Eduardo Santini-Araujo

Ricardo K. Kalil
Franco Bertoni
Yong-Koo Park
Editors

Tumors and Tumor-Like

Lesions of Bone

For Surgical Pathologists,

Orthopedic Surgeons and
Radiologists

123
Tumors and Tumor-Like Lesions of Bone
Eduardo Santini-Araujo • Ricardo K. Kalil
Franco Bertoni • Yong-Koo Park
Editors

Tumors and Tumor-Like

Lesions of Bone
For Surgical Pathologists,
Orthopedic Surgeons and Radiologists
Editors
Eduardo Santini-Araujo Franco Bertoni
Laboratory of Orthopaedic Pathology Villa Erbosa Hospital
Buenos Aires, Argentina University of Bologna
Bologna, Italy
Ricardo K. Kalil
Laboratory of Orthopaedic Pathology Yong-Koo Park
Buenos Aires, Argentina Department of Pathology
Kyung Hee University Hospital
Seoul, Korea, Republic of (South Korea)

ISBN 978-1-4471-6577-4 ISBN 978-1-4471-6578-1 (eBook)

DOI 10.1007/978-1-4471-6578-1

Library of Congress Control Number: 2015939586

Springer London Heidelberg New York Dordrecht

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To our mentors
Fritz Schajowicz and David Dahlin, two giants of orthopedic pathology, stand
behind us all.
K Krishnan Unni, whose experience, knowledge, charisma, and leadership
influenced all of us, being tireless and obstinate in his long-lasting support
and incentive through several years.
To them, we would like to add those people who had a high influence in our
choices and development in pathology, especially R L Cabrini.

Eduardo Santini-Araujo, Ricardo K. Kalil, Franco Bertoni, Yong-Koo Park

To our families
E Santini-Araujo

Wife Romina and sons and daughters, Maria Gala, Martina, Julian, Pedro
Ferreol, and Margarita
R K Kalil

Wife Angela and daughter, sons, and stepsons, Luciana, Sergio, Marcelo,
Marcio, and Mateus
F Bertoni

My beloved family
Y-K Park

My parents, wife Dan-Young, son Byung-Chul, and daughter Ko-Un

To them, our endless love.
Foreword

The present book on bone tumors and related lesions represents the continuity of a “classic” on
bone tumors by Fritz Schajowicz, one of the most outstanding bone pathologists of all times.
The last edition by Springer-Verlag was published over 20 years ago (Histopathological Typing
of Bone Tumors, 1993) and has been for many years a very useful tool for diagnostic histopa-
thologists all over the world.
This new book maintains the philosophy of its predecessor but is adapted to the new chal-
lenges in the clinical and histological diagnosis of these infrequent tumors providing insights
into therapeutic approaches and their prognostic outcome.
In recent years, the clinical approach to bone tumors has been innovated, thanks to the new
diagnostic imaging techniques that complement conventional radiology with CT scan, PET,
and MR, alone or in combination, thanks to which the diagnostic identification of each tumor
entity is much more precise. Also the microscopic phenotyping of tumors and tumor-like
lesions is more efficient based upon the use of fine-needle aspiration cytology, a technique that
requires a profound knowledge of tissue at the histological level and a good understanding of
bone tumor biology. Moreover, histopathology has been enhanced by new methodological
techniques such as electron microscopy and immunohistochemistry, offering the surgical
pathologist unforeseen possibilities for more accurate differential diagnosis of borderline
lesions or doubtful histological tumor types.
Nevertheless, the handling of bone tumors still requires a high degree of specialization for
all those involved in this pathology, as well as demanding cooperation between all
specialists.
Bone tumors are not exclusively age based nor particularly anatomically related; thus, pedi-
atric and adult orthopedists are frequently involved in simultaneous consultations, which is
also the case for radiologists and oncologists. This affects the surgical pathologist who needs
highly specific training in the field and a case-by-case analysis of each patient in close coop-
eration with their clinical colleagues. Precisely one of the major aims of this book is to cover
this necessity, providing the informative doctrine needed for this end.
Today everyone is pressed for time and, when trying to acquire new knowledge on a field or
looking for a precise diagnosis, needs to find clearly explained concepts in a short, readable,
informative format. This guideline has been followed by each author, thus providing a clear
structure to each chapter. Long academic case discussions and details on etiopathological anal-
ysis have been avoided, compiling brief information on the most update available
publications.
Of course no book today can cover all the available literature on a given field or for a par-
ticular tumor type, but should contain, as in this new book on bone tumors, the most up-to-date
data to facilitate the best practical clinical handling of the patient’s pathology.
The present book aims to cover all these objectives, approaching the diagnosis of bone
tumors in a dynamic form and placing the histopathologist at the center of the game, perform-
ing both cytology and histology and working in close cooperation with the radiologist and the
orthopedic surgeon. Nevertheless, the clinical orthopedist and oncologist have to be aware of
the difficulty of some cases in which the true nature of the process is unpredictable or the final

vii
viii Foreword

diagnosis cannot be established with absolute precision. To help in clarifying the tumor type,
each chapter provides clues for the differential diagnosis, facilitating this task.
Today, the new advances in the molecular biology of cancer attract particular attention,
especially in the case of bone disease and bone tumors. Major interest is devoted to this field
and in the practical applications oriented toward the differential diagnosis and prognosis. This
is a completely new field not generally covered by other bone tumor books due to its continu-
ous advances and novelties.
The present book is a collaborative cooperation by numerous highly distinguished bone and
osteoarticular pathologists, under the outstanding guidance of the four main editors: Drs.
Eduardo Santini-Araujo (Argentina), Ricardo K. Kalil (Brazil), Franco Bertoni (Italy), and
Yong-Koo Park (Korea). All are well known in this field, and their multiple contributions to the
literature of bone pathology reinforce the high quality not only of their own chapters but also
that of the ample selection of coauthors heading each chapter. Many of them are leaders in
their field and provide seminal and novel information in a clear and practical format in which
not only high-quality histological images exemplify each chapter but also excellent diagnostic
illustrations complement the comprehensive overview of the patient pathology in which major
clinical insights are also considered.
Particular thanks go to these colleagues, all editors, or authors in their own right, for having
agreed to participate in this new challenge, adding their admirable expertise to the work. In this
context, we want to extend our warmest appreciation to them.
Most essential has been the task performed by Springer-Verlag in providing the orientation
to maintain the high quality of the book and also in accepting the additional costs involved in
producing the comprehensive iconography considered necessary by all four editors to attain
the level of excellence and utility of this book.

Valencia, Spain Antonio Llombart-Bosch, MD, PhD

Preface

The overall intention of this book is to provide day-to-day assistance in tumors and tumor-like
lesions of bone, for general surgical pathologists, radiologists, and orthopedic surgeons, with
practical image diagnosis, histopathological and molecular diagnosis, and basic therapeutic
guidelines.
Our main objective is to provide the essential information that any orthopedic surgeon,
radiologist, and surgical pathologist, whether general or specialized, in practice or training,
needs for evaluating a patient with a lesion in the area of orthopedic pathology.
The philosophy of the book is to offer generous coverage of epidemiology, clinical features,
radiology, pathology, and differential diagnosis not only for the distribution of the statistical
average of the lesion’s features but also to illustrate the standard deviations, including the clues
in the images and histopathology needed to arrive at a sharp differential diagnosis.
To achieve this goal, we gathered a selected team of the more experienced and knowledge-
able people in this field in the world, in pathology, imaging diagnosis, and oncologic orthope-
dic surgery, and who, generously, made available their unsurpassed expertise in order to make
this a most valuable tool for the practical diagnosis of tumors and tumor-like lesions of the
bone.

Buenos Aires, Argentina Eduardo Santini-Araujo

Buenos Aires, Argentina Ricardo K. Kalil
São Paulo, SP, Brazil
Bologna, Italy Franco Bertoni
Seoul, South Korea Yong-Koo Park

ix
Acknowledgments

Our first acknowledgment goes, naturally, to our dear friend and advisor, Antonio Llombart-
Bosch, for his deep involvement and permanent support during the development of this book.
To build this book, we had the inestimable helping hand of selected collaborators, already
mentioned in the preface, and who are listed in the following pages. To them goes our deep
acknowledgment. They were brilliant and added irreplaceable information and data, without
which this book would never have attained its goal and would have not been completed in time.
All the epidemiological drawings and schemes were contributed by Dr. Blas Dios.
Besides them, it is important to mention the importance that some people and institutions
had in the professional evolution of some of us in various ways.
I, Eduardo Santini-Araujo, would like to express my debt of gratitude to my mentor in
Orthopedic Pathology, Prof. Fritz Schajowicz, to whom I had the privilege of assisting for
15 years and also to the University of Buenos Aires, School of Medicine, and especially the
School of Dentistry that under the successive leadership of Profs. R L Cabrini, M E Itoiz, and
M B Guglielmotti allowed me to carry out several research works. In like manner, I would like
to thank the Radiobiology Department of the Atomic Energy National Commission where I
have been working for decades under the tutorship of its Research and Development Director
Dr. R L Cabrini, a mentor in pathology and in life, with the permanent collaboration of my
colleague and friend Dr. A M Ubios. My warm gratitude to the team of the Laboratory of
Orthopedic Pathology in Buenos Aires, especially to Dr. L Olvi and Dr. M L Gonzalez; my
collaborators W Escalante, M Arevalo, M Santini-Araujo, and L Pecina; and to our photogra-
phers T Benitez and A Gonzalez Llanos. And last but not least, I would really like to thank
very much the A. C. Camargo Cancer Center, Sao Paulo, Brazil, especially Drs. J J Salto Jr, F
A Soares, and A Nascimento for generously having treated and taken care of me.
My (Ricardo K. Kalil) deep thanks go to Dr. H H Japp, who influenced me to go into pathol-
ogy, a friend of all time, and then to Dr. Claudio Lemos and Dr. C J Campbell who unselfishly
opened their experience and their files to me in my early steps in Orthopedic Pathology. A
selected team of British pathologists – Drs. H A Sissons, M Catto, and C Godfrey-Price – also
left their permanent print in my background. Then, to Sarah Network of Rehabilitation
Hospitals, in Brazil, by allowing me to start, grow professionally, and get more than 40 years
of experience in the field. The support of its directive body, led by Dr. A Campos da Paz and
Dr. L W Braga, as well as of the whole medical team, was paramount to achieve the high level
of pathology that was attained. The institutional view of the patient as the objective and final
goal of its work influenced definitely the way I look at medicine in general and pathology in
particular. A special mention goes to the exceptional team constituted by my young colleagues
in the institution, Drs. J S Antunes, F S Souza, A Monteiro Jr, H B de Moura, A P B Pinto, I C
Brandao, F Indelli, M I Lima, E B Silveira, and A Lacerda. Also thanks to L Sollaci, the insti-
tution head librarian, for being always at hand with her expert help and advice.
I, Franco Bertoni, thank my colleague Dr. Patrizia Bacchini for her strong support and con-
tribution. I consider myself lucky in having the opportunity to spend time with great mentors
as Drs. Dave Dahlin and Kris Unni that were not only teachers in bone pathology but deep
friends and example in wise style of life.

xi
xii Acknowledgments

I, Yong-Koo Park, would like to express my deep gratitude to my mentors, Drs. Yang, Moon
Ho, and Lee, Jung Dal, for giving me valuable advice and lessons when I was taking the first
step as a pathologist. My sincere thanks go also to Dr. Ryu, Kyung Nam, and the staff of the
Departments of Pathology and Diagnostic Radiology in Kyung Hee University Hospital. In
particular, Ms. Yoon, Minji merits special mention for she has taken on all the stressful, com-
plicated tasks.
Needless to say, to our families, as mentioned in the Dedication, who abdicated of so much
time of living together as well as by taking charge of many of our daily duties, out of pure love,
allowing us to concentrate so much time and effort in the production of this book.
To the editors of Springer-Verlag, especially Joanna Bolesworth who escorted us all the
way with editorial advice and constant contact, we also dedicate a special acknowledgment.

Buenos Aires, Argentina Eduardo Santini-Araujo

Buenos Aires, Argentina Ricardo K. Kalil
São Paulo, SP, Brazil
Bologna, Italy Franco Bertoni
Seoul, South Korea Yong-Koo Park
Contents

Part I Introduction

1 Practical Approach to the Diagnosis of Bone Tumors . . . . . . . . . . . . . . . . . . . 3

Eduardo Zambrano and K. Krishnan Unni
2 An Imaging Approach to Bone Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Darlene M. Holden, Hakan Ilaslan, and Murali Sundaram
3 Methods of Bone Biopsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
Eduardo Santini-Araujo, Ricardo K. Kalil, Blas Dios,
and Rómulo L. Cabrini
4 Basic and Ancillary Techniques in Bone Pathology . . . . . . . . . . . . . . . . . . . . . 73
Yong-Koo Park
5 Grading and Staging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
Yong-Koo Park
6 Surgical Treatment of Tumors and Tumorlike Lesions of Bone . . . . . . . . . . . 89
Brian E. Walczak, Peter S. Rose, Joel M. Post, and Franklin H. Sim

Part II Bone-Forming Tumors

7 Medullary Osteoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109

Liliana G. Olvi, Gustavo M. Lembo, and Eduardo Santini-Araujo
8 Parosteal Osteoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
Liliana G. Olvi, Gustavo M. Lembo, and Eduardo Santini-Araujo
9 Osteoid Osteoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
Liliana G. Olvi, Gustavo M. Lembo, and Eduardo Santini-Araujo
10 Osteoblastoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151
Liliana G. Olvi, Gustavo M. Lembo, Osvaldo Velan,
and Eduardo Santini-Araujo
11 Conventional Central Osteosarcoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175
Franco Bertoni and Patrizia Bacchini
12 Osteosarcoma of the Jaws . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207
María L. Paparella and Rómulo L. Cabrini
13 Parosteal Osteosarcoma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217
Carrie Y. Inwards and Doris Wenger
14 Periosteal Osteosarcoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227
Carrie Y. Inwards and Doris Wenger

xiii
xiv Contents

15 High-Grade Surface Osteosarcoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235

Carrie Y. Inwards and Doris Wenger

Part III Cartilage-Forming Tumors

16 Enchondroma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243
Yong-Koo Park
17 Multiple Enchondromatosis (Ollier’s Disease) . . . . . . . . . . . . . . . . . . . . . . . . . 253
Yong-Koo Park
18 Periosteal Chondroma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259
Yong-Koo Park
19 Osteochondroma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265
Yong-Koo Park
20 Multiple Osteochondromatosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273
Yong-Koo Park
21 Chondroblastoma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277
Yong-Koo Park
22 Chondromyxoid Fibroma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287
Yong-Koo Park
23 Chondrosarcoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295
Sergio Piña-Oviedo, Jae Y. Ro, Alberto G. Ayala, and Yong-Koo Park

Part IV Giant Cell Tumor

24 Giant Cell Tumor of Bone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351

Ricardo K. Kalil

Part V Round Cell Tumors

25 Ewing’s Sarcoma Family of Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369

Isidro Machado and Antonio Llombart-Bosch
26 Lymphoma of Bone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 385
S. Fiona Bonar
27 Myeloma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 413
Michael J. Klein

Part VI Fibrous Tumors

28 Desmoplastic Fibroma of Bone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 427

Ricardo K. Kalil
29 Fibrosarcoma of Bone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 435
Ricardo K. Kalil

Part VII Fibrohistiocytic Tumors

30 Benign Fibrous Histiocytoma of Bone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 443

Ricardo K. Kalil
31 Malignant Fibrous Histiocytoma of Bone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 451
Ricardo K. Kalil
Contents xv

Part VIII Vascular Tumors

32 Hemangioma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 461
Liliana G. Olvi, Maria L. Gonzalez, and Eduardo Santini-Araujo
33 Epithelioid Hemangioma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 479
Ricardo K. Kalil
34 Glomus Tumor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 487
Ricardo K. Kalil
35 Epithelioid Hemangioendothelioma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 495
Ricardo K. Kalil
36 Angiosarcoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 507
Ricardo K. Kalil

Part IX Adamantinoma

37 Adamantinoma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 517
Edward McCarthy

Part X Notochordal Tumors

38 Benign Notochordal Cell Tumor. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 523

Yasuaki Nakashima
39 Chordoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 533
Yasuaki Nakashima

Part XI Leiomyosarcoma

40 Leiomyosarcoma of Bone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 557

Ricardo K. Kalil

Part XII Adipocytic Tumors

41 Lipoma of Bone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 563

Ricardo K. Kalil
42 Liposarcoma of Bone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 569
Ricardo K. Kalil

Part XIII Neurogenic Tumors

43 Schwannoma of Bone. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 577

Ricardo K. Kalil
44 Neurofibroma of Bone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 583
Ricardo K. Kalil

Part XIV Phosphaturic Mesenchymal Tumor

45 Phosphaturic Mesenchymal Tumor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 589

Ricardo K. Kalil
xvi Contents

Part XV Metastatic Carcinoma Involving Bone

46 Metastatic Bone Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 601

Patrizia Bacchini and Franco Bertoni

Part XVI Tumorlike Lesions and Other Conditions That Simulate Primary
Bone Tumors

47 Simple Bone Cyst . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 611

Liliana G. Olvi, Gustavo M. Lembo, Osvaldo Velan,
and Eduardo Santini-Araujo
48 Aneurysmal Bone Cyst . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 635
Liliana G. Olvi, Gustavo M. Lembo, Osvaldo Velan,
and Eduardo Santini-Araujo
49 Juxta-articular Bone Cyst . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 683
Liliana G. Olvi, Gustavo M. Lembo, Osvaldo Velan,
and Eduardo Santini-Araujo
50 Epidermoid Bone Cyst. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 701
Liliana G. Olvi, Maria L. Gonzalez, Osvaldo Velan,
and Eduardo Santini-Araujo
51 Metaphyseal Fibrous Defect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 709
Liliana G. Olvi and Eduardo Santini-Araujo
52 Periosteal Desmoid. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 731
Liliana G. Olvi and Eduardo Santini-Araujo
53 Fibrous Dysplasia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 737
Liliana G. Olvi and Eduardo Santini-Araujo
54 Osteofibrous Dysplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 769
Liliana G. Olvi, Maria L. Gonzalez, and Eduardo Santini-Araujo
55 Myositis Ossificans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 777
Liliana G. Olvi and Eduardo Santini-Araujo
56 Giant Cell Reparative Granuloma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 793
Liliana G. Olvi, Maria L. Gonzalez, and Eduardo Santini-Araujo
57 Central Giant Cell Granuloma of the Jaws. . . . . . . . . . . . . . . . . . . . . . . . . . . . 801
María L. Paparella and Rómulo L. Cabrini
58 Langerhans Cell Histiocytosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 805
Ricardo K. Kalil
59 “Brown Tumor” of Hyperparathyroidism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 815
Liliana G. Olvi and Eduardo Santini-Araujo
60 Avulsion Injury. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 827
Liliana G. Olvi, Maria L. Gonzalez, and Eduardo Santini-Araujo
61 Bizarre Parosteal Osteochondromatous Proliferation . . . . . . . . . . . . . . . . . . . 833
Liliana G. Olvi, Maria L. Gonzalez, and Eduardo Santini-Araujo
62 Fibro-osseous Pseudotumor of Digits. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 841
Liliana G. Olvi and Eduardo Santini-Araujo
Contents xvii

63 Subungual Exostosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 847

Liliana G. Olvi, Maria L. Gonzalez, and Eduardo Santini-Araujo
64 Stress Fracture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 851
Liliana G. Olvi, Maria L. Gonzalez, and Eduardo Santini-Araujo
65 Bone Infarct . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 857
Liliana G. Olvi and Eduardo Santini-Araujo
66 Paget’s Disease of Bone and Sarcoma Complicating
Paget’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 875
Liliana G. Olvi, Maria L. Gonzalez, and Eduardo Santini-Araujo
67 Gaucher Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 895
Michael J. Klein
68 Gout . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 905
Michael J. Klein
69 Osteomyelitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 917
Michael J. Klein
70 Amyloidosis in Bone. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 933
Edward McCarthy
71 Mastocytosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 939
S. Fiona Bonar and Edward McCarthy
72 Erdheim-Chester Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 951
Edward McCarthy
73 Rosai-Dorfman Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 957
Edward McCarthy
74 Transient Osteoporosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 961
Edward McCarthy
75 Traumatic Osteolysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 965
Edward McCarthy
76 Chest Wall Hamartoma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 969
Ricardo K. Kalil
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 973
Contributors

Alberto G. Ayala, MD Department of Pathology and Genomic Medicine,

Methodist Hospital Physician Organization, Houston, TX, USA
Houston Methodist Research Institute, Houston, TX, USA
Weill Cornell Medical College of Cornell University, Houston, TX, USA
Patrizia Bacchini, MD Department of Surgical Pathology, Private Hospital Villa Erbosa,
Bologna, Italy
Franco Bertoni, MD University of Bologna, Bologna, Italy
Surgical Pathology Department, Istituto Rizzoli, Bologna, Italy
Department of Surgical Pathology, Villa Erbosa Hospital, Bologna, Italy
S. Fiona Bonar, MB, BCH, BAO, FRCPI, FRCPath, FRCPA Department of Anatomical
Pathology, Douglass Hanly Moir Pathology, Sydney, NSW, Australia
Rómulo L. Cabrini, MD, PhD Department of Oral Pathology, School of Dentistry,
University of Buenos Aires, Buenos Aires, Argentina
Blas Dios, MD Department of Radiology, “Prof. Dr. Luis Güemes” General Hospital,
Buenos Aires, Argentina
Maria L. Gonzalez, MD Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina
Darlene M. Holden, MD Musculoskeletal Section, Imaging Institute, Cleveland Clinic,
Cleveland, OH, USA
Hakan Ilaslan, MD Department of Diagnostic Radiology, Imaging Institute,
Cleveland Clinic, Cleveland, OH, USA
Carrie Y. Inwards, MD Division of Anatomic Pathology, Mayo Clinic, Rochester,
MN, USA
College of Medicine, Mayo Clinic, Rochester, MN, USA
Ricardo K. Kalil, MD Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina
Department of Pathology, A.C. Camargo Cancer Center, São Paulo, SP, Brazil
Michael J. Klein, MD Department of Pathology and Laboratory Medicine,
Hospital for Special Surgery, New York, NY, USA
Gustavo M. Lembo, MD Department of Pathology, Centenary Hospital Rosario
Santa Fe Argentina, Rosario, Santa Fe, Argentina
Antonio Llombart-Bosch, MD, PhD Department of Pathology, University of Valencia
Medical School, Valencia, Spain

xix
xx Contributors

Isidro Machado, MD Department of Pathology, Instituto Valenciano de Oncologia/IVO,

Valencia, Spain
Edward McCarthy, MD Department of Pathology and Orthopaedic Surgery,
Johns Hopkins Hospital, Baltimore, MD, USA
Yasuaki Nakashima, MD, PhD Laboratory of Anatomic Pathology,
Kyoto University Hospital, Kyoto, Japan
Liliana G. Olvi, MD Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina
Maria L. Paparella, PhD Department of Oral Pathology, School of Dentistry,
University of Buenos Aires, Buenos Aires, Argentina
Yong-Koo Park, MD, PhD Department of Pathology, Kyung Hee University
School of Medicine, Seoul, South Korea
Sergio Piña-Oviedo, MD Department of Pathology, Houston Methodist Hospital,
Houston, TX, USA
Joel M. Post, DO Orthopedic Oncology, Mayo Clinic, Rochester, MN, USA
Jae Y. Ro, MD Department of Pathology and Genomic Medicine,
Houston Methodist Hospital, Weill Cornell University, Houston, TX, USA
Peter S. Rose, MD Department of Orthopaedic Surgery, Mayo Clinic, Rochester,
MN, USA
Eduardo Santini-Araujo, MD, PhD Department of Pathology, School of Medicine and
School of Dentistry, University of Buenos Aires, Buenos Aires, Argentina
Central Army Hospital, Buenos Aires, Argentina
Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina
Franklin H. Sim, MD Department of Orthopaedic Surgery, Mayo Clinic, Rochester,
MN, USA
Murali Sundaram, MD, FRCR Imaging Institute, Cleveland Clinic, Cleveland, OH, USA
K. Krishnan Unni, MD Froedtert/Medical College of Wisconsin Laboratory, Milwaukee,
WI, USA
Osvaldo Velan, MD Department of Radiology, Italian Hospital of Buenos Aires,
Buenos Aires, Argentina
Brian E. Walczak, DO Musculoskeletal Oncology and Reconstruction,
McLaren Cancer Institute – McLaren Macomb, Mount Clemens, MN, USA
Doris Wenger, MD Department of Diagnostic Radiology, Mayo Clinic, Rochester,
MN, USA
Eduardo Zambrano, MD Froedtert/Medical College of Wisconsin Laboratory,
Milwaukee, WI, USA
 Part I
Introduction
 Practical Approach to the Diagnosis
of Bone Tumors 1
Eduardo Zambrano and K. Krishnan Unni

Abstract
As with lesions of any other organ system, many bone tumors are easy to diagnose, but a
few will be difficult. Careful attention to clinical features and roentgenograms should make
most bone tumors straightforward. The plain film is the most important image which is
helpful in diagnosis. Bone tumors are classified depending on the kind of matrix produced
or the cytology of the tumor cells in cases without matrix production. The cases are then
divided into benign and malignant counterparts. The staging system uses two criteria: the
histological grade and extent of the tumor, i.e., where it involved only one compartment or
more than one. The grading system is similar to the one proposed by Broders.

General surgical pathologists have been led to believe that
bone tumors and tumorlike lesions are complicated and
require a specialist pathologist to render a diagnosis. Nothing
could be further from the truth. Bone tumors are not any
more difficult than breast cancer. As with lesions of any other
organ system, many bone tumors are easy to diagnose but a
few will be difficult. On the one hand, roentgenograms are
so important in the diagnosis of bone tumors that familiarity
with them provides a distinct advantage. On the other hand,
bone tumors are extremely uncommon so that most patholo-
gists do not get to see enough of them to feel comfortable.
But careful attention to clinical features and roentgenograms
should make most bone tumors to be straightforward.
Clinical Features
With a few notable exceptions, symptoms are not specific in
bone tumor pathology. Most patients present with pain, swell-
ing, or a pathologic fracture. Osteoid osteoma with its charac-
E. Zambrano, MD (*) • K.K. Unni, MD
Froedtert/Medical College of Wisconsin Laboratory,
Milwaukee, WI, USA
e-mail: ezambrano@stanfordhealthcare.org
teristic pain pattern is a notable exception. Occasionally the
symptoms can be misleading as with Ewing sarcoma, which
may present with fever, suggesting osteomyelitis. Laboratory
investigations are relatively unimportant with the exception
of myeloma with its characteristic serum and urine findings.
Roentgenographic Findings
The term roentgenographic is used in this chapter to include
plain films, computerized tomograms, and magnetic reso-
nance images. Almost without exception, the plain film is the
most important image which is helpful in diagnosis. It is
good practice for pathologists to be reasonably familiar with
the images, although having a competent radiologist’s help is
more important.
Roentgenographic appearance has been classified into
three groups: geographic, moth eaten, and permeative. The
term geographic refers to a lytic area of bone destruction
(Fig. 1.1). If such an area is surrounded by a rim of sclerosis,
a benign process is most likely (Fig. 1.2). If there is a sharp
line of demarcation from normal bone, again, a benign pro-
cess is highly probable (Fig. 1.3). If there is no sharp demar-
cation, an aggressive process is likely (Fig. 1.4).
The roentgenographic appearance is said to be moth eaten
if there are multiple, tiny lucencies admixed with normal

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 3
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_1, © Springer-Verlag London 2015
4 E. Zambrano and K.K. Unni

appearing bone (Fig. 1.5). This appearance suggests an Fibrogenic

aggressive lesion such as lymphoma. Benign: Desmoplastic fibroma
Permeative describes a process in which there are multi- Malignant: Fibrosarcoma
ple tiny lucencies coursing through bone (Fig. 1.6). The
appearance may deceptively look like normal bone. Smooth Muscle
Permeative lesions are usually associated with small cell Benign: Leiomyoma
malignancies such as Ewing sarcoma. It has to be remem- Malignant: Leiomyosarcoma
bered that osteomyelitis can present with any of these pat-
terns and suggest a neoplasm. Tumors of Unknown Origin
Computerized tomograms (CT) are not especially useful Benign: Giant cell tumor
except for identifying small amounts of mineral and Malignant: Malignant giant cell tumor, Ewing sarcoma,
identifying the nidus of osteoid osteoma (Fig. 1.7a–c). It adamantinoma
may also be helpful in anatomically complicated locations
such as the spine. Vascular
Magnetic resonance imaging (MRI) has become rou- Benign: Hemangioma
tine in the management of bone tumors. The features are Malignant: Angiosarcoma, hemangiopericytoma
generally nonspecific and do not help in diagnosis. But it
is the best modality for accurately delineating the extent of Fibrohistiocytic
a tumor. Measurements are made before chemotherapy is Benign: Fibrous histiocytoma
commenced in order to resect the involved segment of bone Malignant: Malignant fibrous histiocytoma
post-chemotherapy.
Notochordal
Malignant: Chordoma
Classification
Lipogenic
Dr. Lichtenstein presented a classification scheme that has Benign: Lipoma
stood the test of time. The tumors are classified depending on Malignant: Liposarcoma
the kind of matrix produced or the cytology of the tumor
cells in cases without matrix production. The cases are then Neurogenic
divided to benign and malignant counterparts. Benign: Neurilemmoma
Malignant: None
In the last published series from the Mayo Clinic,
Classification Scheme malignant tumors were more than twice as common as
benign tumors. This probably does not mean that this is
Chondrogenic the true distribution of malignant tumors and benign
Benign: Osteochondroma, chondroma, chondroblastoma, tumors. Malignant tumors are less likely to be asymptom-
chondromyxoid fibroma atic and more likely to be referred to a major medical
Malignant: Chondrosarcoma and variants center.

Osteogenic
Benign: Osteoid osteoma and osteoblastoma Gross Examination
Malignant: Osteosarcoma and variants
Fine needle biopsies and needle biopsies are done more and
Hematopoietic more frequently in the diagnosis of bone tumors (Fig. 1.8a–c).
Benign: N/A They are excellent for confirming the presence of metastatic
Malignant: Myeloma and lymphoma carcinoma. They are less reliable in benign tumors and
1 Practical Approach to the Diagnosis of Bone Tumors
especially in conditions which mimic neoplasms. One problem
is that more and more special tests are being done and tissue
obtained by fine needle aspiration may not be sufficient.
One important fact to keep in mind with respect to core
needle biopsies and curettage specimens is that more bone
tumors are soft than firm and can be processed without
decalcification. If a large amount of tissue is received
which contains bony fragments, the soft tissue should be
carefully separated from bone so that it can be processed
without decalcification. Even in heavily calcified tissues
one can usually find enough soft material for separate
handling.
For larger resection specimens, one needs very little in the
way of equipment: a band saw, a butcher’s meat saw, and a
device to hold the bone while being cut. It is necessary to
have the bone saw in an enclosed space so that bone dust
does not spread. Our preferred method for handling gross
specimens is to separate the bone and the tumor from the sur-
rounding soft tissues. The bone is then sliced open with a
band saw. Thin slices of bone need to be taken so that
decalcification can be swift. This will cause the least amount
of artifact. The gross specimen should be washed with gentle
brushing to remove the bone dust which is invariably present
after sawing. Not only does the dust allow for a dirty gross
5
photograph but it can be present in the microscopic sections
obscuring an underlying process.
Grading and Staging
The staging system adopted by the Musculoskeletal Tumor
Society has been universally accepted. The staging system
uses two criteria: the histological grade and extent of the
tumor, i.e., where it involved only one compartment or more
than one. The grading system is similar to the one proposed
by Broders almost 100 years ago. The predominant feature
used is nuclear atypia; the second criterion is cellularity. Not
all malignant tumors can be histologically graded.
Chondrosarcomas, osteosarcomas, fibrosarcomas, and angio-
sarcomas can be graded. Small cell malignancies cannot be
graded because they are so monomorphic. For practical pur-
poses, Ewing sarcoma is always considered high grade.
Thus the staging system will be stage I for all low-grade
tumors and stage II for high-grade tumors. For neoplasms
confined to one compartment, the stage is considered A,
whereas if more than one compartment is involved, it is stage
B. All tumors with distant metastasis are stage III regardless
of other considerations.
6 E. Zambrano and K.K. Unni

Fig. 1.1 Plain film image demonstrating geographic pattern in eosino-

philic granuloma of the skull

Fig. 1.3 Fibrous dysplasia in the upper end of a femur with a sharp line
of demarcation (arrow)

Fig. 1.2 Plain film image showing peripheral sclerosis in a metaphy-

seal fibrous defect of the upper end of the tibia
1 Practical Approach to the Diagnosis of Bone Tumors 7

Fig. 1.5 Plain film image: moth-eaten pattern in lymphoma involving

Fig. 1.4 Giant cell tumor of the upper end of a tibia showing no sharp humerus, associated with pathologic fracture
demarcation

Fig. 1.6 Plain film image: permeative pattern with multiple tiny lucen-
cies in Ewing sarcoma of femur
8 E. Zambrano and K.K. Unni

a b

Fig. 1.7 (a–c) Osteoid osteoma in a cervical vertebral lamina. CT scan is helpful in complicated locations such as the spine
1 Practical Approach to the Diagnosis of Bone Tumors 9

a b

Fig. 1.8 (a–c) Fine and core needle biopsies are done more frequently in the diagnosis of bone tumor
10 E. Zambrano and K.K. Unni

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Lyall HA, Constant CR, Wraight EP. Case report: Ewing’s sarcoma in
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 An Imaging Approach to Bone Tumors
2
Darlene M. Holden, Hakan Ilaslan, and Murali Sundaram

Abstract
When evaluating a bone tumor, a systematic approach should be used taking into consid-
eration the clinical and laboratory findings along with the imaging appearance to arrive at
a differential diagnosis. Attention should be paid to the age of the patient and the location
of the lesion, and comparison with prior examinations should be made when possible.
Awareness of the spectrum of non-neoplastic reactive, metabolic, inflammatory, and
infectious as well as iatrogenic and developmental lesions must also be taken into account
as these can mimic a primary bone tumor. Radiographs are the mainstay and most cost-
effective imaging modality for the evaluation of bone tumors. CT and MRI are particu-
larly useful in areas of complex anatomy and for staging.

In the broad realm of malignancies, primary sarcomas of the
bone are rare, accounting for only 0.2 % of all cancers in the
United States, as reported by the National Cancer Institute’s
Surveillance, Epidemiology, and End Results (SEER) pro-
gram. This amounts to 3,010 new cases estimated in 2013, a
small number compared to the 1,660,290 estimated total new
cancer cases. In the adult population, osseous metastatic dis-
ease is vastly more common: the bone is the third most fre-
quent site of metastasis after the lungs and liver. Cancers in
children and adolescents in general are rare; however, pri-
mary malignant bone tumors are more common in this age
group than in adults. Approximately 4 % of all cancers in
children are primary bone sarcomas. The most common is
osteosarcoma, with a smaller incidence of Ewing sarcoma.
The American Cancer Society reports an annual incidence of
D.M. Holden, MD (*)
Musculoskeletal Section, Imaging Institute, Cleveland Clinic,
Cleveland, OH, USA
e-mail: holden_dm@yahoo.com
H. Ilaslan, MD
Department of Diagnostic Radiology, Imaging Institute, Cleveland
Clinic, Cleveland, OH, USA
M. Sundaram, MD, FRCR
Imaging Institute, Cleveland Clinic, Cleveland, OH, USA
800 cases of osteosarcoma, with most cases occurring in
children and young adults and a smaller peak in the elderly
arising de novo, in Paget’s disease, or following radiation.
Chondrosarcoma is the second most common primary sar-
coma of the bone overall and is the most common primary
bone sarcoma in adults, accounting for more than 40 % of
cases per year in the United States. Benign bone tumors and
tumorlike lesions in both children and adults are encountered
more often than primary bone sarcomas. Although the esti-
mated incidence of these benign bone lesions has been
described based on large pathologically proven series, the
actual incidence is likely higher, because many of these
lesions, when incidentally discovered on imaging, are appro-
priately left alone without biopsy because of their established
biological inertia. Additionally because of the asymptomatic
nature of these lesions, many more go undetected. When
evaluating a bone tumor, a systematic approach should be
used, taking into consideration the clinical and laboratory
findings along with the imaging appearance to arrive at a
plausible and limited differential diagnosis. Particular atten-
tion should be paid to the age of the patient and the location
of the lesion, and comparison with prior examinations should
always be made when possible. An awareness of the spec-
trum of nonneoplastic reactive, metabolic, inflammatory, and
infectious as well as iatrogenic and developmental lesions

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 11
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_2, © Springer-Verlag London 2015
12 D.M. Holden et al.

Table 2.1 Most common tumors by patient age Table 2.2 Common tumors and tumorlike lesions by site
Age Tumor Epiphysis
First and second decade Nonossifying fibroma Chondroblastoma (open physis)
Unicameral bone cyst Giant cell tumor (closed physis, subarticular)
Aneurysmal bone cyst Osteomyelitis
Chondroblastoma Clear cell chondrosarcoma
Langerhans cell histiocytosis Metaphysis
Osteosarcoma Nonossifying fibroma (eccentric)
Ewing sarcoma Unicameral bone cyst (central)
Third through fifth decade Giant cell tumor Enchondroma
Lymphoma Aneurysmal bone cyst
Parosteal osteosarcoma Osteoid osteoma
Fourth decade and above Metastasis Osteoblastoma
Myeloma Osteosarcoma
Chondrosarcoma Chondrosarcoma
Chordoma Malignant fibrous histiocytoma
Lymphoma Lymphoma
MFH Diaphysis
Fibrous dysplasia
Enchondroma
must also be taken into account, as these can mimic a pri- Osteofibrous dysplasia
mary bone tumor. In the setting of osteoarthritis, for exam- Adamantinoma
ple, a well-defined lytic subchondral lesion adjacent to the Ewing sarcoma
joint should be recognized as a subchondral cyst and should Periosteal osteosarcoma
not be mistaken for a more sinister lesion. Likewise, a nor- Lymphoma
mal variant supracondylar process of the humerus should not
be confused with an osteochondroma. Iatrogenic lesions Table 2.3 Select benign entities that may be multiple at presentation
such as bone graft harvest sites and bone defects relating to
Brown tumors in hyperparathyroidism
previous surgery (e.g., from biceps tenodesis) can also be
Enchondromatosis
confidently diagnosed by the characteristic location and
Fibrous dysplasia
appearance along with surgical history. When a suspected Hemangiomatosis
neoplastic lesion is encountered, patient care should be opti- Langerhans cell histiocytosis
mized through the use of a team approach, with a collabora- Nonossifying fibromas (Jaffe-Campanacci syndrome)
tive effort between the radiologist, pathologist, and Osteochondromatosis
orthopedic oncologic surgeon. Paget’s disease
Because of the predilection for a certain age and location, SAPHO
these are two critical factors to consider when evaluating a
bone tumor, and this cannot be overemphasized. The differ-
ential diagnosis can be narrowed using these factors even the epiphysis, metaphysis, or diaphysis or in the axial plane,
before taking the imaging appearance into consideration. being intramedullary, cortically based, or occurring on the
Age and location are so important, in fact, that although bone surface), the bone involved can also often limit the dif-
exceptions do exist, when a lesion is found outside of the ferential. In the rib, for example, the most common benign
established age group or at an unusual site, suspicion of the lesion is fibrous dysplasia, whereas the most common malig-
diagnosis is warranted (Tables 2.1 and 2.2). For example, nant lesion is metastasis. Chondrosarcoma, the most com-
chondroblastoma is an epiphyseal lesion found in childhood mon primary malignant rib neoplasm, occurs much less
and should not be considered in the differential for a lytic frequently. In the phalanges of the hand, the most common
lesion at a different site within the bone or after about the bone tumor is an enchondroma, and in the tibia, the classic
second decade. Langerhans cell histiocytosis likewise occurs examples are adamantinoma and osteofibrous dysplasia,
most commonly in children and should not be included in the which occur almost without exception in this location. The
differential for an osteolytic lesion in an adult. After the age number of lesions, as well as additional features such as mar-
of 40, metastatic disease (most commonly from breast, pros- gins, zone of transition, matrix mineralization, and periosteal
tate, lung, renal, or thyroid cancer) or myeloma is far more reaction, can then be used to narrow the differential diagno-
likely than a primary bone tumor. Along with the lesion’s sis. Select benign tumors and tumorlike lesions that may be
location within the bone (either longitudinally centered in multifocal are summarized in Table 2.3.
2 An Imaging Approach to Bone Tumors
Imaging Modalities
Radiographs
Although various imaging modalities are available, radio-
graphs are the mainstay and most cost-effective imaging
modality for the evaluation of bone tumors. Further evalua-
tion, if necessary, would depend on the radiographic interpre-
tation. In some instances, lesions have such a characteristic
radiographic appearance that the diagnosis can be confidently
made with radiographs, and no further imaging is needed.
Nonossifying fibroma and fibrous dysplasia fall into this cat-
egory. Other cases warrant further workup with advanced
imaging studies or tissue sampling to establish the diagnosis.
Radiographs localize the lesion and also provide key discrim-
inating factors used in lesion characterization, including
lesion margins, matrix mineralization, and periosteal reac-
tion. The pattern of destruction and margins are used to deter-
mine the aggressiveness of a lesion. A well-defined lesion
with a sclerotic border is the least aggressive pattern and indi-
cates a slow-growing benign lesion. This can also be seen
with Brodie abscess. A moth-eaten pattern of bony destruc-
tion is a more aggressive pattern and is seen with malignant
lesions and with osteomyelitis. A lesion with a permeative
appearance, cortical destruction, and aggressive periostitis
with or without a soft tissue mass is the most aggressive pat-
tern and is seen with Ewing sarcoma, aggressive malignan-
cies, and infection. Periosteal reaction is likewise used to
predict aggressiveness and can be continuous and solid, usu-
ally seen with a benign slow-growing process, or aggressive,
with laminated, hair-on-end, or sunburst appearance or pro-
ducing a Codman triangle, seen with sarcomas or sometimes
osteomyelitis. The matrix of a lesion is also evaluated to
determine if the tumor is an osteogenic or chondroid lesion.
Chondroid matrix has a characteristic rings-and-arcs or stip-
pled appearance, as is seen in lesions such as enchondroma
and chondrosarcoma. The osteoid matrix has a fluffy or
cloud-like appearance and is seen in bone-forming lesions
such as osteosarcoma. Matrix mineralization is usually easily
identified in lesions located in the extremities; however, when
subtle, computed tomography (CT) can allow for better eval-
uation. CT is also used to detect or characterize lesions in
complex anatomic locations such as the pelvis and spine that
may not be adequately evaluated with radiographs.
Computed Tomography
Computed tomography provides the best evaluation of corti-
cal integrity, osseous remodeling, and matrix mineralization.
Thin-section imaging provides fine bony detail and isotropic
volume acquisition allows for high-quality multiplanar refor-
matting. Subtle matrix mineralization, which can sometimes
13
be faint or undetectable on radiographs, can be seen with CT
and provides evidence of lesion histology. Soft tissue exten-
sion and pathologic fractures that may not be radiographi-
cally apparent can also be seen on CT. CT is particularly
useful for determining the presence of and evaluating the
extent of lesions in locations that may not be seen on radio-
graphs because of complex anatomy, particularly in the pel-
vis, spine, ribs, scapula, and chest wall. In other locations,
magnetic resonance imaging (MRI) is most often used as the
next imaging test as well as for staging. CT however is the
examination of choice when osteoid osteoma is in the dif-
ferential diagnosis, because this imaging modality reliably
demonstrates the nidus, permitting a confident diagnosis and
serving as the basis for planning radiofrequency ablation. CT
is also the imaging modality used most frequently for biopsy
guidance and to evaluate the lungs for metastasis. Because of
hematologic spread, the lungs are the most common site of
metastasis from primary sarcomas of the bone, and with
high-grade sarcomas, most patients will have pulmonary
micrometastasis at presentation.
Magnetic Resonance Imaging
Magnetic resonance imaging is the examination of choice for
the staging of bone tumors and is critical in planning limb
salvage and tissue-sparing surgical procedures. This imaging
technique provides the best evaluation of marrow involve-
ment and, because of exceptional contrast resolution, the
best evaluation of the soft tissue extent of a tumor, including
the relationship to neurovascular structures. Fluid, necrosis,
and hemorrhage are also best seen on MRI. An additional
benefit of this modality is that ionizing radiation is not used.
However, because of chemical shift artifact, MRI provides
suboptimal evaluation of the presence and extent of cortical
involvement and is not very sensitive for the detection of
matrix mineralization. These features are best evaluated with
CT. MRI should always be performed before biopsy and can
direct the biopsy to solid components of a lesion, which
should be sampled to avoid a false-negative result from cys-
tic or necrotic areas of tumor. Typical pulse sequences
include multiplanar T1 and fat-saturated T2 fast spin-echo
images, with coil selection for optimal signal-to-noise ratio
and spatial resolution sufficient to cover the anatomic area of
interest. These sequences provide comprehensive informa-
tion for accurate staging, and we do not believe that
gadolinium-enhanced contrast studies are routinely required
for the staging of bone neoplasms. An important principle to
remember is that when sarcoma is considered, the field of
view should include the entire bone, including the adjacent
joints, to evaluate for skip lesions that may not be detected
with bone scintigraphy and for possible joint involvement.
Another factor that is important for surgical staging of malig-
14
nant lesions is that the entire extent of edema-like signal is
considered the reactive zone which should be removed along
with a rim of uninvolved adjacent tissue. Although MRI is
sensitive for lesion detection and can characterize some
lesions based on their appearance, it is not specific and
necessitates correlation with radiographic features to arrive
at a diagnosis. Discordance between radiographs and MRI
usually occurs with benign lesions that have a propensity to
produce edema-like signal well beyond the confines of the
tumor. Lesions that frequently demonstrate this appearance
are the following: chondroblastoma, osteoid osteoma, LCH,
solid ABC, and Brodie abscess. In general, it is important to
remember that in the absence of fracture, profound edema-
like signal is an exceptional finding with sarcomas of the
bone. Some neoplasms that are frequently encountered with
normal radiographs but abnormal MRI are lymphoma,
metastasis, and myeloma. It is exceptionally rare for a sar-
coma of the bone to be discovered on MRI with normal
radiographs. MRI can be used for treatment follow-up, to
evaluate response to therapy and to assess for possible recur-
rence. When residual or recurrent tumor is suspected,
contrast-enhanced sequences are of value.
Bone Scintigraphy
Bone scintigraphy uses Tc99m-labeled diphosphonates that
bind to hydroxyapatite at sites of osteoblastic activity, result-
ing in increased radionuclide uptake at areas of bone turn-
over. This uptake is nonspecific and occurs in many benign
and malignant bone tumors along with fractures, osteomyeli-
tis, and other nonneoplastic conditions. Abnormal bone
scans should therefore always be correlated with clinical
information and other imaging studies. Scintigraphy is much
more sensitive than radiography and even CT and can iden-
tify abnormalities that are not visualized by these imaging
modalities. In the realm of bone tumor imaging, scintigraphy
is used to confirm that a lesion is solitary when first identified
on a radiograph and is most consistently performed to deter-
mine the distribution of metastasis when this is a consider-
ation based on the initial lesion. Scintigraphy does not
effectively evaluate the intraosseous or soft tissue extent of a
lesion. Although malignant lesions generally tend to have
greater activity than active benign processes, scintigraphy
alone cannot be used for discrimination and should be cor-
related with radiographs. For example, fibrous dysplasia and
Paget’s disease are benign entities that show avid uptake.
Giant cell tumor can have increased uptake about the adja-
cent joint caused by hyperemia and disuse osteoporosis, not
from tumor extension. Tumors such as LCH or chondrosar-
coma may not show increased uptake, and lymphoma,
myeloma, and highly anaplastic tumors often show no uptake
on bone scan. Purely osteolytic tumors such as metastasis
from renal cell or thyroid cancers will show photopenic
D.M. Holden et al.
areas. Bone scintigraphy is also used to follow response to
therapy; however, positron emission tomography (PET)-CT
is gaining favor for this purpose.
Positron Emission Tomography-Computed
Tomography
On a consistent basis, the most valuable role of 18fluorodeox-
yglucose (FDG) positron emission tomography (PET)-CT is
for systemic disease staging, evaluating the skeleton and
lungs for the presence of metastasis, and evaluating the
response to neoadjuvant therapy. PET uses a glucose analog
labeled with fluorine-18 that is administered intravenously to
detect lesions with increased metabolic activity. These images
are fused with those from CT to improve lesion detection and
characterization, including the detection of subcentimeter
lung nodules that would otherwise not be detected with
PEt alone because of their small size. A large retrospective
review comparing bone scintigraphy and 18FDG PET-CT for
the detection of bone metastasis in osteosarcoma found that
PET-CT was more accurate and sensitive for the detection of
osseous metastasis. In patients with Ewing sarcoma, PET-CT
has also been found to allow for more accurate staging than
PEt alone. Given that PET-CT is commonly used for staging
many cancers and lymphoma, it is important to be aware that
some benign bone lesions, including enchondroma and
fibrous dysplasia, are FDG avid, which could result in false-
positive results if not correlated carefully with the CT portion
of the exam. If the diagnosis is not apparent on CT, further
evaluation with radiographs may be warranted. Other poten-
tial causes of false-positive results are fracture and infection.
In contrast, chondrosarcoma, a malignant bone tumor, may be
mistaken for a benign lesion based on its low to moderate
uptake (depending on the grade of the lesion).
Staging
The major contribution of imaging in the management of
malignant bone tumors is local and systemic staging. Local
staging is most consistently achieved with MRI to determine
the intracompartmental extent as well as the presence of
extracompartmental disease and its relationship to neurovas-
cular structures. Systemic staging has largely relied on CT of
the thorax and scintigraphy but is gradually being replaced
by PET-CT.
Image-Guided Biopsy
Image-guided percutaneous or open surgical biopsy is often
required to obtain the histological diagnosis of an indeterminate
or aggressive bone lesion. Percutaneous needle biopsy of
2 An Imaging Approach to Bone Tumors
bone lesions has been shown to be a safe and accurate method
with a very low (1.1 %) complication rate. CT has replaced
fluoroscopic guidance in most institutions as the modality of
choice, often with the use of low-dose techniques to limit
radiation exposure. Nearly all primary and metastatic bone
tumors are visible on CT, which allows for accurate needle
positioning within the lesion. In very rare cases, however,
bone marrow lesions may not be visualized on CT despite
obvious findings on MRI or PET. In these cases, MRI can be
a safe and reliable alternative for guiding the biopsy which
requires MR-safe equipment and expertise. Because metas-
tasis and myeloma are vastly more common than primary
bone tumors, complete workup before biopsy of a lesion is
extremely important, as this can lead to the diagnosis of a
metastatic lesion thought to be a primary bone tumor.
Additionally, when multiple lesions are present, a complete
workup before biopsy will allow detection of the most easily
accessible site for biopsy. MRI should always precede the
biopsy.
The single most important issue to be understood by the
radiologist performing these procedures is compartmental
anatomy. Most treating surgeons remove the biopsy track, so
it is critical for the radiologist performing the procedure not
to compromise the definitive surgical procedure by approach-
ing the lesion through an inappropriate compartment.
Discussing the biopsy approach with the surgeon who will
be carrying out the definitive operation would clarify all
issues before an irreversible biopsy approach is taken. The
details of needles and techniques are beyond the scope of this
chapter.
Image-guided treatments have become popular since the
introduction of radiofrequency ablation of osteoid osteomas
in 1992 by Dr. Rosenthal. Nowadays, many primary and
metastatic bone and soft tissue tumors are successfully
treated or palliated by a variety of image-guided ablation
techniques, including radiofrequency ablation, microwave
ablation, and cryoablation.
Characteristically Benign Lesions
There are several benign lesions with such a radiographically
classic appearance that biopsy or further imaging would be
inappropriate. These commonly encountered lesions would
include in the pediatric and adult population some of the
following.
Nonossifying Fibroma
Nonossifying fibroma (NOF) is a benign fibrous lesion com-
posed of spindle-shaped fibroblasts in a whorled pattern with
scattered giant cells, foam cells, and small amounts of col-
lagen. The lesion is commonly seen in children and adoles-
15
cents, with a reported incidence of 30–40 % prior to skeletal
maturity and a male to female predominance of 2:1. Lesions
can be solitary or multiple and are most often located in the
long bones of the lower extremities, commonly the distal
femur and tibia, with lesions in the upper extremities and
elsewhere being uncommon. Nonossifying fibromas occur in
the metaphyseal region and can extend into the diaphysis as
the bone lengthens with age. Smaller lesions measuring less
than 2–3 cm having the same pathology but centered only in
the cortex are called fibrous cortical defects. Because of
spontaneous healing that occurs with sclerosis filling in from
the periphery with complete regression, it is rare to see non-
ossifying fibromas in adults. These lesions are asymptomatic
unless complicated by a pathologic fracture and are often
discovered incidentally on radiographs or MRI performed
for trauma or other unrelated indications.
The fibrous nature of this lesion results in the character-
istic radiographic appearance of an eccentrically located,
cortically based, mildly expansile radiolucent lesion with a
thin sclerotic margin and some extension into the medullary
space (Fig. 2.1). Larger lesions may be multiloculated or
internally septated with a soap bubble appearance (Fig. 2.2).
Regardless of lesion size, there should be no significant
periosteal reaction. When this classic appearance is seen, no
further imaging is indicated. MRI will demonstrate a corti-
cally based lesion with variable T1 signal intensity depend-
ing on the stage of healing, generally isointense to muscle,
with corresponding low more often than high T2 signal
intensity and a sclerotic low-signal-intensity rim on both
T1- and T2-weighted imaging. The cortex may appear
focally permeated, but there should be no associated soft
tissue mass. Depending on the stage of healing, these lesions
can show mild increased uptake on bone scan and may be
FDG avid.
Nonossifying fibromas have no malignant potential, and
no treatment is needed unless there is a risk of pathologic
fracture. Multiple NOFs can be familial or can occasionally
be seen with neurofibromatosis. The association of multiple
NOFs and café au lait spots has been termed Jaffe-
Campanacci syndrome. Severe cases can have mental retar-
dation, cardiovascular and ocular abnormalities, and
cryptorchidism.
Fibrous Dysplasia
Fibrous dysplasia is a nonhereditary benign disorder of bone
remodeling that results in marrow replacement by fibro-
osseous tissue. There is no gender predominance, and
lesions, which are intramedullary, can be detected at any age.
Fibrous dysplasia can be monostotic or polyostotic, with
monostotic fibrous dysplasia being six to ten times more
common. Monostotic disease does not evolve into polyos-
totic fibrous dysplasia, and lesions generally remain stable in
16
size after puberty. Monostotic lesions are often incidentally
discovered before the age of 30 and most commonly involve
a rib, the femur (particularly the proximal end), the tibia, or
craniofacial bones. Fibrous dysplasia is the most common
benign rib lesion. Polyostotic lesions vary in number, can be
unilateral, involving several bones of one extremity or one
side of the body, or can be bilateral. Lesions tend to be larger
becoming apparent during childhood because of the weak-
ened bone, leading to limb deformities with bowing, pain,
and fractures. One such example is the “shepherd’s crook”
deformity of the hip with coxa vara and bowing of the diaph-
ysis. Pathologic fractures are not uncommon and most com-
monly occur in the proximal femur. In the setting of a femoral
lesion, the ipsilateral pelvis should be closely scrutinized for
involvement because of this close association. Polyostotic
lesions commonly involve the pelvis, femur, tibia, upper
extremities, ribs, craniofacial bones, spine, and shoulder
girdle. Various endocrinopathies can occur with polyostotic
FD; the best known is McCune-Albright syndrome, which
includes polyostotic fibrous dysplasia, precocious puberty,
and café au lait macules. The rare association of fibrous dys-
plasia and benign soft tissue myxomas is called Mazabraud’s
syndrome. It is important to be aware of this association so
as not to confuse a myxoma for sarcoma or malignant trans-
formation of fibrous dysplasia.
Radiographically lesions can have several different pat-
terns depending on the amount of bony trabeculae and
fibrous elements and can have a lucent, mixed, or sclerotic
appearance. The classic appearance in a long bone is a mildly
expansile, well-circumscribed intramedullary lucent lesion
in the diaphysis or metadiaphysis with a ground-glass
appearance and often with a sclerotic border (Figs. 2.3 and
2.4). Lesions can have cortical scalloping, but there should
be no cortical disruption or periosteal reaction unless there is
a pathologic fracture or malignant transformation. Lesions,
particularly in the ribs, but also elsewhere, can show exten-
sive expansion and deformity (Fig. 2.5). Craniofacial lesions
are often unilateral and have a ground-glass or mixed scle-
rotic appearance because of the large osseous component
with bony expansion, which can lead to neurologic dysfunc-
tion or exophthalmos. Leontiasis ossea is a rare facial defor-
mity resulting from involvement of the frontal and facial
bones with the deformity resembling a lion’s face. On MRI,
lesions have variable signal intensity depending on the com-
position of the lesion, showing low to intermediate T1 signal
and low, intermediate, or high signal intensity on T2-weighted
imaging (Fig. 2.6). Enhancement is variable. MRI can also
be used to detect fluid-fluid levels from secondary aneurys-
mal bone cysts. Bone scintigraphy is useful to detect polyos-
totic disease and shows increased uptake on all three phases.
Malignant transformation is rare, occurring in 0.4–1 % of
cases of both monostotic and polyostotic fibrous dysplasia.
Clinically increasing pain is worrisome, with imaging find-
D.M. Holden et al.
ings of lesion enlargement, cortical destruction, and soft tis-
sue mass. Osteosarcoma and fibrosarcoma are the most
common malignancies. Although fibrous dysplasia has a
characteristic appearance, a lesion that can present with sim-
ilar imaging characteristics is low-grade central osteosar-
coma. The discriminating factor is cortical destruction,
which should not be present with fibrous dysplasia.
Enchondroma
Enchondromas are benign intramedullary chondroid lesions
that are thought to occur as a result of ectopic cartilage rests
arising from displacement of the growth plate. These lesions
are usually solitary and are the second most common benign
chondroid tumor after osteochondroma. Although the true
incidence is unknown due to their largely incidental discov-
ery, they account for at least 3 % of all bone tumors.
Enchondromas have been seen in all age groups, but the peak
incidence is in the third and fourth decades. There is no
gender predominance. Lesions are most commonly located
in the metaphysis or metadiaphysis of the appendicular skel-
eton, with the phalanges of the hands being the most com-
mon site; enchondromas are the most common bone tumor
of the hands. The long bones are also commonly involved,
predominantly the femur and proximal humerus.
Imaging characteristics vary depending on location. In
the short tubular bones of the hands and feet, there is a clas-
sic expansile lucent appearance with cortical thinning that is
commonly significant and often only a small amount of
punctuate chondroid calcification (Fig. 2.7). In Fig. 2.8, a
third metatarsal enchondroma with a greater amount of
chondroid calcification is shown. In this location, these
lesions are frequently discovered because of pathologic frac-
ture. In the long bones, where lesions are most often inciden-
tally found, the characteristic appearance is that of an
intramedullary lesion with dense chondroid calcification,
having a “popcorn” or “rings and arcs” appearance without a
discrete sclerotic rim or underlying lucency (Figs. 2.9 and
2.10). Lesions can be entirely calcified. Larger lesions can
show cortical scalloping but should not demonstrate cortical
disruption. Less commonly, the appearance can be that of a
well-circumscribed lucent lesion with a thin sclerotic rim
and faint scattered calcification. When the classic appear-
ance is seen, further imaging is unnecessary and conserva-
tive follow-up is suggested. Infarcts in long bones can
sometimes have a similar radiographic appearance but
should not show endosteal scalloping and often show periph-
eral serpentine calcification. CT will show findings similar to
radiographs but with better evaluation of matrix calcification
as well as the depth and extent of endosteal scalloping. MRI
shows a lobulated lesion with low to intermediate T1 and
high T2 signal intensity because of the high water content of
2 An Imaging Approach to Bone Tumors
the hyaline cartilage, with chondroid calcifications remain-
ing low signal on both T1- and T2-weighted images. On the
T1-weighted images of enchondromas in the long bones,
normal-appearing marrow fat can be seen between the carti-
lage lobules. Lesions show increased uptake on Tc99 MDP
bone scans and this should not be used as an indicator of
malignancy. Imaging features that indicate malignant degen-
eration are lesions that change over time with increased
lucency and resorption of the internal calcifications or those
that show cortical disruption or soft tissue mass. The distinc-
tion between enchondroma and low-grade chondrosarcoma
can sometimes be difficult when there is extensive and deep
cortical scalloping. This will be discussed further in the sec-
tion dealing with chondrosarcoma.
Multiple enchondromatosis is nonhereditary, has variable
severity, typically shows unilateral involvement of the limbs,
and has an increased risk (10–25 %) of malignant transfor-
mation to chondrosarcoma (Fig. 2.11). Ollier’s disease is a
dysplasia of any portion of endochondrally formed bone
with multiple enchondromas and shortened and bowed
bones. Maffucci syndrome is the association of multiple
enchondromas and soft tissue hemangiomas, with greatest
involvement of the hands and feet and the highest risk of
malignant transformation.
Enchondromas located in the epiphysis are known to
occur with multiple enchondromatosis but can also occur in
isolation. The appearance typically is that of a lucent lesion
with well-defined borders and matrix mineralization that can
be extensive. In a large series of solitary epiphyseal enchon-
dromas, lesions were found most commonly in the proximal
humerus and femur. In this series, 55 % of the lesions were
eccentrically located, and the majority extended to the
metaphysis and/or the subchondral bone.
Paget’s Disease
Paget’s disease is a disorder of abnormal bone remodeling
that is common in older adults of European descent, occur-
ring in 3 % of the population over age 40 and in 10 % of the
population over age 80. The etiology is unknown, but the
most widely supported hypothesis is that of a slow viral
infection. There is a slight male predominance and a geo-
graphic predilection, with the disease commonly seen in the
United Kingdom, parts of Western Europe, Australia, New
Zealand, and the United States. It is distinctly rare in China
and most of Africa. Any bone in the body can be involved,
but the axial skeleton, particularly the lumbosacral spine and
pelvis, is affected most often; the skull and proximal femur
are additional common sites. The disease can be monostotic
or, more frequently, polyostotic, with variable involvement
that is commonly progressive with age. The disease is one of
excessive osteoclastic resorption followed by a disorganized
17
osteoblastic response, resulting in larger bones with weaker
than normal bony structure that predisposes the patient to
insufficiency fractures. Clinically, there can be pain with
osseous enlargement and bowing, most commonly lateral
bowing of the femur or anterior bowing of the tibia. Because
of the weakened subchondral bone, osteoarthritis occurs at
an accelerated rate in the adjacent joint, often with concen-
tric narrowing at the joint space without significant osteo-
phyte formation. Acetabular involvement can result in
acetabular protrusion. When there is cranial or vertebral
involvement, neurologic symptoms may occur, caused by
bony enlargement with resulting neural foraminal impinge-
ment. Basilar invagination occurs in as many as 30 % of
patients when the skull base is involved. Because of the
increased osteoblastic activity, the serum alkaline phospha-
tase level is elevated, and because of the osteolysis, there is
also an elevation in urine hydroxyproline level. The disease
is also frequently discovered incidentally during imaging
performed for other indications, and in uncomplicated dis-
ease because of the characteristic appearance, no imaging
other than radiographs is indicated.
The disease progresses through three well-known phases,
with imaging characteristics unique to each stage. In the first
phase, there is excess osteoclastic resorption and replace-
ment of the bone with fibrovascular marrow. The character-
istic finding in the skull is a large, well-defined osteolytic
lesion involving both the inner and outer table, known as
osteoporosis circumscripta. In the long bones, the disease
begins at the epiphysis and appears lytic, extending to the
metadiaphysis with an advancing well-demarcated v-shaped
line between the affected and normal bone; this is character-
istically described as the “blade of grass” appearance. The
exception to this rule is disease occurring in the tibia, where
the process can begin in the tibial tubercle (Fig. 2.12). Next,
there is a mixed lytic and blastic phase, with filling in with
disorganized woven bone with trabecular and cortical thick-
ening. Finally, an osteoblastic phase occurs, with continued
cortical thickening and enlargement of the bone (Figs. 2.13
and 2.14). The skull takes on a “cotton wool” appearance,
and in the spine, the affected vertebra is sclerotic, seen as
either a picture frame or an “ivory vertebral body.” The com-
mon differential for the ivory vertebral body is metastasis or
lymphoma; however, a distinguishing feature of Paget’s dis-
ease is enlargement of the vertebral body, which can also
involve the posterior elements. The sclerotic phase of the
disease can be confused with other disease processes such as
diffuse metastasis or myelofibrosis. Metastasis can be
differentiated by more widespread involvement and lack of
bony expansion with trabecular thickening. Myelofibrosis
will likewise not demonstrate bony enlargement and will
show hepatosplenomegaly. The highest incidence of patho-
logic fractures occurs in the osteoblastic phase, with frac-
tures of the long bowed bones, commonly on the convex
18
side, seen as one or more cortical lucencies known as “banana
fractures” or a complete fracture. Tc99m MDP bone scans
show marked uptake with active disease and can be used to
evaluate disease extent and to identify lesions before they
become radiographically evident. CT shows findings similar
to those seen on radiographs, with cortical and trabecular
thickening and bony enlargement. MRI shows low T1 signal
in areas of sclerosis with marrow fat in areas of inactive dis-
ease and heterogeneous signal with active disease. Even with
active disease, interspersed fatty marrow should be seen.
When there is confusion as to the diagnosis during the
resorptive phase, this preservation of fatty marrow serves as
an indicator of the benign nature of the disease. T2-weighted
images show low signal corresponding to areas of sclerosis
and fat signal intensity in areas of inactive disease, with het-
erogeneous intermediate signal corresponding to active dis-
ease. If the normal marrow fat is replaced, this should raise
concern for neoplasm or edema from fracture.
Sarcomatous transformation occurs in approximately 1 %
of patients with monostotic disease and in up to 10 % with
polyostotic disease. The sarcomas generally occur after the age
of 50; are most common in the femur, pelvis, and humerus; and
are high grade, mostly osteosarcoma. The prognosis is uni-
formly poor. Pain and swelling may herald neoplastic transfor-
mation, which will be seen as lytic areas of bony destruction
with cortical involvement and soft tissue mass. There have
been cases of profound rapid spontaneous osteolysis involving
bones affected by Paget’s disease after immobilization and hip
fracture fixation. The osteolysis can occur several months post-
operatively and it is important to be aware of this entity so as
not to misinterpret it as neoplasm or infection.
Osteogenic Lesions
Tumors in this category are distinguished by their production
of osteoid and are separated into benign and malignant
categories.
Osteoid Osteoma
Osteoid osteoma is a benign neoplasm that represents
approximately 3 % of all primary bone tumors. The actual
lesion is a small oval nidus composed of variably mineral-
ized osteoid trabecula surrounded by vascular fibrous con-
nective tissue. The lesion has been found in patients from the
age of 8 months to 70 years but is most often seen between
the age of 10 and 30, with a male to female ratio of 2:1 to 4:1.
Patients most commonly present with dull or aching pain
that is worse at night and is often relieved by aspirin and
other nonsteroidal anti-inflammatory drugs. Occasionally,
with superficial lesions in the radius, anterior tibia, fingers,
or toes, the presenting symptom is painless swelling or a
D.M. Holden et al.
mass. When there is involvement of the spine, scoliosis is
commonly seen from muscle spasm, with the lesion located
on the concave side of the curvature.
Lesions are categorized as cortical, cancellous (medullary),
or intra-articular depending on the location of the nidus, with
each having a characteristic pattern of associated sclerosis.
The most common type is a small, cortically based nidus in the
center of dense surrounding reactive sclerosis. Although any
bone can be involved, cortically based lesions are most com-
monly found in the diaphysis or metadiaphysis of the femur
and tibia. The characteristic radiographic appearance of the
cortical osteoid osteoma is that of a small lucent nidus usually
less than 1.5–2 cm in size surrounded by a thick reactive rim
of sclerosis (Fig. 2.15). Sometimes the nidus can be calcified
or the sclerosis can be so dense that it obscures the nidus. In
these cases, and to help differentiate an osteoid osteoma from
a stress fracture or Brodie abscess, which can have a similar
appearance, CT should be performed. CT is the examination of
choice because it reliably demonstrates the nidus, permitting a
confident diagnosis and serving as the basis for planning radio-
frequency ablation. With osteoid osteoma, CT will show the
lucent round nidus with or without central mineralized osteoid
rather than a more linear fracture line or a linear serpentine sinus
tract that can sometimes extend to the nearest growth plate in the
case of Brodie abscess. The next most common lesion type is an
intramedullary nidus, which has only a small amount of eccen-
tric sclerosis, most often located away from the nidus (Fig. 2.16).
These lesions are most frequently seen in the femoral neck, pos-
terior elements of the vertebra (particularly the lumbar spine),
and small bones of the hands and feet. The least common type
is the subperiosteal nidus, which displays no surrounding scle-
rosis or cortical thickening. These lesions are most often found
along the medial aspect of the femoral neck and in the hands
and feet, particularly the talus. The typical appearance is that
of a juxtacortical radiolucent or sclerotic nidus with extrinsic
erosion of the adjacent cortex. Lesions that are intra-articular
often present a diagnostic challenge. These most often involve
the hip, are often medullary or subperiosteal, and can be dif-
ficult to see on radiographs as there is little or no adjacent
sclerosis depending on the distance from the joint space.
Periosteal reaction can be seen where the periosteum blends
with the joint capsule and may be extracapsular. Additionally,
the nidus may not be seen with any imaging modality at the
onset of pain and may only be seen when imaging is repeated
months after the onset of symptoms. Regional osteoporosis,
joint effusion, and synovitis may be present, with symptoms
mimicking a synovial inflammatory process or arthritis. CT is
the imaging modality of choice for lesion detection and is par-
ticularly useful for sites such as the axial skeleton, where
lesions may not be seen on radiographs. Bone scintigraphy is
also a sensitive imaging modality for the detection of osteoid
osteoma and can be particularly useful when initial radio-
graphs are negative or symptoms are atypical. Bone scans will
show increased uptake, sometimes with a “double density
2 An Imaging Approach to Bone Tumors
sign” (a central focus of increased uptake corresponding to the
nidus surrounded by a less intense area of uptake). On MRI,
the nidus has intermediate to low T1 signal and variable T2
signal intensity. If the nidus is totally calcified, it will have low
signal on all sequences. Enhancement is variable but com-
monly will be diffuse. The nidus can be difficult to detect on
MRI and occasionally only perilesional edema is seen. It is
important to be aware of the marked adjacent bone marrow
and soft tissue edema that is commonly seen so as not to mis-
diagnose this lesion on MRI.
Although osteoid osteomas can resolve spontaneously, pain
and gastrointestinal symptoms related to long-term NSAID use
often warrant invasive treatment. The current standard of care
for treatment is CT-guided radiofrequency ablation, which has
a high success rate and minimal morbidity (Fig. 2.17). It is
important to remember that the nidus is the lesion that must be
ablated for effective treatment and that the sclerosis, which
may regress after treatment, is reactive to the nidus.
Osteoblastoma
Osteoblastoma is a benign lesion representing approximately
1 % of all primary bone tumors. The histology is very similar
to that of osteoid osteoma but the size, radiographic appear-
ance, and distribution of these lesions differ. Most patients
present between the ages of 10 and 30 years, with a male to
female ratio of 2:1. Pain is the most common symptom but is
less severe that that caused by osteoid osteoma. With osteo-
blastoma, the pain is not more severe at night and is not as
frequently relieved by NSAIDs. There is a predilection for
the spine which is the site of approximately 30 % of lesions.
Lesions are distributed equally among all segments but favor
the posterior elements with common extension into the ver-
tebral body. Lesions in the long bones most often involve the
femur and tibia, occurring most commonly in the metaphysis
or distal diaphysis. Whereas osteoid osteomas are stable and
can show spontaneous regression, osteoblastomas continue
to grow slowly. Osteoblastomas can have three patterns. The
first pattern appears similar to a giant osteoid osteoma but
measures greater than 1.5–2 cm and has less reactive sclero-
sis, although periostitis has been noted to be more promi-
nent. The second pattern is that of an expansile lytic lesion
appearing similar to an aneurysmal bone cyst but also some-
times containing punctate areas of mineralization (Fig. 2.18).
This is the most common appearance of lesions in the spine.
The third pattern is an aggressive-appearing lesion with bony
destruction and scattered mineralization or soft tissue mass.
Up to 20 % of lesions have associated aneurysmal bone cyst.
CT is the best imaging modality for the diagnosis of
osteoblastoma of the spine. MRI is nonspecific and will
show low to intermediate T1 signal and variable T2 signal
with foci that demonstrate low signal intensity correspond-
ing to calcification. Bone scintigraphy will show marked
19
increased Tc99 MDP uptake. The differential diagnosis for
an expansile lesion in the posterior elements of the spine is
an aneurysmal bone cyst. Treatment is radical surgical exci-
sion, and the recurrence rate is 10–15 %.
Osteosarcoma
Osteosarcoma is the most common nonhematologic primary
malignancy of the bone, accounting for approximately 35 %
of primary bone tumors. The tumor is characterized by sar-
comatous stroma that has the ability to produce osteoid or
immature bone. Although there can be a predominance of
other tissue types such as chondroid or fibrous tissue, even a
small amount of osteoid production designates the tumor as
an osteogenic sarcoma. Osteosarcoma has a bimodal age dis-
tribution, with most cases occurring in childhood and a
smaller second peak in older adults. There are varying histo-
logical subtypes, the majority of which can be predicted on
the basis of their radiographic appearance, location, and
patient age. In addition to primary osteosarcoma, which can
be intramedullary or a surface lesion, osteosarcoma can be
secondary, occurring with Paget’s, prior radiation treatment,
bone infarct, or other benign lesions.
Conventional Osteosarcoma
Conventional osteosarcoma is a high-grade intramedullary
neoplasm accounting for approximately 75 % of all osteosar-
comas. The neoplasm occurs most commonly in the second
decade of life, with a male to female ratio of approximately
2:1. The most common site is the metaphysis of the long
bones, with more than 50 % occurring around the knee and
commonly presenting with pain and swelling. Often, the
tumor extends across the growth plate to the epiphysis.
Radiographically, the tumor has a characteristic appearance
which is that of a large mixed lytic and sclerotic lesion with
fluffy or cloud-like osteoid production and aggressive perios-
teal reaction (Fig. 2.19). A soft tissue mass is present in the
majority of cases. Because radiographs are characteristic,
additional imaging is rarely needed for diagnosis but is per-
formed as part of the staging workup and for operative plan-
ning. CT will show findings similar to those of radiographs but
allows for better evaluation of mineralized matrix and the soft
tissue mass (Fig. 2.20). MRI is the best imaging modality for
preoperative evaluation to show the marrow and soft tissue
extent of the tumor, including potential joint involvement and
proximity to neurovascular structures. MRI will show low T1
and increased T2 signal intensity corresponding to the neo-
plasm, with areas of mineralization having low signal on all
sequences. Necrotic areas will follow the signal intensity of
fluid, being low on T1-weighted images and high on
T2-weighted images. MRI is also the best imaging modality to
20
evaluate for skip metastasis, a second area of tumor in the
same bone that is located a variable distance from the primary
site of neoplasm. Because of the possibility of skip metastasis,
when MRI is performed for osteosarcoma, the osseous struc-
ture involved must be imaged in its entirety. Bone scan will
show avid increased uptake on all three phases corresponding
to the primary neoplasm and sites of metastasis. Because the
most common site of metastasis is pulmonary, CT of the chest
should be performed as part of the staging process. Of note,
pulmonary and lymph node metastases can ossify. Treatment
includes chemotherapy and wide resection with limb salvage
in most cases. Prognosis depends on many factors, including
tumor size, the stage at presentation, and preoperative response
to chemotherapy, with >90 % necrosis considered a positive
response. The 5-year survival rate is 60–80 %.
Telangiectatic Osteosarcoma
Telangiectatic osteosarcoma is a rare high-grade intramedul-
lary neoplasm that accounts for less than 4 % of all osteosar-
comas. The sarcoma is largely composed of cystic cavities
containing blood, with the rim and septations lined by high-
grade sarcomatous cells. The distribution (commonly in the
metaphyseal region about the knee), age, and gender predi-
lection are similar to that of conventional osteosarcoma. The
most common presenting symptom is pain, with pathologic
fracture occurring in 25 % of cases. The imaging appearance
differs from that of conventional osteosarcoma and can be
confused with aneurysmal bone cyst. Radiographs show a
destructive expansile osteolytic lesion with ill-defined mar-
gins and only small areas of sclerosis corresponding to oste-
oid matrix (Fig. 2.21a). CT can better demonstrate the osteoid
matrix, cortical destruction, and solid components along with
fluid-fluid levels from necrosis or hemorrhage. Scintigraphy
shows increased uptake with a photopenic center correspond-
ing to the cystic spaces (Fig. 2.21b). MRI shows high T2 sig-
nal loculated blood-filled cystic spaces with fluid-fluid levels
and solid components along the cavitary spaces (Fig. 2.21c–e).
The solid components along the cavitary spaces and small
amount of osteoid matrix within the solid areas of viable tis-
sue differentiate these lesions on imaging from ABC. The
solid components are best seen as enhancing tissue on post-
contrast MRI. It is important to sample these areas of solid
tissue to avoid a false-negative biopsy. Treatment involves
chemotherapy and wide resection with limb salvage. The
prognosis is similar to that of conventional osteosarcoma.
Low-Grade Central Osteosarcoma
Low-grade central (intramedullary) osteosarcoma is
uncommon and represents 1–2 % of all osteosarcomas.
This neoplasm generally occurs in patients in the third
D.M. Holden et al.
decade of life and beyond with no gender predominance.
As with conventional osteosarcoma, the most common
location is the metaphysis of the femur and tibia, often
extending to the epiphysis. The lesion can be found inci-
dentally, or patients may present with vague symptoms
such as pain that has lasted for many months or years.
Lesions are generally large at presentation, with a mean
size of 7.9 cm ± 4.6 cm reported in one study. Various radio-
graphic patterns have been seen, but the lesions generally
have a nonaggressive appearance and can be confused with
benign lesions, usually fibrous dysplasia (Fig. 2.22). The
most common pattern is a large expansile intramedullary
lytic lesion with well-defined margins, a sclerotic rim, and
irregular thick internal trabeculation. The appearance can
also be diffusely sclerotic or can have a mixed lytic and
sclerotic appearance. When a soft tissue mass is seen on
cross-sectional imaging, it tends to be small. If scrutinized
carefully, more aggressive features can often be found,
such as indistinct margins or subtle cortical destruction. CT
or MRI will show these features to a greater extent. The
important point to remember is that if a lesion looks like
fibrous dysplasia but there is cortical destruction, low-
grade central osteosarcoma should be considered. The
long-term prognosis is very good with initial wide exci-
sion; however, if resection is incomplete, there is a ten-
dency for local recurrence with the potential for
dedifferentiation and metastasis. Chemotherapy is not used
for initial treatment.
Parosteal Osteosarcoma
Parosteal osteosarcoma is rare but is the most common sur-
face osteosarcoma. This neoplasm is low grade and arises
from the outer layer of periosteum. There is a slight female
predominance, and patients are usually in their third or fourth
decade of life. The location is metaphyseal and the posterior
aspect of the distal femur is the most common site, followed
by the proximal humerus and tibia. Radiographs show a
large broad-based lobulated densely ossified mass along the
cortex with no aggressive periosteal reaction (Figs. 2.23 and
2.24). The tumor often contains a lucent cleavage plane
between portions of the lesion and cortex. The lesion can be
confused with myositis ossificans both radiographically and
histologically. However, myositis ossificans should show
most dense ossification peripherally and is generally not
attached to the cortical bone. MRI and CT are used to evalu-
ate lesion extent. In our experience, it is not uncommon to
have intramedullary signal change with conventional paros-
teal osteosarcoma, and this has usually represented marrow
edema. Prognosis is very good, with a 91 % 5-year survival
rate. Chemotherapy is not used for treatment. A small per-
centage of lesions contain high-grade areas, and in these
cases, management is changed accordingly.
2 An Imaging Approach to Bone Tumors
Periosteal Osteosarcoma
Periosteal osteosarcoma is the second most common surface
osteosarcoma, encompassing 25 % of all surface osteosarco-
mas. The lesion is very rare, has intermediate grade, and is
highly chondroblastic with only small areas of osteoid. The
age and gender distribution is similar to conventional osteo-
sarcoma. More than 85 % of these lesions occur in the tibia
and femur, but the location within these osseous structures
differs from that of other osteosarcomas, with most lesions
occurring in the diaphysis. The radiographic appearance also
differs from that of other osteosarcomas, showing an area of
cortical thickening with a scalloped area corresponding to
the broad-based, poorly mineralized chondral soft tissue
mass attached to the cortex and aggressive-appearing perios-
titis extending in a perpendicular fashion into the mass
(Fig. 2.25). MRI shows low T1 and high T2 signal corre-
sponding to the largely chondroblastic lesion that wraps
around the bone, usually involving approximately 50 % of
the circumference, with perpendicular periostitis and cortical
thickening showing low signal intensity on all sequences.
Marrow involvement is unusual, and most signal changes in
the adjacent marrow are on account of reactive changes. The
prognosis is better than that of a conventional osteosarcoma
but not as good as parosteal osteosarcoma, with a 10-year
survival rate of 83 % and approximately 15 % of patients
developing metastasis. Treatment involves wide local resec-
tion with limb salvage; chemotherapy is not used.
High-Grade Surface Osteosarcoma
High-grade surface osteosarcoma is extremely rare, represent-
ing less than 1 % of all osteosarcomas. The peak incidence is
in the second and third decade with a male predominance. The
femur is the most common site, and the lesion is diaphyseal.
The imaging appearance of this lesion is similar to that of a
periosteal osteosarcoma but often is more aggressive, with
involvement of the entire circumference of the bone. The
prognosis is similar to that of a conventional osteosarcoma.
Secondary Osteosarcoma
Secondary osteosarcomas are high grade and most commonly
occur as a result of malignant transformation of Paget’s dis-
ease or as the result of previous irradiation. The incidence of
secondary osteosarcoma in Paget’s disease with a solitary site
is approximately 1 %, but this incidence increases with
greater skeletal involvement. Patients are generally older than
50 years when malignant transformation occurs and present
with symptoms of pain and a palpable mass. On imaging, sec-
ondary osteosarcoma appears as an area of lytic destruction
with a soft tissue mass. Prognosis is poor.
21
Radiation can induce both soft tissue sarcomas and sarco-
mas of the bone, the most common of which is high-grade
osteosarcoma. The patient demographic is typically the
fourth decade of life and later, with the risk of malignancy
correlating with the radiation dose which, although variable,
is approximately 50 Gy. Although the latent period varies, it
is generally at least 5 years.
Cartilage Tumors
Cartilage tumors comprise a number of benign and neoplas-
tic lesions with histological similarities that prove or suggest
a relationship to hyaline cartilage.
Osteochondroma
Osteochondroma, also known as an osteocartilaginous exos-
tosis, accounts for 20–50 % of all benign bone tumors and is
the most common benign bone neoplasm as well as the most
common radiation-induced benign bone tumor. This lesion is
caused by displaced chondrocytes from the growth plate that
continue to grow on the surface of the bone. Growth continues
until skeletal maturity and occurs by progressive endochon-
dral ossification of the growing cartilaginous cap. Although
osteochondroma was once considered a hamartoma, muta-
tions affecting genes within the cartilage cap support the idea
of a true neoplastic etiology. Osteochondromas can be soli-
tary or, much less frequently, multiple seen with autosomal
dominant multiple hereditary exostoses. For both solitary and
hereditary disease, there is greater than 60 % male predomi-
nance. Although any portion of the skeleton that forms from
endochondral ossification can be involved, lesions are most
commonly seen about the knee and proximal humerus. In the
long bones, lesions are metaphyseal. Most solitary lesions are
detected incidentally, but these lesions may also present as a
slow-growing palpable firm lump, usually in the second
decade of life. Depending on the location and size of the
lesion, pressure erosion on an adjacent bone, bursa formation,
or neurovascular symptoms can result. Multiple hereditary
exostoses presents earlier in childhood, not only because of
the osteochondromas but also because of associated skeletal
deformities including a pseudo-Madelung deformity of the
forearm with short ulna and radial bowing, angular deformi-
ties of the knees and ankles, bilateral coxa valga with wid-
ened proximal femoral metaphysis, leg length discrepancy,
and short stature (Fig. 2.26). The number of osteochondro-
mas varies even among members of the same family. The
lesions can have unilateral predominance or can be bilateral.
When lesions are located in the long bones, pathognomonic
imaging features, often seen only on one projection, allow for
a confident radiographic diagnosis. The lesion will appear as a
bony protrusion with either a narrow- or broad-based stalk, the
22
cortex and underlying medullary bone of which are continu-
ous with that of the bone of origin. Because of mechanical
forces from the underlying tendons and musculature, lesions
point away from the nearest joint, and the tip is covered by a
hyaline cartilage cap that will not be apparent radiographically
unless it is mineralized. When viewed en face, the lesion
appears as a crescentic rim of sclerosis because of its projec-
tion from the cortex. It is important to remember that the fea-
tures of corticomedullary continuity must be present for the
diagnosis of osteochondroma, and when these lesions involve
the flat bones, cross-sectional imaging can be helpful to make
this distinction. CT and MRI show the relationship between
the osteochondroma and the neurovascular structures; adven-
titial bursa formation, which often occurs about the hip or
along the ventral scapula; and the chondral cap, where malig-
nant transformation to chondrosarcoma can occur. The chon-
dral cap can be difficult to distinguish from adventitial bursa
on CT and on MRI, as these entities can show similar CT den-
sity and similar intermediate T1 and high T2 signal intensity.
In general, MRI is the best modality to evaluate cap thickness.
Contrast is not used, as it does not provide additional signifi-
cant information. Normal thickness of the cartilage cap varies
with age, often measuring 1–3 cm before skeletal maturity and
generally appearing thin or absent in adults, having been
replaced by endochondral ossification.
Worrisome features for malignant transformation include
growth of the lesion after skeletal maturity with bony destruc-
tion, chondral cap measurement (measured from the noncalci-
fied portion of the outer cap) of 2 cm or greater in adults, and
soft tissue mass with scattered calcification. It is important to
remember that a dystrophically calcified chondral cap is nor-
mal in large lesions and is not indicative of malignancy; addi-
tionally, the size of the lesion does not predict malignant
transformation. The malignant potential for solitary osteochon-
droma is <1 % and such malignancies generally occur during
or after the fifth decade of life, whereas with multiple heredi-
tary exostoses, there is a 3–5 % risk of malignant transforma-
tion, generally occurring after the second to third decade of life.
Neoplastic transformation almost always occurs in adults,
more commonly involving axial rather than appendicular
lesions and is overwhelmingly to low-grade chondrosarcoma.
Periosteal Chondroma
Periosteal chondroma, also known as parosteal or juxtacortical
chondroma, is a rare benign tumor composed of hyaline carti-
lage that arises beneath the periosteum. Approximately 75 %
of cases occur in patients aged less than 30 years, with a 3:2
male to female predominance. This lesion is often found inci-
dentally or can present with pain or a mass. In the bone, the
location is metaphyseal. The most common site of involve-
ment is the proximal humerus, followed by the femur and
D.M. Holden et al.
small tubular bones. The average size of lesions is 3–4 cm in
the long bones and 1–2 cm in the small tubular bones.
Radiographs show a juxtacortical radiolucent lesion with scal-
loping of the underlying cortex, sclerosis along the internal
border, and marginal cortical buttressing (Fig. 2.27). There
may be little or no calcification of the chondroid mass, and
approximately 25 % of lesions have a surrounding thin corti-
cal shell. MRI shows a low to intermediate T1 and high T2
signal soft tissue mass along the bone surface with cortical
scalloping and a low-signal-intensity rim. Intramedullary
involvement is rare, as is perilesional or intramedullary edema.
Thin peripheral and septal enhancement is seen after the
administration of gadolinium. Periosteal chondroma is charac-
teristic enough that it rarely warrants a differential diagnosis.
Concerns regarding periosteal chondrosarcoma are largely
based on lesion size and arise if the lesion is larger than 5 cm.
Chondroblastoma
Chondroblastoma is uncommon, representing less than 1 %
of all bone tumors. Chondroblastoma is a benign tumor of
young adults, with 75 % of cases occurring in patients aged
10–20 years, with a mean age of 19 years and a 2:1 male to
female predominance. The most common presentation is
nonspecific pain or swelling; there may also be limited range
of motion or a joint effusion on account of the location. The
lesion is epiphyseal or located in an apophysis such as the
greater trochanter, with common extension to the metaphy-
sis. Lesions are most often located in the femur, proximal
tibia, and proximal humerus. Radiographs show a lytic lesion
with a well-defined border either centrally or eccentrically
located in the epiphysis (Fig. 2.28). The border may show a
partial or complete thin sclerotic rim. A small amount of
matrix mineralization is seen in approximately 30 % of
cases, and thick periostitis is not uncommon, sometimes
occurring in the metaphyseal region at some distance from
the lesion. MRI shows a lesion with low T1 and low to inter-
mediate T2 signal characteristics, the low T2 signal on
account of the chondroblastic nature of the lesion with hemo-
siderin and calcification. Surrounding bone marrow edema is
expected, and there may also be surrounding soft tissue
edema. Enhancement is seen peripherally after the adminis-
tration of gadolinium; however, as this does not provide
additional useful information, contrast is not indicated.
Approximately 15 % of lesions have an associated aneurys-
mal bone cyst with corresponding imaging findings of fluid
signal intensity (low T1, high T2 signal) and fluid-fluid lev-
els. As with all active lesions, bone scintigraphy shows
increased uptake. The majority of lesions demonstrate non-
aggressive behavior and are treated with curettage and cryo-
therapy. The differential diagnosis of a lytic epiphyseal
lesion is bone abscess and Langerhans cell histiocytosis.
2 An Imaging Approach to Bone Tumors
Chondromyxoid Fibroma
Chondromyxoid fibroma is benign and very rare, being the
least common chondroid tumor. This lesion is usually located
in the metaphysis of the long bones and is intramedullary but
eccentrically located. The lesion, which is most commonly
seen around the knee or foot, typically affects young adults
aged less than 30 years who present with slowly progressive
pain. There is a slight male predominance. Radiographs
show a geographic lytic lesion with expansile remodeling
and often coarse trabeculation. Radiographically, chondroid
calcification is only rarely seen. MRI is nonspecific, demon-
strating a lesion with low T1 and high T2 signal intensity.
Chondrosarcoma
Chondrosarcoma is the most common malignant chondroid
tumor and is surpassed in frequency only by osteosarcoma
among the primary nonhematologic bone neoplasms. The
vast majority of these lesions are primary and intramedullary,
although tumors can be secondary or undergo dedifferentia-
tion. Conventional (primary intramedullary) chondrosarcoma
is typically a slow-growing malignancy of adults that most
commonly occurs between the fifth and seventh decades of
life. There is a slight male predominance. The most common
presenting symptoms are pain and a mass. Lesions tend to be
central rather than peripheral and occur with highest fre-
quency in the pelvis, femur, shoulder, and ribs/sternum with a
metaphyseal or metadiaphyseal location in the long bones. It
is rare for chondrosarcoma to involve the small bones of the
hands and feet. These lesions are graded on a scale of 1–3
based primarily on nuclear size and staining, cellularity, and
mitosis. Grade 1 is most common and considered low grade,
with grades 2 and 3 representing intermediate- and high-
grade tumors. Histological grading is the most important
indicator of local recurrence and metastasis. Tumor location
may also factor into prognosis. Pelvic tumors tend to be large
at diagnosis and the more complex pelvic anatomy can make
complete resection with adequate margins difficult.
High-grade conventional chondrosarcomas appear as
expansile, lytic, intramedullary lesions with variable amounts
of amorphous chondroid calcification, areas of cortical
destruction, and cortical thickening along with a soft tissue
mass. Aggressive periosteal reaction will not be present. CT
is the best modality to evaluate chondroid calcifications and
cortical disruption that may be subtle on radiographs. CT will
also often show a soft tissue mass. MRI is used to evaluate the
intramedullary nonmineralized extent of the tumor as well as
the soft tissue extension (Figs. 2.29 and 2.30). The chondroid
matrix appears as intermediate signal on T1-weighted images
and as lobulated high signal on T2-weighted images. Matrix
calcifications will demonstrate uniformly low signal on all
23
sequences. Significant perilesional marrow edema-like signal
should not be seen. After contrast administration there will be
peripheral and septal enhancement. These lesions are treated
with wide resection and reconstruction. Long-term follow-up
is necessary, as recurrence can occur more than 10 years after
treatment. The 5-year survival rate for grade 2 and 3 lesions
combined is 53 %.
Distinguishing enchondroma from low-grade chondrosar-
coma, particularly in the long bones, can be challenging from
an imaging and histological standpoint. These entities have
similar long bone distribution, most commonly being found
in the femur, and accepted microscopic and imaging signs
have shown poor interobserver and intraobserver reliability
rates. Murphey et al. retrospectively evaluated 187 cases of
long bone enchondromas and chondrosarcomas and described
imaging criteria for chondrosarcoma. The characteristics sug-
gestive of malignancy include endosteal scalloping greater
than two thirds of the cortical thickness, cortical thickening or
periosteal reaction, cortical destruction, and soft tissue mass.
It is our experience, however, that small, eccentrically located
benign enchondromas often demonstrate extensive cortical
scalloping and that in this subset of lesions and as an isolated
finding, this does not correlate with malignancy. Lesions with
cortical penetration, however, are indicative of chondrosar-
coma (Fig. 2.31). Pain and lesion size greater than 5 cm have
also been reported to correlate with malignancy. These find-
ings must be correlated with additional features, as many long
bone enchondromas can be incidentally found during workup
for pain related to musculotendinous or bursal conditions or
intrinsic joint pathology. It is not uncommon in a large prac-
tice to see a fair number of enchondromas in the long bones
measuring greater than 5 cm. With borderline cases, follow-
up with imaging is often warranted rather than an invasive
surgical procedure. Because enchondromas are rare in the
pelvis and spine, even when a small, benign-appearing chon-
dral lesion is seen in the axial skeleton, it should be followed.
In the small bones of the hands and feet, chondrosarcoma is
very rare. The new World Health Organization (WHO) clas-
sification of tumors of soft tissue and bone designates grade 1
chondrosarcoma as atypical cartilage tumor/grade 1 chondro-
sarcoma for which the recommended treatment is curettage.
En bloc resection is reserved for grade 2 and 3 chondrosarco-
mas. Low-grade chondrosarcomas almost never present with
metastasis but can recur if treatment is inadequate.
Approximately 10 % of cases of local recurrence show an
increased grade with a worse prognosis. The 5-year survival
rate for low-grade chondrosarcoma is 83 %.
Secondary chondrosarcomas are those arising from a
preexisting enchondroma or osteochondroma. Patients with
secondary chondrosarcomas are typically younger than those
with primary chondrosarcomas. Malignant transformation
with osteochondromas is almost always low grade and occurs
in up to 5 % of patients with multiple hereditary exostoses.
24
The highest risk of malignant transformation is in patients
with multiple enchondromatosis; the risk is higher in patients
with Maffucci syndrome than in those with Ollier’s disease.
Growth of lesions after adulthood with cortical destruction
and soft tissue extension indicates malignant transformation.
Clear cell chondrosarcoma is a rare low-grade lesion
located in the epiphysis, most commonly found in the proxi-
mal femur or the humerus. This diagnosis should be consid-
ered when a lesion with the appearance of a chondroblastoma
is seen in a patient who is older than 30 years (Fig. 2.32). On
MRI, clear cell chondrosarcoma shows only minimal or no
adjacent bone marrow edema as opposed to the expected
prominent marrow edema seen around a chondroblastoma.
Dedifferentiated Chondrosarcoma
Dedifferentiated chondrosarcoma is the development of a
high-grade sarcoma of a noncartilaginous cell type, usually
osteosarcoma or less frequently fibrosarcoma or MFH in a
primary chondrosarcoma. This occurs most frequently in the
sixth decade of life and usually involves the femur, pelvis, or
humerus. Radiographs show features of the primary chon-
drosarcoma along with a large nonmineralized area and cor-
tical destruction (Fig. 2.33). Biopsy should be targeted at
these sites, which suggest dedifferentiation. These lesions
are managed with wide local excision. The prognosis is poor,
with a 5-year survival rate of 13 %.
Periosteal chondrosarcoma is a very rare malignant surface
chondroid lesion that occurs in adults generally in the second
through fourth decades of life, with a male predominance. The
lesion is typically larger than 3–4 cm and occurs in the metaph-
yseal region of the long bones, usually in the distal femur and
humerus. Lesions are also seen in the pelvis, rib, and foot.
Radiographs show a radiolucent lesion with scalloping of the
underlying cortex and underlying sclerosis. The lesion appears
similar to but is generally larger than a periosteal chondroma
and also has an appearance similar to that of periosteal osteo-
sarcoma but without the hair-on-end periosteal reaction.
Extension into the medullary canal is exceedingly rare. As
with all chondroid lesions that show calcification, there is a
rings-and-arcs pattern. MRI shows intermediate to low T1 and
high T2 signal, with low signal on both sequences correspond-
ing to punctuate mineralization. Peripheral enhancement will
be seen after the administration of gadolinium. Local recur-
rence depends on surgical treatment. Metastases are rare.
Notochordal Tumors
Chordoma
Chordoma is a rare, slow-growing, locally aggressive tumor
that arises from embryonic notochordal rests. Histopathology
D.M. Holden et al.
shows characteristic neoplastic cells with vacuolated cyto-
plasm, known as physaliferous cells. This tumor is found in
the axial skeleton, is usually solitary, and is seen in all ages,
with the highest incidence in the fifth to seventh decades of
life. The male to female ratio is approximately 2:1 for
sacrococcygeal lesions and 1:1 for spheno-occipital lesions.
Chordomas are uncommon in African Americans but other-
wise show no racial predilection. The most common loca-
tion is the lower sacrum/coccyx and skull base, followed by
the spine, primarily the cervical or lumbar regions with dif-
fering presentations depending on the location. In the
sacrum, the most common complaint is chronic dull pain,
with possible changes in bowel or bladder function in
patients with large tumors. Lesions in the skull base can
present with headache and neck pain or cranial nerve palsy.
In the spine, the presenting symptoms are pain, numbness,
and weakness. The radiographic appearance is that of a
lytic destructive lesion with variable sclerosis, soft tissue
mass, and possible amorphous calcification. In the sacrum,
a large presacral soft tissue mass is commonly seen
(Fig. 2.34). In all areas, CT and MRI are used to evaluate
the bony and soft tissue extent, with special attention to
nerve root involvement. Vertebral lesions are centrally
located with extension of the soft tissue mass along several
vertebral bodies but without involvement of the disk until
very late in the disease course. Lesions typically show low
T1 and high T2 signal intensity but are heterogeneous in
areas of hemorrhage and necrosis. Contrast enhancement is
variable. On bone scan, chordoma is a cold lesion. Prognosis
depends on the location and size of the lesion at presenta-
tion. These lesions are treated with wide radical excision,
which is challenging because of the complex anatomy,
large size of the tumors, and local invasion at presentation.
Local recurrence is common, with soft tissue nodules
occurring at the resection site. Metastasis usually occurs
late and typically involves the lungs, bone, lymph nodes,
and soft tissue. Metastasis occurs in up to 40 % of tumors
located outside of the skull base.
Benign Notochordal Cell Tumor
Benign notochordal cell tumor (giant notochordal rest) is a
tumor contained entirely within the medullary space without
cortical disruption or adjacent soft tissue extension. These
lesions are usually asymptomatic and have a similar distribu-
tion to that of chordomas. These tumors can be small or may
replace a large extent of the normal vertebral body marrow,
appearing as discrete low T1 and high T2 lesions on MRI
(Fig. 2.35). Mild enhancement may be seen after gadolinium
administration. These lesions are not seen on radiographs
and can be occult or sometimes show faint reactive trabecu-
lar sclerosis on CT. The lesions can be followed with
imaging.
2 An Imaging Approach to Bone Tumors
Ewing Sarcoma
Ewing sarcoma is a highly aggressive primary bone sarcoma
composed of small round cells thought to be derived from
mesenchymal or neural crest stem cells, with the majority of
cases showing a t(11;22) chromosomal translocation. Ewing
sarcoma accounts for 6 % of all primary bone tumors and is
the second most common bone tumor in children after osteo-
sarcoma. The majority of cases occur within the first three
decades of life with a slight male predominance. There is a
strong racial predominance in Caucasians. Lesions are usu-
ally solitary, and although any bone can be involved, most
lesions occur in the long bones, particularly the femur. The
lesion is intramedullary and in the long bones is usually
metadiaphyseal or diaphyseal. Flat bone involvement most
commonly affects the pelvis, followed by the ribs. Presenting
signs are nonspecific and usually include pain and swelling,
with constitutional symptoms such as fever, leukocytosis,
anemia, and weight loss seen in patients with more advanced
disease.
The radiographic appearance of these lesions varies. The
most common appearance is that of a poorly marginated per-
meative osteolytic lesion with aggressive periosteal reaction
with either a laminated (onion skin) or hair-on-end appear-
ance (Fig. 2.36). A soft tissue mass is present in the majority
of cases; this mass may be large compared to the osseous
lesion. Although there is no chondroid or osteoid production,
the lesion can appear osteosclerotic because of reactive bone
and may resemble osteosarcoma, which is approximately
three times more common than Ewing sarcoma. Lesions can
less frequently appear lytic or have a mixed lytic and scle-
rotic appearance. Periosteal involvement without extension
into the medullary canal is exceedingly rare. Osseous
involvement is often extensive at diagnosis and may be
underestimated radiographically. Depending on the appear-
ance, the differential diagnosis includes osteosarcoma,
osteomyelitis, eosinophilic granuloma, lymphoma, and
metastasis. Biopsy is needed for definitive diagnosis. Bone
scintigraphy will show increased uptake. MRI is used to
evaluate the local osseous and soft tissue extent and to assess
for the presence of possible skip metastasis. The marrow-
replacing lesion will be intermediate on T1-weighted imag-
ing and usually low to intermediate on T2-weighted imaging
because of the high cellularity, along with the cortical
destruction and associated soft tissue mass.
Approximately 30 % of patients with Ewing sarcoma
present with metastasis, most commonly to the lungs fol-
lowed by the bones and pleura; therefore, chest CT and bone
scan or PET-CT should be used for staging. This sarcoma is
treated with chemotherapy, radiation, and surgery. The
5-year survival rate depends on the location of the lesion and
stage of the disease at presentation. Because pelvic lesions
are often not radiographically evident unless they are large
and complete resection may be difficult because of the com-
25
plex anatomy in this location, lesions in the pelvis and meta-
static disease at presentation are associated with a poorer
prognosis.
Malignant Fibrohistiocytic Tumor
Malignant fibrous histiocytoma is classified as an undifferen-
tiated high-grade pleomorphic sarcoma in the latest WHO
Classification of Tumors of Soft Tissue and Bone. This sar-
coma occurs in adults, with a peak incidence in the fifth
through seventh decades of life and has a 3:2 male to female
predominance. The sarcoma can occur primarily or second-
arily seen with Paget’s disease, previous radiation, or bone
infarcts. Lesions are most frequently found in the femur and
tibia, followed by the humerus. Lesions commonly occur
about the knee. These sarcomas are intramedullary and typi-
cally metaphyseal but can extend to the diaphysis. Pain of
several months’ duration with or without swelling is the most
common presentation. Radiographs show an aggressive
osteolytic lesion with cortical destruction and soft tissue
extension, which is best seen with MRI. Periosteal reaction
is not common. Imaging characteristics are nonspecific. The
differential diagnosis includes metastasis, plasmacytoma,
and lymphoma. Tissue sampling is needed for diagnosis.
Metastasis occurs most commonly to the lungs, followed by
osseous metastasis. There is a high rate of local recurrence.
These lesions are treated with chemotherapy with wide
resection.
Giant Cell-Rich Tumors
Giant cell tumor is a primary bone neoplasm consisting of
round- or spindle-shaped mononuclear cells with inter-
spersed multinucleated osteoclast-like giant cells. The lesion
is benign but locally aggressive and accounts for approxi-
mately 5 % of all primary bone tumors. The vast majority of
these lesions are solitary. These tumors typically occur after
skeletal maturity, with a peak incidence in the third decade of
life, and they demonstrate a slight female predominance.
Although all ethnic groups are affected, there is a higher
prevalence of these lesions in China than in Western coun-
tries. Symptoms are usually pain and swelling but these
lesions can also present with limited range of motion of the
joint or pathologic fracture. GCT is most frequently found in
the long bones, particularly about the knee in the femur and
tibia. The lesion is typically juxta-articular in location when
it affects the long tubular bones and is usually eccentrically
located. Other sites include the distal radius, proximal
humerus, and the spine, most commonly occurring in the
sacrum (Fig. 2.37). Uncommonly, lesions may be seen in the
flat bones of the pelvis and hands and feet and in the epiphy-
seal equivalents.
26
Radiographically, the lesion appears lytic and expansile
with a well-defined nonsclerotic margin and no matrix min-
eralization (Fig. 2.38a). In up to 50 % of lesions, the margin
can be ill defined with cortical permeation. Bone scintigra-
phy will show increased uptake that can be seen only at the
periphery, the so-called “doughnut sign.” Cross-sectional
imaging is used to evaluate the local extent of the tumor and
the presence of associated soft tissue mass, which can be
seen in the region of cortical permeation. MRI shows a lesion
with low to intermediate T1 and T2 signal corresponding
with the solid component of the tumor, with a thin
low-signal-intensity rim (Fig. 2.38b, c). The lesion will
enhance after contrast administration. Up to 15 % of lesions
may demonstrate secondary aneurysmal bone cyst formation
with cystic areas and fluid-fluid levels.
These tumors are usually treated with curettage with
adjuvants. Local recurrence, seen as new osteolytic bony
destruction, resorption of bone graft, or soft tissue mass
that may ossify around the periphery, has been reported in
up to 50 % of cases and usually occurs within 2 years.
Because of the risk of recurrence or malignant transforma-
tion to high-grade sarcoma either de novo or in a recurrence
many years after treatment, long-term follow-up is neces-
sary. A small percentage of cases result in pulmonary
metastasis, which can be slowly progressive or can regress
spontaneously. There are no imaging or histological defin-
ing features that allow distinction between a giant cell
tumor that will cause pulmonary metastasis and one that
will not. Despite pulmonary metastasis, the prognosis is
usually good.
Giant Cell Reparative Granuloma
Giant cell reparative granuloma is a rare benign reactive
tumorlike lesion most commonly found in the jaw and
small tubular bones of the hands and feet. Very rarely, this
lesion has been found in the long tubular bones. There is a
slight female predominance for gnathic and long bone
lesions and an equal gender distribution for lesions in the
small bones. Lesions are most commonly discovered in the
second and third decades of life, with presenting symptoms of
pain and swelling. The most common location is intramedul-
lary and metaphyseal, sometimes with extension to the diaph-
ysis. In the jaw, hands, and feet, radiographs show an
osteolytic expansile lesion with thinned but intact cortex
(Fig. 2.39). Lesions in the long bones have a variable appear-
ance. These lesions are treated with curettage. The recurrence
rate in the small bones of the hands and feet is up to 50 %, but
definitive treatment is usually established with repeat
curettage.
D.M. Holden et al.
Miscellaneous Lesions
Unicameral Bone Cyst
Unicameral or simple bone cysts are benign lesions of
unknown etiology that occur most commonly in children and
young adults before the age of 20 with a male to female ratio
of approximately 2:1. Lesions are intramedullary and cen-
trally located, occurring most commonly in the metaphysis of
the proximal humerus and femur; involvement of other long
bones is rare. In adults, there is a different distribution, with
simple bone cysts seen in the anterior calcaneus inferior to the
angle of Gissane, the pelvis, talus, and scapula. Radiographs
show an intramedullary well-circumscribed lytic metaphy-
seal or metadiaphyseal lesion of variable size that may be
mildly expansile, often with a thin sclerotic border (Fig. 2.40).
In the long bones, lesions are elongated and can sometimes be
multilocular with thin septations (Fig. 2.41). There should be
no periosteal reaction unless the lesion is complicated by
pathologic fracture, which occurs not infrequently. Otherwise,
the cysts are asymptomatic. With fracture, there can be a
characteristic “fallen fragment sign,” which is a piece of corti-
cal bone seen dependently within the fluid-filled cyst. MRI,
which is not typically indicated, shows a lesion with the sig-
nal intensity of fluid on T1- and T2-weighted sequences.
With contrast, mild enhancement of the thin septations and
walls is seen. Lesions often spontaneously regress.
Aneurysmal Bone Cyst
Aneurysmal bone cyst is a benign lesion composed of multi-
loculated dilated blood-filled spaces lined by thin fibrous
walls. The etiology of these lesions is unknown, but pro-
posed causes have included a vascular anomaly that forms as
a response to previous trauma and an underlying osseous
lesion that is most commonly benign. More recently, t(16;17)
chromosomal translocation found in primary ABCs suggests
a true neoplastic etiology. Approximately 70 % of cases are
primary, with the remainder of ABCs secondary, associated
with underlying lesions, most of which are benign. The most
common underlying lesion is a giant cell tumor, with other
underlying lesions including chondroblastoma, fibrous dys-
plasia, osteoblastoma, nonossifying fibroma, “brown tumor,”
and osteosarcoma. Aneurysmal bone cysts occur most com-
monly in the first or second decade of life and present with
pain and swelling of several months’ duration. If there is
involvement of the spine, neurologic symptoms may be pres-
ent. Although any bone can be involved, the lesion occurs
most frequently in the metaphyseal region of long tubular
bones, with the most common sites including the distal femur
2 An Imaging Approach to Bone Tumors
and tibia, as well as the posterior elements of the vertebra.
The lesion is most commonly intramedullary but can be peri-
osteal or intracortical.
Radiographs will typically show an eccentric or central
expansile lytic lesion with well-defined margins (Fig. 2.42).
The cortex can be so thin that it may be radiographically
imperceptible. CT and MRI show an expansile lesion with
fluid-fluid levels corresponding to layering blood products
with thin low-signal peripheral rim and thin septa that show
enhancement after contrast administration. It is important to
be aware that fluid-fluid levels are not specific for aneurys-
mal bone cyst and may be seen in a large number of benign
and malignant lesions. The primary differential for a primary
aneurysmal bone cyst is telangiectatic osteosarcoma. At
times, differentiating between these lesions can be difficult,
because during the often rapid growing phase of an aneurys-
mal bone cyst, the appearance of this lesion can simulate tel-
angiectatic osteosarcoma with cortical breakthrough and
aggressive periosteal reaction. Discriminating factors that
suggest aneurysmal bone cyst include aneurysmal expan-
sion, a thin surrounding bony shell, thin peripheral rim and
septa, and lack of subtle osteoid matrix. Geographic cortical
destruction with a soft tissue mass, thickened tissue along the
periphery, nodular septal enhancement best appreciated after
contrast administration, and subtle osteoid matrix along the
solid components are suggestive of telangiectatic osteosar-
coma. Bone scan is nonspecific and shows increased periph-
eral uptake with central photopenia corresponding to the
cystic spaces for both ABC and telangiectatic osteosarcoma.
Aneurysmal bone cysts are treated with curettage with cryo-
surgery and bone grafting. Recurrence occurs frequently.
Langerhans Cell Histiocytosis
Langerhans cell histiocytosis encompasses a disease spectrum
that involves the clonal proliferation of histiocytes, with char-
acteristic intracytoplasmic inclusions known as Birbeck gran-
ules, as seen by transmission electron microscopy. Involvement
ranges from a solitary lesion of one bone to disseminated dis-
ease in multiple organs/systems. Previous names for these dis-
eases include histiocytosis X, eosinophilic granuloma,
Hand-Schuller-Christian disease, and Letterer-Siwe disease.
Langerhans cell histiocytosis is rare, with bone lesions repre-
senting approximately 1 % of biopsied primary bone tumors.
Of the organ systems, osseous involvement is most frequent,
and solitary disease is approximately twice as common as
multifocal disease. Lesions can progress with time or sponta-
neously regress. The disease is most commonly seen in
Caucasian children aged 5–15 years, with a 2:1 male to female
predominance. Multifocal disease presents at an earlier age.
27
Although any bone can be involved, lesions are most often
seen in flat bones, usually in the skull and pelvis. The most
common long bone to be involved is the femur, followed by
the humerus, and lesions are intramedullary and are usually
diaphyseal or metaphyseal. Ribs are also commonly involved,
particularly in adults. The location and extent of involvement
affect the presenting symptoms, which may include pain and
swelling. Loose teeth or bleeding gums may be seen with
involvement of the jaw, and fever may be present, which may
cause this disease to be confused with osteomyelitis.
Approximately 15 % of patients with multifocal disease will
have the triad of diabetes insipidus, exophthalmos because of
orbital involvement, and multiple osseous lesions.
Radiographs show a variable appearance, with a lytic
lesion or lesions that appear permeative early on with an
aggressive lamellated periosteal reaction (Fig. 2.43). A
lesion in this stage can mimic Ewing sarcoma, lymphoma, or
osteomyelitis. Over time, lesions become more sharply
defined and may have a thickened cortex and solid periosteal
reaction. A soft tissue mass is also sometimes seen and is
best appreciated with MRI (Fig. 2.44a–c). With healing, a
sclerotic appearance can be seen (Figs. 2.44d and 2.45). In
the skull, lesions appear lytic with sharply defined borders,
often with a beveled edge because of the asymmetric destruc-
tion of the inner and outer table. An island of bone within the
lytic lesion known as a “button sequestrum” can be seen. In
the spine, the lesion can present as vertebral body collapse,
known as “vertebra plana.” Disk spaces should be preserved.
MRI shows low T1 lesions that may be difficult to detect
because of the hematopoietic marrow. On T2-weighted
images, lesions have high signal intensity and are surrounded
by marrow edema. Whole-body MRI can be used to evaluate
the extent of marrow and soft tissue involvement. Bone scin-
tigraphy results are variable, with most but not all lesions
demonstrating increased radiotracer uptake.
Monostotic or limited disease has a benign course and
good prognosis. Multisystem disease can involve any organ
including the skin, central nervous system, lungs, lymphatic
system, hepatobiliary system, and gastrointestinal tract.
Prognosis for multisystem disease varies depending on
involvement of the spleen, liver, and bone marrow (consid-
ered high-risk organs) and on the extent of disease at presen-
tation and response to treatment at 6–12 weeks. Neonates
with high-risk organ involvement have the worst prognosis.
Adamantinoma
Adamantinoma is a rare low-grade primary neoplasm of the
bone composed of epithelial cells in a background of fibrous
or osteofibrous stroma. The lesion accounts for less than 1 %
28
of all primary bone tumors. Adamantinoma is slow growing
but has the potential for aggressive behavior and metastasis.
This lesion is believed to be at one end of a spectrum of
lesions, with osteofibrous dysplasia at one end and adaman-
tinoma at the other. There is a slight male predominance and
patients are typically in their second through fourth decades
of life at presentation, although cases have been reported in
patients aged 3–80 years. The overwhelming majority of
lesions are seen in the tibia with or without a synchronous
lesion in the ipsilateral fibula. Involvement of other long
bones is rare. The presenting symptom is often localized dull
pain and/or swelling of gradual onset, with the duration of
symptoms ranging from months to many years.
Radiographs are the initial and most reliable imaging
modality for diagnosis with most lesions located in the mid-
diaphysis of the tibia (Fig. 2.46). The typical radiographic
appearance is an eccentric expansile cortical or intramedul-
lary lytic lesion with a multilocular “soap bubble” appear-
ance and minimal periosteal reaction. Deformity of the bone
is common, with anterior bowing of the tibia and sclerosis of
the cortical bone. If the lesion is completely intracortical,
imaging features cannot distinguish classic adamantinoma
from osteofibrous dysplasia. Age is an important discrimi-
nating factor. Bone scan shows increased radiotracer uptake
on all three phases. MRI can be used to evaluate the bony and
soft tissue extent of the lesion. On MRI, these lesions dem-
onstrate low T1 signal and high T2 signal. MRI can also
detect tibial skip lesions and lesions in the ipsilateral fibula,
which have been reported in up to 10 % of cases.
Adamantinoma has been known to recur locally and
metastasize not infrequently and sometimes late, most com-
monly to the lungs. Lymph node metastases have also been
reported. Neither imaging findings nor histology are predic-
tive of which patients will develop local recurrence or metas-
tases, which have been reported up to 27 years after initial
treatment. Local recurrence rates vary from 18 % to 32 %,
and metastasis occurs in 15–30 % of cases. Biopsy of a sus-
pected adamantinoma should include the central portion of
the lesion because of the osteofibrous dysplasia pattern that
can be seen particularly at the periphery which could lead to
a false-negative diagnosis. The current treatment of choice is
limb salvage with en bloc resection with wide operative mar-
gins and reconstruction. Long-term follow-up is essential
because of the risk for local recurrence and distant
metastasis.
Osteofibrous Dysplasia
Osteofibrous dysplasia is a rare benign fibro-osseous lesion
of childhood that accounts for approximately 0.2 % of pri-
mary bone tumors. Histologically, the lesion appears similar
D.M. Holden et al.
to fibrous dysplasia, composed of trabeculae of woven bone
with fibrous stroma, but differs in that the bony trabecula has
prominent osteoblastic rimming. The lesion occurs most
commonly in the first decade of life and is located almost
exclusively along the anterior cortex of the tibial diaphysis.
Rarely, lesions have been found in the fibula alone (Fig. 2.47)
or in both the tibia and ipsilateral fibula. The lesion is self-
limited, with slow growth that stops with skeletal maturity
and subsequently regresses. The presenting complaint is
most commonly tibial enlargement and slight anterior tibial
bowing. Lesions can also be found incidentally when imag-
ing is performed for other reasons such as trauma.
Radiographs show a well-marginated intracortical lytic
lesion with one or multiple lucencies along the anterior cor-
tex of the tibial diaphysis surrounded by an area of sclerosis,
as well as cortical thickening. Larger lesions have medullary
involvement. Periosteal reaction, when present, appears
chronic. The differential diagnosis for a lesion with this
appearance is fibrous dysplasia and adamantinoma. Fibrous
dysplasia, when monostotic, is usually intramedullary,
whereas osteofibrous dysplasia is cortical. Age can also be a
helpful discriminating factor, as osteofibrous dysplasia gen-
erally occurs in a younger age group than adamantinoma.
There is no standardized recommendation regarding treat-
ment for this lesion, but the prognosis for osteofibrous dys-
plasia is good, with most lesions undergoing healing with
spontaneous regression after puberty. Because of the high
recurrence rate in skeletally immature patients, some authors
have recommended surgery for extensive lesions after
puberty. Others have suggested that because of the possibil-
ity that the lesion may be an osteofibrous dysplasia-like ada-
mantinoma, which usually follows a benign clinical course
but in rare cases has a risk of progressing to adamantinoma,
surgery may be warranted but generally only after puberty
and only for extensive lesions.
Bizarre Parosteal Osteochondromatous
Proliferation
Bizarre parosteal osteochondromatous proliferation, or Nora
lesion, is a benign fibro-osseous proliferation that predomi-
nantly involves the small bones of the hands and feet and
most commonly occurs in the second and third decades of
life. Lesions in the long bones are much less common. The
lesion can sometimes grow rapidly and presents with pain
and swelling. Radiographs show a smoothly marginated
ossified mass applied to the surface of the bone (Figs. 2.48
and 2.49). As opposed to osteochondroma, there is no corti-
comedullary continuity with this type of lesion. MRI shows
a lesion with low T1 and high T2 signal. Up to 50 % of cases
recur locally after excision.
2 An Imaging Approach to Bone Tumors
a b
Fig. 2.1 NOF of the distal tibia in an 18-year-old man. Anteroposterior
radiograph (a) shows an eccentrically located well-defined radiolucent
lesion with thin sclerotic border and few internal septations. The lesion
extends from the cortex into the medullary canal. There is no periostitis.
Corresponding coronal T1-weighted (b) and T2-weighted (c) MR
images show a sharply defined low-T1- and heterogeneous T2-signal-
Fig. 2.2 NOF of the distal femur in a 19-year-old man. Anteroposterior
radiograph shows a larger well-defined eccentrically located expansile
lesion with multiple septations typical of nonossifying fibroma. The
small amount of periostitis along the lateral cortex superiorly is from a
pathologic fracture
29
c
intensity lesion with a low-signal-intensity rim. Nonossifying fibroma
is a radiographic diagnosis and does not require MRI. The MR images
are shown because radiologists should be comfortable in making the
diagnosis when these lesions are incidentally identified on MRI despite
the variable signal characteristics, which are a manifestation of the his-
tologic composition and stage of healing
30 D.M. Holden et al.

