratesticular Baseline AFP sparing surgery; control
rhabdomyosarcoma serology cord, intraoperative
frozen section

Benign histology confirmed

on frozen section?
Technically salvageable
parenchyma?

NO TO YES TO
EITHER BOTH

Proceed with testis

preserving procedure:
Radical orchiectomy enucleate tumor, sample
parencymal bed as
indicated

Figure 49-1 Treatment algorithm for the prepubertal patient with a painless scrortal mass.

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Ablation
adrenal tumors with, 149
renal tumor with, 207–210, 208t
cryoablation in, 207–208, 208t
CT with, 208, 209
HIFU, 209–210
MRI with, 208, 209
radiofrequency, 208–209, 208t
ACD. See ASTRO Consensus Definition
ACTH. See Adrenocorticotrophic hormone
Acute leukemia (AL)
nongerm cell tumors of, 636
Acute lymphocytic leukemia (ALL)
nongerm cell tumors of, 636, 636f
Acute myelogenous leukemia (AML)
diagnosis of, 179, 180, 180f
Acute urinary retention (AUR)
brachytherapy with, 119
Adaptive cellular therapy
immunotherapy with, 93, 94f
LAK, 93, 94f
TIL, 93, 94f
ADCC. See Antibody-dependent cell-
mediated cytotoxicity
Adenocarcinoma of prostate
androgen deprivation therapy for,
494–502, 497f, 500t, 501t
adjuvant hormonal with radiation
therapy in, 496–498, 497f
alternative approaches with, 507–508
aminoglutethimide in, 495
antiandrogens as, 495
bicalutamide in, 495
CAB with, 505, 506, 508
cyproterone acetate in, 495
EBRT with, 494, 496–498, 499, 500,
501, 502
EORTC and, 496–497, 497f, 501, 501t,
506, 507
estrogen supplementation as, 495
flutamide in, 495
FSH in, 495, 500t
goserelin in, 495
intermittent adenocarcinoma and,
507–508
leuprolide in, 495
LH in, 495, 500t
LHRH in, 495, 496, 498, 500t,
505–507, 508, 511
medroxyprogesterone in, 495
megestrol in, 495
methods of, 494–495
Page numbers followed by f indicate figures; page numbers followed by t indicate tables.
INDEX
Adenocarcinoma of prostate (Continued)
NHT with radiation therapy in, 495–496
nilutamide in, 495
orchiectomy as, 494–495
PEP with, 506
peripheral androgen blockade and, 508
progesterone supplementation as, 495
prostatectomy with, 498–499
radiation therapy with, 495–498, 497f
rationale in, 494
RTOG and, 495–498, 499, 500, 501t,
502
secondary hormonal therapy and, 508
standards of care in, 505–506
timing of, 498, 507
toxicity with, 499
future directions for, 500–502
interstitial brachytherapy for, 483–489,
484f, 484t, 485t, 487t, 489t
BRFS following, 485–489, 485t, 487f,
489f
HDR, 488–489, 489t
historic perspective on, 483
PPB EBRT combined in, 486–488,
487t
PPB technique in, 483–484, 484f
T1-2 cancer with, 488
TPB technique in, 484–485
management of, 465–474, 466t, 468t,
469t, 471t, 472t, 473t, 494–502,
497f, 500t, 501t
general, 494
metastasis of, 505–511, 509t, 510t
bone-directed therapies for, 511
chemotherapy for, 509–511, 510t
hormone therapy for, 505–509, 509t
summary of, 511
outcomes for, 500
particle beam therapy for, 489
prognosis for, 465–474, 466t, 468t, 469t,
471t, 472t, 473t, 494–502, 497f,
500t, 501t
radiation therapy for, 477–489, 478f,
479t, 480t, 481t, 482f, 484f, 484t,
485t, 487t, 489t
ACD with, 479, 483, 485, 487–488
adjuvant hormonal with, 496–498, 497f
ADT and, 479, 480, 482–483, 486, 487,
488
androgen deprivation therapy with,
495–498, 497f
ASTRO with, 479, 481
Adenocarcinoma of prostate (Continued)
biochemical relapse-free survival with,
477, 478, 479–481, 480t, 481t, 482,
482f, 485–489, 485t, 487f, 489f
CT scan with, 478, 483, 484, 484f
CTV with, 478–479, 479f
3DCRT with, 478–479, 478f, 482, 489
dose escalation with, 481–482, 481t
EBRT historic perspective, 478
EBRT technique for, 478–479, 479f
GTV with, 478–479, 479f
HIFU with, 477
IMRT with, 478, 482
MR with, 478, 483
NHT with, 495–496
PSA levels with, 477–478, 479, 480,
481t, 482f, 485, 485f, 486–488, 487t
PTV with, 478–479, 479f
risk stratification with, 478
RTC with, 477
RTOG with, 477, 478, 482, 483, 485
T1-2 PC in, 477, 482–483
timing/duration of hormonal therapy
with, 498
radical prostatectomy for, 465–474, 466t,
468t, 469t, 471t, 472t, 473t
biopsy Gleason sum with, 471, 472f
blood loss during, 469, 469f
cancer control with, 469f, 470–473,
471f, 472f
CT scan assessment with, 466
early complications with, 468–470,
468f, 469f
erectile function after, 474
hospitalization days with, 469f
intraoperative complications with,
468–470, 468f, 469f
late complications with, 470
lymph node metastases with, 472t
mortality with, 468f
MRI assessment with, 466
obturator nerve injury from, 470
outcomes after, 469f, 470–474, 471f,
472f, 473f
patient selection for, 466
PC natural history and, 465–466, 466t
pelvic lymph node dissection with,
467–468
pretreatment risk stratification with,
466–467
PSA risk assessment with, 466–467,
470, 471f
787
788 Index
Adenocarcinoma of prostate (Continued)
PSA survival with, 469f
rectal injury from, 469
results of, 468
risk factors with, 472f, 473f
seminal vesicle involvement with, 472f
treatment rationale, 465
urinary function with, 473, 473f
urinary incontinence after, 473, 473f
regionally advanced, 494–502, 497f, 500t,
501t
androgen deprivation and
prostatectomy for, 498–499
androgen deprivation and radiation
therapy for, 494–498, 497f
androgen deprivation therapy for,
494–502, 497f, 500t, 501t
future directions for, 500–502
outcomes for, 500
prognosis for, 500
toxicity with, 499–500
urethral cancer pathology with, 674
Adenomatoid tumor of epididymis
nongerm cell tumors of, 618t, 633, 633f,
634f
Adenovirus vectors
applications of, 21–22, 21t
attributes in, 21–22, 21t
gene delivery in, 21
gene expression in, 21
gene therapy with, 21–22, 21t, 22f, 26t
vector production in, 21
ADEPT. See Antibody-dependent enzyme-
mediated cytotoxicity
Adrenal carcinoma
adrenal tumors with, 136–137, 136t
adrenocortical, 155–156
classification of, 136t
Cushing’s syndrome with, 136
DHEA with, 136
gynecomastia with, 136
Mitotane with, 136
oligospermia with, 136
Adrenal tumors
ablation for, 149
carcinoma, 136–137, 136t
classification of, 136t
Cushing’s syndrome with, 136
DHEA with, 136
gynecomastia with, 136
Mitotane with, 136
oligospermia with, 136
cryosurgery for, 149
Cushing’s syndrome and, 131, 132–133,
133t, 134f
ACTH with, 132–133
CRH with, 132–133
description of, 132, 155
diagnosis of, 132, 134f, 154t, 155
manifestations of, 133t
diagnosis of, 153–154, 154f, 154t
CT scan in, 153, 154f
Cushing’s syndrome in, 154t
hyperaldosteronism in, 154t
MRI in, 153, 154f
pheochromocytoma in, 154t
Adrenal tumors (Continued)
hyperaldosteronism in, 137–138,
137f, 138f
aldosterone secretion with, 138, 138f
CT scan for, 137f, 138
diagnosis of, 154t, 155
hypernatremia with, 137
hypertension with, 137, 137f, 154–155
hypokalemia with, 137–138, 155
PRA with, 137, 137f
RASS with, 137
secondary, 138
incidentally discovered, 133–136, 135f
CT scan in, 133–136, 135f
MRI in, 134, 135f
ultrasound in, 133
laparoscopic surgery for, 149, 150–151f,
160–167, 161f, 161t, 162f, 163f,
164f, 166t
anterior transperitoneal approach in,
161–164, 162f, 163f
approaches to, 161
complications of, 165
indications for, 160–161, 161t
left adrenalectomy in, 163–165, 163f
malignant tumors in, 167
posterior retroperitoneal approach
in, 165
postoperative care with, 165
preoperative preparation in, 161,
161f
references to, 166t
results of, 165
retroperitoneal technique in, 164, 164f
right adrenalectomy in, 161–163,
162f, 165
transthoracic technique in, 165
pheochromocytoma in, 138–139, 138f,
140t, 141f, 142t, 143f, 148f
APUD with, 139
cardiomyopathy with, 139
CT scan for, 139, 155
diagnosis of, 155
glomus jugulare tumors with, 139, 148f
identifying, 138, 138f, 154t
MEA syndromes with, 139
MIBG scan for, 139, 155
MRI scan for, 139, 141f, 143f, 148f,
155
neurofibromatosis with, 139, 140t
Sturge-Weber syndrome with, 139
surgical approach to, 155
symptoms of, 140t, 155
von Hippel-Landau with, 139, 140t
physiological understanding for,
131, 132f
arterial supply in, 132f
CT in, 131
IVC in, 131, 132f
MRI in, 131
venous drainage in, 132f
summary of, 149
surgery for, 139–149, 142t, 143f, 144f,
145f, 146f, 147f, 148f, 153–167,
154f, 154t, 157f, 158f, 159f, 160f,
161f, 161t, 162f, 163f, 164f, 166t
Adrenal tumors (Continued)
urologic oncology and, 131–151, 132f,
133t, 134f, 135f, 136t, 137f, 138f,
140t, 141f, 142t, 143f, 144f, 145f,
146f, 147f, 148f, 150f, 151f,
153–167
Adrenalectomy
adrenal tumors treated with, 139–149, 142t,
143f, 144f, 145f, 146f, 147f, 148f
approaches to, 141, 142t
Cushing’s syndrome in, 141, 142t
flank approach to, 145–147, 145f, 146f,
156–158, 157f
hyperaldosteronism in, 142t
lateral flank approach in, 156–158, 157f
left, 163–165, 163f
modified posterior approach to, 143–145,
144f, 159, 160f
nephrectomy with, 146, 146f
partial, 148–149, 148f, 167
pheochromocytoma in, 142t
posterior approach to, 142–143, 143f,
159, 159f
preoperative management with, 141, 142t
RCC with, 204–205
right, 161–163, 162f, 165
thoracoabdominal approach to, 158, 158f
transabdominal approach to, 147–148, 147f
Adrenocortical carcinoma
Cushing’s syndrome with, 155
description of, 155–156
Adrenocorticotrophic hormone (ACTH)
Cushing’s syndrome with, 132–133
ADT. See Androgen deprivation therapy
EBRT with, 482–483
PPB with, 487
radiation therapy for adenocarcinoma
with, 479, 480, 482–483, 486, 487,
488
Adult granulosa cell tumors (AGCT)
nongerm cell tumors as, 624–625, 626
AFP. See α-fetoprotein
AGCT. See Adult granulosa cell tumors
Agent Orange
retroperitoneal tumors from, 652
AgNOR. See Silver staining nucleolar
organizer regions
AGR syndrome. See Aniridia, genitourinary
malformations and mental
retardation syndrome
AIS. See Androgen insensitivity syndrome
AJCC. See American Joint Committee of
Cancer
AL. See Acute leukemia
Aldosterone secretion
hyperaldosteronism with, 138, 138f
Alkylating agents
genitourinary cancer treatment with,
67–68
ALL. See Acute lymphocytic leukemia
American Joint Committee of Cancer
(AJCC), 196, 196t, 259
bladder cancer staging with, 308, 319
PC staging with, 462, 549–461
TCC staging of, 274t
testis tumors staging with, 569, 571, 572t

American Society of Therapeutic Radiology
and Oncology (ASTRO)
radiation therapy for adenocarcinoma
with, 479, 481
Amine precursor uptake and
decarboxylation (APUD)
pheochromocytoma with, 139
Aminoglutethimide
androgen deprivation therapy with, 495
AML. See Acute myelogenous leukemia
Amyloidosis
RCC associated with, 174t
Anastomotic margin biopsy
orthotopic bladder substitution with, 444
Androgen deprivation therapy (ADT)
prostate adenocarcinoma treated with,
494–502, 497f, 500t, 501t
adjuvant hormonal with radiation
therapy in, 496–498, 497f
alternative approaches with, 507–508
aminoglutethimide in, 495
antiandrogens as, 495
bicalutamide in, 495
CAB in, 505, 506, 508
cyproterone acetate in, 495
EBRT with, 494, 496–498, 499, 500,
501, 502
EORTC and, 496–497, 497f, 501, 501t
estrogen supplementation as, 495
flutamide in, 495
FSH in, 495, 500t
goserelin in, 495
intermittent ADT in, 507–508
leuprolide in, 495
LH in, 495, 500t
LHRH in, 495, 496, 498, 500t,
505–507, 508, 511
medroxyprogesterone in, 495
megestrol in, 495
methods of, 494–495
NHT with radiation therapy in,
495–496
nilutamide in, 495
orchiectomy as, 494–495
PEP in, 506
peripheral androgen blockade and, 508
progesterone supplementation as, 495
prostatectomy with, 498–499
radiation therapy with, 495–498, 497f
rationale in, 494
RTOG and, 495–498, 499, 500, 501t,
502
secondary hormonal therapy and, 508
standards of care in, 505–506
timing/duration of, 498
timing in, 507
toxicity with, 499
seminal vesicles treatment options with,
562
Androgen insensitivity syndrome (AIS)
SCA with, 622, 624
Angiogenic factors
MVD with, 341–342
TCC with, 341–342
TSP-1 with, 341
VEGF with, 341
Aniridia, genitourinary malformations and
mental retardation syndrome
(AGR syndrome)
Wilms’ tumor with, 754, 754t, 759t
Anorexia
orthotopic bladder substitution with, 453t
Anthracycline antibiotics
genitourinary cancer treatment with, 62f,
63–64
Antiandrogens
androgen deprivation therapy with, 495
Antibody-dependent cell-mediated
cytotoxicity (ADCC)
immunotherapy with, 98t
Antibody-dependent enzyme-mediated
cytotoxicity (ADEPT)
immunotherapy with, 98t
Anticancer antibiotics
anthracycline antibiotics, 62f, 63–64
bleomycin, 61–63, 62f
doxorubicin, 62f, 63–64
mitomycin, 62f, 63
mitoxantrone, 62f, 64
Antifolates
genitourinary cancer treatment with, 70
Antimetabolites
genitourinary cancer treatment with, 70
Antioncogene therapy
gene therapy with, 30–31
APUD. See Amine precursor uptake and
decarboxylation
ASTRO. See American Society of
Therapeutic Radiology and
Oncology
ASTRO Consensus Definition (ACD)
radiation therapy for adenocarcinoma
with, 479, 483, 485, 487–488
Atraumatic urethra dissection
orthotopic bladder substitution with, 446
Bacille Calmette-Guerin (BCG)
bladder cancer treated with, 92–93
IFN and, 92
immunotherapy with, 92–93, 94f
TCC prognostic markers with, 321
TCC with, 276
Balanitis xerotica obliterans (BXO)
penis carcinoma with, 711, 712
Ball electrode
TUR instrumentation with, 359
BCG. See Bacille Calmette-Guerin
Beckwith-Wiedemann syndrome (BWS
syndrome)
Wilms’ tumor with, 754, 754t, 759t
Benchekroun nipple
urinary diversion approach of, 409
Benign lesions
ganglioneuroma as, 652t
hemangiopericytoma as, 652t
leiomyoma as, 652t, 653
lipomas as, 652–653, 652t
myelolipoma as, 652t, 653
retroperitoneal tumors with, 652–653, 652t
Schwannoma as, 652t
BEP. See Bleomycin, etoposide and cisplatin
BHD. See Birt-Hogg-Dubé
Index 789
Bicalutamide
androgen deprivation therapy
with, 495
Bilateral pelvic lymph node dissection
(BPLND)
RPP patient selection and, 528
Biochemical relapse-free survival
(BRFS)
adenocarcinoma of prostate with, 477,
478, 479–481, 480t, 481t, 482,
482f, 485–489, 485t, 487f, 489f
brachytherapy with, 485, 485t
dose escalation and, 481t, 482, 482f
EBRT with, 479–481, 480t
HDR brachytherapy with, 488–489, 489t
PPB alone with, 485–486, 485t
PPB EBRT combined with, 486–488,
487t, 489t
Birt-Hogg-Dubé (BHD)
RCC with, 176, 197t
Bladder cancer. See also Bladder preservation;
Transitional cell carcinoma
cystectomy for, 328–329, 329t
indications for, 328, 329t
partial, 329
radical, 328–329
development pathways of, 303f
dysplasia in, 303f
hyperplasia in, 303f
lymphatic permeation in, 303f
vascular permeation in, 303f
diagnosis of, 301–313, 302f, 303f, 304f
follow-up for, 329–330, 329t
genetic changes with, 304f
invasive carcinoma in, 304f
lymphatic permeation in, 304f
vascular permeation in, 304f
HRQOL with, 108–109
mucosa distant from tumor in, 320
staging of, 301, 302f, 303f, 308–313
AJCC in, 308
carcinoma in situ in, 310
dysplasia in, 312
lymph node involvement in, 311
muscle-invasive cancer in, 310–311
TNM classification in, 308, 309
statistics on, 338
TUR for
anesthesia for, 359
bimanual examination for, 359, 359f
bladder cancer diagnosis with, 306, 338
Bladder-sparing therapy with, 347–348
bladder tumors with, 358–365, 359f,
360f, 364t, 365f
complications with, 362–364
equipment for, 359–360
fluoroscopic cystoscopy for, 365
instrumentation for, 359–360
intraoperative problem management in,
361–362
irrigation fluid in, 361
laser surgery for, 364–365, 364t, 365f
postoperative management in, 362
preparation for, 358–359
primary muscle invasive tumor
treatment with, 362
790 Index