a b

Fig. 2.3 Fibrous dysplasia of the femur in a 65-year-old man. Lateral some focally calcified matrix. Corresponding CT image (b) shows sim-
radiograph (a) shows anterior bowing of the femoral shaft and a long ilar findings, with some calcified matrix proximally and fat attenuation
intramedullary diaphyseal radiolucent lesion with expansile remodeling distally
and endosteal scalloping with hazy “ground-glass” appearance and

Fig. 2.4 Fibrous dysplasia of the proximal right femur in a 52-year-old

woman. Frontal radiograph of the right hip shows a well-defined osteo-
lytic lesion with a thick sclerotic rim
2 An Imaging Approach to Bone Tumors 31

a b c

Fig. 2.5 Fibrous dysplasia of the anterior right rib in a 42-year-old saturated T2-weighted (c) MR images show an expansile lesion with
woman. Axial CT image (a) shows expansile remodeling with cortical low T1 and heterogeneous T2 signal. The most common benign rib
thinning and ground-glass matrix. Sagittal T1-weighted (b) and fat- lesion is fibrous dysplasia

a b c

Fig. 2.6 Fibrous dysplasia of the left ilium. Frontal radiograph of the the expansile nature of the lesion. The cortex is not breached, confirm-
pelvis (a) shows a large trabeculated radiolucent lesion with a sclerotic ing that the lesion is entirely intracompartmental. The cyst-like bright
border in the left ilium extending to the superior acetabulum. Coronal T2 signal superiorly is a finding that can be encountered in fibrous
T1-weighted (b) and fat-saturated T2-weighted (c) MR images show dysplasia
32 D.M. Holden et al.

a b c

Fig. 2.7 Enchondroma of the first metacarpal in a 54-year-old woman. cal MR appearance of a chondroid lesion. Despite the large size of the
Frontal radiograph (a), coronal T1-weighted (b), and fat-saturated lesion, because there is no cortical breakthrough or soft tissue mass, this
T2-weighted (c) MR images show an intramedullary lucent lesion with appearance is consistent with an enchondroma. Primary chondrosar-
chondroid calcification occupying the entire metacarpal shaft with typi- coma of the short tubular bones is an exceptionally rare diagnosis

Fig. 2.8 Enchondroma of the third metatarsal. Oblique radiograph

shows an expansile intramedullary radiolucent lesion in the third meta-
tarsal shaft with chondroid calcification. The location and appearance
of the lesion make for the diagnosis
2 An Imaging Approach to Bone Tumors 33

Fig. 2.9 Proximal humeral enchondroma in a 45-year-old man.

Anteroposterior radiograph shows an intramedullary lesion with stip-
pled chondroid calcifications in the proximal humerus consistent with
enchondroma, at a common site. These lesions are often incidentally
discovered on chest radiographs

a b

Fig. 2.10 Proximal humeral

enchondroma in a 50-year-old
woman. Frontal radiograph (a)
shows a lobulated intramedullary
lesion with dense popcorn-like
calcification, typical for a heavily
calcified enchondroma.
Corresponding CT scan (b)
shows the heavily calcified
enchondroma. There is no
cortical disruption, a critical
negative finding
34 D.M. Holden et al.

a b c

Fig. 2.11 Ollier’s disease in a 29-year-old woman with multiple enchondromas involving the hands (a) ribs, left scapula (b) pelvis, and proximal
femora (c) ribs, left scapula, pelvis, and proximal femora

a b c

Fig. 2.12 Paget’s disease of the tibia. Lateral radiograph (a) shows
anterior bowing of the tibia with cortical thickening and trabecular
coarsening. Note that the tibia is the exception to the rule that Paget’s
disease must start at the end of the bone. T1-weighted coronal (b) and
fat-saturated T2-weighted coronal (c) MR images show low-signal-
intensity cortical thickening. In this stage of inactive disease, the fatty
marrow is preserved on the T1-weighted sequence, whereas there is
heterogeneous increased intramedullary T2 signal, again with low-
T2-signal cortical thickening. Paget’s disease is perhaps the only dis-
ease that we are aware of in which there can be extensive radiographic
abnormality, as in this case, and yet the fatty marrow signal is preserved
on the T1-weighted sequence
2 An Imaging Approach to Bone Tumors 35

Fig. 2.13 Paget’s disease of the left hemipelvis in a 65-year-old man.

Frontal radiograph shows typical findings of cortical thickening and tra-
becular coarsening involving the left hemipelvis

Fig. 2.14 A different patient with Paget’s disease of the left patella
36 D.M. Holden et al.

a b

c d

Fig. 2.16 Osteoid osteoma in the right T11 lamina in an 18-year-old

man. Axial CT image shows the lucent intramedullary nidus in the T11
lamina with a tiny area of central sclerosis and a small amount of eccen-
tric sclerosis posteriorly

Fig. 2.17 Axial CT of T11 shows CT-guided percutaneous placement

of a probe within the nidus in the T11 lamina for radiofrequency
ablation

Fig. 2.15 Osteoid osteoma of the femoral shaft in a 22-year-old man.

Frontal radiograph of the right femur (a) shows a smooth area of corti-
cal thickening along the femoral shaft. Oblique radiograph (b) shows a
small lucent nidus, suggestive of an osteoid osteoma. Sagittal
T1-weighted (c), sagittal fat-saturated T2-weighted (d), and axial fat-
saturated T2-weighted (e) MR images show the small, round, cortically
based nidus surrounded by cortical thickening. Note the surrounding
edema on the sagittal and axial T2-weighted sequences, a common
accompanying finding with this lesion
2 An Imaging Approach to Bone Tumors 37

Fig. 2.18 Osteoblastoma in a 30-year-old man. Axial CT shows an

expansile lytic lesion in the posterior elements of L1 on the right with
cortical disruption. The differential diagnosis was osteoblastoma or
aneurysmal bone cyst based on the location. The diagnosis of osteoblas-
toma was made with biopsy

a b c

Fig. 2.19 Osteosarcoma of the distal femur in a 13-year-old girl.
Frontal radiograph of the distal femur (a) shows an aggressive mixed
osteolytic and sclerotic lesion in the distal femoral metaphysis laterally,
with cortical destruction and aggressive periosteal reaction with
Codman’s triangle at the superior edge. The lesion extends to the phy-
sis. Coronal T1-weighted (b) and coronal fat-saturated T2-weighted (c)
MR images show an aggressive mass centered within the lateral distal
femoral metaphysis with low T1 and heterogeneous high T2 signal
intensity. There is adjacent cortical destruction and soft tissue mass.
The entire femur (entire compartment) was imaged
38 D.M. Holden et al.

Fig. 2.20 Osteosarcoma of the

a b
distal femur. Anteroposterior (a)
and lateral (b) radiographs along
with axial CT image (c) of the
distal femur demonstrate typical
features of osteosarcoma with
extraosseous extension. CT
confirms extensive
intramedullary involvement

c
2 An Imaging Approach to Bone Tumors 39

b c

d e

Fig. 2.21 Telangiectatic osteosarcoma of the proximal fibula in a

19-year-old. Frontal radiograph (a) shows an expansile destructive
osteolytic lesion in the proximal fibula. Whole-body bone scan (b)
shows increased uptake corresponding to the lesion, with central photo-
penia corresponding to the cystic spaces. Coronal T1-weighted (c),
axial fat-saturated T2-weighted (d), and axial contrast-enhanced fat-
saturated T1-weighted (e) MR images show solid elements with fluid-
fluid levels, which suggest a telangiectatic osteosarcoma when viewed
in conjunction with the radiograph. The diagnosis was histologically
confirmed
40 D.M. Holden et al.

Fig. 2.22 Low-grade central

a b
osteosarcoma. Lateral radiograph
of the proximal tibia (a) shows
an osteolytic lesion in the
proximal tibial shaft with some
hazy sclerosis superiorly and
more of a ground-glass type
appearance inferiorly. Coronal
T1-weighted MR image (b)
shows cortical destruction
consistent with an aggressive
lesion rather than fibrous
dysplasia, as suggested
radiographically. This is an
example of a low-grade central
osteosarcoma simulating fibrous
dysplasia

a b

Fig. 2.23 Parosteal

osteosarcoma of the distal femur
in a 30-year-old woman. Frontal
radiograph (a) and axial CT
image (b) show a large,
broad-based, densely ossified
mass on the surface of the distal
femur. CT also shows an
unmineralized soft tissue
component that may represent
cartilage, not an uncommon
finding in typical parosteal
osteosarcomas. In this case, this
finding did not represent
dedifferentiation of a parosteal
osteosarcoma
2 An Imaging Approach to Bone Tumors 41

Fig. 2.24 Parosteal

a b
osteosarcoma of the proximal
tibia. Lateral radiograph (a) and
sagittal (b) and axial (c) CT
images show a densely ossified
mass projecting from the
posterior aspect of the proximal
tibia. CT image shows a partial
cleavage plain between the mass
and tibial cortex. There is no
aggressive periosteal reaction.
Axial T1-weighted (d) and
sagittal fat-saturated postcontrast
T1-weighted (e) MR images
show the relationship of the mass
to the neurovascular structures.
The small amount of posterior
tibial enhancement was reactive,
as histologically there was no
intramedullary involvement. Note
that there is no corticomedullary c d
continuity, distinguishing this
entity from an osteochondroma,
and the mass is dense throughout
as opposed to having the most
dense ossification peripherally, as
would be expected with myositis
ossificans

e
42 D.M. Holden et al.

Fig. 2.25 Periosteal osteosarcoma of the femur in a 13-year-old

a
girl. Frontal radiograph (a) shows an aggressive lesion along the
mid-femoral shaft medially with saucerization of the underlying
cortex and aggressive periosteal reaction. Coronal T1-weighted
(b), coronal fat-saturated T2-weighted (c), and axial fat-saturated
T2-weighted (d) MR images show the large lesion that wraps
around almost half of the circumference of the femur. The
edema-like signal within the medullary cavity was reactive, as
histologically, the marrow was not involved

b c

d
2 An Imaging Approach to Bone Tumors 43

a b c

Fig. 2.26 Multiple hereditary exostoses in a 23-year-old woman. osteochondromas with widening of the proximal femoral metaphysis.
Frontal radiograph of the forearm (a) shows distal radial and ulnar Frontal radiograph of the knees (c) shows multiple distal femoral and
osteochondromas with pseudo-Madelung deformity. Frontal radio- proximal tibial and fibular exostoses. Note the corticomedullary conti-
graph of the pelvis (b) shows multiple pelvic and proximal femoral nuity and that the bony protrusions point away from the nearest joint

a b c

Fig. 2.27 Periosteal chondroma of the proximal humerus in a 38-year- lesion. Sagittal oblique T1-weighted (b) and axial fat-saturated
old woman. Frontal radiograph of the shoulder (a) shows cortical scal- T2-weighted (c) MR images show a soft tissue mass with low T1 and
loping along the medial humeral neck, with sclerosis along the internal high T2 signal intensity along the surface of the bone
border and cortical buttressing at the cranial and caudal margins of the
44 D.M. Holden et al.

a b c

Fig. 2.28 Chondroblastoma of the proximal tibia in a 12-year-old boy. saturated T2-weighted (c) MR images show the lesion to have low T1
Anteroposterior radiograph (a) shows a well-defined lytic lesion in the and heterogeneous low T2 signal with surrounding marrow edema-like
proximal tibial epiphysis. Coronal T1-weighted (b) and coronal fat- signal

a b

c d

Fig. 2.29 Chondrosarcoma of

the scapula in an 83-year-old
woman. Frontal radiograph of the
shoulder (a) shows ill-defined
osteolysis involving the glenoid
with small amorphous areas of
calcification. Sagittal oblique
T1-weighted (b), fat-saturated
T2-weighted (c), and axial
fat-saturated T2-weighted (d)
MR images show the extent of
osseous involvement with a large
lobulated low-T1- and high-T2-
signal-intensity soft tissue mass
centered about the scapular neck
2 An Imaging Approach to Bone Tumors 45

a b c

Fig. 2.30 High-grade chondrosarcoma of the proximal femur in a calcification and cortical destruction. Coronal T1-weighted (b )
45-year-old man. Frontal radiograph of the proximal femur (a) and axial fat-saturated T2-weighted ( c ) MR images show marrow
shows an expansile osteolytic lesion with small areas of matrix replacement and the associated soft tissue mass

a b

Fig. 2.31 Chondrosarcoma of

the distal femur. Frontal
radiograph (a) shows an
eccentrically based osteolytic
lesion in the medial femoral
condyle with chondroid
calcification. Axial CT image
(b) shows that there is cortical
destruction that was not
appreciated radiographically,
indicating chondrosarcoma
46 D.M. Holden et al.

Fig. 2.32 Clear cell chondrosarcoma of the femoral head in a 30-year-

old man. Sagittal T2-weighted MR image of the hip shows a high-
signal lesion in the femoral head. Note the epiphyseal location, which is
most common for this lesion

a b

Fig. 2.33 Dedifferentiated

chondrosarcoma of the proximal c d
femur in a 50-year-old man.
Anteroposterior (a) and frog leg
lateral (b) radiographs of the
proximal femur show a mildly
expansile osteolytic lesion in the
proximal femoral shaft with a
large area of adjacent
mineralization within the soft
tissue posteriorly. Coronal
T1-weighted (c) and axial
fat-saturated T2-weighted (d)
MR images show a marrow-
replacing lesion in the
intertrochanteric region and
proximal femoral shaft, with
cortical destruction posteriorly
and a large soft tissue mass
2 An Imaging Approach to Bone Tumors 47

Fig. 2.34 Chordoma of the

a b
sacrum in a 77-year-old man.
Lateral radiograph of the sacrum
(a) shows sclerosis of the lowest
sacral segment and coccyx. Axial
CT image (b) and sagittal
T1-weighted (c) and axial
fat-saturated T2-weighted (d)
MR images show sclerosis of the
lower sacrum and coccyx with
cortical destruction and a
surrounding lobulated soft tissue
mass with a large presacral
component

c d

a b c

Fig. 2.35 Giant notochordal rest in a 65-year-old woman. Sagittal the lesion had not changed. Sagittal CT image (c) shows a faint round
T1-weighted (a) and STIR (b) MR images show a low-T1- and high- area of sclerosis in the S3 segment. There is no cortical disruption or
STIR-signal-intensity lesion entirely within the S3 segment. soft tissue mass, critical findings that conventional high-quality imag-
Comparison with an examination performed 7 years earlier showed that ing permits to exclude a chordoma
48 D.M. Holden et al.

Fig. 2.36 Ewing sarcoma of the

a b
proximal tibia in a 20-year-old
woman. Anteroposterior (a) and
lateral (b) radiographs of the
proximal tibia show a permeative
appearance involving the
proximal tibial shaft with
associated aggressive periosteal
reaction. Coronal T1-weighted
(c) and axial postcontrast
fat-saturated T1-weighted (d)
MR images show the osseous
involvement, with cortical
destruction posteriorly and large
soft tissue component. Both the
osseous and extraosseous
components enhance after
contrast administration

c d

a b

Fig. 2.37 Giant cell tumor of

the sacrum in a 35-year-old
woman. Axial (a) and sagittal (b)
CT images of the sacrum show
an expansile osteolytic lesion
involving the S2 segment with
mild effacement of the thecal sac
and left S2–S3 neural foramen.
The diagnosis is made based on
the location of the lesion and age
and gender of the patient
2 An Imaging Approach to Bone Tumors 49

a b c

Fig. 2.38 Giant cell tumor of the distal femur in a 40-year-old man. axial fat-saturated T2-weighted (c) images show the extent of the lesion
Anteroposterior radiograph (a) shows a large lytic lesion approaching reaching the articular surface. Note the heterogeneous intermediate sig-
the articular surface of the distal femur. Coronal T1-weighted (b) and nal on the fat-saturated T2-weighted image

Fig. 2.39 Giant cell reparative granuloma of the second metacarpal.

Anteroposterior radiograph shows characteristic findings of an expans-
ile lytic lesion with cortical thinning and multiple internal septations

Fig. 2.40 Unicameral bone cyst of the proximal humerus in a 10-year-

old boy. Anteroposterior radiograph shows a centrally located lytic
lesion in the proximal humeral diaphysis
50 D.M. Holden et al.

Fig. 2.43 LCH of the mid-femoral shaft in a 17-year-old.

Fig. 2.41 Unicameral bone cyst of the proximal humerus in a 15-year- Anteroposterior radiograph shows a permeative lesion in the mid-
old girl. Anteroposterior radiograph shows this large centrally located femoral shaft with aggressive periosteal reaction
lesion to be mildly expansile with few internal septations

a b c

Fig. 2.42 Aneurysmal bone cyst of the proximal humerus in a 17-year- mediate signal on the T1-weighted image and multiple thin septations
old. Anteroposterior radiograph (a) shows an osteolytic lesion in the with fluid-fluid levels on the T2-weighted image. Note that there are no
proximal humeral metaphysis. Sagittal oblique T1-weighted (b) and solid components or soft tissue mass
sagittal oblique fat-saturated T2-weighted (c) MR images show inter-
2 An Imaging Approach to Bone Tumors 51

Fig. 2.44 Langerhans cell

a b
histiocytosis of the left ilium in a
3-year-old boy. Anteroposterior
radiograph of the left hip (a)
shows a permeative osteolytic
lesion in the left acetabulum.
Coronal T1-weighted (b) and
fat-saturated coronal
T2-weighted (c) MR images
show the osseous and soft tissue
edema-like signal commonly
encountered with this lesion.
Frontal radiograph of the left hip
(d) 9 months after biopsy shows
healing of the lesion with
acetabular remodeling

c d

a b

Fig. 2.45 Another case

demonstrating spontaneous
healing of LCH after biopsy
52
Fig. 2.46 Adamantinoma of the tibia in a 67-year-old woman. Lateral
radiograph shows a mildly expansile osteolytic lesion in the mid-tibial
shaft with slightly ill-defined borders and endosteal scalloping
D.M. Holden et al.
Fig. 2.47 Osteofibrous dysplasia. Anteroposterior and lateral radio-
graphs of the tibia and fibula show multiple expansile intracortical
lesions along the mid- and distal fibular shaft with osteolysis and
sclerosis
2 An Imaging Approach to Bone Tumors 53

Fig. 2.49 BPOP of the middle phalanx of the small finger

Fig. 2.48 BPOP of the distal phalanx of the thumb in a 32-year-old

woman. Radiograph of the thumb shows an ossified mass applied to the
cortex along the distal phalanx of the thumb. Note that there is no corti-
comedullary continuity
54 D.M. Holden et al.

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Wilson DJ, editors. Imaging of the musculoskeletal system.
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Welker JA, Henshaw RM, Jelinek J, Shmookler BM, Malawer MM. The
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 Methods of Bone Biopsy
3
Eduardo Santini-Araujo, Ricardo K. Kalil, Blas Dios,
and Rómulo L. Cabrini

Abstract
Biopsy must be done in every patient with a tumor in whom radical surgery or radio- or
chemotherapy is contemplated. Close cooperation between surgeon, radiologist, oncolo-
gist, and pathologist is paramount to arrive at an accurate diagnosis and to avoid complica-
tions. The planning of the biopsy should be done after oncological principles and considering
possible next surgical procedures in order to prevent local recurrences. Two types of biop-
sies may be done: open biopsy and needle biopsy, each method having advantages and
disadvantages that should be considered in each case. With help of the modern image meth-
ods and with a team approach, it is possible to achieve a great degree of accuracy and safety
in needle biopsy procedures.

In orthopedic pathology, a biopsy must be performed after a
very careful screening that includes a careful orthopedic
examination and image studies that may require, besides the
essential conventional radiographs, complementary CT
scans, MRI, or other techniques, evaluated by an experienced
radiologist.
If, after this previous evaluation, the orthopedic surgeon
suspects a process is progressive, aggressive, infectious, or
malignant, a biopsy is required.
Ideally, at this moment a pathologist joins the medical
team, adding his input to the decision to make a biopsy and
to what type of biopsy approach is more adequate to the case.
After the procedure, with the previous knowledge of all clin-
E. Santini-Araujo, MD, PhD (*)
Department of Pathology, School of Medicine
and School of Dentistry, University of Buenos Aires,
Buenos Aires, Argentina
Central Army Hospital, Buenos Aires, Argentina
Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina
e-mail: santiniaraujo@laborpat.com.ar
R.K. Kalil, MD
Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina
Department of Pathology, A.C. Camargo Cancer Center,
São Paulo, SP, Brazil
e-mail: rkkalil@gmail.com
ical information, laboratory data, and images of the patient,
he will be able to fulfill his role in establishing the best diag-
nosis for the affection.
It is important to emphasize that biopsy of bone lesions
should be performed as a final diagnostic step after a
complete clinical and imaging study of the patient.
Dr. Henry Jaffe had put it this way: “Biopsy should be
regarded as a final diagnostic procedure, not a shortcut to
diagnosis.”
Biopsy must be done in every patient with a tumor, in
whom radical surgery, radiotherapy, or chemotherapy is
contemplated.
Bone biopsy is fundamental and plays a key role in the
diagnosis and management of tumors and tumorlike lesions
of bone, frequently underestimated. It constitutes a baseline
guide for the prognosis, treatment, and follow-up.
The technical procedures were under a process of discus-
sion and improvement for decades. Catastrophic potential
B. Dios, MD
Department of Radiology,
“Prof. Dr. Luis Güemes” General Hospital,
Buenos Aires, Argentina
R.L. Cabrini, MD, PhD
Department of Oral Pathology, School of Dentistry,
University of Buenos Aires, Buenos Aires, Argentina

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 57
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_3, © Springer-Verlag London 2015
58
complications may occur when the procedure is not performed
with the right technique or if the diagnosis is incorrect.
Bone biopsy needs a close cooperation between the ortho-
pedic oncologist surgeon, radiologist, clinical oncologist,
pathologist, and cytologist to arrive at an accurate diagnosis
and to avoid complications.
The planning of the biopsy approach is crucial and should
be always carefully done after oncological principles and
considering possible next surgical procedures, in order to
prevent local recurrences.
Two different types of biopsies may be carried out:
1. Surgical (open) biopsy
2. Needle biopsy (fine needle or core needle biopsy)
Surgical Biopsy
Surgical biopsy must be done by an experienced orthopedic
surgeon, preferably the responsible for the future surgical
management of the patient – under the necessary aseptic
conditions and using the correct technique to avoid risks. It is
more important than the final surgery for tumor excision, in
the way that small samples that best represent the tumor for
diagnosis must be obtained, and is, consequently, a crucial
procedure for defining the future management of the patient.
In a surgical, open, biopsy, diagnosis may be deferred.
But an immediate, intraoperatory, histological examination
by frozen sections is recommended in order, at least, to
ascertain the adequacy of the sample obtained. The wound is
closed and the final diagnosis awaits analysis of the pathol-
ogy laboratory after paraffin embedding of the material.
Intraoperatory Biopsy
Frozen sections are particularly useful when the surgical
treatment must be carried out immediately.
As noted above, it should serve at least to inform the
orthopedic surgeon immediately whether the biopsy speci-
men is adequate for diagnosis. It avoids submission of an
inadequate or insufficient tissue to histopathological pro-
cessing, meaning a specimen from the periphery of the lesion
with adjacent healthy tissue, reactive bone formation, or
necrotic tissue. It saves precious time and work.
Only specialized pathologists have sufficient training
with frozen sections of bone lesions to give an immediate
and accurate diagnosis.
Paraffin-Embedded Sections
Most general pathologists prefer to examine sections of the
paraffin-embedded material because the frozen sections do
E. Santini-Araujo et al.
not always allow a clear recognition of histological details. In
these instances, when a trans-operatory biopsy is carried out,
it is restricted to inform the adequacy of the material obtained.
Some bone tumors and tumorlike lesions present difficul-
ties in differential diagnosis – even in paraffin block sec-
tions – and these difficulties are greater in frozen sections.
Needle Biopsy (Fine Needle or Trocar Biopsy)
Percutaneous needle biopsy – fine needle or closed trocar
biopsy – is a well-known technique to obtain cytological and
tissue samples for histopathological studies.
The value of percutaneous needle biopsy in diagnosing
bone lesions has been discussed widely in all important
orthopedic centers.
This method was pioneered in the Memorial Hospital of
New York in 1931. At the time, the exclusive use of a smear
for diagnosing bone pathology was recommended.
In 1947, Frank Ellis started to use paraffin inclusion rou-
tinely for samples obtained by needle biopsy.
Valls, Ottolenghi and Schajowicz developed a method
and an instrument to work as a needle guide to extract speci-
mens from the spine.
Surgical biopsy requires an open procedure to remove tis-
sue for histopathological diagnosis, while fine needle (FN)
or core needle biopsy (CNB) is a percutaneous and less inva-
sive procedure – “closed biopsy procedure” (Fig. 3.1a–d).
The orthopedic surgeon and/or the interventionist radiolo-
gist must choose the type of needle to use in the procedure.
The type of needle to use will depend on:
• The type of lesion
• The site of the lesion
• The interventionist’s expertise
Patient-dependent data, like characteristics of the lesion
and site, determines this decision, including the dynamic
interaction of the professional team.
Types of needle biopsy and possible indications:
• Fine needle aspiration biopsy (FNA) – preferred for cystic
or lytic lesions, bone tumors with soft tissue mass, and
highly destructive and poorly mineralized or non-
mineralized lesions
• Core needle biopsy (CNB) – used in solid or radiodense
lesions or when the needle must perforate a preserved
cortex
• Coaxial technique – for lytic lesions with an osseous shield
The type of lesion determines, besides, the use of other
extractive accessory maneuvers to take out the sample,
including shearing, aspiration, rotation, and multidirectional
back and forth movement of the needle.
It is worthwhile to point out that aspiration is an extractive
maneuver that can be done regardless of the gauge of the
needle, excepting those needles with a Tru-cut mechanism.
3 Methods of Bone Biopsy
Types of Devices
• FNA: Franzen-type needle – gauge sizes 22–18.
• CNB: cutting trocar system, Jamshidi type, gauge sizes
from 16 to 8, Craig, Johanna, Tru-cut.
• Coaxial technique: two needles are necessary – a core
needle, gauge from 14 to 12, is inserted into the bone to
reach the lytic lesion, and a Franzen-type needle, gauge
18–20, is inserted through the core needle to obtain the
sample.
Local anesthesia is adequate for most procedures. It usu-
ally needs the collaboration of the patient and must be
avoided in children or non-collaborative patients. Dependent
on the type of procedure and the patient, a general anesthesia
may be required. The general anesthesia required for a nee-
dle biopsy is usually quite brief, with less risk and cost than
for a surgical biopsy.
Radioscopy or CT should guide the procedure. Once the
patient is in position, a prior image is made in order to con-
firm or plan details of the procedure, like access, trajectory,
and the type of needle to use, as well as its length and gauge
that will vary according to the site, access, and trajectory
planned. After the procedure, it is recommended to make
another image in order to detect any problem that may have
occurred during the procedure, e.g., hematoma, loose frag-
ments, others.
Fine Needle Aspiration Biopsy
FNA aims to reach a diagnosis by a low-risk and low-cost
method.
It has a limited scope and aims to obtain a representative
enough sample at least to adequately characterize morpho-
logically and immunohistochemically a lesion or for tumoral
grading.
The cutting edge of the needle is a very important detail to
consider.
The needle includes a mandrill occluding its lumen with
a cutting edge to facilitate penetration in the tissue of the
path.
When the needle reaches the area to be biopsied, the man-
drill is withdrawn and the needle is pushed forward, cutting
the tissue, and, with the help of extractive maneuvers and
repeated movements, the sample is extracted. The use of a
variable sized syringe may help to keep the fragment inside
the needle (and not loosing it when withdrawing the needle)
(Fig. 3.2a–c).
Deeper and/or harder lesions may require the help of
larger syringes – more than 20 mL.
Friable or easily bleeding tissue requires minimal aspira-
tion, the shearing maneuvers being sometimes sufficient to
obtain enough tissue.
59
The tissue sample is obtained by creating a vacuum by
pulling back with vigorous movement on the plunger of the
syringe, performing a continuous aspiration. The procedure
can be repeated many times without the need of withdrawing
the needle. Sometimes it is useful to partially withdraw the
needle and to redirect it to sample different areas of the
lesion.
When the needle is removed, the sample is pushed out of
it onto the glass slides. The prepared smears are fixed in
96 % alcohol.
Best results may be obtained following these steps:
1. The material is placed at one end of the slide.
2. The end of another slide is placed on top of the first one.
3. Make a clockwise rotational movement with a slight pres-
sure until both slides completely overlap.
4. Finally, the top slide is pulled back so as to perform the
smear.
In the frozen section laboratory, close to the operating
room where the biopsy was performed, it is easy to quick
stain some glass slides with methylene blue or Diff Quick.
An immediate evaluation may be performed by the
pathologist for a diagnosis or for assessment of the adequacy
of the sample and establish the need or not to obtain another
sample.
The unstained smears fixed in alcohol are stained in the
pathology laboratory with H&E, Papanicolaou stain, or other
techniques.
Not only cytological interpretations are made with FN. It
is possible to retrieve sufficient aspirated fragments as to
obtain good histological sections after paraffin embedding.
All the material remaining in the needle and syringe must
be retrieved. Tissue fragments may be retained inside the
needle or in the tip of the syringe. These fragments should be
removed and processed in the same way the fragments inside
the barrel of the syringe are treated.
It is useful to place them in a Petri dish and, using a mag-
nifying glass, carefully separate any clot or portion of tissue.
This material is put in a vial containing 10 % buffered forma-
lin solution to be later paraffin block embedded.
When the sample contains a large amount of serum, it is
necessary to centrifuge the aspirated material.
It is strongly recommended to separate the first sample
and put it in a sterile vial for bacteriological studies, in every
case, and more so when an inflammatory process is
suspected.
Core Needle Biopsy
The use of this technique depends mainly on the lesion under
study. It is particularly indicated in lesions with different
mechanical resistance areas or layers and when a larger sam-
ple is needed.
60
Preparation of the patient and image guidance is similar
to FNA biopsy.
Large needles usually range from gauge 8 to 16.
The shape of the cutting edge and the quality of the steel
are fundamental to achieve an adequate cutting cross section,
in order to avoid its deformation, attrition of the sample, and
compression of sawdust into the marrow spaces.
The cutting edge can be circumferentially oblique, as the
classical Jamshidi, or have a serrated border, like trephines.
The mandrill has a sharp extremity that can be conic or
quadrangular, useful for the easy penetration of the soft tis-
sue of the path, as well as the bone cortex.
If the target area of the biopsy is in the marrow spaces, the
penetration is performed with needle and mandrill together
until the proximal border of the lesion, when the mandrill is
withdrawn and further progression of the needle is done,
with rotatory and back and forth movements.
An image control during the procedure, before extracting
the mandrill, allows confirmation of the adequate position of
the needle.
It is crucial that the sample does not stay retained in the
bone when the needle is withdrawn. To assure retaining the
bone cylinder inside the needle, some needles present a slight
narrowing of its distal diameter.
The extractive maneuvers are partly similar to that
described for FNA. The needle is pushed forward with deli-
cate rotatory and back and forth movements.
The aspiration is of great importance and complements
the previous described maneuvers. The aspiration is sus-
tained for a longer time and submitted to fluctuations in
intensity, facilitating the obtainment of samples of osteoblas-
tic lesions.
The core thus obtained should be pushed back out of the
needle through the trocar with a special extractor device that
usually is part of the biopsy needle set. As some trocars pres-
ent a distal reduction in diameter to improve its retaining
capacity, it may be necessary to push out the sample by the
other end of the needle with the extractor, in order to avoid
crushing the cylinder.
Similar to FNA, in CNB it is possible to make an aspira-
tion using a 20- to 60-mL syringe fitted to the needle. And it
is also extremely useful to separate the first sample for bac-
teriological studies, especially if infection is included in the
differential diagnoses (Fig. 3.3a–c).
It is extremely important to perform a careful examina-
tion, sometimes with the help of a magnifying glass, of the
tissue obtained by the procedure, to separate calcified from
soft tissue, in order to decalcify only bone or hard material.
The CNB samples are usually placed in 10 % buffered
formalin.
Fixed mineralized fragments are, then, submitted to
decalcification with nitric acid, formic acid, or EDTA and
E. Santini-Araujo et al.
thorough washing before embedding in paraffin, sectioning,
and staining with H&E (Fig. 3.4a–d).
The main advantage of CNB over FN is that it preserves
tissue architecture, particularly in solid bone lesion, and so
contributes to the accuracy of the diagnosis. It is especially
useful for typifying and grading bone tumors. It is a useful
technique not only for bone tumors but also for the study of
other nonneoplastic or tumorlike conditions of the bone such
as Paget’s disease, fibrous dysplasia, bone infarcts, infection,
or reactive lesions, with more satisfactory results
(Fig. 3.5a–c).
It is extremely important to remember that, in all cases,
the clots obtained by puncture needle biopsies must be care-
fully stored and processed separately, because they fre-
quently contain cells or groups of cells that are of critical
value for an accurate diagnosis (Fig. 3.6a–e).
Sections for immunohistochemical studies can also be
prepared. When you are leading with scarce material and if
the need of IHC is anticipated, it may be important to get tis-
sue sections for IHC at the same moment that H&E sections
are obtained to prevent exhaustion of the paraffin block
sample.
Coaxial Technique
Two needles are necessary for this technique. A large core
needle, gauge from 14 to 12, is inserted into the bone to
reach the lytic lesion. Once the needle is in place, a CT
image is of great help to assure its correct position within
the lesion. A Franzen-type needle, gauge 18–20, is, then,
inserted through the lumen of the core needle to obtain the
sample.
This method allows repeated sampling without traumatiz-
ing adjacent and intervening tissue. A final sample can be
obtained, if necessary, with the external needle in the highest
interest area.
The coaxial technique can be used to facilitate any needle
biopsy, regardless of its diameter.
The material thus obtained is processed in a similar way
as for FNA and CNB.
In any procedure, the pathologist who will examine the
biopsy and make the diagnosis must have a reasonable train-
ing in bone pathology and know the clinical and image data
of the patient.
Although percutaneous needle biopsy is a well-known
diagnostic procedure, with some important series on this
issue being reported in the last three decades, it did not gain
enough popularity among bone specialists to be used on a
routine basis.
For the last 21 years, our laboratory of orthopedic pathol-
ogy has been employing the previously described tech-
3 Methods of Bone Biopsy
niques, with a high percentage of accurate diagnostic results
in neoplastic and nonneoplastic bone lesions, considering
the 7,375 percutaneous needle biopsies recorded in our files
during the 1986–2007 period. In this series, we have reached
an overall accuracy in diagnosis of 83 %, without false posi-
tives. Of these, 3,171 (43 %) were FNA with an accuracy of
75 %, and 4,204 (57 %) were CNB with an accuracy of
89 %. This series is significantly larger than those previ-
ously reported.
This higher accuracy using CNB, in our experience, is
related to the fact that this method provides a larger amount
of tissue sample for histological study, while maintaining the
possibility of an aspiration procedure.
We have used, routinely, both methods – FNA and CNB –
giving priority to the histopathological interpretation of the
embedded material, with which we have obtained more sat-
isfactory results.
Accurate diagnosis was evaluated in terms of a positive
correlation with the final diagnosis of the surgical specimen
or with at least 2 years of follow-up in patients where a non-
surgical treatment was employed.
It is relevant to point out that this result was obtained
through the examination of a high variety of samples obtained
by different surgeons or interventionist radiologists, in dif-
ferent orthopedic centers, with different imaging data for
each patient, and with different sampling techniques, some-
times without all the necessary imaging support, and per-
formed with different needles and in different kinds of
lesions, like tumors, tumorlike lesions, infections, degenera-
tive pathology, prosthetic interfaces, and others.
In this series, the only standardized unit was the final one,
that is to say, the pathology laboratory where the diagnoses
were made.
On the contrary, in the ideal situation, when all the previ-
ous steps are well standardized, the diagnostic accuracy
increases dramatically.
We consider the abovementioned experience an extraordi-
nary issue to endorse the percutaneous needle biopsy as a
highly useful diagnostic procedure method for the investiga-
tion of bone lesions, in experienced hands.
In our series of procedures performed in 21 years, we had
not had complications producing damage to important organs.
Percutaneous needle biopsy advantages and disadvan-
tages can be summarized as:
Advantages
• Simple method.
• Deep locations can be reached.
• Sampling of lesion at different points and depths
(Fig. 3.7).
• Scarcely traumatic.
• Less bleeding.
61
• Less contaminating.
• Less risk of fracture.
• Less risk for life.
• Local anesthesia can be used (except in children).
• Use in outpatient clinic (Fig. 3.8a–e).
• Optionally guided by image methods.
• Can be repeated if necessary.
• Time and cost saving.
Disadvantages
1. Small amount of material
2. Potential damage to important organs
3. Blind method
It must not be forgotten that more than one biopsy
implies in:
1. Delay in diagnosis
2. Increased morbidity and costs
With the modern image methods and, especially, with CT
scan (Fig. 3.9a, b), it is possible to achieve a great degree of
accuracy and safety in needle biopsy procedures, avoiding
unnecessary damage to intervening compartments and vas-
cular and nervous spaces and succeeding in retrieving a sam-
ple from the very lesional focus (Figs. 3.10 and 3.11a–c). It
is also possible to avoid nonrepresentative areas of the lesion,
like cysts, hemorrhage, and necrosis.
Two of the more experienced bone pathologists have
expressed concepts that are important to highlight:
The accurate interpretation of FNB specimen of bone lesions
requires a high degree of expertise within the specialty, but
this expertise is sparse because of the relative rarity of bone
tumors, their wide morphologic spectrum, and diagnostic
pitfalls.
K.K.Unni
Bone and joint diseases are a mystery to many pathologists. This
is due, in part, to the need for radiographic correlation, and
pathologists are not trained to read x-rays. Pathologists must
examine the radiographs themselves.
E.F. McCarthy
Finally, it is important to insist that an orthopedic surgeon
must never perform a bone excisional biopsy without the
knowledge of its histopathological diagnosis.
An interventionist radiologist must never perform a nee-
dle biopsy without knowing the approach to be applied in
future surgical treatments.
And a pathologist shall never try to make a diagnosis
without knowledge of the clinical history and image
diagnosis.
Indeed, local conditions and experience and the degree of
mutual confidence between orthopedic surgeons, radiolo-
gists, and pathologists must, necessarily, control the practice
adopted in any institution (see Figs. 3.1, 3.2, 3.3, 3.4, 3.5,
3.6, 3.7, 3.8, 3.9, 3.10, and 3.11).
62 E. Santini-Araujo et al.

a b

c d

Fig. 3.1 (a–d) Puncture needle biopsy in cervical spine in a patient with metastatic carcinoma. In cases like this, fine needle or core needle biopsy
is undoubtedly a better alternative than surgical biopsy
3 Methods of Bone Biopsy 63

a b

Fig. 3.2 (a) Fine needle biopsy in a lytic lesion of the sacrum. (b and c) Paraffin-embedded small blood clots clearly show a chordoma
64 E. Santini-Araujo et al.

a b

Fig. 3.3 (a) Infrequent location of a solitary myeloma. The smear (b) and paraffin-embedded blood clots (c) establish the diagnosis of myeloma
3 Methods of Bone Biopsy 65

a b

c d

Fig. 3.4 (a) Lytic lesion of the upper end of a humerus. (b) CT-guided puncture needle biopsy. (c) Low magnification of fragment including
osteosclerotic margin and the tumoral lesion. (d) At high magnification, a diagnosis of chondroblastoma was made
66 E. Santini-Araujo et al.

a c

Fig. 3.5 (a) Core needle biopsy of an osteosarcoma of femur. (b) Microphotograph of the cylinder. (c) The smear shows pleomorphic
cellularity
3 Methods of Bone Biopsy 67

a
b

Fig. 3.6 (a) Giant cell tumor in the lower epiphysis of femur. (b) contains no lesion. (e) In a small blood clot, it is possible to identify a
CT-guided core needle biopsy. (c) Microphotograph at low magnifica- fragment of the lesion corresponding to giant cell tumor
tion showing bone cylinder and blood clots. (d) The bone cylinder
68 E. Santini-Araujo et al.

d e

Fig. 3.6 (continued)

a b

Fig. 3.7 (a and b) Puncture needle biopsy in a vertebral body affected by adenocarcinoma metastasis. In small lesions, the use of CT-guided
biopsy is useful to obtain representative specimen

Fig. 3.8 Tangential approach to an eosinophilic granuloma of the skull

by core needle biopsy
3 Methods of Bone Biopsy 69

a b

c d

Fig. 3.9 (a, b) X-ray and CT of fibrous dysplasia of the jaw. (c) Core needle biopsy in a 6-year-old girl with local anesthesia. (d) Cylinders
obtained. (e) Minimal wound at biopsy site
70 E. Santini-Araujo et al.