Bladder cancer (Continued) Brachytherapy Carcinoma in situ (CIS). See also Testicular
second look resection in, 362 CT-guided, 119 Intraepithelial neoplasia
TCC bladder with, 317–318 outcome of, 119 bladder cancer staging with, 310.339
TCC diagnosis with, 338 procedure for, 119 laparoscopic partial nephrectomy for, 231
technique for, 360–361 HDR, 488–489, 489t penis carcinoma with, 712–713
types of, 338 HRQOL with, 107 seminoma with, 579
Bladder explosion IGT with, 118–122, 120f, 121f Transurethral resection (TUR), 359
TUR complications with, 364 MR-guided, 114f, 115f, 119–122, 120f, Cardiomyopathy
Bladder perforation 121f pheochromocytoma with, 139
TUR complications with, 363 outcome of, 120–122 Carney’s syndrome
Bladder preservation patient selection for, 119 LCCSCT with, 623–624
5-FU, 391t procedure for, 114f, 115f, 119–120, Case histories
5-FU for, 390, 390t 120f, 121f TCC bladder, 330–331
chemotherapy for, 389, 390t TURP and, 119 CDC. See Complement-dependent
combined modality treatment for, penis carcinoma with, 705–706 cytotoxicity
389–397, 390t, 391t, 393f, 394f, prostate adenocarcinoma treated with, CDKI. See Cycle kinase inhibitor
395f, 396t, 397t 483–489, 484f, 484t, 485t, 487t, 489t Cell adhesion molecules (CAMS), 13, 13f
MCV for, 390t BRFS following, 485–489, 485t, 487f, TCC with, 341
monotherapy’s influence on, 389, 390t 489f Cell-cycle regulators
multimodal treatment schema for, 394f historic perspective on, 483 TCC prognosis with, 342–343
multimodality treatment results for, 390, PPB EBRT combined in, 486–488, 487t erb-B-2 in, 342–343
390t PPB technique in, 483–484, 484f P53 in, 342
outcome of, 395f, 396t T1-2 cancer with, 488 retinoblastoma gene in, 342
radiation therapy for, 389, 390t TPB technique in, 484–485 TGF in, 343
RTOG and, 391 radiation oncology with, 40–41, 42f Cellular biology
single agent activity in, 391, 391t ultrasound guided, 118–119 aging/telomerase in, 16
5-FL, 391t BRFS. See Biochemical relapse-free survival aptamers in, 16–17
carboplatin, 391t Bropirimine cancer genes in, 8–10
cisplatin, 391, 391t bladder TCC with, 327 DNA methylation, 9
docetaxel, 391t Bulbourethral DNA repair, 8
doxorubicin, 391t cancer in, 3, 4f oncogenes, 8
gemcitabine, 391t Buschke-Löwenstein tumor suppressor, 8
ifosfamide, 391t penis carcinoma with, 712, 723 viral, 8–9
methotrexate, 391, 391t BWS syndrome. See Beckwith-Wiedemann carcinogens in, 4–5
mitomycin C, 391t syndrome cell cycle in, 11–12, 12f
paclitaxel, 391, 391t BXO. See Balanitis xerotica obliterans cell signaling in, 12f, 14–15, 14f
vinblastine, 391t CGH in, 8
TUR for, 389, 390t, 394f CAB. See Combination androgen blockade epigenetic effects in, 3–4, 4f
TURBIT for, 390t, 392 CAH. See Congenital adrenal hyperplasia familial cancer in, 7–8
Bladder-sparing therapy CAIX. See Carbonic anhydrase IX inflammation in, 5–7, 6t
complications of, 349 Camptothecins microarrays in, 10–11
multimodality approach to, 348 genitourinary cancer treatment with, proteomics in, 10–11
outcomes of, 348–349 72–74, 73f SKY in, 8
quality of life concerns with, 349 irinotecan as, 73–74, 73f stromal epithelial interactions in, 15–16,
rationale for, 347 topotecan as, 73f, 74 15f
single modality approaches to, CAMS. See Cell adhesion molecules tumor cell heterogeneity in, 16–17, 17f
347–348 Cancer genes urologic cancers in, 3–17, 4f, 6t, 10f, 12f,
TCC with, 347–349 DNA methylation, 9 13f, 14f, 15f, 17f
TUR in, 347–348 DNA repair, 8 CGH. See Comparative genome
Bleomycin molecular biology of, 8–10 hybridization
genitourinary cancer treatment with, oncogenes, 8 Chemotherapy
61–63, 62f suppressor, 8 agents used in, 59–74, 60f, 62f, 66f, 69f,
Bleomycin, etoposide and cisplatin viral, 8–9 72f, 73f
(BEP) CAPD. See Continuous ambulatory alkylating agents as, 67–68
NSGCT treatment with, 606 peritoneal dislysis anthracycline antibiotics as, 62f, 63–64
Bone marrow transplantation Carbonic anhydrase IX (CAIX) anticancer antibiotics as, 61–64, 62f
RCC with, 265 RCC with, 176 antifolates as, 70
Bosniak classification, 182, 182t Carboplatin antimetabolites as, 70
Bosniak lesions bladder preservation with, 391t bleomycin as, 61–63, 62f
RCC diagnosis with, 181–182 genitourinary cancer treatment with, camptothecins as, 72–74, 73f
Bowenoid papulosis 60–61, 60f capecitabine as, 71
penis carcinoma with, 712 Carcinogens carboplatin as, 60–61, 60f
Bowen’s disease molecular biology of, 4–5 cisplatin as, 59–60, 60f
penis carcinoma with, 712–713 Carcinoid tumors (CT) cyclophosphamide as, 68
BPLND. See Bilateral pelvic lymph node nongerm cell tumors as, 618t, 632–633, docetaxel as, 66f, 67
dissection 633f doxorubicin as, 62f, 63–64

Chemotherapy (Continued)
epipodophyllotoxin as, 69–70, 69f
estramustine as, 67
etoposide as, 69, 69f
fluoropyrimidines as, 70–71
gemcitabine as, 71–72, 72f
ifosfamide as, 68–69
irinotecan as, 73–74, 73f
methotrexate as, 70
mitomycin as, 62f, 63
mitoxantrone as, 62f, 64
oxaliplatin as, 60f, 61
paclitaxel as, 65–67, 67f
platinum complexes as, 59–61, 60f
taxanes as, 65–67, 67f
thiotepa as, 69
topotecan as, 73f, 74
tubulin modulation drugs as, 64–65
vinca alkaloids as, 64–65
anticancer agent pharmacology of, 54–56
absorption in, 54
distribution in, 54–55
excretion in, 55–56
factors modifying, 56
metabolism in, 55
transport in, 54–55
bladder TCC with, 323–324
doxorubicin in, 324
MMC in, 323–324, 326t
thiotepa in, 323
valrubicin in, 324
drug resistance mechanisms in, 56–58, 57t
models for overcoming, 56–58, 57t
genitourinary cancer treatment with,
51–74, 57t, 59t, 60f, 62f, 66f, 69f,
72f, 73f
macro-pharmacokinetic mechanisms with,
57t
micro-pharmacokinetic mechanisms with,
57t
penis carcinoma with, 718
pharmacodynamic intracellular
mechanisms with, 57t
prostate adenocarcinoma treated with,
509–511, 510t
RMS treated with, 773–774
stage I seminoma with, 586
summary of, 74
TCC radical cystectomy with, 346–347
treatment efficacy assessment for, 58–59,
59t
classification by phase in, 59
explanatory trial in, 58
pragmatic trial in, 58–59
tumor cell biology related to, 51–54
cell cycle control in, 52–53
cell proliferation/apoptosis balance in,
53–54
cellular kinetics in, 52–53
clonality in, 54
EGF in, 51
EGFR in, 52
PC, 53
Chimeric antibodies, 97, 97f
Chromosome
TCC with abnormalities in, 340
Chronic leukemia (CL)
nongerm cell tumors of, 636
CIS. See Carcinoma in situ
CISCA. See Cisplatin, cyclophosphamide,
adriamycin
Cisplatin
bladder preservation with, 391, 391t
genitourinary cancer treatment with,
59–60, 60f
Cisplatin, cyclophosphamide, adriamycin
(CISCA)
TCC chemotherapy treatment with, 281
Cisplatin, methotrexate, vinblastine (CMV)
TCC chemotherapy treatment with, 281
Cisplatin, Velban and bleomycin (PVB)
NSGCT treatment with, 605
CL. See Chronic leukemia
Classic Sertoli cell tumors (CSCT)
nongerm cell tumors as, 622–623, 622f,
623f
pathologic characteristic of, 622–623,
622f, 623f
Clinical target volume (CTV)
brachytherapy and, 119–120
radiation oncology with, 41
radiation therapy for adenocarcinoma
with, 478–479, 479f
CMV. See Cisplatin, methotrexate,
vinblastine
Cold-cup biopsy
TUR equipment including, 360
Colonic conduits
noncontinent cutaneous urinary diversion
with, 404–406, 405f
ileocecal conduit for, 405
sigmoid colon conduit for, 406
transverse colon conduit for, 404–406,
405f
Colony-stimulating factor (CSF)
cytokine therapy with, 92, 93t
HCT with, 93
immunotherapy with, 92, 93, 93t
Combination androgen blockade (CAB)
androgen deprivation therapy with, 505,
506, 508
peripheral androgen blockade and, 508
prostate adenocarcinoma treated with,
505, 506, 508
Comparative genome hybridization
(CGH)
cancer with, 8
Complement-dependent cytotoxicity
(CDC)
immunotherapy with, 98t
Computed tomography (CT). See also
Multidetector spiral computed
tomography
bladder cancer diagnosis with, 302, 304,
306, 339
hyperaldosteronism with, 137f, 138
IGT with, 113–114, 117f, 119
incidentaloma with, 133–136, 135f
MRI v., 182, 187
NSGCT staging with, 601, 603f, 604f,
605f, 611t, 614t
partial nephrectomy for, 230–231
Index 791
Computed tomography (CT) (Continued)
PC staging with, 461
penis carcinoma with, 714
pheochromocytoma with, 139
prostatectomy assessed with, 466
radiation therapy for adenocarcinoma
with, 478, 483, 484, 484f
radical nephrectomy with, 218
RCC staging with, 186–188, 186f
renal diagnosing with, 179–182, 180f,
181f, 182f, 197
renal tumor ablation with, 208, 209
retroperitoneal tumors diagnosis of,
657–658, 657f
RMS evaluation with, 767–768
RPLND with, 642, 647, 647f
seminal vesicles treatment options with,
558, 563f
squamous cell carcinoma of penis with,
696
TCC diagnosis with, 271–272
testis tumors staging with, 569–571
Wilms’ tumor evaluation with, 756,
756f, 758f
Conditionally replication-competent
oncolytic adenovirus (CRAd), 30
Condyloma acuminatum
penis carcinoma with, 712
Congenital adrenal hyperplasia (CAH)
Leydig cell tumors v., 621, 621f
Continent mechanism
appendiceal approach to, 409
Benchekroun nipple approach to, 409
cutaneous urinary diversion with,
409–411, 410f
flap valve approach to, 409
four surgical techniques for, 409
hydraulic valve approach to, 409
intussuscepted nipple valve approach to,
409
pseudoappendiceal approach to, 409
Continent reservoirs
cutaneous urinary diversion with,
411–427, 412f, 413f, 414f, 415f,
416f, 417f, 418–420f, 421f, 422f,
422t, 423–424t, 425f, 426f, 427f,
428f, 436–437
Duke pouch, 422t, 424t
Florida pouch, 422t, 424t
gastric pouch, 424t, 426–427, 427f, 428f,
436–437
Indiana pouch, 416–421, 422t, 423–424t,
425f, 436
Kock pouch, 411–413, 412f, 413f, 423t,
436
LeBag, 422t
Mainz pouch, 414–416, 418–420f, 423t,
436
Penn pouch, 424t, 426, 426f
T pouch, 413–414, 414f, 415f, 416f,
417f, 423t
U. Miami pouch, 424t
UCLA pouch, 422t, 423t
Continuous ambulatory peritoneal dislysis
(CAPD)
RCC with, 174
792 Index
Core Quality of Life Questionnaire
(QLQ-C30)
cutaneous urinary diversion influence in,
437–438, 438t
HRQOL measured with, 105
Corticotropin-releasing hormone (CRH)
Cushing’s syndrome with, 132–133
CRAd. See Conditionally replication-
competent oncolytic adenovirus
CRH. See Corticotropin-releasing hormone
Cryoablation
renal tumor ablation with, 207–208, 208t
Cryosurgery
adrenal tumors with, 149
Cryotherapy
ED with, 118
IGT with, 117–118, 118f
MR image of, 118f
outcomes of, 118
procedure of, 118
Cryptorchid testes
seminoma with, 591
CSCT. See Classic Sertoli cell tumors
CSF. See Colony-stimulating factor
CT. See Carcinoid tumors; Computed
tomography
CT-guided brachytherapy (CTBT)
IGT with, 117
CTBT. See CT-guided brachytherapy
CTV. See Clinical target volume
Cushing’s syndrome
ACTH with, 132–133
adrenal carcinoma with, 136
adrenal tumors and, 131, 132–133, 133t,
134f
adrenalectomy for, 141, 142t
CRH with, 132–133
description of, 132, 155
diagnosis of, 132, 134f, 154t, 155
LCCSCT with, 623
manifestations of, 133t
Cutaneous horn
penis carcinoma with, 712
Cutaneous pyelostomy
noncontinent cutaneous urinary diversion
with, 400, 401f
technique for, 400, 401f
Cutaneous ureterostomy
noncontinent cutaneous urinary diversion
with, 400–401, 402f
technique for, 401, 402f
Cutaneous urinary diversion
complications with, 430–437, 433t, 435t
continent, 406–427, 407f, 408f, 409f,
410f, 412f, 413f, 414f, 415f, 416f,
417f, 418f, 419f, 420f, 421f, 422f,
422t, 423–424t, 425f, 426f, 427f
surgical technique for, 406
continent catheterizable urinary
diversions for, 407–409
continent mechanism in, 409–411, 410f
continent reservoirs for, 411–427, 412f,
413f, 414f, 415f, 416f, 417f,
418–420f, 421f, 422f, 422t,
423–424t, 425f, 426f, 427f, 428f,
436–437
Cutaneous urinary diversion (Continued)
Duke pouch, 422t, 424t
Florida pouch, 422t, 424t
gastric pouch, 424t, 426–427, 427f,
428f, 436–437
ileocecal, 411–416, 412f, 413f, 414f,
415f, 416f, 417f, 418–420f, 421f,
422f, 422t, 423–424t
Indiana pouch, 416–421, 422t,
423–424t, 425f, 436
Kock pouch, 411–413, 412f, 413f, 423t,
436
LeBag, 422t
Mainz pouch, 414–416, 418–420f, 423t,
436
Penn pouch, 424t, 426, 426f
right colon, 416–427, 422t, 423–424t,
425f, 426f, 427f, 428f, 436–437
T pouch, 413–414, 414f, 415f, 416f,
417f, 423t
U. Miami pouch, 424t
UCLA pouch, 422t, 423t
continent v. noncontinent, 399
intraoperative pouch testing for, 411
laparoscopic ileal conduit for, 438, 439t
nasogastric tube for, 400
noncontinent, 400–406, 401f, 402f, 403f,
404f, 405f
colocolostomy in, 405f
colonic conduits for, 404–406, 405f
cutaneous pyelostomy for, 400, 401f
cutaneous ureterostomy for, 400–401,
402f
ileal conduit for, 401–403, 403f, 404f
ileocecal conduit for, 405
jejunal conduit for, 404
rectus fascia incision in, 404f
renal pelvis incision in, 401f
sigmoid colon conduit for, 406
technique, 400, 401, 401f, 402f, 403,
403f, 404f, 405, 405f, 406
transverse colon conduit for, 404–406,
405f
novel techniques for, 438–439, 439t
postoperative care for, 400
preoperative preparation for, 399–400
quality of life with, 437–438, 438t
rectal bladder urinary diversion for,
406–407, 407f, 408f
ureterointestinal anastomoses with,
427–430, 429f, 430f, 431f
Cycle kinase inhibitor (CDKI), 9, 11
Cyclophosphamide
genitourinary cancer treatment with,
68
Cyclosporine (CSA)
HCT with, 93
Cyproterone acetate
androgen deprivation therapy with,
495
Cystectomy. See also Partial cystectomy;
Radical cystectomy
orthotopic bladder substitution with,
445–446, 445f, 446f, 453f
TCC bladder with, 328–329, 329t
indications for, 328, 329t
Cystectomy (Continued)
partial, 329
radical, 328–329
urethrectomy with, 680
Cystogram
orthotopic bladder substitution
with, 449
Cystoprostatectomy
urethrectomy with, 686–688, 687f, 688f,
689f, 690f, 691f, 692f, 693f
pelvic dissection in, 686, 687, 687f,
688f
perineal dissection in, 687–688, 689f,
690f, 691f, 692f, 693f
Cytokine therapy
CSF with, 92, 93, 93t
IFN with, 88–89, 89t, 90t, 91–92, 92f
IL2 with, 88–89, 89t, 90t, 91, 91f, 92, 92f
immunotherapy with, 88–92, 89t, 90t,
91f, 92f
intravesical interferon therapy with, 92
MHC with, 88, 89t
RCC with, 88, 89–92, 90t
superficial bladder cancer treated with, 92
Cytology
TCC prognostic factors with, 320–321
DNA ploidy in, 321
urine in, 320–321
Cytoreductive nephrectomy, 247–248
Denonvilliers’ fascia
Radical cystectomy with, 279f, 377, 378f,
380, 380f
radical prostatectomy incision of, 521f
RRP incision in, 529
wide-field dissection RRP with, 530
Denys-Drash syndrome
Wilms’ tumor with, 753, 758, 759t
DHEA
adrenal carcinoma with, 136
Digital rectal exam (DRE)
PC staging with, 549
RPP patient selection with, 529
US-guided prostate biopsy with, 122
Dioxin
retroperitoneal tumors from, 652
Direct ureterointestinal anstomoses,
427–430, 429f
DLI. See Donor T-cells
Docetaxel
bladder preservation with, 391t
genitourinary cancer treatment with, 66f,
67
Donor T-cells (DLI)
HCT with, 96f
Dorsal venous complex
radical prostatectomy with, 516–519,
518f, 519f, 520f, 521f
Dose volume histograms (DVH)
brachytherapy and, 120
radiation oncology with, 42, 42f
Doxorubicin
bladder preservation with, 391t
bladder TCC with, 324
genitourinary cancer treatment with, 62f,
63–64