Fig. 3.10 Osteoid osteoma of the tibia. Failed procedure of a core

biopsy performed without tomographic guidance
3 Methods of Bone Biopsy 71

a b

Fig. 3.11 (a, b) CT-guided core needle biopsy of a giant cell tumor in the upper end of the tibia. Despite the tomographic guidance (c), the needle
went through the tumor contaminating the adjacent bone tissue
72 E. Santini-Araujo et al.

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 Basic and Ancillary Techniques
in Bone Pathology 4
Yong-Koo Park

Abstract
In skeletal pathology diagnosis, most tumors and tumor-like conditions can be diagnosed
with routine hematoxilin and eosin stain. However, sometimes, this basic technique can
be insufficient. Histochemical methods permit evaluating the state of the ossification pro-
cess and intracellular activated enzymes (PAS, mucin stain, Congo red, von Kossa, etc.).
Electron microscopy, flow cytometry, and histomorphometry have limited diagnostic uses.
Immunohistochemical staining has been a helpful aid, especially in the diagnosis of round-cell
tumors, metastatic disease, Langerhans cell histiocytosis, and vascular tumors. Karyotyping,
molecular cytogenetic techniques such as FISH, and molecular techniques like blotting, PCR,
and others have limited but effective application in some specific bone tumors’ diagnosis.

Basic Technique
The basis of diagnosis of bone tumors is observing the
hematoxylin-eosin-stained slide through a microscope.
Hematoxylin-eosin staining is the most basic and believable
technique in a pathological diagnosis. In skeletal pathology
diagnosis, most of the tumors and tumorlike conditions can
be diagnosed with this simple staining technique. However,
sometimes, the basic staining technique can be incomplete or
insufficient, and hence there exist limitations in diagnosing.
Therefore, many special techniques other than the basic
staining technique give tremendous help in not only diagnos-
ing but also investigating the causes of many diseases.
Histochemistry
Histochemical methods provide tools for manifesting vari-
ous biochemical substances that exist in tissues, which would
undergo various biochemical reactions. Through microscopic
Y.-K. Park, MD, PhD
Department of Pathology, Kyung Hee University
School of Medicine, Seoul, South Korea
e-mail: ykpark0204@gmail.com
evaluation, not only the normal or pathological state of the
ossification process but also intracellular activated enzymes
can be identified.
Periodic Acid-Schiff Stain (PAS Stain) and
Other Special Stains
The basis of this staining technique uses the principle of red-
dish color formation when glycogen in tissues or a similar
chemical compound reacts with periodic acid-Schiff reagent.
When diagnosing bone tumors, staining alone is considered
to be nonspecific. However, verifying the presence of intra-
cytoplasmic glycogen granules using diastase in conjunction
with the PAS staining procedure provides a great diagnostic
value, especially in case of Ewing sarcoma and clear cell
chondrosarcoma. In case of lymphoma or metastatic neuro-
blastoma, it is used as an important differential method
although they appear to be negative.
Mucin staining, used to differentiate metastatic adenocar-
cinoma and chordoma, and argentaffin and argyrophilic
staining, used to diagnose neuroendocrine tumor and to
study the reticulin network for the differential diagnosis of
small cell tumors, are histochemical methods that were used
mostly in the past. Congo red staining is used to diagnose
amyloid, and von Kossa’s staining method is used to stain

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 73
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_4, © Springer-Verlag London 2015
74
calcium. However, a number of histochemical staining meth-
ods and enzyme histochemistry have largely been replaced
by immunohistochemistry, and the frequency of their usage
has been remarkably decreased.
Electron Microscopy
Cytoplasmic and extracytoplasmic ultrastructural examina-
tion takes a very important part in pathological diagnosis.
Electron microscopic examination gives a tremendous help
in understanding the process of many pathological diseases
and investigating the causes. The actual diagnostic field that
receives much help includes adamantinoma of the long bone,
Ewing sarcoma, chordoma of notochordal origin, and
Langerhans cell histiocytosis. On the other hand, many
experiments using electron microscope have been imple-
mented on giant cell tumor or related lesion although they
did not contribute greatly to the diagnostic fields.
In the fields of bone tumors, however, evaluation using
electron microscope has some limitations. First, only small
tissue samples are used in electron microscopic examination.
Therefore, there are realistically no possible tests that can
represent the entire tumor. Second, since it is common to
have most of the parts calcified, the process of decalcifica-
tion has to be completed. Accordingly, too many artifacts
can occur in the sample, which makes the sample difficult to
interpret.
Therefore, in order to improve accuracy in bone tumor
diagnostic criteria using an electron microscope, collecting
and interpreting the specimen must be done simultaneously
through close collaboration with an experienced bone tumor
surgical pathologist.
Flow Cytometry
Another technique to distinguish between a malignant tumor
and a benign one is measuring the amount of DNA in the
cell. Feulgen DNA absorption microfluorometry was used in
the past, but a recent technique uses laser beam to stain the
cell with fluorochrome (propidium iodide) and measures the
flow at constant speed. While the cell is flowing at a constant
speed, the photomultiplier tube detects the fluorescence lev-
els from each cell. These signals are then converted to elec-
tric pulse, which are analyzed and saved by a computer.
Recently, cells are stained with different fluorochromes from
each other, and the technique of using two different laser
beams has been extensively applied. Various fluorochromes
are used in flow cytometry such as propidium iodide, ethid-
ium bromide, and diamidine phenylindole.
The most basic notion in the analysis of this flow cytom-
etry is the fact that a normal cell has diploid DNA content.
A cell goes through the cell compartments of G1, S, and G2 + M
Y.-K. Park
phase when it grows. Normal or nondividing cells (G1) or
quiescent (G0) cells are diploid. The duplication of DNA
happens through the S phase, and DNA duplication is com-
plete to become tetraploid level at G2 + M phase. However,
in case of tumor cells, many aneuploid clones exist often by
abnormal cell division.
If the DNA content of the tumor is close to a diploid pat-
tern, there is generally a more favorable prognosis compared
to a tumor with an aneuploid pattern. Also, in cases where
there is a normal or similar DNA content, there is a histologi-
cal differentiation that is analogous to normal tissue. The
first DNA analysis of primary bone tumors was employed to
obtain diagnostic information for osteosarcoma and chon-
drosarcoma. More research has been under study for other
various bone tumors. Classical osteosarcomas and high-
grade chondrosarcomas exhibited hyperploid pattern,
whereas parosteal osteosarcomas were demonstrated to have
diploid pattern.
It has become an issue whether or not the representation
of an entire tumor by characterization of cell from one part of
the lesion is valid when determining nuclear content by flow
cytometry. Another issue arises during the preparation of
single cell suspension by extracting a sample from solid
tumors. In this process, cells may be more susceptible to
damage by the various enzymatic treatment required to pro-
duce a suspension from solid tumors.
DNA ploidy determination may be an important prognos-
tic factor for a limited number of tumors. Nevertheless, it
may not substitute tumor differentiation and grading that is
histopathologically evaluated.
Histomorphometry of Undecalcified Bone
Most commonly used specimens in diagnosing bone tumors
are derived from decalcified bone sections. Decalcified bone
sections, however, have limited applications in diagnosing
metabolic bone diseases since it cannot differentiate between
unmineralized osteoid and mineralized osteoid. It also can-
not reflect dynamic bone status. Undecalcified bone sections,
on the other hand, permit a distinction to be made as their
bone status is kept intact. The use of tetracycline allows us to
evaluate the dynamic bone status, a critical technique used to
determine bone dynamics in normal state as well. Recent IT
advancement has been a tremendous help in the study of his-
tomorphometry of undecalcified bone sections, and
computer-based image analysis has been adopted in the field
of diagnostic pathology. Computer-assisted function has
made it possible to obtain fast, effective, and accurate histo-
morphometric measurements.
Bone histomorphometry is one of the special techniques
to be conducted to the patients with clinically suspected
osteomalacia and patients under the age of 50 with osteope-
nia and to diagnose aluminum storage disease.
4 Basic and Ancillary Techniques in Bone Pathology
Immunohistochemistry
Immunohistochemistry is the process of detecting antigens
that are present in a specific tissue section using antibodies,
produced artificially, which would bind specifically to the
antigens in biological tissues.
Immunohistochemical methods in diagnostic pathology
have made remarkable advances during the past decade. It is
more sensitive, more specific, and more suitable for dealing
with nonspecific problems. Moreover, the advent of mono-
clonal antibody technology has allowed more precise and
predictive decisions in the field of diagnostic pathology.
In diagnosing bone tumors, the preparation of the tissue
section requires decalcification, which has found to have no
influence on the results of the immunohistochemical staining.
Of many immunohistochemical staining methods, the most
fundamental technique is the immunofluorescence method.
This method uses frozen tissue section, whose antigens would
react directly with the antibodies. The advantage of this
method is that it is able to detect antigens while their architec-
ture is preserved. There, however, exist some limitations in
diagnosis using a frozen section. For instance, frozen tissues
cannot be applied to bone tissue and are best not used for gen-
eral pathological processes. In general, immunofluorescence
analysis is more specific, but a less sensitive method than
immunoenzymatic analyses. An immunohistochemical tech-
nique using formalin-fixed paraffin-embedded tissue has been
developed and has enabled antigen-antibody reactions to yield
more specific results along with the use of various enzymes. It
has now substituted most of the immunofluorescence tech-
niques except in a few cases. A recent application of antigen
retrieval technique has been used successfully to easily detect
antigens even when using antibodies at a low concentration.
Among the advantages listed above, immunohistochemis-
try has two crucial weaknesses for pathologists to consider.
They are false negative and false positive. False negative
means antibodies are present but appear negative in immuno-
histochemical staining test, while false positive gives rise to
positive results when the antibodies in fact are not present.
Appropriate positive and negative controls, therefore, are
required to rule out false-negative or false-positive staining.
When using immunohistochemistry, several factors can
cause false-negative or false-positive results. Antibodies
may fail to detect their target antigen even if the antigen is
present in the tissue for many reasons including, in particu-
lar, low concentration of antigens present, conformation
changes of antigens while the tissue is being processed, inap-
propriate concentration of antibodies being used (mostly
when low concentration), and when the detection system is
not working properly. Long-term exposure to air of the tissue
paraffin block could also cause false-negative results.
Conversely, antibodies can bind nonspecifically to other tar-
gets or cross-react with other antigens, rendering false-
positive results. In order to prevent these drawbacks, staining
75
of control tissues must be performed, simultaneously. In
pathological assessment, false-positive results usually have
more significant consequences than false negatives.
Immunohistochemical staining has been a helpful aid
in discerning the primary site of tumor origin. For instance,
for the differential diagnosis of metastatic carcinoma as well
as adamantinoma, osteofibrous dysplasia, and chordoma,
immunohistochemical markers such as keratins are used.
In the past, diagnosing bone tumors, especially small blue
cell tumors, was challenging. They include Ewing sarcoma,
primitive neuroectodermal tumor, small cell osteosarcoma,
malignant lymphoma, and mesenchymal chondrosarcoma.
Immunohistochemical staining using antibodies to CD99,
however, has allowed the diagnosis to be much simpler and
easier. Langerhans cells of eosinophilic granuloma could be
easily distinguished from chronic osteomyelitis as they appear
positive for CD1a. Several vascular markers are also in fre-
quent use. For example, CD31, CD34, and factor VIII-related
antigen could play a central role when high-grade angiosar-
coma presents features similar to metastatic carcinoma.
Karyotyping
A karyotyping (Greek karyon = nucleus) is about the number
and shape of chromosomes in the nucleus of a cell and also
used for the complete set of chromosomes in an individual
organism. Karyotypes describe the number of chromosomes
depending on their length, banding pattern, centromere’s
position, differences between the sex chromosomes, and
other physical characteristics. The study of karyotypes is
part of cytogenetics, sometimes known as karyology.
Karyotyping is a test to examine chromosomes in a sam-
ple of cells, which can help identify genetic problems as the
cause of a disorder or disease. This test counts the number of
chromosomes and looks for structural changes in
chromosomes.
The test can be performed on almost any tissue, including
the amniotic fluid, blood, bone marrow, and placenta tissue
during pregnancy to feed a growing baby.
The sample is placed into a special dish or tube and
allowed to grow in the laboratory. Cells are later taken from
the new sample and stained. The laboratory specialist uses a
microscope to examine the size, shape, and number of chro-
mosomes in the cell sample. The stained sample is photo-
graphed to observe the arrangement of the chromosomes.
The chromosomes are depicted in a standard format known
as a karyogram or idiogram: in pairs, ordered by size and
centromere’s position for the same size of chromosomes.
Nearly all methods of chromosome banding rely on
harvesting chromosomes in mitosis. This is usually achieved
by treating cells with tubulin inhibitors, such as colchicine or
demecolcine (colcemid), that depolymerize the mitotic spin-
dle and thus arrest the cell at this stage.
76
Chromosome banding methods are either based on stain-
ing chromosomes with a dye or on assaying for a particular
function. The most common methods of dye-based chromo-
some banding are G (Giemsa), R (reverse), C (centromere),
and Q (quinacrine) banding. Bands that show strong staining
are referred to as positive bands; weakly staining bands are
negative bands. Bands are numbered consecutively away
from the centromere on both the short (p) and long (q) arms.
The total number of bands or “resolution” in the human
karyotype depends on how condensed the chromosomes are
and at what stage of mitosis they are in.
However, the staining patterns are not black and white,
but rather different bands stain to different intensities.
G-positive bands are usually just called G bands and likewise
for R-positive (R) bands. Positive C bands contain constitu-
tive heterochromatin. Q bands are considered equivalent to G
bands. The most widely used function-based banding method
is replication banding and is based on the fact that different
bands replicate their DNA at different times during the S
phase of the cell cycle. G bands also correspond to the con-
densed chromomeres of meiotic chromosomes and R bands
to the interchromomeric regions. The total number of bands
or “resolution” in the human karyotype depends on how con-
densed the chromosomes are and at what stage of mitosis
they are in.
G banding and R banding are the most commonly used
techniques for chromosome identification (karyotyping) and
any abnormalities in number, translocations of material from
one chromosome to another, and deletions, inversions, or
amplifications of chromosome segments.
Comparisons of chromosome banding patterns can be
used to confirm evolutionary relationships between species
and also to reveal changes in karyotype that may have been
important in speciation.
Currently, the karyotyping has been augmented by com-
bining cytogenetics with fluorescence in situ hybridization
(FISH). Molecular cytogenetic techniques such as FISH
have been proven effective in diagnostics and recognized as
a valuable addition or even alternative to chromosomal band-
ing. Furthermore, contemporary basic biomedical research
widely applies molecular cytogenetic technologies.
Blotting (Southern, Northern,
and Western Dot)
Southern Blot
Southern blot that was developed by Edwin Southern in
1975 is a method for detection of a specific gene in a com-
plex genome DNA. It combines transfer of enzymatically
chopped and electrophoresis-separated DNA fragments to a
filter membrane and subsequent fragment detection by
Y.-K. Park
isotope-labeled probe hybridization. Other blotting methods
(Northern blot and Western blot depending on RNA or pro-
tein) that employ similar principles have later been named
after Edwin Southern.
Southern blotting is the transfer of DNA fragments from
an electrophoresis gel to a membrane support, resulting in
immobilization of the DNA fragments. The membrane,
therefore, carries a semipermanent reproduction of the band-
ing pattern of the gel. After immobilization, the DNA can be
subjected to hybridization analysis, enabling bands with
sequence similarity to a labeled probe to be identified. When
setting up a Southern transfer, choices must be made between
different types of membranes, transfer buffer, and transfer
method. The most popular membranes are made of nitrocel-
lulose, uncharged nylon, or positively charged nylon. The
basic protocol describes Southern blotting via upward capil-
lary transfer of DNA from an agarose gel onto a nylon or
nitrocellulose membrane, using a high-salt transfer buffer to
promote binding of DNA to the membrane. Immobilization
is achieved by UV irradiation (for nylon) or baking (for
nitrocellulose).
After a radioactively labeled probe is hybridized with
immobilized DNA on the membrane, the hybridized mem-
brane is washed stringently and dried. And then, the radiola-
beled probe bound to target fragments is visualized on X-ray
film, called autoradiography. A nonradioactive probe label-
ing such as DIG also has been developed, which provides
safety and probe stability. Southern blotting has been a popu-
lar technique for routine molecular diagnosis of various
genetic diseases, including the fragile X syndrome, myotonic
dystrophy, Friedreich’s ataxia, Prader-Willi/Angelman syn-
drome, etc.
Northern Blot
The Northern blot technique was developed in 1977 at
Stanford University. Northern blot is a technique to analyze
gene expression by the quantification of mRNA and allows
researchers to observe cellular control or function by deter-
mining the particular gene expression levels in diseased con-
ditions. It involves the use of electrophoresis to separate
RNA samples by size and detects with a hybridization probe,
complementary to part of or the entire target sequence. The
major difference to Southern blot is that RNA, rather than
DNA, is analyzed in the Northern blot.
Northern blotting shows specific gene expression pattern
in various situations including developmental stages, envi-
ronmental stress, pathogen detection, therapeutic monitor-
ing, etc. It was used to show overexpression of oncogenes
and downregulation of tumor suppressor genes in cancerous
cells, compared to normal tissue. Since an upregulated gene
means an abundance of mRNA on the Northern blot, the
4 Basic and Ancillary Techniques in Bone Pathology
expression patterns obtained under given conditions can pro-
vide insight for the function of that gene. Since the RNA is
first separated by size, if only one probe type is used, vari-
ance in the level of each band on the membrane can provide
information about the size of the product, suggesting alterna-
tive splice products of the same gene or repetitive sequence
motifs. The variance in size of a gene product can also indi-
cate deletions or errors in transcript processing.
Western Blot
Western blot, the method originated by Harry Towbin at the
Friedrich Miescher Institute (sometimes called the protein
immunoblot), is a popular technique used to detect specific
proteins in the given sample of a tissue homogenate or
extract. It uses gel electrophoresis to separate native or dena-
tured proteins by the length of the polypeptide. The proteins
are then transferred to a membrane such as nitrocellulose or
PVDF, where they are stained with antibodies specific to the
target protein.
This method is used in the fields of molecular biology,
biochemistry, immunogenetics, proteomics, molecular medi-
cine, and others. For medical uses, Western blot is a confir-
matory test to detect HIV, hepatitis B, bovine spongiform
encephalopathy, and some forms of Lyme disease.
Dot Blot
A dot blot (or slot blot) is a technique for detecting, analyzing,
and identifying DNA, RNA, and protein. It represents a simpli-
fication of the Northern blot, Southern blot, or Western blot
methods. In a dot blot, these biomolecules to be detected are
not separated by electrophoresis. Instead, a mixture containing
the molecule to be detected is applied directly on a membrane
(nylon or nitrocellulose) as a dot and then is spotted through
circular templates directly onto the membrane or paper sub-
strate. Because the complex blotting procedures for the gel
electrophoresis are not required, this method significantly saves
time. It, however, does not provide information on the size of
the target biomolecule. If two different sizes of molecules are
detected, they will appear as a single dot. Dot blots can only
confirm the presence or absence of a biomolecule or those
which can be detected by the DNA probes or the antibody.
For medical purposes, the sensitive dot blot test can be
used to detect the Chlamydia trachomatis infection and other
sexually transmitted diseases. Dot blot is used to detect anti-
diacyltrehalose antibodies in tuberculous patients and
typhoid fever. Therefore, the dot blot test can be useful for
underdeveloped countries, especially, since it is a good posi-
tive predictor of these diseases for countries and regions
lacking in medical facilities and laboratories.
77
PCR and Real-Time PCR
PCR (Polymerase Chain Reaction)
The polymerase chain reaction (PCR) developed in 1983 by
Kary Mullis amplifies a single or a few copies of template
DNA and, as a result, generates millions of copies of a spe-
cific size of DNA sequence.
PCR mimics the in vivo process of DNA replication and
is the in vitro enzymatic synthesis and amplification of spe-
cific DNA sequences.
PCR is now a common and often indispensable technique
in many aspects of biomedical research, for example, detec-
tion of gene mutation in hereditary diseases, analysis of
mRNA expression, diagnosis of infectious agents, DNA
cloning, sequencing, phylogeny, forensic medicine, paternity
testing, and so many others.
PCR requires a certain instrument, the so-called thermal
cycler, capable of thermal cycling for heating and cooling for
double-stranded DNA melting, annealing, and enzymatic
DNA replication.
Basic PCR reactants for DNA amplification are needed in
several components, and reagents are as follows: DNA tem-
plate to be amplified; a pair of short synthetic DNA sequence,
called primer, complimentary to the 5′ and 3′ ends of each of
double-strand DNA; DNA replication enzyme such as Taq
polymerase or a different type of DNA polymerase; deoxy-
nucleotide triphosphates (dNTP) for the synthesis of the new
DNA strand; and buffer solution with magnesium ions and
potassium ions for optimum activity of DNA polymerase.
The majority of PCR methods use thermal cycling, which
repetitively heats and cools the PCR reactants through the
defined series of temperature steps. In the first step in a pro-
cess called denaturation, the double strands of the DNA are
separated at a high temperature. In the second step, called
annealing, the temperature is lowered and the template DNA
hybridizes primers that are complementary to the specific
region of template DNA targeted for amplification.
In the third step, called extension, DNA polymerase syn-
thesizes a new DNA strand using dNTP with template and
primer. Because of high temperature, almost all PCR
employs a heat-stable DNA polymerase such as Taq poly-
merase isolated from Thermus aquaticus.
In detail, this process can be achieved by cyclical altera-
tions of temperature facilitating the DNA strand separation,
hybridization of primers, and polymerization as follows:
First, target DNA is separated into two strands by heating
to 92–98 °C. The temperature is then reduced to between 37
and 55 °C to allow the primers to anneal (the actual tempera-
ture depends on the primer lengths and sequences). Following
annealing, the temperature is increased to 60–72 °C for opti-
mal polymerization. In the first polymerization step, the tar-
get is copied from the primer sites for various distances on
78
each target molecule until the beginning of cycle 2, when the
reaction is heated to 95 °C again, which denatures the newly
synthesized molecules. In the second annealing step, the
primer can bind to the newly synthesized strand, and during
polymerization it can only copy until it reaches the end of the
first primer. Thus, at the end of cycle 2, some newly synthe-
sized DNA of the correct length gets yielded. In subsequent
cycles, these outnumber the target molecules and get
increased by twofold with each cycle. If PCR were 100 %
efficient, one target DNA would become 2n after n cycles. In
practice, 20–40 cycles are commonly used.
The basic detection technique of PCR products is agarose
gel electrophoresis in the presence of ethidium bromide, and
resulting bands after electrophoresis are visualized by
ultraviolet.
If a pair of oligonucleotide primers can be designed to be
complementary to the target molecule such that they can be
extended by a DNA polymerase toward each other, then the
target region can be significantly amplified. Due to the
extreme amplification achievable, it has been demonstrated
that PCR can sometimes amplify as little as one molecule of
the starting template. PCR can also detect one copy of DNA
in 106 genomes. Thus, any source of DNA that provides one
or more target DNA can, in principle, be used as a template
for PCR.
This includes DNA prepared from blood, tissue, forensic
specimens, and paleontological samples or in the laboratory
from bacterial colonies or phage plaques. Whatever the
source is, PCR can only be applied if some sequence infor-
mation is known so that primers can be designed.
Many other variations on the basic PCR technique have
been developed and applied to genomic research suitable for
the purpose.
Real-Time PCR
As an analytical technique, the original PCR method had
some serious limitations. Quantification of PCR product is
very difficult since the PCR gave rise to essentially the same
amount of product independent of the initial amount of DNA
template. This limitation was solved in 1992 by the develop-
ment of real-time PCR.
In real-time PCR, the amount of product formed is moni-
tored during the course of the reaction by monitoring the
fluorescence of dyes or probes introduced into the reaction
that is proportional to the amount of product formed, and the
number of amplification cycles required to obtain a particu-
lar amount of DNA is registered. Assuming a certain ampli-
fication efficiency, which typically is close to a doubling of
the number of DNA per amplification cycle, it is possible to
calculate the number of DNA of the amplified sequence that
Y.-K. Park
was initially present in the sample. With the highly efficient
detection chemistries, sensitive instrumentation, and opti-
mized assays that are available today, the number of DNA
molecules of a particular sequence in a complex sample can
be determined with unprecedented accuracy and sensitivity
sufficient to detect a single molecule. Typical uses of real-
time PCR include pathogen detection, gene expression anal-
ysis, single nucleotide polymorphism (SNP) analysis,
analysis of chromosome aberrations, and, most recently, pro-
tein detection by real-time immuno-PCR.
Real-time PCR is the technique of collecting data through-
out the PCR process as it occurs, thus enabling amplification
and detection into a single step. This is achieved using a vari-
ety of different fluorescent chemistries that correlate PCR
product concentration to fluorescence intensity. Detection
chemistries of fluorescence can be either probe- or non-
probe-based, also referred to as “specific” or “nonspecific,”
respectively. The most widely used non-probe-based chem-
istry detects the intercalating of SYBR® Green I as fluores-
cent dye to double-stranded DNA (amplicon). Probe-based
chemistries make use of amplicon-specific fluorescent
probes, and a fluorescent signal is only generated if the probe
hybridizes with its complementary target. Therefore, probe-
based chemistries allow an additional level of specificity.
Reactions are characterized by the point in time (or PCR
cycle) where the target amplification is first detected. This
value is usually referred to as the cycle threshold (Ct), the
time at which fluorescence intensity is greater than back-
ground fluorescence. Consequently, the greater the quantity
of target DNA in the starting material, the faster a significant
increase in fluorescent signal will appear, yielding a lower Ct.
There are many benefits of using real-time PCR over
other methods to quantify gene expression. It can produce
quantitative data with an accurate dynamic range of 7–8 log
orders of magnitude and does not require post-amplification
manipulation. Real-time PCR assays are 10,000- to 100,000-
fold more sensitive than RNase protection assays, 1,000-fold
more sensitive than dot blot hybridization. It can even detect
a single copy of a specific transcript. In addition, real-time
PCR assays can reliably detect gene expression differences
as small as 23 % between samples and have lower coeffi-
cients of variation (cv: SYBR® Green at 14.2 %; TaqMan® at
24 %) than end point assays such as band densitometry
(44.9 %) and probe hybridization (45.1 %). Real-time PCR
can also discriminate between messenger RNAs (mRNAs)
with almost identical sequences. It requires much less RNA
template than other methods of gene expression analysis and
can yield relatively high throughput given the proper equip-
ment. The disadvantage to real-time PCR is that due to its
extremely high sensitivity, sound experimental design and an
in-depth understanding of normalization techniques are
imperative for accurate conclusions.
4 Basic and Ancillary Techniques in Bone Pathology
Fluorescent In Situ Hybridization, CISH,
and SISH
Fluorescent In Situ Hybridization (FISH)
Fluorescence in situ hybridization (FISH) has been shown to
discriminate between unreplicated and replicated regions of
the genome in interphase nuclei, based on the number of spe-
cific fluorescent signals that can be detected. By examining
the replication status of hybridizing sequences in large num-
bers of individual cells from an asynchronously growing
population, it is possible to deduce a relative order of replica-
tion of different sequences.
The fluorescent in situ hybridization (FISH) technique
involves the labeling of DNA probes with haptens, such as
biotin or digoxigenin, by random priming or by nick transla-
tion. After denaturation the probes are applied to chromo-
somes in situ, as metaphase chromosomes or interphase
nuclei, and DNA-DNA hybridization is allowed to occur.
Hybrids are then detected by means of fluorescently labeled
molecules, which have high affinity for the haptens, and the
signal may be amplified with simultaneous layers of antibod-
ies and antibodies conjugated to fluorescent molecules.
Alternatively, DNA probes may be directly labeled with flu-
orescent molecules such as FITC, Texas red, or the recently
developed cyanine dyes, and in this instance, visualization of
the DNA-DNA hybrids does not require signal detection and
amplification mentioned above.
The improvement of cloned DNA sources, antibodies,
fluorochromes, microscopy and imaging equipment, and
software has allowed us to investigate a variety of scientific
procedures. This unit is divided into five parts—probe prepa-
ration, slide preparation, hybridization, post-hybridization
washes, and interpretation. Probes are prepared by nick
translation or degenerative oligonucleotide primer PCR
(DOP-PCR) using hapten- or fluorochrome-labeled nucleo-
tide. The amount of hapten labels incorporated is quantified
by dot blotting. Cytogenetic slide preparations are suitable
for FISH if they are appropriately aged. These slides may be
used even if they have previously been G banded. In addi-
tion, slides made from paraffin-embedded tissues are suit-
able specimens for hybridization with DNA or protein
nucleic acid (PNA) probes. Hybridization conditions must
be appropriate for both the sample and probe materials: cyto-
genetic slides can be hybridized with DNA and PNA probes,
as can paraffin sections. Post-hybridization wash and detec-
tion conditions vary depending on the probe—indirectly
labeled DNA probes, directly labeled DNA probes, and pep-
tide nucleic acid (PNA) probes.
Small structural chromosomal aberrations are often dif-
ficult to detect with certainty using conventional cytoge-
netic banding methods alone. The problems that can
typically arise in both clinical and cancer cytogenetics are
79
the presence of structural chromosome aberrations with
unidentifiable chromosomal regions or very complex chro-
mosomes (sometimes called marker chromosomes) in
which no recognizable region appears to be present.
Confirmation of the cytogenetic origins of such chromo-
somal aberrations can sometimes be obtained by the judi-
cious application of locus-specific FISH analysis if the
investigator has some general impression regarding a pos-
sible identity. However, such an approach is very subjective
and risky. It requires some knowledge of the specific loci
and available probes likely to be involved in the aberration.
A more systematic approach is to use whole-chromosomal
paints in succession, until the marker chromosome and its
constituents are to be identified. While this strategy will
eventually identify each chromosomal region involved, it is
both costly and time-consuming and may lead to the deple-
tion of valuable patient samples. Recently, some general-
ized screening FISH techniques utilizing sensitive and
differentially labeled chromosome-specific paints have
been developed. They allow the full chromosome comple-
ment to be analyzed to identify unknown aberrations. In
this unit, the commonly available methods will be described
with suggested protocols and approaches to troubleshoot.
There are currently two to three slightly different imaging
systems available that utilize the mechanical rotation of fluo-
rescence excitation filters to distinguish the distinct fluores-
cence of a mixture of chromosomal paints during image
acquisition. Such filter-based systems are generically termed
multicolor FISH. The second more frequently used system,
called spectral karyotyping (SKY), utilizes image analysis
based on Fourier transformation to spectrally analyze the dif-
ferential fluorescence of each chromosomal paint. Both the
SKY and M-FISH methods require the use of human whole-
chromosomal paints that are differentially labeled, so that
each chromosome emits a unique combination of colors fol-
lowing hybridization. This color combination is used for
identification purposes. Each method can be performed as a
laboratory procedure and is capable of identifying the cyto-
genetic origins of all chromosomes in the complement in one
image acquisition step (as in SKY) or through sequential
imaging with specific filters (M-FISH).
Chromogenic In Situ Hybridization (CISH)
Chromogenic in situ hybridization (CISH) is a technique in
which the DNA probe is detected using an immunoperoxi-
dase reaction.
CISH is a combination of in situ hybridization with anti-
bodies or avidin conjugated with enzymes, such as alkaline
phosphatase and peroxidase, to develop a chromogenic reac-
tion similar to IHC staining. The principle of FISH is the
hybridization of a fluorochrome-labeled DNA (probe) with a
80
complementary target DNA sequence. A fluorescent coun-
terstain is applied, and the use of a fluorescent microscope
with appropriate filters is necessary.
This method is very close to FISH but does not require the
use of fluorescence microscopy. Moreover, FISH signals fade
within a few weeks, and the FISH results have to be recorded
with expensive digital systems. This is not the case for CISH
staining. CISH does not require an expensive fluorescence
microscope with multiband pass filters. CISH staining is per-
manent and does not need to be recorded with an expensive
CCD camera. Owing to the similarity with IHC staining,
CISH is also easier to interpret even for pathologists who are
not trained with fluorescence. Moreover, morphology is eas-
ily analyzed on CISH slides, particularly for distinguishing
invasive cancer cells and in situ components. CISH is demon-
strated to be well correlated with FISH. Although FISH and
CISH can neither provide a genome-wide assessment of chro-
mosomal changes nor identify gene mutations in a given
tumor, these techniques have several advantages over other
traditional techniques for cytogenetic analysis. Unlike con-
ventional cytogenetics, FISH/CISH does not require tissue
culturing or mitotic cells and can be applied directly to
interphase nuclei. In addition, FISH/CISH can be applied to
a range of clinical samples, including cell lines; fresh/frozen
samples; cytologic specimens; archival formalin-fixed, par-
affin-embedded material; and tissue microarray sections.
The fact that these techniques can be used with fixed sam-
ples has proven to be useful both in diagnostic pathology
laboratories and as a means to validate the results of
genome-wide molecular genetic analysis in a high-through-
put fashion (e.g., an amplicon identified by means of aCGH
can be validated in a large cohort of samples using tissue
microarrays).
Silver In Situ Hybridization (SISH)
Bright-field in situ hybridization is a molecular technique
that enables visualization of cellular target DNA using
chromogenic (e.g., chromogenic in situ hybridization) or
enzyme metallographic (e.g., silver in situ hybridization)
methods that detect with conventional light microscopy.
Unlike CISH, enzyme metallographic in situ hybridization
utilizes an enzymatic reaction to facilitate the deposition
of metal directly from solution to identify the target site. In
addition to the advantages offered by chromogenic bright-
field in situ hybridization, metallographic in situ hybrid-
ization provides higher sensitivity and resolution for both
amplified and non-amplified genes. Due to limitations of
early nanogold-silver enhancement procedures, which are
cumbersome for routine use, a simplified gold-enhanced
nanogold-streptavidin method, termed gold-facilitated in
situ hybridization (GOLDFISH), was developed. This
Y.-K. Park
technique was initially developed as a simplified way to
qualitatively identify confluent amplification signals in tis-
sue sections rather than a quantitative assessment of discreet
dots. It was subsequently discovered that horseradish per-
oxidase can be used to selectively deposit metal from solu-
tion in the absence of a particulate nucleating agent such as
nanogold. As commercialized enzyme metallography,
EnzMet is known as silver in situ hybridization (SISH). This
advancement has allowed discreet spots of metallic silver
deposition to appear from the enzymatic action of peroxi-
dase on silver acetate in the presence of hydroquinone, at
the target site, allowing a superior quantitative assessment
of gene copy number. The EnzMet Gene Pro assay, a form
of SISH that incorporates concomitant protein detection,
has demonstrated excellent interobserver reproducibility.
The benefits of SISH detection of HER2 include very high
sensitivity with high resolution and signal separation, accu-
rate quantitation of gene amplification, excellent visualiza-
tion of tissue morphology, and adaptability for automation.
Ventana Medical Systems (Tucson, AZ, USA) has
requested an FDA approval for their fully automated
INFORM™ HER2 silver in situ hybridization (SISH) tech-
nology that allows a diagnosis within 6 h and uses metallog-
raphy where the bound HRP catalyzes reduction of silver
acetate to produce a black signal. Furthermore, SISH for
CEP17 can be stained simultaneously on a sequential slide.
SISH scoring is identical to CISH scoring, and HER2/CEP17
SISH shows a good correlation with CISH and
FISH. Furthermore, despite the fact that there is a good
interobserver concordance, a new software application was
developed, the Ventana Image Analysis System (VIAS).
This system makes a digital image of the microscopic field
and counts the HER2 and CEP17 copies in sequential slides.
When the minimal number of tumor cells is reached, the
VIAS system calculates the HER2/CEP17 ratio. The com-
parison of IHC, FISH, CISH, and SISH has found a high
concordance between CISH, IHC, and FISH and showed that
SISH was as reliable as CISH and FISH for the assessment
of HER2 status.
Comparative Genomic Hybridization
and Chromothripsis
Comparative Genomic Hybridization
Comparative genomic hybridization (CGH) was firstly
reported as a new chromosome analysis technique.
Tumor DNA is labeled with a green fluorochrome, mixed
(1:1) with red-labeled normal DNA and hybridized to nor-
mal human metaphase preparations. Originally, metaphase
chromosomes were used for the representation of the
genome, and the location of copy number variations between
4 Basic and Ancillary Techniques in Bone Pathology
test and reference genomic DNA was mapped to the physical
position on the chromosomes. The normal reference DNA
and the metaphases are obtained from a healthy volunteer
and do not need to be from the diseased. The green- and red-
labeled DNA fragments compete for hybridization to their
locus of origin on the chromosomes. The green to red fluo-
rescence ratio measured along the chromosomal axis repre-
sents loss (ratio <1) or gain (ratio >1) of genetic material in
the tumor at that specific locus. Comparative genomic
hybridization (CGH) allows for the detection of chromo-
somal copy number changes without the need for cell cultur-
ing. It gives a global overview of chromosomal gains and
losses throughout the whole genome of a tumor.
Thus, CGH is a relatively fast screening technique that
can point at specific chromosomal regions that might play a
role in the pathogenesis or progression of tumors. With the
CGH results, more specific molecular biological techniques
(such as fluorescence in situ hybridization, loss of heterozy-
gosity analysis, and sequencing) can be used to identify
oncogenes and/or tumor suppressor genes in these regions.
Now chromosomes have largely been replaced by DNA
microarrays containing elements that are mapped directly to
the genome sequence.
Array CGH has been implemented using a wide variety of
techniques. The initial approaches used arrays produced
from large-insert genomic clones such as bacterial artificial
chromosomes (BACs). Producing sufficient BAC DNA of
adequate purity to make arrays is arduous. Several tech-
niques to amplify small amounts of starting material, there-
fore, have been employed. Arrays made from less complex
nucleic acids such as cDNAs, selected PCR products, and
oligonucleotides are also used.
Although CGH has proven to be a useful and reliable tech-
nique in the research and diagnostics of both cancer and
human genetic disorders, the applications involve only gross
abnormalities. Owing to the limited resolution of metaphase
chromosomes, aberrations smaller than 5–10 Mb cannot be
detected using conventional CGH. For the detection of such
abnormalities, a high-resolution technique is required. So far,
FISH is being used mainly for this purpose, but this approach
requires prior knowledge of the target. As the newly intro-
duced microarray-based CGH technique combines the reso-
lution of FISH with the whole-genome screening capacity of
conventional CGH, it holds a great potential for the analysis
of DNA copy number changes in clinical genetics.
With the introduction of microarray-based CGH (array
CGH), the main limitation of conventional CGH, a low reso-
lution, has been overcome. In array CGH, the metaphase
chromosomes are replaced by cloned DNA fragments (100–
200 kb) of which the exact chromosomal location is known.
This allows the detection of aberrations in more detail and,
moreover, makes it possible to map the changes directly onto
the genomic sequence.
81
Chromothripsis
Cancer evokes the accumulation of genetic mutations and
chromosomal rearrangements that have slowly and relent-
lessly overridden a cell’s self-restraints on growth. An
entirely different model of cancer has proposed in the recent
paper that massive genomic rearrangement has been acquired
in a single catastrophic event during cancer development.
Chromothripsis is a one-step catastrophic event which
plays an important role during cancer development. During
chromothripsis, tens to hundreds of genomic rearrangements
can occur within localized regions of the genome and lead to
the simultaneous creation of multiple cancer-driving aberra-
tions. Given that chromothripsis has a cancer-wide incidence
of 2–3 %, its recent discovery has significant implications for
our understanding of tumor biology and evolution.
FISH analysis is widely used for the cytogenetic assess-
ment. Other approaches such as oligonucleotide-based array
comparative genomic hybridization and single nucleotide
polymorphism (SNP) microarray show comparable results,
but also assess all chromosomal regions rather than the cur-
rent standard clinical practice of identifying alterations with
probes targeting only four to five chromosomal sites. The
high-resolution gene copy number analysis afforded by DNA
microarrays provides greater precision in demarcating
boundaries of individual genomic imbalances and uncovers
alterations overlooked by FISH analysis.
Multiplex-fluorescence in situ hybridization (M-FISH)
has been used in chromosomal karyotyping to analyze chro-
mosomal aberrations.
FISH is based on the use of chromosome region-specific,
fluorescent-labeled DNA probes. These probes are cloned
pieces of genomic DNA that are able to detect their comple-
mentary DNA sequences, producing a fluorescent signal
against background. However, this technique requires prior
knowledge of the type and location of expected aberrations
and can only be used for the analysis of a limited number of
chromosomal loci at one time.
Rearrangement screens were performed on genomic
DNA. Array-based massively parallel, paired-end sequenc-
ing to identify somatically acquired genomic rearrangements
in cancer samples has been adopted. SNP microarray analy-
sis for copy number and allelic ratio profiles in bone and the
cell line set were also analyzed by Affymetrix microarrays.
DNA Microarray
Microarray is one of the latest techniques in genome-wide
scale study of molecular biology and medicine. Microarray
technology was developed from Southern blotting in which
fragmented DNA in agarose gel hybridized with a known
DNA probe. Using genetic analysis tools such as Southern
82
blotting, researchers have been able to analyze genes at once
and examine thousands of genes in a single experiment at
any given time by DNA microarray technology. The use of
microarrays for gene expression profiling was first reported
in 1995, and microarray results on a complete eukaryotic
genome of Saccharomyces cerevisiae were reported in 1997.
Basically, the levels of all mRNA species can be mea-
sured, creating an expression profile or transcriptome to
reflect the interplay of a set of expressed genes under micro-
array platform.
Microarray technology will help researchers to learn
more about many different diseases, including cancer, heart
disease, and infectious diseases. With respect to cancer, sci-
entists have classified different types of cancers based on
organs in which the tumors develop. With microarray tech-
nology, it has been possible to further classify the types of
cancers based on the patterns of gene profiling in the tumor
cells.
The microarray experiment is as follows. cDNA from
mRNA gets isolated from two different conditions (e.g., con-
trol and treated), labeled with different fluorochromes such
as Cy3 (green) and Cy5 (red). The resulting mixture of
labeled cDNAs is hybridized to a large number of each gene
probe spotted on a microarray slide. Competitive hybridiza-
tion results are then analyzed by determining the relative
fluorescent intensity at each spot with the use of a microarray
scanner. Genes that are differentially upregulated or down-
regulated in the experiment are discriminated with difference
of spot fluorescence with one label or the other.
Types of Microarrays
DNA microarrays are of oligonucleotide arrays and cDNA
arrays. Commercialized arrays are possible.
The first widely used technology was the spotted cDNA
microarray as mentioned above. The next microarray tech-
nology was in situ-synthesized oligonucleotide arrays, which
utilized photolithographic technology (Affymetrix). Each
gene target is probed by a number of distinct probes (11–20)
collectively termed a probe set although some probes within
a set are known to overlap in sequence.
Biotinylated cDNA, derived from a biological sample, is
hybridized onto the microarray, stained, and scanned for
fluorescence at a single wavelength. This is not a competitive
hybridization method. In order to compare two samples, two
separate microarrays are required.
Spotted oligonucleotide arrays (CodeLink, Amersham)
are made with pre-synthesized 30 mer oligonucleotides
Y.-K. Park
piezoelectrically deposited on a gel-coated plastic film. This
is also a single-dye technique, so sample preparation and
scanning proceed analogous to Affymetrix microarrays. Ink-
jet technology (Agilent) is also used for the in situ synthesis
of oligonucleotide microarrays consisting of probes that are
60 bases long, which is more than twice the length of those
used by Affymetrix. On the other hand, the Affymetrix plat-
form uses several probes to sample a single gene. Agilent
microarrays are similar to the original cDNA arrays because
they use a two-dye technology.
NimbleGen has made fully customizable, photolitho-
graphically manufactured 60 mer arrays. Illumina beaded
oligonucleotide arrays are comprised of thousands of
microwells, each containing a single bead. Each probes a tar-
get gene using >105 copies of a 50 mer oligonucleotide
probe. Beads that carry the same probe are scattered ran-
domly across the microarray, and each chip has a unique
address file, which encodes the identity of each bead. Finally,
Applied Biosystems has made new microarrays based on
chemiluminescence rather than fluorescence. Regardless of
the underlying technology, the raw data always comes in the
same form—the scanned image.
Application of Microarray
Although microarrays can be used to study DNA, RNA, or
protein, the term generally refers to cDNA testing for RNA
expression rather than to protein. The term “expression
arrays” is usually used to denote testing for RNA expression.
A common application of microarrays has been in mea-
suring gene expression, from characterizing cells and pro-
cesses to clinical applications such as tumor classification.
Another very common use of microarrays is in genotyping
and the measurement of genetic variation. The full range of
applications is too numerous to mention; improvements and
adaptations are continually being made.
DNA microarray finds its way in various fields of molecular
biology. This technique has been used efficiently in clinical
diagnostics for identifying disease-related genes with the help
of its biomarkers. It has also been used in various other areas
of biology like genotyping and specifying disease-relevant
genes or agents, analysis on mutation, screening of single
nucleotide polymorphisms (SNPs), detection of chromosome
abnormalities, and overall study of posttranslational modifi-
cations including methylation, acetylation, and alternative
splicing, disease diagnosis, drug discovery, and toxicological
research and in the food industries to detect foodborne patho-
genic bacteria, viruses, and parasites.
4 Basic and Ancillary Techniques in Bone Pathology 83

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 Grading and Staging
5
Yong-Koo Park

Abstract
Grading is applied only to malignant tumors. Usually, a scale of 1–4 is used to grade malig-
nant tumors based on their histological resemblance to “normal counterparts.” Conventional
osteosarcomas are high-grade tumors. Chondrosarcoma is graded on a scale of 1–3. Ewing’s
sarcoma and mesenchymal chondrosarcoma are always regarded as high-grade tumors.
Malignant lymphoma, myeloma, chordoma, and adamantinoma are not graded because
grading has not been proved to correlate with clinical behavior.
Staging is the process of classifying a tumor with respect to its degree of differentiation
as well as its local and distant spread in order to estimate the prognosis of the patient. The
Musculoskeletal Tumor Society adopted staging systems for both benign and malignant
bone tumors. Benign lesions are graded 1 or 2 according to the degree of local aggressive-
ness. A surgical staging system for malignant lesions is accomplished by assessment of the
surgical grade, low or high grade; the local extent, intra- or extracompartmental; and the
presence or absence of regional or distant metastases. Four types of surgical margin are also
recognized: intralesional margin, marginal margin, wide margin, and radical margin.

A grading system in bone tumors is important because of
its relevance to the biological behavior and prognosis of
bone tumors. Grading is applied only to malignant
tumors.
Usually a scale of 1–4 is used to grade malignant tumors.
Grade 1 is designated when one fourth or less of the cells are
undifferentiated; grade 2 is designated when 1/4–2/4 of the
cells are undifferentiated. When 2/4–3/4 of the cells are
undifferentiated, it is grade 3, and when more than 3/4 of the
cells are undifferentiated, it is grade 4.
Malignant tumors are graded based on their histological
resemblance to “normal counterparts.” The degree of nuclear
hyperchromatism and pleomorphism is the main histological
criteria in grading the tumor. Sometimes mitoses and cellu-
larity are also used to grade chondrosarcomas. If the degree
Y.-K. Park, MD, PhD
Department of Pathology,
Kyung Hee University School of Medicine, Seoul, South Korea
e-mail: ykpark0204@gmail.com
of anaplasia is minimal to moderate, the tumor is grade 1 or
2. Those with more severe anaplasia are grade 3 or 4.
FDG PET can be helpful in grading skeletal lesions. All
high-grade sarcomas, lymphomas, and bone metastases
showed a markedly increased glucose metabolism.
Cytofluorometric cellular DNA and RNA content are also
used to grade bone tumors. The RNA/DNA ratio was higher
in well-differentiated tumors than in primitive tumors.
Clinically, grades 1 and 2 are usually regarded as low-
grade tumors, and grade 3 and 4 are considered high
grade.
Osteosarcoma, fibrosarcoma, and malignant fibrous his-
tiocytoma are graded from 1 to 4. Conventional osteosarco-
mas are high-grade tumors. The majority of osteosarcomas
are grade 3 or 4. Low-grade central osteosarcoma and well-
differentiated osteosarcoma are grade 1 or 2. Parosteal
osteosarcomas are low grade and periosteal osteosarcomas
are usually grade 2 or 3. Osteosarcomas of the jaw are usu-
ally grade 2 or 3 with better prognosis than conventional
osteosarcoma. Chondrosarcoma is graded on a scale of
1–3. Grading is especially important in the diagnosis of

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 85
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_5, © Springer-Verlag London 2015
86
chondrosarcoma because of its usefulness in predicting
biological behavior and prognosis. Because the degree of
cellularity and cytologic atypia may vary within a single
lesion, it is important to have a well-sampled specimen
when grading the chondrosarcoma. Grade 1 chondrosar-
coma is a well-differentiated type, containing chondrocytes
with a slight to moderate increase in nuclear size and varia-
tion in shape. Grade 2 chondrosarcoma shows more cellu-
lar and greater degree of nuclear pleomorphism than a
grade 1 lesion. Grade 3 lesion reveals more marked cellular
pleomorphism than a grade 2 chondrosarcoma. At the
periphery of the tumor lobules, increased cellularity is
easily identified.
Angiosarcoma is also divided into three grades. The grad-
ing is based on the degree of nuclear atypia in the endothelial
cells and the extent of vasoformative activities throughout
the tumor. Vascular formation is easily identified in grade 1,
but in grade 2 and 3 lesions, vasoformative features are less
pronounced.
Fibrosarcomas are graded from 1 to 4 depending upon
cellularity, nuclear atypia, and mitotic activities.
Ewing’s sarcoma and mesenchymal chondrosarcoma are
not graded, but regarded as high-grade tumors.
Malignant lymphoma, myeloma, chordoma, and adaman-
tinoma are not graded because grading has not been proved
to correlate with clinical behavior.
Staging of Musculoskeletal Neoplasms
Staging is the process of classifying a tumor, especially a
malignant tumor, with respect to its degree of differentia-
tion as well as its local and distant spread, in order to esti-
mate the prognosis of the patient. This staging system is
based on clinical, radiographic, and histological features
that are believed to be of prognostic importance and may be
useful when comparing the outcomes between groups of
patients.
The Musculoskeletal Tumor Society adopted staging sys-
tems, which were described by Enneking et al. for both
benign and malignant bone tumors.
Benign lesions are classified using Arabic numerals, and
malignant ones, with Roman numerals. Stage 1 benign
lesions are latent lesions having a negligible recurrence rate
following intracapsular excision. Stage 2 benign lesions are
actively growing with a significant recurrence rate after
intracapsular procedures, but a negligible recurrence rate
after marginal en bloc excision. Stage 2 benign lesions are
locally aggressive with extracapsular extensions having a
high recurrence rate after either intracapsular or marginal
procedures (Table 5.1).
Y.-K. Park
Table 5.1 Staging of benign lesions
Stage Description
1 Latent
2 Active
3 Aggressive
A surgical staging system for malignant lesions is most
logically accomplished by assessment of the surgical grade
(G), the local extent (T), and the presence or absence of
regional or distant metastases (M) (Table 5.2).
Any neoplasm can be divided into two grades, low (G1)
and high (G2). In general, low-grade lesions correspond to
Broders I and II and have less than a 25 % chance of metas-
tasis. High-grade lesions (Broders III and IV) have a greater
risk for local recurrence and greater than 25 % chance of
metastasis.
The anatomic extent (T) is subdivided by whether the
lesion is intracompartmental (A) or extracompartmental (B).
Anatomic compartments have natural barriers to block or
delay tumor extension: in bone, the barriers are cortical bone
and articular cartilage; in joint, articular cartilage and joint
capsule; and in soft tissue, the major fascial septa and the
tendinous origins and insertions of muscles.
The presence or absence of metastases (M) is the third
major factor related to both prognosis and surgical
planning.
Stage I is composed of low-grade lesions (G1); stage II,
high-grade lesions (G2); and stage III lesions, those with
either regional or distant metastases (G1 or G2, M1). Stage
I (G1, M0) and II (G2, M0) are further subdivided by the
intracompartmental (T1) and extracompartmental (T2)
settings.
Stage IA is a low-grade, intracompartmental lesion with
no regional or distant metastases (G1, T1, M0); stage IB is a
low-grade, extracompartmental lesion without metastases
(G1, T2, M0); stage IIA is a high-grade, intracompartmental
lesion free of metastases (G2, T2, M0); stage IIB is a high-
grade, extracompartmental lesion without metastases (G2,
T2, M0); and stage III is of either grade and setting with
metastases (G1 or G2, T1 or T2, M1).
Four types of margins based on the relationship of the
surgical margin to the neoplasm and its pseudocapsular reac-
tive zone are recognized. First, an intralesional margin is
accomplished by a procedure in which the dissection passes
within the lesion. With an intralesional margin, the risk of
local recurrence is high. Second, a marginal margin is
achieved by a procedure in which the lesion is removed in
one piece. The plane of dissection is through the pseudocap-
sule or reactive tissue about the lesion. Third, a wide margin
is present if the surgeon has removed the entire tumor with a
5 Grading and Staging 87

Table 5.2 Staging of malignant lesions References

Stage Description
IA Low grade, intracompartmental Anderson MW, Temple HT, Dussault RG, Kaplan PA. Perspective.
Compartmental anatomy: relevance to staging and biopsy of muscu-
IB Low grade, extracompartmental
loskeletal tumors. AJR. 1999;173:1663–71.
IIA High grade, intracompartmental Evans HL, Ayala AG, Romsdahl MM. Prognostic factors in chondro-
IIB High grade, extracompartmental sarcoma of bone. A clinicopathologic analysis with emphasis on
III Any grade, metastatic histologic grading. Cancer. 1977;40:818–31.
Inwards CY, Unni KK. Classification and grading of bone sarcomas.
Hematol Oncol Clin N Am. 1995;9:545–69.
Table 5.3 Surgical margins Peabody TD, Gibbs CP, Simon MA. Current concepts review.
Evaluation and staging of musculoskeletal neoplasms. J Bone Joint
Type Plane of dissection
Surg. 1998;80-A:1204–18.
Intralesional Within lesion Sanerkin NG. The diagnosis and grading of chondrosarcoma of bone. A
Marginal Within reactive zone – extracapsular combined cytologic and histologic approach. Cancer. 1980;45:
Wide Beyond reactive zone through normal tissue 582–94.
within compartment Schulte M, Brecht-Krauss D, Heymer B, Guhlmann A, Hartwig E,
Radical Normal tissue extracompartmental Sarkar MR, Diederichs CG, Von Baer A, Kotzerke J, Reske
SN. Grading of tumors and tumorlike lesions of bone: evaluation by
FDG PET. J Nucl Med. 2000;41:1695–701.
cuff of normal tissue. Fourth, a radical margin is achieved by Takeshita H, Kusuzaki K, Kuzuhara A, Tsuji Y, Ashihara T, Gebhardt
MC, Mankin HJ, Springfield DS, Hirasawa Y. Anticancer Res.
a procedure in which the lesion, pseudocapsule, reactive 2001;21:1271–8.
zone, and all of the involved muscles or bone are removed as Wolf RE, Enneking WF. The staging and surgery of musculoskeletal
one block (Table 5.3). neoplasms. Orthop Clin N Am. 1996;27:473–81.
 Surgical Treatment of Tumors
and Tumorlike Lesions of Bone 6
Brian E. Walczak, Peter S. Rose, Joel M. Post,
and Franklin H. Sim

Abstract
The surgical treatment of tumors and tumorlike lesions of bone involves a multidisciplinary
team approach. Workup begins with a detailed history, physical exam, and imaging. Biopsy
and obtaining an accurate histologic diagnosis is an important step in the ability to defini-
tively surgically manage these lesions. Surgical resection principles and adequate margins
are important aspects of being able to obtain local control. Limb-sparing principles are
largely employed if neurovascular structures can be preserved and a level of function main-
tained. Tumor grade and location dictate the type of excision required, and mechanical,
chemical, and thermal adjuncts can be employed to further reduce the risk of recurrence in
low-grade or benign tumors. High-grade and some aggressive benign tumors require a wide
excision, and various reconstruction options, such as endoprosthesis and alloprosthetic
composites, can be used to help restore function. Special anatomic considerations (axial
skeleton) can make wide excision challenging. Ultimately the surgical treatment of bone
tumors provides unique challenges for surgeons, and advances in imaging, surgical tech-
niques, prosthetic design, and adjuvant treatments have continued to assist surgeons in
improving functional outcomes.

Introduction for limb salvage procedures provided a surgery with

Surgical advances, such as improved biomaterials, computer
navigation, and effective adjuncts (e.g., chemotherapy and
radiation therapy), have broadened the oncology surgeon’s
arsenal. Fundamentally, bone lesions can be treated with
either limb-sacrificing or limb-sparing surgery. Although
each case is unique, it is helpful to understand the principles
behind surgical resection and how it impacts not only the
disease but also the patient’s function. Patients are selected
B.E. Walczak, DO
Musculoskeletal Oncology and Reconstruction, McLaren Cancer
Institute – McLaren Macomb, Mount Clemens, MN, USA
P.S. Rose, MD • F.H. Sim, MD (*)
Department of Orthopaedic Surgery, Mayo Clinic,
Rochester, MN, USA
e-mail: sim.franklin@mayo.edu
J.M. Post, DO
Orthopedic Oncology, Mayo Clinic, Rochester, MN, USA
equivalent oncologic control compared to amputation can be
achieved and a limb with greater function than an amputation
with a modern prosthesis will result.
Definitive surgical management follows appropriate preop-
erative workup including imaging, biopsy, and staging.
Essentially, the surgeon must answer three basic questions prior
to surgery to plan successful treatment. This includes where the
lesion is (physical exam and imaging), what the lesion is (the
biopsy and tissue diagnosis), and where the lesion is not (the
staging studies). Once these questions have been answered, the
patient and surgeon are able to make an informed decision for
optimal surgical treatment and what adjuvants (if any) to employ.
Biopsy
Once an osseous lesion is discovered, the decision as to the
most effective treatment demands thorough clinical, roent-
genographic, and pathologic evaluations. The aggressiveness

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 89
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_6, © Springer-Verlag London 2015
90
of surgical treatment is based on an accurate histologic diag-
nosis. Although some lesions have determinant characteris-
tics on imaging, most will require a biopsy to establish
diagnosis prior to treatment. Fundamentally, the biopsy can
be done closed or open. Closed biopsies do not require a sur-
gical incision and are done percutaneously with a core needle
and image guidance. Advantages of percutaneous needle
biopsy are the accurate placement with image guidance,
small biopsy tract, and no delay in treatment for a biopsy site
to heal. However, the adequacy of specimen is limited and
can be nondiagnostic up to 20–30 % of the time. Moreover,
a close rapport between the bone pathologist and tumor sur-
geon is essential. Other disadvantages include possible post-
procedure hematoma and contamination (Table 6.1).
Open biopsy procedures mitigate some of the potential dis-
advantages of closed biopsies. Adequacy of specimen can be
assured at the time of surgery with frozen section, and there-
fore, the surgeon can be certain an accurate diagnosis can be
made. However, open biopsies must be planned keeping
future definitive surgical procedures in mind. Placement of the
biopsy incision can facilitate a future successful oncologic
resection (see Figs. 6.1 and 6.2). Important considerations of
the open biopsy are listed in Table 6.2. Open biopsies do
potentially expose a greater area of tissue to tumor contamina-
tion and usually do not have the benefit of sophisticated image
guidance to direct sampling toward specific areas of the tumor.
Ultimately, both closed and open biopsies can reliably
yield diagnostic tissue to guide treatment. The decision
between the two is usually heavily influenced by institutional
practice patterns, and no studies have shown a clear benefit
for one approach over the other.
Amputation
Limb Sacrificing
Amputation is the removal of the affected limb. Resection
level is an important consideration. The margin of surgical
resection must be planned before surgery based upon preop-
erative imaging studies, and the planned function of the
remaining limb should be known. Ideally, a multidisciplinary
team assists with the surgical, functional, and social con-
cerns prior to the procedure. The level of resection is defined
by a combination of adequate bony resection to remove the
lesion with an appropriate margin as well as allowing an
adequate soft tissue envelope to cover the residual limb.
Although many patients opt for limb-preserving surgery,
amputation continues to be a viable option for select
lesions, particularly if recurrent or locally advanced. In
fact, a successful amputation may allow the patient to par-
ticipate in activities that would otherwise not be possible
with traditional reconstructions used in limb salvage. In
some circumstances, the aggressiveness of the lesion or the
extent of surgical excision precludes limb-sparing options
B.E. Walczak et al.
and mandates amputation. Relative indications for amputa-
tion include encasement of major neurovascular structures
and inability to perform successful vascular bypass, patho-
logic fracture with hematoma violating compartment
boundaries, severe infection, immature skeletal age with
predicted leg-length discrepancy >8 cm, extensive soft tis-
sue involvement, and joint contamination.
Limb Sparing
With the advances in preoperative imaging, improved under-
standing of the biologic behavior of bone lesions, and
improvements in implant design and biologic materials,
amputation has had fewer indications. Most patients with
both benign and malignant lesions are candidates for limb
salvage. That said, the surgeon must understand the disease
process in order to plan a surgical resection that removes the
lesion adequately and maintains function of the limb. Ideally,
limb salvage should not delay adjuvant therapy, have rates of
local recurrence and overall survival no worse than amputa-
tion, and provide enduring reconstruction options that main-
tain a functional limb equal or superior to that which would
be achieved with amputation.
Surgical Margins
It is helpful to understand the principles of limb-sparing
resection. Fundamentally, the extent of surgical treatment of
bone lesions can be classified by the margin achieved. The
surgical margin is classified as intralesional, marginal, wide,
or radical by its relationship to the lesion and its “compart-
ment” that it resides within (Table 6.3). Oftentimes the sur-
geon may be required to use more than one plane of dissection
in order to save the limb. In this case, the surgeon may
describe the various margins in relation to all of its anatomic
boundaries or by its narrowest plane of dissection. The ulti-
mate oncological margin of the procedure is defined by the
closest margin achieved.
Intralesional Excision
Nonmalignant tumors and select low-grade malignancies
(e.g., low-grade chondrosarcoma of the extremities) may
be treated with intralesional excision. By definition, intra-
lesional excision has a plane of dissection that directly
enters the lesion, violating its pseudocapsule and remov-
ing the pathology. Intralesional excision can be used for
juxta-articular lesions as well as metadiaphyseal lesions.
Benign spine and pelvic lesions are also amendable to
intralesional procedures.
Meticulous dissection down to the bone is essential for
adequate visualization and exposure for proper resection.
6 Surgical Treatment of Tumors and Tumorlike Lesions of Bone 91

Table 6.1 Comparison of the advantages and disadvantages of closed and open biopsies
Types of biopsies Advantages Disadvantages
Closed
1. Core needle or fine need aspiration 1. Inexpensive 1. Insufficient sample (up to 35 %)
2. Image-guided percutaneous biopsy 2. No delay in treatment 2. Difficulty in performing sophisticated
3. Fewer operative risks histogenic studies
4. Identify by tattooing site of biopsy 3. Hematoma
4. Bone tumors are difficult to sample
5. Need experienced cytopathologist
Open
1. Incisional 1. More material for pathology 1. Inappropriate placement
2. Excisional 2. Able to obtain absolute hemostasis 2. Infection
3. Dissemination of tumor
4. Cost
5. Logistics of operating time
6. Delay in initiation of neoadjuvant treatment

Table 6.2 Principles of open biopsy Table 6.4 Types of adjuvants that are used to extend the margins of an
intralesional excision
1. Biopsy site needs to be excised with resection
2. Need to know definitive surgical approach Chemical
3. Stay within a single compartment 1. Hydrogen peroxide
4. Avoid neurovascular structures 2. Distilled water
5. Strict hemostasis 3. Alcohol
6. No transverse incisions (except along the clavicle or ribs) 4. Phenol
7. Use caution around limb girdles Mechanical
1. High-speed burr
2. Curettage
Table 6.3 Classification of surgical margins
Thermal
Intralesional excision Plane of dissection passes within the 1. Argon beam coagulator
lesion. Pseudocapsule of the tumor is 2. Electrocautery
entered (e.g., curettage)
3. Polymethylmethacrylate (PMMA)
Marginal excision Pseudocapsule of the tumor is not entered.
4. Liquid nitrogen
Plane of dissection passes through the
reactive zone. Microscopic disease may be 5. Cryoprobes
left behind
Wide excision Plane of dissection passes through a cuff
of normal tissue Mechanical Adjuvants
Radical excision Removal of entire compartment of origin;
complete extirpation of an entire bone
Mechanical adjuvant treats microscopic disease by essential
debridement. High-speed burring is one of the most com-
Intraoperative imaging is often useful for localization and monly employed examples of a mechanical adjunct. Not
extent of the lesion. The cortical bone is then opened with only does the high-speed burr debride the walls of the cavity,
the use of either a drill and osteotome or pencil-tip burr. the heat generated during the procedure may also add a
The cortical window should be made in a round or oval thermal component as well. Complete exteriorization of the
fashion and should be large enough to completely exteri- lesion is important in order to be able to access the entire
orize the lesion. Squared edges should be avoided because cavity.
of the stress raiser effects and difficulty with full exterior-
ization of the lesion, which is needed for complete
removal of the pathology. The bone lesion is then removed Chemical Adjuvants
with the use of surgical instruments like curettes with care
taken to avoid contamination into the approach tissues. Various chemicals have been employed as adjuvants in the
Once all gross tumor is removed, the cavity is usually setting of intralesional curettage. The ability of liquid to per-
treated with the use of an adjuvant to reduce the risk of recur- meate into the endosteal scaffolding and reach places that
rence. Adjuvants include a combination of chemical, ther- may be inaccessible for mechanical treatments is the main
mal, or mechanical and are useful in treating microscopic advantage of chemical adjuvants. However, the surgeon must
cells that are thought to escape the initial curettage remain cautious as some chemicals, such as phenol, are caus-
(Table 6.4). It is thought that microscopic cells that are left tic and can cause damage to the surrounding bone, soft tis-
behind increase the likelihood of local failure. sue, and vital structures (e.g., nerves, cartilage, joints, and
92
muscle). Even less toxic chemical applicators (e.g., hydro-
gen peroxide) are messy and can be difficult to contain.
Therefore, it is important that the intralesional procedure
assures that the treated cavity is contained prior to the use of
these agents.
Thermal Adjuvants
Thermal adjuvants are also used to help in the treatment of
these lesions. As with its chemical counterparts, thermal
applications have the ability to affect surrounding structures,
and the surgeon must be cognizant of the surgical “topogra-
phy” prior to using these agents. Some surgeons believe that
polymethyl methacrylate (PMMA), bone cement, is useful in
this capacity. The exothermic polymerization of the bone
cement increases the temperature of the lesion and theoreti-
cally can cause necrosis of a layer of endosteal cells hopefully
eradicating lesional tissue. Additionally, an advantage of
PMMA is its structural properties which primarily include its
compressive strength making it a useful tool when managing
juxta-articular lesion. It also has the advantage of allowing
the surgeon to detect recurrence because the PMMA provides
a permanent contrast for future surveillance. Although bone
cement has certain advantages, it too has the potential for
inadvertent extravasation if the lesion is uncontained.
Additionally, there is evidence that the heat can damage artic-
ular cartilage when used close to the subchondral bone.
Cautery can also be used as a thermal agent. The argon
beam coagulator is the classic example of this type of use.
Often referred to as the argon “laser,” the cautery is not a
laser, but rather makes use of a supply of argon gas to effec-
tively treat the lesional surface. An alternative to the argon
beam coagulator is using a standard electrocautery. By turn-
ing the electrocautery up and using it in a fulgurate setting,
the surgeon can thermally treat the lesion in a similar fashion
as the argon beam coagulator. These have the advantage of
giving the surgeon more control over treating the lesion.
However, as with mechanical adjuvants, full exteriorization
is necessary to access the cavity. Often it may be extremely
difficult if not impossible for the surgeon to treat the entirety
of the lesion completely. If a heat-based thermal adjuvant is
used, it should not follow the use of any flammable chemical
adjuvants. Liquid nitrogen or the use of cryoprobes can also
be used as a thermal adjuvant. No study has established the
superiority of one thermal adjuvant over the other, and the
selection is usually influenced by surgeon preference and
institutional practice patterns.
Most often, more than one if not all types of adjuvants are
employed with extended intralesional surgical procedures. In
order to prevent contamination of debris that occurs with
high-speed burring, the lesion is often treated with chemical
or thermal adjuvants first. Moreover, argon coagulation and
some chemical adjuvants (e.g., phenol) stain the walls of the
B.E. Walczak et al.
cavity and can provide the surgeon with a guide to a very
controlled and complete treatment. The burr can then be used
to remove this layer leaving no doubt that the entire lesion
was treated. The cycle can then be repeated, effectively
extending the boundary, or margin, of the lesion into the nor-
mal bone.
Once all gross disease has been removed and microscopic
disease has been treated with the use of adjuvants, the
remaining cavity will then have to be addressed. Occasionally,
small lesions or those that are in limited weight-bearing
areas may be left to fill in and heal on their own. However,
the majority will require filling with a bone substitute
(Fig. 6.3). Bone cement (PMMA) has utility as both an adju-
vant and a bone filler. It provides immediate strength, pre-
vents articular collapse, and provides a permanent contrast to
identify recurrence (Fig. 6.4). Moreover, it is useful as a bio-
logical carrier for local antibiotic delivery. However, its use
around joints must be judiciously utilized to avoid extravasa-
tion and can make future surgical procedures more difficult.
Marginal Excision
Treatment of active benign tumors is occasionally treated in
a marginal manner. This is especially true when bone stock
is at a minimum and a wide margin may remove more bone
than is necessary. A marginal margin does not violate the
lesion’s pseudocapsule and maintains a narrow plane of dis-
section adjacent to the reactive zone. Indications for a mar-
ginal margin are active or aggressive benign tumors,
palliative procedures (e.g., metastatic disease), or nearby
joints when bone stock can be preserved. A classic example
of a marginal excision of a benign bone tumor is the removal
of an osteochondroma through its stalk. Adjuvants can also
be used with marginal margins to mitigate the risk of recur-
rence or relapse (Fig. 6.5).
Wide Excision
Nearly all malignant tumors and select benign aggressive
tumors are treated with a margin of normal bone and soft tis-
sue. Although the exact amount of “normal” tissue that
defines a wide margin varies by institution, a wide margin
has a cuff of nonreactive normal tissue peripheral to all its
margins. Thus, a safe margin circumferentially exists around
the lesion, theoretically eliminating satellite cells. However,
since the entire bone is not removed, skip lesions are poten-
tially left behind, thus stressing the importance of appropri-
ate staging prior to embarking on a large surgical resection.
The location and extent of the tumor must be favorable to
enable removal with margins sufficient to prevent recurrence
but not so extensive as to exclude restoration of useful func-
tion. Moreover, en bloc resection is often the end result with
6 Surgical Treatment of Tumors and Tumorlike Lesions of Bone
wide excisions of bone lesions. This often requires removal
of a large segment of the adjacent joint and necessitates a
major reconstruction effort to ensure useful function
(Figs. 6.6 and 6.7). In recent years, technological advances in
prosthetic design and biomaterials have provided surgeons
with options that would have previously required radical
resection of the entire bone. This has been advantageous
both for skeletally mature patients and even more so for the
skeletally immature. Advances in the understanding of the
biomechanical properties of the pelvis and spine, as well as
the improvements in implant design, have allowed surgeons
to treat lesions of the pelvis and spine with wide resection
and reconstruction. We have successfully treated juxta-
articular acetabular tumors and lesions of the axial skeleton
with wide local excision and reconstruction. The use of com-
puter navigation has been employed in these difficult cases
to ensure a safe oncological margin while helping the sur-
geon navigate around vital anatomic structures.
Wide Intercalary Excision (Rotationplasty)
Rotationplasty is an intercalary wide excision and is a dura-
ble alternative to amputation. First described for a patient
with tuberculosis, Van Nes popularized the procedure about
the knee for management of proximal femoral focal defi-
ciency (PFFD). For optimal postoperative function, the
patient requires both adequate ankle range of motion and
plantar flexion strength, along with a sensate foot. Most
commonly used for lesions about the knee, rotationplasty is
an option for those involving the femur and hip as well as the
upper extremity. Although rotationplasty can be done at any
age, ideally patients will be old enough to accurately predict
leg length at maturity and young enough to functionally
adapt postoperatively. It becomes increasingly difficult to
predict growth in children younger than about 4 years old.
Absolute contraindications include sciatic nerve involve-
ment and/or dysfunction, ankle stiffness, and motor loss
resulting from aggressive soft tissue resection. Preoperative
planning is imperative for a successful outcome. Psychosocial
implications must be addressed because of the impact it will
have on the patient and their family.
Radical Excision
A radical margin involves removal of the entire compart-
ment. In terms of bone lesions, radical excision is the removal
of the entire bone. Indications for radical resection include
lesions that involve all or enough of the bone precluding
meaningful reconstruction, failed joint implants, and skip
lesions. Advances in prosthetic design are providing unique
opportunities to attempt bone-conserving procedures over en
bloc resection of the entire bone. However, there continues to
be a role for radical resection (Fig. 6.8).
93
Special Considerations
Pelvic Lesions
The anatomic constraints and proximity to visceral structures
make bone tumors and lesions of the pelvis challenging to treat.
When the patient will be left with a functioning joint, an intact
major peripheral nerve, and a patent artery, attempt at limb sal-
vage is a reasonable option. However, if the lesion requires
such an aggressive resection whereby sacrificing the joint is
necessary and cannot be reliably reconstructed, all major
peripheral nerves are involved, and perfusion to the limb is sac-
rificed and unable to be revascularized, and then high-level
amputation should be considered. The most commonly used
classification for innominate resection, or internal hemipelvec-
tomy, is by Enneking and Dunham (Type I, iliac wing; Type II,
periacetabular; Type III, pubis). As with other bone lesions, the
number one priority is to remove the lesion safely with an
appropriate surgical margin. Successfully accomplishing this in
the pelvis often requires a multidisciplinary team approach.
Wide excision of the ilium or pubis (Type I and III internal
hemipelvectomy) that preserves the patient’s native hip joint
can often be accomplished without the need for reconstruc-
tion. Type II internal hemipelvectomies are uniquely chal-
lenging. The hip joint, pelvic anatomy, and visceral structures
make this resection one of the most challenging surgical pro-
cedures. Three-dimensional imaging modalities, intraopera-
tive navigation, and improved reconstructive techniques have
assisted surgeons with this type of resection. Once the sur-
geon has removed the lesion, various reconstructive efforts
are employed to reconstruct the hip. There is no ideal method
that reliably restores a native acetabular structure. Each
method of reconstruction has its unique advantages and dis-
advantages. Removal of the tumor without reconstruction
(pseudoarthrosis) proves reliable for wound healing and pain
control postoperatively and allows for reasonable use of the
extremity. Pelvic allografts have been utilized to reproduce a
native pelvis. Massive allografts can have quite variable
treatment outcomes, ranging from near-normal function to
rapid and catastrophic failure. Because of the unpredictable
nature of these reconstructions, they are used in carefully
selected cases. Various prosthetic implants have been used
with variable success. The saddle prosthesis is quite simple
to perform and provides short-term success; however longer
follow-up has consistently proven disappointing and it has
fallen out of favor. Recent advances in soft porous metals
(e.g., tantalum) have allowed surgeons the ability to gain
ingrowth into the remaining bone of the pelvic ring and allow
reconstruction that would otherwise be impossible (Fig. 6.9).
Interventional techniques have proven successful in pelvic
lesions that allow for intralesional surgery; the most common
use is in the setting of metastatic disease. Metastatic tumor
that involves the weight-bearing supra-acetabular region has
responded reliably to cryoablation and percutaneous cemen-
tation and has partially replaced the need for traditional open
surgical procedures (e.g., Harrington techniques).
94
Spine
Like the pelvis, the spine is bounded by important visceral
structures that makes wide excision challenging. Local suc-
cess of most aggressive benign or malignant lesions is
directly proportional to obtaining a clear margin. However,
many times surgical resection is too morbid and reconstruc-
tion has not been reliable. Advances in surgical techniques
and reconstruction have allowed surgeons to confidently
offer patients safe removal of the lesion and with the ability
for successful reconstruction.
Lesions of the sacrum and lumbar spine are some of the
most challenging locations to safely remove due to the prox-
imity of nerves, blood vessels, and visceral structures. Even
when resection is possible, soft tissue coverage must also be
considered.
Fortunately, primary malignancies of the mobile spine are
very rare; however they do occur. Overall survival and local
recurrence is worse than similar lesions of the extremity,
likely attributable to the difficulty the surgeon has with
obtaining acceptable surgical margins. Computer navigation
has improved the accuracy of surgical resection and is often
employed in this capacity.
B.E. Walczak et al.
Shoulder Girdle
Lesions of the proximal humerus and scapula have also been
difficult to treat. Unlike lesions of the spine and pelvis that make
wide excision difficult, lesions of the proximal humerus and
scapula can be easily excised. What makes the shoulder difficult
is reconstruction. The authors have successfully treated primary
malignant tumors of the shoulder region with a combination of
scapulothoracic fusion, tendon transfers, allografts, and custom
modular prosthetics (Fig. 6.10). Currently, there is interest in
utilizing the reverse shoulder replacement in the face of massive
bone loss. Options are to reestablish bone stock with an allo-
prosthetic composite or reconstruct with a modular prosthesis.
Conclusion
The surgical treatment of bone tumors provides unique
challenges for surgeons. Advances in preoperative imaging,
intraoperative imaging (e.g., computer navigation) and sur-
gical techniques, prosthetic design, and adjuvant treatments
(chemotherapy and radiation) and improved understanding
of the biologic behavior of these rare lesions continue to
assist surgeons in improving functional outcomes.
6 Surgical Treatment of Tumors and Tumorlike Lesions of Bone 95

Fig. 6.1 An appropriately placed biopsy tract about the distal tibia in
line with subsequent planned excision

Fig. 6.2 An inappropriately placed transverse open biopsy and neces-

sary resection for flap coverage
96 B.E. Walczak et al.

a b c

Fig. 6.3 (a) Lateral right knee radiograph demonstrating a chon- treatment with the argon beam coagulator. (d) Allograft bone graft
droblastoma of the distal femur. (b) Axial STIR MRI demonstrating substitute is used to fill the contained defect
the epiphyseal-based chondroblastoma. (c) Adjuvant intralesional
6 Surgical Treatment of Tumors and Tumorlike Lesions of Bone 97

Fig. 6.4 AP radiograph of a left knee demonstrating the use of poly-

methylmethacrylate status-post curettage of a giant cell tumor of the
distal tibia
98 B.E. Walczak et al.

a b

d e

Fig. 6.5 (a) AP and lateral (b) radiographs of the left knee demonstrat- (d) Argon beam coagulator is used as an adjuvant thermal treatment to
ing a pathologic intra-articular fracture of the lateral femoral condyle. mitigate the risk of recurrence. (e) The distal femur is reconstructed
(c) Intraoperative photo showing the lateral femoral condyle resection. with use of a hemi-allograft and internal fixation
6 Surgical Treatment of Tumors and Tumorlike Lesions of Bone 99

a c

Fig. 6.6 (a) AP pelvis and coronal T2 MRI (b) demonstrating a biopsy-proven high-grade small round blue cell sarcoma of the right femoral neck.
(c) AP and lateral (d, e) radiographs of a cemented right proximal femur modular endoprosthesis
100 B.E. Walczak et al.

a b

c d

Fig. 6.7 (a) AP and lateral (b) radiographs of a right knee demonstrat- tissue mass (c) AP and lateral (d) radiographs of a cemented right distal
ing a mixed lytic and sclerotic destructive lesion of a biopsy-proven femur modular endoprosthesis
osteosarcoma of the distal femoral metaphysis with associated soft
6 Surgical Treatment of Tumors and Tumorlike Lesions of Bone 101

a b c

e f

Fig. 6.8 (a) Coronal T1 MRI demonstrating low-signal-intensity of the resected total femur. (d) Intraoperative photo demonstrating total
lesion of the proximal femoral metaphysis consistent with biopsy- femur endoprosthesis and (e, f) AP radiographs of the left femur dem-
proven Ewing’s sarcoma. (b) Coronal T1 MRI of the distal femur from onstrating the cemented, hinged left total femur endoprosthesis
the same patient demonstrating a skip lesion. (c) En bloc gross specimen
102 B.E. Walczak et al.

a b

c d

Fig. 6.9 (a) AP pelvis radiograph demonstrating a left lytic supra- sarcoma. (e) Clinical photo of the tantalum acetabular shell and aug-
acetabular lesion. (b) Coronal T2 MRI demonstrating increased peri- ments used for a complex periacetabular reconstruction. (f)
acetabular marrow. (c) Model of the iliac segment to be replaced. Postoperative AP radiograph of a custom periacetabular complex total
(d) Clinical photo of the resected en bloc specimen of grade 2 chondro- hip reconstruction with the use of tantalum augments
6 Surgical Treatment of Tumors and Tumorlike Lesions of Bone 103

e f

Fig. 6.9 (continued)

104 B.E. Walczak et al.

a c

Fig. 6.10 (a) AP and axillary lateral (b) radiographs of a biopsy-proven high-grade chondrosarcoma with associated soft tissue mass. (c) AP
humerus radiograph of a proximal humerus alloprosthetic composite used for reconstruction after en bloc proximal humerus resection
6 Surgical Treatment of Tumors and Tumorlike Lesions of Bone 105

Recommended Reading Leeson MC, Lippitt SB. Thermal aspects of the use of polymethylmeth-
acrylate in large metaphyseal defects in bone. Clin Orthop Relat
Res. 1993;295:239–45.
Biermann JS, Holt GE, Lewis VO, Schwartz HS, Yaszemski MJ.
Lewis VO, Wei A, Mendoza T, Primus F, Peabody T, Simon MA. Argon
Metastatic bone disease: diagnosis, evaluation, and treatment.
beam coagulation as an adjuvant for local control of giant cell
J Bone Joint Surg Am. 2009;91(6):1518–30.
tumor. Clin Orthop Relat Res. 2007;454(1):192–7.
Callstrom MR, Charboneau J, Goetz MP, Rubin J, Atwell TD, Farrell
Link MP, Goorin AM, Miser AW, Green AA, Pratt CB, Belasco JB,
MA, et al. Image-guided ablation of painful metastatic bone tumors:
et al. The effect of adjuvant chemotherapy on relapse-free survival
a new and effective approach to a difficult problem. Skeletal Radiol.
in patients with osteosarcoma of the extremity. N Engl J Med.
2006;35:1–15.
1986;314(25):1600–6.
Capanna R, Sudanese A, Baldini N, Campanacci M. Phenol as an adju-
Mankin HJ, Lange TA, Spanier SS. The hazards of biopsy in patients
vant in the control of local recurrence of benign neoplasms of bone
with malignant primary bone and soft-tissue tumors. Clin Orthop
treated by curettage. Ital J Orthop Traumatol. 1985;11(3):331–8.
Relat Res. 2006;450:4–10.
DiCaprio MR, Friedlaender GE. Malignant bone tumors: limb sparing
Mavrogenis AF, Papagelopoulos PJ, Katonis P, Galanis EC, Wenger
versus amputation. J Am Acad Orthop Surg. 2003;11(1):25–37.
DE, Sim FH, et al. Percutaneous osteoplasty for pelvic and spine
Dickey ID, Hugan RR, Fuchs B, Yaszemski MJ, Sim FH. Reconstruction
metastases. Orthopedics. 2006;29(4):315–23.
after total sacrectomy; early experience with a new surgical tech-
McGarry SV. Extended curettage for benign bone lesions. Tech Orthop.
nique. Clin Orthop Relat Res. 2005;438:42–50.
2007;22(2):121–6.
Eilber F, Giuliano A, Eckardt J, Patterson K, Moseley S, Goodnight
Meyers PA, Gorlick R, Heller G, Casper E, Lane J, Huvos AG, et al.
J. Adjuvant chemotherapy for osteosarcoma: a randomized prospec-
Intensification of preoperative chemotherapy for osteogenic sar-
tive trial. J Clin Oncol. 1987;5(1):21–6.
coma: results of the Memorial Sloan-Kettering (T12) protocol.
Enneking WF, Dunham WK. Resection and reconstruction for primary
J Clin Oncol. 1998;16(7):2452–8.
neoplasms involving the innominate bone. J Bone Joint Surg Am.
Picci P, Sangiorgi L, Rougraff BT, Neff JR, Casadei R, Campanacci M.
1978;60(6):731–46.
Relationship of chemotherapy-induced necrosis and surgical margins to
Enneking WF, Maale FE. The effect of inadvertent tumor contamina-
local recurrence in osteosarcoma. J Clin Oncol. 1994;12(12):2699–05.
tion of wounds during the surgical resection of musculoskeletal neo-
Quinn R. Surgical margins. In: Damron TA, editor. Oncology and basic
plasms. Cancer. 1988;62(7):1251–6.
science. Philadelphia: Wolters Kluwer/Lippincott Williams and
Enneking WF, Spanier SS, Goodman MA. A system for the surgical
Wilkins; 2008.
staging of musculoskeletal sarcoma. Clin Orthop Relat Res.
Satcher RL. How intraoperative navigation is changing musculoskeletal
1980;153:106–20.
tumor surgery. Orthop Clin North Am. 2013;44:645–56.
Fa K, Rose PS, Yanagisawa M, Lewallen DG, Sim FH. Surgical
Schoenfeld AJ, Hornicek FJ, Pedlow FX, Kobayashi W, Garcia RT,
technique: porous tantalum reconstruction for destructive nonpri-
Delaney TF, et al. Osteosarcoma of the spine: experience in 26
mary periacetabular tumors. Clin Orthop Relat Res. 2012;470(2):
patients treated at the Massachusetts General Hospital. Spine J.
594–601.
2010;10(8):708–14.
Fuchs B, Kotajarvi BR, Kaufman KR, Sim FH. Functional outcome of
Sim FH. Diagnosis and treatment of bone tumors: a team approach (A
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Mayo Clinic Monograph). New Jersey: Slack, Inc.; 1983.
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Simon MA, Springfield D. Surgery for bone and soft-tissue tumors.
Goorin AM, Schwartzetruber DJ, Devidas M, Gebhardt MC, Ayala AG,
Philadelphia: Lippincott-Raven; 1998.
Harris MB, et al. Presurgical chemotherapy compared with immedi-
Talac R, Yaszemski MJ, Currier BL, Fuchs B, Dekutoski MB, Kim CW,
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et al. Relationship between surgical margins and local recurrence in
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2003;21(8):1574–80.
Tjardes T, Shafizadeh S, Rixen D, Parrrath T, Bouillon B, Stenhausen
Grogran TJ, Eckardt J. Phenol cauterization versus liquid nitrogen
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van der Heijden L, van de Sande MA, Heineken AC, Fiocco M, Nelissen
Gupta SK, Alassaf N, Harrop AR, Kiefer GN. Principles of rotation-
R, Dijkstra S. Mid-term outcome after curettage with polymethyl-
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Healey JH, Morris CD, Athanasian EA, Boland PJ. Compress knee
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failure. Clin Orthop Relat Res. 2013;471(3):774–83.
Van Nes C. Rotation-plasty for congenital defects of the femur: making
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results of saddle prosthesis after resection of periacetabular tumors.
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Clin Orthop Relat Res. 2013;471(1):324–31.
Virkus WW, Marshall D, Enneking WF, Scarborough MT. The effect of
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Walczak BE, Irwin RB. Sarcoma chemotherapy. J Am Acad Orthop
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Leerapun T, Hugate RR, Inwards CY, Scully SP, Sim FH. Surgical man-
Wolf RE, Enneking WF. The staging and surgery of musculoskeletal
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Clin Orthop Relat Res. 2007;463(10):166–72.
 Part II
Bone-Forming Tumors
 Medullary Osteoma
7
Liliana G. Olvi, Gustavo M. Lembo,
and Eduardo Santini-Araujo

Abstract
Medullary osteoma is a benign solitary bone-forming tumor arising in the medullary cavity
of bone and consisting histologically in mature bone predominantly cortical laminar.

Medullary Osteoma bones, and flat bones. By image and histology, the lesions
are similar to medullary osteomas.
Definition

• Benign solitary bone-forming tumor consisting in mature Synonyms

bone tissue with a predominant cortical laminar struc-
ture, within the medullary cavity and with a very slow • Enostoma
growth. • Bone island
• Osteopoikilosis is an autosomal dominant-inherited syn- • Bone fleck
drome characterized by the presence of multiple bilateral, • Enostosis
symmetric enostomas, distributed mostly in metaphyseal
and epiphyseal areas of tubular bones, carpal and tarsal
Etiology

• Unknown
• Are considered hamartomatous lesions
L.G. Olvi, MD
Laboratory of Orthopaedic Pathology,
Buenos Aires, Argentina Clinical Features
G.M. Lembo, MD
Department of Pathology, Centenary Hospital Rosario Epidemiology
Santa Fe Argentina, Rosario, Santa Fe, Argentina
E. Santini-Araujo, MD, PhD (*) • Real incidence is unknown.
Laboratory of Orthopaedic Pathology,
Buenos Aires, Argentina
Sex
Department of Pathology, School of Medicine and
School of Dentistry, University of Buenos Aires, • No sex predominance
Buenos Aires, Argentina
Central Army Hospital, Buenos Aires, Argentina Age
e-mail: santiniaraujo@laborpat.com.ar • More frequent in adults. Rare in children

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 109
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_7, © Springer-Verlag London 2015
110 L.G. Olvi et al.

Sites of Involvement • Rarely, the differential may include cystic sclerosing

angiomatosis.
• Pelvis, ribs, and upper end of femur.
• In long bones they are more frequent in the epiphysis.
• Any bone may be involved. Pathology

Gross Features
Clinical Symptoms and Signs
• In resected specimens, frequently for other reasons, the
• Generally discovered incidentally, after a roentgenologic lesion is well demarcated, tan-white, compact with
examination for other reasons irregular border and included in the intramedullary
• Asymptomatic cancellous bone, intermingled with surrounding
• Exceptionally produce mild pain trabeculae.
• In most cases it is 2–10 mm in greatest diameter. Rarely,
it may be larger.
Image Diagnosis

Radiographic Features Histological Features

• Sclerotic small round or ovoid intramedullary lesion.
• In ovoid enostomas, long axis is parallel to the host bone’s
long axis.
• The periphery of the lesion commonly is irregular and
spiculated due to the continuity with the medullary can-
cellous bone trabeculae.
• Large lesion frequently contact with the endosteal surface
of the cortex, without cortical involvement or periosteal
reaction.
• Histologically, it is composed by mature lamellar corti-
cal bone with haversian systems and interstitial
lamellae.
• Sometimes, areas of woven bone are seen.
• The sclerotic bone shows occasional areas of necrosis.
• Osteoblasts lining trabecular surfaces are typically
flat.
• The periphery of the lesion continues with the native bone
trabeculae.

CT Features Pathologic Differential Diagnosis

• Stellate lesion with cortical density Osteoblastic Sclerotic Metastases (in Adults)
• New bone formation is not lamellar and surrounds malig-
nant carcinoma cells.
MRI Features • Immunohistochemistry may be helpful by the expression
of cytokeratins.
• Low signal in T1- and T2-weighted images like cortical
bone
Prognosis

Bone Scan • Usually not association with morbidity.

• Malignant transformation is not reported.
• Usually cold
• Sometimes very slow uptake
Treatment

Image Differential Diagnosis • After roentgenographic diagnosis, no treatment is

In Large Lesions
• In adolescents: low-grade intramedullary osteosarcoma
• In adults: osteoblastic sclerotic metastases of carcinoma.
Its presentation is more frequently multiple than that of
enostoma.
required.
• In large lesions biopsy is suggested to exclude low-grade
osteosarcoma in adolescents and sclerotic metastases of
carcinoma in adults.
• Large, with unusual X-ray features or painful lesions
must be biopsied.
7 Medullary Osteoma 111

Images

See Figs. 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, and 7.9 for
illustrations of medullary osteoma.

Fig. 7.2 Enostoma located in the upper end of the femur. The periph-
ery of the lesion is irregular and spiculated due to the continuity with
medullary bone trabeculae

Fig. 7.1 X-ray of the humerus. In the metaphyseal area, the sclerotic
round intramedullary lesion corresponds to an enostoma

a b c

Fig. 7.3 (a–c) Roentgenograms and MRI of an enostoma located in the tibial epiphysis. By MRI, the lesion presents low signal in T1- and
T2-weighted images similar to cortical bone
112 L.G. Olvi et al.

a b

Fig. 7.4 (a, b) An enostoma in lower femoral epiphysis. In ovoid enostomas, long axis is parallel to the host bone’s long axis. (c–e) MRI of the lesion
7 Medullary Osteoma 113

a b

Fig. 7.5 (a) Radiograph of an enostoma in the upper metaphysis of a femur. (b) The bone scan showing very slow uptake

a b

Fig. 7.6 (a) Enostoma involving the iliac bone. The lesion is round and radiodense. (b) CT scan of the lesion. Note the homogeneous radiodensity
and the irregular periphery
114 L.G. Olvi et al.

a b

c
d

Fig. 7.7 (a, b) X-ray showing a radiodense lesion in a vertebral body. (c, d) CT scan, with the typical images of a bone island
7 Medullary Osteoma 115

a b

Fig. 7.8 (a, b) Roentgenograms showing an enostoma in the upper shaft of femur. Large lesions frequently contact with the endosteal surface of
the cortex. (c, d) MRI shows that the lesion contacts with the cortex without involvement or periosteal reaction
116 L.G. Olvi et al.

a b

Fig. 7.9 (a, b) Core needle biopsies. Low-power magnification of enostomas. The lesion is constituted by mature bone trabeculae and fat marrow
7 Medullary Osteoma 117

Recommended Reading Larrea-Oyarbide N, Valmaseda-Castellon E, Berini-Aytes L, Gay-

Medullary Osteoma
Gardner EJ. Follow-up study of a family group exhibiting dominant
inheritance for a syndrome including intestinal polyps, osteomas,
fibromas and epidermal cysts. Am J Hum Genet. 1962;14:
376–90.
Greenpan A, Klein MJ. Giant bone island. Skelet Radiol. 1996;20:
85–90.
Greenspan A. Bone island (enostosis): current concept-a review. Skelet
Radiol. 1995;24:111–5.
Escoda C. Osteomas of the craniofacial region. Review of 106
cases. J Oral Pathol Med. 2008;37:38–42.
O’Connell JX, Rosenthal DI, Mankin HJ, Rosenberg AE. Solitary osteoma
of a long bone: a case report. J Bone Joint Surg. 1993;75A:1830–4.
Schajowicz F. Osteoma. In: Tumors and tumorlike lesions of bone and
joints. New York: Springer; 1981. p. 25–34.
Zhang Y, Castori M, Ferranti G, Paradisi M, Wordsworth BP. Novel and
recurrent germline LEMD3 mutations causing Buschke-Ollendorff
syndrome and osteopoikilosis but not isolated melorheostosis. Clin
Genet. 2009;75(6):556–61.
 Parosteal Osteoma
8
Liliana G. Olvi, Gustavo M. Lembo,
and Eduardo Santini-Araujo

Abstract
Parosteal osteoma is a benign tumor arising in the surface of a bone. Histologically the
lesion consists of mature laminar bone.

Definition Etiology

• Α benign solitary juxtacortical bone-forming tumor, con- • Unknown

sisting of mature bone tissue with predominantly laminar
structure and very slow growth
Clinical Features

Synonyms Epidemiology

• Juxtacortical osteoma Sex

• In craniofacial bones: conventional classic osteoma –
“ivory exostosis”
• In the palate: torus palatinus
• In the jaw: torus mandibularis
L.G. Olvi, MD
Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina
G.M. Lembo, MD
Department of Pathology, Centenary Hospital Rosario Santa
Fe Argentina, Rosario, Santa Fe, Argentina
E. Santini-Araujo, MD, PhD (*)
Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina
Department of Pathology, School of Medicine and School of
Dentistry, University of Buenos Aires,
Buenos Aires, Argentina
Central Army Hospital, Buenos Aires, Argentina
e-mail: santiniaraujo@laborpat.com.ar
• In craniofacial bones, it is more frequent in females
with a rate of 2:1. In long bones, it is more frequent in
males.
Age
• In craniofacial bones, it affects all age groups. In long
bones, it is more common between the fourth and sixth
decades.
Sites of Involvement
• Craniofacial bones, higher incidence:
– Frontal, ethmoid sinus, more frequent locations.
– Paranasal sinus, sphenoid sinus.
– In the cranium, it may arise in outer or inner bone surfaces.
– In gnathic bones: palate and mandible.

119
E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists,
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_8, © Springer-Verlag London 2015
120 L.G. Olvi et al.

• In long bones, they are less frequent: CT Features

– Femur and tibia
– Located exclusively at the external bone surface
• Infrequent in the vertebral column.
Clinical Symptoms and Signs
• Well-defined lesion arising from the surface of the bone
with cortical density.
• In larger lesions, the underlying cortex may show radiolu-
cencies corresponding to blood vessels that feed the
tumor.

• In craniofacial bones:
– Obstruction of the ostium of a paranasal sinus; second- MRI Features
ary mucocele
– In orbital location: proptosis, dacryocystitis, double or • Low signal in T1- and T2-weighted images like the corti-
blurred vision cal bone.
– Facial asymmetry • In craniofacial bones, T2-weighted images can help to
• In palate and jaws: recognize hyperintense mucocele.
– Large lesions can interfere with chewing.
• In long bones:
– Often asymptomatic. Bone Scan
– Commonly discovered incidentally.
– First complaint: swelling, slow increase in size, and • Usually cold
hard consistency palpable mass. • Sometimes very slow uptake
– Exceptionally produce mild pain.
– Usually solitary.
– Multiple tumors may be associated with Gardner syn- Image Differential Diagnosis
drome, a familiar disease with autosomal dominant
inheritance, consisting of: Osteochondroma
Colonic polyposis – premalignant disease – and • In sessile type sometimes the differential is more
colonic cancer may be present at the time of difficult.
diagnosis. • Lower density.
Osteomas. • Shows irregular calcification of the cartilage-capped surface.
Dental anomalies. • The underlying cortex is classically discontinued, and the
Epidermal inclusion cysts. metaphyseal spongiosa is continuous with the tumor
Soft tissue tumors. spongiosa.
All parts of the skeleton may be involved.
• In the vertebral column: Parosteal Osteosarcoma
– Extremely infrequent, spinal cord or nerve • Densely ossified juxtacortical round or oval mass attached
compression to the underlying cortex.
• Well-formed periosteal reaction is absent.
• Frequently, a characteristic finding is a radiolucent line
Image Diagnosis between the cortex and the tumor, except at its site of
attachment.
Radiographic Features • CT and MRI can demonstrate lytic areas, usually at the
surface corresponding to neoplastic cartilage.
• Radiodense, elongated, and lobulated surface bone mass. • Occasionally, cortical thickening under the tumor.
• Well demarcated from the peripheral soft tissue. • In advanced cases cortical destruction and medullary
• Lesion is attached to the cortical surface with a broad invasion.
base.
• Cortex is not involved. Myositis Ossificans: Mature Lesions
• Dense periosteal reaction in the borders of the lesion is • Very similar radiographic lesions
frequently seen. • More commonly attached to the cortex in the diaphyseal
• Rarely, juxtacortical osteomas in long bones are com- region
posed of trabecular or cancellous bone and are less • Limited by a more calcified rim at its periphery, whereas
radiodense lesions. the center is more radiolucent; zonation effect
• In cranial bones, lesions may arise in outer or inner bone • Absence of a broad base of attachment to the underlying
surfaces. cortex
8 Parosteal Osteoma
Melorheostosis
• Characteristic “dripping candle wax” pattern over the sur-
face of the cortex
• Frequently affects more than one bone
• Associated with skin sclerotic lesions
Pathology
Gross Features
• In resected specimens: is dense and compact (ivory-like),
tan white.
• Adjacent to the underlying cortex.
• Well-defined margins, often lobulated.
• A thin fibrous membrane covers its surface and is in con-
tinuity with the periosteum.
• In most cases, it is less than 2 cm in greatest diameter;
rarely larger.
• Rarely, the lesion is predominantly spongious – cancellous,
spongious, or trabecular type.
Histological Features
• Histologically, it is composed by mature thick lamellar
trabeculae or forming a dense bony mass similar to the
cortical bone with haversian systems.
• Intertrabecular medullary spaces are narrow, with adipose
or active marrow – not in the spongious type. The surface
of the bone usually does not show osteoblastic or osteo-
clastic activity.
• Sometimes, areas of woven bone are seen.
• Few parosteal osteomas are composed of cancellous-type
bone and fatty marrow.
• Absence of cartilaginous cap covered the surface.
• The sclerotic bone may show areas of necrosis.
• Osteoblasts lining surfaces are typically flat. Osteocytes
in lacunae are small.
• Rarely, some lesions may show an indolent fibrous
component.
Pathologic Differential Diagnosis
Parosteal Osteosarcoma
• Low-grade malignant tumor.
• Extensive bone trabecula formation with a parallel ten-
dency of arrangement.
• Immature woven bone in different stages of maturation
may be seen.
• Osteoblasts surrounding trabeculae are spindle – inactive –
and, occasionally, more hypertrophic.
121
• Fibrous stroma presents numerous spindle cells with little
pleomorphism, few mitosis, and moderate collagen fibers.
Similar to a low-grade fibrosarcoma.
• Foci of low-grade chondrosarcoma may be present, and
frequently a superficial cap of low-grade chondrosarcoma
partially covers the surface of the tumor.
Myositis Ossificans: Mature Lesions
• A more cellular lesion.
• A more organized shell of woven and parallel lamellar bone.
• The lesion is separated from the surrounding muscle by a
zone of myxoid fibrous tissue.
• The peripheral muscle shows atrophic changes and
inflammatory infiltrates.
• The clue and hallmark for diagnosis is the presence of a
zoning phenomenon or zoning effect.
Osteochondroma: Sessile Type
• Cartilaginous cap in the surface.
• The cap has a similar aspect to that of normal growth
cartilage.
• Endochondral ossification is present.
• Trabeculae of endochondral ossification present calcified
cartilage into their bone lamellar matrix.
• The underlying cortex is classically discontinued, and the
metaphyseal spongiosa is continuous with the tumor spon-
giosa that contains active hematopoietic or fatty marrow.
• The cartilaginous surface cap is thicker in young children
and becomes thinner or sometimes disappears in adults.
Melorheostosis
• Mixed pattern with lamellar bone and areas of woven
bone. Polarized light may be helpful to differentiate both
patterns.
Prognosis
• Excellent.
• Recurrences are not reported.
• Malignant transformation is not reported.
Treatment
• Excision. Indicated in patients with pain or for aesthetic
reasons.
• In large lesions of long bones, biopsy is suggested to
exclude parosteal osteosarcoma.
Images
See Figs. 8.1, 8.2, 8.3, 8.4, 8.5, and 8.6 for illustrations of
parosteal osteoma.
122 L.G. Olvi et al.

b c

Fig. 8.1 (a) Lateral x-ray of the skull. Note the oval sclerotic lesion in the temporoparietal area. (b, c) CT scan shows a dense homogeneous lesion
protruding from the outer table. The diploe and the inner table are not involved
8 Parosteal Osteoma 123

b c

Fig. 8.2 (a, b) X-ray showing a homogeneous sclerotic mass in the frontal bone of the skull. (c) MRI clearly shows a parosteal osteoma arising
in the inner table of the skull projecting into the frontal lobe
124 L.G. Olvi et al.

c f

Fig. 8.3 (a, b) Anteroposterior and lateral x-ray of the skull. Note a base. In large lesions the underlying cortex may show radiolucencies
surface radiodense mass. (c, d) Coronal and axial CT scan clearly that correspond to blood vessels that feed the tumor. (e) Gross surgical
defines the lesion as a parosteal osteoma arising in the outer table of the specimen. (f) Cut surface of the lesion. Dense and compact (ivory-like)
parietal bone. The lesion is attached to the cortical surface with a broad lesion with well-defined margins
8 Parosteal Osteoma 125

Fig. 8.4 Parosteal osteoma of a long bone. Anteroposterior roentgeno- Fig. 8.5 Lateral x-ray of the tibia. The parosteal osteoma protrudes
gram of the femur with a well-defined ossifying parosteal mass in the from the posterior cortex
upper femoral shaft
126 L.G. Olvi et al.

Recommended Reading
Bertoni F, Unni KK, Beabout JW, Sim FH. Parosteal osteoma of bones
other than of skull and face. Cancer. 1995;75:2466–73.
Bullough PG. Ivory exostosis of the skull. Postgrad Med J.
1965;41:277–81.

Fig. 8.6 Microphotograph at low magnification of a parosteal oste-

oma. The lesion is a dense bony mass similar to the cortical bone with
haversian systems
 Osteoid Osteoma
9
Liliana G. Olvi, Gustavo M. Lembo,
and Eduardo Santini-Araujo

Abstract
Benign osteoid and bone-forming tumor which has limited growth potential, with classic
pain symptomatology, and consists of a small core or nidus – less than 2 cm in diameter –
surrounded by a typical conspicuous zone of reactive sclerotic bone. It has a high inci-
dence – 12 % of all benign tumors. It is more frequent in males, and 50 % of patients are in
the second decade. Seventy percent arise in tubular bones – most frequently the upper end
and lower end of the femur, tibia, and humerus. Fifteen percent occur in the spine in the
posterior elements. Pain is the classic symptom – more intense at night and relieved dra-
matically by aspirin. Roentgenographic appearance of the nidus is characteristic, round or
oval surrounded by sclerosis. Twenty-five percent present with mineralization of the central
area. They may arise in cortical, subperiosteal, or medullary areas. CT is the most useful
method to show the nidus. The bone scan shows an extremely hot spot. Histologically the
nidus is composed of haphazard anastomosing immature osteoid and bone trabeculae lined
by uniform osteoblasts and a few multinucleated giant cells. The bone marrow is composed
of a loose fibrovascular stroma. The prognosis is excellent. Percutaneous radiofrequency
ablation is the treatment of choice and in the spine, excision.

Definition nucleated giant cells of osteoclastic type, surrounded by a

typical conspicuous zone of reactive sclerotic bone
• Benign osteoid and bone-forming tumor with limited
growth potential, with classic pain symptomatology,
consisting of a small core or nidus – less than 2 cm in Synonyms
diameter – made up of an interlacing network of immature
trabeculae lined by numerous osteoblasts, scattered multi- • Circumscribed osteoblastoma

L.G. Olvi, MD
Etiology
Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina
• Unknown
G.M. Lembo, MD
Department of Pathology, Centenary Hospital Rosario
Santa Fe Argentina, Rosario, Santa Fe, Argentina
E. Santini-Araujo, MD, PhD (*) Clinical Features
Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina
Department of Pathology, School of Medicine and School of Epidemiology
Dentistry, University of Buenos Aires, Buenos Aires, Argentina
Central Army Hospital, Buenos Aires, Argentina • High incidence: 12 % of all benign bone tumors; 3 % of
e-mail: santiniaraujo@laborpat.com.ar all bone tumors

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 127
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_9, © Springer-Verlag London 2015
128 L.G. Olvi et al.

Sex Sites of Involvement

• More frequent in males than females (2–3:1)
• More than 70 % in long tubular bones. Most frequent
Age sites: upper end of femur neck and trochanter and lower
• Fifty percent of the patients are in the second decade, end of femur, tibia, and humerus. Metacarpal, metatar-
22 % in the first, and 20 % in the third decades. Rare in sal, and phalanges sites are relatively frequent. Osteoid
older patients. osteomas arise more frequently in metaphysis and
diaphysis. Epiphyseal locations are infrequent. More
common in cortex or subperiosteal location. Less com-
mon intramedullary.
9 Osteoid Osteoma 129

• Fifteen percent in spine. In the vertebral column, it tends CT Features

to involve the posterior elements – 90 %.
• The most useful method to show the nidus, especially
when nidus is masked by sclerosis.
Clinical Symptoms and Signs • Round small, well-demarcated lesion. Often presents
with central mineralization.
• Pain is the classic and most frequent symptom and is
practically diagnostic.
– More intense at night. MRI Features
– Sometimes referred to a nearby joint – mimicking
inflammatory arthritis. • Of limited utility
– Relieved dramatically by aspirin and nonsteroidal anti- • Low signal in T1
inflammatory medication. • High signal intensity in T2 with peripheral and soft tissue
• Painful local swelling in superficial bones. edema –sometimes in great amounts
• Atrophy of muscles in affected limb, localized swelling, • Angio-MRI: useful in demonstrating the hypervascular-
and tenderness. ized nidus
• In joints: swelling, joint effusions, joint pain, and limited
motion in tumors localized in periarticular bones, mim-
icking inflammatory arthritis. Bone Scan
• When in a lower extremity, the patient presents with a
limp. • Extremely hot spot
• Lesions located near the growth plate may cause over-
growth of bone and bone length discrepancy.
• In small bones of the hands and feet, important swelling Image Differential Diagnosis
may mimic infection.
• When in spine: painful scoliosis with the concavity at the Intraosseous Abscess (Brodie Abscess)
side of the lesion, due to paravertebral muscle spasm. • Lytic area
Symptoms may mimic lumbar disc disease. • Lack central calcification
• Osteoid osteoma is usually a solitary lesion. • Massive bone peripheral sclerosis
• Mature periosteal bone formation
• In angio-MRI: less vascularized lesion
Image Diagnosis
Intracortical Hemangioma
Radiographic Features • Circumscribed small osteolytic intracortical lesion
• Surrounded by a large zone of sclerotic bone
• Nidus – less than 2 cm – is characteristic, round and osteo-
lytic in most cases. Twenty-five percent present with min- Stress Fracture
eralization of the central area or a ringlike calcified central • Transverse fracture: on the tension side.
area – “target pattern.” The nidus is surrounded by sclerosis. • Oblique fracture: on the compression side.
• Three types of location: • Later on, an intramedullary horizontal sclerotic zone
– Cortical repairs the lucent line.
– Subperiosteal • Diffuse periosteal bone reaction overlying the sclerotic
– Medullary area.
• Cortical: the most frequent and classic location.
Characteristic and striking perifocal reactive sclerosis.
• Subperiosteal: the nidus abuts to the soft tissue, raising Pathology
the periosteum, which produces a usually thick layer of
reactive bone formation. Gross Features
• Medullary: mild perifocal bone sclerosis.
• Extensive sclerosis may mask the nidus in nearly 25 % of • In resection specimens, the nidus is comprised in a block
cases. of sclerotic bone.
130 L.G. Olvi et al.

• In most cases the lesion is round or oval, less than 1 cm in
greatest diameter and no more than 2 cm.
• Fragmented specimens are frequently submitted.
• The nidus has a reddish and hyperemic aspect.
• The center of the nidus is often chalky and gritty white or
grayish.
• In cases in which the nidus is difficult to identify, the
pathologist must cut the specimen in slabs no more than
5 mm thick and radiograph it.
• Another procedure is to label the nidus with preoperative
tetracycline, because the nidus will stand out under ultra-
violet light.
– Prostaglandin E2, prostacyclins, and COX-2 overex-
pression in tumoral osteoblasts.
Pathologic Differential Diagnosis
Osteoblastoma
• Both tumors are morphologically similar.
OB
– More than 2 cm in diameter
– Lacks sclerotic peripheral reactive area

OO
Histological Features – Less than 2 cm in diameter
– Limited growth potential
• Histologically, the nidus is composed by haphazard anasto- – Intense reactive sclerotic bone around the nidus
mosing immature osteoid and bone trabeculae, lined by uni-
form osteoblasts, with round regular nuclei and abundant Intraosseous Abscess (Brodie Abscess)
cytoplasm and a few benign multinucleated giant cells of • Typically shows granulation tissue and inflammatory
osteoclastic type embedded in a loose fibrovascular stroma. cells
• Isolated osteoblasts may show an epithelioid aspect, but • Polymorphonuclear leukocyte infiltrates fibrinous
nuclear pleomorphism or atypia is absent. exudate
• In the central part of the nidus, immature mineralized tis- • Necrotic bone with focal surface erosion secondary to
sue may predominate, and it is responsible for the radio- enzymatic digestion
graphic images of more dense central area.
• Cartilage is not present. Intraosseous Hemangioma
• The surrounding sclerotic area is composed of cancellous • Newly formed cavernous capillaries
bone tissue with thickened trabeculae separated by a • Reactive bone formation
richly vascularized fibrous connective tissue, varying to a
densely sclerotic compact bone.
• Occasionally, long-standing lesions may present central Ancillary Techniques
areas of the nidus with a more mature bone tissue, with
typical “mosaic” pattern similar of Paget’s disease of bone. Genetics
• Tumors localized in periarticular sites frequently are • Monosomies and abnormalities of 22q chromosome
associated with reactive angiohyperplastic synovitis,
mimicking rheumatoid arthritis.
• Findings associated with the mechanism of pain are: Prognosis
– Extremely vascularized lesion.
– Peripheral sclerosis. • Excellent prognosis.
– Increased tension. • Osteoid osteomas do not metastasize.
– Fibrous zones surrounding the nidus with increase of
blood vessels.
– Special silver impregnation techniques demonstrate Treatment
axons of nerve fibers associated with blood vessels
within the nidus. This feature is uncommon in other • Percutaneous radiofrequency ablation is the treatment of
bone tumors and practically seen exclusively in oste- choice. More than 90 % of success. Not recommended in
oid osteomas. spine locations.
– Expression of S100 and neurofilament by immunohis- • Percutaneous ablation of the nidus by CT-guided core-
tochemistry confirms the former findings. drill excision.
9 Osteoid Osteoma 131

• In selected cases: wide excision or block resection of the Images

lesion.
• Surgical procedures potentially weaken the cortex.
• In spine: excision. Structural allograft or bone grafting
with bone chips may be needed.
See Figs. 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 9.10, 9.11,
9.12, 9.13, 9.14, 9.15, 9.16, 9.17, 9.18, 9.19, 9.20, 9.21, 9.22,
9.23, 9.24, 9.25, 9.26, and 9.27 for illustrations of osteoid
osteoma.

Fig. 9.1 (a, b) Well-delimited a b

lytic intracortical lesion of
proximal femur. (c) CT scan
shows radiolucent nidus with
sclerosis and periosteal reaction

c
132 L.G. Olvi et al.

a b

Fig. 9.2 (a) X-ray shows intertrochanteric lytic image surrounded by sclerotic bone. (b) Axial CT shows a lytic lesion with central mineralization
and perilesional sclerotic bone. (c) Hot spot with Tc99
9 Osteoid Osteoma 133

a b

Fig. 9.3 (a) X-ray: Intertrochanteric lytic lesion with central miner- formation. The medullary cavity shows a mild adjacent zone of reac-
alization and peripheral bone sclerosis. (b) CT shows lucent nidus tive sclerosis. (c) CT-guided core needle biopsy. (d) Bone scan shows
with central mineralization surrounded by a thick periosteal new bone a hot spot in the proximal femur
134 L.G. Olvi et al.

a b

Fig. 9.4 (a, b) Infrequent ovoid osteoid osteoma with long axis parallel to the host bone. (c, d) Axial CT
9 Osteoid Osteoma 135

a b

Fig. 9.5 Osteoid osteoma of femoral neck. (a, b) CT scan with nidus peripheral sclerosis. (c) Gross specimen. Round, well-delimited nidus, sur-
rounded by thick sclerotic bone
136 L.G. Olvi et al.

a b

Fig. 9.6 (a) Cortical osteoid osteoma with dense periosteal reaction. Gross specimen shows a congestive nidus. (d) Low-power photomicro-
Puncture needle control. (b) Axial CT scan with the typical target pat- graph showing the nidus and surrounding sclerotic bone
tern due to central mineralization with intense periosteal reaction. (c)
9 Osteoid Osteoma 137

a b

Fig. 9.7 (a, b) Typical intracortical osteoid osteoma with periosteal and endosteal bone reaction

a b

Fig. 9.8 (a) Osteoid osteoma on the surface of the cortex, showing an oval lucency. (b) Axial CT scan, showing nidus of osteoid osteoma with
light periosteal reaction
138 L.G. Olvi et al.

a b

Fig. 9.9 (a) Plain X-ray and (b) axial CT scan showing intracortical nidus in the shaft of the tibia

Fig. 9.10 Unusual ovoid and longitudinal osteoid osteoma surrounded

by bone reaction of tibial shaft
9 Osteoid Osteoma 139

a b

Fig. 9.11 (a) X-ray with target pattern of osteoid osteoma in proximal fibula. Slab and X-ray of the gross specimen. (b) Microphotograph at low
magnification showing the cortical nidus surrounded by reactive endosteal bone and periosteal reaction

Fig. 9.12 X-ray of spine with concavity at the side of the nidus associ-
ated with painful scoliosis
140 L.G. Olvi et al.

a b

Fig. 9.13 (a) Anteroposterior X-ray of lumbar vertebra with scoliosis due to paravertebral muscle spasms. (b) CT axial view shows expanded
well-delimited lesion with focal radiodensities in a lateral aspect of posterior elements of vertebra
9 Osteoid Osteoma 141

a c

Fig. 9.14 (a) X-ray shows a mixed lesion located in the posterior arch between the fourth and fifth cervical vertebrae. (b) CT scan shows a highly
radiodense nidus. (c) Bone scan shows a hot spot in the lesion
142 L.G. Olvi et al.

a b

Fig. 9.15 (a) Osteoid osteoma in the posterior elements of the second cervical vertebra. (b) CT scan confirms that it is the most useful method to
show the nidus. (c) Core needle CT-guided biopsy is our favorite method to obtain diagnostic material
9 Osteoid Osteoma 143

Fig. 9.17 Periosteal osteoid osteoma located in the humeral shaft with
b high periosteal reaction surrounding the nidus

Fig. 9.16 (a) Osteoid osteoma located in cervical spine. In this case it
is difficult to localize the lesion in X-ray. (b) CT scan is a better tool to
localize the nidus of osteoid osteoma
144 L.G. Olvi et al.

a b

Fig. 9.18 (a) Radiographic lytic image of osteoid osteoma located in (c) MRI. The lesion is isointense to muscle on T1-weighted image;
the ulnar shaft with broad peripheral reaction. (b) CT shows the sub- (d) T2-weighted image shows increased signal intensity due to periph-
periosteal location of the nidus with erosion of the underlying cortex. eral edema
9 Osteoid Osteoma 145

a b

Fig. 9.19 (a) Anteroposterior and (b) lateral radiograph shows a typical nidus of osteoid osteoma, with central mineralization
146 L.G. Olvi et al.

Fig. 9.20 (a) Anteroposterior

a b
radiograph showing a nidus in
the upper end of the first
phalanx. (b) Scintigram
shows uptake with Tc99 body
scan

Fig. 9.22 Radiographic lesion of osteoid osteoma surrounded by

Fig. 9.21 (a) Lateral X-ray with lytic image of osteoid osteoma. dense sclerotic bone in the diaphysis of the fifth metatarsal bone
(b) CT scan with the typical “target” feature
9 Osteoid Osteoma 147

Fig. 9.24 Low-power microphotograph of a resected osteoid osteoma

showing clearly the nidus with some foci of bone mineralization with-
out the surrounding reactive bone sclerosis

Fig. 9.25 Photomicrograph showing the typical immature trabeculae

lined by osteoblasts and some multinucleated giant cell of osteoclastic
type. At the right, reactive bone sclerosis. The immature trabeculae are
haphazardly interconnected. The matrix of the tumoral trabeculae var-
ies in color depending on the mineralization

Fig. 9.23 (a) Gross specimen: slab of a resected osteoid osteoma.

(b) X-ray of the specimen
148 L.G. Olvi et al.

Fig. 9.26 Peripheral areas of osteoid osteoma showing the surround-

ing sclerosis and the osteoid tumoral trabeculae separated by loose
fibrovascular stroma

Fig. 9.27 Long-standing lesions may present central areas of the nidus
with a more mature bone tissue, with a “mosaic” pattern similar to
Paget’s disease of bone
9 Osteoid Osteoma 149

Recommended Reading Klein MH, Shankman S. Osteoid osteoma: radiologic and pathologic
correlation. Skeletal Radiol. 1992;21:23–31.
Migues A, Velan O, Solari G, Pace G, Slullitel G, Araujo ES. Osteoid
Baruffi MR, Volpon JB, Neto JB, Casartelli C. Osteoid osteomas with
osteoma of the calcaneus: percutaneous radiofrequency ablation.
chromosome alterations involving 22q. Cancer Genet Cytogenet.
J Foot Ankle Surg. 2005;44(6):469–72.
2001;124(2):127–31.
Muscolo DL, Velan O, Pineda Acero G, Ayerza MA, Calabrese ME,
Greenspand A. Benign-forming lesions: osteoma, osteoid osteoma and
Santini AE. Osteoid osteoma of the hip. Percutaneous resection
osteoblastoma. Skeletal Radiol. 1993;22:485–500.
guided by computed tomography. Clin Orthop Relat Res.
Jaffe HL. Benign osteoblastoma. Bull Hosp Joint Dis. 1956;17:
1995;310:170–5.
141–51.
Rosenthal DI. Radiofrequency treatment. Orthop Clin North Am.
Keim HA, Reina EG. Osteoid osteoma as a cause of scoliosis. J Bone
2006;37(3):475–84, VIII.
Joint Surg Am. 1975;57:159–63.
 Osteoblastoma
10
Liliana G. Olvi, Gustavo M. Lembo, Osvaldo Velan,
and Eduardo Santini-Araujo

Abstract
Osteoblastoma is a benign osteoid and bone-forming tumor with numerous osteoblasts lining
immature bone trabeculae and scattered multinucleated giant cells of osteoclastic type and a
loose fibrovascular stroma. It lacks peripheral bone sclerosis. Diameter is greater than 2 cm. The
incidence is greater in males than in females (2:1). The first two decades of life account for
more than 70 % of cases. Sites of involvement: One-third in spine, where in vertebrae, osteoblas-
toma tends to involve the posterior elements, and one-third in tubular bones with predilection for
proximal and distal femur and proximal tibia and proximal humerus. The radiographic appear-
ance is quite variable and often nonspecific. The lesion is oval and expansile but usually well
defined. It may be radiolucent, radiodense, or mixed. Histologically, the lesion is similar to the
“nidus” of osteoid osteoma. Osteoblastoma is usually very well circumscribed. The lesion is
composed by anastomosing immature osteoid and bone trabeculae embedded in a loose fibro-
vascular stroma. Treatment is wide excision or en bloc resection of the lesion.

Definition Etiology

• Osteoblastoma is a benign osteoid and bone-forming • Unknown

tumor with numerous osteoblasts lining immature bone
trabeculae and scattered multinucleated giant cells of
osteoclastic type and a loose fibrovascular stroma. It lacks Clinical Features
peripheral bone sclerosis. Diameter is greater than 2 cm.
Epidemiology

Synonyms • Greater incidence in males than females (2:1).

• The first two decades of life accounts for more than 70 %
• Genuine osteoblastoma of cases.
• Giant osteoid osteoma

L.G. Olvi, MD
Laboratory of Orthopaedic Pathology,
Buenos Aires, Argentina E. Santini-Araujo, MD, PhD (*)
Laboratory of Orthopaedic Pathology,
G.M. Lembo, MD
Buenos Aires, Argentina
Department of Pathology,
Centenary Hospital Rosario Santa Fe Argentina, Department of Pathology, School of Medicine and School of
Rosario, Santa Fe, Argentina Dentistry, University of Buenos Aires,
Buenos Aires, Argentina
O. Velan, MD
Depatment of Radiology, Italian Hospital of Buenos Aires, Central Army Hospital, Buenos Aires, Argentina
Buenos Aires, Argentina e-mail: santiniaraujo@laborpat.com.ar

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 151
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_10, © Springer-Verlag London 2015
152
Sites of Involvement
• One-third in spine: In vertebrae, osteoblastoma tends to
involve the posterior elements. Most common locations in
the spine are, by frequency, cervical, lumbar, thoracic,
and sacral.
• One-third in tubular bones: Predilection for proximal and
distal femur, proximal tibia, and proximal humerus.
• Appendicular lesion bone location: metaphyseal, 45 %;
diaphyseal, 35 %; and epiphyseal, 20 %.
• Osteoblastoma may have medullary, cortical, or perios-
teal location.
• Less frequent in craniofacial and foot and ankle bones.
• In maxillary bones, most lesions are cementoblastomas.
Clinical Symptoms and Signs
• Pain in 87 % of patients, usually of long duration without
the features of osteoid osteoma.
L.G. Olvi et al.
• Local swelling, tenderness, and warmth.
• In the lower extremities the patient may present with a limp.
• When in spine: numbness and tingling. Paraparesis and
paraplegia due to compression of the cord or nerve roots
may appear. Scoliosis or atrophy of regional muscle
groups in the area.
• Osteoblastoma has been associated with systemic “toxic”
symptoms in a small number of patients, which cure with
the excision of the tumor.
Image Diagnosis
Radiographic Features
• The radiographic appearance is quite variable and often
nonspecific.
• The lesion is oval and expansile but usually well defined.
• It may be radiolucent, radiodense, or mixed.
• It may have medullary, cortical, or periosteal location.
10 Osteoblastoma
• Osteoblastoma in the vertebral column tends to involve the
posterior elements, 57 %, and almost never involves the ver-
tebral body alone, less than 3 %. It can involve two or more
adjacent segments. It produces scoliosis similar to that of
osteoid osteoma due to a unilateral spasticity of spinal mus-
cles. Half the lesions show radiodense ossifications.
• On the basis of radiographic features, the lesions are
thought to be:
– Benign: 70 %
– Indeterminate: 20 %
– Malignant: 10 %
• In jaw bones, lesions that are ossified and located in the
periapical region of a tooth and surrounded by a radiolu-
cent halo are, probably, cementoblastomas.
• In some cases osteoblastoma presents ill-defined margins
with erosion of the cortex and involvement of surround-
ing soft tissues.
• Some cases may show periosteal reaction.
CT Features
• Osteoblastoma in spine is best visualized by a CT scan.
• Well-circumscribed expansile lesion.
MRI Features
• Low signal in T1
• High signal intensity in T2
• May present dark spots corresponding to mineralized
deposits
• Peripheral edema best shown by using contrast
• Useful for appreciation of cystic degeneration
Bone Scan
• The lesion is hot.
Image Differential Diagnosis
Osteoid Osteoma
• Nidus – less than 2 cm – is round and osteolytic. Some lesions
present mineralization of the central area, “target pattern.”
• The nidus is surrounded by sclerosis.
• Three types of location: cortical, subperiosteal, and
medullary.
• Extensive sclerosis may mask the nidus in nearly 25 % of
cases.
• CT scan is the most useful method to show the nidus, espe-
cially when a heavy surrounding sclerosis masks the nidus.
153
Osteosarcoma
• Some osteoblastomas are locally aggressive and may
destroy the cortex, mimicking a malignant neoplasm.
• More than 10 % of osteoblastomas show an aggressive
appearance on x-ray.
• On the other hand, there are some osteosarcomas that
appear indolent in the roentgenograms.
• Conventional osteosarcoma is a metaphyseal permeative
and destructive lesion.
• Osteosarcoma is a poorly defined lesion without a scle-
rotic rim.
• Osteosarcoma usually destroys the cortex and develops a
soft tissue mass.
• Periosteal reaction is common in osteosarcomas, with a
Codman triangle, onionskin, or sunburst pattern.
ABC: When in Spine
• Area of lucency situated eccentrically in the medullary
cavity in the metaphysis of a long bone.
• Most ABCs are completely lytic, but a few contain traces
of mineral.
• Frequently presents a multiloculated appearance.
• Later, a “ballooned” or “aneurysmal” cystic expansion of
the affected bone – “blow out” – is evident. Usually forms
a thin sclerotic rim of ossification due to periosteal new
bone formation.
• When in spine, more than one vertebral segment is com-
monly affected.
• In other bones, ABC may cross joints and involve an adja-
cent bone.
• CT and MRI highlight the internal septation, the cystic
nature, and the fluid-fluid levels.
Pathology
Gross Features
• The lesions are reasonably well circumscribed and delin-
eated from the surrounding bone tissue.
• Reddish, hemorrhagic, friable, and granular.
• A small percentage of lesions may show cystic
changes.
• Sometimes the vascularity is so great that hemostasis may
be problematic at surgery.
• Average diameter: 3–6 cm.
Histological Features
• Histologically, the lesion is similar to the “nidus” of oste-
oid osteoma.
• Osteoblastoma is usually very well circumscribed.
154
• The edge may show parallel well-formed bone trabeculae
and tends to show maturation or zonation, appearing well
limited, with no tendency to permeate the surrounding
bone.
• The lesion does not infiltrate the surrounding native bone
tissue.
• The lesion is composed of anastomosing immature oste-
oid and bone trabeculae embedded in a loose fibrovascu-
lar stroma – vessels with wide lumina – usually associated
with few benign multinucleated giant cells of osteoclastic
type.
• Osteoblasts lining the trabeculae are uniform and do not
fill the intertrabecular bone marrow spaces.
• Lace-like osteoid may be present.
• Rarely, mitotic figures may by numerous. Lacks atypical
mitoses.
• Areas of secondary aneurysmal bone cyst are seen in
approximately 10 % of osteoblastomas.
• Clear-cut chondroid matrix differentiation is seen in a
small percentage (6 %) of typical osteoblastomas.
• Epithelioid osteoblasts – larger than conventional osteo-
blasts – with large nuclei and prominent nucleoli are
found in a small number of cases.
• In rare instances, large osteoblasts with bizarre and degen-
erative nuclei are seen.
• Necrosis is usually not present.
• Histological features that may be misinterpreted and lead
to an overdiagnosis are:
– Presence of lace-like osteoid
– High cellularity
– Foci of cartilage
– Numerous mitotic figures
• A rare type of osteoblastoma is the multifocal sclerosing
osteoblastoma, which can be medullary, central, or endos-
teal and peripheral or juxtacortical:
– Presents a multifocal growth pattern.
– Roentgenological and gross features: more than one
circumscribed lesion with the appearance of the central
“nidus” of osteoid osteoma – “multifocal osteoid oste-
oma” – enclosed in a block of reactive sclerotic bone.
– Histologically defined by multiple small foci of typical
osteoblastoma separated by a proliferating bone and
fibrous tissue.
– A few may have a predominant proliferation of epithe-
lioid cells.
– Eventually, a nodule composed exclusively by epithe-
lioid cells can mimic metastatic carcinoma.
• “Out of the average” findings:
– Cystic change
– Chondroid matrix
L.G. Olvi et al.
– Epithelioid osteoblasts
– Pseudomalignant osteoblasts
These findings do not represent a different clinical behav-
ior and are not sufficient to consider, when they are present,
different variants of osteoblastoma.
Pathologic Differential Diagnosis
Osteoid Osteoma
• Less than 2 cm in diameter
• Sclerotic peripheral reactive area
ABC: In Vertebral Location
• Less sclerotic lesion
• Woven trabeculae in a fibrogenic stroma with haphaz-
ardly distributed multinucleated giant cells
• Cavernomatous spaces filled with blood
• Lace-like or powdery calcifications with a basophilic blue
appearance (“blue bone”), peculiar chondroid-like zones,
and pink parallel seams of fibrillary osteoid beneath the
lining of the septum are typical and relatively specific fea-
tures of ABC.
Osteosarcoma (Especially Osteoblastoma-Like
Osteosarcoma)
• Generally, osteoblastomas have an x-ray appearance, that
is, of a benign lesion, but some of them may show fea-
tures suggestive of malignancy.
• Some osteoblastomas are locally aggressive and may
destroy the cortex, mimicking a malignant neoplasm.
• More than 10 % of osteoblastomas show an aggressive
appearance on x-ray.
• On the other hand, there are some osteosarcomas that
appear indolent in the roentgenograms.
• Some osteoblastomas may show histologically thick and
well-formed trabeculae but also lace-like osteoid trabecu-
lae (20 % of cases). These histological areas can lead to
an overdiagnosis of osteosarcoma.
• On the other hand, some osteosarcomas are microscopi-
cally bland and show areas indistinguishable from those
of osteoblastoma.
• To complicate this scenario:
– Some authors have reported osteoblastomas that
undergo malignant transformation.
– Some authors have reported “pseudomalignant osteo-
blastomas” with bizarre nuclei similar to those that are
seen in neurilemmomas and ancient schwannomas.
– Some authors have suggested that there is a distinct
subgroup of osteoblastomas that have a peculiar
10 Osteoblastoma
histological pattern and a more aggressive clinical
behavior and termed them “aggressive
osteoblastomas”.
– Some authors described “malignant osteoblastomas”
as a non-metastasizing but locally aggressive variant.
• The concept of osteosarcoma resembling osteoblastoma
or osteoblastoma-like osteosarcoma is relevant and serves
to clarify that most of the so-called malignant osteoblas-
tomas and aggressive osteoblastomas are really osteosar-
comas that resemble osteoblastomas.
• Osteoblastoma-like osteosarcoma presents large areas of
deceptively bland proliferated tissue. The tumor resem-
bles osteoblastoma under low-power microscopy, with
abundant bone production as well as formed bone trabec-
ulae. Trabeculae are rimmed with plump osteoblasts with
eosinophilic cytoplasm and round nuclei with prominent
nucleoli. The pink cytoplasm gives the cells an “epitheli-
oid appearance.” Tumor cells are present not only lining
the bone trabeculae but also in the bone marrow spaces
between the trabeculae, giving the lesion a cellular
appearance. Trabeculae of native bone are encased by
neoplastic tissue.
In summary, the differential diagnosis between osteoblas-
toma and osteosarcoma is made on a histological basis:
Osteoblastoma shows:
• Sharp circumscription
• Lack of permeation on surrounding bone
• Presence of a fibrovascular connective tissue between
bone trabeculae with a loose arrangement
• Single layer of osteoblasts lining the bone trabeculae
Osteosarcoma presents:
• Permeation on the surface and infiltrative growth pattern
• Entrapment of host bone trabeculae
• Sheets of osteoblasts without bone production between
bone trabeculae
• Frank nuclear atypia, abundant and atypical mitosis
Fibrous Dysplasia
• Irregular curvilinear immature trabeculae in a bland spin-
dle cells’ fibrous component
• Rounded cementum-like corps
• Foam cells, multinucleated giant cells, benign chondroid
areas, myxoid, or secondary aneurysmal bone cyst change
may occur.
155
Osteofibrous Dysplasia
• Immature curvilinear bone trabeculae rimmed by plump
osteoblasts
• Spindle cells in a dense collagenous stroma
• Expression of cytokeratins in myofibroblastic cells,
absent in osteoblastoma
Genetics
• Specific cytogenetic data are not found.
Prognosis
• Good prognosis.
• Recurrences may occur in less than 20 % in cases and are
treated by curettage.
• Reported cases with malignant transformation are
extremely rare. It is preferable to think that the original
diagnosis was incorrect.
• Some osteoblastomas do tend to behave aggressively
locally. This partially relates to the fact that many of these
are in locations where surgical removal is necessarily
incomplete.
• Osteoblastomas do not metastasize.
Treatment
• Wide excision or en bloc resection of the lesion.
• In spine: excision or curettage with complete removal of
the lesion preserving the roots.
• Structural allograft or bone grafting with bone chips are
frequently needed.
• Radiotherapy must be avoided for potential risk of malig-
nant transformation.
Images
See Figs. 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9,
10.10, 10.11, 10.12, 10.13, 10.14, 10.15, 10.16, 10.17,
10.18, 10.19, 10.20, 10.21, 10.22, 10.23, 10.24, 10.25,
10.26, 10.27, 10.28, and 10.29 for illustrations of
osteoblastoma.
156 L.G. Olvi et al.

a b c

Fig. 10.1 The radiographic appearance is quite varied. The lesion may be radiolucent (a), radiodense (b), or mixed (c)

a b c

Fig. 10.2 Osteoblastoma may be intramedullary (a), cortical (b), or periosteal (c)
10 Osteoblastoma 157

Fig. 10.3 (a) Radiograph of

osteoblastoma of the skull. (b) In a b
total body scan with Tc-99 ms,
the lesion is “hot”

a b

Fig. 10.4 (a) Osteoblastoma in

vertebral column tends to involve
the posterior elements, similar to
aneurysmal bone cyst. (b)
Osteoblastoma in spine is best
visualized by CT scan
158 L.G. Olvi et al.

a b c

Fig. 10.5 (a–c) Similar to aneurysmal bone cyst, osteoblastoma in spine can involve two or more adjacent segments. (d) Gross specimen with
hemorrhagic areas
10 Osteoblastoma 159

Fig. 10.6 (a) Scoliosis similar to that of osteoma osteoid is seen in

osteoblastoma due to unilateral spasticity of spinal muscles. (b)
CT-guided needle biopsy of lesion
160 L.G. Olvi et al.

Fig. 10.7 Osteoblastoma characteristically arising in the posterior or dorsal elements of vertebrae as seen in radiograph (a) and CT scan (b)
10 Osteoblastoma 161

Fig. 10.8 In a few cases, the

lesion compromises both, a b
posterior elements and the
vertebral body as seen by
conventional radiography (a),
MRI (b) and CT (c)

c
162 L.G. Olvi et al.

a b

Fig. 10.9 Rarely, osteoblastoma involves the vertebral body alone, as can barely be seen by conventional radiography (a) and more easily identi-
fied by CT (b) and bone scan (c)

a b

Fig. 10.10 Osteoblastoma is usually very well circumscribed with little or no peripheral sclerosis. CT scan (a) and microscopic panoramic view
(b) of a sacral lesion demonstrate this feature
10 Osteoblastoma 163

Fig. 10.11 Histologically, the edge of osteoblastoma tends to show

maturation or “zonation” with presence of peripheral well-formed par-
allel bony trabeculae

Fig. 10.13 Areas of secondary aneurysmal bone cyst are seen in

approximately 10 % of osteoblastomas. X-ray (a), MRI and CT (b)
show a large such lesion in the upper thorax, showing cavities with
fluid-fluid levels. Medium power microscopic view (c) of same lesion
with osteoblastoma tissue at left and cystic changes at right

Fig. 10.12 Osteoblastoma is composed by anastomosing osteoid and

bony trabeculae embedded in a loose fibrovascular stroma, usually
associated with few benign giant cells of osteoclastic type. A single
layer of osteoblasts that do not totally fill the intertrabecular spaces
lines the trabeculae
164 L.G. Olvi et al.

Fig. 10.13 (continued)

10 Osteoblastoma 165

a b

Fig. 10.14 Microscopic clear-cut chondroid matrix (a and c) is seen in a small percentage of cases of otherwise typical osteoblastoma (b)
166 L.G. Olvi et al.

a b

Fig. 10.15 Potentially misinterpreted histological features are (a) lace-like osteoid, (b) high cellularity, and (c) foci of cartilage
10 Osteoblastoma 167

Fig. 10.16 Generally, osteoblastoma has an x-ray appearance that is of

a benign lesion

a b

Fig. 10.17 Some of them may show x-ray features suggestive of malignancy (a), like in this distal tibia where the lesion is locally aggressive and
destroys the cortex, features that mimic malignant neoplasm. (b) Microscopy shows bland histology
168 L.G. Olvi et al.

a b c

Fig. 10.18 Some osteoblastomas show an aggressive appearance on images (a–c). Macrophotography of same lesion (d)

a b

Fig. 10.19 Some osteosarcomas

may appear indolent on the
roentgenograms (a) and CT
imaging (b)
10 Osteoblastoma 169

Fig. 10.20 Osteoblastoma may show histologically, in rare instances,

Fig. 10.21 Osteosarcoma showing cytologically bland microscopic
large osteoblasts with bizarre and degenerative nuclei
areas, simulating osteoblastoma

a b

Fig. 10.22 A number of osteoblastomas have a histological pattern characterized by epithelioid osteoblasts (a and b) and small areas of osteoid
matrix
170 L.G. Olvi et al.

a b

Fig. 10.23 Osteoblastoma-like osteosarcoma. (a) X-ray, (b) CT scan plasm with prominent nucleoli. (g) The pink cytoplasm gives them an
and (c) bone scan. (d) Gross specimen. (e) This osteoblastoma-like epithelioid appearance. (h) Areas of cartilage are common in osteoblas-
osteosarcoma contains large areas of deceptively bland tissue. toma-like osteosarcoma. (i) Areas of lace-like osteoid in osteoblas-
(f) Trabeculae are rimmed with plump cells that have eosinophilic cyto- toma-like osteosarcoma
10 Osteoblastoma 171

f g

h i

Fig. 10.23 (continued)

172 L.G. Olvi et al.

Fig. 10.24 Osteoblastoma. Lack of permeation of the surrounding Fig. 10.26 Osteoblastoma. Single layer of osteoblasts lining the bone
bone trabeculae

Fig. 10.27 Osteosarcoma. Permeation of the cortex

Fig. 10.25 Osteoblastoma. Presence of a fibrovascular connective tis-

sue between bone trabeculae with a loose arrangement
10 Osteoblastoma 173

a b

Fig. 10.28 (a, b) Osteosarcoma. Low and high magnifications showing the entrapment of host bone trabeculae
174 L.G. Olvi et al.

Recommended Reading
Bertoni F, Unni KK, McLeod RA, Dahlin DC. Osteosarcoma resem-
bling osteoblastoma. Cancer. 1985;55:416–26.
Bertoni F, Donati D, Bacchini CP, Martini A, Picci P, Campanacci M.
The morphologic spectrum of osteoblastoma (OBL): is its “aggres-
sive” nature predictable (abstract)? Mod Pathol. 1993;6:3a.
Dorfman HD. Malignant transformation of benign bone lesion. Proc
Nat Conf. 1972;7:901–13.
Dorfman HD, Weiss SW. Borderline osteoblastic tumors: problems in
the differential diagnosis of aggressive osteoblastoma and low grade
osteosarcoma. Semin Diagn Pathol. 1984;1:215–34.
Jaffe HL. Benign osteoblastoma. Bull Hosp Joint Dis. 1956;17:
141–51.
Kalil RK. Osteoblastoma-like osteosarcoma. San Diego: International
Skeletal Society; 2011.
Lichtenstein L. Benign osteoblastoma. A category of osteoid and bone
forming tumor other than classical osteoid osteoma, which may be
mistaken for giant cell tumor or osteogenic sarcoma. Cancer.
1956;9:1044–52.
Merryweather R, Middlemiss JH, Sanerkin NG. Malignant transforma-
tion of osteoblastoma. J Bone Joint Surg. 1980;62B:381–4.
Schajowicz F. Tumors and tumorlike lesions of bone and joints.
New York/Heidelberg/Berlin: Springer-Verlag; 1981.
Schajowicz F, Lemos C. Malignant osteoblastoma. J Bone Joint Surg.
1976;58B:202–11.
Unni KK. Dahlin’s bone tumors. 5th ed. Philadelphia: Lippincott-
Raven; 2010.

Fig. 10.29 Osteosarcoma. Sheets of osteoblasts without bone produc-

tion between bony tumoral trabeculae
 Conventional Central Osteosarcoma
11
Franco Bertoni and Patrizia Bacchini

Abstract
Conventional central osteosarcoma (CCO) is a high-grade intraosseous malignant bone
tumor. The neoplastic cells produce osteoid or bone. A CCO is considered to be primary
when the host bone is normal. A CCO is said to be secondary when the host bone is affected
by other pathologic conditions. There is a slight male predominance. It has a bimodal age
distribution: the majority of cases are diagnosed between 10 and 14 years of age, and there
is a second smaller peak in older adults (>40 years old). They originate in the long bone
metaphysis (90 %), especially in the knee region and proximal humerus (locations with
the most proliferative growth plates). The radiographic appearance of primary CCO varies
greatly, depending on the amount of ossification/calcification and the amount of the lytic
component. Tumors may be completely lytic or predominantly sclerotic, but they usually
demonstrate a combination of these features. The presence of a purely sarcomatous stroma
and the direct formation of tumoral osteoid and bone by the malignant connective tissue
cells are the characteristic histological features. Histologic subtypes (variants) of primary
CCO are osteoblastic (sclerotic type), chondroblastic, fibroblastic (malignant fibrous his-
tiocytoma-like), giant cell-rich, osteoblastoma-like, epithelioid, chondroblastoma-like, tel-
angiectatic/hemorrhagic, small cell, chondromyxoid fibroma-like, plasmacytoma-like, and
multicentric (synchronous and metachronous). Treatment includes preoperative chemo-
therapy (neoadjuvant). Surgical approach is through surgical resection with wide surgical
margins (negative margins). The biopsy tract has to be removed with the tumor. Amputation
is done if necessary as well as post-op chemotherapy.

Definition
F. Bertoni, MD (*) • A conventional central osteosarcoma (CCO) high-grade
Department of Surgical Pathology, University of Bologna,
intraosseous sarcoma containing neoplastic bone-
Bologna, Italy
producing cells (WHO 2013)
Surgical Pathology Department,
• Pitfalls: Tumor-producing bones (but no osteosarcoma)
Istituto Rizzoli, Bologna, Italy
have to be excluded such as myoepithelial carcinoma,
Department of Surgical Pathology,
bone-producing synovial sarcoma, bone-producing meta-
Villa Erbosa Hospital, Bologna, Italy
e-mail: proffrancobertoni@gmail.com static sclerosing carcinoma, and Ewing’s sarcoma with
osteoid matrix.
P. Bacchini, MD
Department of Surgical Pathology, • A CCO is considered to be primary when the host bone is
Private Hospital Villa Erbosa, Bologna, Italy normal.

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 175
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_11, © Springer-Verlag London 2015
176
• A CCO is said to be secondary when the host bone is
affected by pathologic conditions, such as:
– Paget’s disease
– Radiation exposure for benign lesions (postradiation
sarcoma)
– Occasionally benign lesions (fibrous dysplasia, osteo-
blastoma, bone infarct, or foreign body) without radia-
tion therapy
– In patients who underwent total hip arthroplasty
implanted with a prosthesis and metal hardware
– In patients with low-grade chondrosarcomas (dediffer-
entiated chondrosarcoma)
– In patients with certain genetic abnormalities (Li-
Fraumeni, hereditary retinoblastoma, Rothmund-
Thomson syndrome, Bloom syndrome)
– Secondary CCO is more common in adults.
Synonyms
• Osteogenic sarcoma
Etiology
• The etiology of primary CCOs as well as secondary
CCOs is unknown.
Clinical Features
Epidemiology
Primary CCO
Primary CCO is the most common high-grade sarcoma
found in the bone (with the exception of myeloma and bone
metastases).
F. Bertoni and P. Bacchini
• It represents 27.5 % of all malignant tumors and 19.2 %
of all bone tumors at the Mayo Clinic.
Sex
• There is a slight male predominance.
Age
• It has a bimodal age distribution: the majority of cases are
diagnosed between 10 and 14 years of age, and there is a
second smaller peak in older adults (>40 years old).
Secondary CCO
• Patients with Paget’s disease have a low risk of develop-
ing sarcoma (1 %); it is most common in male patients
with polyostotic disease, and the peak incidence is in the
seventh decade. In a Mayo Clinic series of 73 sarcomas
present with Paget’s disease, 61 are osteosarcomas.
• Conventional central osteosarcoma is the most common
radiation-induced sarcoma (2.7–5.5 %) of all sarcomas in
more advanced age (>40 years).
• Conventional central osteosarcomas are rarely associated
with other conditions: bone infarct, benign bone tumors,
and metal prosthetic joints and hardware. They are sec-
ondary CCOs and affect older patients (>40 years).
11 Conventional Central Osteosarcoma
Sites of Involvement
• Primary osteosarcoma: For the most part they originate
in the long bone metaphysis (90 %), especially in the
knee region and proximal humerus (locations with the
most proliferative growth plates). The diaphysis is
involved in 9 %; the epiphysis is implicated only rarely.
Tumors involving the jaw, pelvis, and spine tend to occur
in older patients. There is occasional involvement of the
small bones of the extremities.
• Secondary osteosarcomas in Paget’s disease are most
common in the pelvis, femur, humerus, skull, sacrum, and
spine, with 15–20 % of the cases being multifocal. Their
distribution parallels the distribution of the skeletal sites
involved.
• In secondary postradiation CCOs, the pelvis and the
shoulder regions are the most common regions involved.
177
• In secondary CCOs in mature patients, only 39 % of the
tumors arise in the long tubular bones, and, in comparison
to primary CCO, the axial skeleton is the most common
site.
Clinical Symptoms and Signs
In Primary CCO
• Pain and swelling are the main symptoms.
• Larger tumors may restrict the range of motion and inter-
fere with musculoskeletal functions, and synovial effu-
sion may be present.
• Patients with CCO are only rarely asymptomatic. The
duration of symptoms varies from a few weeks to several
months before diagnosis. Symptoms in excess of a 1-year
duration are very rarely reported.
178
• Joint effusion may be present when the tumor extends to
the periarticular structures and bone extremities.
In Secondary CCO
• A progressive increase in swelling, progressive localized
pain (indicating rapid progression of disease), and a pal-
pable mass suggest a malignant evolution in Paget’s dis-
ease and in patients with a history of irradiation for benign
conditions of the bone.
• At best, a latency period of 2 years or longer between
radiation treatment and the origin of the osteosarcoma is
expected. Rapid progression of the disease is also an omi-
nous sign in patients with a benign bone lesion, such as a
cartilaginous tumor, fibrodysplasia, or bone infarct.
• Evidence of pathologic fracture through the destructive
mass is rare (5–10 % of cases).
• Laboratory tests in primary and secondary CCOs show
elevated serum alkaline phosphatase in 50 % of the
patients (due to osteoblastic activity).
Image Diagnosis
Radiographic Features
• The radiographic appearance of primary CCO varies
greatly, depending on the amount of ossification/calcifica-
tion and the amount of the lytic component.
• Tumors may be completely lytic or predominantly
sclerotic, but they usually demonstrate a combination of
these features.
• In purely lytic lesions, there is an elevated probability that
histology will show a telangiectatic (hemorrhagic) high-
grade osteosarcoma.
• The tumor is rarely confined to the epiphysis, and at times
at imaging, it can be deceptive due to its completely
benign appearance.
• Ten percent of the lesions are diaphyseal.
• The destructive process may be limited to the medulla,
but the cortex is usually involved as well, and it is nearly
always perforated by the growing tumor.
• As the tumor growth progresses through the cortex into
the soft tissue, a prominent mass can be identified which
is contiguous to the bone (having a “cloud-like”
radiodense appearance).
• The proliferated bone produced by the neoplastic cells
contains various degrees of density, causing this “cloud-
like” appearance with ill-defined margins.
CT and MRI Features
• Computed tomography (CT) and magnetic resonance
imaging (MRI) are routinely used for preoperative stag-
ing studies in patients having osteosarcoma.
F. Bertoni and P. Bacchini
• When the periosteum is elevated by the perforating tumor,
nonneoplastic bone is deposited in parallel layers
(onionskin-like) or has a radiating appearance (sunburst),
and a Codman triangle is identified, namely, the angle
created by the cortex and the elevated periosteum.
• Periosteal reaction (reactive woven bone) occurs between
the cortex and the periosteum elevated by the tumor.
Bone Scan
• Hot in primary and metastatic lesions
• Secondary CCOs have the same features as those
described for primary CCOs, but the affected bone dis-
plays the findings characteristic of an underlying disease
process.
• In Paget’s disease osteosarcoma, bone enlargement and
alteration of shape and contour together with obscured
corticomedullary demarcation (all of which are character-
istic of Paget’s disease) are associated with an extensive
osteolytic pattern or, less frequently, mixed and osteoblas-
tic patterns. Computed tomography imaging shows bone
destruction and a cortical breakthrough and extension into
the soft tissue with cloudy opacity.
• In bone infarct, secondary osteosarcoma appears to be
irregular areas of destruction within, or sometimes at the
edge of the infarct: they are ill-defined irregular, lytic
lesions of the metaphysis with focal areas of calcification
at the periphery, which corresponds to a bone infarct.
Image Differential Diagnosis
• Primary myoepithelial carcinoma in the bone
• Chondrosarcoma grade 3
• Dedifferentiated chondrosarcoma
• Synovial sarcoma involving the bone
• Hypertrophic callus (present in osteogenesis imperfecta
or stress fractures)
Pathology
Gross Features
• A CCO usually presents as a large metaphyseal, intra-
medullary mass.
• The metaphyseal plate is frequently destroyed by the
tumor which extends down practically to the articular
cartilage.
• Rupture of the cortex and a soft tissue mass can also be
detected. They form eccentric or circumferential soft tis-
sue components, peripherally displacing the periosteum.
• The tumor forms a massive gritty partially hemorrhagic
necrotic soft tissue mass.
11 Conventional Central Osteosarcoma
• The cartilaginous component, which is sometimes focally
myxoid or mucinous, is underlined by non-mineralized
glistening gray areas.
• The tumor may focally spread extensively in the marrow
cavity, and areas of medullary involvement are rarely
detected intracompartmentally. They consist of firm,
ovoid, tannish-white nodules both adjacent to and distant
from the main mass.
• Computed tomography and MRI are very useful in detect-
ing this type of marrow involvement.
• Secondary CCOs grossly show the same features as pri-
mary osteosarcomas, but the bone concerned occasionally
displays findings characteristic of the underlying disease
process.
• In Paget’s sarcoma, the possibility of identifying the
thickened cortex and medulla seen in Paget disease
exists.
• Radiation osteitis (trabecular coarsening and cortical
lysis) is occasionally present (50 % of cases – WHO) in
postradiation osteosarcoma.
• Osteosarcomas found in other benign conditions do not
grossly differ from primary CCOs, but occasionally old
bone infarcts, fibrous dysplasia, osteochondroma, or
osteopoikilosis may be detected in the host bone harbor-
ing the osteosarcoma.
Histological Features
Primary CCO
• The presence of a purely sarcomatous stroma and the
direct formation of tumoral osteoid and bone by the
malignant connective tissue cells are the characteristic
histological features reported in the literature.
• The histologic classification of CCO depends on:
1. The product of the malignant cells (osteoid, bone) and
the dominant histologic differentiation pattern observed:
osteoblastic, chondroblastic, and fibroblastic
2. The cytology of malignant cells (epithelioid, plas-
macytoid, fusiform, ovoid, small round, mono- or
multinucleated cells, spindle-stellate cells) and both
their arrangement and relationship with the matrix
(architecture)
• The prominent differentiation (osteoblastic, chondroblas-
tic, and fibroblastic of the malignant connective tissues)
underscores the wide variation of aspects seen in the his-
topathology of osteosarcomas.
• The amount of osteoid/bone produced by the malignant
cells may be minimal or there may be extensive areas.
• The associated necrosis and hemorrhage contribute exten-
sively to the variability of the histologic presentation of a
CCO.
• The tumor growth is permeating, namely, infiltrating
between the cancellous bone of the host bony trabeculae
and the cortical bone.
179
Table 11.1 Histologic subtypes (variants) of primary CCO
Osteoblastic (sclerotic type)
Chondroblastic
Fibroblastic (malignant fibrous histiocytoma-like)
Giant cell-rich
Osteoblastoma-like
Epithelioid
Chondroblastoma-like
Telangiectatic/hemorrhagic
Small cell
Chondromyxoid fibroma-like
Plasmacytoma-like
• This aggressive growing pattern results in the destructive
permeation of preexisting trabeculae of the cancellous
bone and the cortex and extension into the soft tissues.
• Classification according to the abovementioned: The vast
majority of CCOs are classified as osteoblastic (56 % at
the Mayo Clinic, 76–80 % WHO).
• Matrix: Osteoid/bone in a fine lace-like network between
the individual tumor cells, with focal or extensive
calcification.
• Matrix bony trabeculae: Thin and anastomosing or thick
and well formed.
• When the mature bony trabeculae are very prominent and
intermixed with the host bone trabeculae, rendering iden-
tification of the tumor cells difficult, the tumor is extremely
sclerotic, and it is called a sclerotic osteosarcoma.
• When a CCO shows chondroid differentiation together,
with osteoid/bone production, in which the malignant
cells are in lacunae and form lobules, with the crowded
peripheral spindle cells forming hypercellular sheets, the
pattern is called a chondroblastic-type CCO. In the Mayo
Clinic series, 20 % of CCOs are chondroblastic, and in the
WHO series, 10–13 % are chondroblastic.
• Occasionally a CCO along with the osteoid/bone extra-
cellular matrix shows prominent spindle- shaped cells in
a herringbone arrangement. This pattern is termed fibro-
blastic osteosarcoma (24 % in the Mayo Clinic series,
10 % in the WHO series).
• When a storiform pattern and extensive pleomorphism of
the malignant cells are present, this pattern is called osteo-
genic fibroblastic osteosarcoma, a malignant fibrous
histiocytoma-like variant. It is a variety of fibroblastic
osteosarcoma having pleomorphic cells in a storiform
arrangement.
• Histologic variations exist in conventional central osteo-
sarcoma (Table 11.1).
Giant Cell-Rich Osteosarcoma
• In some CCOs the multinucleated giant cells are so
numerous as to mimic the features of a giant-cell tumor.
• Mononuclear cells, in between the giant cells, may
show severe anaplasia; however, when the mono-
nuclear cells show only subtle cytologic atypia, the
180
differential diagnosis with a giant-cell tumor can
be very difficult, and this morphologic appearance
accounts for the histologic variety of CCO called giant
cell-rich osteosarcoma.
• When such a tumor is present in an unusual location (for
a giant-cell tumor,) such as in the metaphysis or diaphy-
sis, serious consideration should be given to calling it an
osteosarcoma.
• The major problem when the location is good for a giant-
cell tumor and the cytologic atypia is not prominent.
• Accurate radiographic evaluation, clinical history, and
behavior may help in the differential diagnosis.
Osteoblastoma-Like Osteosarcoma
• Some CCOs may produce regular trabeculae of the woven
bone littered with osteoblasts, thus simulating the appear-
ance of an osteoblastoma. This histologic configuration
was called osteoblastoma-like osteosarcoma.
• In this case the radiographic features may be indistin-
guishable from a typical osteoblastoma, and only the per-
meative growing pattern and the presence of sheets of
monomorphic malignant cells without matrix will help in
the differential diagnosis.
• In biopsies with small amount of material, the diagnosis is
sometimes not possible.
Epithelioid Osteosarcoma
• Some CCOs may have irregular bony trabeculae lined
with malignant cells with an epithelioid appearance (epi-
thelioid osteosarcoma).
• Immunohistochemistry can occasionally confirm the
focal epithelial differentiation.
• In an adult patient, the epithelioid configuration of the
osteoblasts suggests the differential diagnosis with meta-
static carcinoma.
• Gland-like formation is unusual in CCOs, but it is possi-
ble to see cells showing epithelioid cytologic features and
clustering of the tumor cells in CCOs.
• The epithelioid cells may have a rosette-like configura-
tion with the production of matrix in the center.
• It is sometimes possible to see sheets of epithelioid cells
with pink cytoplasm, vesicular nuclei, and prominent cen-
tral nucleoli, with varying amounts of osteoid.
• When such a lesion is present in young patients, a CCO
should be suspected. In older patients, primary or second-
ary CCO has to be differentiated from metastatic osteo-
genic carcinoma or from primary or metastatic
myoepithelial carcinoma in the bone.
Chondroblastoma-Like Osteosarcoma
• Some CCOs have tumor cells which simulate a chondro-
blastoma: chondroblastoma-like osteosarcoma.
• Sheets of round-oval cells, without well-defined cellular
borders having a syncytial-like arrangement are observed.
F. Bertoni and P. Bacchini
• In spite of its similarity to chondroblastoma, the extra-
epiphyseal location is a useful hint in recognizing the
osteosarcoma simulating a chondroblastoma.
• Unfortunately, in the case of having subtle atypia, it is
very difficult or impossible to reach a diagnosis especially
if the lesion is in an appropriate location for a chondro-
blastoma and there is only a small amount of diagnostic
tissue.
Telangiectatic Osteosarcoma
• Occasionally, a CCO is completely lytic, grossly simi-
lar to a bag of blood and having histologically large
hemorrhagic areas with septa, as in aneurysmal bone
cyst.
• The cells of the septa are highly malignant and pleomor-
phic, or there may only be highly malignant pleomorphic
cells in a bloody background without any specific
pattern.
• Generally osteoid matrix is minimal.
• These are the histological features indicative of a telangi-
ectatic or hemorrhagic osteosarcoma.
Small-Cell Osteosarcoma
• A CCO is rarely characterized by a lace-like osteoid pro-
duction associated with small cells which resemble lym-
phoma or Ewing’s sarcoma (1.5 % in WHO series).
• The small cells may be round, oval, or spindle-shaped.
• A small-cell osteosarcoma having a mineralized osteoid
matrix is present when the translocation of an Ewing’s
sarcoma is lacking and TdT markers for lymphoblastic
B- and T-cell lymphoma and Fli-1 are negative. In addi-
tion, a mesenchymal chondrosarcoma may occasionally
be suspected in the differential diagnosis with a small-cell
osteosarcoma. Molecular biology can help in making the
differential diagnosis.
Chondromyxoid Fibroma-Like Osteosarcoma
• At times, a chondroblastic-type CCO may have extremely
myxoid areas with a hypocellular center and a concentra-
tion of tumor cells toward the periphery.
• The myxoid lobular appearance simulates chondromyx-
oid fibroma, and the highly malignant cytology along
with osteoid production is indicative of a chondromyxoid
fibroma-like osteosarcoma.
Osteosarcoma Mimicking a Plasma Cell Myeloma
• Very rarely is it possible to see a high-grade osteosarcoma
with unusual histological features mimicking a plasma
cell myeloma, presenting with synchronous/metachro-
nous multifocal osseous tumors.
• The following immunostains all give negative reactions:
CD3, CD20, CD43, CD79a, CD138, epithelial membrane
antigen (EMA), lysozyme, myeloperoxidase, vimentin,
and, kappa/lambda chains. In situ hybridization is
11 Conventional Central Osteosarcoma
negative for kappa and lambda immunoglobulin (IG) light
chains.
Multicentric Osteosarcoma
• Very rarely osteosarcoma may develop in several bones.
This variant “CCO multicentric osteosarcoma” may have
two distinct presentations: synchronous and
metachronous.
Specific histological features have resulted in the need to
subclassify CCOs (see Table 11.1). However, no relationship
exists:
1. Between histologic subtypes (varieties), treatment, and
prognosis.
2. These histologic variants of CCO account of no more
than 10–15 % of all CCO.
Secondary CCO
• It reproduces the histologic subtypes (variants) of a pri-
mary CCO, with osteoblastic (sclerotic) type, fibroblastic
(MFH-like), and chondroblastic high-grade varieties.
• The most common histologic subtype of Paget’s sarcoma
is an osteosarcoma, although fibrosarcoma, chondrosar-
coma, and malignant fibrous histiocytoma can also occur.
The osteosarcoma may have an osteoblastic, fibroblastic,
and/or chondroblastic appearance in decreasing order of
frequency. Variants, such as telangiectatic or small-cell
osteosarcomas, have been reported.
• Osteosarcomas associated with benign lesions, such as
osteomyelitis, have rarely been reported, but it is impera-
tive that it be recognized because it is much more malig-
nant than the other malignancies associated with
osteomyelitis, such as secondary squamous carcinoma.
• Sarcomas in fibrous dysplasia have frequently been asso-
ciated with radiotherapy, but a small percentage of
patients had not undergone this treatment, so the tumors
could not be considered postradiation sarcomas.
Osteoblastic, fibroblastic, and chondroblastic types of
osteosarcoma have been reported to be associated with
fibrous dysplasia in patients who have not undergone
radiotherapy. All were high-grade highly malignant
lesions, with a poor prognosis.
• The bone infarct-sarcoma risk is very low and is difficult
to assess, as many bone infarcts are asymptomatic. The
microscopic features are related to malignant fibrous his-
tiocytoma and rarely to high- and low-grade
CCO. Peripheral areas of bone infarct are sometimes
identified adjacent to a CCO. Dead bone trabeculae, gran-
ulation tissue, and fat necrosis with dystrophic calcifica-
tions and with highly malignant cell-producing bone are
the feature of these secondary osteosarcomas.
• Postradiation-induced sarcomas include osteosarcomas,
chondrosarcomas, and malignant fibrous histiocytomas;
these sarcomas do not differ from their conventional pri-
mary counterparts. They are high-grade sarcomas which
181
are frequently associated histologically with radiation
osteitis with the necrotic bone and reparative changes and
with elevated cellular proliferation of fibroblastic tissue
and reactive new bone. Atypical mesenchymal cells, with
pleomorphic and hyperchromatic nuclei, characterize the
reparative changes in close proximity with the high-grade
induced osteosarcomas.
• Sarcomas have been reported to arise at the site of metal-
lic implants; however, this phenomenon is very rare. The
most frequent type is high-grade osteosarcoma which
does not differ from its conventional primary
counterpart.
Pathologic Differential Diagnosis
Benign
• Fracture callus, hypertrophic callus, stress, and/or insuf-
ficiency fracture
• Myositis ossificans
• Benign parosteal osteocartilaginous proliferations (Nora’s
disease)
• Aneurysmal bone cyst
• Osteoblastoma
• Giant-cell tumor
Malignant
• Chondrosarcoma
• Fibrosarcoma (malignant fibrous histiocytoma)
• Dedifferentiated chondrosarcoma
• Ewing’s sarcoma
• Metastatic carcinoma
• Myoepithelial carcinoma
• Synovial sarcoma
Exuberant/Hypertrophic Callus
• Some rare conditions such as osteogenesis imperfecta or
osteopetrosis are predisposing factors for the develop-
ment of exuberant callus.
• The early and later stages of hyperplastic callus may be
present as continuity among various microscopic ele-
ments, namely, hypercellular areas containing spindle
cells with early osteoid formation and an interconnecting
network of reactive bone with prominent osteoblastic
rimming, juxtaposed hyaline cartilage and trabecular
bone.
• It usually presents brisk mitotic figures without atypia,
but in unusual sclerotic cases, the differential diagnosis
with malignancy may be very complicated.
Stress Fracture, Insufficiency Fracture,
Avulsion Fracture
• An unnoticed stress fracture and/or insufficiency fracture
in adulthood, or an avulsion fracture in a young athlete,
182
may pose problems for differential diagnosis between
reactive lesion and osteosarcoma.
Florid Reactive Periostitis and Bizarre Parosteal
Osteochondromatous Proliferation
• Less-frequent surface lesions such as florid reactive peri-
ostitis and bizarre parosteal osteochondromatous prolif-
erations (Nora’s disease) may be mistaken for a surface
or central osteosarcoma in acral parts or in the long
bones.
• Nora’s lesion, a cup-shaped cartilaginous exostotic lesion in
which disorganized islands of hyaline cartilage blends with
the woven bone and basophilic blue bone in a fibrous back
ground are helpful features in the diagnosis of this lesion.
Myositis Ossificans
• On X-ray, the periphery of the lesion is mineralized both
grossly and histologically, whereas there is a lack of min-
eralization at the center (zonation).
• On histology the center of the lesion has a fasciitis-like
appearance, mitoses rich.
• No atypia or necrosis.
• The well-organized architecture of myositis ossificans is
completely lost in osteosarcomas, and prominent bone
production is present in the center of an osteosarcoma.
Aneurysmal Bone Cyst
• It may mimic a telangiectatic (hemorrhagic) osteosarcoma.
• Neither the lining cells nor the cells in the septa demon-
strate atypia.
• The numerous mitotic figures are also not atypical as they
are in telangiectatic osteosarcomas.
Osteoblastoma
• The distinction between an osteoblastoma and an
osteoblastoma-like osteosarcoma can be difficult.
• In an osteosarcoma, there is an infiltrating growth pattern
of the lesion in between the host trabeculae.
• In an osteoblastoma, there are interconnecting trabeculae
lined by plump osteoblasts with no infiltration of the sur-
rounding host bone.
• These are the morphologic cornerstones of the differential
diagnosis between the two lesions.
Giant-Cell Tumor
• The distinction between giant cell-rich osteosarcoma and
a giant-cell tumor can be problematic.
• In a giant-cell tumor, the reactive bone is frequently found
at the periphery and inside the tumor. The bone is lined by
osteoblasts with no atypia of the cells.
• In a giant cell-rich osteosarcoma, the bone is produced
directly by the highly malignant stromal cells.
F. Bertoni and P. Bacchini
Chondrosarcoma
• Chondroblastic osteosarcoma and chondrosarcoma can
be difficult to distinguish, especially in the pelvis, or in
some osteosarcomas of the jaw.
• A cartilaginous tumor with marked atypia, particularly
in young patients, is highly suspicious for
osteosarcoma.
• Radiological imaging can be very helpful in differentiat-
ing one from the other. The presence of IDH1 or IDH2
mutations suggests a diagnosis of chondrosarcoma.
Fibrosarcoma (Malignant Fibrous Histiocytoma)
• This type of tumor can sometimes be difficult to differen-
tiate from fibroblastic osteosarcoma.
• The presence of bone production by the malignant cells is
the marker of an osteosarcoma.
• The osteoblastic differentiation may be confirmed by
nuclear positivity with SATB2.
• The differential diagnosis is not so critical since both have
similar treatments, namely, neoadjuvant chemotherapy
followed by surgical resection with wide margins.
Dedifferentiated Chondrosarcoma
• When defining a tumor as a dedifferentiated chondrosar-
coma, it is important to note the presence of a preexisting
(synchronous or metachronous) low grade chondrosar-
coma and high-grade sarcoma.
• When the tumor is characterized by highly malignant
sarcoma cells which produce a bone in an adult patient,
careful research of a cartilaginous component will
confirm the diagnosis of a dedifferentiated
chondrosarcoma.
Ewing’s Sarcoma
• Ewing’s sarcoma has to be differentiated from a small-
cell osteosarcoma which may mimic Ewing’s sarcoma.
• Rearrangement of Ewing’s sarcoma breaks point region
(EWSR) 1 gene, along with CD 99 and Fli-1, and negative
terminal deoxynucleotidyl transferase (TdT) will help in
recognizing an Ewing’s sarcoma.
• Histologically, bone production is the peculiar aspect of
an osteosarcoma, but bone production may sometimes be
present in an otherwise genetic molecularly proven
Ewing’s tumor.
Myoepithelial Carcinoma
• It may be indistinguishable from an osteoblastic
osteosarcoma.
• The following markers, CK, EMA, actin, desmin, S100,
and glial fibrillary acidic protein (GFAP) are extremely
positive in a myoepithelial carcinoma in spite of the bone
production present in both tumors.
11 Conventional Central Osteosarcoma
Synovial Sarcoma
• Synovial sarcoma, monophasic type, can involve the soft
tissue as well as be primary in the bone.
• In both situations the lesion may produce bone.
• CK and EMA positivity and X:18 translocation are useful
hints in reaching the differential diagnosis.
Phosphaturic Mesenchymal Tumor
• It is a distinctive mesenchymal tumor associated with
oncogenic osteomalacia.
• There are fascicles of spindle cells with scattered blood
vessels (occasionally having a hemangiopericytomatous
arrangement) with myxochondroid stroma and an osteoid
matrix (crunchy calcification) producing a lytic appear-
ance with faint areas of mineralization scattered within
the mass.
• Some malignant tumors resemble an undifferentiated sar-
coma with matrix production simulating an osteosarcoma.
• The tumor expresses fibroblastic growth factor 23 and
hypophosphatemia. These tumors are occasionally
multicystic.
Ancillary Techniques
• No specific markers exist. Frequently expressed antigens
include osteocalcin, osteonectin, S100, actin, smooth
muscle actin (SMA), neuron-specific enolase (NSE),
CD99, and rarely CK and EMA. Moreover SATB2 is a
marker of osteoblastic differentiation which is useful
when difficulty is encountered in deciding whether the
extracellular matrix is osteoid or collagen, or has an undif-
ferentiated appearance as in the case of small biopsies.
• The lack of osteoid matrix does not exclude an osteoge-
netic property of the neoplstic cells.
• However, SATB2 nuclear positivity may help in identify-
ing the osteogenic phenotype. This feature along with the
malignant appearance of the bone-producing surrounding
cells will help in the CCO diagnosis.
• Problems in clinical application of biomarkers in osteo-
sarcoma: The value of P16 immunoreactivity in predict-
ing histological response to neoadjuvant chemotherapy in
osteosarcoma was reported. This finding was the only sta-
tistically significant variable in a multivariate analysis.
• The relationship between P-glycoprotein expression in
osteosarcomas and its relationship to the extent of the
necrosis in resected specimens of post-neoadjuvant che-
motherapy and patient outcome remained controversial.
Genetics
In CCO the complexity of chromosomal alterations, genetic
events, and various factors involved in local growth and dis-
183
semination is the major drawback in performing new treat-
ment in CCO.
Virtually all osteosarcomas contain clonal chromosomal
aberrations. The aberrations are complex with an abundance
of numerical and structural alterations, but no specific trans-
location has been identified in CCOs.
Prognosis
Primary CCO
• Primary CCO relapse-free survival: The rates reported
vary from 50 % to 80 % (median 70 %).
• Patients presenting with metastases/recurrent disease:
survival rate <20 %.
• Predictors of good outcome:
– Localized disease.
– Ninety percent or more induced necrosis.
– Complete resection: these are associated with a 5-year
survival rate of 80 %.
• Predictors of poor outcome:
– Proximal extremity location
– Axial skeletal involvement
– Large size/volume
– Detectable metastasis at diagnosis
– Poor response to preoperative chemotherapy
Secondary CCO
• Osteosarcoma in Paget’s disease: It has a dismal progno-
sis; medial survival is 8–21 months, and the 5-year sur-
vival rate for osteosarcomas is 8 % as compared to the
current 50–80 % 5-year survival rate for a primary
CCO. Tumor site, stage, and type of therapy are not sig-
nificant indicators of prognosis.
• Radiation osteosarcoma: The prognosis is worse for pel-
vic, vertebral, and shoulder girdle (axial skeletal loca-
tions) osteosarcomas.
• In secondary CCO there is no correlation between the his-
tological response to neoadjuvant chemotherapy and the
prognosis.
Treatment
Primary CCO
• Surgical approach: surgical resection with wide surgical
margins (negative margins). The biopsy tract has to be
removed with the tumor.
184 F. Bertoni and P. Bacchini