DRE. See Digital rectal exam
Duke pouch
complications with, 435t
continent colon pouches compared to, 422t
continent reservoirs compared to, 424t
reoperation rate with, 435t
urinary diversion with, 422t, 424t, 435t
DVH. See Dose volume histograms
Dyspepsia
orthotopic bladder substitution with, 453t
Dysplasia
urethral cancer pathology with, 673–674
Eastern Cooperative Oncology Group patient
performance status (ECOG PS)
RCC staging with, 186–187, 186t,
260–261
EBRT. See External beam radiation therapy
ECE. See Extracapsular extension
ECM. See Extracellular matrix
ECOG PS. See Eastern Cooperative
Oncology Group patient
performance status
ED. See Erectile dysfunction
EGCT. See Extragonadal germ cell tumors
EGF. See Epidermal growth factor
EGFR. See Epidermal growth factor receptor
18-fluoro-2-d3oxyglucose (FDG)
bladder cancer diagnosis with, 306, 339
RCC diagnosis with, 183, 188–189
Endopelvic fascia
radical prostatectomy incision of,
515–516, 517f, 518f
EORTC. See European Organization for
Research and Treatment of Cancer
EPIC. See Expanded Prostate Cancer Index-
Composite
Epidermal growth factor (EGF)
tumor cell biology and, 51
Epidermal growth factor receptor (EGFR)
tumor cell biology and, 52
Epidermoid cysts
nongerm cell tumors of, 618t, 627–628,
627f, 628f
testicular tumors in pediatrics, 781–782
Epigenetic effects
HAT in, 3–4
HDAC in, 4
methylation in, 4
RNAi in, 4
urologic cancers with, 3–4, 4f
Epipodophyllotoxin
genitourinary cancer treatment with,
69–70, 69f
Erb-B-2
TCC prognosis with, 342–343
Erectile dysfunction (ED)
cryotherapy with, 118
Erythrocytosis
RCC associated with, 174t
Erythroplasia of Queyrat
penis carcinoma with, 710–711
Estramustine
chemotherapy with, 67
Estrogen supplementation
androgen deprivation therapy with, 495
Etoposide
genitourinary cancer treatment with, 69, 69f
European Organization for Research and
Treatment of Cancer (EORTC)
androgen deprivation therapy and,
496–497, 497f, 501, 501t, 506, 507
HRQOL measured with, 105
Expanded Prostate Cancer
Index-Composite (EPIC)
HRQOL measured with, 105
External beam radiation therapy (EBRT)
ADT and, 479, 480, 482–483, 486, 487,
488
androgen deprivation therapy for, 494,
496–498, 499, 500, 501, 502
BRFS through, 479–482, 480t, 481t
CT scan with, 478, 483, 484, 484f
3DCRT with, 478–479, 478f, 482, 489
dose escalation with, 481–482, 481t
HCT with, 95t
historic perspective of, 478, 478f
HRQOL with, 107, 108, 108t
IMRT with, 478
interstitial brachytherapy with, 483–489,
484f, 484t, 485t, 487t, 489t
BRFS following, 485
historic perspective on, 483
PPB technique in, 483–484, 484f,
486–488, 487t
TPB technique in, 484–485
MR with, 478, 483
penis carcinoma with, 704, 705t
prostate adenocarcinoma treated with,
477–489, 478f, 479t, 480t, 481t,
482f, 484f, 484t, 485t, 487t, 489t
PSA levels with, 486–488, 487t
radiation oncology with, 39–40, 40f
RMS treated with, 773–774
seminal vesicles treatment options with,
558, 560f
T1-2 PC in, 477, 482–483
technique of, 478–479, 479t
CTV with, 478–479, 479t
GTV with, 478–479, 479t
PTV with, 478–479, 479t
Extracapsular extension (ECE)
IGT influence on, 117
PC staging with, 461
Extracellular matrix (ECM), 11, 12f, 13f
Extragonadal germ cell tumors (EGCT)
seminoma with, 591
Extramustine
genitourinary cancer treatment with, 67
FACT. See Functional Assessment of Cancer
Therapy
Familial renal oncocytoma
RCC with, 176–177
Fatigue
orthotopic bladder substitution with, 453t
FDA. See Food and Drug Administration
FDG. See 18-fluoro-2-d3oxyglucose
FDP. See Fibrin gradation products
α-fetoprotein (AFP)
nongerm cell tumors with, 617, 626
serum tumor markers of, 568, 596, 598
Index 793
Fibrin gradation products (FDP)
bladder cancer diagnosis with, 305
Fibrosarcoma
malignant lesions of, 653t, 656
Fine needle aspiration (FNA)
RCC with, 197–198
FISH. See Fluorescent in situ
hybridization
5-fluorouracil (5-FU)
Bladder preservation with, 391t
5-FU. See 5-fluorouracil
Flap valve
urinary diversion approach of, 409
Flexible cystoscope
TUR equipment including, 360
Florida pouch
complications with, 435t
continent colon pouches compared to,
422t
continent reservoirs compared to, 424t
reoperation rate with, 435t
urinary diversion with, 422t, 424t, 435t
Fluorescent in situ hybridization (FISH)
bladder cancer diagnosis with, 305
TCC prognostic markers with, 321
Fluoropyrimidines
genitourinary cancer treatment with,
70–71
Fluoroscopic cystoscopy
TUR with, 365
Flutamide
androgen deprivation therapy with, 495
Focused ultrasound surgery (FUS)
IGT with, 114, 116, 122
Follicle stimulating hormone (FSH)
androgen deprivation therapy for, 495,
500t
Food and Drug Administration (FDA)
IL-2 approval by, 88
valrubicin approval by, 324
Fossa navicularis cancer, 675, 677t
FSH. See Follicle stimulating hormone
Functional Assessment of Cancer Therapy
(FACT)
cutaneous urinary diversion influence in,
438t
HRQOL measured with, 105
G-CSF. See Granulocyte colony-stimulating
factor
Ganglioneuroma
benign lesions of, 652t
Gastric pouch
complications with, 436–437
continent reservoirs compared to, 424t
urinary diversion with, 424t, 426–427,
427f, 428f, 436–437
Gastrointestinal anastomosis (GIA)
LRN with, 247, 249f
GCT. See Testis tumors
Gemcitabine
bladder preservation with, 391t
Gene therapy
adenovirus vectors for, 21–22, 21t, 22f, 26t
antioncogene therapy for, 30–31, 31f
antisense construct approach to, 30–31
794 Index
Gene therapy (Continued)
emerging vectors for, 25
future directions in, 33–34, 33f
gene transfer vectors for, 18–19
liposomal gene transfer for, 21t, 24–25,
24f, 25f, 26t
modified vector tropism in, 33–34
molecular targets of, 25–33, 26t, 27f,
31f, 32f
direct induction of, 26t, 29–30
immunogene therapy (ex vivo) in,
25–28, 26t, 27f
immunogene therapy (in vivo) in, 23f,
26t, 28–29
nonviral vectors for, 21t, 24–25, 24f,
25f, 26t
oncolytic virotherapy for, 30
other delivery systems for, 25
poxvirus vectors for, 21t, 22–24, 23f, 26t
restricted transgene expression in, 34
retrovirus vectors for, 19–21, 19f, 20f,
21t, 26t
ribozyme construct approach to, 30–31, 31f
summary of, 34
target cell death with, 26t, 29–30
targeting vector specificity in, 33–34, 33f
transcriptional targeting in, 34
tumor suppressor gene restoration in,
31–33, 32f
urologic cancers treated with, 18–34, 19f,
20f, 21t, 22f, 23f, 24f, 25f, 26t, 27f,
31f, 32f, 33f
Genitourinary cancer
agents used against, 59–74, 60f, 62f, 66f,
69f, 72f, 73f
alkylating agents as, 67–68
anthracycline antibiotics as, 62f, 63–64
anticancer antibiotics as, 61–64, 62f
antifolates as, 70
antimetabolites as, 70
bleomycin as, 61–63, 62f
camptothecins as, 72–74, 73f
capecitabine as, 71
carboplatin as, 60–61, 60f
cisplatin as, 59–60, 60f
cyclophosphamide as, 68
docetaxel as, 66f, 67
doxorubicin as, 62f, 63–64
epipodophyllotoxin as, 69–70, 69f
estramustine as, 67
etoposide as, 69, 69f
fluoropyrimidines as, 70–71
gemcitabine as, 71–72, 72f
ifosfamide as, 68–69
irinotecan as, 73–74, 73f
methotrexate as, 70
mitomycin as, 62f, 63
mitoxantrone as, 62f, 64
oxaliplatin as, 60f, 61
paclitaxel as, 65–67, 67f
platinum complexes as, 59–61, 60f
taxanes as, 65–67, 67f
thiotepa as, 69
topotecan as, 73f, 74
tubulin modulation drugs as, 64–65
vinca alkaloids as, 64–65
Genitourinary cancer (Continued)
anticancer agent pharmacology for, 54–56
absorption in, 54
distribution in, 54–55
excretion in, 55–56
factors modifying, 56
metabolism in, 55
transport in, 54–55
chemotherapy principles for, 51–74, 57t,
59t, 60f, 62f, 66f, 69f, 72f, 73f
drug resistance mechanisms with, 56–58, 57t
models for overcoming, 56–58, 57t
macro-pharmacokinetic mechanisms
with, 57t
micro-pharmacokinetic mechanisms
with, 57t
pharmacodynamic intracellular
mechanisms with, 57t
summary of, 74
treatment efficacy assessment for, 58–59,
59t
classification by phase in, 59
explanatory trial in, 58
pragmatic trial in, 58–59
tumor cell biology and, 51–54
cell cycle control in, 52–53
cell proliferation/apoptosis balance in,
53–54
cellular kinetics in, 52–53
clonality in, 54
EGF in, 51
EGFR in, 52
PC, 53
Gerota’s fascia
radical nephrectomy with, 224f, 226, 239
GF. See Growth factor
GIA. See Gastrointestinal anastomosis
Giant condyloma acuminatum
penis carcinoma with, 712
Gleason score
radical prostatectomy with, 471, 472f
seminal vesicles diagnosis of, 556, 556t, 564f
Glomus jugulare tumors
pheochromocytoma with, 139, 148f
Glucose transporter (GLUT-1)
RCC with, 176
GLUT-1. See Glucose transporter
Glutathione (GSH), 57
TCC prognosis with, 343
Glutathione-S-transferase pi (GSTPi)
inflammation with, 5–6, 6t
GM-CSF. See Granulocyte-macrophage
colony-stimulating factor
Gonadal stromal tumors, 782
Gonadoblastoma, 782
Goserelin
androgen deprivation therapy with, 495
Graft-versus-host disease (GVHD)
HCT with, 93, 95–96, 97
Graft-versus-leukemia (GVL)
HCT with, 93
Graft-versus-tumor (GVT)
HCT with, 93, 96f, 97
Granulocyte colony-stimulating factor
(G-CSF)
cytokine therapy with, 92
Granulocyte colony-stimulating factor
(Continued)
HCT with, 93
immunotherapy with, 92, 93
Granulocyte-macrophage colony-
stimulating factor (GM-CSF)
cytokine therapy with, 92, 93t
HCT with, 93
immunotherapy with, 92, 93, 93t, 264
Granulosa cell tumors
clinical presentation of, 624–625
evaluation of, 626
management of, 626
nongerm cell tumors as, 618t, 624–626,
625f, 626f
pathologic characteristic of, 625–626,
625f, 626f
Gross tumor volume (GTV)
radiation oncology with, 41
radiation therapy for adenocarcinoma
with, 478–479, 479f
Growth factor (GF), 12–14, 12f, 13f
GSH. See Glutathione
GSTPi. See Glutathione-S-transferase pi
GTV. See Gross tumor volume
GVHD. See Graft-versus-host disease
GVL. See Graft-versus-leukemia
GVT. See Graft-versus-tumor
Gynecomastia
adrenal carcinoma with, 136
HA. See Hyaluronic acid
HA stimulating activity (HASA)
Wilms’ tumor pathology with, 761
HAL. See Hand-assisted laparoscopy
HAMA. See Human antimouse antibody
Hand-assisted laparoscopy (HAL)
LRN with, 199
HASA. See HA stimulating activity
HAT. See Histone acetyl transferases
HCG. See Human chorionic
gonadotropin
HCT. See Hematopoietic cell
transplantation
HDAC. See Histone deacetylation
HDR techniques. See High-dose rate
techniques
Health-related quality of life (HRQOL)
brachytherapy influencing, 107
cutaneous urinary diversion with,
437–438, 438t
EBRT influencing, 107, 108, 108t
established instruments for, 104–105
cancer-specific, 105
EORTC as, 105
EPIC as, 105
FACT as, 105
general, 104–105
NHP as, 104
QLQ-C30 as, 105
QWB as, 104
SF-36 as, 104
SIP as, 104
UCLA PCI as, 105
urologic malignancy specific, 105
IB influencing, 107–108, 108t

Health-related quality of life (Continued)
instrument methodology for, 102–104,
103t, 104t
IPSS measuring, 107
RP v. WW in, 107
specific urologic malignancies with,
105–109, 108t
bladder cancer in, 108–109
kidney cancer in, 109
prostate cancer in, 105–108, 108t
testicular cancer in, 109
summary of, 109
urologic oncology issues with, 102–109,
103t, 104t, 108t
Hemangiopericytoma
benign lesions of, 652t
malignant lesions of, 653t, 657
Hematologic tumors
nongerm cell tumors of, 618t, 633–636, 635f
Hematopoietic cell transplantation (HCT)
CSA and, 93
CSF and, 93
DLI with, 96f
GVHD with, 93, 95–96, 97
GVL with, 93
GVT with, 93, 96f, 97
immunotherapy with, 93–97, 95t, 96f
myeloablative condition in, 95, 95t, 96f
RCC treated with, 95–97, 96f
T-cells with, 93, 96, 96f
XRT conditioning for, 95t
Hemorrhage
TUR complications with, 362–363
Hereditary leiomyomatosis renal carcinoma
(HLRC)
RCC with, 177
Hereditary papillary renal carcinoma (HPRC)
RCC with, 176, 197t
Hereditary prostate cancer (HPC), 7
HIF. See Hypoxia-inducible factor
HIFU. See High-intensity focused ultrasound
High-dose rate (HDR) techniques
prostate adenocarcinoma treated with,
488–489, 489t
radiation oncology with, 41
High-intensity focused ultrasound (HIFU)
radiation therapy for adenocarcinoma
with, 477
renal tumor ablation with, 209–210
High performance liquid chromatography
(HPLC), 66
High telomerase reverse transcriptase
(hTERT)
Wilms’ tumor pathology with, 780
Histone acetyl transferases (HAT)
epigenetic effects with, 3–4
Histone deacetylation (HDAC)
epigenetic effects with, 4
HIV. See Human immunodeficiency virus
HLRC. See Hereditary leiomyomatosis
renal carcinoma
Hormone-refractory PC (HRPC), 57
Hormone therapy. See Androgen
deprivation therapy
Horner’s syndrome
neuroblastoma with, 742, 748
Horseshoe kidney
seminoma with, 592
HPC. See Hereditary prostate cancer
HPLC. See High performance liquid
chromatography
HPRC. See Hereditary papillary renal
carcinoma
HPV. See Human papillomavirus
HRPC. See Hormone-refractory PC
hTERT. See High telomerase reverse
transcriptase
Human antimouse antibody (HAMA)
immunotherapy with, 97–98, 98t
Human chorionic gonadotropin (HCG)
serum tumor markers of, 568, 597, 599
Human immunodeficiency virus (HIV)
seminoma patients with, 592
testis tumors and, 637
Human papillomavirus (HPV)
penis carcinoma with, 711
squamous cell carcinoma of penis with,
695–696, 710
Humanized antibodies, 97
Hyaluronic acid (HA)
Wilms’ tumor pathology with, 761
Hydraulic valve
urinary diversion approach of, 409
Hyperaldosteronism
adrenal tumors with, 137–138, 137f,
138f
adrenalectomy for, 142t
aldosterone secretion with, 138, 138f
CT scan for, 137f, 138
diagnosis of, 154t
hypernatremia with, 137
hypertension with, 137, 137f
hypokalemia with, 137–138
PRA with, 137, 137f
RASS with, 137
secondary, 138
Hypercalcemia
RCC associated with, 174t
Hyperchloremic metabolic acidosis
cutaneous urinary diversion with, 433t
Hyperkalemia
cutaneous urinary diversion with, 433t
Hypernatremia, 137
Hypertension
hyperaldosteronism with, 137, 137f
RCC associated with, 174t
Hypochloremic metabolic acidosis
cutaneous urinary diversion with, 433t
Hypokalemia
cutaneous urinary diversion with, 433t
hyperaldosteronism with, 137–138
Hypoxia-inducible factor (HIF)
RCC with, 176
IB. See Interstitial brachytherapy
IBD. See Inflammatory bowel disease
ICU. See Intensive care unit
IFN. See Interferon
Ifosfamide
bladder preservation with, 391t
genitourinary cancer treatment with,
68–69
Index 795
IGCCCG. See International Germ Cell
Cancer Collaborative
IGT. See Image-guided therapy
IL-2. See Interleukin-2
Ileal conduit
noncontinent cutaneous urinary diversion
with, 401–403, 403f, 404f
technique for, 403, 403f, 404f
Ileal segment resection
orthotopic bladder substitution with, 446,
447f, 448f
Ileocecal conduit
noncontinent cutaneous urinary diversion
with, 405
ILNR. See Intralobar nephrogenic rest
Image-guided therapy (IGT)
brachytherapy with, 118–122, 120f,
121f
CT-guided, 119
MR-guided, 114f, 115f, 119–122, 120f,
121f
ultrasound guided, 118–119
cryotherapy for, 117–118, 118f
ED with, 118
MR image of, 118f
outcomes of, 118
procedure of, 118
CT in, 113–114, 117f, 119
CTBT with, 117
current applications overview of,
115–116, 115f
diagnosis in, 122–123
ECE minimized with, 117
FUS in, 114, 116, 122
history of, 113–114, 114f
image processing role of, 116, 117f
minimal invasiveness of, 113–125, 114f,
115f, 117f, 118f, 120f, 121f, 123f,
124f
MR-guided prostate biopsy in, 123–124,
123f, 124f
procedure for, 123–124
MRBT with, 117
MRI in, 113–125, 114f, 115f, 117f, 118f,
120f, 121f, 123f, 124f
MRT in, 114, 115
rapid growth in, 113
summary of, 124–125
surgery focused ultrasound in, 122
outcome of, 122
procedure for, 122
prostate cancer with, 122
therapy/image integration with, 116
TRUS in, 114, 117, 118, 122
US-guided prostate biopsy in,
122–123
DRE with, 122
procedure for, 122–123
ImmunoCyt
bladder cancer diagnosis with, 305
Immunogene therapy
ex vivo, 25–28, 26t, 27f
gene therapy with, 23f, 25–29, 26t, 27f
in vivo, 23f, 26t, 28–29
Immunosuppression
patients seminoma with, 590
796 Index
Immunotherapy
adaptive cellular therapy as, 93, 94f
LAK, 93, 94f
TIL, 93, 94f
basic guidelines for, 88–98, 89t, 90t, 91f,
92f, 93t, 94f, 95t, 96f, 97f, 98t
BCG as, 92–93, 94f, 324–326, 326t
bladder TCC with, 324–326, 326t
CIS with, 325, 326t
prophylaxis with, 325–326
bladder TCC with, 324–327
bropirimine in, 327
cytokine therapy in, 88–92, 89t, 90t, 91f,
92f
CSF with, 92, 93t
IFN with, 88–89, 89t, 90t, 91–92, 92f
IL2 with, 88–89, 89t, 90t, 91, 91f,
92, 92f
intravesical interferon therapy
with, 92
MHC with, 88, 89t
RCC with, 88, 89–92, 90t
superficial bladder cancer treated
with, 92
HAMA in, 97–98, 98t
HCT as, 93–97, 95t, 96f
CSA and, 93
CSF and, 93
DLI with, 96f
GVHD with, 93, 95–96, 97
GVL with, 93
GVT with, 93, 96f, 97
myeloablative condition in, 95, 95t, 96f
RCC treated with, 95–97, 96f
T-cells with, 93, 96, 96f
XRT conditioning for, 95t
IFN in, 326
KLH in, 326–327
monoclonal antibodies in, 97–98,
97f, 98t
IMRT. See Intensity modulated radiation
therapy
Incidentaloma
adrenal tumors as, 133–136, 135f
CT scan in, 133–136, 135f
MRI in, 134, 135f
ultrasound in, 133
Indiana pouch
complications with, 435t, 436
continent reservoirs compared to, 423t
reoperation rate with, 435t
technique for, 420–421, 422t, 425f
urinary diversion with, 416–421, 422t,
423–424t, 425f, 435t, 436
Inferior vena cava (IVC)
adrenal anatomy with, 131, 132f
RCC involvement with, 261
tumor thrombus with, 203–204, 203t,
204f, 227f, 228f, 229, 229f
Inflammation
GSTPi in, 5–6, 6t
molecular biology of, 5–7, 6t
PIN in, 5
ROS in, 5–6
Inflammatory bowel disease (IBD)
seminoma with, 590
Intensity modulated radiation therapy
(IMRT)
radiation oncology with, 42–43, 42f, 43f
radiation therapy for adenocarcinoma
with, 478
retroperitoneal tumors with, 664
Intensive care unit (ICU)
radical cystectomy with, 384
Interferon (IFN)
background of, 88–89, 89t
bladder TCC treated with, 326
immunotherapy with, 88–89, 89t, 90t,
91–92, 92f
intravesical interferon therapy with, 92
RCC treatment with, 89, 90t, 91–92,
263
superficial bladder cancer treated with, 92
systemic therapy with, 263
Interleukin-2 (IL-2)
background of, 88–89, 89t
FDA approval of, 88, 263
immunotherapy with, 88–89, 89t, 90t, 91,
91f, 92, 92f
RCC treatment with, 88, 89, 90t, 91–92,
263–264
systemic therapy with, 263–264
International Germ Cell Cancer
Collaborative (IGCCCG)
NSGCT treatment and, 606, 611t, 615
testis tumors staging of, 571, 573t
International Prostate Symptom Score
(IPSS)
HRQOL with, 107
Interstitial brachytherapy (IB)
HRQOL with, 107–108, 108t
Intralobar nephrogenic rest (ILNR)
Wilms’ tumor pathology with, 758–759,
758f
Intraoperative radiation therapy (IORT)
retroperitoneal tumors with, 664
Intraperitoneal rupture
cutaneous urinary diversion with, 434
Intravenous pyelogram (IVP)
bladder Cancer diagnosis with, 302
RCC diagnosing with, 178, 178f, 197
upper urinary tract TCC with, 287
Intravesical interferon therapy
superficial bladder cancer treated with, 92
Intravesical therapy
bladder TCC with, 322–327, 322t,
326t
chemotherapy for, 323–324
doxorubicin in, 324
MMC in, 323–324, 326t
thiotepa in, 323
valrubicin in, 324
combination therapy, 327
immunotherapy for, 324–327
BCG in, 324–326, 326t
bropirimine in, 327
IFN in, 326
KLH in, 326–327
rationale for, 322–323, 322t
recommendations in, 327
Intussuscepted nipple valve
urinary diversion approach of, 409
Ionizing radiation (IR)
apoptosis in, 45–46
cellular repair response in, 44
cellular target interacts with, 43–44
cycle and, 45
DNA damage accumulation with, 44, 45
DNA repair following, 45
induced cell death with, 45–46
necrosis in, 45–46
normal tissue protection in, 44–45
OER in, 43
PLDR in, 44
radiation oncology with, 43–46
radiation sensitizers for, 44
radioprotector agents in, 44–45
ROS with, 43–44
SLDR in, 44
therapeutic ratio in, 44, 45
tumor cell interactions with, 43
tumoricidal effect enhancement in, 44
IORT. See Intraoperative radiation
therapy
IPSS. See International Prostate Symptom
Score
IR. See Ionizing radiation
Irinotecan
genitourinary cancer treatment with,
73–74, 73f
IVC. See Inferior vena cava
IVP. See Intravenous pyelogram
Jackson staging system
penis carcinoma with, 714, 715t
Penis SCC with, 701t, 702
Jejunal conduit
noncontinent cutaneous urinary diversion
with, 404
JGCT. See Juvenile granulosa cell tumors
Juvenile granulosa cell tumors (JGCT)
nongerm cell tumors as, 625, 625f, 626
Keyhole-limpet hemocyanin (KLH)
bladder TCC with, 326–327
Kidney cancer
HRQOL with, 109
KLH. See Keyhole-limpet hemocyanin
Klinefelter’s syndrome
LCT with, 619
Kock pouch
complications with, 435t, 436
continent reservoirs compared to, 423t
reoperation rate with, 435t
technique for, 411–413, 412f, 413f
urinary diversion with, 411–413, 412f,
413f, 423t, 435t, 436
L-(methyl)-11C-methionine (LCM)
bladder cancer diagnosis with, 306
Lactate dehydrogenase (LDH)
serum tumor markers of, 568, 597, 599
LAK. See Lymphokine-activated killer cells
Laparoscopic adrenalectomy
adrenal tumors with, 149, 150–151f
Laparoscopic ileal conduit
cutaneous urinary diversion with, 438,
439t

Laparoscopic nephroureterectomy
TCC with, 278–279
Laparoscopic partial nephrectomy
complications of, 252–283
contraindications for, 249
financial analysis of, 283
indications for, 249
renal hypothermia with
Endocatch II bag in, 250, 254f
renal parenchymal repair in, 253f
results of, 250–252, 255t
technique for, 249–250, 250t, 251f, 252f,
253f
bulldog clamp in, 251f
methylene blue injection in, 252f
Satinsky clamp in, 251f
Laparoscopic radical nephrectomy (LRN)
approach selection for, 237–238
complications of, 241, 243t, 244t
concomitant adrenalectomy with,
245–246
contra-indications for, 237
cytoreductive, 247–248
financial implications of, 248
follow-up for, 246t
indications for, 237
larger renal tumors with, 245, 247t
oncologic outcome of, 244–245
ORN v., 201–203, 202t, 247t
blood loss in, 202t
convalescence time in, 202t, 247t
mean tumor size in, 247t
morcellation in, 202–203
oncologic adequacy in, 201–202
operating room time in, 202t, 247t
postoperative complications in, 247t
RCC with, 199–203, 202t, 237–248, 238f,
239f, 240f, 241f, 242t, 243t, 244t,
245f, 246t, 247t, 248t, 249f
renal vein involvement with, 246–247,
248t, 249f
results of, 241, 242t
specimen extraction with, 241–244, 245f
female, 244, 245f
male, 244
technique for, 200–201, 238–240, 238f,
239f, 240f, 241f
balloon dilation in, 240f
clip-applier in, 239f
GIA stapler in, 247, 249f
HAL, 201
retroperitoneal, 200–201, 239–240,
240f, 241f
transperitoneal, 200, 238–239, 238f,
239f
three approaches to, 199
HAL, 199
retroperitoneal, 199
transperitoneal, 199
Laparoscopic renal hypothermia, 250,
254f
Large cell calcifying Sertoli cell tumors
(LCCSCT)
Carney’s syndrome with, 623–624
Cushing’s syndrome with, 623
nongerm cell tumors as, 622, 623–624
Large cell calcifying Sertoli cell tumors
(LCCSCT) (Continued)
pathologic characteristic of, 623–624,
625f
Peutz-Jeghers syndrome with, 623
Laser surgery
advantages/disadvantages with, 364–365
bladder tumor recurrence rate with, 365
techniques of, 364
TUR with, 364–365, 364t, 365f
types of
CO2, 364t
diode, 364t
Ho:Yag, 364, 364t
KTP, 364, 364t
Nd:Yag, 364, 364t, 365, 365f
Laser therapy
penis with, 704–705, 705t
complications in, 705
effectiveness with, 705, 705t
surgical technique in, 704–705
LCCSCT. See Large cell calcifying Sertoli
cell tumors
LCM. See L-(methyl)-11C-methionine
LCT. See Leydig cell tumors
LDH. See Lactate dehydrogenase
LeBag
continent colon pouches compared to, 422t
urinary diversion with, 422t
Leiomyoma
benign lesions of, 652t, 653
Leiomyosarcoma
malignant lesions of, 653t, 654–655
Leukemia
nongerm cell tumors of, 618t, 636, 636f
Leuprolide
androgen deprivation therapy with, 495
Leydig cell tumors (LCT)
CAH v., 621, 621f
clinical presentation of, 618–619
evaluation of, 621–622
Klinefelter’s syndrome with, 619
management of, 621–622
nongerm cell tumors of, 618–622, 618f,
618t, 619f, 620f, 621f
pathologic characteristics of, 619–621,
620f
Reinke’s crystals in, 619, 621
LH. See Luteinizing hormone
LHRH. See Luteinizing hormone releasing
hormone
Lichen sclerosis et atrophicus (LSA)
Penis carcinoma with, 710
Lipomas
benign lesions of, 652–653, 652t
Liposarcoma
malignant lesions of, 653–654, 653t, 654f,
655f
Liposomal gene transfer
applications of, 21t, 25
attributes in, 21t, 25
gene delivery in, 24–25, 24f, 25f
gene expression in, 25
gene therapy with, 21t, 24–25, 24f, 25f,
26t
vector production in, 24
Index 797
LRN. See Laparoscopic radical nephrectomy
LSA. See Lichen sclerosis et atrophicus
Luteinizing hormone (LH)
androgen deprivation therapy for, 495,
500t
Luteinizing hormone releasing hormone
(LHRH)
androgen deprivation therapy with, 495,
496, 498, 500t, 505–507, 508, 511
seminal vesicles treatment options with,
560f
Lymph nodes
bladder cancer staging with, 311
radical prostatectomy with, 472f
RCC involvement with, 261
TCC staging with, 274t
testis tumors staging of, 571, 572t
Lymphadenectomy
avoiding complications with, 730–731
classic inguinal type, 732
considerations in, 730
modified inguinal type, 729f, 731–732,
732f
pelvic
radical cystectomy with, 373–374, 375f,
376f
penectomy and, 728, 729f,
730–732, 732f
radical nephrectomy with, 222
radical prostatectomy with, 515
RCC with, 205–206, 205f
TCC radical cystectomy with, 345–346
technique of, 728f, 729f, 731
Lymphangiogram
testis tumors staging with, 570
Lymphokine-activated killer cells (LAK)
immunotherapy with, 93, 94f
Macrophage scavenger receptor (MSR-1)
prostate cancer, 5, 6t
Magnetic resonance (MR), 113
Mainz pouch
complications with, 435t, 436
continent reservoirs compared to, 423t
reoperation rate with, 435t
technique for, 414–416, 418–420f
urinary diversion with, 414–416,
418–420f, 423t, 435t, 436
Malignant fibrous histiocytoma (MFH)
malignant lesions of, 652, 653t, 655–656,
656f
Malignant lesions
fibrosarcoma as, 653t, 656
leiomyosarcoma as, 653t, 654–655
liposarcoma as, 653–654, 653t, 654f, 655f
malignant fibrous histiocytoma as, 653t,
655–656, 656f
malignant hemangiopericytoma as,
653t, 657
retroperitoneal tumors with, 653–657,
653t, 654f, 655f, 656f
rhabdomyosarcoma as, 653t, 656–657
Malignant lymphoma (ML)
clinical presentation of, 633–634
evaluation of, 634–636
management of, 634–636
798 Index
Malignant lymphoma (ML) (Continued)
nongerm cell tumors of, 618t,
633–636, 635f
pathologic characteristics of, 634, 635f
Malignant mesothelioma (MM)
clinical presentation of, 629–630, 630f
evaluation of, 631
management of, 631
nongerm cell tumors of, 629–631,
630f, 631f
pathologic characteristics of,
630–631, 631f
Massachusetts General Hospital (MGH),
392, 393
MDCT. See Multidetector spiral computed
tomography
MDR. See Multidrug resistance
MEA syndrome. See Multiendocrine
adenopathy syndrome
Medroxyprogesterone
androgen deprivation therapy with, 495
Megestrol
androgen deprivation therapy
with, 495
Metabolic acidosis
orthotopic bladder substitution with, 450,
453t
Metaiodobenzylguanidine (MIBG)
pheochromocytoma scanned for, 139, 155
Metaplasia
urethral cancer pathology with, 673
Metastatic tumors
nongerm cell tumors as, 618t, 631–632,
632f
Methotrexate
bladder preservation with, 391, 391t
genitourinary cancer treatment with, 70
Methotrexate, vinblastine, adriamycin,
cyclophosphamide (MVAC)
TCC chemotherapy treatment with, 281
TCC prognosis with, 343
Methylation
epigenetic effects with, 4
MFH. See Malignant fibrous histiocytoma
MGH. See Massachusetts General Hospital
MIBG. See Metaiodobenzylguanidine
Microvessel density (MVD)
RCC with, 175
TCC prognosis with, 341–342
Mitomycin C (MMC)
bladder preservation with, 391t
bladder TCC with, 323–324, 326t
genitourinary cancer treatment with,
62f, 63
Mitotane
adrenal carcinoma with, 136
Mitoxantrone
genitourinary cancer treatment with, 62f,
64
ML. See Malignant lymphoma
MM. See Malignant mesothelioma
MMC. See Mitomycin C
Mohs’ micrographic surgery for, 704, 723
complications in, 704
effectiveness of, 704
fixed tissue technique in, 704
Mohs’ micrographic surgery for, (Continued) MR imaging (MRI) (Continued)
fresh tissue technique in, 704 renal tumor ablation with, 208, 209
technique in, 704 retroperitoneal tumors diagnosis with,
Molecular biology 658
aging/telomerase in, 16 RMS evaluation with, 772–774
aptamers in, 16–17 Seminal vesicles diagnosis with, 557
cancer genes in, 8–10 squamous cell carcinoma of penis, 696
DNA methylation, 9 TCC diagnosis with, 271–272
DNA repair, 8 temperature sensitivity of, 116
oncogenes, 8 Wilms’ tumor evaluation with, 756
suppressor, 8 MR therapy (MRT)
viral, 8–9 IGT with, 114, 115
carcinogens in, 4–5 MRBT. See MR-guided brachytherapy
cell cycle in, 11–12, 12f MRI. See MR imaging
cell signaling in, 12f, 14–15, 14f MRT. See MR therapy
CGH in, 8 MSR-1. See Macrophage scavenger receptor
epigenetic effects in, 3–4, 4f Multidetector spiral computed tomography
familial cancer in, 7–8 (MDCT)
inflammation in, 5–7, 6t renal diagnosing with, 179
microarrays in, 10–11 Multidrug resistance (MDR)
proteomics in, 10–11 TCC prognosis with, 343
SKY in, 8 Multiendocrine adenopathy syndrome
stromal epithelial interactions in, (MEA syndrome)
15–16, 15f pheochromocytoma with, 139
tumor cell heterogeneity in, 16–17, 17f MVAC. See Methotrexate, vinblastine,
urologic cancers in, 3–17, 4f, 6t, 10f, 12f, adriamycin, cyclophosphamide
13f, 14f, 15f, 17f MVD. See Microvessel density
Monoclonal antibodies Myeloablative condition
immunotherapy with, 97–98, 97f, 98t HCT with, 95, 95t, 96f
Montsouris technique Myelolipoma
laparoscopic radical prostatectomy with, benign lesions of, 652t, 653
537
Morcellation NAD. See Nicotinamide-adenine
ORN v. LRN with, 202–203 dinucleotide
MR. See Magnetic resonance National Bladder Cancer Collaborative
MR-guided brachytherapy (MRBT) Group, 303
IGT with, 114f, 115f, 117, 119–122, 120f, National Wilms’ Tumor Study Group
121f (NWTSG), 753, 756, 758,
outcome of, 120–122 762–764
patient selection for, 119 Nausea
procedure for, 114f, 115f, 119–120, 120f, orthotopic bladder substitution with, 453t
121f Nephrectomy
TURP and, 119 adrenalectomy with, 146, 146f
MR imaging (MRI) cytoreductive, 247–248
bladder cancer diagnosis with, 302, 304, laparoscopic partial
306–307, 339 complications of, 252–283
CT v., 182, 187 contraindications for, 249
current applications overview of, financial analysis of, 283
115–116, 115f indications for, 249
FUS guided by, 116 renal hypothermia with, 250, 254f
history of, 113–114, 114f renal parenchymal repair in, 253f
IGT with, 113–125, 114f, 115f, 117f, results of, 250–252, 255t
118f, 120f, 121f, 123f, 124f technique for, 249–250, 250t, 251f,
incidentaloma with, 134, 135f 252f, 253f
laser therapy with, 116 laparoscopic radical
NSGCT staging with, 600 approach selection for, 237–238
PC staging with, 461 complications of, 241, 243t, 244t
penis carcinoma with, 714–717 concomitant adrenalectomy with,
pheochromocytoma with, 139, 141f, 143f, 245–246
148f contra-indications for, 237
prostatectomy assessed with, 466 financial implications of, 248
radiation therapy for adenocarcinoma follow-up for, 246t
with, 478, 483 indications for, 237
radical nephrectomy with, 218 larger renal tumors with, 245, 247t
RCC diagnosing with, 182, 183f, 197 oncologic outcome of, 244–245
RCC staging with, 186f, 187–188 ORN v., 201–203, 202t, 247t