• Amputation is necessary if: • Unusual anatomic locations of the tumor, such as the
– Major vessels and nerves are tumor involved. axial skeleton and the cranial/facial bones
– The tumor involves regions which cannot be
reconstructed.
– Pathologic fracture or surgical intervention has con- Low-Grade Central Osteosarcoma (LGCOS)
taminated a large volume of tissue.
Definition

Preoperative Chemotherapy (Neoadjuvant) • A low-grade bone-forming neoplasm which arises within

the medullary bone cavity.
Therapeutic Goals
• To diminish tumor size:
– The tumor may undergo more extensive mineraliza- Etiology
tion, often with a thick pseudocapsule, thus facilitating
resection. • Unknown
– Evaluation of the effectiveness chemotherapy is by his-
tologic assessment of the degree of tumoral necrosis.
The assessment of necrosis involves evaluating a slide Clinical Features
of the center of the tumor and a sampling of the tissue
on both sides of the central portion (on histology). Epidemiology
• A good response and important prognostic indicator is • An LGCOS is rare. It represents 1–2 % of all
considered to be ≥90 % necrosis. osteosarcomas.
• The extent of necrosis consequent to neoadjuvant chemo-
therapy may be used to alter postoperative regimes. Sex
• There is a slight female predominance.
Treatment Difficulties (Major Drawbacks)
in Secondary Osteosarcomas Age
• The high grade of the tumor: • Patients tend to be somewhat older than patients with con-
– Older patients (decreased immunity, poor general ventional osteosarcomas. In fact, 52 % of the patients
health, low tolerance for chemotherapy and were in the third decade of life.
radiotherapy)
11 Conventional Central Osteosarcoma 185

Sites of Involvement • The majority of the lesions have indistinct margins (sug-
• Eighty-one percent of the cases involved the long tubular gesting an aggressive process), and more than 50 % of the
bones (for the most part, the distal femur and the proximal cases have cortical destruction and extension into the soft
tibia). tissue.
• A few cases have been reported in the flat bones and in the • However, a fair number of patients (up to one-third,
small bones of the hands and feet. WHO) have sharp well-defined margins with a scle-
rotic radiopaque appearance suggestive of a benign
Clinical Symptoms and Signs lesion.
• The symptoms usually begin with local pain and/or
swelling. Image Differential Diagnosis
• The duration of the symptoms may be quite long (several Desmoplastic Fibroma in the Bone
months/years). • Desmoplastic fibroma and LGCOS may have a similar
overlapping appearance.
• The lesion extends to the end of the bone, has a trabecu-
Image Diagnosis lated appearance, and destroys the cortex focally.

Radiographic Features Fibrous Dysplasia

• Imaging shows large lesions involving the metadiaphy- • Usually has well-defined zone of rarefaction which is
seal region of the long bones which often extend to the frequently surrounded by a narrow rim of the sclerotic
end of the long bones having a trabeculated appearance. bone.
186
• Therefore, the differential diagnosis with an LGCOS hav-
ing sharp well-defined margins can be a problem.
Pathology
Gross Features
• An LGCOS has a white and firm fibrous whorled appear-
ance; the lesion arises within the intramedullary cavity and
appears to be well demarcated, but bone expansion and
rupture through the cortex may be present.
Histological Features
• An LGCOS consists of spindle-shaped cells (showing
only little cytologic atypia) arranged in an interlacing pat-
tern with permeation of the cancellous bony trabeculae
surrounding the lesion, the fatty marrow, and the cortical
bone.
• There is a variable amount of osteoid/bone production
showing different patterns: regular bony trabeculae simu-
lating the appearance of parosteal osteosarcoma and long
longitudinal seams of the lamellar bone.
• Other patterns may have scanty osteoid and a desmoid
appearance, or osteoid/bone in the form of anastomosing,
branching, and curved bony trabeculae, simulating the
appearance of Chinese letter in a fibrous dysplasia.
• On low power, there is the appearance of well-developed
bony trabeculae surrounded by a hypocellular spindle cell
stroma, lacking the significant atypia and focally pagetoid
bone appearance; only occasionally are mitotic figures
present.
Pathology Differential Diagnosis
Fibrous Dysplasia
• There is no permeation of the preexisting bone, bone mar-
row, or soft tissue extension.
• The demonstration of a GNAS1 mutation can help in the
differential diagnosis with LGCOS. The absence of over-
expression of MDM2 and CDK4 may be useful hints in
ruling out LGCOS.
Desmoplastic Fibroma in the Bone
• It has elongated strands of well-differentiated spindle
cells; they may be confused with LGCOS, but the perme-
ative growing pattern is not as diffuse as in LGCOS, and
bone production is lacking.
• The absence of MDM2 and CDK4 overexpression may
help in the differential diagnosis with LGCOS.
F. Bertoni and P. Bacchini
Leiomyosarcoma of the Bone
• Spindle cell bundles are arranged at right angles.
• The nuclei are elongated and blunt ended (cigar-shaped).
• It is positive for smooth muscle actin, desmin, and keratin.
Ancillary Techniques
• Immunohistochemical detection of MDM2 and CDK4
has recently been reported to provide a useful diagnostic
tool in confirming LGCOS.
• Fibrous dysplasia and benign fibro-osseous lesions are
negative for these markers.
• When the appearances of the extracellular matrix is
equivocal (i.e., collagenous stroma vs. osteoid) or there is
the presence of undifferentiated tumor in a small biopsy
sample, the use of SATB2, an immunohistochemical
marker of osteoblastic differentiation, may provide a use-
ful hint (reactivity may be a problem in specimens after
extensive decalcification has taken place).
Genetics
• Amplification of MDM2 and CDK4 is present in LGCOS.
• In this osteosarcoma variety the complex chromosomal
aberrations, as in CCO, are lacking.
Prognosis
• The prognosis regarding LGCOS is excellent.
• Metastasis is rare, and the overall 5-year survival rate is
90 %.
• Ten percent of these cases had dedifferentiation at the
time of recurrence.
Treatment
• Wide resection is the treatment of choice.
• Chemotherapy is reserved for cases with dedifferentiation.
Images
See Figs. 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9,
11.10, 11.11, 11.12, 11.13, 11.14, 11.15, 11.16, 11.17, 11.18,
11.19, 11.20, 11.21, 11.22, 11.23, 11.24, 11.25, 11.26, 11.27,
11.28, 11.29, 11.30, 11.31, 11.32, 11.33, and 11.34 for illus-
trations of conventional central osteosarcoma Figs. 11.35,
11.36, 11.37 and 11.38.
11 Conventional Central Osteosarcoma 187

a b c

Fig. 11.1 (a–c) Anteroposterior and lateral x-ray and MRI of an osteo- The tumor extends into the soft tissue. A conspicuous Codman’s trian-
sarcoma involving the tibial proximal metaphysis and diaphysis violat- gle is present. (d) Gross specimen of an “en bloc” transepiphyseal
ing the growth plate and transgressing the cortex, forming a large mass. resection
188 F. Bertoni and P. Bacchini

Fig. 11.2 A tumor arising in the

medullary cavity and extending
through the cortex into the soft
tissue. The tumor mechanically
lifts the periosteum, depositing
reactive bone during the process
forming a Codman’s triangle.
X-ray of the specimen

a b

Fig. 11.3 (a) Microscopically highly malignant cells making neoplastic bone and osteoid. (b) Scaffolding bone tumor over native trabeculae;
cells show the so-called “normalization” pattern
11 Conventional Central Osteosarcoma 189

Fig. 11.4 An osteosarcoma of the proximal humerus metaphysis, extending into the epiphysis and toward the diaphysis, rupturing the cortex, and
forming a large circumferential soft tissue mass. X-ray of the specimen

Fig. 11.5 Abundant neoplastic bone in the form of irregular intercon-

necting lace-like trabeculae of the woven bone is a feature of an osteo-
blastic high-grade central osteosarcoma. The tumor permeates the
central bone and surrounds the preexisting trabeculae
190 F. Bertoni and P. Bacchini

Fig. 11.6 AP radiograph of the pelvis: an expansile focally sclerotic and lytic osteosarcoma of the ischium

Fig. 11.7 Gross appearance of a chondroblastic osteosarcoma. There is an aggressive destructive growth appearance, destruction of the cancel-
lous bone, and extension of the cortical bone with soft tissue. X-ray of the surgical specimen confirms this pattern
11 Conventional Central Osteosarcoma 191

Fig. 11.8 On histology, there is chondroblastic differentiation; large

areas of neoplastic hyaline cartilage showing transition into coarse lace-
like neoplastic osteoid

Fig. 11.10 A proximal destructive neoplasm of the fibula, mainly

osteolytic: cortex destruction and large soft tissue mass are identified.
The lesion is centered on the proximal epiphysis and metaphysis of the
fibula

Fig. 11.9 On high power, atypical cytologic features and necrosis are
identified along with osteoid production
192 F. Bertoni and P. Bacchini

Fig. 11.11 On CT, the soft

tissue mass is more evident

a b

Fig. 11.12 (a) The patient was treated with preoperative systemic che- malignant spindle cells arranged in fascicles. There is fatty marrow per-
motherapy. Grossly: the pink-white portion of the tumor is viable, meation and a malignant spindle cell population merging with the
whereas the yellow portions are necrotic. A very distinct, abrupt border coarse-woven tumor bone
is identified. (b) A fibroblastic osteosarcoma showing cytologically
11 Conventional Central Osteosarcoma 193

Fig. 11.13 Telangiectatic osteosarcoma in the proximal tibia metaph- tion and soft tissue extension are identified. The lesion is approaching
ysis apparently confined to the bone. However, extensive cortical viola- the epiphyseal growth plate, but there is no violation of the open epiph-
tion is detected. The hemorrhagic tumor component is composed of a yseal growing plate. The patient was treated preoperatively with sys-
“bag of blood”: variable-sized cysts filled with blood. Cortical destruc- temic chemotherapy. Focal areas of viable tumor are identifiable
194 F. Bertoni and P. Bacchini

Fig. 11.14 Histology, on low power, shows extensive cystic changes

with focal areas of an infiltrative pattern between the host trabeculae
11 Conventional Central Osteosarcoma 195

Fig. 11.15 The cyst wall has a variable thickness and contains cytologically highly malignant pleomorphic cells with focal areas of mineralized
neoplastic bone, encasing the cellular proliferation. There is a prominent malignant giant-cell component

Fig. 11.16 A sclerotic and lytic aggressive tumor involving the metaphysis and partially the epiphysis of the proximal humerus with rupture of
the cortex and soft tissue extension
196 F. Bertoni and P. Bacchini

Fig. 11.17 The tumoral cells (on the left side) resemble those of a
chondroblastoma. They are round, oval and have moderate amounts of
eosinophilic cytoplasm, irregular grooved nuclei, and scattered giant
cells which then merge with the spindle cells showing osteoid lace-like
and chicken-wire calcification

Fig. 11.18 This is an example of chondroblastoma-like osteosarcoma infiltrating the marrow fat and showing matrix production with cytologic
malignant tumor cells
11 Conventional Central Osteosarcoma 197

Fig. 11.20 Histology, on low power, shows many large osteoclast-like

giant cells scattered throughout the tumor. The differential diagnosis
with a giant-cell tumor: cytologically malignant tumor cells and neo-
plastic bone

Fig. 11.19 An aggressive, lytic tumor involving the distal metaphysis

of the femur and partially involving the epiphysis. The margins toward
the proximal cancellous bone are indistinct and permeating. The medial
border looks well defined with a distinct Codman’s triangle formed by
the intersection of the lifted reactive periosteum with the host cortex

Fig. 11.21 Both features are identified on the high-power view of this case of giant cell-rich osteosarcoma
198 F. Bertoni and P. Bacchini

Fig. 11.23 Histology: There is a prominent malignant round, ovoid

cell proliferation which has indistinct margins; the cells are growing in
sheets associated with eosinophilic tumor bone (this feature helps in the
differential diagnosis with other round cell malignancies, including car-
cinoma, lymphoma, and sarcoma). In this round cell osteosarcoma, the
round cells have variable amounts of cytoplasm with fine chromatin

Fig. 11.22 This is a bone-forming tumor of the metadiaphysis of the

proximal tibia. This type of tumor grows aggressively, permeating the
central part of the tibia and extending into the soft parts

Fig. 11.25 Osteoblastoma-like osteosarcoma is difficult to recognize

and has to be differentiated from osteoblastoma. The radiographic
appearance of this case is an example of osteoblastoma-like osteosar-
coma in which not only the histology but also the X-ray shows overlap-
ping with an osteoblastoma: location in the posterior elements of the
spine. The lesion is mainly lytic and focally sclerotic, associated with
expansion of the host bone, with scattered foci of matrix mineralization
and soft tissue mass

Fig. 11.24 CD99 is positive (as in Ewing’s tumor), but molecular biol-
ogy tests were negative for Ewings’s sarcoma. Only very rarely does
Ewing’s tumor have bone production; molecular biology studies are
helpful in overcoming this pitfall
11 Conventional Central Osteosarcoma 199

a b

Fig. 11.26 (a, b) Histologically, there is similarity with osteoblas- lamellar bone is embedded in an osteogenetic background cell prolif-
toma; well-formed trabeculae of the woven bone are lined by prominent eration. This infiltrative appearance confirms the osteoblastoma-like
layers of osteoblasts associated with moderate atypia. Preexisting osteosarcoma diagnosis

Fig. 11.27 Sagittal CT demonstrated a bone-forming tumor of the distal metaphysis of the femur, with bone expansion and cortical involvement.
Axial CT: the protruding bone lesion and the CT show a destructive intramedullary lesion with cortical involvement
200 F. Bertoni and P. Bacchini

Fig. 11.28 The wide resection slab section along with a radiograph of the surgical specimen confirms the expansile lesion with cortical
involvement

a b

Fig. 11.29 The whole-mount

low-power view (a) shows an
osteogenic tumor which involves
the major part of the distal
metaphysis of the femur. The
tumor has eroded through the
cortex (b) and shows minimal
involvement of the epiphysis
11 Conventional Central Osteosarcoma 201

Fig. 11.30 A well-differentiated osteosarcoma shows a long subparal-

lel stream of bone. The intervening intertrabecular spaces are occupied
by a spindle cell population (similar to parosteal osteosarcoma)

Fig. 11.31 The neoplastic spindle cells show minimal atypia and pres- Pagetoid bone and minimal atypia of the spindle cells are a useful hint
ent an infiltrating growing pattern of the surrounding host trabeculae. in recognizing low-grade central osteosarcoma. MDM2 and CDK4
The differential diagnosis is fibrous dysplasia, but in fibrous dysplasia, overexpression are useful diagnostic tools
there is no infiltration of the surrounding host bone or of the soft tissue.
202 F. Bertoni and P. Bacchini

Fig. 11.32 Paget osteosarcoma:

Radiographic anteroposterior and
lateral view: areas of irregular
density with a cotton wool-like
appearance interspersed with
radiolucent areas. The distal
femur is enlarged and the
contours are altered due to
cortical destruction and soft
tissue extension of the lesion

Fig. 11.33 (a) Grossly, the surgical specimen shows a coarse cortex embedded on a sarcoma-like appearance lesion showing high-grade
and enlarged lesion with extensive bone destruction and soft tissue malignant pleomorphic morphologic features
extension. (b) Histology shows bony trabeculae in a “mosaic pattern”
11 Conventional Central Osteosarcoma 203

Fig. 11.34 High-grade central osteosarcoma of the proximal humerus

after preoperative chemotherapy, gross appearance of the central tumor
slide after sectioning to create smaller fragments, idendified by letters
and numbers in this picture. Assessment of necrosis should be carried Fig. 11.35 Whole-mount of the slab section of proximal humerus
out by histologically evaluating a slide of the central tumor and sam- showing the relationship between the tumor and the surrounding bone
pling the remaining two halves. The tumor demonstrates excellent
response with necrosis of all of the tumor cells (Huvos grade 4)

Fig. 11.36 The mineralized lace-like matrix is a marker of areas previ-

ously inhabited by the neoplasm. Furthermore, granulation tissue and
fibrous stroma are present along with degenerative “atypical cells”
204 F. Bertoni and P. Bacchini

a b

Fig. 11.37 (a, b) These pre-necrotic changes due to chemotherapy consist of bizarre nuclei, homogenization of chromatin, and cytoplasm
vacuolization

a b

Fig. 11.38 (a) CT scan showing a peripheral metastatic nodule in right lung. (b) Low power microscopy shows small osteosarcoma metastatic
nodule in the lung
11 Conventional Central Osteosarcoma 205

Fig. 11.39 Pulmonary block from an autopsy showing multiple

peripheral metastatic nodules in an osteosarcoma patient
206 F. Bertoni and P. Bacchini

Recommended Reading Huvos AG, Higinbotham NL, Miller TR. Bone sarcomas arising in
fibrous dysplasia. J Bone Joint Surg Am. 1972;54(5):1047–56.
Huvos AG, Rosen G, Bretsky SS, Butler A. Telangiectatic osteogenic
Arlen M, Higinbotham NL, Huvos AG, Marcove RC, Miller T, Shah
sarcoma: a clinicopathologic study of 124 patients. Cancer.
IC. Radiation-induced sarcoma of bone. Cancer.
1982;49(8):1679–89.
1971;28(5):1087–99.
Kurt AM, Unni KK, McLeod RA, Pritchard DJ. Low-grade intraosse-
Bacchini P, Inwards C, Biscaglia R, Picci P, Bertoni F. Chondroblastoma-
ous osteosarcoma. Cancer. 1990;65(6):1418–28.
like osteosarcoma. Orthopedics. 1999;22(3):337–9.
Marcove RC, Sheth DS, Healey J, Huvos A, Rosen G, Meyers P. Limb-
Bacci G, Longhi A, Cesari M, Versari M, Bertoni F. Influence of local
sparing surgery for extremity sarcoma. Cancer Invest.
recurrence on survival in patients with extremity osteosarcoma
1994;12(5):497–504.
treated with neoadjuvant chemotherapy: the experience of a single
Matsuno T, Unni KK, McLeod RA, Dahlin DC. Telangiectatic osteo-
institution with 44 patients. Cancer. 2006;106(12):2701–6.
genic sarcoma. Cancer. 1976;38(6):2538–47.
Bertoni F, Unni KK, McLeod RA, Dahlin DC. Osteosarcoma resem-
Mervak TR, Unni KK, Pritchard DJ, McLeod RA. Telangiectatic osteo-
bling osteoblastoma. Cancer. 1985;55(2):416–26.
sarcoma. Clin Orthop Relat Res. 1991;270:135–9.
Bertoni F, Bacchini P, Fabbri N, Mercuri M, Picci P, Ruggieri P, et al.
Mirra JM, Bullough PG, Marcove RC, Jacobs B, Huvos AG. Malignant
Osteosarcoma. Low-grade intraosseous-type osteosarcoma,
fibrous histiocytoma and osteosarcoma in association with bone
histologically resembling parosteal osteosarcoma, fibrous dyspla-
infarcts; report of four cases, two in caisson workers. J Bone Joint
sia, and desmoplastic fibroma. Cancer. 1993a;71(2):338–45.
Surg Am. 1974;56(5):932–40.
Bertoni F, Bacchini P, Donati D, Martini A, Picci P, Campanacci
Nakajima H, Sim FH, Bond JR, Unni KK. Small cell osteosarcoma of
M. Osteoblastoma-like osteosarcoma. The Rizzoli Institute experi-
bone. Review of 72 cases. Cancer. 1997;79(11):2095–106.
ence. Mod Pathol. 1993b;6(6):707–16.
Nora FE, Unni KK, Pritchard DJ, Dahlin DC. Osteosarcoma of
Bertoni F, Bacchini P, Staals EL. Giant cell-rich osteosarcoma.
extragnathic craniofacial bones. Mayo Clin Proc. 1983;58(4):
Orthopedics. 2003;26(2):179–81.
268–72.
Campanacci M, Bertoni F, Capanna R, Cervellati C. Central osteosar-
Porretta CA, Dahlin DC, Janes JM. Sarcoma in Paget’s disease of bone.
coma of low grade malignancy. Ital J Orthop Traumatol.
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1981;7(1):71–8.
Rosen G, Tan C, Sanmaneechai A, Beattie Jr EJ, Marcove R, Murphy
Corradi D, Wenger DE, Bertoni F, Bacchini P, Bosio S, Goldoni M,
ML. The rationale for multiple drug chemotherapy in the treatment
et al. Multicentric osteosarcoma: clinicopathologic and radiographic
of osteogenic sarcoma. Cancer. 1975;35(3 suppl):936–45.
study of 56 cases. Am J Clin Pathol. 2011;136(5):799–807.
Rosen G, Marcove RC, Caparros B, Nirenberg A, Kosloff C, Huvos
Dahlin DC, Coventry MB. Osteogenic sarcoma. A study of six hundred
AG. Primary osteogenic sarcoma: the rationale for preoperative che-
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Enneking WF, Kagan A. “Skip” metastases in osteosarcoma. Cancer.
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1975;36(6):2192–205.
et al. Preoperative chemotherapy for osteogenic sarcoma: selection
Farr GH, Huvos AG, Marcove RC, Higinbotham NL, Foote Jr
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the primary tumor to preoperative chemotherapy. Cancer.
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1982;49(6):1221–30.
Fitzgerald Jr RH, Dahlin DC, Sim FH. Multiple metachronous osteo-
Sim FH, Cupps RE, Dahlin DC, Ivins JC. Postradiation sarcoma of
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2006;11(4):412–23.
 Osteosarcoma of the Jaws
12
María L. Paparella and Rómulo L. Cabrini

Abstract
Osteosarcoma of the jaw is rare considering that its incidence varies between 5 % and 13 %
of total osteosarcomas. It accounts for 10 % of primary aggressive and malignant tumors of
the jaws and for 8 % of all malignant lesions including metastatic and lymphoproliferative
tumors. It differs from conventional osteosarcoma of long bones in a number of aspects (age
of onset, predominant differentiation pattern, grade of malignancy, prognosis, clinical
course, response to treatment, cause of death).

Definition Clinical Features

• Osteosarcoma is a primary malignant tumor of bone in Epidemiology

which the neoplastic cells produce osteoid or bone that,
when occurring in the jaws, present special clinical, radio-
graphic, and pathological characteristics.
Synonyms
• Osteogenic sarcoma of the jaws
Etiology
• It accounts for 10 % of primary aggressive and malignant
tumors of the jaws and for 8 % of all malignant lesions
including metastatic and lymphoproliferative tumors.
• According to the case series published in the literature, it
accounts for 2–13 % of all osteosarcomas of the
skeleton.
• Unlike conventional osteosarcoma of the long bones,
osteosarcoma of the jaws presents during the fourth or
fifth decade of life, when skeletal growth and develop-
ment is complete.

• Unknown Sex
• Osteosarcoma of the jaws is associated with radiotherapy • The incidence in men and women is similar (1:1).
of the head and neck and with preexisting bone lesions:
Paget’s disease, dysplastic lesions (fibrous dysplasia), and Age
tumors (cemento-ossifying fibroma). • It is more frequent in the 4th and 5th decades of life.

M.L. Paparella, PhD (*) • R.L. Cabrini, MD, PhD
Department of Oral Pathology, School of Dentistry,
University of Buenos Aires, Buenos Aires, Argentina
e-mail: mluisapaparella@gmail.com
Sites of Involvement
• Osteosarcoma of the jaws has a predilection for the man-
dible, mainly the posterior region of the mandibular
body – premolar and molar regions.

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 207
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_12, © Springer-Verlag London 2015
208
Clinical Symptoms and Signs
• Clinical manifestations are not specific for osteosarcoma
of the jaws and can include:
– Swelling with or without pain
– Increase in tumor growth after tooth extraction
– Tooth mobility and/or tooth loss
– Paresthesia
Image Diagnosis
• There are no typical radiographic features.
• Radiographically, lesions are usually mixed, though they
can be radiolucent or radio-opaque, depending on the
destruction of normal bone and the mineralization of the
newly formed osteoid.
• Destruction of the cortical plates (buccal, palatal/lingual,
or basal) is observed.
• Twenty-five percent of cases show a sunray appearance. This
pattern, studied on occlusal radiographs and axial CT scan
sections, corresponds to peripheral mineralization of the
tumor in the areas invading the surrounding soft tissues.
• Destruction of the alveolar cortical plates and loss of the
periodontal space are frequently observed in the tooth-
alveolar component. Enlargement of the periodontal
space, displacement of teeth, diastema formation, and
root resorption are also observed.
• When the lesion involves the mandibular canal, destruc-
tion of the cortical plates of the canal is observed.
Pathology
Gross Features
• Gross features vary greatly and depend on the formation
and mineralization of tumoral osteoid or bone and the
predominant cell differentiation pattern.
• Images of the surgical specimen must be obtained in order
to define the cutting planes and adequate resection mar-
gins to evaluate possible recurrence.
Histopathological Features
• Microscopic examination reveals tumor bone or osteoid
formed by atypical cells. The main cellular differentiation
patterns are osteoblastic, chondroblastic, and fibroblastic,
and more than one pattern can occur in the same tumor.
Myxoid, fibrohistiocytic, epithelioid, small cell, and rich
in giant cell patterns are less frequently observed.
• The osteoblastic subtype shows osteoid matrix and/or
immature tumor bone formation. The neoplastic cells,
which produce the tumor bone, are pleomorphic and have
M.L. Paparella and R.L. Cabrini
hyperchromatic nuclei sometimes exhibiting an increase
in the number of mitoses, including atypical images.
Infiltration of bone marrow and replacement with neo-
plastic cells and destruction of the previously existing
laminar trabeculae are observed; deposition of tumor
bone upon previously existing normal bone trabeculae
(scaffolding) can also occur. When a considerable amount
of tumor matrix is produced, the neoplastic cells in the
matrix are usually small with pyknotic nuclei and mini-
mal atypia.
• Most osteosarcomas of the jaws have areas of chondro-
blastic differentiation. Nevertheless, extensive areas of
chondroid matrix must be present to establish diagnosis
of chondroblastic osteosarcoma. The cells in the areas of
chondroblastic differentiation are arranged in a lobulated
structure. In the center of these lobulated areas, the atypi-
cal chondrocytes are inside lacunar spaces and surrounded
by neoplastic hyaline cartilage, with different degrees of
mineralization. The peripheral areas show greater cellu-
larity and tumor osteoid formation. The finding of these
areas, however small, is determinant for diagnosis and
rules out chondrosarcoma.
• Irrespective of the cell differentiation pattern, most osteo-
sarcomas of the jaws have a lesser degree of histological
malignancy than osteosarcomas of long bones.
Prognosis
• Unless surgical treatment is undertaken, prognosis is bad
and death is usually related to local invasion.
• Metastases are rare and are usually observed in advanced
stages of the disease.
• Prognosis depends on obtaining tumor-free surgical mar-
gins (which is directly related to tumor size, anatomical
localization, and surgical accessibility), controlling local
invasion, and the presence/absence of metastases.
• Statistical data on survival at 5 years vary greatly, with
values ranging from 5 % to 80 %.
Treatment
• The treatment of choice is surgery, with wide resection
margins of 1.5–2 cm.
• There are no precise data on the effectiveness of chemo-
therapy or radiotherapy; the latter treatments are used in
cases of incomplete excision, margin involvement, or
inoperable or recurrent tumors.
Images
See Figs. 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, and 12.8 for
illustrations of osteosarcoma of the jaws.
12 Osteosarcoma of the Jaws 209

Fig. 12.1 Periapical and occlusal radiographs showing a mixed lesion with ill-defined borders in the alveolar ridge, with destruction of the
alveolar cortical plate

Fig. 12.2 Periapical and occlusal radiographs showing a well-defined mixed lesion in the alveolar ridge, between the central incisors, with
displacement of teeth
210 M.L. Paparella and R.L. Cabrini

Fig. 12.3 Lateral craniofacial and occlusal radiographs exhibiting a sclerotic radiodense lesion in the maxilla

Fig. 12.4 MR images evidencing a large radiolucent lesion in the ascending ramus
12 Osteosarcoma of the Jaws 211

Fig. 12.5 CT scan images showing a large tumor involving the maxilla and maxillary sinus with extension into the soft tissues
212 M.L. Paparella and R.L. Cabrini

Fig. 12.6 CT scan images showing destruction of the lingual plate and tumor invasion into soft tissues of the floor of the mouth

Fig. 12.7 Gross specimen and radiograph images of the specimen

12 Osteosarcoma of the Jaws 213

Fig. 12.8 Microscopic images of osteosarcoma of the jaw (hematoxy- (c) fibroblastic pattern, (d) stellate myxoid cells, (e) fibrohistiocytic pat-
lin-eosin). (a) Note atypical cell proliferation and osteoid matrix forma- tern, and (f) epithelioid pattern
tion, (b) atypical chondroid tissue with cell and nuclear pleomorphism,
214 M.L. Paparella and R.L. Cabrini

Fig. 12.8 (continued)

12 Osteosarcoma of the Jaws 215

Fig. 12.8 (continued)

216
d e
Fig. 12.8 (continued)
Recommended Reading
Bennett J, Thomas G, Evans A, Speight P. Osteosarcoma of the jaws: a
30-year retrospective review. Oral Surg Oral Med Oral Pathol Oral
Radiol Endod. 2000;90:323–33.
Bertoni F, Dallera P, Bacchini P, Marchetti C, Campobassi A. The
Istituto Rizzoli Beretta experience with osteosarcoma of the jaw.
Cancer. 1991;68:1555–63.
Clark J, Unni K, Dahlin D, Devin K. Osteosarcoma of the jaw. Cancer.
1983;51:2311–6.
Dahlin D, Coventry M. Osteogenic sarcoma: a study of six hundred
cases. J Bone Joint Surg. 1967;49:101–10.
Dahlin D, Unni K. Osteosarcoma of bone and its important recogniz-
able varieties. Am J Surg Pathol. 1977;1:61–72.
Fletcher C, Unni K, Mertens F. World Health Organization Classification
of Tumours. Pathology and genetics tumours of soft tissue and bone.
Lyon: International Agency for Research on Cancer (IARC); 2002.
M.L. Paparella and R.L. Cabrini
Garrington G, Scofield H, Cornyn J, Hooker S. Osteosarcoma of the
jaw. Analysis of 56 cases. Cancer. 1967;20:377–91.
Ha P, Eisele D, Frassica F, Zahurak M, McCarthy E. Osteosarcoma of
the head and neck: a review of the Johns Hopkins experience.
Laryngoscope. 1999;109:964–9.
Kassir R, Rassekh C, Kinsella J, Segas J, Carrau R, Hokanson J.
Osteosarcoma of the head and neck: meta-analysis of nonrandom-
ized studies. Laryngoscope. 1997;107:56–61.
Paparella ML, Olvi LG, Brandizzi D, Keszler A, Santini Araujo E,
Cabrini RL. Osteosarcoma of the jaw: an analysis of 74 cases.
Histopathology. 2013;63:551–7. doi:10.1111/his.12191.
Raymond A, Spires J, Ayala A, Chawla S, Lee Y, Benjamin R, et al.
Osteosarcoma of head and neck. Lab Invest. 1989;60:76A.
Saito K, Unni K. Osteosarcoma of the jaw bones. Int J Oral Maxillofac
Surg. 1999;28:34.
Schajowicz F. Histological typing of tumours of bone. WHO interna-
tional histological typing of tumours. Berlin: Springer; 1993.
 Parosteal Osteosarcoma
13
Carrie Y. Inwards and Doris Wenger

Abstract
Parosteal osteosarcoma is a low-grade, malignant, bone-forming tumor that arises on the
surface of bone. It has a slight female predominance. 60 % are diagnosed in the third and
fourth decades of life. The vast majority involve the metaphysis of the femur, humerus, or
tibia. Radiologically, it is a large, heavily mineralized mass with lobulated morphology
adherent to the cortex in the metaphyseal region of the underlying bone. Histologically, the
lesion shows long trabeculae of woven bone arranged in a parallel-oriented pattern sur-
rounded by a hypocellular population of minimally atypical spindle cells in collagenous
stroma.

Definition Etiology

• A low-grade, malignant, bone-forming tumor that arises • Unknown

on the surface of bone

Clinical Features
Synonyms
Epidemiology
• Juxtacortical osteosarcoma, juxtacortical low-grade
osteosarcoma • The most common type of surface osteosarcoma
• 4 % of all osteosarcomas
• 1 % of primary malignant bone tumors

Sex
C.Y. Inwards, MD (*) • Slight female predominance
Division of Anatomic Pathology, Mayo Clinic,
Rochester, MN, USA
College of Medicine, Mayo Clinic, Rochester, MN, USA
e-mail: inwards.carrie@mayo.edu Age
D. Wenger, MD
Department of Diagnostic Radiology, Mayo Clinic, • 60 % diagnosed in the third and fourth decades of life.
Rochester, MN, USA • Mean age is 28 years.

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 217
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_13, © Springer-Verlag London 2015
218 C.Y. Inwards and D. Wenger

Sites of Involvement • Mass is typically heavily mineralized throughout, includ-

ing the surface.
• The vast majority involve the metaphysis of the femur, • Underlying cortex often thickened with thick indolent
humerus, or tibia. periosteal new bone formation.
• The most common location is the posterior distal • Large tumors encircle the bone.
femur.
• Rare sites included the craniofacial bones, clavicle, pelvis,
and spine. CT Features

• Large heavily mineralized mass attached to the surface of

Signs and Symptoms the bone.
• May show clear space between mass and cortex as the
• Slowly enlarging swelling or mass mass encircles the bone.
• Occasionally pain in the region of the mass • Minimal unmineralized soft tissue component.
• Significant unmineralized peripheral soft tissue mass or
significant intramedullary component raises concern for
Imaging Findings dedifferentiation.

Radiographic Features
MRI Features
• Large, heavily mineralized mass with lobulated morphol-
ogy adherent to the cortex in the metaphyseal region of • Ossified regions have low signal intensity on T1- and
the underlying bone. T2-weighted images.
13 Parosteal Osteosarcoma
• Focal unmineralized area with predominantly high signal
intensity on T2-weighted images or significant intramed-
ullary involvement raises concern for dedifferentiation.
• The most useful modality to assess the status of medul-
lary involvement (approximately 50 % of tumors), usu-
ally representing <25 % of the cross-sectional area.
Bone Scan
• Increased uptake
Imaging Differential Diagnosis
Myositis Ossificans
• May or may not be attached to the cortex, but with epicen-
ter in muscle
• More mineralized peripherally due to zonation pattern of
ossification
• Often contain internal fat on MRI or CT indicative of
mature benign ossification
Osteochondroma
• Continuity of the cortical and cancellous bone between
the lesion and the parent bone
Pathology
Gross Features
• Heavily ossified, hard, tan-white, somewhat lobulated
mass attached to the underlying cortical bone.
• Occasionally the tumor wraps around underlying bone.
• Approximately 50 % contain white-gray areas of hyaline
cartilage located either on the surface, a feature mimick-
ing osteochondroma, or within the tumor.
• Invasion of medullary cavity in 25–40 % of low-grade
tumors and up to 50 % of dedifferentiated tumors.
• Soft, fleshy areas may correspond to progression (dedif-
ferentiation) to a high-grade sarcoma.
• Size usually ranges between 4 and 10 cm in greatest
dimension.
Histological Features
• Long trabeculae of woven bone arranged in a parallel-
oriented pattern surrounded by a hypocellular population
219
of minimally atypical spindle cells in collagenous
stroma.
• Rare mitotic figures.
• Fascicles of cells with elongated nuclei with little to no
abnormal chromatin.
• Spindle cell component with moderate cellularity and
cytologic atypia in a minority of tumors.
• Varied appearances of bone include prominent cement
lines (“pagetoid appearance”), irregularly shaped trabecu-
lae (fibrous dysplasia-like), solid areas, and an anasto-
mosing pattern.
• Hyaline cartilage with minimal atypia to low-grade
malignant features presents as a cap (“osteochondroma-
like”) or islands within the tumor.
• Adipose tissue, with or without bone marrow, situated
between bone trabeculae in 15 % of tumors.
• Areas of dedifferentiation to a high-grade sarcoma
(osteosarcoma, spindle cell sarcoma, or undifferenti-
ated pleomorphic sarcoma) in 15–43 % of tumors.
Occurs at initial diagnosis or more commonly in recur-
rent tumor.
Histologic Differential Diagnosis
Osteochondroma
• Intertrabecular spaces filled with fatty hematopoietic
marrow devoid of a spindle cell component
• Benign cartilage cap in all tumors
Heterotopic Ossification
• Zonated maturation of spindle cell component into the
bone
• Hypercellular spindle cell component with brisk mitotic
activity
Osteoma
• Dense, mature cortical-type bone throughout the tumor
• No cartilage component
Ancillary Studies
Immunohistochemistry
• Coupling of MDM2 and CDK4 immunostains reportedly
shows variable amounts of nuclear positivity for at least
one marker in approximately 90 % of cases.
220 C.Y. Inwards and D. Wenger

Genetics Treatment

• Cytogenetic karyotype shows one or more supernumerary • Surgical resection with a wide margin
ring chromosomes. • Adjuvant chemotherapy for dedifferentiated tumors
• Ring chromosomes contain amplified material from chro-
mosomal region 12q13-15.
• Target genes MDM2 and CDK4 amplified in up to 85 % Images
of tumors.
See Figs. 13.1, 13.2, 13.3, 13.4, 13.5, 13.6, 13.7, 13.8, 13.9,
13.10, 13.11, 13.12, and 13.13 for illustrations of parosteal
Prognosis osteosarcoma.

• Almost no capacity for metastasis

• Medullary involvement not associated with a poorer
prognosis
• Metastatic rate of 28–47 % for dedifferentiated tumors
13 Parosteal Osteosarcoma 221

Fig. 13.1 Parosteal a b

osteosarcoma. (a) AP radiograph
of the left humerus of a
27-year-old female shows a
heavily mineralized mass
involving a long segment of the
humerus that extends from the
proximal metaphysis to the distal
diaphysis. The coronal CT (b),
coronal T1-weighted MR (c), and
coronal fat-suppressed
T2-weighted MR (d) images
show that the mass involves the
surface of the bone with no
evidence of medullary
involvement. The T2-weighted
image (d) shows reactive edema
in the medullary canal of the
humerus, but the coronal
T1-weighted MRI shows
preservation of marrow fat signal,
confirming the lack of tumor
involvement of the medullary
canal. The predominantly low
signal intensity of the mass on T2
correlates with the heavily
c d e
mineralized tumor matrix. The
axial CT (e) shows the heavily
mineralized mass encircling the
humeral diaphysis

a b

Fig. 13.2 Parosteal sarcoma.

Axial and sagittal CT images
(a, b) of the distal right femur of
a 62-year-old male show a
heavily mineralized mass along
the posterior aspect of the distal
femoral metadiaphysis. The mass
is intimately associated with the
surface of the bone and shows no
evidence of medullary
involvement
222 C.Y. Inwards and D. Wenger

Fig. 13.3 Dedifferentiated a c

parosteal osteosarcoma. AP b
radiograph (a) and axial
unenhanced CT (b) of the
humerus of a 19-year-old female
show a heavily mineralized mass
on the surface of the mid-
humeral diaphysis with osteoid
matrix and marked associated
cortical thickening typical of a
parosteal osteosarcoma. In
addition, there is an ill-defined
sclerotic lesion in the shaft of the
humerus just distal to the e
d
dominant parosteal mass. The
axial CT through the latter region
confirms that this represents a
sclerotic intramedullary lesion
with osteoid matrix (c). The
sagittal T1 (d) and sagittal STIR
(e) MR images nicely illustrate
that there are two distinct
components of the lesion, which
raises the possibility of
dedifferentiation of the parosteal
osteosarcoma

Fig. 13.5 Parosteal osteosarcoma forming a broad-based attachment

to the surface of the distal femur. A gray-white area peripherally repre-
sents a hyaline cartilaginous cap. The thickened underlying cortical
bone is associated with periosteal new bone formation

Fig. 13.4 Parosteal osteosarcoma forming a tan-white solid mass

attached to the posterior surface of the distal femur
13 Parosteal Osteosarcoma 223

a b

Fig. 13.6 Low (a) and intermediate magnification (b) of parosteal osteosarcoma demonstrating long trabeculae of woven bone (“streamers”)
arranged parallel to each other. The bone is surrounded by a hypocellular population of bland spindle cells

Fig. 13.7 The tumor cells of parosteal osteosarcoma showing no cyto- Fig. 13.8 An area in parosteal osteosarcoma containing irregularly
logic atypia shaped trabeculae of bone in a pattern that resembles fibrous dysplasia
224 C.Y. Inwards and D. Wenger

a b

Fig. 13.9 (a, b) Parosteal osteosarcoma with thickened trabeculae of woven bone containing cement lines. This pattern resembles Paget disease

a b

Fig. 13.10 (a) Parosteal osteosarcoma composed of broad areas with (left) and without (right) bone production. (b) The spindle-shaped tumor
cells contain mild to moderately enlarged nuclei
13 Parosteal Osteosarcoma 225

Fig. 13.11 Parosteal osteosarcoma with a cartilage cap resembling Fig. 13.12 Island of hyaline cartilage within the central portion of a
osteochondroma. However, the underlying trabeculae of bone are sur- parosteal osteosarcoma
rounded by stroma containing bland spindle cells rather than fat and
hematopoietic marrow characteristic of osteochondroma

a b

Fig. 13.13 Dedifferentiated parosteal osteosarcoma. (a) Low magnifi- trating this area of dedifferentiation characterized by cytologic pleo-
cation shows a broad hypercellular zone containing cells with cytologic morphism and an atypical mitotic figure
atypia within a parosteal osteosarcoma. (b) Higher magnification illus-
226 C.Y. Inwards and D. Wenger

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Orlando C, Bacchini P, Pazzagli M, Picci P. Analysis of 12q13–15
Temple HT, Scully SP, O'Keefe RJ, Katapurum S, Mankin HJ. Clinical
genes in parosteal osteosarcoma. Clin Orthop Relat Res. 2000;(377):
outcome of 38 patients with juxtacortical osteosarcoma. Clin Orthop
195–204.
Relat Res. 2000;373:208–17.
Jelinek JS, Murphey MD, Kransdorf MJ, Shmookler BM, Malawer
Unni KK, Dahlin DC, Beabout JW, Ivins JC. Parosteal osteogenic sar-
MM, Hur RC. Parosteal osteosarcoma: value of MR imaging and
coma. Cancer. 1976;37(5):2466–75.
CT in the prediction of histologic grade. Radiology. 1996;201(3):
Wold LE, Unni KK, Beabout JW, Sim FH, Dahlin DC. Dedifferentiated
837–42.
parosteal osteosarcoma. J Bone Joint Surg Am. 1984;66(1):53–9.
Mejia-Guerrero S, Quejada M, Gokgoz N, Gill M, Parkes RK, Wunder
Yoshida A, Ushiku T, Motoi T, Shibata T, Beppu Y, Fukayama M,
JS, Andrulis IL. Characterization of the 12q15 MDM2 and 12q13-
Tsuda H. Immunohistochemical analysis of MDM2 and CDK4
14 CDK4 amplicons and clinical correlations in osteosarcoma.
distinguishes low-grade osteosarcoma from benign mimics. Mod
Genes Chromosomes Cancer. 2010;49(6):518–25.
Pathol. 2010;23(9):1279–88.
Okada K, Frassica FJ, Sim FH, Beabout JW, Bond JR, Unni KK.
Yoshida A, Ushiku T, Motoi T, Beppu Y, Fukayama M, Tsuda H,
Parosteal osteosarcoma. A clinicopathological study. J Bone Joint
Shibata T. MDM2 and CDK4 immunohistochemical coexpression
Surg Am. 1994;76(3):366–78.
in high-grade osteosarcoma: correlation with a dedifferentiated
Revell MP, Deshmukh N, Grimer RJ, Carter SR, Tillman RM. Periosteal
subtype. Am J Surg Pathol. 2012;36(3):423–31.
osteosarcoma: a review of 17 cases with mean follow-up of 52
months. Sarcoma. 2002;6(4):123–30.
 Periosteal Osteosarcoma
14
Carrie Y. Inwards and Doris Wenger

Abstract
Periosteal osteosarcoma is an intermediate-grade chondroblastic osteosarcoma arising on
the surface of the bone. It has a slight female predominance. Majority of patients are in the
second and third decades of life. The median age is 18 years and average age 22 years. The
most common location is the femur followed by the tibia. Less common sites include the
humerus, fibula, ulna, and pelvis. Majority involve the diaphyseal region of the bone.
Radiologically, the image shows a broad-based attachment of mass to the cortex in the
diaphyseal region of the long bone. Histologically, it predominately contains lobules of
malignant hyaline cartilage with obvious cytologic atypia. Peripheral condensation and
spindling of the tumor cells are commonly seen. Lesser amount of malignant osteoid, often
in the form of spicules arrayed perpendicular to the cortical surface, is usually found in the
center of the cartilage lobules. Treatment is surgical resection with a wide margin. The role
of neoadjuvant and adjuvant chemotherapy is unclear.

Definition Clinical Features

• An intermediate-grade chondroblastic osteosarcoma aris- Epidemiology

ing on the surface of the bone
• One to two percent of all osteosarcomas

Synonyms Sex
• Slight female predominance
• Juxtacortical chondroblastic osteosarcoma
Age
Etiology • Majority of patients are in the second and third decades of
life.
• Unknown • Median age: 18 years; average age: 22 years.

C.Y. Inwards, MD (*)

Division of Anatomic Pathology, Mayo Clinic,
Sites of Involvement
Rochester, MN, USA
• The most common location is the femur followed by the
College of Medicine, Mayo Clinic, Rochester, MN, USA
e-mail: inwards.carrie@mayo.edu tibia.
• Less common sites include the humerus, fibula, ulna, and
D. Wenger, MD
Department of Diagnostic Radiology, Mayo Clinic, pelvis.
Rochester, MN, USA • Majority involve the diaphyseal region of the bone.

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 227
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_14, © Springer-Verlag London 2015
228
Clinical Signs and Symptoms
• Swelling or mass and pain
Image Diagnosis
Radiographic Features
• Broad-based attachment of mass to the cortex in the
diaphyseal region of the long bone
• Cortical thickening and scalloping of the underlying bone
• Periosteal reaction, aggressive and nonaggressive, frequently
perpendicular to the osseous long axis (the so-called “hair on
end” appearance) extending into surrounding soft tissue
CT Features
• Heterogeneous mass intimately associated with the peri-
osteal surface of the bone with mineralized and nonmin-
eralized components
• Cortical thickening and periosteal reaction at the site of
attachment
• Variable degree of mineralization of the mass, with min-
eralization typically more marked near the base
• Nonmineralized component may be of low attenuation
reflecting myxoid change within the chondroid tissue
• Well-defined margins
MRI Features
• Heterogeneous solid mass with mixed signal characteris-
tics on T1 and T2. Soft tissue component often has signal
intensity which is isointense or hypointense relative to
muscle on T1-weighted images, heterogeneous but pre-
dominately hyperintense signal intensity on T2-weighted
images, and prominent regions with minimal to no
enhancement with gadolinium reflecting the myxoid
component of the chondroid tissue.
• Well-defined margins.
• Cortical thickening and scalloping.
• Areas of poorly marginated hazy abnormal signal inten-
sity (low signal on T1-weighted images and high signal
on T2-weighted images) in the soft tissues and marrow
about the mass compatible with reactive change.
Bone Scan
• Marked uptake of radionuclide, eccentrically positioned
on the bone
C.Y. Inwards and D. Wenger
Imaging Differential Diagnosis
Parosteal Osteosarcoma
• Involves the metaphyseal region of the underlying
bone
• More heavily mineralized with mineralization throughout
the entire lesion, including the surface of the mass
Parosteal Chondrosarcoma
• Involves the metaphyseal region of the underlying
bone
• Lacks perpendicular periosteal reaction
High-Grade Surface Osteosarcoma
• Usually surrounds a greater amount of the bone
circumference
• Lacks features of myxoid change suggestive of cartilagi-
nous component (low attenuation at CT, hyperintense sig-
nal intensity on T2-weighted and minimal enhancement
on gadolinium-enhanced MR images)
Pathology
Gross Features
• Firm, lobulated gray-white mass resembling cartilage.
• Broad-based attachment to the underlying bone.
• Tumor wraps around the underlying bone with occasional
full circumferential envelopment.
• Well-defined outer pushing margin.
• Focal cortical erosion by the tumor with minimal medul-
lary invasion only rarely present.
• Average size: 10 cm.
Histological Features
• Predominately contains lobules of malignant hyaline car-
tilage with obvious cytologic atypia. Peripheral conden-
sation and spindling of the tumor cells are commonly
seen.
• Cartilage matrix may contain areas with myxoid
change.
• Lesser amount of malignant osteoid, often in the form
of spicules arrayed perpendicular to the cortical sur-
face, is usually found in the center of the cartilage
lobules.
14 Periosteal Osteosarcoma
• Occasionally, areas composed of malignant spindle cells,
with or without osteoid formation, blend with the hyaline
cartilage portion of the tumor.
• The degree of cytologic atypia places these tumors into an
intermediate-grade osteosarcoma.
Pathologic Differential Diagnosis
Parosteal Osteosarcoma
• Predominately composed of low-grade fibro-osseous tis-
sue. Low-grade cartilage a minor component
Parosteal Chondrosarcoma
• Entire tumor composed of malignant hyaline cartilage
with or without focal areas of bland metaplastic bone
formation
High-Grade Surface Osteosarcoma
• Composed of high-grade tumor cells producing abundant
malignant osteoid
Bizarre Parosteal Osteochondromatous
Proliferation
• Contains a cytologically benign cartilage cap that under-
goes enchondral ossification to trabeculae of the bone sur-
rounded by a bland fibrovascular stroma
229
Osteochondroma
• Benign cartilage cap undergoing enchondral ossification
into benign underlying trabeculae of the bone surrounded
by fatty marrow
Genetics
• No consistent cytogenetic abnormalities
Prognosis
• Better prognosis when compared to intramedullary con-
ventional osteosarcoma
• Overall 5-year and 10-year survival of 89 % and 84 %,
respectively
• Local recurrence uncommon, but associated with a higher
incidence of metastases and death
Treatment
• Surgical resection with a wide margin
• Amputation only if an adequate surgical margin cannot be
achieved by en bloc resection
• Role of neoadjuvant and adjuvant chemotherapy unclear
Images
See Figs. 14.1, 14.2, 14.3, 14.4, 14.5, 14.6, 14.7, and 14.8 for
illustrations of periosteal osteosarcoma.
230 C.Y. Inwards and D. Wenger

Fig. 14.1 AP radiograph (a) of

a b
a 15-year-old male shows a
region of cortical thickening,
aggressive periosteal reaction,
and subtle matrix production
along the medial aspect of the
proximal tibial diaphysis with the
suggestion of an associated
unmineralized soft tissue mass.
The axial and sagittal T1 (b, d)
and axial and sagittal fat-
suppressed T2 weighted (c, e)
MR images show that the mass
involves the surface of the bone
without involvement of the
medullary canal. The mass is
heterogeneous with a region of
predominantly low T2 signal
intensity near the attachment to
the cortex that correlates with the
periosteal reaction and matrix
production on the radiograph. In
addition, there is an
unmineralized component to the
soft tissue mass with nonspecific c
intermediate T1 and hyperintense
T2 signal
14 Periosteal Osteosarcoma 231

Fig. 14.1 (continued)

d e

Fig. 14.3 Periosteal osteosarcoma showing histological features of a

chondroblastic osteosarcoma. The malignant osteoid forms spicules of
bone arranged perpendicular to the surface of the underlying cortical
bone

Fig. 14.2 Periosteal osteosarcoma forming a surface-based mass

involving the diaphyseal portion of the underlying bone. The tumor
contains zones of gray-white tissue reflecting areas of cartilaginous
differentiation
232 C.Y. Inwards and D. Wenger

Fig. 14.4 Periosteal osteosarcoma composed of an intermediate-grade Fig. 14.7 Spicules of malignant osteoid within the central portion of a
chondroblastic osteosarcoma cartilaginous nodule in periosteal osteosarcoma

Fig. 14.5 The predominant tissue type in periosteal osteosarcoma is Fig. 14.8 Peripheral condensation of tumor cells at the periphery of
malignant hyaline cartilage the cartilaginous nodules is frequently seen in periosteal osteosarcoma

Fig. 14.6 Periosteal osteosarcoma containing nodules of malignant

hyaline cartilage permeating peripheral portions of fibrous tissue
14 Periosteal Osteosarcoma 233

Recommended Reading Murphey MD, Jelinek JS, Temple HT, Flemming DJ, Gannon
FH. Imaging of periosteal osteosarcoma: radiologic-pathologic
comparison. Radiology. 2004;233(1):129–38. Epub 2004 Aug 27.
Cesari M, Alberghini M, Vanel D, Palmerini E, Staals EL, Longhi A,
Revell MP, Deshmukh N, Grimer RJ, Carter SR, Tillman RM. Periosteal
et al. Periosteal osteosarcoma: a single-institution experience.
osteosarcoma: a review of 17 cases with mean follow-up of
Cancer. 2011;117(8):1731–5. doi:10.1002/cncr.25718. Epub 2010
52 months. Sarcoma. 2002;6(4):123–30.
Nov 8.
Rose PS, Dickey ID, Wenger DE, Unni KK, Sim FH. Periosteal osteo-
Grimer RJ, Bielack S, Flege S, Cannon SR, Foleras G, Andreeff I,
sarcoma: long-term outcome and risk of late recurrence. Clin
European Musculo Skeletal Oncology Society, et al. Periosteal
Orthop Relat Res. 2006;453:314–7.
osteosarcoma–a European review of outcome. Eur J Cancer.
Unni KK, Dahlin DC, Beabout JW. Periosteal osteogenic sarcoma.
2005;41(18):2806–11. Epub 2005 Nov 14.
Cancer. 1976;37(5):2476–85.
 High-Grade Surface Osteosarcoma
15
Carrie Y. Inwards and Doris Wenger

Abstract
High-grade surface osteosarcoma is a high-grade bone-forming neoplasm which arises on
the surface of the bone. It has a male predominance. Peak incidence is in the second decade
of life. A majority of patients are in the second and third decades of life. Radiologically, the
lesion presents a large mass with a broad-based attachment to the underlying bone. There is
a dense to moderate mineralization with a fluffy immature appearance. There is partial cor-
tical destruction and periosteal new bone. Histologically, it is identical to conventional
osteosarcoma (osteoblastic, chondroblastic, fibroblastic subtypes). All tumors are high
grade. Treatment consists of neoadjuvant chemotherapy followed by surgical resection with
a wide margin.

Definition Clinical Features

• A high-grade bone-forming neoplasm that arises on the Epidemiology

surface of bone
• <1 % of all osteosarcoma
• The least common type of surface osteosarcoma
Synonyms
Sex
• High-grade juxtacortical osteosarcoma • Male predominance

Age
Etiology • Peak incidence in the second decade of life
• Majority of patients in the second and third decades of life
• Unknown

C.Y. Inwards, MD (*)

Division of Anatomic Pathology, Mayo Clinic,
Sites of Involvement
Rochester, MN, USA
• Located on the surface of the bone
College of Medicine, Mayo Clinic, Rochester, MN, USA
e-mail: inwards.carrie@mayo.edu • Most commonly involves the femur followed by the tibia
and humerus
D. Wenger, MD
Department of Diagnostic Radiology, Mayo Clinic, • Arises in the diaphyseal region of the underlying bone.
Rochester, MN, USA Less commonly in the diaphyseal-metaphyseal region

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 235
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_15, © Springer-Verlag London 2015
236
Clinical Signs and Symptoms
• Mass or swelling
• Pain
Image Diagnosis
Radiographic Features
• Large mass with a broad-based attachment to the
underlying bone.
• Dense to moderate mineralization with a fluffy immature
appearance.
• Partial cortical destruction and periosteal new bone.
• Ill-defined soft tissue margin.
• Average maximum dimension is 11 cm.
• Large tumors encircle the bone.
CT Features
• Heterogeneous mass composed of high-density mineral-
ized areas and low-density nonmineralized areas
• Useful in delineating extent of tumor
• Minimal medullary involvement in approximately 50 %
of tumors
MRI Features
• Heterogeneous appearance with mixed low- and high-
signal intensity on T1- and T2-weighted images
• Useful for delineating anatomic extent of tumor, particu-
larly medullary canal involvement
Bone Scan
• Increased uptake
Imaging Differential Diagnosis
Periosteal Osteosarcoma
• Similar anatomic location and imaging findings
• More frequently demonstrate imaging findings consistent
with cartilaginous tissue
C.Y. Inwards and D. Wenger
Parosteal Osteosarcoma
• More heavily and homogeneously mineralized from base
to periphery.
• The radiolucent zone that can be seen between the tumor
and underlying bone is not typically seen in high-grade
surface osteosarcoma.
• More commonly involves the metaphyseal region of the
underlying bone.
Pathology
Gross Features
• Lobulated mass situated on the surface of the bone
associated with cortical erosion.
• The vast majority of the tumor is located outside the bone
with only minimal medullary involvement.
• Heterogeneous cut surface reflecting varied tissue types
such as ossified areas, firm; cartilaginous areas, gray
white; fibrous areas, soft or rubbery tan white.
Histological Features
• Identical to conventional osteosarcoma (osteoblastic,
chondroblastic, fibroblastic subtypes).
• All tumors are high grade.
• No areas of low-grade osteosarcoma (dedifferentiated
parosteal osteosarcoma).
Histologic Differential Diagnosis
Parosteal Osteosarcoma
• Entire tumor is low-grade osteosarcoma.
• Cartilaginous areas are low grade.
Periosteal Osteosarcoma
• An intermediate-grade osteosarcoma
• Greater amount of malignant cartilage component than
malignant bone-forming component
15 High-Grade Surface Osteosarcoma 237

Genetics Treatment

• Unknown due to lack of published reports. • Neoadjuvant chemotherapy followed by surgical resec-
• MDM2 and CDK4 amplification supports a diagnosis of tion with a wide margin
dedifferentiated parosteal osteosarcoma over high-grade
surface osteosarcoma.
Images

Prognosis See Figs. 15.1, 15.2, 15.3, 15.4, and 15.5 for illustrations of
high-grade surface osteosarcoma.
• Similar to conventional osteosarcoma
• Five-year disease-free survival: 70 %
• Overall 5-year survival: 82 %
238
a b
d e
Fig. 15.1 AP radiograph of the left humerus (a) of a 29-year-old
female with a high-grade surface osteosarcoma shows a mixed density,
partially mineralized mass involving the mid and proximal humeral
diaphysis with mineral pattern indicative of osteoid matrix. Axial soft
tissue (b) and coronal bone (c) CT images nicely illustrate that the
lesion is attached to the cortex of the humerus and is markedly hetero-
geneous with areas of osteoid and soft tissue attenuation. Although
C.Y. Inwards and D. Wenger
c
f
somewhat more heavily mineralized near the attachment to the bone,
the mineral is scattered throughout the mass. Coronal T1-weighted
images (d and e) show preservation of the marrow fat signal in the adja-
cent humeral diaphysis and, therefore, confirm lack of tumor involve-
ment in the medullary canal. Axial fat-suppressed T2-weighted MR
images (f and g) show the anatomic extent of the mass in the soft tissues
with large heterogeneous bulky tumor masses posteriorly and medially
15 High-Grade Surface Osteosarcoma 239

Fig. 15.4 This high-grade surface osteosarcoma contains cartilagi-

nous differentiation, consistent with chondroblastic osteosarcoma

Fig. 15.2 Large high-grade surface osteosarcoma encircling most of

the underlying femur. There is no intramedullary invasion

Fig. 15.5 High-grade surface osteosarcoma with microscopic features

of osteoblastic osteosarcoma. The histological features are identical to
those of an intramedullary conventional osteoblastic osteosarcoma,
high grade

Fig. 15.3 High-grade surface osteosarcoma showing features of osteo-

blastic osteosarcoma, high grade. The tumor contains abundant malig-
nant osteoid intimately associated with pleomorphic tumor cells
240 C.Y. Inwards and D. Wenger

Recommended Reading Vanel D, Picci P, De Paolis M, Mercuri M. Radiological study of 12

high-grade surface osteosarcomas. Skeletal Radiol. 2001;30(12):
667–71. Epub 2001 Aug 30.
Okada K, Unni KK, Swee RG, Sim FH. High-grade surface osteosar-
Wold LE, Unni KK, Beabout JW, Pritchard DJ. High-grade surface
coma: a clinicopathologic study of 46 cases. Cancer. 1999;85(5):
osteosarcomas. Am J Surg Pathol. 1984;8(3):181–6.
1044–54.
Staals EL, Bacchini P, Bertoni F. High-grade surface osteosarcoma: a
review of 25 cases from the Rizzoli Institute. Cancer. 2008;112(7):
1592–9.
 Part III
Cartilage-Forming Tumors
 Enchondroma
16
Yong-Koo Park

Abstract
Enchondroma is a common benign intramedullary neoplasm, composed of mature hyaline
cartilage. Enchondromas account for 10–25 % of all benign bone tumors. It is more fre-
quent in females. Most common from the second to the sixth decades with a peak in the
fourth and fifth decades.
It is most frequently found on the small tubular bones of the hands. Among the long
tubular bones, enchondroma occurs more frequently in the proximal humerus and proximal
and distal femur and tibia. Histological features are variable according to the location of the
lesion. Accordingly, it is very important to consider the location of the lesion together with
the radiological findings and clinical features. Enchondromas are composed of mature hya-
line cartilage arranged in lobules. Cartilaginous lobules are surrounded by normal bone
marrow. When treatment is needed, simple curettage is the appropriate treatment.

Definition Epidemiology

• Enchondroma is a common benign intramedullary
neoplasm, composed of mature hyaline cartilage.
Synonyms
• Enchondromas account for 10–25 % of all benign bone
tumors.
• However, this likely does not reflect its true incidence
since most tumors are detected incidentally, and biopsy is
not performed.