Nephrectomy (Continued)
RCC with, 199–203, 202t, 237–248,
238f, 239f, 240f, 241f, 242t, 243t,
244t, 245f, 246t, 247t, 248t, 249f
renal vein involvement with, 246–247,
248t, 249f
results of, 241, 242t
specimen extraction with, 241–244,
245f
technique for, 200–201, 238–240, 238f,
239f, 240f, 241f
three approaches to, 199
open radical, 198–199, 199f, 201–203, 202t
hilar vessel division in, 199f
technique for, 198–199, 199f
ORN v. LRN, 201–203, 202t
blood loss in, 202t
convalescence time in, 202t
morcellation in, 202–203
oncologic adequacy in, 201–202
operating room time in, 202t
partial, 230–235, 233f, 234f
AML with, 235
CT for, 230–231
segmental polar, 232, 233f
simple enucleation, 235
in situ, 231
transverse resection, 234–235, 234f
wedge resection, 232–234, 234f
radical laparoscopic
HAL, 199
ORN v., 201–203, 202t
RCC with, 199–203, 202t
retroperitoneal, 199, 200–201
technique for, 200–201
three approaches to, 199
transperitoneal, 199, 200
radical type, 218–230, 219f, 220f, 221f,
222f, 223f, 224f, 225f, 226f, 227f,
228f, 229f, 230t
anterior subcostal transperitoneal
incision in, 220, 220f, 221f
bilateral subcostal incision in, 220
CT scan for, 218
diaphragmatic incision in, 220
evaluation for, 218–219
Gerota’s fascia in, 224f, 226, 239
indications for, 218–219
IVC with, 222–226, 227f, 228f
left side, 220–222, 224f, 225f
lymphadenectomy with, 222
MRI for, 218
renal vein in, 224f
right side, 222, 225f
ring retractor with, 224f
suprahepatic vena cava with, 226–230,
228f, 229f
surgical anatomy with, 219, 219f
surgical incisions in, 219–220, 220f,
221f, 222f
TEE for, 218
thoracoabdominal approach in, 220,
222f, 223f
thrombectomy with, 227f
RCC with, 206–207
advanced disease with, 206
Nephrectomy (Continued)
partial version of, 206–207
surgical margin in, 207
technique in, 207
Nephroblastoma. See Wilms’ tumor
Nephroureterectomy
laparoscopic, 278–279, 280t
laparoscopic v. open, 280t
open, 277–278, 280t
TCC with, 277–279, 280t
Nerve preservation
orthotopic bladder substitution with,
445–446, 445f, 446f
Nesbit technique
orthotopic bladder substitution with, 449f
Neuroblastoma
classification of, 741–742
diagnostic evaluation of, 743–744, 743t,
744f, 745f
etiology of, 739–740
future considerations with, 751–752
Horner’s syndrome with, 742, 748
incidence of, 740
pathology of, 740–742, 740f, 741f, 742f
presentation of, 742–743
prognostic considerations with, 744, 747t
staging of, 744, 746t
treatment for, 744–750
Neurofibromatosis
pheochromocytoma with, 139, 140t
Neuromyopathy
RCC associated with, 174t
Neuron-specific enolase (NSE)
serum tumor markers of, 568
Wilms’ tumor pathology with, 761
Neurovascular bundles
laparoscopic radical prostatectomy
dissection of, 538
radical prostatectomy with separation of,
519, 521f
NHP. See Nottingham health profile
NHT with radiation therapy in
androgen deprivation therapy for, 495–496
Nicotinamide-adenine dinucleotide
(NAD), 11
Nilutamide
androgen deprivation therapy with, 495
NMP-22. See Nuclear matrix protein
Nongerm cell tumors
acquired immunodeficiency syndrome
with, 637
adenomatoid tumor of epididymis as,
618t, 633, 633f, 634f
carcinoid tumors of, 618t, 632–633, 633f
epidermoid cysts as, 618t, 627–628, 627f,
628f
generalized stroma tumors of, 636–637
granulosa cell tumors as, 618t, 624–626,
625f, 626f
clinical presentation of, 624–625
evaluation of, 626
management of, 626
pathologic characteristic of, 625–626,
625f, 626f
hematologic tumors of, 618t, 633–636, 635f
HIV and, 637
Index 799
Nongerm cell tumors (Continued)
leukemia as, 618t, 636, 636f
Leydig cell tumors as, 618–622, 618f,
618t, 619f, 620f, 621f
CAH v., 621, 621f
clinical presentation of, 618–619
evaluation of, 621–622
Klinefelter’s syndrome with, 619
management of, 621–622
pathologic characteristics of, 619–621,
620f
Reinke’s crystals in, 619, 621
malignant lymphoma as, 618t, 633–636,
635f
clinical presentation of, 633–634
evaluation of, 634–636
management of, 634–636
pathologic characteristics of, 634, 635f
malignant mesothelioma as, 629–631,
630f, 631f
clinical presentation of, 629–630, 630f
evaluation of, 631
management of, 631
pathologic characteristics of, 630–631,
631f
metastatic tumors of, 618t, 631–632, 632f
miscellaneous tumors of, 627–636, 627f,
628f, 629f, 630f, 631f, 632f, 633f,
634f, 635f, 636f
mixed sex cord/gonadal stromal tumors
as, 626–637, 627f, 628f, 629f, 630f,
631f, 632f, 633f, 634f, 635f, 636f
ovarian surface epithelial type tumors
of, 637
plasmacytoma as, 618t, 636, 636f
Rete testis carcinoma as, 628–629, 629f
clinical presentation of, 628
evaluation of, 628–629
management of, 628–629
pathologic characteristics of, 628, 629f
Sertoli cell tumors as, 618t, 622–624,
622f, 623f, 624f, 625f
clinical presentation of, 622
evaluation of, 624
management of, 624
pathologic characteristics of, 622–624,
622f, 623f, 624f, 625f
sex cord/stromal origin with, 618–626,
618f, 618t, 619f, 620f, 621f, 622f,
623f, 624f, 625f, 626f
testis tumors as, 617–637, 618f, 618t,
619f, 620f, 621f, 622f, 623f, 624f,
625f, 626f, 627f, 628f, 629f, 630f,
631f, 632f, 633f, 634f, 635f, 636f
Nonseminomatous germ cell tumors
(NSGCT)
clinical staging of, 598–600, 601f, 602f,
603f, 604f, 604t, 605t
CT scan for, 600, 602f, 603f, 604f,
610t, 613t
designations in, 600, 604t, 605t
imaging studies for, 600, 601f, 602f,
603f, 604f
MRI for, 600
PET scan for, 600
serum markers for, 598
800 Index
Nonseminomatous germ cell tumors
(NSGCT) (Continued)
diagnosis of, 597, 598f, 599f, 600f
ultrasound for, 597, 598f, 599f, 600f
pathology of, 598–600, 600t
AJCC classifications of, 599, 604
radical v. partial orchiectomy for, 598
serum tumor markers of, 568
AFP, 568, 597, 599
HCG, 568, 597, 599
LDH, 568, 597, 599
NSE, 568
NSGCT, 568
PLAP, 568, 597
summary of, 615
treatment by stage for, 607f, 608–615,
609f, 610f, 612f, 613f, 614t
stage I, 609–611, 612f, 613f
stage IIA/IIB, 611–615, 612f,
614t
stage IIC/III, 607, 609f, 610f, 612f,
613f, 615
treatment tools for, 601–608, 607f, 608f,
609f, 610f, 611t
adjuvant chemotherapy as, 606
BEP as, 606
high-stage disease with chemotherapy
as, 606–607
IGCCCG with, 606, 611t, 615
observation as, 601, 611t
postchemotherapy RPLND as,
604–606, 607f
primary RPLND as, 601–604, 607f,
608f, 609f, 610f, 611t
primary shot course chemotherapy as,
606
PVB as, 606
salvage chemotherapy as, 607–608
second-line chemotherapy as, 607–608
Nonviral vectors
applications of, 21t, 25
attributes in, 21t, 25
gene delivery in, 24–25, 24f, 25f
gene expression in, 25
gene therapy with, 21t, 24–25, 24f, 25f,
26t
vector production in, 24
Nottingham health profile (NHP)
HRQOL measured with, 104
NSE. See Neuron-specific enolase
NSGCT. See Nonseminomatous germ cell
tumors
Nuclear matrix protein (NMP-22)
bladder cancer diagnosis with, 305
Obturator nerve reflex
TUR complications with, 363
OER. See Oxygen enhancement ratio
Oligospermia
adrenal carcinoma with, 136
Oncocytoma
familial renal, 176–177
RCC mimicked by, 181f
RCC risk factor of, 196t
Oncologic adaquacy
ORN v. LRN with, 201–202
Oncolytic virotherapy
gene therapy with, 30
Open nephroureterectomy
TCC with, 277–278
Open radical nephrectomy (ORN)
LRN v., 201–203, 202t
blood loss in, 202t
convalescence time in, 202t
mean tumor size in, 247t
morcellation in, 202–203
oncologic adequacy in, 201–202
operating room time in, 202t
postoperative complications in, 247t
RCC with, 198–199, 199f, 201–203, 202t,
247t
Orchiectomy
androgen deprivation therapy with,
494–495
ORN. See Open radical nephrectomy
Orthotopic bladder substitution
long-term follow-up for, 452–454, 454t
blood tests in, 454t
body weight in, 454t
bone scan in, 454t
chest x-ray in, 454t
clinical examination in, 454t
CT scan in, 454t
folic acid in, 454t
IVU in, 454t
postvoid residual in, 454t
renal ultrasound in, 454t
urethral wash cytology in, 454t
urine culture in, 454t
males/females with, 443–454, 445f, 446f,
447f, 448f, 449f, 450f, 451f, 452f,
453f, 453t, 454t
operative technique for, 444–448, 445f,
446f, 447f, 448f, 449f, 450f, 451f,
452f, 453f
atraumatic urethra dissection as, 446
bipolar electrocautery in, 446
bladder construction as, 447–448, 450f,
451f, 453f
cystectomy as, 445–446, 445f, 446f,
453f
ileal segment resection as, 446, 447f,
448f
mesenteric window close in, 448f
nerve preservation in, 445–446, 445f,
446f
Nesbit technique in, 449f
orthotopic ileal bladder substitute as,
446, 447f, 448f
U-shaped distal ileum in, 450f
ureteroileal anastomosis as, 446–447,
449f, 450f
ureters in, 446
urethral anastomosis as, 447–448, 450f,
451f, 453f
patient assessment for, 443–444
postoperative management for, 448–452,
453t
anorexia in, 453t
cystogram for, 449
dyspepsia in, 453t
fatigue in, 453t
Orthotopic bladder substitution (Continued)
heartburn in, 453t
Laplace’s law in, 450
late period, 449–450
metabolic acidosis in, 450, 453t
metabolic acidosis symptoms in, 453t
metabolic management in, 450–452,
453t
nausea in, 453t
sitting in, 449
ultrasound in, 449
vomiting in, 453t
weight loss in, 453t
preoperative patient selection for,
443–444
anastomotic margin biopsy in, 444
bowel function in, 444
compliance in, 443
continence in, 444
general preparation for, 444
hepatic function in, 444
mental capacity in, 443
renal function in, 443–444
urethral recurrence in, 444
Oxaliplatin
genitourinary cancer treatment with,
60f, 61
Oxygen enhancement ratio (OER), 43
P53 gene
TCC prognosis with, 342
Paclitaxel
bladder preservation with, 391, 391t
genitourinary cancer treatment with,
65–67, 67f
Papillary transitional cell carcinoma
urethral cancer pathology with, 674
Papillary urothelial neoplasms of low
malignant potential (PUNLMP)
TCC staging with, 274
Parastomal hernias
cutaneous urinary diversion with, 431
Paratesticular tumors
retroperitoneal tumors with, 667
Partial cystectomy, 368–369
Particle beam therapy
prostate adenocarcinoma treated with,
489
PC. See Prostate cancer
PCNA. See Proliferating cell nuclear
antigen
PCSM. See Prostate cancer-specific
mortality
PDGF. See Platelet-derived growth factor
Pediatric testicular tumors, 780–785
Penectomy
partial penis, 703, 723–725, 724f
complications in, 703
impact of, 704
results in, 703
surgical technique in, 703
total penis, 703–704, 725–726, 725f
complications in, 704
impact of, 704
surgical technique in, 703
Penile urethra cancer, 675, 677t

Penis
brachytherapy for, 705–706
external beam radiation for, 706, 707t
inguinal node management with,
706–707, 707f
invasive carcinoma of, 710–718, 715t, 716t
Buschke-Löwenstein tumor in, 712,
723
laser therapy for, 704–705, 705t
complications in, 705
lymphadenectomy for, 728f, 729f,
730–732, 732f
Mohs’ micrographic surgery for, 704, 723
partial penectomy for, 703
radiation therapy for, 705
SCC of, 695–697, 697t, 699–701, 701t,
702, 702t
summary of carcinoma of, 707
superficial carcinoma of, 699–707, 700f,
701t, 702t, 705t, 706t, 707f, 707t
superficial SCC of, 702–703
surgical procedures for, 723–732, 724f,
725f, 726f, 727f, 728f, 729f, 732f
total penectomy for, 703–704
complications in, 704
impact of, 704
surgical technique in, 703
Penn pouch
complications with, 435t
continent reservoirs compared to, 424t
reoperation rate with, 435t
urinary diversion with, 424t, 426, 426f, 435t
PEP. See Polyestradiol phosphate
Percutaneous needle aspiration cytology
RCC diagnosis with, 189, 189t
Perilobar nephrogenic rest (PLNR)
Wilms’ tumor pathology with, 758–759,
758f
Permanent prostate brachytherapy (PPB)
prostate adenocarcinoma treated with,
483–484, 484f, 486–488, 487t
PET. See Positron emission tomography
Peutz-Jeghers syndrome
LCCSCT with, 623
Pharmacology of anticancer agents
absorption in, 54
distribution in, 54–55
drug resistance mechanisms with, 56–58,
57t
models for overcoming, 56–58, 57t
excretion in, 55–56
factors modifying, 56
genitourinary cancer and, 54–56
macro-pharmacokinetic mechanisms
with, 57t
metabolism in, 55
micro-pharmacokinetic mechanisms
with, 57t
pharmacodynamic intracellular
mechanisms with, 57t
transport in, 54–55
Pheochromocytoma
adrenal tumors with, 138–139, 138f, 140t,
141f, 142t, 143f, 148f
adrenalectomy for, 142t
APUD with, 139
Index 801
Pheochromocytoma Prostate cancer (PC)
cardiomyopathy with, 139 cell proliferation/apoptosis balance in, 53
CT scan for, 139 detection of, 460f, 461f, 462f, 463f,
glomus jugulare tumors with, 139, 148f 549–463
identifying, 138, 138f, 154t GSTPi in, 5–6, 6t
MEA syndromes with, 139 HPC and, 7
MIBG scan for, 139, 155 HRQOL with, 105–108, 108t
MRI scan for, 139, 141f, 143f, 148f brachytherapy influencing, 107
neurofibromatosis with, 139, 140t EBRT influencing, 107, 108, 108t
Sturge-Weber syndrome with, 139 IB influencing, 107–108, 108t
symptoms of, 140t IPSS measuring, 107
von Hippel-Landau with, 139, 140t RP v. WW in, 107
PIN. See Prostatic interepithelial neoplasia inflammation with, 5–7, 6t
Placental alkaline phosphatase (PLAP) localized, 547–552
serum tumor markers of, 568, 597 operative complication with, 548–449
Planning target volume (PTV) patient selection with, 548
radiation oncology with, 41, 42f postoperative complication with,
radiation therapy for adenocarcinoma 449–552
with, 478–479, 479f surgical approaches to, 547–548
PLAP. See Placental alkaline phosphatase MR-guided biopsy for, 123–124, 123f,
Plasma renin activity (PRA) 124f
hyperaldosteronism with, 137, 137f procedure in, 123–124
Plasmacytoma MRBT for, 120f
nongerm cell tumors of, 618t, 636, 636f MSR-1 in, 5, 6t
Platelet-derived growth factor (PDGF), 9 natural history of, 465–466, 466t
Platinum complexes PIN in, 5
carboplatin, 60–61, 60f RNASEL in, 5, 6t
cisplatin, 59–60, 60f ROS in, 5–6
genitourinary cancer treatment with, staging of, 460f, 461f, 462f, 463f, 549–463
59–61, 60f AJCC system for, 462, 549–461
oxaliplatin, 60f, 61 combined modality, 460f, 461f,
PLDR. See Potentially lethal damage repair 549–461
PLNR. See Perilobar nephrogenic rest CT scan in, 461
Polyestradiol phosphate (PEP) DRE with, 549
androgen deprivation therapy with, 506 ECE in, 461
Positron emission tomography (PET) MRI in, 461
bladder cancer diagnosis with, 305, 307, PCSM with, 460f, 461f, 462, 463, 549
339 pretreatment nomograms in, 263f,
FDG with, 183, 188–189, 339 461–262
NSGCT staging with, 600 prognostic factors in, 460f, 461f, 462f,
RCC diagnosing with, 178, 182–183, 463f, 549–463
188–189, 197 PSA in, 460f, 461f, 462f, 463f,
testis tumors staging with, 570 549–463
Potentially lethal damage repair (PLDR), 44 radiologic, 461, 462f
Pouchitis RT with, 460f, 461f, 462f, 463, 463f,
cutaneous urinary diversion with, 434 549
Poxvirus vectors summary for, 262
applications of, 21t, 23–24 SVI in, 461
attributes in, 21t, 23–24 TRUS in, 461
gene delivery in, 23 TURP with, 549
gene expression in, 23 surgery focused ultrasound for, 122
gene therapy with, 21t, 22–24, 23f, 26t outcome of, 122
vector production in, 19f, 22–23 procedure for, 122
PPB. See Permanent prostate brachytherapy surgical treatment complications with,
PRA. See Plasma renin activity 547–552
Prepubertal testicular tumours, 780–785 bladder neck contracture, 549
Pretreatment nomograms early postoperative, 549
PC staging with, 263f, 461–262 erectile dysfunction, 451–452
Progesterone supplementation late postoperative, 549–452
androgen deprivation therapy with, 495 operative, 547–549
Proliferating cell nuclear antigen (PCNA) postoperative, 549–452
RCC with, 175 quality of life as, 452
Prostate cancer (PC). See also urinary incontinence, 450–451
Adenocarcinoma of prostate US-guided biopsy for, 122–123
bulbourethral v., 3, 4f DRE with, 122
burnt meat and, 5 procedure for, 122–123
802 Index
Prostate cancer-specific mortality (PCSM)
PC staging with, 460f, 461f, 462, 463, 549
Prostate-specific antigen (PSA)
external beam radiation therapy with,
460f, 461f
PC staging with, 460f, 461f, 462f, 463f,
549–463
pretreatment nomogram for, 463f
radiation therapy for adenocarcinoma
with, 477–478, 479, 480, 481t,
482f, 485, 485f, 486–488
radical prostatectomy with, 462f
RPP patient selection with, 528
seminal vesicles diagnosis of, 555–558,
556t, 557t, 561, 562, 564f
Prostate-specific membrane antigen (PSMA)
immunotherapy with, 98
Prostatic interepithelial neoplasia (PIN)
prostate cancer with, 5
Prostatic pedicles
laparoscopic radical prostatectomy
dissection of, 538
radical prostatectomy with transection/
control of, 519–522, 522f
Prostatic urethra
CIS only, 328f
cystoprostatectomy for, 328f
ductal, 328f
intravesical therapy for, 328f
stromal invasion, 328f
TCC in, 327–328, 328f
Prostatic urethral cancer, 675–676, 677t
PSA. See Prostate-specific antigen
PSMA. See Prostate-specific membrane
antigen
Psoralen and ultraviolet A (PUVA)
penis carcinoma photochemotherapy
with, 709, 711
PTV. See Planning target volume
Puboprostatic ligaments
radical prostatectomy incision of,
515–516, 517f
PUNLMP. See Papillary urothelial
neoplasms of low malignant
potential
PUVA. See Psoralen and ultraviolet A
PVB. See Cisplatin, Velban and bleomycin
PVB as
NSGCT treatment with, 606
QLQ-C30. See Core Quality of Life
Questionnaire
Quality of well-being scale (QWB)
HRQOL measured with, 104
QWB. See Quality of well-being scale
Radiation oncology
applications of, 39–48, 40f, 41f, 42f, 43f,
47t
brachytherapy in, 40–41, 42f
clinical practice of, 46–47, 47t
acute/chronic radiation sequelae in, 47
adjuvant RT in, 46
definitive RT in, 46
palliative RT in, 46
RT in, 46–47
Radiation oncology
CTV in, 41
DVH in, 42, 42f
EBRT in, 39–40, 40f
GTV in, 41
HDR techniques for, 41
IMRT in, 42–43, 42f, 43f
ionizing radiation in, 41–46
apoptosis in, 45–46
cellular repair response in, 44
cellular target interacts with, 43–44
cycle and, 45
DNA damage accumulation with,
44, 45
DNA repair following, 45
induced cell death with, 45–46
necrosis in, 45–46
normal tissue protection in, 44–45
OER in, 43
PLDR in, 44
radiation oncology with, 43–46
radiation sensitizers for, 44
radioprotector agents in, 44–45
ROS with, 43–44
SLDR in, 44
therapeutic ratio in, 44, 45
tumor cell interactions with, 43
physics of, 39–41, 40f, 41f
principles of, 39–48, 40f, 41f, 42f, 43f, 47t
PTV in, 41, 42f
summary of, 47–48
treatment planning/delivery for, 41–43,
42f, 43f
Radiation sensitizers, 44
Radiation Therapy Oncology Group
(RTOG)
androgen deprivation therapy and,
495–498, 499, 500, 501t, 502
bladder preservation and, 391, 391t
radiation therapy for adenocarcinoma
with, 477, 478, 482, 483, 485
Radiation therapy (RT). See also
Brachytherapy
males urethral cancer with, 680
PC staging with, 460f, 461f, 462f, 463,
463f, 549
penis carcinoma with, 705, 718
prostate adenocarcinoma treated with,
477–489, 478f, 479t, 480t, 481t,
482f, 484f, 484t, 485t, 487t, 489t
ACD with, 479, 483, 485, 487–488
adjuvant hormonal with, 496–498, 497f
ADT and, 479, 480, 482–483, 486, 487,
488
androgen deprivation therapy with,
495–498, 497f
ASTRO with, 479, 481
biochemical relapse-free survival with,
477, 478, 479–481, 480t, 481t, 482,
482f, 485–489, 485t, 487f, 489f
CT scan with, 478, 483, 484, 484f
CTV with, 478–479, 479f
3DCRT with, 478–479, 478f, 482, 489
dose escalation with, 481–482, 481t
EBRT historic perspective, 478
EBRT technique for, 478–479, 479f
Radiation therapy (RT) (Continued)
GTV with, 478–479, 479f
HIFU with, 477
IMRT with, 478, 482
MR with, 478, 483
NHT with, 495–496
PSA levels in, 486–488, 487t
PSA with, 477–478, 479, 480, 481t,
482f, 485, 485f, 486–488
PTV with, 478–479, 479f
risk stratification with, 478
RTC with, 477
RTOG with, 477, 478, 482, 483, 485
T1-2 PC in, 477, 482–483
timing/duration of hormonal therapy
with, 498
retroperitoneal tumors with, 664
RMS treated with, 773–774
seminal vesicles treatment options with,
557–558, 557t
stage I seminoma with, 587–588
Radical cystectomy
abdominal exploration in, 370
adjuvant v. neoadjuvant, 346–347
bladder treated with, 368, 369–387, 370f,
371f, 372f, 373f, 375f, 376f, 377f,
378f, 379f, 380f, 381f, 382f, 383f,
384f, 385f, 386f
bowel mobilization in, 370–372, 372f,
373f
chemotherapy with, 346–347
complications of, 346
Denonvilliers’ fascia in, 279f, 377, 378f,
380, 380f
discussion of, 385–387
dorsal venous complex in, 380, 381f, 382f
female patient anterior dissection in,
382–384, 383f, 384f, 385f, 386f
female pelvic sagittal section in, 386f
females with, 345
gauze sponge withdrawing in, 376f
ICU for, 384
iliac artery skeletonizing in, 375f
incision in, 370, 371f
lateral vascular pedicle ligation in,
374–375, 377f
lymphadenectomy with, 345–346
male patient anterior dissection in,
378–382, 381f, 382f
males with, 344–345
outcomes of, 346
overhead pelvic view in, 372f, 373f
overview of, 343–344
patient positioning in, 370, 370f
pelvic lymphadenectomy with, 373–374,
375f, 376f
peritoneum incision in, 378f
posterior pedicle ligation in, 375–378,
378f, 379f, 380f
postoperative care for, 384–385
preoperative evaluation for, 344, 369–370
counseling in, 369–370
patients over 50 in, 369
preparation for, 344
TCC with, 343–347
urachal remnant excision in, 371f

Radical cystectomy (Continued)
ureteral dissection in, 372
vaginal incision in, 383f
vaginal wall dissection in, 384f, 385f
vascular pedicle isolation in, 377f
Radical orchiectomy
CT scan with, 642, 647, 647f
general considerations for, 641–642
RPLND for low-stage disease with,
642–647, 643f, 644f, 645f, 646f
left-sided nerve-sparing in, 645–646,
646f
postoperative management in, 646
right nerve-sparing in, 643–645, 645f,
646f
technique for, 643–647, 643f, 644f,
645f, 646f
RPLND for postchemotherapy disease
with, 647–649, 647f, 648f, 649f
indications for, 647–648, 647f
special considerations for, 649, 649f
technique of, 648–649, 648f
RPLND with, 641–649, 643f, 644f, 645f,
646f, 647f, 648f, 649f
summary of, 649
Radical perineal prostatectomy (RPP),
528–534, 531f, 532f, 534f, 534t
complications of, 530–531
disease control with, 531–532, 531f, 532f
fecal incontinence following, 533
modification of, 530
nerve-sparing, 530
wide-field dissection, 530
patient selection for, 528–529
BPLND with, 528
DRE in, 529
PSA levels in, 528
potency following, 533
quality of life following, 533–534
summary of, 534
surgical technique for, 529–530
urinary continence following, 532
Radical prostatectomy. See also Radical
perineal prostatectomy
adenocarcinoma of prostate with,
465–474, 466t, 468t, 469t, 471t,
472t, 473t
anatomic nerve-sparing retropubic,
514–527, 516f, 517f, 518f, 519f,
520f, 521f, 522f, 523f, 524f,
525f
bladder neck transection/reconstruction
for, 522, 523f
cancer control outcome of, 525
complications of, 526
Denonvilliers’ fascia incision for, 521f
dorsal venous ligation/transection for,
516–519, 518f, 519f, 520f, 521f
endopelvic fascia incision for, 515–516,
517f, 518f
limited pelvic lymphadenectomy for,
515
neurovascular bundies separation for,
519, 521f
patient selection for, 514–515
potency outcome of, 526
Radical prostatectomy (Continued)
prostatic pedicles transection/control
for, 519–522, 522f
puboprostatic ligaments incision for,
515–516, 517f
summary of, 526
surgical technique for, 515–523, 516f,
517f, 518f, 519f, 520f, 521f, 522f,
523f, 524f, 525f
urinary continence outcome of,
525–526
vesico-urethral anastomosis for,
522–523, 524f, 525f
androgen deprivation therapy with,
498–499
biopsy Gleason sum with, 471, 472f
blood loss during, 469, 469f
cancer control with, 469f, 470–473, 471f,
472f
CT scan assessment with, 466
early complications with, 468–470, 468f,
469f
erectile function after, 474
hospitalization days with, 469f
intraoperative complications with,
468–470, 468f, 469f
laparoscopic, 536–544, 540t, 542t, 543t
anastomotic leaks from, 541
anastomotic stenosis from, 542
anatomic contraindications for, 537
anesthetic contraindications for,
536–537
anterior phase in, 537
blood loss from, 539, 540t
contraindications for, 536–537
difficult cases for, 537
digestive injuries from, 541
extraperitoneal approach for, 538–539
history of, 536
impotence from, 541–542, 543t
indications for, 536
insufflation/trocar positioning
complications for, 539
intraoperative complications for, 539
main operation steps for, 537–538
material for, 537
medical preparation for, 537
Montsouris technique in, 537
neurovascular bundles dissection in,
538
number of trocars for, 538
oncological results from, 542–544
patient installation in, 537
patient positioning complications
for, 539
perioperative complications for,
539–542, 540t
posterior phase in, 537
postoperative complications for, 541
postoperative management for, 538
prostatic pedicles dissection in, 538
specimen extraction complications
for, 541
specimen extraction in, 538
surgical technique for, 537–538
thromboembolic complications for, 541
Index 803
Radical prostatectomy (Continued)
transperitoneal approach to, 537
transperitoneal approach variants for,
538
ureteric injuries from, 540t, 541
urethra section in, 538
urinary incontinence from, 541
vesicoprostatic dissection in, 538
vesicourethral anastomosis in, 538
late complications with, 470
lymph node metastases with, 472t
mortality with, 468f
MRI assessment with, 466
obturator nerve injury from, 470
outcomes after, 469f, 470–474, 471f, 472f,
473f
patient selection for, 466
PC natural history and, 465–466, 466t
pelvic lymph node dissection with,
467–468
pretreatment risk stratification with,
466–467
PSA risk assessment with, 466–467, 470,
471f
PSA survival with, 469f
rectal injury from, 469
remote-controlled assisted, 544
results of, 468
risk factors with, 472f, 473f
seminal vesicle involvement with, 472f
treatment rationale, 465
urinary function with, 473, 473f
urinary incontinence after, 473, 473f
Radical prostatectomy (RP)
HRQOL with, 107
PSA with, 459, 462f
Radiofrequency ablation
RCC with, 208–209, 208t
RAND Medical Outcomes Study (SF-36)
cutaneous urinary diversion influence in,
437–438, 438t
HRQOL measured with, 104
Randomized clinical trial (RTC)
radiation therapy for adenocarcinoma
with, 477
RASS. See Renin-angiotensin-aldosterone
system
RCC. See Renal cell carcinoma
Reabsorption syndrome
TUR complications with, 363–364
Reactive oxygen species (ROS)
inflammation with, 5–6
IR with, 43–44
Rectal bladder urinary diversion
cutaneous urinary diversion with,
406–407, 407f, 408f
taenia incision in, 407f
technique in, 407, 407f, 408f
ureterointestinal anastomosis in, 407f
ureterosigmoidostomy in, 406–407
Reinke’s crystals
LCT with, 619, 621
Renal cell carcinoma (RCC)
active immunotherapy for, 264
heat shock protein with, 264
VHL gene with, 264
804 Index
Renal cell carcinoma (RCC) (Continued)
adrenalectomy with, 204–205
advanced, 258–265, 259f, 260f, 262f, 263f
amyloidosis associated with, 174t
anemia associated with, 174t
antiangiogenic for, 264–265
biopsy for, 197–198
bone marrow transplantation for, 265
cachexia associated with, 174t
chemotherapy for, 265
classification of, 177–178, 177t, 196, 196t
Bellini’s duct, 177, 177t
Benign neoplasms, 196t
chromophobe cell, 177, 177t, 196, 196t
collecting duct, 177, 177t, 196t
conventional type, 196t
metanephric adenoma, 196t
oncocytoma, 196t
papillary, 177, 177t, 196t
renal medullary, 177–178, 177t
unclassified type, 178, 196t
clinical presentation with, 174–175, 174t,
195–196
cytokine therapy for, 88, 89–92, 90t
diagnosing of, 173–183, 174t, 177t, 178f,
179f, 180f, 181f, 182f, 182t, 183f,
197
AML in, 179, 180, 180f
Bosniak classification in, 182, 182t
Bosniak lesions in, 181
CT for, 179–182, 180f, 181f, 182f, 197
FDG for, 183, 188–189
imaging evaluation for, 178
IVP for, 178, 178f, 197
MDCT for, 179
MRI for, 182, 183f, 197
nuclear medicine and, 182–183
oncocytoma mimicked in, 181f
percutaneous biopsy in, 189, 189t
percutaneous needle aspiration cytology
in, 189, 189t
PET for, 178, 182–183, 188–189, 197
ultrasonography for, 178–179, 179f,
197
disease progression in, 189
enteropathy associated with, 174t
epidemiology of, 195–196, 258–262, 259f,
260f
grade with, 259–260
histology with, 259–260
IVC involvement with, 261
patient evaluation with, 261
patient performance status with, 260
prognosis in, 259
tumor stage in, 259, 259f
UISS with, 260–261, 260f
erythrocytosis associated with, 174t
etiology of, 173–174
fever associated with, 174t
FNA for, 197–198
grade of, 259–260
HCT for, 95–97, 96f
hepatic-dysfunction associated with, 174t
histology of, 259–260
histopathology of, 196, 196t
hypercalcemia associated with, 174t
Renal cell carcinoma (RCC) (Continued)
hypertension associated with, 174t
immunotherapy for, 88, 89–92, 90t,
95–97, 96f
incidence rates of, 173
inheritance of, 176–177
BHD in, 176, 197t
familial renal oncocytoma in, 176–177
GLUT-1 in, 176
HLRC in, 177
HPRC in, 176, 197t
TGF in, 176
tuberous sclerosis in, 197t
VHL in, 176, 197t
laparoscopic partial nephrectomy for,
230–235, 233f, 234f
AML with, 235
complications of, 252–283
contraindications for, 249
CT for, 230–231
financial analysis of, 283
indications for, 249
renal hypothermia with, 250, 254f
renal parenchymal repair in, 253f
results of, 250–252, 255t
segmental polar, 232, 233f
simple enucleation, 235
in situ, 231
technique for, 249–250, 250t, 251f,
252f, 253f
transverse resection, 234–235, 234f
wedge resection, 232–234, 234f
laparoscopic radical nephrectomy for,
199–203, 202t
approach selection for, 237–238
complications of, 241, 243t, 244t
concomitant adrenalectomy with,
245–246
contra-indications for, 237
cytoreductive, 247–248
financial implications of, 248
follow-up for, 246t
HAL, 199, 201
indications for, 237
larger renal tumors with, 245, 247t
oncologic outcome of, 244–245
ORN v., 201–203, 202t, 247t
RCC with, 199–203, 202t, 237–248,
238f, 239f, 240f, 241f, 242t, 243t,
244t, 245f, 246t, 247t, 248t, 249f
renal vein involvement with, 246–247,
248t, 249f
results of, 241, 242t
retroperitoneal, 199, 200–201
specimen extraction with, 241–244, 245f
technique for, 200–201, 238–240, 238f,
239f, 240f, 241f
three approaches to, 199
transperitoneal, 199, 200
localized, 195–212, 196t, 197t, 199f, 202t,
203t, 204f, 205f, 208f, 210t
lymphadenectomy with, 205–206, 205f
metastatic, 262–263, 263f
IFN for, 262
nephrectomy in, 262–263, 263f
SWOG study of, 262–263
Renal cell carcinoma (RCC) (Continued)
molecular genetics with, 176–177
molecular markers with, 175–176
AgNOR, 175
CAIX protein, 176
HIF, 176
MVD, 175
PCNA, 175
VHL protein, 176
monitoring for recurrence with, 189
nephrectomy with, 206–207
advanced disease with, 206
partial type, 206–207
surgical margin in, 207
technique in, 207
neuromyopathy associated with, 174t
novel therapies for, 264–265
open radical nephrectomy for, 198–199,
199f, 201–203, 202t
LRN v., 201–203, 202t
technique for, 198–199, 199f
paraneoplastic syndromes associated with,
174–175, 174t
passive immunotherapy for, 264
TIL with, 264
pathology of, 177–178, 177t
patient performance status with, 260
prognostic factors for, 210–211, 210t
TNM classification with, 210–211,
210t
radical nephrectomy for, 218–230, 219f,
220f, 221f, 222f, 223f, 224f, 225f,
226f, 227f, 228f, 229f, 230t
anterior subcostal transperitoneal
incision in, 220, 220f, 221f
bilateral subcostal incision in, 220
CT scan for, 218
diaphragmatic incision in, 220
evaluation for, 218–219
Gerota’s fascia in, 224f, 226, 239
indications for, 218–219
IVC with, 222–226, 227f, 228f
left side, 220–222, 224f, 225f
lymphadenectomy with, 222
MRI for, 218
renal vein in, 224f
right side, 222, 225f
ring retractor with, 224f
suprahepatic vena cava with, 226–230,
228f, 229f
surgical anatomy with, 219, 219f
surgical incisions in, 219–220, 220f,
221f, 222f
TEE for, 218
thoracoabdominal approach in, 220,
222f, 223f
thrombectomy with, 227f
renal tumor ablation with, 207–210, 208t
cryoablation in, 207–208, 208t
CT with, 208, 209
HIFU, 209–210
MRI with, 208, 209
radiofrequency, 208–209, 208t
retroperitoneal tumors, 665–666, 665t
risk factors with, 173–174, 196–197, 197t
screening for, 211

Renal cell carcinoma (RCC) (Continued)
SEER reporting of, 173
serum markers with, 175
staging of, 183–189, 183f, 184–185t, 186f,
186t, 187f, 188f, 189t, 259
CT in, 186–188, 186f
ECOG PS in, 186–187, 186t, 260–261
MRI in, 186f, 187–188
Robson classification in, 183, 183f
TNM system in, 183–185, 184–185t,
186, 186t, 259, 259f, 260
UISS in, 186–187, 186t, 259–260, 260f
Stauffer’s syndrome associated with, 174t
summary of, 212
surgery for, 218–235, 219f, 220f, 221f,
222f, 223f, 224f, 225f, 226f, 227f,
228f, 229f, 230t, 233f, 234f
indications for, 198
systemic therapy for, 263–264
IFN in, 263
IL-2 in, 263–264
treatment of, 258–265, 259f, 260f, 262f,
263f
tumor biopsy for, 197–198
tumor thrombus with, 203–204, 203t,
204f, 227f, 228f, 229, 229f
Renal hypothermia nephrectomy
Endocatch II bag in, 250, 254f
Renin-angiotensin-aldosterone system
(RASS)
hyperaldosteronism with, 137
Rete testis carcinoma (RTC)
clinical presentation of, 628
evaluation of, 628–629
management of, 628–629
nongerm cell tumors of, 628–629, 629f
pathologic characteristics of, 628, 629f
Retinoblastoma gene
TCC with, 342
Retroperitoneal lymph node dissection
(RPLND)
CT scan with, 642, 647, 647f
low-stage disease treated with, 642–647,
643f, 644f, 645f, 646f
left-sided nerve-sparing in, 645–646,
646f
postoperative management in, 646
right nerve-sparing in, 643–645, 645f,
646f
technique for, 643–647, 643f, 644f,
645f, 646f
NSGCT treatment with, 600–605, 606f,
607f, 608f, 609f, 610t
postchemotherapy, 603–605, 606f
primary, 600–603, 606f, 607f, 608f,
609f, 610t
postchemotherapy disease treated with,
647–649, 647f, 648f, 649f
indications for, 647–648, 647f
special considerations for, 649, 649f
technique of, 648–649, 648f
radical orchiectomy with, 641–649, 643f,
644f, 645f, 646f, 647f, 648f, 649f
general considerations for, 641–642
summary of, 649
testis tumors staging with, 570, 571
Retroperitoneal technique
laparoscopic surgery with, 164, 164f
Retroperitoneal tumors
adult urinary tract sarcoma and, 665, 665t
Agent Orange and, 652
benign lesions with, 652–653, 652t
ganglioneuroma as, 652t
hemangiopericytoma as, 652t
leiomyoma as, 652t, 653
lipomas as, 652–653, 652t
myelolipoma as, 652t, 653
Schwannoma as, 652t
chemotherapy for, 664–665
metastatic disease and, 664–665
diagnosis of, 657–658, 657f
CT scan in, 657–658, 657f
MRI in, 658
dioxin and, 652
incidence/etiology of, 651–652
malignant lesions with, 653–657, 653t,
654f, 655f, 656f
fibrosarcoma as, 653t, 656
leiomyosarcoma as, 653t, 654–655
liposarcoma as, 653–654, 653t, 654f,
655f
malignant fibrous histiocytoma as, 653t,
655–656, 656f
malignant hemangiopericytoma as,
653t, 657
rhabdomyosarcoma as, 653t, 656–657
paratesticular tumors with, 667
pathology of, 652–657, 652t, 653t, 654f,
655f, 656f
prostate with, 666–667
radiation therapy for, 664
IMRT, 664
IORT, 664
renal sarcoma and, 665–666
staging of, 658, 659t–661t
summary of, 667–668
surgery for, 658–663, 661t, 662f, 662t
operative technique in, 658–663, 661t,
662f, 662t
organs sacrificed during, 662t
partial v. complete resection in, 658,
661t
transabdominal approach in, 662f
surgical outcome for, 663–664, 663f,
664
urinary bladder with, 666
wood preservatives and, 652
Retrovirus vectors
applications of, 20–21
attributes in, 20–21
gene delivery in, 19
gene expression in, 19–20, 19f
gene therapy with, 19–21, 19f, 20f,
21t, 26
vector production in, 19
Rhabdomyosarcoma (RMS)
bladder/prostate treatment for, 774–775
bladder primaries surgery in, 774–775
chemotherapy in, 774
outcome of, 775
prostate primaries surgery in, 775
radiation therapy in, 774
Index 805
Rhabdomyosarcoma (RMS) (Continued)
complications with, 776
evaluation of, 772–773, 772f
CT scan for, 772–773
MRI for, 772–773
general approach to, 773–774
chemotherapy for, 773–774
radiation therapy for, 773–774
relapse with, 774
surgery for, 774
XRT for, 773–774
histologic subtypes of, 772f
malignant lesions of, 653t, 656–657
molecular biology of, 771–772, 772f
paratestis treatment for, 775–776
chemotherapy in, 775
outcome for, 775–776
radiation therapy in, 775
surgery in, 775
pathology of, 771–772, 772f
pediatric scrotal mass and,
presentation of, 772–773, 772f
staging of, 773, 773t
summary of, 776
vagina/uterus treatment for, 775
chemotherapy in, 775
outcome for, 775
radiation therapy in, 775
Ring retractor
radical nephrectomy with, 224f
RMS. See Rhabdomyosarcoma
RNASEL
prostate cancer with, 5, 6t
Robson classification in
RCC staging with, 183, 183f
ROS. See Reactive oxygen species
RP. See Radical prostatectomy
RPLND. See Retroperitoneal lymph node
disection; Retroperitoneal lymph
node dissection
RPP. See Radical perineal prostatectomy
RT, Radiation therapy
RTC. See Randomized clinical trial; Rete
testis carcinoma
RTOG. See Radiation Therapy Oncology
Group
SAMS. See Substratum adhesion
molecules
SCA. See Sertoli cell adenoma
SCC. See Squamous cell carcinoma
Schwannoma
benign lesions of, 652t
Sclerosing Sertoli cell tumors (SSCT)
nongerm cell tumors as, 622, 623
pathologic characteristic of, 623
SCT. See Sertoli cell tumors
Second malignant neoplasms (SMN)
Wilms’ tumor with, 767
SEER. See U.S. Surveillance, Epidemiology,
and End Results
Seminal vesical biopsy (SVB)
Seminal vesicles diagnosis of, 555, 556t
Seminal vesicle invasion (SVI)
brachytherapy and, 119
PC staging with, 461
806 Index
Seminal vesicles
diagnosis of, 555–557, 556f, 556t
Gleason score in, 556, 556t, 564f
MRI in, 557
PSA in, 555–558, 556t, 557t, 561, 562,
564f
SVB in, 555, 556t
transrectal ultrasound in, 555, 556f
treatment options for, 557–565, 557t,
559f, 560f, 561f, 562f, 563f, 564f
adjuvant radiation therapy, 557–558,
557t
androgen deprivation in, 562
CT scan with, 558, 563f
EBRT in, 558, 560f
hormone therapy in, 562
laparoscopy in, 558
LHRH in, 560f
multimodal, 558–565, 560f, 561f, 562f,
563f, 564f
Seminoma
clinical stage I management of, 585–588,
586t
adjuvant radiation therapy in, 587–588
primary chemotherapy in, 588
prognostic factors in, 586–587, 586t
surveillance’s role in, 585–587, 586t
clinical stage II management of, 588–589
clinical stage III management of, 589–590
cryptorchid testes with, 593
early detection of, 584–585
EGCT with, 593
epidemiology of, 579–580
etiology of, 579
HIV patients with, 592
immunosuppression patients with, 592
noncompliant patients with, 593
other issues with, 591–592
pathology of, 581, 582t–584t
prevention of, 584–585
primary surgery for, 580–581
residual masses management for, 591
spread pattern of, 581–584
staging for, 580–581, 582t–584t
summary of, 593
symptoms of, 580
TIN with, 581
treatment effects with, 590–591
chronic, 590–591
fertility in, 591
late gonadal toxicity in, 590
psychologic toxicity in, 590–591
second malignancy in, 590
unusual cases management for, 591–592
bilateral tumors in, 592
high HCG patients in, 591–592
horseshoe/ectopic kidney in, 592
IBD in, 592
Sertoli cell adenoma (SCA)
nongerm cell tumors as, 622, 624, 624f,
625f
pathologic characteristic of, 624, 624f,
625f
Sertoli cell tumors (SCT)
clinical presentation of, 622
evaluation of, 624
Sertoli cell tumors (SCT)
management of, 624
nongerm cell tumors as, 618t, 622–624,
622f, 623f, 624f, 625f
pathologic characteristics of, 622–624,
622f, 623f, 624f, 625f
Serum tumor markers
AFP, 568, 597
HCG, 568, 597
LDH, 568, 597
NSE, 568
NSGCT, 568
PLAP, 568, 597
testis tumors with, 568
SF-36. See RAND Medical Outcomes Study
Sickness impact profile (SIP)
HRQOL measured with, 104
Sigmoid colon conduit
noncontinent cutaneous urinary diversion
with, 406
Silver staining nucleolar organizer regions
(AgNOR)
RCC with, 175
Simpson-Golabi-Behmel syndrome
Wilms’ tumor with, 755
SIOP. See Société International d’Oncologie
Pédiatrique
SIP. See Sickness impact profile
SKY. See Spectral karyotyping
SLDR. See Sublethal damage repair
SMN. See Second malignant neoplasms
Société International d’Oncologie
Pédiatrique (SIOP)
Wilms’ tumor with, 753, 762, 764–766,
765f
cooperative group trials for, 764–766,
765f
Southwest Oncology Group (SWOG)
bladder TTC study by, 325
metastatic RCC study by, 262–263
Spectral karyotyping (SKY)
cancer with, 8
SPL. See Surgical Planning Laboratory
Squamous cell carcinoma (SCC)
chemotherapy treatment in, 718
inguinal lymph node treatment for,
716–718, 716t
penis with
brachytherapy for, 705–706
circumcision for, 702–703, 710
classification of, 697t
CT scan with, 696
diagnosis of, 700–701
diagnosis/staging of, 695–697, 697t
differential diagnosis of, 695–696
epidemiology of, 695
external beam radiation for, 706, 707t
grading in, 700, 701t
histology in, 701
HPV in, 695–696, 710
incidence of, 695
inguinal node management with,
706–707, 707f
Jackson staging system for, 701t, 702
laboratory studies in, 696
laser therapy for, 704–705, 705t
Squamous cell carcinoma (SCC) (Continued)
Mohs’ micrographic surgery for, 704, 723
MRI with, 696
natural history of, 700
occurrence of, 723
partial penectomy for, 703
presentation in, 696, 699–700
radiation therapy for, 705
staging in, 696–697, 701–702, 701t
staging systems for, 697, 697t
summary of carcinoma of, 707
superficial carcinoma of, 699–707, 700f,
701t, 702–703, 702t, 705t, 706t,
707f, 707t
surgical excision for, 702
symptoms in, 696, 699–700
TNM staging system for, 702, 702t
total penectomy for, 703–704
primary lesion treatment for, 715–716
radiation therapy for, 718
urethral cancer pathology with, 674
SSCT. See Sclerosing Sertoli cell tumors
Stauffer’s syndrome
RCC associated with, 174t
Stoma stenosis
cutaneous urinary diversion with, 431
Stone formation
cutaneous urinary diversion with, 434
Stromal epithelial interactions, 15–16, 15f
Sturge-Weber syndrome
pheochromocytoma with, 139
Sublethal damage repair (SLDR), 44
Substratum adhesion molecules (SAMS), 13f
Suprahepatic vena cava
radical nephrectomy with, 226–230, 228f,
229f
Surgery
adrenal gland approach in, 156
adrenal tumors with, 139–149, 142t, 143f,
144f, 145f, 146f, 147f, 148f,
153–167, 154f, 154t, 157f, 158f,
159f, 160f, 161f, 161t, 162f, 163f,
164f, 166t
anatomic nerve-sparing radical
prostatectomy, 514–527, 516f,
517f, 518f, 519f, 520f, 521f, 522f,
523f, 524f, 525f
bladder neck transection/reconstruction
for, 522, 523f
Denonvilliers’ fascia incision
for, 521f
dorsal venous ligation/transection for,
516–519, 518f, 519f, 520f, 521f
endopelvic fascia incision for, 515–516,
517f, 518f
limited pelvic lymphadenectomy for, 515
neurovascular bundies separation for,
519, 521f
patient selection for, 514–515
prostatic pedicles transection/control
for, 519–522, 522f
puboprostatic ligaments incision for,
515–516, 517f
vesico-urethral anastomosis for,
522–523, 524f, 525f
anatomy in, 156