• Chondroma. This term is also applied to benign cartilage

neoplasias of soft tissue or periosteal origin. Sex

• More frequent in females

Etiology

• Unknown Age

• Most common from the second to the sixth decades with

a peak in the fourth and fifth decades

Y.-K. Park, MD, PhD

Department of Pathology, Kyung Hee University School of
Medicine, Seoul, South Korea
e-mail: ykpark0204@gmail.com

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 243
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_16, © Springer-Verlag London 2015
244
Sites of Involvement
• Most frequently on the small tubular bones of the hands,
where it is the most common tumor.
• Among the long tubular bones, enchondroma occurs more
frequently in the proximal humerus and proximal and dis-
tal femur and tibia.
• Rarely involves the pelvic bone, ribs, scapula, or
sternum.
• Enchondroma in the spine is very rare.
• Almost never occurs in the craniofacial bones, that
develop through intramembranous ossification.
Clinical Symptoms and Signs
• Usually found on routine radiologic examination or as hot
spots on the bone scan without specific symptoms.
• The majority is asymptomatic.
• In the hands and feet, enchondromas present as a palpa-
ble swelling with or without pain. In this location, they
Y.-K. Park
are frequently associated with pathological fracture and
pain.
• Chondroid tumors located in hands and feet, in subperios-
teal location, and in the lining of joint capsules are almost
certain to be clinically benign.
• The behavior of a cartilage neoplasm is best predicted
having in mind if the lesion is growing or not. Clinical,
radiographic, and microscopic features should be inter-
preted in the light of this information.
• Enchondromas usually do not grow after puberty.
Image Diagnosis
Radiographic Features
• A sharply defined border, mild endosteal scalloping, and
calcifications resembling a ring or an arc characterize the
radiographic findings of enchondroma of the hand or
foot.
• Spotty calcifications are frequently seen.
16 Enchondroma
• Sometimes, calcifications may be dense (Fig. 16.1).
• Cortical expansion or pathological fracture is a potential
feature, mainly in tumors of the hands and feet.
• Since enchondroma is a common type of benign tumor,
solitary bone lesions with well-defined margins and scal-
lopings of the endosteum in a bone of the hand should be
considered an enchondroma until proven otherwise.
• Enchondroma also shows typical radiological features on
other sites. In long tubular bones, it shows a central or
eccentric location with an osteolytic lesion and calcifica-
tion in the medullary portion. Radiographic findings of
enchondroma appearing in flat or irregular, nontubular
bone may be hard to recognize (Fig. 16.2).
CT Features
• Provides better evaluation of the cortical endosteal sur-
face in medullary located lesions of long tubular bones.
• It is a better technique for the study of lesions located in areas
of difficult radiographic assessment, like the axial skeleton.
MRI Features
• On MRI, the margin of the tumor is well defined by a low
signal intensity on T1-weighted images and a high signal
intensity on T2-weighted images.
• Lobulated margins of the tumor are typical, and also low
signal intensity is seen at the calcified zones.
• The x-ray volume of the enchondroma overlaps the vol-
ume of the lesion as seen on MRI.
Image Differential Diagnosis
Low-Grade Chondrosarcoma
• Differentiating between a low-grade chondrosarcoma and
enchondroma can be challenging, and radiology is a use-
ful adjunct in this process.
• Radiologically, chondrosarcoma of the long bone exhibits
expansion of bone and thickening of the cortex.
• On x-ray and CT of tubular bones, extensive endosteal
scalloping, cortical expansion, cortical thinning or thick-
ening, cortical permeation, and ambiguous matrix calcifi-
cation suggest chondrosarcoma.
• Peripheral marrow edema around the lesion, subperios-
teal edema, and mass in soft tissue, as seen in MRI, are
findings that point toward low-grade chondrosarcoma.
• MRI volume of the lesion bigger than x-ray volume is
also suggestive of malignancy.
245
• Epiphyseal location of the tumor also strongly suggests
chondrosarcoma.
Pathology
Gross Features
• Most enchondromas are curetted, so that it is very rare to
examine an intact gross specimen.
• Most enchondromas show confluent masses of bluish,
semi-translucent hyaline cartilage with a distinct lobular
arrangement.
• The size of the lobule varies from millimeter to 1 cm. It is
very rare to find one greater than 5 cm in size.
• The periphery of the lesion is somewhat irregular, since
individual lobules bulge into the surrounding marrow
spaces.
• Punctuate calcifications seen on radiographic imaging
can be appreciated grossly.
• Multiple enchondromas show a similar gross appearance
to that of solitary tumors. However, in multiple enchon-
dromas, normal marrow elements encircle the well-
circumscribed nodules, which are often mistaken for an
aggressive pattern of permeation.
Histological Features
• Histological features are variable according to the loca-
tion of the lesion. Accordingly, it is very important to con-
sider the location of the lesion together with the
radiological findings and clinical features.
• Enchondromas are composed of mature hyaline cartilage
arranged in lobules.
• Cartilaginous lobules are surrounded by normal bone
marrow (Fig. 16.3).
• Enchondral ossification may also be seen.
• Other lobules of enchondroma are frequently partially
encased by mature lamellar bone.
• In general, there is low cellularity and abundant extracel-
lular matrix (Fig. 16.4). In enchondromas of the hands
and feet, there may be a higher cellularity.
• Usually, chondrocytes are located in lacunae, and the
nucleus has a small round regular appearance. On a low-
power view, the nucleus is hardly visible. Rarely, chon-
drocytes can be seen as clusters or sheets. Occasionally,
chondrocytes can be seen as large cells or double-nucleated
cells (Fig. 16.5) but lacking cytological atypia.
• Calcification can be observed as fine purple-colored gran-
ular precipitate or a big mass (Fig. 16.6).
246
• Prominent myxoid change or necrosis is hardly ever
observed in enchondromas. However, they can be
observed occasionally in the small bones of the hands and
feet. When these histological features are present, even if
the cellularity is low, the possibility of malignancy should
be considered.
• In case of small bones of the hands and feet, to make diag-
nosis of malignancy, there should be extreme hypercellu-
larity, nuclei pleomorphism, and marked myxoid changes.
• Calcifying or ossifying enchondroma is a variant that
sometimes can be present at the metaphyseal region of the
long bone. In this occasion, enchondroma can be seen as
radiologically dense ringlike or flocculent agglomerated
and heavily calcified and ossified radiopacities.
Histologically, the lesion consists of mature hyaline
cartilage and heavily calcified or ossified material with
small scarce cartilage cells.
Pathologic Differential Diagnosis
Low-Grade Chondrosarcoma
• Especially if arising in the metaphysis of the long bone in
middle-aged to elderly patients.
• Grossly, mucoid or myxoid changes are frequently
observed in chondrosarcoma and only rarely in
enchondromas.
• Enchondroma does not show cortical erosion. Also, histo-
logically, increased cellularity, marked myxoid change of
the stroma, and cytologic features of malignancy are
observed in chondrosarcoma.
• Separation of cartilage lobules by fibrous bands is seen in
low-grade chondrosarcoma.
• In addition, the most important differential diagnostic
feature is intramedullary invasion. In chondrosarcoma,
the trabeculae of preexisting bone are embedded in the
tumor tissue – entrapment of native trabeculae.
• Radiographically, enchondromas of the small bones of the
hands and feet show cortical thinning; however, micro-
scopic permeation into the cortical tissue is not observed.
• Enchondromas of the pelvis, spine, ribs, and sternum are
very rare. Chondroid lesions occurring in these locations
should be considered as aggressive cartilage lesions if
they are not reactive or metaplastic in nature.
Fibrous Dysplasia
• Chondroid differentiation observed in fibrous dysplasia is
also different from enchondroma. This can be differenti-
ated on the basis that in fibrochondroid dysplasia, fibro-
osseous elements are found in addition to cartilaginous
nodules.
Y.-K. Park
Ancillary Techniques
Genetics
• Somatic heterozygous mutations in IDH1 or IDH2 in
87 % of enchondromas, 81 % of Ollier disease, and 77 %
of Maffucci syndrome have been reported.
• A diploid pattern with low cell proliferative activity is
present in typical enchondromas using DNA flow cyto-
metric/cytofluorometric studies.
• Diploid or near diploid complements with simple struc-
tural abnormalities in chromosome 6 and 12 using
conventional cytogenetic analysis have also been reported.
• HMGA2 gene has been shown to demonstrate altered
transcriptional activity through various mecha-
nisms in enchondroma, soft tissue chondroma, and
chondrosarcoma.
• A mutant PTH/PTHrp (parathyroid hormone/parathyroid
hormone-related protein) type I receptor in Ollier disease
was identified which sends abnormal signals through the
Indian Hedgehog pathway in vitro and causes
enchondroma-like lesion in transgenic mice. This mutant
receptor constitutively activates Hedgehog signaling, and
excessive Hedgehog signaling is sufficient to cause for-
mation of enchondroma-like lesions.
• Indian Hedgehog (IHH) signaling has been thought to be
critical in normal growth plate cartilage differentiation
and maturation and appears to be absent in enchondro-
mas, while parathyroid-related protein (PTHrP) signaling
is active, independent of IHH signaling.
• Cytogenetic analysis of low-grade chondrosarcoma in a
patient with Ollier disease revealed an interstitial deletion
del(1) (p11p31.2) as the only chromosomal abnormality.
Such patients are thought to be at risk of developing chon-
drosarcoma as del(1p) is frequent in chondrosarcoma.
• In autopsy-based studies of Ollier disease patients, inacti-
vation of putative tumor suppressor genes at 9p21 and
13q14, and overexpression of p53, has also been identi-
fied in chondrosarcomas and their metastasis but absent in
enchondroma.
• The immunohistochemistry, Western analysis, and real-
time RT-PCR showed significantly higher expression of
NOV in enchondromas.
• A correlation between INK4A/p16 protein expression
and tumor grade in malignant cartilaginous tumors
along with the retention of INK4A/p16 expression
in enchondromas indicates that the loss of expression
may be an important event during tumor progression
from enchondroma to conventional central chondrosar-
coma and in the progression in grade after recurrence of
chondrosarcoma.
16 Enchondroma
• Loss of chromosomes 16p, 17p, 22q, or 19 is common in
benign cartilaginous tumors.
• Mutation of Rb in the early mesenchyme of p107-mutant
mice was shown to result in severe cartilage defects in the
growth plates of long bones. It led to inappropriate chon-
drocyte proliferation that persisted after birth and the for-
mation of enchondromas in the growth plates as early as
8 weeks of age of mouse. Genetic crosses revealed that
development of these tumorigenic lesions was E2f3
dependent.
Prognosis
• On very rare occasions, enchondroma can recur several
years later, or when it recurred, it can be low-grade
chondrosarcoma.
Fig. 16.1 The radiograph shows a well-defined osteolytic bone lesion
at the proximal shaft of the proximal phalanx of the third finger. There
are stippled calcifications within lesion
247
Treatment
• It is unnecessary to treat solitary enchondroma of the long
bone or flat bones found incidentally. In this instance,
radiological follow-up is necessary.
• On any occasion, when treatment is needed, simple curet-
tage is the appropriate treatment.
• Radiographically, if the lesion is benign or very low-grade
malignant, it should be removed completely.
• Most of the enchondromas of the small bones of the hands
and feet must be treated because of the possibility of path-
ological fracture.
Images
See Figs. 16.1, 16.2, 16.3, 16.4, 16.5, 16.6, 16.7, 16.8, 16.9,
and 16.10 for illustrations of enchondroma.
Fig. 16.2 The radiograph of distal femur shows conglomeration of
stippled calcification in the medullary cavity. The endosteal margins are
normal in appearance
248 Y.-K. Park

Fig. 16.3 Low power shows lobular hyaline cartilage tumor with sharp Fig. 16.4 At low-power view, the hyaline cartilage tumors are blue-
circumscription by normal trabecular bone gray in color. Chondromas show a lobulated pattern with low
cellularity

Fig. 16.5 At higher-power view, the cytologic features of the chondro- Fig. 16.6 Occasionally at the periphery of the cartilage lobule, calcifi-
cytes are small dark nuclei, single nucleus in a lacunar space cation is evident

Fig. 16.7 Enchondroma. Encasing of neoplastic cartilage nodule by

newly formed bone
16 Enchondroma 249

Fig. 16.8 Enchondroma tissue growing in medular space, without

involvement of the bone cortex

a b

Fig. 16.9 (a) Radiograph of a lytic enchondroma in the meta-diaphysis of a humerus. (b) MRI, T2-weighted image, of same lesion. The radio-
graphic volume of the lesion overlaps with that of the MRI
250
Fig. 16.10 Radiograph and T2-weighted MRI of an enchondroma of the humeral metaphysis
Recommended Reading
Alho A, Skjeldal S, Pettersen EO, et al. Aneuploidy in benign tumors
and nonneoplastic lesions of musculoskeletal tissues. Cancer.
1994;73:1200–5.
Bovee J, van Roggen JFG, Cleton-Jansen AM, et al. Malignant progres-
sion in multiple enchondromatosis (Ollier’s disease): an autopsy-
based molecular genetic study. Hum Pathol. 2000;31:1299–303.
Bridge JA, Persons DL, Neff JR, Bhatia P. Clonal karyotypic aberra-
tions in enchondromas. Cancer Detect Prev. 1992;16:215–9.
Buddingh EP, Naumann S, Nelson M, et al. Cytogenetic findings in
benign cartilaginous neoplasms. Cancer Genet Cytogenet.
2003;141:164–8.
Culver Jr JE, Sweet DE, McCue FC. Chondrosarcoma of the hand aris-
ing from a pre-existent benign solitary enchondroma. Clin Orthop
Relat Res. 1975;113:128–31.
Dahlen A, Mertens F, Rydholm A, et al. Fusion, disruption, and expres-
sion of HMGA2 in bone and soft tissue chondromas. Mod Pathol.
2003;16:1132–40.
Gunawan B, Weber M, Bergmann F, et al. Clonal chromosome abnor-
malities in enchondromas and chondrosarcomas. Cancer Genet
Cytogenet. 2000;120:127–30.
Y.-K. Park
Hopyan S, Gokgoz N, Poon R, et al. A mutant PTH/PTHrP type I
receptor in enchondromatosis. Nat Genet. 2002;30:306–10.
Kusuzaki K, Murata H, Takeshita H, et al. Usefulness of cytofluoromet-
ric DNA ploidy analysis in distinguishing benign cartilaginous
tumors from chondrosarcomas. Mod Pathol. 1999;12:863–72.
Landman AS, Danielian PS, Lees JA. Loss of pRB and p107 disrupts
cartilage development and promotes enchondroma formation.
Oncogene. 2013;32:4798–805.
Mirra JM. Intramedullary cartilage- and chondroid-producing tumors.
In: Bone tumors. Clinical, radiologic, and pathologic correlations.
Philadelphia: Lee & Febiger; 1989.
Morrison C, Radmacher M, Mohammed N, et al. MYC amplification
and polysomy 8 in chondrosarcoma: array comparative genomic
hybridization, fluorescent in situ hybridization, and association with
outcome. J Clin Oncol. 2005;23:9369–76.
Ozaki T, Wai D, Schafer KL, et al. Comparative genomic hybridization
in cartilaginous tumors. Anticancer Res. 2004;24:1721–5.
Ozisik YY, Meloni AM, Spanier SS, et al. Deletion 1p in a low-grade
chondrosarcoma in a patient with Ollier disease. Cancer Genet
Cytogenet. 1998;105:128–33.
Pansuriya TC, van Eijk R, d’Adamo P, et al. Somatic mosaic IDH1 and
IDH2 mutations are associated with enchondroma and spindle cell
16 Enchondroma
hemangioma in Ollier disease and Maffucci syndrome. Nat Genet.
2011;43:1256.
Rozeman LB, Sangiorgi L, Briaire-de Bruijn IH, et al. Enchondromatosis
(Ollier disease, Maffucci syndrome) is not caused by the PTHR1
mutations p.R150 C. Hum Mutat. 2004;24:466–73.
Rozeman LB, Hameetman L, Cleton-Jansen AM, et al. Absence of IHH
and retention of PTHrP signalling in enchondromas and central
chondrosarcomas. J Pathol. 2005;205:476–82.
Sawyer JR, Swanson CM, Luckacs JL, et al. Evidence of an association
between 6q13-21 chromosome aberrations and locally aggressive
behavior in patients with cartilage tumors. Cancer.
1998;82:474–83.
Schajowicz F. Cartilage forming tumors. In: Tumors and tumor like
lesions of bone. 2nd ed. Berlin: Springer; 1994. p. 141–59.
251
Shimizu K, Kotoura Y, Nishijima N, Nakamura T. Enchondroma of the
distal phalanx of the hand. J Bone Joint Surg Am. 1997;79:898–900.
Teyssier JR, Ferre D. Frequent clonal chromosomal changes in human
non-malignant tumors. Int J Cancer. 1989;44:828–32.
Unni KK. Dahlin’s bone tumors, General aspects and data on 11087
cases. 5th ed. Philadelphia: Lippincott-Raven; 1996. p. 25–40.
Van Beerendonk HM, Rozeman LB, Taminiau AHM, et al. Molecular
analysis of the INK4A/INK4A-ARF gene locus in conventional
(central) chondrosarcomas and enchondromas: indication of an
important gene for tumor progression. J Pathol. 2004;202:359–66.
Yu C, Le AT, Yeger H, et al. NOV (CCN3) regulation in the growth
plate and CCN family member expression in cartilage neoplasia.
J Pathol. 2003;201:609–15.
 Multiple Enchondromatosis (Ollier’s
Disease) 17
Yong-Koo Park

Abstract
Multiple enchondromatosis (Ollier’s disease) is a rare, nonhereditary developmental abnor-
mality involving defective endochondral ossification. It is characterized by multiple intraos-
seous and subperiosteal cartilaginous tumors, ranging in size from microscopic foci to
bulky masses. The skeleton is most frequently affected unilaterally, but bilateral involve-
ment is also observed. The association of enchondromatosis with multiple hemangiomas of
soft tissue was reported in 1881 by Maffucci (18 years before Ollier), and this clinical pre-
sentation is generally referred to as “Maffucci’s syndrome.”

Definition Etiology

• A rare, nonhereditary developmental abnormality involv-
ing defective endochondral ossification. It is character-
ized by multiple intraosseous and subperiosteal
cartilaginous tumors, ranging in size from microscopic
foci to bulky masses.
• The skeleton is most frequently affected unilaterally, but
bilateral involvement is also observed.
• The association of enchondromatosis with multiple hem-
angiomas of soft tissue was reported in 1881 by Maffucci
(18 years before Ollier), and this clinical presentation is
generally referred to as “Maffucci’s syndrome.”
• It represents an anomaly of skeletal development, without
hereditary or familial influence, and is apparently related
to heterotopic proliferation of epiphyseal chondroblasts
with consecutive failure of endochondral ossification and
shortening of the involved long bones.
Epidemiology
Age
• The disease is diagnosed in childhood, most of the times.

Synonyms
Sex
• Chondrodysplasia
• Skeletal enchondromatosis • There is no sex difference.

Sites of Involvement
Y.-K. Park, MD, PhD
• The hands and feet are the most common sites of involve-
Department of Pathology, Kyung Hee University School
of Medicine, Seoul, South Korea ment, followed by the femur, humerus, and forearm.
e-mail: ykpark0204@gmail.com • Flat bones can be involved in severe cases.

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 253
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_17, © Springer-Verlag London 2015
254
• In most cases, it occurs in a single extremity or one side
of the body. In bilateral involvement, one side of the body
is more severely affected than the other.
• The ribs and scapula are rarely involved.
Clinical Symptoms and Signs
• Most of the patients show symptoms within several years
after birth. They display skeletal deformities such as short
stature or localized swelling.
• Occasionally, pathologic fracture can be a presenting
symptom.
• Involved bones and extent of skeletal involvement vary
from patient to patient. It can present as multifocal in one
or two bones or, in severe cases, can be present as general-
ized skeletal involvement.
Image Diagnosis
• Enchondromatosis has characteristic radiographic find-
ings, making it possible to diagnose by plain
radiography.
• The lesions involve the metaphysis and diaphysis and
appear as linear or pillar-shaped radiolucent lesions that
are oriented obliquely to the long axis of the bone.
Calcification is also a feature (Figs. 17.1).
• “Popcorn”-like cartilaginous-type calcification is typi-
cally present.
• In some cases, bone erosion and hypertrophy of the corti-
cal surface can be observed.
• A portion of the lesion can regress while the bone is grow-
ing, and after normal growth has stopped, there is usually
no increase in size.
• However, if there is a change in size after normal growth
has stopped, malignant transformation should be
considered.
• In Maffucci’s syndrome, the cartilaginous lesions are
associated with benign soft tissue hemangiomas which,
characteristically, show small rounded calcified images,
corresponding to phleboliths.
Image Differential Diagnosis
Secondary Low-Grade Chondrosarcoma
• Clinically in the patients with multiple enchondromas, if
the new lesion occurs or the pain is aggravated, we have
to consider the possibility of chondrosarcoma.
Y.-K. Park
• Bone permeation and a change in the calcification pattern
of any previously known lesion must be suspected of
malignant transformation.
Pathology
Gross Features
• The affected bones are often expanded and somewhat
shortened due to the presence of bluish masses or islands
of cartilage that are arranged as multiple nodules, measur-
ing from one to several centimeters, surrounded by nor-
mal bone marrow.
• The lesion may extent through the cortical bone to involve
the periosteum or the surrounding soft tissue.
Histological Features
• Histologically, the microscopic appearance of enchondro-
matosis in both Ollier’s disease and Maffucci’s syndrome
is quite similar to that seen in enchondroma (Fig. 17.3).
• However, increased cellularity is a common feature of the
lesions of enchondromatosis, regardless of the site
involved, with enlarged nuclei and double-nucleated cells
(Fig. 17.4). These histological characteristics can lead to
a misdiagnosis of chondrosarcoma.
Pathologic Differential Diagnosis
Low-Grade Chondrosarcoma
• Especially in the metaphysis of the long bone in middle-
aged to elderly patients.
• Grossly, mucoid or myxoid changes are frequently observed
in chondrosarcoma and only rarely in chondromatosis.
• Enchondromatosis lesions do not show cortical erosion.
Also, histologically, marked myxoid change of the stroma
and cytologic features of malignancy are observed in
chondrosarcoma.
• Separation of cartilage lobules by fibrous bands is seen in
low-grade chondrosarcoma.
• In addition, the most important differential diagnostic
feature is intramedullary invasion. In chondrosarcoma,
the trabeculae of preexisting bone are embedded in the
tumor tissue – entrapment of native trabeculae.
• Radiographically, enchondromas of the small bones of the
hands and feet show cortical thinning; however, micro-
scopic permeation into the cortical tissue is not observed.
17 Multiple Enchondromatosis (Ollier’s Disease)
Ancillary Techniques
Genetics
• IDH1 and IDH2 mutations were found in majority of the
Ollier’s disease and Maffucci’s syndrome patients.
• In the patients with Ollier’s disease, heterozygous muta-
tion in the PTH receptor gene, PTHR1, was reported.
• Also in cases from the nonrecurrent enchondromatosis,
specific copy number alterations were found at FAM86D,
PRKG1, and ANKS1B, and loss of heterozygosity with
copy number loss of chromosome 6 was also found in two
cases of enchondromatosis.
• In several different groups of enchondromatosis, patients
expressed loss of function mutations in the PTPN11 gene,
recessive mutations of ACP5, and heterozygous missense
mutations in COL2A1.
Prognosis
• The prognosis is dependent on the lesion extent and dis-
ease severity.
• In Ollier’s disease, the incidence of malignant transfor-
mation is 25 %, and it is considered to be higher in
Fig. 17.1 Radiograph shows multiple enchondromas involving whole
digits and metacarpal bones leading to extreme deformity
255
Maffucci’s syndrome. The majority of these cases are
low-grade chondrosarcoma.
• Chondrosarcoma develops by age 40 in approximately
25 % of patients with Ollier’s disease.
• High-grade osteosarcoma and dedifferentiated chondro-
sarcoma have been described in Ollier’s.
Treatment
• There is no specific ways to treat Ollier’s disease or
Maffucci’s syndrome; however, treatment should primar-
ily focus on alleviating symptoms due to skeletal
deformities.
• Skeletal deformity can be surgically corrected or, in
severe swelling or deformity cases, amputation can be
done.
Images
See Figs. 17.1, 17.2, 17.3, 17.4, 17.5, 17.6, 17.7, and 17.8 for
illustrations of Ollier’s disease.
Fig. 17.2 Gross specimen, as illustrated in Fig. 17.1, shows numerous
grayish-blue cartilage masses within the marrow cavity of the phalan-
geal bones
256 Y.-K. Park

Fig. 17.5 Specimen photography showing several medullar enchon-

dromas in a same bone
Fig. 17.3 Low-power microscopic view shows lobulated cartilage
masses and rich cellularity

Fig. 17.4 At the periphery of the cartilage lobule, there are enlarged
nuclei and binucleation of the chondrocytes, associated with myxoid
matrix degeneration
17 Multiple Enchondromatosis (Ollier’s Disease) 257

Fig. 17.6 AP and lateral

radiographs of a case of Ollier’s
disease showing characteristic
finger-like longitudinal chon-
dromatous proliferations

Fig. 17.7 Macroscopic demonstration of fingerlike chondromatous

proliferations in Ollier’s disease
258
a b
Fig. 17.8 Enchondromatosis (Ollier’s disease). Radiographs of femur (a) and tibia (b) showing multiple deformities caused by large enchon-
droma lesions in metaphyseal location. Lesions present characteristic elongated ridges and disseminated calcified spots
Recommended Reading
Bowen ME, Boyden E, Holm IA, et al. Loss of function mutations in
PTPN11 cause metachondromatosis. But not Ollier disease of
Maffucci syndrome. PLoS Genet. 2011;7(e1002050):1–11.
Brien EW, Mirra JM, Luck Jr JV. Benign and malignant cartilage
tumors of bone and joint: their anatomic and theoretical basis with
an emphasis on radiology, pathology and clinical biology.
II. Juxtacortical cartilage tumors. Skelet Radiol. 1999;28:1–20.
Couvineau A, Wouters V, Bertrand G, et al. PTHR1 mutations associ-
ated with Ollier disease result in receptor loss of function. Hum Mol
Genet. 2008;17:2766–75.
Hopyan S, Gokgoz N, Poon R, Gensure RC, et al. A mutant PTH/
PTHrP type I receptor in enchondromatosis. Nat Genet.
2002;30:306–10.
Lausch E, Janecke A, Bros M, et al. Genetic deficiency of tartrate-
resistant acid phosphatase associated with skeletal dysplasia,
cerebral calcifications and autoimmunity. Nat Genet. 2011;43:
132–7.
Y.-K. Park
Lewis RJ, Ketcham AS. Maffucci’s syndrome: functional and neoplas-
tic significance: case report and review of the literature. J Bone Joint
Surg Am. 1973;55:1465–79.
Liu J, Hudkins PG, Swee RG, et al. Bone sarcomas associated with
Ollier’s disease. Cancer. 1987;59:1376–85.
Pansuriya TC, van Eijk R, d’Adamo P, et al. Somatic mosaic IDH1 and
IDH2 mutations are associated with enchondroma and spindle cell
hemangioma in Ollier disease and Maffucci syndrome. Nat Genet.
2011;43:1256–61.
Pansyriya TC, Oosting J, Krenacs T, et al. Genome-wide analysis of
Ollier disease: is it all in the genes? Orphanet J Rare Dis.
2011;6:2–12.
Schwartz HS, Zimmerman NB, Simon MA, et al. The malignant poten-
tial of enchondromatosis. J Bone Joint Surg Am. 1987;69:269–74.
Sobreira NL, Cirulli ET, Avramopoulos D, et al. Whole genome
sequencing of a single proband together with linkage analysis identi-
fies a Mendelian disease gene. PLoS Genet. 2010;6(1000991):1–6.
Tran Mau-Teem F, Boualam A, Barat-Houari M, et al.
Dysspondyloenchondromatosis without COL2A1 mutation. Possible
genetic heterogeneity. Am J Med Genet A. 2014;164A:169–773.
 Periosteal Chondroma
18
Yong-Koo Park

Abstract
Periosteal chondroma is a benign hyaline cartilage tumor of the bone surface that develops
from the periosteum. Male patients are more commonly affected than female patients.
Patients are usually between ages 10 and 30 years. The proximal humerus is the single most
frequently affected site followed by the distal femur. On radiographs, periosteal chondro-
mas appear as one or more cortically situated, lobulated soft tissue masses with erosion or
cortical saucerization. There may be associated medullary sclerosis and periostitis.
Histologically periosteal chondromas show characteristic lobules of hyaline cartilage.
Treatment is conservative surgical excision.

Definition Epidemiology

• A benign hyaline cartilage tumor of the bone surface that • Rare lesions and accounts for less than 1 % of all benign
develops from the periosteum chondromas

Synonyms Sex

• Juxtacortical chondroma • Male patients are more commonly affected than female
• Parosteal chondroma patients.
• Surface chondroma

Age
Etiology
• Patients are usually between ages 10 and 30 years.
• Uncertain

Sites of Involvement

• The proximal humerus is the single most frequently

affected site followed by the distal femur.
• In long bones, tumors usually arise in the metaphysis.
Y.-K. Park, MD, PhD • The small tubular bones are also common sites of
Department of Pathology,
involvement.
Kyung Hee University School
of Medicine, Seoul, South Korea
e-mail: ykpark0204@gmail.com

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 259
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_18, © Springer-Verlag London 2015
260
Clinical Symptoms and Signs
• Periosteal chondroma presents as palpable, often painful
masses.
• Sometimes periosteal chondromas are found near tendon
insertion sites and disturb their motion.
Image Diagnosis
Radiographic Features
• On radiographs, periosteal chondromas appear as one or
more cortically situated, lobulated soft tissue masses with
erosion or cortical saucerization.
• There may be associated medullary sclerosis and
periostitis.
• Cortical buttressing and thickening are typical findings at
the distal and proximal margins of the tumor (Fig. 18.1).
• Chondroid calcifications are observed in about half the
tumors, and some show extensive calcification.
• Even when they do not have any chondroid calcification,
the shape of the cortical defect suggests the diagnosis.
The tumor does not involve the medullary cavity.
CT Features
• CT shows detailed calcification and saucerlike cortical
erosion of the bone. Cortical scalloping with variable
degree of sclerosis is seen related to buttresses of perios-
teal new bone.
MRI Features
• On MR imaging, tumor shows low to intermediate signal
intensity on the T1-weighted images and high signal
intensity on the T2-weighted image. Calcification and
matrix mineralization of the tumor appear as decreased
signal intensity areas on all pulse sequences.
• Images with contrast enhancement show variable find-
ings. However, in general, the tumor shows the peripheral
and septal pattern enhancement of cartilage lesions.
Image Differential Diagnosis
Periosteal Chondrosarcoma
• The most reliable diagnostic criterion would be the size of
the lesion. Malignancy should be suspected when bigger
than 3 cm. Periosteal chondrosarcomas are usually large
(over 5 cm) and show no radiologic evidence of solid
Y.-K. Park
periosteal new bone buttressing at the margins, which is a
characteristic finding of periosteal chondroma.
Periosteal Osteosarcoma
• Periosteal osteosarcoma can be recognized by the feath-
ery perpendicular calcific striae seen on radiographs.
Periosteal osteosarcomas lack the characteristic periosteal
new bone buttress formation typical of periosteal chon-
dromas and tend to fade into the soft tissues.
Pathology
Gross Features
• Grossly, periosteal chondroma is a well-circumscribed,
lobulated cartilaginous mass.
• The outer surface is covered by fibrous periosteum of the
involved bone.
• The cortex underneath is indented and thickened.
Scalloping and erosion of the underlying cortex may be
seen.
• The tumors are usually less than 3 cm in greatest dimen-
sion. Any surface cartilage lesion larger than 3–5 cm
should be suspected to be malignant.
Histological Features
• Periosteal chondromas show characteristic lobules of
hyaline cartilage (Fig. 18.2).
• This cartilage tumor is well delimited and does not pene-
trate into the bone nor permeate the surrounding soft tis-
sues (Fig. 18.3).
• The cartilage is mildly cellular, and the nuclei are plump
and hyperchromatic. Double-nucleated cells are common,
and moderate myxoid change may be seen in the matrix.
Pathologic Differential Diagnosis
Periosteal Chondrosarcoma
• Periosteal chondrosarcomas are usually 5 cm in diameter
or larger. Microscopically, periosteal chondrosarcomas
show variation in size and shape of nuclei and frequent
multinucleated chondrocytes. Also periosteal chondrosar-
comas permeate into surrounding soft tissue and lack the
limiting periosteal shell that is present in periosteal
chondromas.
Periosteal Osteosarcoma
• Microscopically, periosteal osteosarcomas have
predominant areas of chondrosarcoma. Spindled primitive
18 Periosteal Chondroma
mesenchymal cells are seen between and in the periphery
of the chondroid lobules. It is usually of a higher grade in
the chondroid, more superficial areas, and osteosarcoma
is typically represented in the deep, next to the bone sur-
face, areas.
Ancillary Techniques
Genetics
• Cytogenetic abnormalities have been studied in few cases
of periosteal chondroma.
• One case reported in the literature showed structural
changes of the same band on both chromosome 12 homo-
logues, leading to speculation that a homozygous gene
alteration, possibly an inactivating mutation of a tumor
suppressor gene, was the salient DNA-level event.
261
• An abnormality of the long arm of chromosome 4 has also
been detected in two cases.
Prognosis
• Recurrence rate following any type of surgical resection
is very low.
Treatment
• Conservative surgical excision.
• Curettage of the eroded, sclerotic cortical bone and resec-
tion of the overlying perichondrium.
• In selected sites such as the ribs and fibula, segmental
resection is preferred over curettage.
262 Y.-K. Park

Fig. 18.3 The underlying cortical bone shows scalloping. The hyaline
cartilage does not penetrate the underlying cortical bones

Fig. 18.1 Radiograph of the proximal femur revealing cortical erosion

(saucerization) along the medial margin. Inferior margin of the lesion
shows a cortical beak

Fig. 18.2 At low-power magnification, the lesion shows characteristic

lobular hyaline cartilage
18 Periosteal Chondroma 263

Recommended Reading Lewis MM, Kenan S, Yabut SM, et al. Periosteal chondroma: a report
of ten cases and review of the literature. Clin Orthop Relat Res.
1990;256:185–92.
Bauer TW, Dorman HD, Latham Jr JT. Periosteal chondroma: a
Lichtenstein L, Hall JE. Periosteal chondroma. A distinctive benign
clinicopathologic study of 23 cases. Am J Surg Pathol. 1982;6:
cartilage tumor. J Bone Joint Surg Am. 1952;34:691–7.
631–7.
Mandahl N, Willen H, Rydholm A, et al. Rearrangement of band q13 on
Boriani S, Bacchini P, Bertoni F, et al. Periosteal chondroma. A review
both chromosomes 12 in a periosteal chondroma. Genes Chromosom
of twenty cases. J Bone Joint Surg Am. 1983;65:205–12.
Cancer. 1993;6:121–3.
Brien EW, Mirra JM, Luck Jr JV, et al. Benign and malignant cartilage
Nojima T, Unni KK, McLeod RA. Periosteal chondroma and periosteal
tumors of bone and joint: their anatomic and theoretical basis with
chondrosarcoma. Am J Surg Pathol. 1985;9:666–77.
an emphasis on radiology, pathology and clinical biology.
Tallini G, Dorman H, Brys P, et al. Correlation between clinicopatho-
II. Juxtacortical cartilage tumors. Skelet Radiol. 1999;28:1–20.
logical features and karyotype in 100 cartilaginous and chordoid
Buddingh EP, Naumann S, Nelson M, et al. Cytogenetic findings in
tumors. A report from the Chromosomes and Morphology (CHAMP)
benign cartilaginous neoplasms. Cancer Genet Cytogenet. 2003;
Collaborative Study Group. J Pathol. 2002;196:194–203.
141:164–8.
Unni KK. Dahlin’s Bone tumors. General aspects and data on 11,087
Jaffe HL. Juxtacortical chondroma. Bull Hosp Joint Dis. 1956;17:
cases. 5th ed. Philadelphia: Lippincott-Raven; 1996. p. 25–35.
20–9.
 Osteochondroma
19
Yong-Koo Park

Abstract
Osteochondroma is a benign cartilaginous outgrowing neoplasm arising from the surface of
the long bone consisting of cartilage-capped bony overgrowth with extension of native bone
marrow. It is the most common primary bone tumor. It is approximately 1.5 times more
common in male than female. About half the cases occur in the second decade of life. There
is predilection for the distal femur, followed by the proximal humerus and proximal tibia.
Roentgenograms show a pedunculated or sessile protuberance from the long bone metaphy-
sis. The cortex of the host bone flares out into the osteochondroma cortex. The cartilage cap
is covered by a thin periosteal membrane. The limit between the cartilage cap and the
underlying cancellous bone shows endochondral ossification, closely mimicking a normal
epiphyseal plate. Treatment is surgical excision with the entire cartilage cap.

Definition • Morphologically, there is herniation and separation of a

fragment of the epiphyseal plate.
• A benign cartilaginous outgrowing neoplasm arising from
the surface of the long bone consisting of cartilage-capped
bony overgrowth with extension of native bone marrow Epidemiology

• It is the most common primary bone tumor.

Synonyms

• Cartilaginous exostosis Sex

• Approximately 1.5 times more common in male than

Etiology female

• Clonal loss or rearrangement of 8q24.1 or 11p11–12, the

chromosomal loci of the EXT1 and EXT2 genes, is Age
reported as a possible basic genetic defect leading to
osteochondroma development. • About half the cases occur in the second decade of life.

Y.-K. Park, MD, PhD

Department of Pathology, Kyung Hee University School
of Medicine, Seoul, South Korea
e-mail: ykpark0204@gmail.com

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 265
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_19, © Springer-Verlag London 2015
266
Sites of Involvement
• Predilection for the distal femur, followed by the proxi-
mal humerus and proximal tibia
• Infrequent in the bones of the hands and feet
Clinical and Signs
• Palpable mass over the affected bone.
• Pain and swelling resulted from fracture of pedunculated
osteochondroma.
• Rarely symptoms due to compression of adjacent nerves,
vascular structures or tendons and bursa formation.
Image Diagnosis
• Roentgenograms show a pedunculated or sessile protu-
berance from the long bone metaphysis (Fig. 19.1).
Y.-K. Park
• Growth in a direction away from the epiphysis toward
diaphysis (Fig. 19.2).
• The cortex of the host bone flares out into the osteochon-
droma cortex (Fig. 19.2).
• CT and MRI can demonstrate cartilage cap (Figs. 19.3
and 19.4).
• Medullary cavity of osteochondroma is continuous with
host bone medullary cavity (Fig. 19.4).
Image Differential Diagnosis
Parosteal Osteosarcoma
• The cortex of the host bone is intact and parallel to the
other side of the bone, different from osteochondroma,
where the cortex and the medullary cavity are continuous
with the lesion.
• Osteochondroma interferes with the tubulation of the host
bone, whereas parosteal osteosarcoma does not.
19 Osteochondroma
Bizarre Parosteal Osteochondromatous
Proliferation
• Same criteria as for parosteal osteosarcoma
Myositis Ossificans
• The cortex of the host bone is intact.
• There is no cartilage outer layer.
• There is a central lucency surrounded by the maturing
bone – zoning phenomenon.
• Presents a rapid evolution and limited growth.
Pathology
Gross Features
• Surface is covered by thin periosteal membrane.
Sometimes a bursa may develop over the lesion.
• Cut surface reveals thin cartilage cap (usually less than
1 cm in thickness), bluish transparent and smooth with
underlying trabecular bone (Fig. 19.5).
Histological Features
• The cartilage cap is covered by a thin periosteal mem-
brane (Fig. 19.6).
• The limit between the cartilage cap and the underlying
cancellous bone shows endochondral ossification,
closely mimicking a normal epiphyseal plate (Fig. 19.7).
The new trabecules include rests of calcified cartilage
matrix.
• The chondrocytes are arranged in a linear pattern without
nuclear atypia or binucleation (Fig. 19.8).
• Normal-appearing fatty or hematopoietic bone marrow is
present (Fig. 19.6).
Pathologic Differential Diagnosis
Parosteal Osteosarcoma
• The cortex of the host bone is intact.
• The cartilage and bone show well-differentiated atypical
features of malignancy.
267
• Does not present the endochondral plate seen in
osteochondroma.
• The bone marrow is replaced by slightly atypical fibrous
tissue.
Secondary Chondrosarcoma Arising
from Osteochondroma
• Shows a thicker cartilaginous cap, more than 2 cm
thick.
• Cartilage is atypical.
Bizarre Parosteal Osteochondromatous
Proliferation
• Also has a cartilage cap, but the cartilaginous tissue
underneath is irregularly mixed with bone, osteoid, and
spindle-celled collagenous tissue.
• The bone cortex is preserved.
Ancillary Techniques
Genetics
• Clonal karyotypic abnormalities involving loci 8q24.1
(EXT1) and 11p11–12 (EXT2) are revealed in patients
with sporadic and hereditary osteochondromas.
• Mutations in EXT1 or EXT2 in patients with hereditary
osteochondromas are germline mutations with combined
loss of the remaining wild-type allele and homozygous
deletions in solitary osteochondroma.
• Twenty point mutations and one large deletion in EXT1
and EXT2 genes.
Prognosis
• Recurrence is associated with incomplete removal of the
cartilage cap.
• Multiple recurrences are suggestive of secondary malig-
nant transformation.
Treatment
Surgical excision with the entire cartilage cap
268 Y.-K. Park

a b

Fig. 19.1 (a) A-P radiograph of a typical pedunculated enchondroma. (b) Lateral view shows the lesion superimposed to the host bone and its
rounded implantation site
19 Osteochondroma 269

Fig. 19.2 Radiograph of the distal femur shows an osteochondroma

projecting from the distal femur. Cortical and medullary continuity is
Fig. 19.3 Radiograph of a sessile osteochondroma. The medullary bone
seen
of the host is seen in continuity with the medulla of the lesion
270 Y.-K. Park

Fig. 19.6 At low power, osteochondroma shows peripheral perios-

teum covering with hyaline cartilage and trabecular bones

Fig. 19.4 MRI of previous lesion emphasizing the aspect of the con-
tinuous bone medulla

Fig. 19.7 Hyaline cartilage cap is reminiscent of normal growth plate

Fig. 19.5 Panoramic microphotograph of a pedunculated osteochondroma

Fig. 19.8 At high-power view, chondrocytes show dark small nuclei

without cytologic atypia
19 Osteochondroma 271

Recommended Reading Mertens F, Rydholm A, Kreicbergs A, et al. Loss of chromosome band

8q24 in sporadic osteocartilaginous exostoses. Genes Chromosom
Cancer. 1994;9:8–12.
Bridge JA, Nelson M, Orndal C, et al. Clonal karyotypic abnormalities
Reijinders CM, Waaijer CJ, Hamilton A, et al. No haploinsufficiency
of the hereditary multiple exostoses chromosomal loci 8q24.1
but loss of heterozygosity for EXT in multiple osteochondromas.
(EXT1) and 11p11-12(EXT2) in patients with sporadic and heredi-
Am J Pathol. 2010;177:1946–57.
tary osteochondromas. Cancer. 1998;82:1657–63.
Zuntini M, Pedrii E, Parra A, et al. Genetic models of osteochondroma
Ciavarella M, Coco M, Baorda F, et al. 20 novel point mutations and
onset and neoplastic progression: evidence for mechanisms alterna-
one large deletion in EXT1 and EXT2 genes: report of diagnostic
tive to EXT genes inactivation. Oncogene. 2010;29:3827–34.
screening in a large Italian cohort of patients affected by hereditary
multiple exostosis. Gene. 2013;515:339–48.
Jones KB, Piombo V, Searby C, et al. A mouse model of osteochondro-
magenesis from clonal inactivation of Ext1 in chondrocytes. Proc
Natl Acad Sci USA. 2010;107:2054–9.
 Multiple Osteochondromatosis
20
Yong-Koo Park

Abstract
Multiple osteochondromatosis is a familial disease characterized by multiple osteochondro-
mas, defect in metaphyseal remodeling, and asymmetric longitudinal growth retardation. There
is a greater incidence in males than females (7:3). It was often first discovered at a younger age
than solitary form. There is a predilection for the metaphyseal regions around the knee, hip, and
shoulder joints. Radiologically individual lesions are similar to those of solitary form.
The lesions have the same gross and microscopic appearances as seen in solitary osteo-
chondroma. The development of secondary malignancy varies from 5 % to 25 %. The treat-
ment should be considered to correct deformities or functional disturbances.

Definition Epidemiology

• A familial disease characterized by multiple osteochon- Sex

dromas, defect in metaphyseal remodeling, and asymmet-
ric longitudinal growth retardation
Synonyms
• Greater incidence in males than females (7:3)
Age
• Often first discovered at a younger age than solitary form

• Hereditary multiple exostoses Sites of Involvement

• Diaphyseal aclasis
• Hereditary deforming chondrodysplasia • Predilection for the metaphyseal regions around the knee,
• Ehrenfried disease hip, and shoulder joints.
• The innominate bone and scapula are often affected.

Clinical Features

Etiology Clinical Symptoms and Signs

• Inherited autosomal dominant disorders • Multiple palpable masses and deformities generally dis-
• Incomplete penetrance in females covered after the age of 2 years.
• Some patients may experience spinal cord compression
due to vertebral lesions.
Y.-K. Park, MD, PhD
Department of Pathology, Kyung Hee University
School of Medicine, Seoul, South Korea
e-mail: ykpark0204@gmail.com

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 273
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_20, © Springer-Verlag London 2015
274
Image Diagnosis
• Individual lesions are similar to those of solitary form
(Fig. 20.1).
• The deformities are frequently observed.
Pathology
Gross and Histologic Features
• The lesions have the same gross and microscopic appearances
as seen in solitary osteochondroma (Figs. 20.2 and 20.3).
Ancillary Techniques
Genetics
• There is evidence that mutations in these two EXT1 and
EXT2 genes are responsible for over 70 % of the EXT
cases of osteochondromatosis. Among the 49 EXT1
mutations, there are 9 nonsense, 21 frameshift, and 5
splice site mutations; 2 in-frame deletions of 1 and 5
amino acids, respectively; and 12 missense mutations.
For EXT2, 8 nonsense, 11 frameshift, 3 splice site, and 3
missense mutations are described. The majority of these
mutations are mutations causing loss of function, which is
consistent with the presumed tumor suppressor function
of the EXT genes.
• Mutations in exostosin-1 (EXT1) or exostosin-2 (EXT2),
both tumor suppressor genes of the EXT gene family, are
associated with multiple osteochondromatosis. All mem-
Y.-K. Park
bers of this multigene family encode glycosyltransferases
involved in the adhesion and/or polymerization of heparin
sulfate (HS) chains at HS proteoglycans (HSPGs). HSPGs
have been shown to play a role in the diffusion of Ihh,
thereby regulating chondrocyte proliferation and differen-
tiation. EXT1 is located at 8q24.11–q24.13 and comprises
11 exons, whereas the 16 exon EXT2 is located at 11p12–
p11. To date, an EXT1 or EXT2 mutation is detected in
70–95 % of affected individuals. EXT1 mutations are
detected in +/−65 % of cases versus +/−35 % EXT2 muta-
tions in multiple osteochondromatosis patient cohorts.
• Jamsheer et al. demonstrated EXT1 and EXT2 heterozy-
gous mutations in 54.6 % and 30.3 % probands, respec-
tively, which represents a total of 84.9 % index cases.
Prognosis
• The development of secondary malignancy varies from
5 % to 25 %.
• Most of the secondary malignancies have been
chondrosarcomas.
• A few osteosarcomas have also been reported.
Treatment
• The treatment should be considered to correct deformities
or functional disturbances, such as reduction of joint
motion and/or pain due to pressure phenomenon or bursa
formation.
20 Multiple Osteochondromatosis 275

Fig. 20.2 Outer surface of one of the multiple osteochondromas shows

multi-knobby appearance with gray-white calcified areas

Fig. 20.1 X-ray shows multiple osteochondromas arising from the

distal meta- and diaphysis of the distal femur, proximal tibia and fibula
276 Y.-K. Park

Recommended Reading
Jaffe HL. Tumors and tumorous conditions of the bones and joints.
Philadelphia: Lea & Febiger; 1958. p. 150–62.
Jamsheer A, Socha M, Sowińska-Seidler A, Telega K, Trzeciak T,
Latos-Bieleńska A. Mutational screening of EXT1 and EXT2 genes
in Polish patients with hereditary multiple exostoses. J Appl Genet.
2014;55:183–8.
Jennes I, Pedrini E, Zuntini M, Mordenti M, Balkassmi S, Asteggiano
CG, et al. Multiple osteochondromas: mutation update and descrip-
tion of the multiple osteochondromas mutation database (MOdb).
Hum Mutat. 2009;30:1620–7.
Johnston II CE, Sklar F. Multiple hereditary exostoses with spinal cord
compression. Orthopedics. 1988;11:1213–6.
Matsuno T, Ichioka Y, Yagi T, Ishii S. Spindle-cell sarcoma in patients
who have osteochondromatosis. A report of two cases. J Bone Joint
Surg Am. 1988;70:137–41.
Tian C, Yan R, Wen S, et al. A splice mutation and mRNA decay of
EXT2 provoke hereditary multiple exostoses. PLoS One.
2014;9:e94848.
Wuyts W, Van Hul W. Molecular basis of multiple exostoses: mutations
in the EXT1 and EXT2 genes. Hum Mutat. 2000;15:220–7.

Fig. 20.3 Cut surface shows hyaline cartilage cap with myxoid
degeneration
 Chondroblastoma
21
Yong-Koo Park

Abstract
Chondroblastoma is a benign cartilage-forming neoplasm occurring in the epiphyses of
immature long bones. It is more common in male. The peak incidence is between 10 and
25 years of age. Typically, chondroblastoma occurs in the epiphyses of the long bones.
More than 75 % of the cases develop at the epiphyseal and epimetaphyseal region of the
distal and proximal femur, proximal tibia, and proximal humerus. Radiologically, chondro-
blastoma is usually located in the medullary portion and arises either at the epiphysis or
apophysis of the long tubular bone. Extension to the metaphysis can be seen at times. The
lesion consists in well-defined, geographic bone destruction with either a spherical or an
oval shape. There are amorphous calcific foci within the lesion. Histologically, the basic
cells are chondroblast. There are randomly distributed multinucleated giant cells. Immature
chondroid matrix that appears as variably sized nodules composed of light-staining, amor-
phous, bluish to eosinophilic material surrounded by chondroblasts is typically present.
Most chondroblastomas are appropriately treated by curettage.

Definition Clinical Features

• A benign cartilage-forming neoplasm occurring in the Etiology

epiphyses of immature long bones
• Unknown

Synonyms
Epidemiology
• Calcifying giant cell tumor
• Epiphyseal chondromatous giant cell tumor • Relatively uncommon and accounts for less than 1 % of
all bone tumors
• Corresponds to one-fifth of the giant cell tumors

Sex
• More common in male. Male and female ratio varies
depending on the study and is approximately 1.4 to 2:1.

Age
Y.-K. Park, MD, PhD
Department of Pathology, Kyung Hee University
• The peak incidence is between 10 and 25 years of age.
School of Medicine, Seoul, South Korea • Cases involving the skull or temporal bone are more com-
e-mail: ykpark0204@gmail.com mon among patients in their 40s and 50s.

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 277
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_21, © Springer-Verlag London 2015
278
Sites of Involvement
• Typically, chondroblastoma occurs in the epiphyses of
the long bones. While the occurrence is typically at the
end of the major tubular bones, it can also occur at a
secondary ossification center, such as the greater
trochanter.
• More than 75 % of the cases develop at the epiphyseal and
epimetaphyseal region of the distal and proximal femur,
proximal tibia, and proximal humerus.
• Chondroblastoma can also occur at the epiphyseal equiv-
alent sites of the flat bone such as the acetabulum and
iliac crest. Though rare, however, chondroblastoma may
arise in the patella, calcaneus, or other tarsal bones which
are one of the typical occurrence sites of the
chondroblastoma.
• Cases involving the craniofacial bone can be found in the
base of the skull and temporal bone (Fig. 21.11).
• Occasionally, multifocal synchronous chondroblastomas
were reported.
Y.-K. Park
Clinical Symptoms and Signs
• A typical clinical presentation is localized pain. That may
occur as a singular incident to prolonged episodes lasting
several months or years.
• In addition, the patient can also suffer from swelling, gait
disturbances, and joint stiffness.
• A few patients may also experience knee joint effusion.
• Furthermore, tumoral involvement of the temporal bone
may result in hearing loss, tinnitus, or vertigo.
• On physical examination, patients usually report tender-
ness in the affected area along with limitation of motion
and muscular atrophy.
Image Diagnosis
Radiographic Features
• Chondroblastoma is usually located in the medullary por-
tion and arises either at the epiphysis or apophysis of the
21 Chondroblastoma
long tubular bone (Fig. 21.12). Extension to the metaphy-
sis can be seen at times (Fig. 21.1).
• The size of chondroblastoma is usually less than 5–6 cm.
Conventional radiographs typically demonstrate well-
defined, geographic bone destruction with either a spheri-
cal or an oval shape (Fig. 21.2).
• There are amorphous calcific foci within the lesion. In
rare cases, extensive calcifications can be seen on plain
radiograph. The lesion shows a marginal sclerotic rim on
plain radiograph, and it shows expansion of the cortex
with periosteal reaction in cases of extension to the cortex
(Fig. 21.3).
• However, pathological fracture is not frequently seen. In a
typical case, the contour of the involved bone is not usu-
ally changed.
MRI Features
• On MR imaging, chondroblastoma shows low signal
intensity on T1-weighted images and variable signal
intensity on T2-weighted images. Sometimes, the lesion
shows perilesional high signal intensity on T2-weighted
images, indicating inflammatory or edematous changes.
Image Differential Diagnosis
Giant Cell Tumor
• Most giant cell tumors develop in skeletally mature adult
patients. Radiographically, chondroblastoma shows a
more distinct delineation than giant cell tumors which
typically lack a reactive sclerotic margin.
Clear Cell Chondrosarcoma
• Is a more aggressive lesion, frequently expanding the
bone and permeating the cortex
Pathology
Gross Features
• Since chondroblastoma is usually small, it is treated by
curettage.
• Grossly, it appears as fragments of soft pink to gray tumor
tissue with occasional zones of hemorrhage and
calcification.
• Small cystic spaces can be commonly found.
• On rare occasions, the boundary of the resected specimen
is well delineated and a sclerotic rim is observed.
• Occasionally, the cystic change is so prominent that it
resembles an aneurysmal bone cyst.
279
Histological Features
• Histologically, the basic cells are chondroblast. Typical
chondroblasts are oval shaped and have well-defined
cytoplasmic border. They are rather uniform round to
polygonal in shape (Fig. 21.4). The cytoplasm ranges
from pink to focally clear and with distinct cell borders
(Fig. 21.5).
• The nucleus is located in the central portion of the cyto-
plasm and is oval or round shaped. A longitudinal groove
is typical, accounting for the so-called “coffee bean”
appearance. There is one or two inconspicuous nucleolus.
Usually chondroblasts are packed in pseudo-lobulated
sheets.
• There are randomly distributed multinucleated giant cells
which have 5–40 nuclei. Another diagnostic clue is imma-
ture chondroid matrix that appears as variably sized nod-
ules composed of light-staining, amorphous, bluish to
eosinophilic material surrounded by chondroblasts
(Figs. 21.6 and 21.7).
• Mature hyaline cartilage is very rarely present.
Ossification can occur, occasionally abundant. Especially,
this kind of ossification is frequently observed in talus
and calcaneus lesions. A fine network of pericellular cal-
cification is found around the degenerating tumor cells,
which is often called “chicken wire calcification”
(Figs. 21.8 and 21.9).
• Mitosis can be found in the mononuclear cells,
although uncommon. Atypical mitosis is extremely
infrequent.
• Often individual chondroblasts can show considerable
cytologic atypia such as enlarged, irregular, and hyper-
chromatic nuclei. However, this finding is not indicative
of malignant disease and has no impact on patient
prognosis.
• Focally spindle cell change can be seen in chondro-
blastoma and it is very difficult to diagnose. Brown
to yellow granular pigment is frequently observed
in skull chondroblastomas, which serves as a very use-
ful feature for diagnosis. These are iron-staining
positive.
• Secondary aneurysmal bone cystic change is present in
about one-third of chondroblastomas (Fig. 21.10). In
most cases, this cystic change is observed at the micro-
scopic level.
• Occasionally, this secondary cystic change is very pro-
nounced and chondroblastoma itself is only present as a
mural nodule.
• By electron microscopic examination, chondroblasts
show deep indentation of the nuclear membrane, abun-
dant rough endoplasmic reticulum, and long cytoplasmic
processes. These findings are quite characteristic for fetal
chondroblasts.
280
Pathologic Differential Diagnosis
Giant Cell Tumor
• Histologically, the mononuclear cells in giant cell tumors
lack the characteristic longitudinal groove seen in chon-
droblastoma. In addition, chicken wire calcification and
pink chondroid matrix are also lacking in giant cell tumors.
Chondromyxoid Fibroma
• Chondromyxoid fibroma develops in a similar age group
as chondroblastoma. However, chondroblastoma occurs
mostly at the epiphysis of the long bone, while
chondromyxoid fibroma develops in the metaphysic of
the long bone. Histologically, chondromyxoid fibroma
shows characteristic lobulated growth pattern with a myx-
oid background. In a biopsy sample, mononuclear cells in
chondromyxoid fibroma are quite similar to chondro-
blasts. The characteristic calcification pattern in chondro-
blastoma is observed in chondromyxoid fibroma.
Clear Cell Chondrosarcoma
• Clear cell chondrosarcoma also must be differentiated
from chondroblastoma in older patients.
• Histologically, in clear cell chondrosarcoma, malignant
chondrocytes and large cells with clear cytoplasm are
observed, which are not shown in chondroblastoma.
Osteoblastoma
• In rare cases of chondroblastoma with abundant ossifica-
tion, a diagnosis of osteoblastoma should be considered.
Osteosarcoma
• On very rare occasions, the osteosarcoma
chondroblastoma-like variant can mimic chondroblas-
toma closely. However, in osteosarcoma, the tumor cells
are arranged in a sheetlike pattern and there are obvious
atypical cells. In addition, these atypical cells permeate
surrounding trabecular bones.
Ancillary Techniques
• Immunohistochemically, the mononuclear cells of chon-
droblastoma express S-100 protein and vimentin. In
addition, there are a few reports of them expressing cyto-
keratin. Recent studies revealed SOX9 and DOG1 posi-
tivity in cellular areas of chondroblastoma. Also,
osteoprotegerin is highly expressed in the stromal cells
of chondroblastoma.
Genetics
• According to flow cytometric studies, most chondroblas-
tomas are diploid with low proliferative fractions.
However, there are some near-diploid aneuploid cells.
Y.-K. Park
• Clonal abnormalities have been described in several
benign and at least in one aggressive chondroblastoma.
Chromosomal structural abnormalities involving chromo-
somes 5 and 8 have also been reported.
• The CORS-26 (collagenous repeat-containing sequence
of 26-kDa protein) gene has been localized to the short
arm of chromosome 5. CORS-26 mRNA is strongly
expressed in chondroblastoma, and this gene may play a
significant role in the pathogenesis of chondroblastoma.
A higher level of PTHHR1, bcl-2, and FGFR-3 in chon-
droblastoma, which are cartilage growth plate signaling
molecules, was reported. These findings suggest that
chondroblastoma is a neoplasm that originates from a
mesenchymal cell committed toward chondrogenesis via
active growth plate signaling pathways.
• Chondroblastoma associated with joint inflammation
shows considerably increased COX-2 expression.
Superoxide dismutase 1, tartrate-resistant acid phospha-
tase 5, and cathepsin K, which are expressed in osteoclas-
tic giant cells, are more highly expressed in
chondroblastoma. In addition, versican and perlecan
expression has been significantly downregulated in chon-
droblastoma. However, the clinical significance of these
changes is subject to further investigation.
Prognosis
• Recurrence rates vary between 6 % and 15 %. Recurrences
are also treated by curettage. Local recurrence occurs
more commonly in flat bones as opposed to long bones. In
the temporal bone, approximately 50 % of the cases of
chondroblastoma recur.
• On rare occasions, chondroblastoma grows or recurs
aggressively so that the bone is destroyed. In such cases,
resection may be indicated. The clinical term “aggressive
chondroblastoma” has been used; however, this is not a
pathological term.
• Rarely, a histologically benign chondroblastoma may
present with pulmonary metastasis. However, these
metastases are clinically nonprogressive. Only simple
surgical excision or simple observation is needed. Due to
its extreme rarity, there are insufficient data to evaluate
the prognosis in pulmonary metastatic chondroblastoma.
• There are reports of extremely rare cases of malignant
transformation in chondroblastoma.
Treatment
• Most chondroblastomas are appropriately treated by
curettage with or without bone graft.
• Radiotherapy, which can cause postradiation sarcoma, is
not indicated.
21 Chondroblastoma 281

Fig. 21.2 The radiograph of the femoral head shows a round osteolytic
bone lesion at the subchondral portion. The lesion is confined to the
epiphysis

Fig. 21.1 The radiograph of the femural proximal end with a chondro-
blastoma located in the greater trochanter (an apophysis)

a b

Fig. 21.3 Radiograph (a) and MRI (b) of a knee show an epiphyseal lytic lesion bordered by sclerotic bone rim
282 Y.-K. Park

Fig. 21.4 At low-power view, there are numerous giant cells and oval- Fig. 21.7 Occasionally, this pink matrix shows acellular lobulated
shaped chondroblasts appearance

Fig. 21.5 High power illustrating oval-shaped chondroblasts with cen- Fig. 21.8 Typical example of chickenwire calcification showing peri-
tral groove and giant cells cellular thin lines of calcification

Fig. 21.6 Chondroblastoma shows eosinophilic to amorphous pink Fig. 21.9 In this area, more dense mineralization is present, with sug-
fibrochondroid matrix gestive “chickenwire” pattern.
21 Chondroblastoma 283

Fig. 21.10 Secondary aneurysmal cystic changes are evident

a b

Fig. 21.11 Radiograph (a) and CT scan (b) of a chondroblastoma located in a temporal bone
284
a b
Fig. 21.12 Radiograph (a) and CT scan (b) of a chondroblastoma in a femoral condyle. Lytic lesion with mottled calcified spots and peripheral
sclerotic rim
Recommended Reading
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 Chondromyxoid Fibroma
22
Yong-Koo Park

Abstract
Chondromyxoid fibroma is a benign tumor composed of spindle or stellate cells forming
lobules and with abundant myxoid and/or chondroid intercellular material. There is a male
predominance. More than half of the cases develop in the second and third decades of life.
Most cases of CMF occur in the metaphysis of tubular bones of the lower extremity.
Approximately one-third of the cases are diagnosed around the knee joint, and the proximal
tibial metaphysis is the most common site of involvement, followed by the distal femoral
metaphysis. Rarely, there are reports of cases that involve flat bones. Radiologically, sharply
circumscribed radiolucent lesion with an elongated shape is seen. Cortical expansion,
exuberant endosteal sclerosis, and coarse trabeculation can be seen. The primary and
preferable treatment of chondromyxoid fibroma should be en bloc resection.

Definition Clinical Features

A benign tumor composed of spindle or stellate cells forming Epidemiology

lobules. There are abundant myxoid and/or chondroid inter-
cellular materials. • Chondromyxoid fibroma (CMF) is extremely rare and
accounts for less than 1 % of all bone tumors.
• It represents approximately 2 % of benign bone tumors.
Synonyms • There is a male predominance.
• More than half of the cases develop in the second and
Previously it was considered to be myxoma or myxomatous third decades of life.
variant of a giant cell tumor.

Y.-K. Park, MD, PhD

Department of Pathology, Kyung Hee University
School of Medicine, Seoul, South Korea
e-mail: ykpark0204@gmail.com

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 287
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_22, © Springer-Verlag London 2015
288
Sites of Involvement
• Most cases of CMF occur in the metaphysis of tubular
bones of the lower extremity.
• Approximately one-third of the cases are diagnosed
around the knee joint, especially the proximal tibial
metaphysis which is the most common site of involve-
ment and followed by the distal femoral metaphysis.
• Rarely there are reports of cases that involve cortical
bones.
• Small bones of the feet are among the frequently involved
site.
• Upper extremity involvement is rare.
• In the pelvis, the ilium is the most frequent site of
involvement.
• Other than that, there were reports to occur in the cranio-
facial bones, ribs, spine, clavicle, calcaneus, and
sternum.
Y.-K. Park
Clinical Symptoms and Signs
• Clinically, patients present with pain that can persist for
several months to several years or local swelling.
• On very rare occasions, they suffer from rickets which is
reported as an oncogenic osteomalacia.
Image Diagnosis
Radiographic Features
• Mainly located in the metaphysis of long tubular bones
and appears as a sharply circumscribed radiolucent lesion
with an elongated shape of varying size of about 2–10 cm
in largest diameter. Cortical expansion, exuberant endos-
teal sclerosis, and coarse trabeculation can be seen
(Figs. 22.1 and 22.2).
22 Chondromyxoid Fibroma
• Extensive periostitis and pathological fracture are rare,
and calcification is infrequent.
• The lesion is sharply defined and eccentrically located.
Large lesions can be seen as hemispheric osseous defects
with destruction of cortex.
• Chondromyxoid fibroma arising in a flat bone may show
irregular contours with osteolysis and bone expansion
(Fig. 22.3).
CT Features
• At CT, the extent of bone involvement can be better
evaluated.
MRI Features
• On MRI, chondromyxoid fibroma shows a multilobulated
pattern, with low signal intensity on T1-weighted images
and high signal intensity on T2-weighted images. With
contrast injection, the central portion of the lesion may
show no enhancement due to the myxoid component.
Image Differential Diagnosis
Chondrosarcoma
• Chondrosarcoma may be mistaken for chondromyxoid
fibroma and vice versa, especially if the lesion involves
the pelvic bones. Chondrosarcoma usually has a more
aggressive picture, is poorly circumscribed, and contains
calcification.
Fibrous Dysplasia
• FD shares, in numerous cases, the peripheral sclerosis
seen in CMF, but the lesion is denser, with the so-called
ground glass appearance in the center.
Pathology
Gross Features
• Most often, CMF has been treated by curettage, so it is
not usual to observe an intact gross specimen.
• Curettage specimens are composed of a blue-gray or
white tissue that rarely shows necrosis, cystic change, or
liquefaction (Fig. 22.4).
• Typical hyaline cartilage is not present.
• When the surrounding bone is available for evaluation,
the tumor’s multilobulated appearance and sharp delinea-
tion from the bone can be appreciated (Fig. 22.5).
289
Histological Features
• CMF has distinct microscopic features characterized by
variably sized sharply demarcated lobules. These lobules
vary in size, ranging from easily visible under low-power
view to smaller ones (Fig. 22.6). The lobules tend to be
hypocellular centrally with greater cellularity at the
periphery (Fig. 22.7).
• The lesional cells are spindled to stellate and are distrib-
uted in an abundant extracellular chondroid matrix
(Fig. 22.8). Frequently, there is abundant pink cytoplasm,
producing an epithelioid appearance (Fig. 22.9).
• The lobules are separated by fibrous bands (Fig. 22.10).
The fibrous bands contain blood vessels and giant cells.
• Approximately 50 % of CMF cases have scattered benign
giant cells. Large bizarre hyperchromatic nuclei can be
seen in 20–30 % of cases; however, they are usually focal
and associated with large amounts of cytoplasm, some-
times with smudgy or degenerative features.
• Mitoses are extremely rare in CMF, and atypical mitoses
have not been noted.
• Microscopic cystic or liquefactive change is uncommon
and is usually focal, when present. Well-formed hyaline
cartilage is present in less than 20 % of cases.
• Calcification is present in about one third of cases, as
either fine granules or denser and plaques (Fig. 22.11).
Hemosiderin deposition is present at the lobular periphery
associated with inflammatory cells and lymphocytes.
• Areas of secondary aneurysmal bone cyst are rarely seen.
Peripheral isolated tumoral nodules may be seen at the
sclerotic medullary margin.
Pathology Differential Diagnosis
Chondrosarcoma
• Histologically, high-grade chondrosarcomas can be dif-
ferentiated from a rare bizarre CMF by (1) brisk mitotic
activity, (2) permeation of marrow spaces by tumor cells,
and (3) the appearance of the myxoid stroma which stains
more uniformly in CMF.
• Low-grade chondrosarcoma has an infiltrative pattern,
with entrapment of native trabecules, and is less
vascularized.
• Another important distinguishing feature is the presence
of multinucleated giant cells, which are common in chon-
dromyxoid fibroma but extremely rare in
chondrosarcomas.
Enchondroma
• Enchondroma is constituted by lobules of mature carti-
lage and frequently presents foci of enchondral ossifica-
tion, features not seen in CMF.
290
Chondroblastoma
• Chondroblastoma is practically always an epiphyseal
located lesion. Infrequent cases of CMF can have cellular
areas extremely similar to chondroblastoma.
• Chondroblastoma has a more differentiated cartilaginous
appearance and also presents the so-called chickenwire
calcification areas.
Extragnathic Myxoma
• Extragnathic myxoma may be distinguished from CMF
by its lack of a lobular growth pattern and the absence of
pleomorphism or atypia in the stellate or spindle cells.
Furthermore, from a practical point of view, extragnathic
myxoma is very rare.
Ancillary Techniques
Immunohistochemistry
• S-100 protein has been reported in chondromyxoid
fibroma especially within the area that exhibits more
mature chondroblastic differentiation. In the loose myx-
oid areas, S-100 protein may show only focal positivity.
• At the periphery of the lobules, smooth muscle actin and
CD34 have been noted. Ultrastructurally, the stellate cells
have irregular cell processes, scalloped cell membranes,
cytoplasmic fibrils and glycogen, and features of both
chondroblastic and fibroblastic differentiation.
Genetics
• Only limited cytogenetic studies have been done on chon-
dromyxoid fibroma.
• Clonal abnormalities of chromosome 6 appear to be non-
random. In particular, rearrangements of the long arm of
chromosome 6 at bands q13 and q25 are recurrent.
• Pronounced expression of hydrated proteoglycans
(major constituent of the myxoid matrix) and focal
expression of collagen type II (a marker of chondrocytic
Y.-K. Park
cell differentiation) as well as collagen types I, III, and
VI are characteristic of matrix composition and gene
expression pattern in chondromyxoid fibroma.
• In CMF, N-cadherin, PTHLH, and PTHR1 are
expressed at a significantly lower level than in articular
chondrocytes; however, conversely significantly higher
expression of cyclin D1, p16, and Bcl2 has also been
reported.
• There is a report that TGF-β1 derived partial myofibro-
blastic differentiation in chondromyxoid fibroma. There
are higher expression levels of CD166, cyclin D1, and
p16INK4A in chondromyxoid fibroma, in contradiction
to low levels present in high-grade chondrosarcoma.
Prognosis
• The primary treatment of CMF should be en bloc
resection.
• Treatment with curettage and bone grafting is associated
with approximately 15 % recurrence rate. Recurrences
do not correlate with any histological features of the
lesion.
• An interesting and rare complication is soft tissue growth
of nodules secondary to implementation during surgery.
• Malignant transformation of chondromyxoid fibroma has
rarely been reported in the literatures. However, it remains
a pathologic curiosity.
Treatment
• The primary and preferable treatment of chondromyxoid
fibroma should be en bloc resection.
• Some chondromyxoid fibroma may be treated by curet-
tage and bone grafting.
• Radiation therapy has been used to treat surgically inac-
cessible tumors.
22 Chondromyxoid Fibroma 291

Fig. 22.2 The radiograph shows a well-defined osteolytic bone lesion

at the first metatarsal bone. The cortical margin is partially disrupted at
the medial margin

Fig. 22.1 The radiograph of the distal femur shows an expansile

osteolytic metaphyseal lytic lesion

Fig. 22.3 CT scan shows large irregular osteolytic and expansile

lesion in a rib
292 Y.-K. Park

Fig. 22.4 Gross features of chondromyxoid fibroma show yellow-

white lobulated appearance

Fig. 22.7 At the periphery of the lobule, there are giant cells and
mononuclear cells showing oval to spindle nuclei and pink cytoplasm

Fig. 22.5 Gross features of Fig. 22.3 show gray-white lobulated myx-
oid appearance (Courtesy by Soonchunhyang Hospital)

Fig. 22.8 In the lobule, elongated or stellate cells present in an abun-

dant extracellular chondroid matrix

Fig. 22.6 Low power of chondromyxoid fibroma shows characteristic

lobular configuration, relatively hypocellular and peripheral hypercel-
lular areas

Fig. 22.9 At higher magnification, the central portion of tumor shows

elongated to spindle, stellate cells admixed with myxoid stroma
22 Chondromyxoid Fibroma 293

Fig. 22.10 The peripheral cells are more spindled to polyhedral Fig. 22.11 Occasionally, this type of coarse calcification in the lobule
shaped, simulating chondroblastoma, and appear to separate the lobules is present
by fibrous bands

a b

Fig. 22.12 Lateral view radiograph (a) and MRI (b) of a typical chondromyxoid fibroma. Lytic lesion with sclerotic border in its more typical
location
294
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 Chondrosarcoma
23
Sergio Piña-Oviedo, Jae Y. Ro, Alberto G. Ayala,
and Yong-Koo Park

Abstract
Chondrosarcoma (CHS) represents 20–30 % of all malignant bone neoplasms and is the
second most common solid malignant tumor of bone after ostegosarcoma. CHS is classified
as primary or secondary if the tumor arises de novo or develops in a preexisting benign
cartilage neoplasm (enchondroma or osteochondroma), respectively. By the same token,
CHS is classified according to its anatomic location within a bone as central when it is
located in the medullary cavity of a long bone (80–85 % of cases) or peripheral (about
10–15 % of cases) or juxtacortical or periosteal when the tumor is located on the surface of
a bone (<1 % of cases). Microscopically, CHS is a group of different clinicopathological
entities in which the common denominator is the presence of hyaline cartilage. The most
common is the primary or conventional CHS that represents 85 % of all the CHSs and is a
tumor composed predominantly of hyaline cartilage in various stages of differentiation. Its
variants include a specific cell component such as a high-grade sarcoma component in
dedifferentiated CHS, clear cells in clear-cell CHS, and a small-cell component in mesen-
chymal CHS. Each one of these subtypes has distinct clinical, radiological, histological, and
genetic features.
Secondary chondrosarcoma may arise in a sporadic osteochondroma, in a genetic syn-
drome characterized by multiple osteochondromas (hereditary multiple exostosis), or in
skeletal enchondromatosis (Ollier or Maffucci diseases). The prognosis of CHS depends on
the histological grade, stage, and location of the tumor. According to the National Cancer
Data Base Report, the relative 5-year survival rate of CHS is approximately 75 %, and
patients who survive the first 10 years after diagnosis of conventional CHS will die of other
causes rather than from CHS-related events. High-grade (grade 3) conventional CHS and
dedifferentiated and mesenchymal CHSs account for those cases with less favorable
prognosis.

S. Piña-Oviedo, MD Houston Methodist Research Institute,

Department of Pathology and Genomic Medicine, Houston, TX, USA
Houston Methodist Hospital,
Weill Cornell Medical College of Cornell University,
Houston, TX, USA
Houston, TX, USA
J.Y. Ro, MD e-mail: aayala@houstonmethodist.org
Department of Pathology and Genomic Medicine,
Y.-K. Park, MD, PhD
Houston Methodist Hospital, Weill Cornell University,
Department of Pathology, Kyung Hee University
Houston, TX, USA
School of Medicine, Seoul, South Korea
A.G. Ayala, MD (*) e-mail: ykpark0204@gmail.com
Department of Pathology and Genomic Medicine,
Methodist Hospital Physician Organization, Houston, TX, USA

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 295
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_23, © Springer-Verlag London 2015
296 S. Piña-Oviedo et al.

Dedifferentiated chondrosarcoma is a rare malignant neoplasm characterized by a high-

grade, nonchondroid sarcoma such as malignant fibrous histiocytoma, osteosarcoma, fibro-
sarcoma, rhabdomyosarcoma, or angiosarcoma associated with and apparently arising from
a low-grade cartilage-forming tumor. Slightly more males than females are affected.
The age range is wide, but the majority of tumors occur in patients over the fourth decade.
The peak age incidence is the sixth decade of life. Sites of involvement are similar to
ordinary chondrosarcoma. Radiographically, the existence of the two components (low- and
high-grade) of dedifferentiated chondrosarcoma can frequently be recognized. Histologically,
the hallmark of dedifferentiated chondrosarcoma is the coexistence of its two components:
a low-grade cartilaginous precursor lesion and a high-grade sarcoma. Treatment: In general,
the dedifferentiated component is more resistant to chemotherapy and radiation therapy
than de novo malignant fibrous histiocytoma or osteosarcoma.
Mesenchymal chondrosarcoma is a rare distinct malignant neoplasm characterized by
the presence of solid, highly cellular areas composed of round or slightly spindled primitive
mesenchymal cells with foci of cartilaginous differentiation. The noncartilaginous elements
usually predominate, and such lesions can be confused histologically with Ewing’s sar-
coma, malignant lymphoma, or hemangiopericytoma. There is no sex predilection. Usually,
it affects young adults and teenagers. The peak incidence is during the fourth followed by
the third decade of life but can be seen at any age. Sites of involvement: It favors the max-
illa, mandible, ribs, and vertebrae. Radiologically, a lytic defect that often contains stippled
densities corresponding to small islands of mineralized cartilage is present. Radical surgery
is the best therapy.
Clear-cell chondrosarcoma is a rare low-grade malignancy characterized by rounded
cells with conspicuous clear or vacuolated cytoplasm and by a cartilaginous or chondroid
matrix in at least some areas. Scattered osteoclast-type giant cells, occasional bone trabecu-
lae, and aneurysmal bone cyst–like areas may also be present. It is a rare tumor that accounts
for less than 2 % of all chondrosarcomas. The reported sex ratio, male to female, is 2:1. The
peak incidence is in the fourth and fifth decades of life; however, individual cases are
reported from the second to the seventh decades. The most common location is distal femur,
followed by proximal humerus, proximal femur, proximal tibia, vertebrae, and ribs.
Radiographically, one of the most constant findings is the propensity for the tumor to
involve the epiphysis of a long bone and extend to the articular cartilage. The most common
roentgenographic pattern is that of a purely lucent lesion. En bloc resection including a
margin of normal bone and soft tissue is the treatment of choice.

Introduction Table 23.1 Classification of chondrosarcoma (CHS)

Quoting the famous bone and soft tissue pathologists Louis
Lichtenstein and Henry Jaffe from their original cartilagi-
nous classification, chondrosarcoma (CHS) is an uncommon
malignancy “that develops from full-fledged cartilage”. It
represents 20–30 % of all malignant bone neoplasms and is
the second most common solid malignant tumor of the bone
after osteosarcoma. The estimated incidence is 1 in 200,000
per year in the United States. CHS is classified as primary or
secondary if the tumor arises de novo or develops in a preex-
isting benign cartilage neoplasm (enchondroma or osteo-
chondroma), respectively. By the same token, CHS is
classified according to its anatomic location within a bone as
central when it is located in the medullary cavity of a long
bone (80–85 % of cases) or peripheral (about 10–15 % of
cases) or juxtacortical or periosteal when the tumor is located
on the surface of a bone (<1 % of cases) (see Table 23.1).
By origin
Primary CHS (arising de novo)
Secondary CHS (arising from the cartilage cap of an
osteochondroma, from sporadic enchondroma, or in skeletal
enchondromatosis or osteochondromatosis)
By anatomic location
CHS of the axial skeleton (craniofacial region, ribs, spine, and
pelvis)
CHS of the appendicular skeleton (long bones of extremities, hands,
and feet)
By location within the bone
Central or intramedullary (usually arising in an enchondroma)
Central (intramedullary) conventional CHS
Peripheral CHS
Peripheral primary CHS (including periosteal/juxtacortical
CHS)
Peripheral secondary CHS (usually arising from the cartilage cap
of an osteochondroma)
23 Chondrosarcoma 297

Table 23.2 Characteristics of chondrosarcoma subtypes

5-year
Frequency and gender Histologic grade (Lichtenstein and survival rate
Subtype predilection (M:F) Peak age (years old) Jaffe classification) (%)a
Conventional 85 % 40–60 Low, intermediate, or high grade 70
(central and peripheral) 1.5–2:1 (grades 1–3)
Periosteal or juxtacortical <1 % 20–50 Commonly low grade, rare 93
Slight male predilection intermediate, to high grade
grades 1–3)
Dedifferentiated 10 % 50–60 High grade (grade 3) 0
1:1
Mesenchymal 2–10 % 10–20 High grade (grade 3) 48
1:1
Clear cell <2 % 20–30 Low grade (grade 1) 100
2.5:1
a
Information based on the Surveillance, Epidemiology, and End Results (SEER) database after analysis of 2,890 patients with CHS

Microscopically, CHS is a group of different, clinicopatho- Synonyms

logical entities in which the common denominator is the
presence of hyaline cartilage. The most common is the pri- Intramedullary CHS; Central CHS; Typical CHS;
mary or conventional CHS that represents 85 % of all the Chondrosarcoma, NOS
CHSs and is a tumor composed predominantly of hyaline
cartilage in various stages of differentiation. Its variants
include a specific cell component such as a high-grade sar- Etiology
coma component in dedifferentiated CHS, clear cells in clear
cell CHS, and a small cell component in mesenchymal The etiology of conventional primary CHS is unknown.
CHS. Each one of these subtypes has distinct clinical, radio- However, several genetic abnormalities and molecular alter-
logical, histologic, and genetic features (see Table 23.2). ations have been recently found and are thought to be related
Secondary CHS may arise in a sporadic osteochondroma, to the pathogenesis and/or progression of CHS (see
in a genetic syndrome characterized by multiple osteochon- Genetics).
dromas (hereditary multiple exostosis), or in skeletal enchon-
dromatosis (Ollier or Maffucci diseases).
The prognosis of CHS depends on the histologic grade,
stage, and location of the tumor. According to the National Clinical Features
Cancer Data Base Report, the relative 5-year survival rate
of CHS is approximately 75 %, and patients who survive Epidemiology
the first 10 years after diagnosis of conventional CHS will Conventional intramedullary CHS is the most common type
die of other causes rather than from CHS-related events. of primary CHS (85 % of the cases). It is a tumor that pre-
High-grade (grade 3) conventional CHS and dedifferenti- dominantly affects adults from 30 to 70 years with a peak
ated and mesenchymal CHSs account for those cases with incidence at 40–60 years. The male to female ratio is 1.5–2
less favorable prognosis. Extraskeletal myxoid CHS is not to 1. Conventional intramedullary CHS is very rare in
discussed in this chapter, because this tumor is a soft tissue children.
tumor.

Primary Chondrosarcoma: Conventional
Intramedullary Chondrosarcoma
Definition
Conventional CHS is a rare malignant tumor that shows car-
tilage differentiation. The tumor is usually found in the med-
ullary cavity of a long bone but some arise on the surface of
the bone.
Sites of Involvement
Conventional CHS can present in any bone that develops by
endochondral ossification. The frequent sites involved are
the proximal femur, the iliac bone of the pelvis, the proximal
humerus, the distal femur, and the ribs. Less frequent sites of
involvement include the spine, the scapula, and the sternum.
Craniofacial involvement as well as involvement of the neck,
radius, ulna, clavicle, patella, and small tubular bones is rare.
CHSs arising in specific anatomic locations are discussed
below.
298
Clinical Symptoms and Signs
The clinical symptoms are usually nonspecific and may vary
based on the size and aggressiveness (grade) of the tumor.
The most common symptom of low-grade tumors is local-
ized pain followed by local swelling (80 % of cases). Pain,
however, may be related to osteoarthritis of a nearby joint.
Patients may also complain of a pulling sensation or
restriction of movement of the adjacent joint. The symptoms
usually have an insidious onset but may be progressive,
being worse at night, and may last for months to years. Fast
growing tumors may present with excruciating pain. Tumors
from the pelvis usually produce urinary symptoms, such as
frequency and/or obstruction, or may mimic a “muscle pull”
in the groin. Pathologic fractures may be the initial presenta-
tion in less than a third of cases.
Image Diagnosis
Radiographic Findings
Plain films are still the best screening tool to determine if a
lesion is cartilaginous in origin. Primary conventional CHS
S. Piña-Oviedo et al.
involving the long bones is more commonly seen in the
proximal femur followed by the proximal humerus. In the
femur, the intertrochanteric area, the metaphysis, and not
uncommonly the diaphysis are the common sites involved.
In the humerus, the epiphysis-metaphysis is commonly
affected.
Typical radiologic findings include expansion and remod-
eling of the medullary cavity of the bone with endosteal
scalloping and with or without periosteal reaction. The
lesions usually show a lytic pattern typically with a back-
ground of punctate calcifications, referred to as “popcorn”
or “ringlet” calcifications (Figs. 23.1, 23.2, and 23.3).
Detection of these calcifications is diagnostic of cartilage
tumors by imaging but is not sufficient to discern between a
benign, borderline, or malignant chondromatous neoplasm.
Enchondromas and intramedullary low-grade CHSs often
share similar radiological features. A benign or borderline
intramedullary tumor is favored when the lesion is small,
lacks expansion of the medullary cavity, and shows absence
of endosteal scalloping, cortical destruction, infiltrative pat-
tern, or a lytic component (Figs. 23.1 and 23.2). In contrast,
a suspicion for a high-grade intramedullary CHS should
arise when a lesion is large, has produced expansion of the
23 Chondrosarcoma
medullary cavity, and shows endosteal scalloping, especially
if the lesion is painful (Fig. 23.4). Endosteal scalloping is a
sign of aggressiveness in a central cartilaginous lesion but
does not confirm the diagnosis of malignancy. Endosteal
scalloping greater than two-thirds of the normal thickness of
the long bone cortex is more predictable of CHS than
enchondroma.
Features strongly suggestive of CHS include destruction
of the bone cortex, extension into the adjacent soft tissues,
and permeative changes (so-called moth-eaten pattern). Of
these, only permeation is the most reliable sign of malig-
nancy (Figs. 23.5 and 23.6).
Computer Tomography (CT) Features
CT and magnetic resonance imaging (MRI) scans are better
modalities of imaging to evaluate the extent of the disease
within or outside the bone. CT scan can evaluate the pres-
ence of cortical involvement, degree of endosteal scalloping,
presence of soft tissue extension, and presence of lobulation
and of matrix mineralization and can depict low attenuation
rate due to the high water content of the cartilaginous matrix.
In contrast, high-grade lesions may show increased attenua-
tion due to the increased cellularity and less amount of water
in the matrix.
Magnetic Resonance Imaging (MRI) Features
MRI provides an excellent way to evaluate the extent of
marrow involvement and the presence of soft tissue inva-
sion. Cross sections of the entire cortical circumference
evaluate endosteal scalloping (two-thirds scalloping of the
cortical thickness) as well as cortical remodeling and peri-
osteal reaction. A recent study showed that formation of
new periosteal bone reaction may occur in the absence of
direct periosteal involvement by CHS of the femur, and
thus, interpretation of tumor infiltration by MRI should be
done cautiously. Likewise, CHS may extend into the soft
tissues without evident findings on the MRI. Because of the
high water content of the cartilage matrix in CHSs, marrow
replacement appears as low to intermediate signal intensity
on T1-weighted images and as high signal intensity on
T2-weighted images (Fig. 23.7). Areas of matrix mineral-
ization have low signal intensity in MRI sequences and are
better visualized in plain radiographs or a CT scan. Low-
grade CHSs show septal enhancement on gadolinium-
enhanced MRI. High-grade lesions frequently present
homogeneous or less frequently heterogeneous diffuse
enhancement.
Bone Scan
Approximately 80 % of intramedullary conventional CHSs
show marked increase of radionuclide uptake (greater than
the iliac spines) compared to enchondromas (20 % of cases).
CHSs usually show heterogeneous radionuclide uptake.
299
Image Differential Diagnosis
As mentioned above, low- to intermediate-grade CHSs
share similar radiological features with enchondromas. By
location, low- grade CHSs are usually found in the axial
skeleton and in flat bones compared to enchondromas which
are more common in the appendicular skeleton. Inner corti-
cal scalloping greater than two-thirds of the cortical
thickness, periosteal reaction, cortical destruction, extension
of an intramedullary mass into the soft tissues with
peritumoral edema (better appreciated on water-sensitive
MRI imaging sequences), and increased uptake of radionu-
clide at bone scintigraphy are all features that strongly
suggest the diagnosis of CHS.
Pathology
Biopsy
As with any bone lesion, cartilaginous tumors can be
approached with either closed or open biopsy procedures.
Core needle biopsy (CNB) or fine needle aspiration (FNA)
may yield sufficient diagnostic tissue for the identification
of cell type, namely, in the case of cartilaginous tumors.
CNB and FNA are done simultaneously and have the
advantage of being easily done under local anesthesia uti-
lizing radiologically guided imaging by an interventional
radiologist. However, an open biopsy is equally effective
but is costly and necessitates an operating room. Whether
one technique or the other is elected for biopsy, the main
disadvantage in biopsies of cartilaginous tumors is the sam-
pling error that may lead into a wrong diagnosis. It should
be stated that a tumor depicting typical calcifications (i.e.,
popcorn or ringlet type of calcifications) on radiologic
examination is diagnostic of a cartilaginous tumor, so that
there is no need to prove by histology that such lesion is of
cartilaginous origin. For this reason, we do not advocate
any type of biopsy for a lesion that can be recognized radio-
logically as being a cartilaginous tumor. However, when
there are lytic areas within a radiologically typical carti-
laginous tumor or permeation of the cortex strongly sug-
gests a high-grade component, a CNB/FNA may have a
role in the diagnosis. Such biopsy should target the suspi-
cious areas for a high-grade component such as is the case
of a mesenchymal CHS, dedifferentiated CHS, or a high-
grade CHS.
Gross Features
Conventional intramedullary CHSs are tumors usually larger
than 5 cm located in the medullary cavity of bones. Typically,
the medullary cavity is expanded. Low- to intermediate-
grade CHSs have a gray-white to bluish-gray cut surface and
lobulated borders (Figs. 23.1, 23.2, 23.5, and 23.8). They
300
usually have a firm consistency but may be soft, mucoid, or
gelatinous or may even have a gritty cut surface with punc-
tate calcifications (Fig. 23.3). Areas of endosteal scalloping
and thickening of the periosteum are seen in long bones
(Figs. 23.2 and 23.4). High-grade CHSs are gray-white and
fleshy, with myxoid changes, hemorrhage, or necrosis
(Fig. 23.6). The tumor usually extends from the medullary
cavity into the adjacent soft tissues with infiltration and
destruction of the cortical bone and periosteum (Figs. 23.9
and 23.10).
For the purpose of this discussion, the term “enchon-
droma” is not utilized for cartilaginous lesions of the long
bones in adult persons (see below). However, we recognize
that they exist.
Histology
The histologic features of CHSs are basically divided into
two categories: benign/low-grade lesions and tumors that are
cytologically malignant.
Borderline/Low-Grade Chondrosarcomas
Benign/low-grade (borderline/enchondroma/low-grade
CHS) cartilaginous lesions are difficult to assess histologi-
cally even when there is abundant tumor tissue. Histologically,
these lesions are generally made up of well-differentiated
hyaline cartilage without mitotic activity, pleomorphic
nuclei, or significant cellularity (Fig. 23.11). Degenerative
myxoid change may be present in these lesions and is char-
acterized by myxoid change associated with pyknotic degen-
erating nuclei; in contrast, “neoplastic myxoid change” is
defined as myxoid change associated with actively prolifer-
ating cartilaginous cells with definitive cellular atypia and
partial or complete disappearance of the lacunar arrange-
ment. Thus, benign/borderline or low-grade cartilaginous
tumors are composed of lobules of hyaline cartilage with
variable degree of cellularity and degenerative myxoid
change and with or without calcifications. Chondrocytes
usually show pyknotic nuclei with the size of a mature lym-
phocyte but larger nuclei may be present, especially in cel-
lular areas. In the latter, the nuclei are enlarged and may
contain a fine chromatin pattern and prominent nucleoli, but
mitotic activity is not observed. Neoplastic myxoid change is
not present. These cells are invariably located within well-
defined lacunae (Figs. 23.11 and 23.12). Occasional double
nuclei may be present but double nuclei have no pathologic
significance since binucleate chondrocytes are commonly
seen with the cartilaginous body of a callous from a fracture/
repair or in the physis of growth in a child. In contrast,
aggressive lesions radiologically demonstrating expansion
of the medullary cavity and associated endosteal scalloping
depicting benign/low-grade morphology as previously
described are the crux of the radiologists and pathologists.
The radiologist may read these lesions as “aggressive, cannot
S. Piña-Oviedo et al.
rule out CHS” or “consistent with low-grade CHS.” The
pathologist may equally interpret the histology of this lesion
as “borderline malignancy or low-grade CHS” (Fig. 23.5).
Is a lesion an enchondroma? Or is it a borderline/low-
grade CHS? This distinction is challenging, and many
authors have attempted to define it. Thus, Mirra et al. felt that
enchondromas are characterized by nodules of hyaline carti-
lage encased by marrow elements of lamellar bone. On the
other hand, low-grade CHSs tend to infiltrate between bone
spicules, replace marrow fat, and surround lamellar bone.
Looking into Mirra’s illustrations of the low-grade CHSs, it
becomes obvious that his tumors are depicting a neoplastic
myxoid pattern and the cellularity is no longer made up of
hyaline cartilage in lacunae but atypical chondroid cells
(Fig. 23.13). Is it important to diagnose these lesions as
benign or low-grade malignancy? The answer is probably
not! These lesions should be surgically treated the same way.
High-Grade Cartilaginous Tumors
High-grade CHSs are not a diagnostic problem on histologic
examination. They are characterized by a cellular cartilagi-
nous proliferation of distinctively abnormal cells. Although
there may be focal retention of the lacunar arrangement, this
pattern is usually lost. The core of the tumor is made up of
cytologically abnormal cells containing round, spindle, or
pleomorphic nuclei and reduced amount of cytoplasm
(Fig. 23.14). Mitotic activity is present but is not overwhelm-
ing. One has to look at many fields on a high magnification
(×400) to find mitoses (Fig. 23.15). In Evans et al.’s grading
system, the finding of two or more mitoses per ten high-
power fields (HPFs) indicates a high-grade CHS. However, if
a cartilaginous tumor shows many mitoses that are very easy
to find, the tumor is most likely a chondroblastic osteosar-
coma or a dedifferentiated CHS. Neoplastic myxoid change,
namely, neoplastic cells separated by basophilic extracellular
material with no lacunar formation, is usually present
(Fig. 23.16). Extension of CHS through the Haversian canal-
like channels into the soft tissues without obvious bone
destruction may be observed, but such change is an extremely
rare finding in the usual practice of pathology examination.
So when there is definitive cellular atypia, increased cel-
lularity, spindling, and the presence/absence of mitoses and
myxoid change, the term CHS is justified.
Grading
There is a direct relationship between the histologic differen-
tiation and the grade of CHSs. Grade 1 or low-grade CHSs
are similar to benign cartilage lesions (enchondromas and
osteochondromas) and are characterized by cells in lacunae
without nuclear atypia and without mitotic activity.
Evans et al.’s grading system is a three-tier system (grade
1–3) where grade 1 lesions consist of a paucicellular prolifera-
tion of cartilaginous cells in lacunae (the size of a mature lym-
23 Chondrosarcoma
phocyte) with no nuclear atypia or mitotic activity (Figs. 23.11
and 23.12). Degenerative myxoid change characterized by
relatively acellular myxoid with chondroid cells containing
pyknotic nuclei may be present. Grade 2 lesions are cellular
lesions that retain the lacunar pattern. The cells exhibit vari-
ability in the size of nuclei, which may have a fine nuclear
chromatin pattern and a prominent nucleolus, and usually have
abundant cytoplasm. However, there is no significant nuclear
atypia or neoplastic myxoid change. Grade 3 lesions are cel-
lular tumors depicting significant nuclear atypia and partial or
complete loss of lacunar arrangement and must show ≥2 mito-
ses per 10 HPFs counted in the most cellular areas (Figs. 23.14
and 23.15). Two of the authors (A.G.A. and J.Y.R.) have
refined this grading system by splitting the grade 2 into grade
2a and grade 2b (Fig. 23.17). Grade 2a lesions are cellular
lesions with retention of the lacunar pattern, no nuclear atypia,
and no mitotic activity. Grade 2b lesions consist of cartilagi-
nous tumors that are cellular with partial or no retention of the
lacunar pattern, none or one mitosis in ten HPFs, and charac-
teristically exhibiting neoplastic myxoid change. Applying this
grade system, grade 1 and grade 2a are tumors that may recur
but do not metastasize. On the other hand, grade 2b and grade
3 lesions metastasize in about 60 % of the cases (Fig. 23.18,
top). Grade 1 and grade 2a may recur, and the patient may die
of uncontrolled local recurrence but such tumors do not metas-
tasize. If one is to fuse grade 1 and 2a and grade 2b and grade
3, the survival curves are identical (Fig. 23.18, bottom).
Therefore, well-differentiated low-grade lesions (grade 1 and
2a) may recur and grow but do not metastasize, while poorly
differentiated high-grade lesions (grade 2b and 3) have a dis-
tinctive potential for distant metastasis.
In summary, high-grade CHSs have potential for distant
metastasis and are characterized by the presence of at least
two mitoses per ten HPFs, nuclear atypia, and neoplastic
myxoid change. Mitoses, however, are difficult to find.
Caution is given to the readers that if there are abundant
mitoses, the tumor is most likely a chondroblastic osteosar-
coma or a dedifferentiated CHS.
In our view, we prefer to interpret the benign/low-grade
lesions (composed of purely hyaline “cartilage proliferation
without neoplastic myxoid change or mitoses) as “cartilage
tumor grade 1 or 2a” (depending on the cellularity) and com-
ment that such lesion may recur but will not metastasize. In con-
trast, high-grade lesions (grade 2b and 3) will be called CHSs
stating that they have definitive potential for distant metastasis.
Immunohistochemistry
In general, immunohistochemistry is not needed for the diag-
nosis of low-grade conventional CHSs. However, a useful
marker of benign and malignant chondrocytes is the S100 pro-
tein. Several other immunohistochemical markers (Ki-67,
MCM6, tenascin, A disintegrin, metalloproteinases, ezrin,
telomerase) have been used to mark cartilage in an attempt to
301
differentiate benign from low-grade cartilaginous lesions, but
most of these studies need further investigation. Importantly, if
osteoid material surrounded by atypical cells is recognized
within the lesion, an osteosarcoma with chondroblastic differ-
entiation and not a cartilaginous tumor should be suspected.
Ancillary Techniques
Genetics
CHSs show heterogeneous cytogenetic findings. Low-grade
tumors show near diploidy, whereas high-grade tumors dem-
onstrate more complex karyotypes. Cytogenetic abnormali-
ties include several alterations including duplication or
deletion of portions of or complete chromosomes as well as
translocations. Single nucleotide polymorphism (SNP)
arrays performed in CHSs have shown that these tumors first
lose chromosomes and then duplicate their entire genome
(autosomal loss of heterozygosity or LOH) as early events,
and in later stages, the tumor cells acquire complex karyo-
types after polydiploidization, additional gains, and losses or
rearrangements of genetic material. Chromosome banding
analysis and DNA flow cytometry has shown that deletions
at 6q, 10p, 11p or 11q, 13q, and 22q loci are associated with
impaired metastasis-free survival in CHSs. Overexpression
of the protein p53 and mutations on chromosome 17 at the
locus of the TP53 gene are present in almost all high-grade
CHSs and suggest that mutation of p53 is a late event in the
progression of this tumor. Amplification of 12q13 and loss of
9p21 are some of the more consistent genetic aberrations
found in conventional CHS. The gene located in the 12q13
locus encodes the protein MDM2, a negative regulator of
p53. The 9p21 locus harbors the genes of two cell cycle regu-
lators, CDKN21/p16/INK4A and INK4Ap14ARF. Loss of
p16/INK4A is restricted to high-grade CHS, suggesting a
role in the progression of low- to high-grade CHS. Gene
expression profiles of CHS (pre-chondrogenic and chondro-
genic phenotype) have been established on the basis of
chondrogenesis-relevant genes. This genetic profile permits
distinction between grade 1 and grade 3 CHS and further
stratifies grade 2 CHS in two groups, and a pre-chondrogenic
or chondrogenic phenotype of a tumor could potentially be
used as a good prognostic marker for clinical behavior.
In general, CHS follows the same parameters of tumor
physiology including the self-sufficiency without the need of
growth signals, resistance to growth inhibitory signals, anti-
apoptotic mechanisms, uncontrolled proliferation, increased
angiogenesis, invasion, and metastatic potential.
To date, several molecular markers and potential thera-
peutic targets have been identified for CHS, including the
platelet-derived growth factor receptor (PDGFR), estrogen
signaling, matrix metalloproteinase-1 (MMP-1), histone
deacetylase, and vascular endothelial growth factor-A
302
(VEGF-A). However, any of these markers have shown to
correlate with the progression and behavior of CHS better
than with the current histologic grading system. The reader
is referred to more detailed reviews on the topic . The
Hedgehog molecule, p53, cyclin-dependent kinase 4
(CDK4), hypoxia-inducible factor-1α (HIF-1α), several
MMPs, the anti-apoptotic protein survivin, and SRC and
AKT not only are important for the development of central
CHS but also represent potential therapeutic targets. The
Indian Hedgehog (IHH)/parathyroid hormone-like hor-
mone (PTHLH, also known as parathyroid hormone-related
protein or PTHRP) pathway normally regulates in a very
delicate fashion the development of endochondral bone
and maintains the growth of the endochondral plate at a
constant thickness. Induction of IHH/PTHLH and reactiva-
tion of bcl-2, a downstream molecule of this pathway, are
implicated in the pathogenesis and progression of conven-
tional CHS, and bcl-2 may represent a reliable marker to
distinguish between enchondroma and low-grade CHS
(Fig. 23.19).
CHS differentiation may be reflected in the presence of
particular types of extracellular components. Collagen types
II and X and the proteoglycan aggrecan may represent mark-
ers of a mature neoplastic phenotype and good prognosis in
CHS compared to collagen type I which indicates a transi-
tion to a more proliferative “dedifferentiated” phenotype.
Hypermutability of the collagen II gene, COL2A1, which
results in impaired collagen II synthesis, has been identified
in about 40 % of CHSs by exome sequencing. The bone mor-
phogenetic protein (BMP) and the transforming growth fac-
tor β (TGFβ) signaling pathways are active in central CHS
cells, which could also represent important axis for the pro-
gression of CHS and as regulators of a “dedifferentiated”
phenotype. Gene expression profiling in CHSs have shown
that the protein JunB is higher in grade I CHSs compared to
enchondromas and that CHS progression is associated with
downregulation of matrix-related genes, increase in
glycolysis-related genes, but decreased in oxidative-
phosphorylation-related genes.
Overexpression of the enzyme cyclooxygenase-2 (COX-
2, also known as prostaglandin-endoperoxide synthase) has
also been proposed as a marker associated with high histo-
logic grade and poor prognosis in CHS. However, the use of
the COX-2 inhibitor, celecoxib, in CHS cell lines and a xeno-
graft model of CHS failed to demonstrate complete remis-
sion of the tumor. Overall, however, none of these markers
provides independent prognostic information.
In 2011, heterozygous somatic mutations of the isocitrate
dehydrogenase 1 (IDH1) were identified in 56 % of benign
and malignant cartilaginous neoplasms, except from periph-
eral CHSs and osteochondromas. About 40 % of the cases
harbored the R132C mutation, which correlated with immu-
nohistochemical detection of the IDH1-mutated protein in
S. Piña-Oviedo et al.
paraffin-embedded tissues. However, no correlation between
IDH1 mutation and tumor grade was found. Importantly, the
IDH1 mutation may represent a promising marker for the
distinction between dedifferentiated CHS with osteosarco-
matous differentiation and chondroblastic osteosarcoma.
The enzyme IDH1 converts isocitrate to D-2-hydroxyglutarate
instead of α-ketoglutarate with several consequences, includ-
ing the activation of HIF-1α, an important molecule involved
in cartilage proliferation, tumor angiogenesis, and cell
proliferation in CHS.
Downregulation of several micro-RNAs has been detected
in CHS compared to normal cartilage. Further studies are
needed to understand the role of these novel molecules in the
pathogenesis of CHSs.
Prognosis
Histologic grade is the single most important predictor of
metastasis in CHS, with an inverse relationship between
histologic grade and prognosis. Survival rates vary from
study to study, and this may depend on the subjectivity of the
interpretation of a cartilaginous neoplasm (Reliability of his-
topathologic and radiologic grading of cartilaginous neo-
plasms in long bones). The overall 5-year survival rate from
the Surveillance, Epidemiology, and End Results (SEER)
study was 70 %, close to the one reported by the Mayo Clinic
on 77 % of 5-year survival rate for low-grade tumors. The
overall survival rate for high-grade tumors is approximately
50 %. Nevertheless, a more recent study from Italy has
shown that grade 1 CHSs have a 5-year survival of 92 %.
Grade 2 and 3 CHSs are significantly associated with meta-
static potential and have a 5-year survival rate of 77 %. Local
recurrence occurs in 13–20 % of cases, and approximately
13 % of CHSs will recur as higher-grade lesions. Recurrence
is higher in CHS of the axial skeleton. In a recent study of
115 patients with conventional intramedullary CHS, local
recurrence and presence of distant metastasis was associated
with a decline in overall survival regardless of the tumor
grade. The presence of a pathologic fracture at diagnosis led
to a decrease in overall survival in patients with CHS of the
lower extremity but not in those tumors of the upper extrem-
ity. Also, the age of the patient (<40 years old), tumor vol-
ume (<100 cm3), and tumor location (appendicular vs. axial
skeleton) were associated with better prognosis. Additional
parameters such as tumor necrosis, mitotic rate, and inade-
quate surgical resection margins may be associated with
poor prognosis.
CHSs of the appendicular skeleton have a better survival
rate and lower recurrence in comparison with axial tumors.
Our experience is similar. However, it should be stated that
tumors of the extremities are easier to remove surgically than
lesions of the axial skeleton.
23 Chondrosarcoma
Treatment
The aim of the therapy for a CHS is to resect the tumor
regardless of the grade. However, the surgical approach has
to be performed according to the clinico-radiologic presen-
tation of the lesion. Surgery varies from curettage with
bone or cement packing for non-aggressive lesions to en
bloc resection with clean margins for aggressive lesions or
malignant tumors. The key for success is to obtain clean
surgical margins. The histologic examination is very impor-
tant after the tumor has been resected because low-grade
CHSs may recur if incompletely excised whereas high-
grade (grade 3) tumors may develop distant metastasis.
Thus, local recurrences are related to incomplete surgical
excisions while metastases are related to the high grade of
a lesion.
Chemotherapy and radiotherapy have no role in the
primary management of CHS. However, radiotherapy may
be utilized as a form of palliation.
Conventional Chondrosarcoma Located
in Specific Anatomical Sites
As mentioned previously, CHS may be located essentially in
any bone of the body (axial or appendicular skeleton) with
involvement of the pelvis, ribs and sternum, the hands and
feet, the vertebral spine, and the craniofacial region. Some of
these tumors are discussed below.
Chondrosarcoma of the Hands and Feet
Definition
A conventional primary CHS that arises in the small bones of
the hand or in the bones of the feet.
Synonyms
Primary CHS of the hands and feet; CHS of the phalanx;
Phalangeal CHS
Etiology
The etiology of conventional primary CHS of the hand and
feet is unknown. The tumor possibly shares similar genetic
abnormalities as those seen in conventional intramedullary
CHS. See Genetics for Conventional Intramedullary CHS.
Epidemiology
The development of malignant cartilaginous tumors in the
hand and foot bones occurs in less than 5 % of all CHS cases,
whereas enchondromas are extremely common. However,
CHS is the most frequent malignant tumor in this location. In
a study of 35 cases of phalangeal CHS, the median age at the
303
time of diagnosis was 67 years (range 21–87 years) with a
slight female predominance.
Site
This type of CHS develops far more commonly in the hand
than in the foot. Within the hand, the fifth digit has the highest
incidence of CHS and the fourth is the least involved. The
proximal phalanges are the most common site affected. In
the foot, the calcaneus is the bone most commonly involved.
Clinical Symptoms and Signs
Localized pain is the most frequent symptom at presentation.
Fracture is unusual.
Image Diagnosis
Radiographic Features
CHSs of the hand and foot are radiolucent lesions (average
size, 3 cm) with occasional punctuate calcifications that
generally show destruction of the cortical bone with exten-
sion into the adjacent soft tissue (Fig. 23.20). Presence of a
soft tissue mass is a more reliable way to discern whether a
lesion is benign or malignant.
Image Differential Diagnosis
The main differential diagnosis is enchondroma. This benign
lesion is confined to the medullary cavity of the hand and
foot bones without cortical bone destruction.
Pathology
Gross Features
Similar to those described in conventional intramedullary
CHS. Because of its location in small bones, the median size
of these tumors is smaller (3 cm, range 1–8 cm).
Histologic Features
CHSs in these regions may be low- or high-grade tumors as
seen in conventional intramedullary CHS.
Pathologic Differential Diagnosis
CHSs of the hands and feet are lesions that radiologically
are clearly malignant showing definitive extension of the
tumor from the medullary cavity into the adjacent soft tis-
sue generally forming a large soft tissue mass. Histologically,
they may be low grade or high grade (Fig. 23.21).
Enchondromas are far more common in the bones of the
hand than in the bones of the foot. They cause expansion of
the medullary cavity and not uncommonly expand the
entire length of a metacarpal bone. Enchondromas may
present an associated fracture, but they do not show exten-
sion into the soft tissues. If a lesion does not show clear-cut
evidence of high-grade malignancy, the best a pathologist
can do is to call the lesion “cellular” or “atypical” refrain-
ing from making a diagnosis of CHS. While benign carti-
304
laginous lesions may recur, recurrences are rare and take a
long time to come back.
Ancillary Techniques
Genetics
The tumor possibly shares similar genetic abnormalities as
those seen in conventional intramedullary CHS (see Genetics
for Conventional Intramedullary CHS).
Prognosis
CHSs of the hands and feet are typically low-grade CHSs
that may recur locally but do not metastasize. In a series of
35 cases of CHS of the phalanx, 10 of 15 tumors recurred
after local therapy, whereas no tumor recurred after radical
surgical resection. Conversely, CHSs of the calcaneus and
talus bones are more likely to metastasize.
Treatment
If a complete curettage is diagnosed as a low-grade CHS,
close follow-up is an option that the clinician has to make. If
the curettage was incomplete, either a second curettage should
be done depending on the radiologic presentation or a com-
plete surgical resection with clean margins should be done
with the latter option being curative in the majority of cases.
Chondrosarcoma of the Craniofacial Region
Definition
A conventional primary CHS that arises in the head and neck
area, typically from the base of the skull.
Synonyms
CHS of the base of the skull; CHS of the head and neck;
Sinonasal CHS
Etiology
The tumor originates from cartilaginous rests from the
synchondroses of the basilar skull bones, which are formed
by endochondral ossification during the fetal life. The tumor
possibly shares similar genetic abnormalities as those seen in
conventional intramedullary CHS (see Genetics in this
section and Genetics for Conventional Intramedullary CHS).
Epidemiology
Craniofacial CHS represents 2 % of all conventional CHSs.
In a study of 200 cases of CHS of the skull base, the age of
presentation ranged from 10 to 79 years (median of 39 years)
with a slight female predominance.
Site
As the name implies, craniofacial CHS is a tumor that arises
in the base of the skull. The most frequently affected site is
the temporo-occipital junction (66 %), followed by the clivus
(28 %) and the sphenoid and ethmoid bones (6 %).
S. Piña-Oviedo et al.
Clinical Symptoms and Signs
Patients develop neurologic and/or vascular symptoms asso-
ciated with the region of the brain affected by the tumor
growth (compression of the brainstem or of the cavernous
sinuses). Swelling of the cheek and proptosis has been
described in one case.
Image Diagnosis
Radiographic Features
Because of the complex anatomy of the craniofacial region,
CT scan and/or MRI is the preferred method for the evalua-
tion of skull base CHSs.
CT Features
CHS of the skull base shows cranial bone destruction usually
with an associated soft tissue mass with areas of punctuate
calcifications.
MRI Features
Bone destruction and a large soft tissue mass are better eval-
uated with this technique (Fig. 23.22). MRI is optimal for
identifying areas of tumor extension but not to detect subtle
matrix calcification. CHSs have lack of perfusion after
administration of contrast compared to other tumors found in
this location that enter the differential diagnosis, such as
chordoma, meningioma, or metastasis.
Image Differential Diagnosis
Chordoma arises in similar anatomic locations, particularly
the clivus. Other tumors, such as osteosarcoma with exten-
sive cartilaginous component, should be considered in the
differential. A skull base meningioma or a metastasis should
also be considered.
Pathology
Gross Features
Similar features to the description for conventional intra-
medullary CHS.
Histologic Features
In a study of 200 cases of CHS of the skull base, approxi-
mately 50 % of the tumors were classified as grade 1,
28.5 % as mixed grade 1 and 2, and 21 % as pure grade 2
CHS. No high-grade features have been reported in this
region. Importantly, the majority of CHSs of the skull base
produces a hyaline matrix with a myxoid component
(Fig. 23.22).
Pathologic Differential Diagnosis
The main differential diagnosis of skull base CHS located in
the clivus is chordoma. CHSs in this location commonly
contain myxoid matrix and may resemble histologically the
myxoid matrix seen in chordoma. In fact, some of these have
been termed “chordoid CHSs.” Chordomas may also show
focal production of cartilaginous matrix. Physaliferous cells
23 Chondrosarcoma
are seen in chordoma but not in CHSs, but they may not be
present in a small biopsy of chordoma. In this setting, immu-
nohistochemistry for S100 protein, SOX9, pan-cytokeratin,
epithelial membrane antigen (EMA), and brachyury may be
necessary to establish the right diagnosis. CHSs are positive
for S100 protein and SOX9 and negative for cytokeratin,
EMA, and brachyury, whereas chordoma shows the inverse
staining profile. Distinction between CHS and chordoma is
crucial because CHSs have an excellent prognosis compared
to the more aggressive course of chordomas. In addition,
chordomas grow more rapidly and tend to occur a decade
later than CHSs.
Ancillary Techniques
Genetics
The tumor possibly shares similar genetic abnormalities as
those seen in conventional intramedullary CHS (see Genetics
for Conventional Intramedullary CHS). The TGFβ and BMP
pathways are activated in chondrocytes with resulting activa-
tion of ERK signaling, upregulation of MMPs, and destruc-
tion of the extracellular matrix, related to aggressive behavior.
Similarly to conventional central CHS, IDH1 R132C muta-
tions have been detected in 46 % of 13 intracranial CHS. This
molecular test may be helpful to differentiate intracranial
CHS from chordomas, which failed to demonstrate mutation
of IDH1.
Prognosis
Craniofacial CHSs have an excellent prognosis. Both 5- and
10-year disease-specific survival are 99 %. Conversely, the
5- and 10-year disease-specific survival rates of chordoma
are 51 % and 35 %, respectively. Tumors larger than 5 cm
were associated with a lower 5-year survival rate in one
study.
Treatment
The best treatment option is surgery and proton beam irra-
diation with survivals close to 100 %. From a review of the
literature and analysis of 161 cases of sinonasal CHS, the use
of radiotherapy for prevention of local recurrence after sub-
total or total resection has not been effective, but the use of
radiotherapy in addition to surgery has shown benefits in
terms of survival.
Periosteal (Juxtacortical) Chondrosarcoma
Definition
This tumor is a low-grade primary conventional CHS that
arises from the external surface of long bones, hence the
name. It was originally described in 1955 by Louis
Lichtenstein.
305
Synonyms
Periosteal CHS; juxtacortical CHS
Etiology
The etiology of periosteal CHS is unknown. The tumor
possibly shares similar genetic abnormalities as those seen in
conventional intramedullary CHS (see Genetics for this
lesion and for conventional intramedullary CHS).
Epidemiology
Periosteal CHS is a rare type of CHS (<1 %) and represents
<0.5 % of all bone tumors. The peak incidence is 20–50 years
of age (earlier than conventional intramedullary CHS) with a
slight male predominance.
Site
Periosteal CHS usually develops in the metaphyseal region
of long bones, particularly the femur, the humerus, and less
frequently in the tibia and fibula.
Clinical Symptoms and Signs
Periosteal CHS has no specific symptomatology. Most
patients develop mild to moderate pain and a slow-growing
palpable and painless mass in the affected region.
Image Diagnosis
Radiographic Features
Juxtacortical CHS tends to affect the metaphysis of the
involved bone and is observed as a radiolucent mass adjacent
to the cortex with well-defined cellular borders containing
the typical “popcorn,” “ringlet,” or punctate calcifications
(Fig. 23.23).
CT Features
This tumor is located adjacent to the cortex and has a round
or oval shape. The cortex underlying the lesions may be
eroded, thickened, or normal. Juxtacortical CHS has low
attenuation due to the high water content of the cartilage
matrix and may display calcific densities. As mentioned
previously, matrix mineralization is better visualized on CT
scan than on MRI. Peripheral enhancement is usually seen
after contrast administration.
306
MRI Features
Juxtacortical CHS has well-delineated borders at the bone
surface. Due to the high water content, the cartilage matrix
shows low to intermediate signal intensity on T1-weighted
images and bright signal on T1-weighted sequences
(Fig. 23.23). Typical septal and peripheral enhancement is
observed after administration of contrast material. MRI is
the most sensitive method to identify intramedullary spread
and/or soft tissue extension.
Image Differential Diagnosis
The differential diagnosis includes juxtacortical chondroma
and periosteal osteosarcoma. The latter tends to involve the
mid-diaphysis of a long bone, rather than the metaphysis. On
X-rays, periosteal osteosarcoma is a small – rather than
large – radiolucent mass with spicules of reactive bone
perpendicular to the underlying cortex.
Pathology
Gross Features
Periosteal CHS is usually a large soft tissue round to oval
mass with sharp borders with a mean size of 8 cm. The mass
is covered by a fibrous pseudocapsule that is continuous with
the underlying periosteum. On cut section, the tumor has a
gritty cut surface and is white and lobulated with recogniz-
able cartilaginous matrix and scattered calcifications
(Fig. 23.24).
Histologic Features
Periosteal CHS is typically a low-grade tumor with similar
features as seen in grade 1 or 2 CHS (Fig. 23.25). Despite the
low-grade features, nodules of tumor can invade the
surrounding soft tissues (Fig. 23.24, right). The amount of
myxoid matrix varies from case to case. However, if osteoid
matrix is present, the lesion should not be classified as a CHS
as it may represent a periosteal osteosarcoma. Invasion into
the medullary cavity of bone is not frequent and may occur
by extension of the tumor through the Volkmann’s canal.
Pathologic Differential Diagnosis
The main differential should be established with periosteal
osteosarcoma and periosteal chondroma. Periosteal osteosar-
coma was initially defined as a “juxtacortical CHS” until
K. Krishnan Unni and collaborators at the Mayo Clinic iden-
tified it as a form of osteosarcoma. It usually develops in
individuals younger than those that are affected by periosteal
CHS (10–30 years) and develops most commonly in the mid-
diaphysis of the proximal tibia. In contrast to periosteal CHS,
osteosarcoma of this region is more painful, grows rapidly,
and presents as a small mass by radiology. Histologically,
periosteal osteosarcoma shows a combination of low- to
S. Piña-Oviedo et al.
intermediate-grade CHS component capped by a high-grade
osteosarcomatous component. Periosteal chondroma is a
benign cartilaginous tumor that affects individuals in the
second and third decades of life. It arises more commonly in
the metaphysis of the proximal humerus, followed by the
femur and the short tubular bones of the hands and feet. The
tumor is small (1–3 cm) and slow growing with more regular
borders than periosteal CHS, and it develops within or under
the periosteum. Periosteal chondroma is composed of hya-
line cartilage with or without myxoid change. Even though
periosteal chondroma may exhibit hypercellularity, plump
nuclei, and binucleate cells, there is lack of anaplastic fea-
tures and penetration of the tumor into the cancellous bone.
Periosteal CHS should not be confused with secondary
peripheral CHS, which is a different entity with different
prognosis (see next section).
Ancillary Techniques
Genetics
Heterozygous somatic mutations of IDH1 (R132C) represent
a common genetic alteration in benign and malignant carti-
laginous lesions, including periosteal cartilaginous tumors.
Juxtacortical CHSs may share other genetic abnormalities as
those seen in conventional intramedullary CHS.
Prognosis
Periosteal CHS has a good prognosis compared to intramed-
ullary CHS. The tumor may recur locally. Metastatic disease
is relatively uncommon, and dedifferentiation is extremely
uncommon. In a long-term study of 24 patients with perios-
teal CHS from 2006, 29 % of patients had one or more local
recurrence and 25 % died of pulmonary metastases. The
overall 5-year metastasis-free survival was 83 %, number
that decreased in patients with grade 2 CHS (50 %) when
compared to those with grade 1 tumors (94 %).
Treatment
Wide surgical excision is the treatment of choice for perios-
teal CHS.
Secondary Chondrosarcoma
Secondary CHSs are tumors that develop in a preexisting
benign cartilage neoplasm, namely, enchondroma or osteo-
chondroma, and represent 10–15 % of all malignant carti-
laginous tumors. Similar to primary CHS, secondary CHS
23 Chondrosarcoma
can be divided by its location within a bone as central or
peripheral. Both tumors have different molecular and genetic
abnormalities. Secondary peripheral CHSs are far more
common than secondary central CHSs and will be discussed
first.
Secondary Peripheral Chondrosarcoma
Definition
Secondary peripheral CHS develops in a preexisting solitary
osteochondroma or in osteochondromatosis, also known as
hereditary multiple exostoses.
Synonyms
CHS arising in osteochondroma; CHS arising in osteochon-
dromatosis; Exostotic CHS
Etiology
Osteochondroma or exostosis is the most common benign
bone tumor and presents as a solitary lesion in 85 % of cases.
Osteochondroma is a sessile or pedunculated tumor covered
by a hyaline cartilage cap that grows from the metaphysis out
and away from the near articular joint. Typically, the con-
tents of medullary cavity of the bone are continuous with the
cancellous bone of the osteochondroma. Osteochondroma
affects young patients, and the tumor grows slowly until
skeletal maturity is reached in puberty. Secondary peripheral
CHS arises in 1 % of solitary osteochondromas and in 3–5 %
of patients with osteochondromatosis. The osteochondroma-
toses are a group of autosomal dominant disorders where
patients develop multiple osteochondromas. One of the
osteochondromatosis is the hereditary multiple exostosis
(HME) syndrome. HME is characterized by the formation of
multiple, usually symmetrical osteochondromas. LOH in
certain genes implicated in the normal production of proteo-
glycans has been implicated in the pathogenesis of solitary
osteochondromas and HME syndrome (See also Genetics).
Epidemiology
Secondary peripheral CHS arising in a solitary osteochon-
droma usually manifests in adults 50–55 years. In contrast,
CHS arising in HME typically develops in younger patients
(25–30 years of age). Males are more commonly affected.
Cartilaginous malignant transformation is an uncommon
event before age 20.
307
Site
Secondary peripheral CHSs arise in the same sites affected
by osteochondromas. Although in HME the long bones of
the upper and lower extremities are more severely affected
than the bones from the appendicular skeleton (ribs, spine,
scapula, and pelvis), in one study of 46 patients with HME,
secondary peripheral CHSs develop preferentially in the flat
bones.
Clinical Symptoms and Signs
The symptoms of secondary peripheral CHS are nonspecific,
but malignant cartilaginous transformation should be sus-
pected when an osteochondroma is painful or continues to
grow after reaching the age of skeletal maturity. Tumors may
progress rapidly when located in the pelvis, shoulders, or hips.
Image Diagnosis
Radiographic Features
In accordance with the clinical picture, secondary peripheral
CHS should be suspected radiologically when a previously
unmodified osteochondroma shows continued growth after
closure of the growth plates, develops an irregular or ill-
defined surface, shows focal areas of internal radiolucency,
presents with erosion and/or destruction of adjacent bone, or
is accompanied by a soft tissue mass with scattered or irregu-
lar calcifications after skeletal maturity (Fig. 23.26). Since
the cap of an osteochondroma is usually 6–8 mm thick, the
presence a cap larger than 2 cm after skeletal maturity has
completed is very suggestive of malignant transformation.
Nevertheless, the definitive diagnosis of malignancy should
be established histologically.
CT Scan and MRI Features
Both methods provide excellent yield of the malignant trans-
formation of an osteochondroma with characteristic shape of
calcifications/ossifications, lobulated growth, septations,
septal enhancement, and necrosis. CT and MRI are the most
useful techniques to accurately measure the thickness of the
cartilage cap in an osteochondroma, compared to simple
X-rays. A hyaline cartilage cap greater than 2 cm thick after
skeletal maturity is highly suggestive of malignant transfor-
mation and can be easily distinguished from adjacent soft
tissues on high contrast T2-weighted sequences. A recent
study showed that when using 2 cm as a cutoff to distinguish
between osteochondroma from secondary peripheral CHS,
CT and MRI showed sensitivities and specificities of 100 %
and 95 % and 100 % and 98 %, respectively, with a rate of
interobserver agreement of 88 %.
308
Pathology
Gross Features
Secondary peripheral CHS has a gray-white to bluish-gray
cut surface and demonstrates thickening of the cartilage cap
in an osteochondroma that is greater than 2 cm. The presence
of cartilaginous matrix is similar to other CHSs, and the
remaining areas of osteochondroma may show focal
calcification (Fig. 23.26).
Histologic Features
CHS arising in solitary osteochondroma is usually a low-
grade tumor with rare instances showing dedifferentiation or
multifocal disease. Microscopically, the area of cartilage cap
shows loss of the cartilaginous columnar architecture, and
fibrous bands appear between lobules of cartilage. Like con-
ventional primary CHS, the presence of nuclear atypia, mito-
ses, and myxoid change indicates a higher-grade lesion.
Pathologic Differential Diagnosis
Like the problematic distinction between enchondroma and
low-grade primary central CHS, differentiation of osteo-
chondroma from low-grade secondary peripheral CHS is
challenging. An analysis of 38 cases of low-grade secondary
peripheral CHS arising in HME by expert bone pathologists
showed a diagnosis agreement of 78 %. Besides presence of
a thin cartilage cap, identification of nodularity, binucleate
cells, irregular calcifications, cystic/mucoid degeneration,
and necrosis was not helpful in pointing towards malignant
transformation in osteochondroma, and thus, a multidisci-
plinary approach (clinical, radiologic, and pathologic) to
these lesions is mandatory. On the other hand, increased
mitoses, nuclear pleomorphism, and true myxoid change are
reliable features to discern between low-grade and high-
grade secondary peripheral CHS. Secondary peripheral CHS
should be distinguished also from osteosarcoma or chondro-
blastic osteosarcoma. The latter will show malignant osteoid
matrix which should not be present in CHS.
Ancillary Techniques
Genetics
HME syndrome is caused by mutations in the genes exosto-
sin-1 (EXT1) and exostosin-2 (EXT2). EXT1 is located on
chromosome 8q24.11–q24.13, and EXT2 is present on chro-
mosome 11p11–12. Mutations in these genes (nonsense,
frame shift, or splice-site mutations) cause premature termi-
nation of the EXT proteins with loss of protein function.
EXT1 and EXT2 proteins are glycosyltransferases implicated
in the biosynthesis of heparan sulfate proteoglycan (HSPG),
a glycoprotein present in the chondrocyte cell membrane and
S. Piña-Oviedo et al.
the extracellular cartilaginous matrix (Fig. 23.27).
Inactivation of both alleles of EXT1/EXT2 fails to produce
normal HSPG, creating a disruption in the diffusion gradient
of growth factors (IHH, PTHLH, and the fibroblast growth
factor [FGF]) and other molecules needed to maintain the
balance in growth and polarity of the epiphyseal growth
plate. These events result in the formation of an osteochon-
droma (Fig. 23.28). Cells that are homozygous for EXT
mutations (EXT -/-) lack the ability to respond to polarity
signals, begin growing out of the bone, and recruit normal
chondrocytes to form an osteochondroma. LOH of the EXT
genes has been found in solitary osteochondromas and in
HME syndrome. However, LOH is not always present in
osteochondromas possibly due to the mosaicism of the carti-
lage cap, which contains EXT-deficient as well as non-
mutated chondrocytes. Detection of a second mutation in
osteochondromas depends on the amount of wild-type and
mutated EXT proteins.
As mentioned in the section of conventional primary
CHS, the IHH/PTHLH signaling pathway functions to main-
tain the growth of the endochondral plate at a constant
thickness using a tightly regulated paracrine feedback loop
that modulates the proliferation and differentiation of
chondrocytes (see Genetics for conventional intramedullary
CHS, Fig. 23.19). Deregulation of the IHH/PTHLH signal-
ing pathway has repercussions on the balance of chondrocyte
maturation and prevents the formation of peripheral bone
near the epiphyseal growth plate, which plays a crucial role
in the pathogenesis of osteochondromas. IHH signaling is
also involved in the formation of the bony collar during
endochondral ossification. Thus, combination of events
(EXT protein mutations and IHH deregulation) is implicated
in the pathogenesis of osteochondroma.
For unknown reasons, IHH/PTHLH and FGF are mostly
absent in osteochondromas but are reexpressed with the
progression of osteochondroma towards secondary periph-
eral CHS. Upregulation of the IHH/PTHLH pathway and
reactivation of bcl-2 are implicated in the malignant
transformation of osteochondroma (Fig. 23.28).
Prognosis
The majority of secondary peripheral CHSs are low-grade
tumors with a good overall prognosis and a long-term
survival of 70–90 %. Local recurrence of the tumor depends
on the adequate resection of tumor margins. The local
recurrence rate varies from 0 to 15 % in cases with wide mar-
gins of resection compared to 57–78 % in cases with only
intralesional resection or close margin resection. Medullary
invasion may present in a third of the patients. Metastases are
uncommon. There is no clinical or prognostic difference
23 Chondrosarcoma
between secondary peripheral CHS arising in solitary osteo-
chondroma or in HME.
Treatment
Surgery with wide resection margins, including a portion of
the underlying bone, is the preferred treatment to decrease
the risk of local recurrence and achieve long-term disease-
free survival.
Secondary Central Chondrosarcoma
Definition
Secondary central CHS is a malignancy that arises in enchon-
dromatoses, such as Ollier or Maffucci disease.
Synonyms
CHS arising in enchondromatosis
Etiology
Possible genetic mutation of the parathyroid hormone recep-
tor type I (PTHR1) gene (see Genetics), but this finding is not
constantly identified in these lesions.
Epidemiology
The incidence of CHS in patients with Ollier or Maffucci
disease has been reported in the range of 15–30 %. Secondary
CHS arising in sporadic enchondroma is an extremely rare
event occurring in <1 % of cases.
Site
Bones usually involved by enchondromas include long bones
of the extremities and long bones of the hands and feet.
Clinical Symptoms and Signs
Ollier disease is the prototypic disease in the enchondroma-
tosis or a disorder characterized by the development of mul-
tiple enchondromas (nonhereditary disorders). It was named
after the French orthopedic surgeon Louis Xavier Édouard
309
Léopold Ollier, who described the first case of the disease in
1898. Basically, any bone formed by endochondral ossifica-
tion can be affected, but bones formed by membranous
ossification – skull and face – may be rarely involved.
Enchondromas develop in any part of a bone (epiphysis,
metaphysis, or diaphysis) and typically present as asymmet-
ric and/or unilateral lesions in the lower extremities, but
bilateral lesions in the hands and feet are also seen. The
biological behavior of enchondromas (size, number, loca-
tion, and evolution) varies among each patient. Maffucci’s
disease was originally recognized in 1881 by the Italian
pathologist Angelo Maffucci, who described a syndrome
associated with multiple enchondromas and spindle cell
hemangiomas. Malignant transformation in the setting of
enchondromatoses can be suspected if a patient develops
pain or a new soft tissue mass appears in the affected area or
develops a pathologic fracture. The risk of developing CHS
is higher for patients with enchondromas located in long
bones or axial skeleton, particularly the pelvis. Unifocal dis-
ease is more common, but multifocal disease may occur in
about 30 % of patients .
Image Diagnosis
CHS should be suspected whenever an enchondroma dem-
onstrates cortical destruction and extension into the sur-
rounding soft tissue. Fractures that occur without significant
trauma can be identified. The radiological features of CHS
on CT scan and MRI are identical to those described for pri-
mary CHSs (see above).
Pathology
Enchondromas in Ollier and Maffucci syndromes are benign
cartilaginous lesions, but if they exhibit abundant myxoid
change, invasion to the soft tissues, presence of nuclear
atypia, and mitoses, they represent a transformation into a
CHS. The main differential diagnosis remains between an
enchondroma and a low-grade CHS.
Ancillary Techniques
Genetics
The detection of a mutation on the PTHR1 gene (p.R150C)
and its relationship to enchondromatoses remain controver-
sial. Similar to HME pathogenesis, mutation of the PTHR1
gene causes disruption of the normal IHH/PTHLH feedback
loop causing constitutive activation of the Hedgehog signal-
ing (Fig. 23.28). On the other hand, somatic heterozygous
310
mutations in IDH1 (R132C) or IDH2 (R172S) have been
detected in >80 % of enchondromas and 70 % spindle cell
hemangiomas in Ollier and Maffucci disease, respectively.
Up to 81 % (35/43) of patients with Ollier disease and 77 %
(10/13) of patients with Maffucci disease commonly carry
mutations of IDH1 (98 %) and less frequently in IDH2 (2 %).
This novel finding was also confirmed by immunohisto-
chemistry using an antibody against IDH1 R312H in tissues
of these patients, which demonstrated a somatic mosaicism.
As mentioned above, a recent study demonstrated that pri-
mary CHSs harbor mutations in IDH1 or IDH2 genes.
Detection of similar molecular abnormalities in Ollier and
Maffucci diseases strongly suggest that IDH1 and IDH2
S. Piña-Oviedo et al.
mutations have a causal rather than bystander role in tumori-
genesis in enchondromatoses.
Additionally, IDH mutations correlated with a CpG island
methylator phenotype indicating that hypermethylation is
also important in the pathogenesis of these syndromes.
Prognosis
The prognosis of CHS arising in enchondromatosis is similar to
that of conventional CHS. However, prognosis may vary
depending on the location and grade of the tumor. Enchondromas
from the pelvis have a higher risk for malignant transformation.
23 Chondrosarcoma 311

Fig. 23.1 Low-grade central CHS of the humerus. Left, the radio-
graphic image shows the medullary cavity filled by a mass with punc-
tate (popcorn or ringlet) calcifications. There is minimal endosteal
scalloping and no cortical bone permeation. Right, same lesion after
resection; the medullary cavity is not expanded but is partially occupied
by a gray-white lobulated mass. This patient presented with pain in the
shoulder that awakened her at night

Fig. 23.2 Low-grade central CHS of the proximal tibia. Left, the X-ray
shows minimal expansion of the medullary cavity, endosteal scalloping
with a periosteal reaction. Right, same lesion after resection; the medul-
lary cavity is expanded and replaced by a gray-white lobulated mass
312 S. Piña-Oviedo et al.

Fig. 23.3 CHS arising in the

surface of the ischium. Left, the
ischial spine is involved by a
large cartilaginous lesion that
shows prominent calcification
including ringlet calcifications at
the periphery (arrows). Right,
same lesion after resection; the
mass is composed of multiple
lobules of cartilage calcified at
the periphery, which correspond
to the ringlet calcifications seen
on the radiograph

Fig. 23.4 Central CHS of the femur. Extensive diaphyseal lesion

extending into the intertrochanteric area. The medullary cavity is
expanded, and there is endosteal scalloping but there is no break-
through. Note that in the mid-diaphysis, there is an irregular area
depicting myxoid change (arrow). These are signs of aggressiveness of
the lesion, and the myxoid change strongly suggests a high-grade lesion
23 Chondrosarcoma 313

Fig. 23.5 Low-grade CHS with

breakthrough of the cortex. Left,
this tumor shows an aggressive
behavior with involvement of the
cortex. The bone shows a
prominent periosteal reaction.
Stippled calcifications are seen
within the mass, indicative of a
cartilaginous lesion. Right, same
lesion after resection; the cortical
bone is thickened with presence
of cartilaginous lobules within
the cortex, cortical disruption,
and extension into the
periosteum. Despite the
involvement of the cortex,
histologically, the lesion was low
grade

Fig. 23.6 CHS with myxoid changes. This tumor is radiolucent and changes. Minimal soft tissue periosteal extension is present. Bone per-
without calcifications. There is expansion of the trochanter and with meation and myxoid change strongly suggest a high-grade cartilagi-
bone cortical permeation (arrows). Right, the mass has marked myxoid nous neoplasm
314 S. Piña-Oviedo et al.

Fig. 23.7 Magnetic resonance

imaging (MRI) is a better
technique to evaluate the extent
of marrow involvement and
identify invasion into the soft
tissues. On T1-weighted images
(left), CHSs show low to
intermediate signal due to the
high water content of the
cartilaginous matrix (asterisk).
Compare the signal intensity of
this lesion with the skeletal
muscle around the humerus. On
the other hand, CHSs have high
signal intensity on T2-weighted
images (right). This cartilaginous
lesion is pushing through the
cortical bone but does not invade
into the soft tissues

Fig. 23.8 Low-grade CHS of

the scapula. Note the gray-white
lobulated cut surface and stippled
calcifications
23 Chondrosarcoma 315

Fig. 23.9 High-grade CHS of

the femur. Left, the trochanter
and intertrochanteric areas are
occupied by a mass with similar
signal as that of skeletal muscle.
There is cortical bone permeation
without a soft tissue mass. Right,
the gross image shows a pearly
white mass with myxoid change

Fig. 23.10 High-grade CHS of

the humerus. Left, the mass
occupies the head of the humerus
and extends into the
glenohumeral joint. Right, gross
image. The mass has areas of
cartilage as well as prominent
myxoid changes
316 S. Piña-Oviedo et al.

Fig. 23.11 Low-grade

CHS. This lesion is characterized
by a mildly cellular proliferation
of mature cartilaginous tissue
with cells in lacunar spaces. At
higher magnification (right), the
chondrocytes exhibit pyknotic
nuclei, about the size of a mature
lymphocyte without nuclear
atypia, mitotic activity, or
presence of stromal myxoid
change

Fig. 23.12 Different

morphologic spectrum of
low-grade CHS. Left, this
cartilaginous tumor shows
mature cartilaginous matrix and
more increased cellularity
compared to Fig. 23.11. The cells
have pyknotic nuclei with rare
binucleate cells. Right, this other
low-grade CHS shows mildly
increased cellularity with
chondrocytes retaining the
lacunar formation and a more
stellate morphology. No mitotic
figures or myxoid change is seen
in any case
23 Chondrosarcoma 317

Fig. 23.13 CHS grade 2a. This cartilaginous lesion permeates between
bone trabeculae and the lacunar arrangement, although still present,
begins to fade and a myxoid stromal pattern begins to appear
Fig. 23.14 High-grade CHS. Microscopic picture of the mass from
Fig. 23.9. The tumor is composed of a hypercellular tumor with diffuse
myxoid change, cells with nuclear enlargement, and occasional nucleo-
lus. Note a tripolar mitosis in the upper right corner (arrow). The lacu-
nar arrangement is completely lost

Fig. 23.15 High-grade

CHS. Mitotic figures (arrows)
are easily found in grade 3 CHSs
318 S. Piña-Oviedo et al.

Fig. 23.17 Ayala’s subdivision of grade 2 CHSs. Grade 2a cartilagi-

Fig. 23.16 CHS grade 2b. There is extension of a cartilaginous tumor
between bone trabeculae. This cartilaginous tumor has lost the lacunar
arrangement and shows diffuse myxoid change with cellular atypia.
Myxoid change is not a feature of low-grade CHSs
nous tumors maintain a lacunar arrangement and do not show nuclear
atypia or mitotic activity. Grade 2b CHSs have increased cellularity,
show partial or no retention of the lacunar pattern, may have one or no
mitoses per ten HPFs, and contain myxoid matrix

1.1

C 1.0
u
m .90
m
u .80
l
a .70
t
i .60 Grade
v 3
.50
e 3-censored
S .40 2B
u
r .30 2B-censored
v 2A
i .20
Chondrosarcoma : all grades 2A-censored
v
.10 1
a
l 0.0 1-censored
0 100 200 300 400 500

C 1.1
u
m 1.0
m
u .90
l .80
a
t .70
i
v .60
Fig. 23.18 Cumulative survival e
.50
charts in patients with CHSs. S
Grade 1 and 2a CHS and grade u .40
2b and 3 CHS (top chart) are r
.30
grouped into identical survival v 2B & 3
Chondrosarcoma: grade 1
i .20
rates (see bottom chart). Grade 1 & 2a vs 2b & 3 2B & 3 censored
v
and 2a may recur but do not a .10 1 & 2A
metastasize and have a good l
prognosis. In contrast, CHS 0.0 1 & 2A censored
0 100 200 300 400 500
grade 2b and 3 metastasize in
about 60 % of the cases Time in Months
23 Chondrosarcoma
Fig. 23.19 The endochondral plate growth balance is regulated by the
IHH/PHTLH pathway. Chondrocytes from the pre-hypertrophic zone
produce Indian hedgehog (IHH) which binds its receptor Patched
(PTCH) in hypertrophic chondrocytes to induce the production of para-
thyroid hormone-like hormone (PTHLH). The latter binds its receptor
(PTHR) in chondrocytes from the resting zone and induces prolifera-
tion by different mechanisms (proliferative zone), including reactiva-
tion of bcl-2. As a regulatory feedback, PHTR-PTHLH downstream
319
signals decrease the production of IHH, thus maintaining a constant
thickness at the growth plate. In addition, increased bcl-2 is capable to
decrease the production of IHH. These molecules travel through the
different zones of the growth plate by diffusion (see also Fig. 23.27).
Alterations in the IHH/PTHLH pathway and abnormal activation of
bcl-2, among other mechanisms, are involved in the development of
central CHS (Figure elaborated by Sergio Piña-Oviedo)
320 S. Piña-Oviedo et al.

Fig. 23.20 CHS of the hand. Left, this radiograph of the right hand in lesion shows and expanded metacarpal bone with heterogeneous inten-
oblique position shows a radiolucent lesion in the second metacarpal sities (arrow)
bone with punctate calcifications (arrow). Right, MRI at the level of the

Fig. 23.21 Histologic image from the mass on Fig. 23.20. Low-grade
CHS with hypercellularity and bone permeation
23 Chondrosarcoma 321

Fig. 23.22 CHS of the base of the skull. Left, the T2-weighted coronal is a low-grade CHS permeating into the bone. Right bottom, note the
MRI of the head demonstrates a mass with hyperintense signal involv- increased cellularity, focal myxoid component of the matrix, and the
ing the right wing of the sphenoid bone (arrows). Right top, the tumor presence of binucleate chondrocytes

Fig. 23.23 Periosteal or juxtacortical CHS. Left, this oval-shaped lesion has a low to intermediate signal intensity on T1. Note the con-
tumor is located at the metaphysis of the humerus and has the typical tinuation of the tumor capsule with the periosteum of the humerus
features of CHS with ringlet calcifications (arrow). Right, on MRI, the (arrow)
322 S. Piña-Oviedo et al.

Fig. 23.24 Periosteal or juxtacortical CHS. Gross image (left) and full ules of cartilage. Right, focal invasion into the bone is seen at the
montage (right) of the lesion from Fig. 23.23. The tumor has well- inferior aspect of the tumor
defined borders, is surrounded by a capsule, and contains mature lob-
23 Chondrosarcoma 323

Fig. 23.25 Periosteal or juxtacortical CHS. The tumor is composed of

lobules of hypercellular cartilage and features of a low-grade CHS

Fig. 23.26 Secondary peripheral CHS. This patient with osteochon- radiolucency, irregular calcifications, and extension into the soft tis-
dromatosis presented with painful enlargement of a pelvic osteochon- sues. Right, there are multiple lobules of cartilage that measure more
droma. Left, the tumor has an ill-defined surface with areas of than 2 cm in thickness and focal areas of calcification
324 S. Piña-Oviedo et al.

Fig. 23.27 Function of

exostosin-1 and 2 (EXT1–2).
These glycosyltransferases
transfer sulfate groups to
proteoglycans to generate
heparan sulfate proteoglycan
(HSPG), a major component of
the cartilage matrix. Since
cartilage is avascular, the
cartilage matrix composition
allows the diffusion of molecules
to different regions in the absence
of blood vessels. HSPG is also
found in the membrane of
chondrocytes, where it can bind
to several molecules, including
IHH. Mutation on EXT1 and
EXT2 leads to abnormal or
decreased production of HSPG,
which results in an abnormal
cartilage matrix that does not
permit a proper diffusion of
molecules within the growth
plate. These alterations are
implicated in the formation of
osteochondromas (genetic and/or
sporadic) (Figure elaborated by
Sergio Piña-Oviedo)
23 Chondrosarcoma
Fig. 23.28 Mechanisms of pathogenesis in central and peripheral sec-
ondary CHSs. Similar to central CHS, peripheral CHS arises from
abnormalities in the growth plate. Mutations of EXT1 and/or EXT2
result in an abnormal cartilage matrix that may produce dysregulation or
abnormal diffusion of IHH, PTHLH, and other growth factors within
the growth plate. Eventually, these events result in the formation of a
sporadic osteochondroma or in osteochondromatosis (i.e., HME). Due
to unknown mechanisms, when reactivation of PTHLH and activation
of bcl-2 occur, osteochondromas may progress to a low-grade periph-
eral CHS. On the other hand, central peripheral CHS may occur in the
325
setting of sporadic enchondroma or enchondromatosis. The genetic
alterations associated with sporadic enchondroma remain unknown.
Enchondromatosis may occur due to mutations in PTHR1 or possibly
due to mutations in IDH1/IDH2 as recently discovered (see text). Again,
enchondromas may progress to low-grade central CHS after activation
of PTHLH and bcl-2. Progression to high-grade CHS is related with the
different additional genetic abnormalities mentioned in the figure. The
role of COX-2 and IDH1/IDH2 mutations in the development of sec-
ondary CHSs is unknown, and further studies are needed to address
their role in these tumors (Figure elaborated by Sergio Piña-Oviedo)
326
Dedifferentiated Chondrosarcoma
Yong-Koo Park
Definition
• A rare malignant neoplasm characterized by a high-grade,
nonchondroid sarcoma, such as malignant fibrous histio-
cytoma, osteosarcoma, fibrosarcoma, rhabdomyosar-
coma, or angiosarcoma, associated with, and apparently
arising from, a low-grade, cartilage-forming tumor.
Etiology
• Dedifferentiated chondrosarcoma almost always origi-
nates from a central chondrosarcoma.
Y.-K. Park, MD, PhD
Department of Pathology, Kyung Hee University
School of Medicine, Seoul, South Korea
e-mail: ykpark0204@gmail.com
S. Piña-Oviedo et al.
• Sometimes it may arise from a preexistent enchondroma
and even from Ollier disease.
• A small number of dedifferentiated chondrosarcomas
develop in an osteochondroma or in osteochondro-
matosis.
Epidemiology
• Represents approximately 10–11 % of all chondrosarcomas.
Sex
• Slightly more males than females are affected.
Age
• The age range is wide, but the majority of tumors occur in
patients over the fourth decade. The peak age incidence is the
sixth decade of life.
23 Chondrosarcoma
Sites of Involvement
• Similar to ordinary chondrosarcoma.
• The femur is the most frequently involved bone, compris-
ing nearly 35 % of all cases, followed by the pelvis
(30 %), the humerus (15 %), the rib, and the scapula.
Clinical Symptoms and Signs
• Pain is the predominant symptom in more than 94 % of
patients.
• Other symptoms include mass and pathological fracture.
• The duration of symptoms is variable, ranging from 1 to
36 months.
Image Diagnosis
Radiographic Features
• Radiographically, the existence of the two components
(low- and high-grade) of dedifferentiated chondrosar-
coma can frequently be recognized.
• The distinctive radiographic findings are medullary cal-
cific foci, cortical permeation, and extraosseous masses.
• Characteristically, the lesions have a bimorphic pattern,
with an area of a low-grade tumor tissue, with frequent
calcifications, juxtaposed to a lytic area of more aggres-
sive destructive changes.
• Around 50 % of the cases show a soft-tissue mass and
13 % show pathological fracture.
CT and MRI Features
• Computed tomography and magnetic resonance imag-
ing are techniques used for more accurate resolution of
smaller lytic areas of dedifferentiation or the presence
of a residual calcified tumor within large lytic areas.
These imaging techniques also help in evaluating the
extent and relationships of any associated soft tissue
component.
Image Differential Diagnosis
• Any high-grade sarcoma – the bimorphic pattern, when
identified in the images, helps in the differential diagnosis.
Pathology
Gross Features
• The diagnosis of dedifferentiated chondrosarcoma is gen-
erally obvious on examination of the gross specimen.
• The intramedullary portion of the centrally located tumors
has the usual gray-white appearance of lobulated carti-
laginous tumors.
327
• The fleshy, dedifferentiated portion is usually, but not
always, extraosseous. This high-grade sarcomatous compo-
nent may show hemorrhage and necrosis. Cortical disrup-
tion and extension into soft tissue are frequently present.
Histological Features
• The hallmark of dedifferentiated chondrosarcoma is the
coexistence of its two components: a low-grade cartilagi-
nous precursor lesion and a high-grade sarcoma.
• Typically, the chondrosarcoma component is often a low-
grade (Grade 1 or 2) chondrosarcoma. It is also reported that
high-grade chondrosarcoma can predominate.
• Predominant noncartilaginous component has varied
from case to case. Undifferentiated high-grade sarcoma
and fibrosarcoma account for most of the dedifferentiated
tumor.
• High-grade spindle cells are typically arranged in a stori-
form pattern with intermixed giant cells.
• Rhabdomyoblastic differentiation, osteosarcoma, fea-
tures of smooth muscle differentiation, as well as giant
cell features, may also be present.
Pathologic Differential Diagnosis
High-Grade Conventional Chondrosarcoma
• Distinct biphasic character of dedifferentiated chondro-
sarcoma with sharp demarcation of the two components is
lacking.
Mesenchymal Chondrosarcoma
• Mesenchymal chondrosarcoma has its cartilaginous
component speckled throughout the tumor and mixed
with the spindle cell or small round cell noncartilaginous
component showing typical hemangiopericytomatous
area.
Chondroblastic Osteosarcoma
• Chondroblastic osteosarcoma has neoplastic osteoid
irregularly mixed with usually high-grade cartilage, and it
lacks two grossly separate malignant elements.
Malignant Fibrous Histiocytoma
• Malignant fibrous histiocytoma is excluded by the pres-
ence of cartilage.
Fibrosarcoma
• Fibrosarcoma is excluded by the presence of cartilage.
Ancillary Techniques
Immunohistochemistry
• The two components of dedifferentiated chondrosarcoma
have distinct immunohistochemical profiles.
328
• Low-grade cartilage lesion is strongly positive for S-100
protein, whereas the high-grade component is typically
negative for S-100 protein.
• This high-grade area may, on occasion, show focal posi-
tivity for smooth and skeletal muscle and epithelial mark-
ers such as smooth muscle actin, desmin, myoglobin,
keratin, and epithelial membrane antigen.
• Diffuse strong nuclear staining for p53 is seen in the high-
grade noncartilaginous component, regardless of the his-
tological type. The low-grade cartilaginous component
was found to be negative for p53.
Genetics
• Localized point mutation of G to C in codon 276 was
reported in one case of dedifferentiated chondrosarcoma.
These results suggest that p53 mutations are present in a
minority of dedifferentiated chondrosarcomas.
• Molecular genetic characterization of dedifferentiated
chondrosarcoma provided strong evidence for a monoclonal
origin, since both components share an identical p53 muta-
tion and the deletion of the same copies of chromosome 13.
• H-ras oncogene mutation using polymerase chain reac-
tion-restriction fragment length polymorphism analysis
was reported.
• Studies on IDH1/2, p53, and retinoblastoma pathways in
dedifferentiated chondrosarcoma showed that they were
affected in 50 %, 59 %, and 85 %, respectively.
S. Piña-Oviedo et al.
Prognosis
• Has a poor prognosis, with patients rarely surviving more
than 2 years.
• Local recurrence has been reported in up to 50 % of cases
after excision, with much better control of local disease after
radical amputation.
• Mean survival has been as short as 6 months, and 5-year rates
of survival as low as 10–13 %.
• Widespread hematogenous metastases are the rule, and the
response to chemotherapy is poor.
Treatment
• In general, the dedifferentiated component is more resis-
tant to chemotherapy and radiation therapy than de novo
malignant fibrous histiocytoma or osteosarcoma.
• Patients receiving chemotherapy, and in whom wide
margins of excision were achieved at operation, may do
better.
See Figs. 23.29, 23.30, 23.31, 23.32, 23.33, 23.34, 23.35,
23.36, 23.37, 23.38, 23.39, and 23.40 for illustrations of
Dedifferentiated Chondrosarcoma.
23 Chondrosarcoma 329

Fig. 23.30 The gross appearance correlates with Fig. 23.29 showing
cortical destruction with cartilage lesion and extraosseous soft tissue
tumors (Courtesy of Chungnam National University)
Fig. 23.29 Dedifferentiated Chondrosarcoma. Radiograph of femur
showing extensive bone destruction with endosteal erosion and soft tis-
sue mass. Figs. 23.29, 23.30, 23.31, 23.32, 23.33, 23.34, and 23.35
from same case

Fig. 23.31 Low power view shows typical bimorphic pattern charac-
terized by low-grade chondrosarcoma and high grade spindle cell sar- Fig. 23.32 The chondroid lesion shows low-grade chondrosarcoma
coma areas area
330 S. Piña-Oviedo et al.

Fig. 23.33 High-grade chondrosarcoma lesion is seen in upper right

area

Fig. 23.34 High-grade undifferentiated spindle cell sarcoma is Fig. 23.35 In this area fibrosarcomatous lesion is present
associated
23 Chondrosarcoma 331

a b

Fig. 23.36 Dedifferentiated Chondrosarcoma. Radiograph (a) and drosarcoma and a proximal and lateral lytic area corresponding to
coronal CT scan (b) show a lesion in the upper end of tibia with two high-grade sarcoma that destroys cortex and invade soft tissue
components, a lower calcified one corresponding to low-grade chon-

Fig. 23.37 Medium power microphotography of lesion of Fig. 23.36

shows the two histologic components, low grade at left and high grade
at right, represented by osteosarcoma in this lesion
332 S. Piña-Oviedo et al.

Fig. 23.38 Hemisection of a dedifferentiated chondrosarcoma con-

taining mainly the well-differentiated component. Same specimen as Fig. 23.39 Hemisection of the same specimen of dedifferentiated
Fig. 23.39 chondrosarcoma of Fig. 23.38. The dedifferentiated component is
evident

Fig. 23.40 Microscopy of the

interface between the differenti-
ated (left) and the dedifferenti-
ated (right) components of the
same lesion of Fig. 23.38 and
Fig. 23.39
23 Chondrosarcoma 333

Mesenchymal Chondrosarcoma Etiology

Yong-Koo Park • The etiology of mesenchymal chondrosarcoma is unknown.

Epidemiology
Definition
• Corresponds to about 2 % of all chondrosarcomas.
• A rare, distinct malignant neoplasm characterized by the
presence of solid, highly cellular areas composed of round or Age
slightly spindled primitive mesenchymal cells with foci of • Usually young adults and teenagers. The peak incidence
cartilaginous differentiation. is during the fourth followed by the third decade of life
• The noncartilaginous elements usually predominate, but can be seen at any age.
and such lesions can be confused histologically with
Ewing’s sarcoma, malignant lymphoma, or hemangio- Sex
pericytoma. • There is no sex predilection.

Y.-K. Park, MD, PhD

Department of Pathology, Kyung Hee University
School of Medicine, Seoul, South Korea
e-mail: ykpark0204@gmail.com
334
Sites of Involvement
• Favors the maxilla, mandible, ribs, and vertebrae.
• The ilium and calcaneous are often affected in older
patients.
• The pelvis and femur are additional common sites of
involvement.
• Approximately 30 % of mesenchymal chondrosarcomas
present as extraskeletal soft tissue lesions.
• There are also case reports of primary mesenchymal
chondrosarcoma involving the meninges, lung, kidney,
orbit, hyoid bone, and cranial cavity.
Clinical Symptoms and Signs
• Presenting complaints typically consist of pain and, occa-
sionally, swelling. Duration of symptoms vary widely
from days to about 2 years.
• In some patients, the tumor was an incidental finding of
X-ray examination for other causes.
Image Diagnosis
• Radiologically, a lytic defect that often contains stippled
densities corresponding to small islands of mineralized
cartilage is present.
• It is often eccentrically located in bone.
• Stippled calcifications are frequently present and may
coalesce to form large, discrete opacities.
• Most mesenchymal chondrosarcomas have an indistinct
border. Some have sharply defined or rarely sclerotic
margins.
• The cortex is destroyed in approximately half of the cases,
with associated extension of tumors into the adjacent soft
tissues.
• The radiological features of mesenchymal chondrosar-
coma are not specific; however, they usually suggest a
malignant tumor, probably of cartilaginous origin.
Image Differential Diagnosis
• There are no specific imaging criteria for establishing a
reliable differential diagnosis with other benign and
malignant lesions.
Pathology
Gross Features
• Typically gray to pink, firm or soft, and usually well
defined.
• Sometimes there are foci of calcification.
S. Piña-Oviedo et al.
• The tumor may have an overall lobulated margin and
large areas of heavily calcified tissue.
• Zones of necrosis and hemorrhage may be present.
Histological Features
• Small foci of hyaline cartilage are seen admixed or
blended with predominant areas composed of small round
cells. These foci are sharply demarcated from the sur-
rounding cells and show focal calcification and endo-
chondral bone formation. The cartilage is cytologically
low grade.
• The principal histological elements are sheets of small
round cells with scant cytoplasm and hyperchromatic
nuclei.
• Sometimes the cells are spindle shaped. These cells are
often arranged in a pattern suggestive of
hemangiopericytoma.
• The nuclei usually have irregular clumping of the chro-
matin and small nucleoli.
• Regardless of the shape of the cells, they tend to be only
modestly pleomorphic.
• Mitotic figures are usually sparse, but may on occasion be
numerous.
• The cells within the cartilage tend to have round or ovoid
nuclei similar to those seen in the surrounding stromal cells.
• May contain amorphous, sharply demarcated islands of
collagen resembling osteoid. These dense islands lack the
delicate, lace-like appearance of the osteoid in osteosar-
comas, including the small-cell variant.
Pathologic Differential Diagnosis
Ewing’s Sarcoma
• May be mimicked by areas that have broad sheets of small
cells.
• However, the presence of cartilaginous-type calcification
should suggest the correct diagnosis.
• Immunohistochemistry may be necessary, especially in
small biopsies. Although both tumors may be positive for
CD99, the small-cell components of mesenchymal chon-
drosarcoma are positive for SOX9 and negative for FLI-1.
Small-Cell Osteosarcoma
• Small-cell osteosarcoma is distinguished from mesenchy-
mal chondrosarcoma mainly by the presence, although
often focal, of lace-like osteoid.
Dedifferentiated Chondrosarcoma
• Dedifferentiated chondrosarcoma differs by having two
grossly separate components. The cartilage of this tumor
is not interspersed in the noncartilaginous stroma, as is
seen in mesenchymal chondrosarcoma.
23 Chondrosarcoma
Ancillary Techniques
Immunohistochemistry
• Vimentin positive, neuron-specific enolase focal positive,
S-100 protein and CD99 positive, and smooth muscle
actin negative although some positivity has been reported
with this marker.
• S-100 protein expression in the chondroid area has been
described to be most distinctive in this tumor.
• Positive for SOX9 and negative for FLI-1 in the small-cell
components of mesenchymal chondrosarcoma.
Genetics
• Mutational alteration of the p54 tumor suppressor gene
and p16 oncogene in mesenchymal chondrosarcomas was
hardly studied.
• In mesenchymal chondrosarcoma, more than 60 % of
cases were shown to present nuclear p53 positive staining.
Quantitative DNA/PCR analysis revealed that 18.2 % of
the cases carried significantly reduced low levels of p53,
indicating the genomic deletion of the gene in these
tumors, and 21.2 % of tumors showed abnormally low
levels of p16 amplification.
• Flow cytometry of eight tumors studied revealed a diploid
pattern in six, aneuploidy in two, and a wide range of
S-phase fractions. Also the survival rate may be shortened
for those patients with a high S-phase fraction and a high
Ki-67 staining frequency.
• A novel HEY1-NCOA2 fusion was identified by 5’
RACE, representing an in-frame fusion of HEY1 exon 4
to NCOA2 exon 13 in mesenchymal chondrosarcoma.
335
• The IDH1/2, p53, and retinoblastoma pathways were
demonstrated to be affected in 0, 39, and 70 % in mesen-
chymal chondrosarcomas.
Prognosis
• The prognosis is completely unpredictable.
• Some patients present with widespread metastasis and die
soon.
• The 5-year survival rate is around 50 %, and the 10-year
survival rate around 28 %.
• Metastases, however, may not appear until 5–22 years
after the initial diagnosis, and typically involve the lungs,
other bones, lymph nodes, and viscera.
Treatment
The treatment of choice is wide local excision. In 26 patients
with mesenchymal CHS, the disease-free survival in patients
between 5 and 10 years after surgical remission of disease was
76 % with chemotherapy compared to 17 % without it. In another
study analyzing 30 cases of mesenchymal CHS with localized
disease, patients who did not receive radiotherapy failed to show
local overall, disease-free, metastasis-free, or local recurrence-
free survival with or without addition of chemotherapy.
See Figs. 23.41, 23.42, 23.43, 23.44, 23.45, 23.46,
23.47, 23.48, and 23.49 for illustrations of Mesenchymal
Chondrosarcoma.
336 S. Piña-Oviedo et al.

Fig. 23.43 The tumor shows nodular brownish appearance with foci
of bluish chondroid areas

Fig. 23.41 Mesnchymal Chondrosarcoma. Radiograph of left 9th rib

shows destruction of the anterior arc with dense calcified foci
Figs. 23.41, 23.42, 23.43, and 23.44 from same case.

Fig. 23.44 At low power view, there are scattered hypocellular chon-
droid zone and hypercellular cellular areas. The cellular areas are com-
posed of small round cells

Fig. 23.42 Gross photography of lesion in Fig. 23.39 shows large soft
tissue fishflesh-like mass and intraosseous lesion with frequent gray-
white calcification areas
23 Chondrosarcoma 337

a b

Fig. 23.45 (a) The hypercelullar areas show small round blue cells, similar to those of small cell osteosarcoma and hemangiopericytoma. (b) In
area, tumor shows characteristic vascular pattern, so called hemangiopericytomatous pattern, stag-horn like vascular spaces

Fig. 23.46 High power view of small cells show round ovoid nuclei Fig. 23.47 Sometimes, a peripheral osteoid, or bone formation is evi-
with stippled chromatin patterns and occasional small nucleoli dent. The differential diagnosis in such cases should consider small cell
osteosarcoma
338 S. Piña-Oviedo et al.

Fig. 23.48 (a) Macrophoto-

graphy of a mesenchymal a b
chondrosarcoma in the distal end
of a femur with soft tissue
extension of the tumor. (b)
Specimen radiograph. Lytic
lesion involving metaphysis and
epiphysis of femur, with no
peripheral sclerosis, and stippled
foci of mineralization distributed
in the lesion. The soft tissue
extension is densely mineralized
and its connection with the bone
lesion is not visible in this
section

Fig. 23.49 Microphotography showing a basically blue round cell

tumor with a focus of chondroid matrix production
23 Chondrosarcoma 339

Clear Cell Chondrosarcoma Epidemiology

Yong-Koo Park • A rare tumor that accounts for less than 2 % of all
chondrosarcomas.

Sex
Definition • The reported sex ratio, male to female, is 2:1.

• A rare low-grade malignancy, characterized by rounded Age

cells with conspicuous clear or vacuolated cytoplasm and • The peak incidence is in fourth and fifth decades of life;
by a cartilaginous or chondroid matrix in at least some however, individual cases are reported from the second to
areas. Scattered osteoclast-type giant cells, occasional seventh decades.
bone trabeculae, and aneurysmal bone cyst-like areas
may also be present. Sites of Involvement
• The most common location is distal femur, followed by
proximal humerus, proximal femur, proximal tibia, and
Etiology vertebrae and ribs.
• The skull, ischium, ulna, and phalanx are also sites of
• The etiology of clear cell chondrosarcoma is involvement.
unknown. • The scapula, pelvis, and talus may also be involved.