Surgery (Continued)
approaches to, 141, 142t
Cushing’s syndrome in, 141, 142t
cutaneous urinary diversion in
appendiceal approach to, 409
Benchekroun nipple approach to, 409
colocolostomy in, 405f
colonic conduits for, 404–406, 405f
complications with, 430–437, 433t,
435t
continent, 406–427, 407f, 408f, 409f,
410f, 412f, 413f, 414f, 415f, 416f,
417f, 418f, 419f, 420f, 421f, 422f,
422t, 423–424t, 425f, 426f, 427f
continent catheterizable urinary
diversions for, 407–409
continent mechanism in, 409–411, 410f
continent reservoirs for, 411–427, 412f,
413f, 414f, 415f, 416f, 417f,
418–420f, 421f, 422f, 422t,
423–424t, 425f, 426f, 427f, 428f,
436–437
continent v. noncontinent, 399
cutaneous pyelostomy for, 400, 401f
cutaneous ureterostomy for, 400–401,
402f
Duke pouch, 422t, 424t
flap valve approach to, 409
Florida pouch, 422t, 424t
four surgical techniques for, 409
gastric pouch, 424t, 426–427, 427f,
428f, 436–437
hydraulic valve approach to, 409
ileal conduit for, 401–403, 403f, 404f
ileocecal, 411–416, 412f, 413f, 414f,
415f, 416f, 417f, 418–420f, 421f,
422f, 422t, 423–424t
ileocecal conduit for, 405
Indiana pouch, 416–421, 422t,
423–424t, 425f, 436
intraoperative pouch testing for, 411
intussuscepted nipple valve approach
to, 409
jejunal conduit for, 404
Kock pouch, 411–413, 412f, 413f, 423t,
436
laparoscopic ileal conduit for, 438, 439t
LeBag, 422t
Mainz pouch, 414–416, 418–420f, 423t,
436
nasogastric tube for, 400
noncontinent, 400–406, 401f, 402f,
403f, 404f, 405f
novel techniques for, 438–439, 439t
Penn pouch, 424t, 426, 426f
postoperative care for, 400
preoperative preparation for,
399–400
pseudoappendiceal approach to, 409
quality of life with, 437–438, 438t
rectal bladder urinary diversion for,
406–407, 407f, 408f
rectus fascia incision in, 404f
renal pelvis incision in, 401f
right colon, 416–427, 422t, 423–424t,
425f, 426f, 427f, 428f, 436–437
Surgery (Continued)
sigmoid colon conduit for, 406
T pouch, 413–414, 414f, 415f, 416f,
417f, 423t
taenia incision in, 407f
transverse colon conduit for, 404–406,
405f
U. Miami pouch, 424t
UCLA pouch, 422t, 423t
ureterointestinal anastomoses with,
407f, 427–430, 429f, 430f, 431f
ureterosigmoidostomy in, 406–407
Wallace technique for, 430, 430f
flank approach to, 145–147, 145f, 146f,
156–158, 157f
hyperaldosteronism in, 142t
laparoscopic partial nephrectomy
complications of, 252–283
contraindications for, 249
financial analysis of, 283
indications for, 249
renal hypothermia with, 250, 254f
renal parenchymal repair in, 253f
results of, 250–252, 255t
technique for, 249–250, 250t, 251f,
252f, 253f
laparoscopic radical nephrectomy,
218–230, 219f, 220f, 221f, 222f,
223f, 224f, 225f, 226f, 227f, 228f,
229f, 230t
anterior subcostal transperitoneal
incision in, 220, 220f, 221f
approach selection for, 237–238
bilateral subcostal incision in, 220
complications of, 241, 243t, 244t
concomitant adrenalectomy with,
245–246
contra-indications for, 237
CT scan for, 218
cytoreductive, 247–248
diaphragmatic incision in, 220
evaluation for, 218–219
financial implications of, 248
follow-up for, 246t
Gerota’s fascia in, 224f, 226, 239
indications for, 218–219, 237
IVC with, 222–226, 227f, 228f
larger renal tumors with, 245, 247t
left side, 220–222, 224f, 225f
lymphadenectomy with, 222
MRI for, 218
oncologic outcome of, 244–245
ORN v., 201–203, 202t, 247t
RCC with, 199–203, 202t, 237–248,
238f, 239f, 240f, 241f, 242t, 243t,
244t, 245f, 246t, 247t, 248t, 249f
renal vein in, 224f
renal vein involvement with, 246–247,
248t, 249f
results of, 241, 242t
right side, 222, 225f
ring retractor with, 224f
specimen extraction with, 241–244,
245f
suprahepatic vena cava with, 226–230,
228f, 229f
Index 807
Surgery (Continued)
surgical anatomy with, 219, 219f
surgical incisions in, 219–220, 220f,
221f, 222f
technique for, 200–201, 238–240, 238f,
239f, 240f, 241f
TEE for, 218
thoracoabdominal approach in, 220,
222f, 223f
three approaches to, 199
thrombectomy with, 227f
laparoscopic radical prostatectomy,
537–538
anterior phase in, 537
main operation steps for, 537–538
medical preparation for, 537
Montsouris technique in, 537
neurovascular bundles dissection in,
538
patient installation in, 537
posterior phase in, 537
prostatic pedicles dissection in, 538
specimen extraction in, 538
transperitoneal approach to, 537
urethra section in, 538
vesicoprostatic dissection in, 538
vesicourethral anastomosis in, 538
lateral flank approach in, 156–158, 157f
lymphadenectomy in, 728f, 729f,
730–732, 732f
management of TCC through, 274–279,
275t, 277t, 279f
modified posterior approach to, 143–145,
144f, 159, 160f
nephrectomy with, 146, 146f
neuroblastoma treatment with,
746–750
open radical nephrectomy (ORN)
LRN v., 201–203, 202t
RCC with, 198–199, 199f, 201–203,
202t, 247t
open surgical techniques in, 156–159,
158f, 159f, 160f
orthotopic bladder substitution, 443–454,
445f, 446f, 447f, 448f, 449f, 450f,
451f, 452f, 453f, 453t, 454t
atraumatic urethra dissection as, 446
bipolar electrocautery in, 446
bladder construction as, 447–448, 450f,
451f, 453f
cystectomy as, 445–446, 445f, 446f,
453f
ileal segment resection as, 446, 447f,
448f
long-term follow-up for, 452–454, 454t
mesenteric window close in, 448f
metabolic acidosis in, 450, 453t
nerve preservation in, 445–446, 445f,
446f
Nesbit technique in, 449f
operative technique for, 444–448, 445f,
446f, 447f, 448f, 449f, 450f, 451f,
452f, 453f
orthotopic ileal bladder substitute as,
446, 447f, 448f
patient assessment for, 443–444
808 Index
Surgery (Continued)
postoperative management for,
448–452, 453t
preoperative patient selection for,
443–444
U-shaped distal ileum in, 450f
ureteroileal anastomosis as, 446–447,
449f, 450f
ureters in, 446
urethral anastomosis as, 447–448, 450f,
451f, 453f
partial adrenalectomy in, 148–149,
148f
partial nephrectomy for, 230–235, 233f,
234f
AML with, 235
CT for, 230–231
segmental polar, 232, 233f
simple enucleation, 235
in situ, 231
transverse resection, 234–235, 234f
wedge resection, 232–234, 234f
partial penectomy in, 701
PC treatment complications with,
547–552
pheochromocytoma in, 142t
posterior approach to, 142–143, 143f,
159, 159f
preoperative management with, 141, 142t,
156
procedures for penis in, 723–732, 724f,
725f, 726f, 727f, 728f, 729f,
732f
radical cystectomy
abdominal exploration in, 370
adjuvant v. neoadjuvant, 346–347
bladder treated with, 368, 369–387,
370f, 371f, 372f, 373f, 375f, 376f,
377f, 378f, 379f, 380f, 381f, 382f,
383f, 384f, 385f, 386f
bowel mobilization in, 370–372, 372f,
373f
chemotherapy with, 346–347
complications of, 346
Denonvilliers’ fascia in, 279f, 377, 378f,
380, 380f
discussion of, 385–387
dorsal venous complex in, 380, 381f,
382f
female patient anterior dissection in,
382–384, 383f, 384f, 385f, 386f
female pelvic sagittal section in, 386f
females with, 345
gauze sponge withdrawing in, 376f
ICU for, 384
iliac artery skeletonizing in, 375f
incision in, 370, 371f
lateral vascular pedicle ligation in,
374–375, 377f
lymphadenectomy with, 345–346
male patient anterior dissection in,
378–382, 381f, 382f
males with, 344–345
outcomes of, 346
overhead pelvic view in, 372f, 373f
overview of, 343–344
Surgery (Continued)
patient positioning in, 370, 370f
pelvic lymphadenectomy with,
373–374, 375f, 376f
peritoneum incision in, 378f
posterior pedicle ligation in, 375–378,
378f, 379f, 380f
postoperative care for, 384–385
preoperative evaluation for, 344,
369–370
preparation for, 344
TCC with, 343–347
urachal remnant excision in, 371f
ureteral dissection in, 372
vaginal incision in, 383f
vaginal wall dissection in, 384f, 385f
vascular pedicle isolation in, 377f
radical laproscopic, 149, 150–151f,
160–167, 161f, 161t, 162f, 163f,
164f, 166t
radical perineal prostatectomy,
529–530
radical prostatectomy, 465–474, 466t,
468t, 469t, 471t, 472t, 473t
biopsy Gleason sum with, 471, 472f
blood loss during, 469, 469f
cancer control with, 469f, 470–473,
471f, 472f
CT scan assessment with, 466
early complications with, 468–470,
468f, 469f
erectile function after, 474
hospitalization days with, 469f
intraoperative complications with,
468–470, 468f, 469f
late complications with, 470
lymph node metastases with, 472t
mortality with, 468f
MRI assessment with, 466
obturator nerve injury from, 470
outcomes after, 469f, 470–474, 471f,
472f, 473f
patient selection for, 466
PC natural history and, 465–466,
466t
pelvic lymph node dissection with,
467–468
pretreatment risk stratification with,
466–467
PSA risk assessment with, 466–467,
470, 471f
PSA survival with, 469f
rectal injury from, 469
results of, 468
risk factors with, 472f, 473f
seminal vesicle involvement
with, 472f
treatment rationale, 465
urinary function with, 473, 473f
urinary incontinence after, 473, 473f
RCC, indications for, 198
RMS treated with, 774–776
seminoma, 578–579
TCC with, 276–279, 277t, 279f, 287–296,
288f, 289f, 290f, 291f, 292f, 293f,
294f, 295f, 296f
Surgery (Continued)
endoscopic management for, 293–295,
295f, 296f
laparoscopic nephroureterectomy in,
278–279, 280t, 289–291, 290f,
291f
laparoscopic v. open
nephroureterectomy in, 219f, 220f,
280t
open nephron-sparing surgery for,
291–293, 292f, 293f
open nephroureterectomy in, 277–278,
280t, 287–289, 289f, 291f
open segmental ureterectomy for,
292–293, 293f, 294f
partial ureterectomy in, 276–277,
277t
thoracoabdominal approach to, 158, 158f
total penectomy for, 703–704
complications in, 704
impact of, 704
surgical technique in, 703
transabdominal approach to, 147–148,
147f, 158–159, 158f
TUR
anesthesia for, 359
bimanual examination for, 359, 359f
bladder cancer diagnosis with,
306, 338
Bladder-sparing therapy with,
347–348
bladder tumors with, 358–365, 359f,
360f, 364t, 365f
complications with, 362–364
equipment for, 359–360
fluoroscopic cystoscopy for, 365
instrumentation for, 359–360
intraoperative problem management in,
361–362
irrigation fluid in, 361
laser surgery for, 364–365, 364t,
365f
postoperative management in, 362
preparation for, 358–359
primary muscle invasive tumor
treatment with, 362
second look resection in, 362
TCC bladder with, 317–318
TCC diagnosis with, 338
technique for, 360–361
Surgical Planning Laboratory
(SPL), 119
SVB. See Seminal vesical biopsy
SVI. See Seminal vesicle invasion
SWOG. See Southwest Oncology
Group
Systemic therapy
IFN in, 263
IL-2 in, 263–264
RCC with, 263–264
T-cells
HCT with, 93, 96, 96f
T pouch
complications with, 435t
continent reservoirs compared to, 423t

T pouch (Continued)
reoperation rate with, 435t
technique for, 413–414, 414f, 415f, 416f,
417f
urinary diversion with, 413–414, 414f,
415f, 416f, 417f, 423t, 435t
Taxanes
docetaxel as, 66f, 67
genitourinary cancer treatment with,
65–67, 67f
paclitaxel as, 65–67, 67f
TCC. See Transitional cell carcinoma
TEE. See Transesophageal
echocardiography
Telomerase
urologic cancers with, 16
Telomeric repeat amplification protocol
(TRAP)
TCC diagnosis with, 272
Temporary prostate brachytherapy
(TPB)
prostate adenocarcinoma treated with,
484–485, 488, 489t
BRFS with, 488, 489t
technique in, 484–485
Teratoma, testis tumors, 781
Testicular cancer
HRQOL with, 109
Testicular germ cell tumors (GCT). See
Testis tumors
Testicular intraepithelial neoplasia (TIN)
seminoma with, 581
Testis tumors
diagnosis of, 567–568
introduction, 567
presentation of, 567–568
imaging of, 568–569
nongerm cell tumors of, 617–637, 618f,
618t, 619f, 620f, 621f, 622f, 623f,
624f, 625f, 626f, 627f, 628f, 629f,
630f, 631f, 632f, 633f, 634f, 635f,
636f
acquired immunodeficiency syndrome
with, 637
adenomatoid tumor of epididymis as,
618t, 633, 633f, 634f
carcinoid tumors of, 618t, 632–633,
633f
epidermoid cysts as, 618t, 627–628,
627f, 628f
generalized stroma tumors of, 636–637
granulosa cell tumors as, 618t,
624–626, 625f, 626f
hematologic tumors of, 618t, 633–636,
635f
HIV and, 637
Klinefelter’s syndrome with, 619
leukemia as, 618t, 636, 636f
Leydig cell tumors as, 618–622, 618f,
618t, 619f, 620f, 621f
malignant lymphoma as, 618t, 633–636,
635f
malignant mesothelioma as, 629–631,
630f, 631f
metastatic tumors of, 618t, 631–632,
632f
Testis tumors (Continued)
miscellaneous tumors of, 627–636,
627f, 628f, 629f, 630f, 631f, 632f,
633f, 634f, 635f, 636f
mixed sex cord/gonadal stromal tumors
as, 626–637, 627f, 628f, 629f, 630f,
631f, 632f, 633f, 634f, 635f, 636f
ovarian surface epithelial type tumors
of, 637
plasmacytoma as, 618t, 636, 636f
Reinke’s crystals in, 619, 621
Rete testis carcinoma as, 628–629, 629f
Sertoli cell tumors as, 618t, 622–624,
622f, 623f, 624f, 625f
sex cord/stromal origin with, 618–626,
618f, 618t, 619f, 620f, 621f, 622f,
623f, 624f, 625f, 626f
serum tumor markers of, 568
AFP, 568
HCG, 568
LDH, 568
NSE, 568
NSGCT, 568
PLAP, 568
staging of, 569–574, 572t, 573t, 574t
AJCC in, 569, 571, 572t
bipedal lymphangiogram for, 570
CT scan for, 569–571
distant metastasis in, 571, 572t
IGCCCG with, 571, 573t
introduction to, 569
modalities of, 569–571
PET scan for, 570
primary tumor in, 571, 572t
regional lymph nodes in, 571, 572t
RPLND for, 570, 571
serum tumor markers in, 571, 572t
TGF. See Transforming growth factor
Therapeutic radiation (RT)
adjuvant, 46
definitive, 46
palliative, 46
radiation oncology clinical practice and,
46–47, 47t
Thiotepa
bladder TCC with, 323
genitourinary cancer treatment with, 69
Three-dimensional conformal radiation
therapy (3DCRT)
radiation therapy for adenocarcinoma
with, 478–479, 478f, 482, 489
3D Slicer surgical simulation software, 119,
120f
3DCRT. See Three-dimensional conformal
radiation therapy
Thrombenectomy
radical nephrectomy with, 227f
Thrombospondin-1 (TSP-1)
TCC prognosis with, 341
TIL. See Tumor-infiltrating lymphocytes
TIN. See Testicular Intraepithelial neoplasia
TNF. See Tumor necrosis factor
TNM. See Tumor, nodes, and metastasis
Topotecan
genitourinary cancer treatment with, 73f,
74
Index 809
Toxicity
androgen deprivation therapy with, 499
TRAIL. See Tumor necrosis factor-related
apoptosis-inducing ligand
Transesophageal echocardiography (TEE)
radical nephrectomy for, 218
Transforming growth factor (TGF)
RCC with, 176
TCC prognosis with, 343
Transitional cell carcinoma (TCC)
biologic prognostic markers for, 321–322
BCG in, 321
blood group antigens as, 321
cytogenic markers as, 321–322
FISH as, 321
molecular genetic markers as, 321–322
tumor cell products as, 321
WTG in, 321
bladder-sparing therapy for, 347–349
bladder with, 317–331, 318t, 322t, 326t,
328f, 329t, 330t
chemotherapy for, 279–281, 323–324
CISCA regimen in, 281
CMV regimen in, 281
doxorubicin in, 324
MMC in, 323–324, 326t
MVAC regimen in, 281
thiotepa in, 323
valrubicin in, 324
cytologic prognostic factors for, 320–321
DNA ploidy in, 321
urine cytology in, 320–321
diagnosis of, 270–272, 271f, 272f, 273f
bladder mucosa distant from tumor in,
320
CT scan in, 271–272, 273f, 339
cytology in, 272, 273f
endoscopic evaluation in, 272
MRI in, 271–272, 339
other markers in, 272
radiographic evaluation in, 270–272,
271f, 272f, 273f
TRAP in, 272
tumor extent evaluation in, 338–340
tumor metastatic evaluation in, 339
tumor stage and growth in, 338–339
endoscopic management of, 274–276,
275t, 317–318, 320
etiology in, 269–270
evaluation of, 269–274, 271f, 272f, 273f,
274t, 317
grading of, 274, 318
histopathology of, 272–274, 319
intravesical therapy for, 322–327, 322t,
326t
BCG in, 324–326, 326t
bropirimine in, 327
chemotherapy, 323–324
combination therapy, 327
doxorubicin in, 324
IFN in, 326
immunotherapy in, 324–327
KLH in, 326–327
MMC in, 323–324, 326t
rationale for, 322–323, 322t
recommendations in, 327
810 Index
Transitional cell carcinoma (TCC)
(Continued)
thiotepa in, 323
valrubicin in, 324
management of, 338–349
outcome for, 281–282
prognosis for, 320–322, 338–349
angiogenic factors with, 341–342
biologic markers in, 321–322
cell adhesion molecules with, 341
cell-cycle regulators with, 342–343
chromosomal abnormalities with, 340
conclusion about, 343
cytologic factors in, 320–321
erb-B-2 with, 342–343
genetic determinants with, 343
growth events with, 340–341
MDR gene with, 343
MVAC with, 343
MVD with, 341–342
P53 with, 342
retinoblastoma gene with, 342
summary of, 349
TGF with, 343
treatment response with, 343
TSP-1 with, 341
VEGF with, 341
prostatic urethra with, 327–328, 328f
CIS only, 328f
cystoprostatectomy for, 328f
ductal, 328f
intravesical therapy for, 328f
stromal invasion, 328f
radiation therapy for, 281
radical cystectomy for, 343–347
adjuvant v. neoadjuvant, 346–347
chemotherapy with, 346–347
complications of, 346
females with, 345
lymphadenectomy with, 345–346
males with, 344–345
outcomes of, 346
overview of, 343–344
preoperative evaluation for, 344
preparation for, 344
renal pelvis and ureter with, 269–282,
271f, 272f, 273f, 274t, 275t, 277t,
279f, 280t
staging of, 274, 274t, 319–320
AJCC in, 274t, 319
distant metastasis in, 274t
lymph nodes in, 274t
primary tumor in, 274t
PUNLMP in, 274
reproducibility of, 319–320
TNM in, 274, 274t
surgical approaches to, 276–279, 277t,
279f, 287–296, 288f, 289f, 290f,
291f, 292f, 293f, 294f, 295f, 296f
endoscopic management for, 293–295,
295f, 296f, 317–318
laparoscopic nephroureterectomy in,
278–279, 280t, 289–291, 290f, 291f
laparoscopic v. open
nephroureterectomy in, 219f, 220f,
280t
Transitional cell carcinoma (TCC)
(Continued)
open nephron-sparing surgery for,
291–293, 292f, 293f
open nephroureterectomy in, 277–278,
280t, 287–289, 289f, 291f
open segmental ureterectomy for,
292–293, 293f, 294f
partial ureterectomy in, 276–277, 277t
surgical management of, 274–279, 275t,
277t, 279f
BCG with, 276
percutaneous resection with, 276
results of, 277, 279f
SEER on, 277, 279f
survival with, 279f
treatment of, 274–282, 275t, 277t, 279f,
280t
upper urinary tract, 287–296, 288f, 289f,
290f, 291f, 292f, 293f, 294f, 295f,
296f
endoscopic management for, 293–295,
295f, 296f
initial evaluation for, 287
IVP for, 287
laparoscopic radical
nephroureterectomy for, 289–291,
290f, 291f
open nephron-sparing surgery for,
291–293, 292f, 293f
open radical nephroureterectomy for,
287–289, 289f, 291f
open segmental ureterectomy for,
292–293, 293f, 294f
Transrectal US (TRUS)
IGT with, 114, 117, 118, 122
PC staging with, 461
seminal vesicles diagnosis with, 555, 556f
Transurethral resection of bladder tumor
(TURBIT)
bladder preservation, 390t, 392
Transurethral resection of the prostate
(TURP)
brachytherapy and, 119
PC staging with, 549
Transurethral resection (TUR)
anesthesia for, 359
bimanual examination for, 359, 359f
bladder cancer diagnosis with, 306, 338
bladder preservation with, 389, 390t, 394f
Bladder-sparing therapy with, 347–348
bladder tumors with, 358–365, 359f, 360f,
364t, 365f
complications with, 362–364
bladder explosion in, 364
bladder perforation in, 363
hemorrhage in, 362–363
obturator nerve reflex in, 363
reabsorption syndrome in, 363–364
ureteral orifice injury in, 363
urinary infection in, 363
urinary stricture in, 363
equipment for, 359–360
cold-cup biopsy in, 360
flexible cystoscope in, 360
video endoscopy in, 360
Transurethral resection (TUR) (Continued)
fluoroscopic cystoscopy for, 365
instrumentation for, 359–360
ball electrode as, 359
CIS with, 359
intraoperative problem management in,
361–362
irrigation fluid in, 361
laser surgery for, 364–365, 364t,
365f
advantages/disadvantages with,
364–365
bladder tumor recurrence rate with,
365
techniques of, 364
types of, 364t
postoperative management in, 362
preparation for, 358–359
CT scan in, 358
IVP in, 358
primary muscle invasive tumor treatment
with, 362
second look resection in, 362
TCC bladder with, 317–318
TCC diagnosis with, 338
technique for, 360–361
Transverse colon conduit
noncontinent cutaneous urinary diversion
with, 404–406, 405f
TRAP. See Telomeric repeat amplification
protocol
TRUS. See Transrectal US
TSP-1. See Thrombospondin-1
Tubulin modulation drugs
genitourinary cancer treatment with,
64–65
Tumor, nodes, and metastasis (TNM)
bladder cancer staging with, 308, 309
penis carcinoma staging with, 714,
715t
Penis SCC staging with, 700, 700t
RCC prognostic factors with, 210–211,
210t
RCC staging with, 183–185, 184–185t,
186, 186t, 259, 259f
TCC staging with, 274, 274t
Tumor-infiltrating lymphocytes (TIL)
immunotherapy with, 93, 94f, 264
Tumor necrosis factor-related apoptosis-
inducing ligand (TRAIL), 92
Tumor necrosis factor (TNF), 12
Tumor thrombus
RCC with, 203–204, 203t, 204f, 227f,
228f, 229, 229f
Tunneled ureterointestinal anstomoses, 430
TUR. See Transurethral resection
TURBIT. See Transurethral resection
of bladder tumor
TURP. See Transurethral resection of the
prostate
U. Miami pouch
complications with, 435t
continent reservoirs compared to, 424t
reoperation rate with, 435t
urinary diversion with, 424t, 435t

UCLA Integrated Staging System (UISS)
RCC grade with, 259
RCC staging with, 186–187, 186t, 260, 260f
UCLA PCI. See University of California,
Los Angeles Prostate Cancer Index
UCLA pouch
complications with, 435t
continent colon pouches compared to, 422t
continent reservoirs compared to, 423t
reoperation rate with, 435t
urinary diversion with, 422t, 423t, 435t
UICC. See Union Internationale Contre le
Cancer
UISS. See UCLA Integrated Staging System
Ultrasound (US). See also Focused
ultrasound surgery
brachytherapy guided by, 118–119
AUR with, 119
outcome of, 119
procedure for, 118–119
incidentaloma with, 133
NSGCT diagnosis with, 597, 598f, 599f,
600f
prostate cancer surgery focused with, 122
RCC diagnosing with, 178–179, 179f, 197
renal tumor ablation with, 209–210
Wilms’ tumor evaluation with, 756, 756f
Union Internationale Contre le Cancer
(UICC), 196, 196t, 259
University of California, Los Angeles Prostate
Cancer Index (UCLA PCI)
HRQOL measured with, 105
Upper urinary tract
transitional cell carcinoma in
endoscopic management for, 293–295,
295f, 296f
initial evaluation for, 287
IVP for, 287
laparoscopic radical
nephroureterectomy for, 289–291,
290f, 291f
open nephron-sparing surgery for,
291–293, 292f, 293f
open radical nephroureterectomy for,
287–289, 289f, 291f
open segmental ureterectomy for,
292–293, 293f, 294f
Ureteral orifice injury
TUR complications with, 363
Ureteral-small bowel anstomoses, 427–430,
429f
Ureterectomy
partial
TCC with, 276–277, 277t
Ureterocolonic anstomoses, 430, 431f
Ureteroileal anastomosis
orthotopic bladder substitution with,
446–447, 449f, 450f
Ureterointestinal anastomotic
cutaneous urinary diversion complications
with, 431, 432t
cutaneous urinary diversion with,
427–430, 429f, 430f, 431f
direct type, 427–430, 429f
rectal bladder urinary diversion with, 407f
refluxing v. nonrefluxing, 427
Ureterointestinal anastomotic (Continued)
small bowel, 427–430, 429f
tunneled, 430
ureterocolonic, 430, 431f
Wallace technique for, 430, 430f
Ureterosigmoidostomy
cutaneous urinary diversion complications
with, 434–436
Ureterosignoidostomy
rectal bladder urinary diversion with,
406–407
Ureters
orthotopic bladder substitution with, 446
Urethral anastomosis
orthotopic bladder substitution with,
447–448, 450f, 451f, 453f
Urethral cancer
evaluation of, 675, 676t
females with, 680–682, 680f, 681t, 682f
fossa navicularis, 675, 677t
males with, 673–680, 674f, 676t, 677f,
677t, 678f, 679f
multimodal therapy for, 680
operative techniques for, 676–680,
677f, 678f, 679f
radiation therapy for, 680
urethrectomy with cystectomy for, 680
natural history of, 675–676
partial/total urethrectomy for, 676–680,
677f, 678f, 679f
pathology of, 673–680, 674f, 676t, 677f,
677t, 678f, 679f
penile urethra, 675, 677t
prostatic urethral cancer as, 675–676,
677t
staging of, 675, 676t
treatment of, 675, 677t
Urethral recurrence
orthotopic bladder substitution with,
444
Urethrectomy
cystectomy with, 680
females urethral cancer with, 681–682,
682f
indications for, 686
male urethral cancer with, 676–680, 677f,
678f, 679f
operative technique for, 686–692, 687f,
688f, 689f, 690f, 691f, 692f, 693f,
694f
bulbar urethral arteries in, 691f
bulbocavernous muscle division in, 689f
cystoprostatectomy with, 686–688,
687f, 688f, 689f, 690f, 691f, 692f,
693f
electrocautery in, 689f
female urethrectomy in, 690
larger distal tumors in, 691–692
patient position in, 687f
pelvic dissection in, 686–687, 687f,
688f
perineal dissection in, 687, 688, 689f,
690f, 691f, 692f, 693f
proximal tumors in, 691–692
small distal tumors in, 690–691, 693f,
694f
Index 811
Urethrectomy (Continued)
total male anterior urethrectomy in,
688–690
summary of, 692
Urethrovesical anastomosis
RRP with, 529
Urinary infection
TUR complications with, 363
Urinary stricture
TUR complications with, 363
Urologic cancers
adenovirus vectors gene therapy for,
21–22, 21t, 22f, 26t
aging/telomerase with, 16
aptamers with, 16–17
bulbourethral with, 3, 4f
cancer genes and, 8–10
carcinogens in, 4–5
cell cycle with, 11–12, 12f
cell signaling with, 12f, 14–15, 14f
cellular biology of, 3–17, 4f, 6t, 10f, 12f,
13f, 14f, 15f, 17f
CGH with, 8
enigmas of, 3, 4f
epigenetic effects in, 3–4, 4f
families and, 7–8
gene therapy for, 18–34, 19f, 20f, 21t,
22f, 23f, 24f, 25f, 26t, 27f, 31f,
32f, 33f
gene therapy molecular targets of, 25–33,
26t, 27f, 31f, 32f
gene transfer vectors for, 18–19
inflammation with, 5–7, 6t
liposomal gene transfer for, 21t, 24–25,
24f, 25f, 26t
microarrays with, 10–11
modified vector tropism in, 33–34
molecular biology of, 3–17, 4f, 6t, 10f,
12f, 13f, 14f, 15f, 17f
nature v. nurture in, 4
nonviral vectors gene therapy for, 21t,
24–25, 24f, 25f, 26t
oncolytic virotherapy for, 30
poxvirus vectors therapy for, 21t, 22–24,
23f, 26t
prostate with, 3, 4f
proteomics with, 10–11
restricted transgene expression
in, 34
retrovirus vectors therapy for, 19–21, 19f,
20f, 21t, 26t
ribozyme construct approach to, 30–31,
31f
SKY with, 8
stromal epithelial interactions with,
15–16, 15f
target cell death with, 26t, 29–30
targeting vector specificity in,
33–34, 33f
transcriptional targeting gene therapy
for, 34
tumor cell heterogeneity in, 16–17,
17f
tumor suppressor gene restoration for,
31–33, 32f
US. See Ultrasound
812 Index
U.S. Surveillance, Epidemiology, and End
Results (SEER)
RCC reported by, 173
TCC surgical results from, 277, 279f
Valrubicin
bladder TCC with, 324
Vascular endocrine growth factor (VEGF)
Wilms’ tumor pathology with, 761
Vascular endothelial growth factor (VEGF)
immunotherapy with, 98
RCC antiangiogenic with, 264–265
TCC prognosis with, 341
VEGF. See Vascular endocrine growth
factor; Vascular endothelial growth
factor
Verrucous carcinoma
penis carcinoma with, 712
Vesico-urethral anastomosis
radical prostatectomy with, 522–523,
524f, 525f
Vesicoprostatic dissection
laparoscopic radical prostatectomy with,
538
Vesicourethral anastomosis
laparoscopic radical prostatectomy with,
538
VHL. See Von Hippel-Lindau
Video endoscopy
TUR equipment including, 360
Vinblastine
bladder preservation with, 391t
Vinca alkaloids
genitourinary cancer treatment with,
64–65
Vomiting
orthotopic bladder substitution with, 453t
Von Hippel-Lindau (VHL)
gene, 31
immunotherapy with, 264
pheochromocytoma with, 139, 140t
RCC with, 176, 197t, 264
Vysion
bladder cancer diagnosis with, 305
WAGR syndrome. See Wilms’ tumor and
AGR syndrome
Wallace technique
ureterointestinal anastomoses with, 430,
430f
Watchful waiting (WW)
HRQOL with, 107
WHO. See World Health Organization
Wilms’ tumor
AGR syndrome with, 754, 754t, 759t
bilateral Wilms’ tumor and, 766
BWS syndrome with, 754, 754t, 759t
clinical presentation of, 755
cooperative group trials for, 762–766,
764t, 765f
NWTS-1, 763
NWTS-2, 763
NWTS-3, 763
NWTS-4, 763
NWTS-5, 763–764, 764t
SIOP in, 764–766, 765f
Denys-Drash syndrome with, 753, 758,
759t
differential diagnosis of, 757, 758f
epidemiology of, 753–754, 754t
genetics of, 754–755
late effects of treatment for, 767
pathology of, 757–761, 758f, 758t, 760t
biologic parameters in, 759–761
HA with, 761
HASA with, 761
hTERT with, 760
ILNR with, 758–759, 758f
NSE with, 761
PLNR with, 758–759, 758f
precursor lesions in, 758–759, 758f,
758t, 760t
VEGF with, 761
postoperative evaluation of, 755–757,
756f
CT scan for, 756, 756f, 758f
MRI for, 756
ultrasound for, 756, 756f
prognostic consideration for, 761, 761t
relapse treatment for, 766–767
Simpson-Golabi-Behmel syndrome with,
754
SMN with, 767
surgical management of, 761–762
WAGR syndrome with, 754, 758, 759t
Wilms’ tumor and AGR syndrome (WAGR
syndrome)
Wilms’ tumor with, 754, 758, 759t
Wilms’ tumor gene (WTG)
TCC prognostic markers with, 321
Wood preservatives
retroperitoneal tumors from, 652
World Health Organization (WHO), 196,
302
WTG. See Wilms’ tumor gene
WW. See Watchful waiting
XRT. See External beam radiation therapy