Y.-K. Park, MD, PhD

Department of Pathology, Kyung Hee University
School of Medicine, Seoul, South Korea
e-mail: ykpark0204@gmail.com
340
Clinical Symptoms and Signs
• Predominantly, local pain of significant duration. About
half of the patients had symptoms lasting 1 year or less, one
third from 1 to 5 years, and a few for longer than 5 years.
Image Diagnosis
• Radiographically, one of the most constant findings is the
propensity for the tumor to involve the epiphysis of a long
bone and extend to the articular cartilage.
• The majority of the cases extend to the metaphysis.
Rarely, other site of the bone is involved.
• The most common roentgenographic pattern is that of a
purely lucent lesion. About a third of the cases are lucent
with areas of calcification within the tumor. The character
of the calcification is more like that seen in
chondroblastoma.
• A sharp interface between tumor and normal bone is usu-
ally found, frequently with a sclerotic rim; indistinct mar-
gin is seen in less than half of the cases. The cortex of the
bone is thinned in the majority of cases and not disrupted
in 75 %.
Image Differential Diagnosis
Chondroblastoma
• In its classical epiphyseal location, chondroblastoma may
be radiologically indistinguishable. Clear cell chondro-
sarcoma is a more aggressive lesion, frequently expand-
ing the bone and permeating the cortex.
Pathology
Gross Features
• The cartilaginous nature of the tumor is not always read-
ily identifiable on a gross specimen.
• The inner wall presents bony ridges and depressed zones
lined by a smooth grayish-white to reddish-brown
membrane.
• The lesion tends to be soft and solid, and corresponds
grossly to the amount and nature of secondary structures
such as an aneurysmal bone cyst, as seen
microscopically.
Histological Features
• The tumor cells are arranged in an indistinct microlobular
pattern, separated by delicate fibrovascular stroma.
• The microscopic hallmark of the lesion is the clear cell,
whose nucleus is centrally situated, round, and of even
chromatin distribution. The surrounding cytoplasm is
S. Piña-Oviedo et al.
empty, with occasional peripheral cytoplasmic eosino-
philic condensations. Cytoplasmic borders are distinct.
• Most of the tumors have a few benign giant cells,
which are practically never seen in usual
chondrosarcoma.
• Mitotic figures are rare.
• Small or larger areas of conventional chondrosarcoma,
typically grade 2, are identified in more than half of the
cases. In some areas, it shows invasive pattern of growth.
• Areas of calcification and bone formation are present.
Pathologic Differential Diagnosis
Chondroblastoma
• Because of its location in the epiphyseal end of the long
bones, it is a major differential diagnosis.
• Chondroblastoma cells are oval or spindle shaped and
have smaller and lightly eosinophilic cytoplasm, in con-
trast to the cells of clear cell chondrosarcoma.
Metastatic Clear Cell Carcinoma such as Renal Cell
Carcinoma
• Metastatic clear cell carcinoma such as renal cell carci-
noma may cytologically resemble clear cell chondrosar-
coma. However, in metastatic clear cell carcinoma, it can
be distinguished by the absence of a chondroid matrix and
by the immunohistochemical demonstration of S-100
protein, which is intensely positive in clear cell chondro-
sarcoma cells. Renal cell carcinoma exhibits large
amounts of epithelial membrane antigen and cytokeratin,
and is often also vimentin positive.
Ancillary Techniques
Immunohistochemistry
• Strongly positive for S-100 protein and vimentin, and
negative for cytofilaments (cytokeratin, actin, and
desmin).
• The giant cells are negative for S-100 protein, but posi-
tive for CD68, and considered to be of non-neoplastic
origin.
• Osteonectin is also noted in clear cell chondrosarcoma;
therefore, an osteoblastic differentiation of this tumor was
also suggested.
• Parathyroid hormone-like protein and platelet-derived
growth hormone and its receptor were observed in clear
cell chondrosarcoma cells.
Electron Microscopy
• Show the features of chondrocytes, and contain large
amounts of glycogen, which is responsible for the clear-
cell appearance of their cytoplasm, and which can be
documented histochemically by the demonstration of
large amounts of material positive for periodic acid-Schiff
23 Chondrosarcoma
stain, which is diastase sensitive in the cytoplasm of these
cells.
• Immunohistochemical analysis demonstrated that about
25 % showed patchy positive nuclear staining for p53 and
18 % showed diffuse positive nuclear staining patterns.
More than half of the cases studied were negative for p53
immunostaining.
Genetics
• Quantitative DNA/PCR analysis revealed that none of the
cases studied showed significantly reduced levels of p53
amplification (<0.50), strongly suggesting an allelic dele-
tion of the p53 gene.
• In contrast, however, DNA/PCR-SSCP analysis failed to
detect any types of mutations resulting in amino acid sub-
stitution within exons 5–9 regions of the gene.
• Studies of P16CDKN2a and Bcl10 gene mutation in clear
cell chondrosarcoma reflected the very low incidence of
genetic alterations of the p16CDKN2a gene and Bcl10
mutation was absent.
• Her-2/neu oncogene status by real-time PCR in clear cell
chondrosarcoma was absent.
• The IDH1/2, p53, and retinoblastoma pathways were
affected in 0 %, 9 %, and 95 % of clear cell chondrosarco-
mas, respectively.
341
Prognosis
• Low-grade malignant tumor and can be cured by en bloc
excision.
• Recurrences occur in most patients with less than wide
resection and carry a 15 % risk of death from dissemi-
nated disease.
• The most frequent metastatic focus is the lung.
• Very rare cases of dedifferentiation were described.
Treatment
• En bloc resection including a margin of normal bone and
soft tissue is the treatment of choice.
• Simple excision or curettage carries an 80 % risk of local
recurrence.
See Figs. 23.50, 23.51, 23.52, 23.53, 23.54, 23.55, 23.56,
23.57, 23.58, 23.59, 23.60, and 23.61 for illustrations of
Clear Cell Chondrosarcoma.
342 S. Piña-Oviedo et al.

Fig. 23.50 Clear cell chondrosarcoma. The radiograph of right femo-

ral head shows a well-defined osteolytic bone lesion with marginal scle-
rosis (Courtesy by Samsung Medical Center)

Fig. 23.52 Clear cell chondrosarcoma. The tibial diaphysis shows

poorly marginated osteolytic lesion, an unusual location

Fig. 23.53 The gross specimen of illustration shown in Fig. 23.52.

The tumor shows dark brownish and focal myxoid appearance and foci
of spotty calcification. Hemorrhagic areas are previous biopsy site

Fig. 23.51 Clear cell chondrosarcoma. This radiograph shows more

advanced lesion in the proximal humerus, featuring extensive osteolytic
lesion
23 Chondrosarcoma 343

Fig. 23.54 This clear cell chondrosarcoma shows clear cells, whose Fig. 23.56 At low power view, there is invasive growth through the
nuclei are centrally situated, round, and of even chromatin distribution preexisting trabecular bones

Fig. 23.57 Areas of calcification are present

Fig. 23.55 Also noted are numerous giant cells, which is another char-
acteristic finding in clear cell chondrosarcoma
344 S. Piña-Oviedo et al.

a b

Fig. 23.58 (a) Macrophotography of a CCChS in tibial proximal Specimen radiograph. Well-delimited but no perpheral sclerosis in the
epiphysis with no clear limits, hemorrhagic, red-whitish cut surface, medullar limits, cortical permeation; the lesion is lytic with spotted
gritty and friable areas, and external extension to the soft parts. (b) flocular and irregular radiodensities

Fig. 23.59 Medium power magnification microphotography. Osteoid

islets production amid diffusely distributed neoplastic clear cells.
Some giant cells are also seen. Picture characteristic of clear cell Fig. 23.61 Microphotograph showing areas of chondroid differentia-
chondrosarcoma tion, also seen in clear cell chondrosarcoma

Fig. 23.60 Typical microscopic appearance of clear cell chondrosarcoma

23 Chondrosarcoma
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 Part IV
Giant Cell Tumor
 Giant Cell Tumor of Bone
24
Ricardo K. Kalil

Abstract
Giant cell tumor of bone is a locally aggressive primary bone neoplasm constituted by pro-
liferating mononuclear or plump spindle cells among which there are numerous macro-
phages and evenly distributed large multinucleated osteoclast-like giant cells that can, on
occasion, undergo malignant transformation. They express proteins suggesting a mesen-
chymal origin and a preosteoblastic phenotype. It corresponds to 5 % of all primary neopla-
sias of the bone. It is slightly more common in females, and its main incidence is between
20 and 45 years of age. It has a major preference for the epiphysis of the long bones, about
half the cases occurring about the knee, and is very rare in patients with open physis.
Recurrence is frequent and histologically benign lung metastases can occur. Complete sur-
gical excision is the treatment of choice.

Definition mal origin and a preosteoblastic phenotype. They recruit

• A locally aggressive, primary bone neoplasm with prolif-
erating mononuclear ovoid or plump spindle cells among
which there are numerous macrophages and evenly dis-
tributed large multinucleated osteoclast-like giant cells
that can, on occasion, undergo malignant transformation.
Synonyms
• Osteoclastoma
Etiology
• There are no definite established causes.
• The neoplastic cells are the mononuclear cells of the
stroma. They express proteins suggesting a mesenchy-
R.K. Kalil, MD
Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina
Department of Pathology, A.C. Camargo Cancer Center,
São Paulo, SP, Brazil
e-mail: rkkalil@gmail.com
vascular monocytes and induce them to proliferate, dif-
ferentiate, and join into multinucleated giant cells
mainly through linking its RANK-ligand to the RANK
receptors expressed by the monocytes. This mechanism
is said to also intensify the giant cells’ bone-resorbing
capacity.
• Its suggested phenotype might be related to focal osteoid
bone production not rarely seen in GCT and in its occa-
sional lung metastases. And it can also explain the new
bone formation in patients treated with denosumab, in
whom the giant cells are eliminated.
• On the other side, giant cells’ action to resorb bone and to
suppress the differentiation of the stromal cells into osteo-
blasts may preclude a larger bone production.
• Recently, miR-126 and Smad3 were identified in relation
to osteoclast differentiation and bone resorption pro-
cesses, in GCT, thus playing an important role in giant
cell formation and in the osteolytic lesion.
• p53 mutations may play a role in tumor recurrence and
in malignization of GCTs through interactions with
GPX-1.
• GCT can be secondary to Paget’s disease.

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 351
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_24, © Springer-Verlag London 2015
352
Epidemiology
• It corresponds to 5 % of all primary neoplasias of the
bone and 20 % of all benign tumors of the bone.
Sex
• Slightly more common in females (1.5:1)
Age
• Main incidence between 20 and 45 years of age.
• Very rare in patients with open physis.
• It appears to be more common in South India and China,
where an incidence up to 20 % of bone tumors has been
reported.
R.K. Kalil
Sites of Involvement
• It has a major preference for the epiphysis of the long
bones, about half of the cases occurring about the knee:
distal femur, proximal tibia, and proximal fibula.
• After the knee, the distal radius and upper humerus are
frequent locations.
• It also occurs in apophyses like the greater trochanter of
the femur.
• In the rare occasions where GCT is seen in a skeleton
with open physis, it is seen in the metaphysis or the shaft
of the bone.
• About 15 % of the cases affect flat bones, pelvis, sacrum,
vertebrae, etc.
• It is exceptional in the scapula, ribs, skull, and mandibula.
• Hands and feet are also rare locations.
• Exceptionally, GCT is seen in multiple sites, and, in this
instance, it may be difficult to distinguish multicentricity
from metastatization.
24 Giant Cell Tumor of Bone
Clinical Symptoms and Signs
• Local pain and the presence of a tender mass is the usual
presentation.
• Limitation of movements of the adjacent joint is seen in
large tumors.
• Pathological fracture occurs in an average of 5 % of the
cases at presentation.
Image Diagnosis
• More than in any other tumor, the joint analyses of clini-
cal data, especially patient’s age, imaging, and pathologic
findings are extremely important to achieve a correct
diagnosis.
Radiographic Features
• Conventional radiograph typically shows an epiphyseal,
eccentric, lytic lesion with no peripheral sclerosis, extend-
ing to the subchondral bone, in a patient with closed
physes.
• Trabeculation is sometimes seen, and it seems to be
related to less aggressive lesions.
• The margins of the lesions may or may not be well
defined.
• GCT can present signs of aggressiveness, like a broad
transition zone, cortical thinning, cortical destruction, and
soft tissue mass.
• Pathological fracture in load-bearing bones is commonly
associated with telescoping of the bone fragments.
• Non-load-bearing bones, like the radius and humerus,
usually host larger tumors.
CT Features
• CT complements the study with important details, such as
better defining the limits of the lesion, eventual mineral-
ization, characteristic eccentric position, limits with the
articular cartilage, and absence of peripheral sclerosis.
Pseudotrabeculation, represented by osseous ridges, is
emphasized by this image method.
MRI Features
• MRI shows, in T1-weighted images, an intermediary or
attenuated signal intensity; in sequences for fluid there is
353
an intense signal and heterogeneous enhancement with
contrast media.
• Fluid-fluid levels, either on CT or MRI, suggest the for-
mation of secondary aneurysmal bone cyst, reported in
14 % of cases.
Image Differential Diagnosis
Aneurysmal Bone Cyst
• When located in an epiphysis, this is the more common
image differential diagnosis to consider; except for the
usual metaphyseal location, it may be impossible to dif-
ferentiate ABC from a GCT with predominant secondary
ABC-like changes; imaging is fundamental to spot non-
cystic areas to orient biopsy.
Chondroblastoma
• It has a similar preference for epiphyseal localization, but
the presence of calcifications, peripheral sclerosis, and
younger age can suggest the diagnosis before the biopsy.
Clear Cell Chondrosarcoma
• Also for its epiphyseal localization, CCCS can be consid-
ered in the differential diagnosis; more frequent mineral
deposits and the identification of some chondroid matrix
by MRI, present in a third of the cases, may help in the
diagnosis.
Giant Cell-Rich Osteosarcoma and Telangiectatic
Osteosarcoma
• Like GCT with secondary ABC-like changes, both these
OS variants can present fluid-fluid levels and are the most
important confusions to avoid. Close attention to clinical
data, as age and site, is essential in getting important clues
to consider before the biopsy.
Chordoma
• It may be difficult to differentiate from a GCT of the
sacrum, but chordoma is more frequently located in the
midline than GCT.
Pathology
Gross Features
• The cut surface of a whole specimen will show an epiphy-
seal eccentrical lesion, with somewhat circumscribed but
ill-defined limits.
• The tumor may press the articular cartilage, rarely tres-
passing it; invasion of the adjacent joint, when it occurs,
354
is preferentially by way of destruction of the lateral bone
cortex and through the synovial capsule.
• Larger tumors are seen to extend and involve the
metaphysis.
• The tumor tissue itself has a heterogeneous appearance,
is fleshy or friable, and has dark brown with yellowish
areas of degeneration or necrosis and hemorrhagic
areas.
• Extensive, solid, whitish-pink, fleshy areas in a large
tumor may suggest aggressiveness or malignization.
• The bone cortex may be destroyed by the tumor, which
may expand to the adjacent soft parts and produce a thin
periosteal reactive bony shell.
• Fragments obtained by curettage are irregular, reddish-
brown membranous, or friable.
Histological Features
• Efforts have to be made to select those areas unaffected
by secondary changes for examination.
• At the microscopic level, the classical picture includes the
presence of a great number of multinucleated giant cells
more or less uniformly distributed among a variable num-
ber of plump, round or spindle, mononucleated stromal
cells.
• Giant cells can be very large, sometimes with more than
100 nuclei.
• The mononuclear cells of the stroma have abundant
eosinophilic cytoplasm, and nuclei are traditionally com-
pared to those of the giant cells, which are large with little
chromatin and one or two inconspicuous nucleoli.
• Stromal cells may predominate in some areas.
• A variable number of typical mitotic pictures can be seen.
• Atypical mitoses suggest malignancy.
• Fibrous tissue and collections of foamy macrophages
may be present as well as areas of hemorrhage and hemo-
siderin deposits due to a rich vascular network.
• Reactive-like immature bone can be seen focally and may
be due to the possible preosteoblastic phenotype of the
stromal cells. It can be more frequent in cases of patho-
logical fracture.
• The margins of the tumor can show permeation, including
occasional vascular permeation, but the cells will pre-
serve their benign, typical appearance.
• The same can be said of the histology of the metastatic
nodules.
• These two last findings, by themselves, have no prognos-
tic value.
• The lesion sometimes penetrates into the marrow spaces
between trabeculae, where there is no reactive bone for-
mation or fibrous membrane. This feature explains the
frequency of recurrences after curettage made without
chemical cauterization.
R.K. Kalil
Pathology Differential Diagnosis
Aneurysmal Bone Cyst
• GCT frequently presents small ABC-like areas that, when
abundant, prompt this differential diagnosis. GCT, how-
ever, contains at least some solid component representing
the neoplasia which must be located to target a biopsy. In
ABC eventual solid areas are histologically constituted by
secondary changes.
Giant Cell-Rich Osteosarcoma and Telangiectatic
Osteosarcoma
• Attention to clinical data, as age and site, is paramount.
• These osteosarcoma variants have very atypical cells as
well as atypical mitoses. Adequate sampling has to be
made in order to find bone production by the neoplastic
cells, which define the diagnosis.
Giant Cell Reparative Granuloma
• This is a lesion more frequently affecting the long bones
of hands and feet, where GCT is rare, and presents a
reactive tissue aspect, where osteoid production can be
seen, and frequent foci of hemorrhage, where the giant
cells tend to concentrate.
“Brown Tumor” of Hyperparathyroidism
• Multinucleated giant cells, usually smaller than in GCT,
can be very frequent in a “brown tumor,” and its stroma is
more fibrogenic, with a greater tendency to spindling of
the mononuclear cells; hemosiderin deposits are abun-
dant; tunneling bone resorption or “cutting cones” of cor-
tex or bone trabeculae are suggestive of this lesion.
Clinical and laboratory data confirm the diagnosis.
Benign Fibrous Histiocytoma
• Clusters of giant cells, usually smaller than in GCT, are
seen in this lesion among a spindle cell stroma with a sto-
riform arrangement; lipid and hemosiderin-laden histio-
cytes are usually present.
Ancillary Techniques
Immunohistochemistry
Giant cells are positive for CD68, CD45, and CD33.
Genetics
Cytogenetics
• Telomeric association is found in stromal cells in 50–70 %
of the cases and can be of help in a differential diagnosis.
This is not yet known to be related to prognosis.
24 Giant Cell Tumor of Bone
• Histone H3.3 alterations, specifically in H3F3A, leading
to p.Gly34Trp changes were found, were restricted to the
stroma cell population of GCT, and were not detected in
osteoclasts or their precursors.
Prognosis
• Local recurrence is reported in 15–50 % of the cases, usu-
ally related to curettage, especially curettage without
chemical cauterization.
• Metastases to the lungs can occur in up to 5 % of the cases,
probably by tumor embolization and implantation in the
lung. There are reports of metastases to other sites, such as
the breast, heart, skin, and lymph nodes. Metastases are
histologically benign, very similar to the primary tumor,
and peripheral ossification can be seen in the metastatic
nodules. They are indolent and most of the cases will not
need treatment, as they rarely are life-threatening.
• Surgical manipulation and location in distal radio are
related to a greater risk of metastasis.
• Malignancy in GCT: Malignization, a rare occurrence, is
usually seen in somewhat older patients. Histologically,
malignancy in giant cell tumors can appear as fibrosar-
coma, osteosarcoma, or malignant fibrous histiocytoma.
Malignization can be primary, when it appears next to a
benign GCT at the time of the first diagnosis, or second-
ary, when it appears at the primary site many years after
GCT initial diagnosis, more frequently after radiotherapy.
There are no reports of malignant cases in the hands and
feet. To be certain of the diagnosis of malignant giant cell
Fig. 24.1 GCT. (a) Radiograph
of the knee. Large lytic,
apparently multiloculated lesion
occupying the distal epiphysis and
metaphysis of the femur. There is
no clear cortical disruption.
(b) Lateral view of the same
lesion. Although breaking the
cortex, the lesion appears
contained by periosteal bone a b
reaction
355
tumor, the pathologist must be able to demonstrate zones
of typical benign giant cell tumor in the malignant neo-
plasm under appraisal or in previous tissue obtained from
the same neoplasm.
Treatment
• Surgical excision is the treatment of choice for GCT, and
this could mean curettage with chemical cauterization or
en bloc excision.
• There will be sites where a complete excision could be
very difficult or undesirable, like the spine including the
sacrum. Radiotherapy and tumor embolization have been
applied to these instances. When considering radiother-
apy, one has always to have in mind the risk of producing
a radio-related secondary malignant neoplasia.
• The monoclonal antibody denosumab has been recently
introduced as an adjunct treatment to these difficult cases.
It prevents union of the stromal cells RANK-ligand to the
RANK receptor of the monocytes and giant cells, thus
avoiding proliferation and differentiation and, conse-
quently, tumoral bone resorption.
Images
See Figs. 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9,
24.10, 24.11, 24.12, 24.13, 24.14, 24.15, 24.16, 24.17, 24.18,
24.19, 24.20, 24.21, 24.22, 24.23, 24.24, 24.25, 24.26, and
24.27 for illustrations of giant cell tumor of the bone.
356 R.K. Kalil

a b

c d

Fig. 24.2 GCT. (a) Radiograph of another lesion in the distal femur. (c, d) MRI T1-weighted image with fat saturation before and after con-
Typical eccentric lytic lesion well delimited but with no peripheral trast injection. Lesion shows enhancement with a few small areas of
sclerosis. (b) MPR CT of same lesion shows clear limits, no reactive low-signal, possible necrotic or cystic areas
sclerosis, and thinned, slighted expanded cortex. Apparent solid lesion.
24 Giant Cell Tumor of Bone 357

a c

Fig. 24.3 GCT. (a) Radiograph showing a lytic and permeative lesion depicts a lesion involving epiphysis and metaphysis, isointense with the
in the proximal end of a humerus. (b) CT of same lesion shows a lytic muscle, and involvement of the adjacent soft parts. Cortex about the
lesion, with density of soft parts and a few small areas of mineral depos- lesion is not identified in this image, and a wide transition zone into the
its. The cortex is thinned and deformed. (c) MRI T1-weighted image medullary space may suggest higher aggressivity
358 R.K. Kalil

Fig. 24.4 GCT. (a) Radiograph of destructive lesion in the proximal

end of the first phalanx of the second finger, expanding the bone and
permeating the cortex. No or very slight medullary reactive sclerosis.
(b) CT shows a totally lytic lesion, expanding the bone, well delimited
and with an interrupted very thin shell of reactive bone around it
24 Giant Cell Tumor of Bone 359

a b c

Fig. 24.5 GCT. (a) Radiograph of an epiphyso-metaphyseal multi- image shows a large lesion, isointense with muscle, well delimited in
loculated lytic lesion in the proximal tibia. This image cannot identify a relation to bone marrow. Involvement of adjacent soft parts is larger
clear limit between lesion and normal bone marrow. Lateral cortical than appeared in the radiograph. (c) MRI with contrast shows a septated
permeation and no visible periosteal reaction. (b) MRI T1-weighted but uniform enhancement of the lesional area

Fig. 24.6 (a) Radiograph of a

GCT in the distal end of the
radius. Lesion looks aggressive,
somewhat infiltrative, with
cortical permeation and with
expansion to the adjacent soft
parts. (b) Specimen photography
of same lesion as (a). Aggressive
lesion in the epiphysis and
metaphysis of the radius,
destroying the cortex and
involving soft tissue and the ulna.
Solid, soft, pinkish tissue, with
central necrotic area, aspect a b
suggestive of high aggressiveness
360 R.K. Kalil

Fig. 24.8 MPR CT of GCT in the distal end of the femur. Pathological
fracture with impaction of proximal fragment into the distal one
Fig. 24.7 Radiograph of GCT in a fibula. “Bubbly” lytic lesion with
some peripheral marrow and periosteal sclerotic reaction
24 Giant Cell Tumor of Bone 361

a b

Fig. 24.9 (a) CT with contrast demonstrates a large GCT in the sacrum as previous figure shows characteristic fluid-fluid levels of secondary
with secondary ABC formation, a frequent finding. Cystic areas pre- ABC areas in a GCT
dominate over solid ones. (b) MRI T2-weighted image of same lesion

Fig. 24.11 GCT in the distal femur showing a spongy or bubbly

aspect. Periosteal reaction is clearly seen

Fig. 24.10 Macrophotography of GCT in the distal femur. Tan to hem-

orrhagic soft solid areas admixed with friable and cystic hemorrhagic
areas Fig. 24.12 GCT of the distal femur. Yellowish areas suggest extensive
degenerative changes. Hemorrhagic and cystic areas are also seen
362 R.K. Kalil

Fig. 24.13 (a) GCT in proximal a

end of the humerus, solid b
pinkish-red tissue with friable
hemorrhagic areas. Same case as
Fig. 24.3. (b) Specimen
radiograph of lesion in previous
figure. Lytic lesion, no peripheral
sclerosis, possibly originating in
the humeral trochanter, an
apophysis

a b

Fig. 24.14 (a) GCT in the

proximal humerus with a
characteristic tan to hemorrhagic
aspect, partly solid, partly friable,
and cystic, with yellowish-white
areas of degenerative and reactive
fibrous areas. (b) Specimen
radiograph of lesion in previous
figure. Lesion devoid of any
mineral deposits, with slight or
no peripheral bone reaction but
well delimited
24 Giant Cell Tumor of Bone 363

Fig. 24.15 (a) GCT in the distal

a b
radius. Solid, multinodular
tumor, with a soft consistency
and characteristic brownish color.
(b) Specimen radiograph of
lesion in previous figure. Lytic
lesion, absence of mineral
deposition, cortical expansion,
and clear limits. Expanded
periosteal bone shell covers the
external limits of the lesion

Fig. 24.16 Characteristic macroscopic aspect of curetted fragments of

a GCT. Irregular, soft or friable, tan or hemorrhagic fragmented tissue

Fig. 24.17 Large number of multinucleated giant cells more or less

evenly distributed in the tissue
364 R.K. Kalil

Fig. 24.18 Nuclei of multinucleated giant cells have the same aspect Fig. 24.21 Spindle cell proliferation may dominate the picture in
as those of the mononuclear cells of the stroma sometimes large areas

Fig. 24.19 Giant cells may have more than 100 nuclei Fig. 24.22 Foamy histiocytes and inflammatory cells may be seen in
peripheral or degenerative areas

Fig. 24.20 Some cases may present brisk mitotic activity. Mitoses, Fig. 24.23 Areas of reactive bone may be seen in a few GCTs, espe-
however, are always typical in conventional GCT of the bone cially in cases of pathological fracture
24 Giant Cell Tumor of Bone 365

Fig. 24.24 Invasion of soft tissue may seen in conventional, nonmalig- Fig. 24.26 Areas constituted by proliferated undifferentiated pleo-
nant GCT morphic cells and atypical mitoses suggest malignancy in GCT

Fig. 24.25 Neoplastic tissue may be seen in the lumen of blood ves- Fig. 24.27 Lung metastasis in conventional or malignant GCT com-
sels in the periphery of conventional GCTs monly presents peripheral areas of bone or osteoid production
366 R.K. Kalil

Recommended Reading Lau YS, Sabokbar A, Gibbons CL, Giele H, Athanasou N. Phenotypic
and molecular studies of giant-cell tumors of bone and soft tissue.
Hum Pathol. 2005;36(9):945–54.
Alberghini M, Kliskey K, Krenacs T, Picci P, Kindblom L, Forsyth R,
Lou Z, Yang Y, Ren T, Tang S, Peng X, Lu Q, Sun Y, Guo W. Smad3
Athanasou NA. Morphological and immunophenotypic features of
is the key to transforming growth factor-β1-induced osteoclast dif-
primary and metastatic giant cell tumour of bone. Virchows Arch.
ferentiation in giant cell tumor of bone. Med Oncol.
2010;456(1):97–103.
2013;30(3):606.
Behjati S, Tarpey PS, Presneau N, Scheipl S, Pillay N, Van Loo P,
Okubo T, Saito T, Mitomi H, Takagi T, Torigoe T, Suehara Y, Kaneko
Wedge DC, Cooke SL, Gundem G, Davies H, Nik-Zainal S, Martin
K, Yao T. p53 mutations may be involved in malignant transforma-
S, McLaren S, Goody V, Robinson B, Butler A, Teague JW, Halai
tion of giant cell tumor of bone through interaction with GPX1.
D, Khatri B, Myklebost O, Baumhoer D, Jundt G, Hamoudi R,
Virchows Arch. 2013;463(1):67–77.
Tirabosco R, Amary MF, Futreal PA, Stratton MR, Campbell PJ,
Rutkowski P, Przybył J, Switaj T. Genetics of rare mesenchymal
Flanagan AM. Distinct H3F3A and H3F3B driver mutations define
tumors: implications for targeted treatment in DFSP, ASPS, CCS,
chondroblastoma and giant cell tumor of bone. Nat Genet.
GCTB and PEComa. Int J Biochem Cell Biol. 2014. doi:10.1016/j.
2013;45(12):1479–82.
biocel.2014.03.024. Apr 2. pii: S1357-2725(14)00099-5. [Epub
Bertoni F, Bacchini P, Staals EL. Malignancy in giant cell tumor of
ahead of print].
bone. Cancer. 2003;97(10):2520–9.
Schajowicz F. Tumors and tumor-like lesions of bone and joints. Berlin:
Chakarun CJ, Forrester DM, Gottsegen CJ, Patel DB, White EA,
Springer-Verlag; 1981.
Matcuk Jr GR. Radiographics. 2013;33(1):197–211. doi:10.1148/
Schütte HE, Taconis WK. Giant cell tumor in children and adolescents.
rg.331125089.
Skelet Radiol. 1993;22(3):173–6.
Cowan RW, Singh G. Giant cell tumor of bone: a basic science perspec-
Unni KK, Inwards C. Dahlin’s bone tumors. 6th ed. Philadelphia:
tive. Bone. 2013;52(1):238–46.
Lippincott Williams & Wilkins; 2010. p. 179–83.
Fain JS, Unni KK, Beabout JW, Rock MG. Nonepiphyseal giant cell
Won KY, Kalil RK, Kim YW, Park YK. RANK signalling in bone
tumor of the long bones. Clinical, radiologic, and pathologic study.
lesions with osteoclast-like giant cells. Pathology.
Cancer. 1993;71(11):3514–9.
2011;43(4):318–21.
Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F. WHO classifica-
Wu Z, Yin H, Liu T, Yan W, Li Z, Chen J, Chen H, Wang T, Jiang Z,
tion of tumors of soft tissue and bone. Lyon: IARC; 2013. p. 302–4.
Zhou W, Xiao J. MiR-126-5p regulates osteoclast differentiation
Gong L, Liu W, Sun X, Sajdik C, Tian X, Niu X, Huang X. Histological
and bone resorption in giant cell tumor through inhibition of
and clinical characteristics of malignant giant cell tumor of bone.
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Virchows Arch. 2012;460(3):327–34.
 Part V
Round Cell Tumors
 Ewing’s Sarcoma Family of Tumors
25
Isidro Machado and Antonio Llombart-Bosch

Abstract
Ewing’s sarcoma family of tumors (ESFT) is a family of small round cell sarcomas with
specific molecular alterations showing a spectrum of neuroectodermal differentiation.
There is a slightly greater incidence in males than females. The first two decades of life
account for 80 % of patients (age at diagnosis ranges from 13 to 19 years), being more
uncommon in adults and elderly patients and more frequent in white (Caucasian) people.
It is most frequently osseous in origin, but around 10 % of cases arise in extraskeletal
soft tissues. Predilection for the diaphysis or metadiaphysis of long tubular bones and flat
bones is mainly of the pelvis and ribs. Radiologically it is an indefinite osteolytic lesion
mainly involving the diaphysis of a long tubular bone with or without extension into adja-
cent soft tissue areas. Appearance is variable, fluctuating from osteolytic to sclerotic,
although lytic bone lesions predominate with moth-eaten permeative features. It has a lami-
nated or multilayered periosteal reaction (onion skin-like) pattern. It has less frequent per-
pendicular (sunburst type) reactive bone. Saucerization of the bone causes a concave
expansion of the long tubular bones in periosteal tumors.
Histologically it consists in a diffuse proliferation of small round cells fluctuating
between undifferentiated patterns (conventional Ewing’s sarcoma) and histology deserving
neuroectodermal differentiation with Homer-Wright pseudorosettes (the so-called PNET).
Immunohistochemistry studies are useful to confirm the diagnosis with CD99, CAV-1, and
neural and neuroendocrine markers.
Molecular biology: ESFT is genetically defined by specific chromosomal translocation
resulting in a fusion of the EWSR1 gene with a member of the ETS family of transcription fac-
tors: Fli1 (85–90 %), ERG, FEV, ETV1, and ETV4. Treatment: systemic chemotherapy com-
bined with surgery and/or radiotherapy depending on the location and size of the neoplasm.

Definition Synonyms

• A family of small round cell sarcomas with specific • Ewing’s sarcoma (ES)
molecular alterations showing a spectrum of neuroecto- • Peripheral neuroectodermal tumor (PNET)
dermal differentiation • Askin tumor
• Peripheral neuroepithelioma

I. Machado, MD (*)
Department of Pathology, Instituto Valenciano de Oncologia/IVO,
Valencia, Spain
Etiology
e-mail: isidro.machado@uv.es
A. Llombart-Bosch, MD
• Cell of origin is unknown.
Department of Pathology, University of Valencia Medical School, • Main consensus favors a mesenchymal stem cell ori-
Valencia, Spain gin, although neuroectodermal markers, among others,

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 369
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_25, © Springer-Verlag London 2015
370
are expressed influenced by the EWSR1/ETS gene
fusion.
Clinical Features
Epidemiology
• Constitutes <10 % of primary malignant bone tumors
• Most frequent sarcoma after osteosarcoma in children and
young adults. Annual incidence of 3 cases/1,000,000
• High-grade malignancy in which approximately 75 % of cases
are localized at diagnosis and 25 % are initially metastatic
Sex
• Slightly greater incidence in males than females.
Age
• The first two decades of life account for 80 % of patients
(age at diagnosis ranges from 13 to 19 years), being more
uncommon in adults and elderly patients and more fre-
quent in white (Caucasian) people.
I. Machado and A. Llombart-Bosch
Sites of Involvement
• Most frequently osseous in origin (Figs. 25.1, 25.2, and
25.3), but around 10 % of cases arise in extraskeletal soft
tissues.
• Extraskeletal location can be present as an extension
(Fig. 25.1f) from a primary bone tumor (parosteal or peri-
osteal location).
• Predilection for the diaphysis or metadiaphysis of long
tubular bones (Fig. 25.1a–c) and flat bones mainly of the
pelvis (Fig. 25.3) and ribs.
• Can affect appendicular or axial bones.
• Occasional superficial location.
Clinical Symptoms and Signs
• Pain and enlarging mass associated with swollen soft
tissue.
• Systemic symptoms.
• Pathologic fracture is infrequent.
• There is a need to improve diagnostic tests to identify
Ewing’s sarcoma.
25 Ewing’s Sarcoma Family of Tumors
Image Diagnosis
Radiographic Features
• No features specific for ESFT.
• Indefinite osteolytic lesion mainly involving the diaphysis
of a long tubular bone with or without extension into adja-
cent soft tissue areas (Figs. 25.1a, 25.2a, and 36.3a).
• Appearance is variable, fluctuating from osteolytic
(Fig. 25.1a) to sclerotic, although lytic bone lesions pre-
dominate with moth-eaten permeative features.
• Laminated or multilayered periosteal reaction (onion
skin-like) pattern (Fig. 25.10). Less frequent perpendicu-
lar (sunburst type) reactive bone.
• Saucerization of bone causes a concave expansion of the
long tubular bones in periosteal tumors.
• Tumors reduce in size in some cases after therapy/chemo-
therapy (Fig. 25.9).
CT Features
• Destructive intraosseous tumor with soft tissue extension
(Fig. 25.2b).
• Soft tissue calcification is uncommon.
MRI Features
• Usually confirms the tumor extension (bone and/or soft
tissue mass) (Figs. 25.1b, e and 25.3b, c) and the relation
with adjacent anatomical sites
• Useful to determine tumor response to chemotherapy
Bone Scan
• Tumor and metastasis uptake (Fig. 25.3c), therefore use-
ful for clinical staging
Image Differential Diagnosis
Osteosarcoma
• Medullary and cortical bone destruction, aggressive peri-
osteal reaction (Codman triangle); tumor matrix ossifica-
tion is variable depending on the amount of bone tumor
formation, calcified matrix, and osteoid production.
Osteomyelitis
• The earliest changes are seen in adjacent soft tissues with
swelling and loss of normal fat planes. An effusion may
be seen in an adjacent joint. Periosteal reaction and peri-
371
osteal thickening are variable. CT is better for identifying
a sequestrum.
Metastasis
• Metastatic lesions can have almost any appearance. They
can mimic a benign lesion or an aggressive primary bone
tumor. The appearance on CT will depend on the degree
of mineralization of the metastasis. It can be a lytic or
sclerotic lesion.
Hemolymphoid Tumors (Lymphoma,
Leukemia, Langerhans Cell Histiocytosis)
• Solitary or multiple punched-out lytic lesions with or
without sclerotic rim
Pathology
Gross Features
• Intramedullary location is frequent with a tan-white or
tan-gray hemorrhagic mass with cortical, periosteal, and
soft tissue extension (Fig. 25.1c).
• Irregular and destructive bone cortex with subperiosteal
nests and periosteal elevation.
• Soft tissue extension can be present extending bone mar-
gins and exceeding intraosseous component (Figs. 25.2d
and 25.3d). Soft tissue tumor mass larger than 10 cm in
size favors a poor prognosis.
• Post chemo- or radiotherapy, the neoplasm may
reabsorb.
Histological Features
• Diffuse proliferation of small round cells fluctuating
between undifferentiated patterns (conventional Ewing’s
sarcoma) (Fig. 25.4a) and histology deserving neuroecto-
dermal differentiation with Homer-Wright pseudorosettes
(so-called PNET) (Fig. 25.4b). Presence of atypical vari-
ants mainly based upon cell size.
• Small round cells with round to oval nuclei, inconspicu-
ous nucleoli, and scant, eosinophilic, or clear cytoplasm.
Also denominated: “small round blue cell tumor” because
of the intense H/E dark nuclear staining.
• Stroma can be scant or fibrotic or with sclerosis and lace-
like appearance. Rich neoangiogenesis and hemorrhagic
lacunae (vascular Es/PNET).
• Geographic necrosis is frequent, and apoptosis/mitosis
varies from case to case.
• Mainly the tumor cells display abundant PAS-positive
glycogen, but occasional cases are negative (10 %).
372
• Three larger categories appear according to their pre-
dominant morphological criteria: conventional/classical/
typical ES, PNET with neuroectodermal features, and
atypical ES comprising subtypes distinct from the other
two types.
• Atypical ES include ES with spindle cells (Fig. 25.4c),
adamantinoma-like ES (Fig. 25.4d), large-cell variant ES
(Fig. 25.4e), vascular/hemangioendothelial ES, and scle-
rotic ES (Fig. 25.4f).
Pathologic Differential Diagnosis
Small-Cell Osteosarcoma
• Major cell heterogeneity and osteoid matrix (Fig. 25.7a)
production with focal lace-like osteoid.
• GAL1 and SATB2 immunoexpression. Osteonectin posi-
tive (quite unspecific).
• Possibility of EWSR1 rearrangement has been
communicated.
• Reactive bone osteogenesis in an ESFT may be present
(Fig. 25.5c, e).
Undifferentiated Synovial Sarcoma
• Very rare in bone.
• Small-cell ES-like and focal epithelioid cell clusters.
• SYT rearrangement, CD99 immunoexpression is moder-
ate, with frequent EMA positivity (Fig. 25.7c, d).
Bone Lymphoma
• CD99 can be positive in lymphoblastic variant, EWSR1 rear-
rangement negative, lymphoid markers immunoexpression
(Fig. 25.7e). For details see chapter devoted to this topic.
Rhabdomyosarcoma (Fig. 25.7f)
• Muscle differentiation by immunohistochemistry and/or
ultrastructural studies. CD99 focal positive or negative
• Specific translocation in alveolar variant (PAX3-FOXOA1
or PAX7-FOXOA1), EWSR1 negative
Neuroblastoma
• Only in children and very sporadically in young adult
I. Machado and A. Llombart-Bosch
• Flexner-Wintersteiner rosettes, CD99 negative, EWSR1
negative, MYCN amplification, ganglion cell differentiation
Bone Myoepithelial Carcinoma
• Very few cases described.
• Similar to myoepithelial carcinoma of soft tissue.
• S100, calponin and epithelial expression (CK and/or
EMA), and EWSR1 or FUS rearrangement. EWSR1/
POUF5F1 gene fusion and less frequent EWSR1/PBX1 or
EWSR1/ZNF444 can be detected.
Alveolar Soft Part Sarcoma Located
in the Bone
• Isolated cases described
• Similar histology as in soft tissue
• TFE3 positive
Ewing-Like Sarcomas/Undifferentiated
Sarcomas
Considering clinical features and tumor location, the
differential diagnosis should include:
• Heterogeneous group of small round blue cell tumors
mimicking ESFT, CD99 positive (variable expression
intensity) (Fig. 25.8e, f), occasional epithelial immunoex-
pression for cytokeratin. WT1 positivity in CIC/DUX-4
sarcomas. CCNB3, blc2, CD177 positivity by immuno-
histochemistry in BCOR/CNNB3 sarcomas. EWSR1 and
FUS rearrangements negative. CIC/DUX4 or BCOR/
CNNB3 gene fusions may be present.
• For Bone and soft tissue ESFT: small-cell osteosarcoma
(Fig. 25.7a, b), undifferentiated synovial sarcoma
(Fig. 25.7c, d), chondrosarcoma (Fig. 25.8a), myoepithe-
lial carcinoma, clear-cell sarcoma, lymphomas
(Fig. 25.7e), and metastatic carcinoma
• For Extraskeletal ESFT: undifferentiated carcinoma, neu-
roendocrine carcinomas, desmoplastic small round cell
tumor (Fig. 25.8b), small round cell GIST, and
lymphomas
• For Superficial ESFT: Merkel cell carcinoma (Fig. 25.8c),
myoepithelial tumor, lymphomas and small-cell mela-
noma, and epithelioid sarcoma
• For ESFT in elderly patients: metastatic carcinoma, lym-
phomas, and myeloma
• For ESFT in pediatric patients: neuroblastoma, rhabdo-
myosarcoma (Fig. 25.7f), malignant rhabdoid tumor
(Fig. 25.8d), Wilms’ tumor, and leukemia/lymphoma
25 Ewing’s Sarcoma Family of Tumors
Ancillary Techniques
Immunohistochemistry Studies
• CD99 strongly positive with membranous and/or
cytoplasmic staining in more than 98 % of ESFT
(Fig. 25.5d).
• CAV-1 strongly positive with membranous staining in
more than 95 % of Ewing’s tumor. The CD99-negative
ESFT nearly always express CAV-1.
• Fli-1, HNK-1, and ERG are frequently expressed in
ESFT.
• Neural and neuroendocrine markers are positive in iso-
lated cases of PNET.
• Epithelial differentiation (CK-AE1/AE3) is present in
20 % of ESFT (Fig. 25.5f). In addition EMA, cell adhe-
sion molecules (desmoplakin), and CEA can be positive
in a low proportion of tumors.
• ESFT does not reveal muscular differentiation by IHC
studies.
Ultrastructure
• Undifferentiated stem-like cells, closely packed with cell-
to-cell attachment.
• Principal cells with abundant cytoplasm and extensive
glycogen deposits and occasional membrane-bound neu-
rosecretory granules
• Neuroectodermal differentiation: pseudorosettes and cells
with neuritic and synaptic-like processes
• Focally basal lamina and intercellular junctions (hemides-
mosome) in tumor cells with epithelial appearance
• Rich tumor capillary neogenesis with vascular mimicry
Molecular Biology
• ESFT are genetically defined by specific chromosomal
translocation (Fig. 25.6a) resulting in a fusion of the
EWSR1 gene with a member of the ETS family of tran-
scription factors: Fli1 (85–90 %) (Fig. 25.6b, c), ERG,
FEV, ETV1, and ETV4.
• Less frequent translocations involve EWSR1 and POUF1,
PATZ1, SP3, and NFATc2
373
• EWSR1-negative tumor reveals FUS/ERG or FUS/FEV
gene fusions.
• EWSR1- and FUS-negative tumors with Ewing’s mor-
phology should be searched for to exclude BCOR/CNNB3
or CIC/DUX4 gene fusion.
Prognosis
• Prognosis is impacted by the presence of distant metas-
tasis at the time of diagnosis (vascular metastasis
mainly in the lung), tumor site, and size of the extraos-
seous extension, as well the presence of local
recurrence.
• The 5-year survival rate of nonmetastatic disease
approaches 70 %; cases that are metastatic and those that
recur have 5-year survival rates of less than 20 %.
Incidence of late recurrence at 10 years is 9.4 %, rising to
13 % at 20 years. Subsequent malignant neoplasms occur
in 9 % of survivors.
• Pathological and biological prognostic factors include
percentage of chemotherapy-related tumor necrosis
(similar to osteosarcoma evaluation) atypical variant of
ES, p16 deletion, p53 mutation, high proliferation index
(Ki-67), p-mTOR/p27 expression, and gains of 1q, 8q,
and 20.
• The type of gene fusion has not been confirmed to offer
any prognostic value.
Treatment
• There is an urgent need to improve cure rates for local-
ized, metastatic, and recurrent disease.
• Systemic chemotherapy combined with surgery and/or
radiotherapy depending on the location and size of the
neoplasm.
• Vincristine, doxorubicin, and cyclophosphamide alternat-
ing with ifosfamide and etoposide (VDC/IE) remain the
chemotherapy regimes in ESFT.
• Emergent targeted therapeutics offer many exciting pos-
sibilities, and striking clinical responses for IGF-1R
inhibitors have been documented.
• The role of immunotherapies remains to be established in
clinical studies.
374 I. Machado and A. Llombart-Bosch

a b c

d e f

Fig. 25.1 Ewing’s sarcoma with osteolytic lesion involving a long tubu- lesion in upper femoral shaft, and extension into soft tissue: (d) conven-
lar bone, upper metaphysis of a femur, without extension into soft tissue: tional radiology, (e) MRI, (f) macroscopically, intramedullary location
(a) conventional radiography, (b) magnetic resonance imaging (MRI), (c) with cortical, periosteal, and soft tissue extension
grossly intramedullary tumor location. Ewing’s sarcoma with osteolytic
25 Ewing’s Sarcoma Family of Tumors 375

Fig. 25.2 Costal Ewing’s sarcoma with osteolytic

lesion and extension into soft tissue (Askin tumor).
a c
(a) Conventional radiography, (b) computed
tomography (CT scan), and (c) grossly large mass
with bone and extensive soft tissue involvement

b
376 I. Machado and A. Llombart-Bosch

a b

d e

Fig. 25.3 Pelvis Ewing’s sarcoma with flat bone involvement and extension into soft tissue area: (a) conventional radiology, (b and c) MRI,
(d) bone scan, (e) macroscopic iliac tumor infiltration
25 Ewing’s Sarcoma Family of Tumors 377

a b

c d

e f

Fig. 25.4 (a) Conventional Ewing’s sarcoma, hematoxylin/eosin 40×; (d) atypical Ewing’s sarcoma (adamantinoma-like) variant H&E
(H&E) 20×, (b) PNET with Homer-Wright pseudorosettes formation, 20×; (e) atypical Ewing’s sarcoma (large-cell variant) H&E 40×; and
H&E 20×; (c) atypical Ewing’s sarcoma with spindle cell pattern, H&E (f) sclerosing Ewing’s sarcoma, H&E 20×
378 I. Machado and A. Llombart-Bosch

a b

c d

e f

Fig. 25.5 (a) A 23-year-old man with iliac mass in magnetic reso- (d) strong CD99 immunoexpression in tumor cells 20×; (e) osteonectin
nance imaging. (b) Atypical Ewing’s sarcoma with large cell, H&E 40× positivity in reactive bone and osteoblastic cells but negative in Ewing’s
(EWSR1 rearrangement was detected by FISH and RT-PCR); (c) atypi- tumor cells, 20×; and (f) strong CK (AE/1/AE3) in atypical Ewing’s
cal Ewing’s sarcoma with reactive osteoid formation H&E 40×; sarcoma 40×
25 Ewing’s Sarcoma Family of Tumors 379

a b

Fig. 25.6 (a) FISH analysis in Ewing’s sarcoma shows cells with
translocations involving EWSR1, one fused (yellow) or very near (red-
green) signal and the other unpaired signals split into one green and one
red, (b) sequencing of the genomic fusion junctions of EWS-FLI1, (c)
agarose gel showing fusion gene by PCR. Case (4,5,8,11) positive for
EWSR1/FLI1 (7-6) gene fusion. M = size marker; band a = EWSR1
exon 7-Fli exon 5 fusion; band b = EWSR1 exon 7-Fli exon 6 fusion;
line 16 = control case EWSR1 exon 7-Fli exon 6; line 17 = control case
EWSR1 exon 7-Fli exon 5; and line 18 = control normal tissue (normal
human leukocytes)
380 I. Machado and A. Llombart-Bosch

a b

c d

e f

Fig. 25.7 (a) Small-cell osteosarcoma with malignant osteoid forma- 20×; (d) EMA immunohistochemical expression in undifferentiated
tion, H&E 40×; (b) small-cell osteosarcoma with strong osteonectin synovial sarcoma, 40×; (e) high-grade B-cell non-Hodgkin lymphoma of
immunoexpression 40×; (c) undifferentiated synovial sarcoma, H&E the bone, H&E 20×; and (f) embryonal rhabdomyosarcoma, H&E 20×
25 Ewing’s Sarcoma Family of Tumors 381

a b

c d

e f

Fig. 25.8 (a) Soft tissue chondrosarcoma, H&E 20×; (b) intra-abdominal soft tissue undifferentiated sarcoma with CIC/DUX4 gene fusion H&E
desmoplastic small round cell tumor, H&E 20×; (c) Merkel cell carci- 20×; and (f) strong membranous and cytoplasmic CD99 immunoexpres-
noma, H&E 20×; (d) malignant rhabdoid tumor, H&E 40×; (e) high-grade sion in undifferentiated sarcoma with CIC/DUX4 gene fusion, 20×
382 I. Machado and A. Llombart-Bosch

a c

Fig. 25.9 (a) Radiograph of Ewing, sarcoma in the lower end of a humerus with a permeative pattern and diaphyseal periosteal reaction. (b) Axial
MRI image showing important soft tissue involvement. (c) Gross specimen after chemotherapy treatment
25 Ewing’s Sarcoma Family of Tumors 383

Fig. 25.10 Gross specimen (b) and respective radiograph (a) of an Ewing’ sarcoma of a distal femur; onionskin pattern of periosteal reaction is seen
384
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rangement. Adv Anat Pathol. 2013;20(2):75–85.
Folpe AL, Hill CE, Parham DM, et al. Immunohistochemical detection
of FLI-1 protein expression: a study of 132 round cell tumors with
emphasis on CD99-positive mimics of Ewing’s sarcoma/primitive
neuroectodermal tumor. Am J Surg Pathol. 2000;24(12):1657–62.
Folpe AL, Goldblum JR, Rubin BP, et al. Morphologic and immuno-
phenotypic diversity in Ewing family tumors: a study of 66 geneti-
cally confirmed cases. Am J Surg Pathol. 2005;29(8):1025–33.
Kovar H, Alonso J, Aman P, et al. The first European interdisciplinary
Ewing sarcoma research summit. Front Oncol. 2012;2:54.
Le Deley MC, Delattre O, Schaefer KL, et al. Impact of EWS-ETS
fusion type on disease progression in Ewing’s sarcoma/peripheral
primitive neuroectodermal tumor: prospective results from the
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1982–8.
Llombart-Bosch A, Contesso G, Peydro-Olaya A. Histology, immuno-
histochemistry, and electron microscopy of small round cell tumors
of bone. Semin Diagn Pathol. 1996;13(3):153–70.
Llombart-Bosch A, Machado I, Navarro S, et al. Histological heteroge-
neity of Ewing’s sarcoma/PNET: an immunohistochemical analysis
of 415 genetically confirmed cases with clinical support. Virchows
Arch. 2009;455(5):397–411.
López-Guerrero JA, Machado I, Scotlandi K, et al. Clinicopathological
significance of cell cycle regulation markers in a large series of
genetically confirmed Ewing’s sarcoma family of tumors. Int J
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Machado I, Llombart-Bosch A. Myogenic differentiation in Ewing sar-
coma family of tumors. Am J Surg Pathol. 2011;35(3):464.
Machado I, Alberghini M, Giner F, et al. Histopathological character-
ization of small cell osteosarcoma with immunohistochemistry and
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molecular genetic support. A study of 10 cases. Histopathology.
2010;57(1):162–7.
Machado I, Navarro S, López-Guerrero JA, et al. Epithelial marker
expression does not rule out a diagnosis of Ewing’s sarcoma family
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Machado I, Noguera R, Mateos EA, et al. The many faces of atypical
Ewing’s sarcoma. A true entity mimicking sarcomas, carcinomas
and lymphomas. Virchows Arch. 2011b;458(3):281–90.
Machado I, López Guerrero JA, Navarro S, et al. Galectin-1 (GAL-1)
expression is a useful tool to differentiate between small cell osteo-
sarcoma and Ewing sarcoma. Virchows Arch. 2013a;462(6):
665–71.
Machado I, Traves V, Cruz J, et al. Superficial small round-cell tumors
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 Lymphoma of Bone
26
S. Fiona Bonar

Abstract
Neoplasm is composed of malignant lymphoid cells (B cells, T cells, and rarely null cells),
arising in persistent red marrow and producing a mass-like lesion in bone with or without
involvement of local regional nodes. Primary bone lymphoma initially only involves bone,
either at a single site or in multiple bones in the absence of supraregional or other extranodal
diseases. Plasma cell neoplasms are excluded. There is a slight male predominance (from
1.3:1 to 1.8:1 in most studies). Most are adults over the age of 40 (mean is 40–65 in larger
series). It can occur at any age (documented from 1.5 to 87 years). Red marrow of the long
bones and axial skeleton is most frequently involved. Plain radiographs show a spectrum of
changes varying from normal or minimal subtle changes to diffuse permeative destruction
of the bone. Histologically a diffuse growth pattern is usual. Permeation of marrow spaces
occurs, the cells surrounding and entrapping the host bone which usually remains otherwise
intact. Residual marrow fat is also often present. Appropriate immunophenotyping is neces-
sary in all cases for adequate clarification. Current optimal treatment regimens for adults
include combined chemotherapy and radiotherapy.

Definition • The most common form, diffuse large B-cell lymphoma,

• Neoplasm composed of malignant lymphoid cells (B
cells, T cells, and rarely null cells), arising in persistent
red marrow and producing a mass-like lesion in bone with
or without involvement of local regional nodes.
• Primary bone lymphoma initially only involves bone,
either at a single site or in multiple bones in the absence
of supraregional or other extranodal diseases.
• Plasma cell neoplasms are excluded.
Etiology
not otherwise specified, is of unknown etiology.
• Underlying immunodeficiency may be a risk factor:
– Such tumors may be EBV positive.
• Occasional reported cases have occurred in a setting of
infection by human immunodeficiency virus and in osteo-
myelitis and Paget’s disease of the bone. The significance
of the latter is doubtful.
• Some authors suggest that primary bone lymphoma in
most cases is a de novo diffuse large B-cell lymphoma
with a genetic relationship to germinal center-like lym-
phomas. Some authors have suggested that specific hom-
ing factors to bone apply.

• Most primary lymphomas of bone are sporadic.

S.F. Bonar, MB, BCH, BAO, FRCPI, FRCPath, FRCPA
Department of Anatomical Pathology, Douglass Hanly
Moir Pathology, Sydney, NSW, Australia
e-mail: fbonar@optusnet.com.au
Synonyms
• Primary non-Hodgkin lymphoma of bone.
• (“Reticulum cell sarcoma” is no longer appropriate.)

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 385
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_26, © Springer-Verlag London 2015
386 S.F. Bonar

Epidemiology Sites of Involvement

Primary bone lymphoma is rare:
• Accounts for 5 % (range 3–7 %) of all primary bone
malignancies.
• Constitutes less than 5 % of all extranodal lymphomas.
• Constitutes less than 2 % of all lymphomas in adults.
• In children with lymphoma up to 5 % have primary skel-
etal disease.
Sex
• There is a slight male predominance (from 1.3:1 to
1.8:1 in most studies).
Age
• Red marrow of the long bones and axial skeleton is most
frequently involved.
• Less common locations include the skull and craniofacial
bones.
• Involvement of the small bones in hands and feet is
extremely rare.
In the long bones:
• The femur is the most commonly affected single bone,
followed by the humerus.
• Lesser numbers occur in the tibia and fibula.
• Occasional cases occur in the radius and ulna.
In the axial skeleton:
• The spine and pelvis predominate.
• Occasional cases occur in the ribs, clavicle, sternum, and
scapula.

• Most are adults over the age of 40 (mean is 40–65 in
larger series).
• Can occur at any age (documented from 1.5 to
87 years).
Clinical Signs and Symptoms
• Localized bone pain occurs in 70–80 % of patients.
• Approximately 20–30 % have swelling or a palpable mass.
26 Lymphoma of Bone
• Duration of symptoms is usually of the order of several
months.
• Lymphoma of the spine commonly presents with neuro-
logical deficit.
• Pathologic fracture of long bones occurs in approximately
15 % of cases.
• Systemic symptoms are rare, seen in approximately 5 %
of cases.
• Paraneoplastic phenomena, e.g., hypercalcemia, are very rare.
Image Features
• Findings are variable and overall nonspecific.
• Plain radiographs show a spectrum of changes varying
from normal or minimal subtle changes to diffuse perme-
ative destruction of the bone.
• Multiple modality imaging is most informative (i.e., com-
bined x-ray, CT, MRI, and bone scan) although each is
essentially nonspecific.
• Multiple bone involvement is noted in approximately
20 % of cases.
Radiographic Features
• Seventy percent are lytic.
• Twenty-eight percent are of mixed lytic and sclerotic
appearance.
• Two percent are totally sclerotic.
• In most cases (75 %) a permeative/moth-eaten appear-
ance is seen representing multiple small poorly defined
radiolucencies within the affected area of the bone which
overall is poorly marginated.
• In 60 % a periosteal reaction is noted which has an aggres-
sive appearance characterized by a single- or multiple-
layered appearance (onion skin), usually with interrupted
or discontinuous areas.
• In 50–75 % of cases a soft tissue mass of variable size
occurs (optimally identified by CT in 80 % of these and
by MRI in all cases).
• In 22 % pathological fracture is present.
• In 16 % sequestrum can be identified (best seen on CT).
• In 4 % of cases the tumor crosses joints (particularly in
the vertebral column and sacroiliac joints).
• In 5 % of cases the changes are either very subtle or not
identifiable on plain radiograph.
The MRI, CT, and bone scan findings are essentially nonspe-
cific in nature. FDG PET scan characteristically shows increased
glucose avidity in the affected area, is useful for identifying dis-
ease elsewhere, and helps evaluate response to therapy.
Bone scan usually shows increased isotope uptake that is:
• Marked in 65 %
387
• Moderate in 35 %
• Negative in less than 2 % of cases
CT scan is useful for identification of:
• Permeative pattern
• Areas of cortical destruction
• Soft tissue mass
• Sequestrum formation
MRI Features
• Will confirm lesional tissue in cases with subtle radio-
graphic changes.
• Helps identify cortical destruction.
• Clarifies the intra- and extraosseous extent of the lesion.
• Lesional tissue is usually:
– Low or intermediate signal intensity on T1-weighted
imaging
– High signal intensity on T2-weighted imaging
– Shows homogeneous and diffuse enhancement of soft
tissue component
– Shows homogeneous or heterogeneous enhancement
of intraosseous component (depending on intermin-
gled marrow elements and stromal fibrosis)
– MRI also allows identification of peritumoral and mar-
row edema which are T2 hyperintense.
– With stromal fibrosis both T1- and T2-weighted
images may be of lower signal intensity.
Less common imaging findings are documented including:
• Cortical distribution only
• Lesions confined to the mid-diaphysis
• Lesions with geographic margins
• Lesions with aneurysmal features
• Joint extension
General Comments
Most cases of primary lymphoma of bone:
• Are solitary in nature (80 %).
• Occur in the metadiaphysis of long bones.
• Extensive involvement of the bone is not unusual.
• Are characterized by radiolucencies with a permeative
pattern.
• With minimal or mild cortical destruction.
• With a layered periosteal reaction.
• And with an associated soft tissue mass.
Features highly suggestive of lymphoma:
• Identification of a soft tissue mass on CT or on MR asso-
ciated with marrow disease without excessive cortical
destruction
• An abnormal bone scan, MRI, or CT with marrow replace-
ment in a setting of a virtually normal radiograph
388
Image Differential Diagnosis
• The imaging findings of lymphoma are similar to that
seen in other small round blue cell tumors (including
Ewing tumor) in all of which tumor cells percolate
through the Haversian system gaining access to the soft
tissue component but leaving the cortex virtually intact.
• The differential diagnosis therefore includes all the other
forms of small round blue cell tumors which can be seen
in various age groups.
In children
– Ewing tumor
– Neuroblastoma
– Leukemia
– Langerhans cell histiocytosis
– Osteomyelitis
In teens and young adults
– Ewing tumor
– Leukemia
– Lytic osteosarcoma
– Langerhans cell histiocytosis
– Osteomyelitis
In adults
– Myeloma/plasmacytoma
– Metastasis
– Langerhans cell histiocytosis
– Osteomyelitis
• In general, sequestrum formation is seen in a setting of
osteomyelitis, Langerhans cell histiocytosis, and lym-
phoma and occasionally in bone sarcomas and desmo-
plastic fibroma.
Given that the imaging findings are essentially nonspe-
cific for lymphoma, histological confirmation for accurate
diagnosis is always required.
Pathology
Gross Features
• Excision specimens are extremely rare as therapy usually
comprises chemotherapy and/or radiotherapy after biopsy.
Occasionally, surgical excision may be done in a setting
of pathologic fracture or other complicating processes.
• In excision specimens, the tumor usually has a fish-flesh
appearance similar to that seen in nodal lymphoma:
– The intraosseous component has poorly defined mar-
gins with intermingled residual bone trabeculae
imparting a gritty consistency. Permeation by tumor
through the Haversian system with destruction of the
cortex may be seen.
S.F. Bonar
– If reactive sclerosis is present, the gross specimen may
be very hard.
• Biopsy material (which is the more common specimen
received) is similar:
– Comprising of soft friable pale fleshy tissue which
may be hemorrhagic.
– It may be firm related to fibrosis.
– It may be hard related to sclerosis.
Handling of Tissue
Sampling of fleshy tissue in areas without bone and avoiding
necrotic areas will optimize morphological examination,
immunophenotyping, and other ancillary techniques includ-
ing molecular and genetic studies:
• In hard specimens, the fleshy fragments should be gently teased
out in order to avoid prolonged decalcification with conse-
quent suboptimal morphology and immunophenotyping.
• If the tissue can be handled in the intraoperative setting or
as soon as possible in the fresh state, cytological touch
preparations can be performed which helps to optimize
assessment of the cytological features, particularly in a
setting of accompanying sclerosis and fibrosis.
• Flow cytometric analysis of fresh lesional tissue should
always be performed:
– Although flow cytometry can be performed on tissue
fragments retrieved from core biopsy, the cells have to
be released from the accompanying stroma.
– In our experience, direct aspiration of the lesional tis-
sue in an intraoperative or intrabiopsy setting improves
the cell yield and surface antibody retrieval.
Biopsy material must be handled with care in order to:
• Avoid crushing artifact which is common particularly in
the setting of stromal fibrosis
• Retrieve material for flow cytometric analysis
• Retrieve material for accurate morphological assessment
• Retrieve material for accurate immunohistochemical
testing
• Retrieve material for genetic studies
Harder biopsies may require significant decalcification.
After attempting to retrieve and tease out the soft tissue com-
ponent and prepare touch smears, gentler methods of decal-
cification (e.g., EDTA) are optimal.
Histopathology
• A diffuse growth pattern is usual.
• Permeation of marrow spaces occurs, the cells surrounding
and entrapping the host bone which usually remains other-
wise intact. Residual marrow fat is also often present.
• Accompanying reactive bone sclerosis may occur which
in some has a pagetoid appearance.
26 Lymphoma of Bone
• Crush artifact is very common, more so than in all other
small round blue cell tumors. In some this is extensive
making morphological assessment challenging and some-
times precluding it (hence the value of cytology smears).
• Variable stromal fibrosis is seen with fine reticulin fibers
surrounding individual cells.
• In some, more prominent fibrosis of the stroma is noted in
which crushed and distorted cells are embedded:
– The fibrosis may have a fasciculated or storiform
architecture imparting a spindling appearance to the
cells and simulating sarcoma.
– Occasionally the cells are arranged in a linear single
file manner within the fibrous tissue simulating meta-
static carcinoma.
• Clustering of cells with a pseudo-organoid or alveolar
pattern may be seen simulating carcinoma, and in some
this impression is accentuated by clearing of the cyto-
plasm or even signet-ring change.
• Accompanying inflammatory cells are common occasion-
ally masking the neoplastic cells:
– Intermingled nonneoplastic lymphocytes are common
in which T cells predominate.
– In some instances eosinophils may be seen prompting
consideration of Langerhans cell histiocytosis and
Hodgkin lymphoma.
– Neutrophils may even occur, leading to misinterpreta-
tion as osteomyelitis.
• Morphologically most diffuse large B-cell lymphomas
have a centroblastic morphology in which the cells have a
polymorphous appearance:
– Variation and shape and size are common.
– Nuclei are large and irregular and often cleaved and
may be mono- and/or multilobulated.
– Nuclear chromatin is usually finely clumped.
– Nucleoli may be prominent and two or three may be
seen.
– The cytoplasm is amphophilic and usually inconspicu-
ous with tendency to smearing.
• Occasionally mixed centroblastic and centrocytic forms
are seen with a mixture of small intermediate and larger
lymphoid cells.
• Occasionally immunoblastic forms predominate:
– The cells have distinct round nuclear borders and a
single prominent nucleolus.
– Abundant amphophilic cytoplasm may be seen.
• Necrosis may be extensive making interpretation diffi-
cult; however, in many cases retention of CD20 immuno-
reactivity can be demonstrated.
• In rarer primary bone lymphomas, specific morphological
features may be seen similar to that expected in nodal
disease:
– Anaplastic large cell lymphoma:
Is characterized by marked nuclear variability in size
and shape
389
Has large cells with horseshoe- or kidney-shaped
nuclei known as “hallmark” cells
– Lymphoblastic lymphoma, most often seen in
children:
Is usually characterized by sheets of cells with rounded
nuclei and a fine stippled chromatin pattern
Simulates Ewing sarcoma in particular
– T-cell lymphomas have irregular cleaving of nuclei.
– Burkitt lymphoma comprises:
A monotonous population of medium-sized cells
Round nuclei with finely clumped dispersed chromatin
Multiple basophilic medium-sized nucleoli
Deeply basophilic cytoplasm with lipid vacuoles
Brisk proliferation with frequent mitoses and apopto-
sis resulting in a starry sky pattern
– Low-grade lymphomas are rare, most cases reflecting
secondary involvement rather than primary bone lym-
phoma. Findings include:
Sheets of small- to intermediate-sized lymphoid cells
with nuclear irregularities. Nucleoli are usually
inconspicuous. Mitotic activity is low and cellular
apoptosis not expected.
Occasional documented cases include:
• Follicular lymphoma
• Mantle cell lymphoma
• Marginal lymphoma
• Well-differentiated lymphocytic lymphoma
– Osseous Hodgkin disease as a primary presenting phe-
nomenon is extremely rare:
Most cases represent secondary involvement.
Nodular sclerosing and mixed cellularity subtypes are
most common.
Bone marrow fibrosis with a mixed infiltrate including
eosinophils, lymphocytes, histiocytes (sometimes
with granuloma formation), and in some instances
admixed neutrophils may be seen.
Intermingled large cells with prominent nucleoli repre-
senting lacunar cells or Reed-Sternberg cells/Reed-
Sternberg variants are variably distributed.
Appropriate immunophenotyping is necessary in all cases
for adequate clarification. In addition, immunophenotype
allows differentiation from other mimics including small
round blue cell tumors of the bone.
Flow cytometric analysis for B- and T-cell clonal abnor-
malities should be undertaken.
Genetic studies may be needed to establish the diagnosis
in some cases.
Cytological Findings
• FNA cytology is very useful in differentiating small round
blue cell tumors from other primary bone malignancies
and from metastatic carcinoma and melanoma.
390
• This technique is best used as an adjunct to histological
assessment and in combination with flow cytometry and
genetic testing if necessary.
• As the majority of lymphomas of the bone are of large
cell type, aspirates are usually highly cellular.
• Tumor cells usually comprise naked nuclei with marked
nuclear variability in shape and size with irregular nuclear
borders.
• Distinct nucleoli and scattered mitotic figures may be
seen.
• Lymphoglandular bodies representing cytoplasmic frag-
ments are identifiable in the background and allow confir-
mation of lymphoid origin.
Ancillary techniques
Immunohistochemical Findings
Primary bone lymphomas should be assessed with an immu-
nohistochemical profile as would be performed in their nodal
counterparts. The panel of antibodies therefore will depend
on the morphological findings.
Most Are Mature B-Cell Neoplasms
• Cells express CD45 and CD20 in most cases.
• CD19 and CD79a are positive.
• PAX5 expression is variable, decorating multilobated
cells in particular.
• Approximately 50 % are of germinal center B-cell type:
– CD10 and BCL6 positive
– CD10 negative, BCL6 positive, MUM1 negative
• Some are indeterminate:
– CD10 negative, BCL6 positive, MUM1 unknown
• Some are of post-germinal center phenotype:
– CD10 negative, BCL6 negative
– CD10 negative, BCL6 positive, MUM1 positive
• BCL2, MUM1, P53, and CD44 expression is variable.
• Intermingled small mature T cells are decorated by CD3.
• MIB1 proliferation rate varies but is usually high and greater
than 40 % and may be more than 90 % in some cases.
• Cyclin D1 is negative.
Anaplastic Large Cell Lymphoma
• Most are of T-cell lineage; however, CD3 may be negative,
and a panel of T-cell markers should be performed including
CD2, CD4, CD5, and CD8 (the latter is usually negative).
• The large atypical cells are consistently CD30 positive
with membranous staining and accentuated staining in the
Golgi area.
• Cytotoxic-associated antigens including T1A, granzyme
B, and perforin are usually positive.
S.F. Bonar
• These tumors may be ALK positive or ALK negative:
– (ALK1 expression t(2:5) reflects fusion of the ALK gene
(anaplastic lymphoma kinase) on chromosome 2 with
the nucleophosphin gene (NPN) on chromosome 5.)
• Most ALK-positive tumors express EMA.
• In some cases loss of several T-cell antigens results in a
null cell phenotype.
• These tumors are negative for EBV.
• CD15 and PAX5 are useful to exclude Hodgkin lymphoma.
Lymphoblastic Lymphoma
• In the bone these are usually of precursor B origin; how-
ever, they are negative for CD45 and CD20.
• They usually express CD79a, CD19, and PAX5.
• They are always positive for TdT.
• Positivity for CD99 and FLI1 may mimic Ewing sarcoma;
thus, TdT expression is critical in clarification of the true
nature of the neoplasm.
• T-cell lymphoblastic lymphomas are also TdT positive,
and other T-cell lineage antigens should be identifiable.
T-cell lymphomas are very rare:
• They variably express a variety of T-cell antigens includ-
ing CD3, CD5, CD2, CD4, and less frequently CD8.
• T-cell receptor gene rearrangement studies may need to
be performed for clarification.
Burkitt Lymphoma
• B-cell proliferation thus positivity for CD19, CD20, and
22 is expected.
• CD10, BCL6, and CD43 are positive.
• There is strong membrane staining for IgM.
• BCL2 and TdT are negative.
• A proliferative rate of 100 % is expected.
• These tumors have an immunoglobulin heavy chain:
MYC translocation (band 8q24 to the IgG heavy chain
region in 4q32).
Hodgkin Lymphoma
• Atypical lacunar cells, Reed-Sternberg cells, and Reed-
Sternberg variants express CD30 and CD15.
EMA is negative.Genetic Findings
• Specific data on the genetic abnormalities of primary
lymphoma of the bone are lacking. In those in which the
lymphoma reflects a manifestation of systemic disease,
the genetic abnormalities are similar to those of their
extraskeletal counterparts.
• Rare studies using interface FISH testing in primary dif-
fuse large B-cell lymphoma of the bone identified
BCL2/18q21 breakpoints, MYC/8q24 breakpoints, and
BCL6/3q27 breakpoints.
26 Lymphoma of Bone
• Array-based comparative genomic hybridization analysis
(array-CGH) performed in nine cases and confirmed by
FISH found several recurrent genomic aberrations includ-
ing gain of 1q and amplification of 2p16.1. These findings
were associated with a germinal center-like phenotype
and differ from chromosomal aberrations found in other
extranodal lymphomas, substantiating the notion that pri-
mary lymphoma of the bone is a distinct entity, clinico-
pathologically and at the genomic level.
Pathological Differential Diagnosis
This will depend on the age of the patient.
In children and young adults, lymphoma of the bone must
be differentiated from:
• Other small round blue cell tumors including in
particular:
– Ewing sarcoma:
Negative for lymphoid markers CD45 and CD20.
Strong membranous positivity for CD99 is noted.
Nuclear positivity for FLI1 is expected.
As these markers may also be positive in lymphoblas-
tic lymphoma, it is imperative that TdT be per-
formed which will be negative in Ewing sarcoma.
Ancillary testing including in situ hybridization and
molecular genetics to identify the characteristic bal-
anced translocations and fusions seen in Ewing’s
may be required.
• These include:
– FISH testing: Break-apart probes show rear-
rangement for the EWSR1 gene at 22q12.
– Cytogenetic studies: Several balanced trans-
locations and fusions involving EWSR1 and
ETS family genes occur:
EWSR1 – FLI1 fusion in 90 % of cases
EWSR1 – ERG fusion in 5–10 % of cases
– “Atypical Ewing” sarcoma: A recently identified sar-
coma of the bone and soft tissue characterized by a
CIC-DUX4 translocation which also forms part of the
differential diagnosis:
Lymphoid markers are negative.
– Metastatic neuroblastoma and rhabdomyosarcoma
should be excluded:
Neural markers (NSE, synaptophysin, chromogranin A,
CD56, and NB84) are positive in neuroblastoma.
Myoid markers (actin, desmin, and myogenin) are pos-
itive in rhabdomyosarcoma.
Lymphoid markers are negative in both.
– Small cell osteosarcoma:
Malignant lacelike immature osteoid production is
expected.
Lymphoid markers are negative.
391
In adults the main differential diagnoses include:
• Metastatic carcinoma:
– Cell are cytokeratin positive.
– Lymphoid markers are negative.
– CD99 is negative.
• Metastatic melanoma may mimic any tumor:
– Melanocytic markers S-100 protein, SOX10, melan A,
and HMB45 are positive, S100 and SOX10 most reli-
ably so.
– Lymphoid markers are negative.
• Myeloma/plasmacytoma:
– Strongly positive for CD138 with light chain restric-
tion for kappa and lambda light chains (supported by
appropriate flow cytometric analysis).
– There may be weak CD45 and CD20 positivity at
most, contrasting with strong positivity expected in
large cell lymphoma.
In adults and children the differential also includes:
• Leukemic infiltrate/myeloid/granulocytic sarcoma:
– Myeloperoxidase stain and CD43 show characteristic
granulocytic differentiation, not seen in lymphoma.
• Osteomyelitis may be considered particularly in a setting
of Hodgkin disease:
– A polymorphous inflammatory infiltrate is identified.
– Reed-Sternberg cells and variants are not expected.
– CD15 and CD30 are negative.
– Intermingled neutrophils may be seen in some cases.
• Langerhans cell histiocytosis:
– A mixed inflammatory infiltrate is prevalent, usually
with generous eosinophils.
– Cells with indented coffee bean nuclei and generous
amphophilic cytoplasm are present.
– These express CD1a, S-100 protein, and langerin.
– CD45, CD20, CD30, and CD15 are negative.
In general:
• A combination of lymphoid markers including CD45,
CD20, CD3 confirms lymphoma.
• TdT will allow recognition of lymphoblastic lymphoma
particularly in the setting where CD99 and FLI1 are posi-
tive similar to that seen in Ewing sarcoma.
• Cytokeratins and, less commonly, melanocytic markers
may be necessary in adults to exclude metastasis.
• In the appropriate morphological background, CD15 and
CD30 will allow distinction between anaplastic large cell
lymphoma (CD30 positive, CD15 negative) and Hodgkin
lymphoma (CD30 and CD15 positive).
• Langerhans cell histiocytosis is CD1a, langerin, and
S-100 protein positive.
• Myeloperoxidase will exclude granulocytic sarcoma/
leukemia.
• In myeloma there is weak CD45 and CD20 staining at
most; plasma cell markers including CD138 are positive,
and light chain restriction is demonstrable.
392
Appropriate flow cytometric analysis greatly enhances
correct classification of lymphoma and myeloma. Retention
of tissue for cytogenetic studies will allow gene rearrange-
ment studies to be undertaken as necessary.
Prognosis
• Primary bone lymphoma is by and large a homogeneous
entity (DLBCL) with a favorable prognosis.
• Current therapeutic regimens are largely effective.
• Diffuse large B-cell lymphoma with localized disease at
presentation and optimal treatment has:
– A 5-year disease-free survival as high as 90 %; in some
series this reaches 100 %.
– Overall survival rates that vary from 60 % to 90 % in
most series.
– Negative influences reflecting the most important fac-
tors related to outcome including:
Advanced stage at presentation
Age over 60 at presentation
– Gene expression profiling of germinal center B pheno-
type vs. activated cell phenotype has not detected any
difference in outcome in the cohort of cases of primary
bone diffuse large B-cell lymphoma which have been
studied.
– Thus far no specific statistically significant molecular
or biologic prognostic factors apply.
• Rarer forms of bone lymphoma appear to have a less
favorable prognosis in many instances; however, signifi-
cant numbers of such cases are not available for accurate
assessment.
• In anaplastic large-cell lymphoma, the presence of multi-
focal disease, ALK-negative disease, necrosis, and an
older age portends a poor prognosis.
Treatment
• In general the principles relevant to the treatment of non-
Hodgkin lymphoma at other sites are applied.
• Current optimal treatment regimens for adults include
combined chemotherapy and radiotherapy:
– CHOP chemotherapy (cyclophosphamide, doxorubi-
cin, vincristine, and prednisone) is used in all cases.
S.F. Bonar
– Recent studies show that supplementation with ritux-
imab is beneficial.
– Although radiotherapy is a valuable tool in local dis-
ease control, if used alone recurrence is common and it
is inadequate for preventing recurrence even with stage
I disease.
• Most current therapeutic regimens recommend chemo-
therapy with a CHOP regimen and accompanying ritux-
imab followed by radiotherapy.
• Documented patient cohorts are small, and none have
been subjected to prospective clinical trials.
• With chemotherapy:
– Eighty to ninety percent of patients show a complete
response to treatment.
– Seventy-five percent of those with multiple bone
involvement respond completely.
– Five to ten percent of patients show partial response.
– In most series overall survival at 8–9 years is approxi-
mately 70 %.
– The addition of rituximab showed that the 3-year
progress-free survival rose from 52 % to 88 %.
• Radiotherapy doses used vary from 2,000 to 6,150 cGy.
• The median dose is of the order of 4,400 cGy.
• A recent study suggests that there is no loss of efficacy at
2,400 cGy for indolent lymphoma and 3,000 cGy for
more aggressive forms.
• In children:
– Chemotherapy alone is used and is highly effective.
– This avoids long-term complications of radiotherapy.
• Hodgkin disease is commonly localized and treated with
radiotherapy.
• Surgical intervention is required only for:
– Diagnosis
– Impending or actual fracture
– Segmental defects in long bones especially in the
lower limbs
– Articular or skeletal collapse due to necrosis
Images
See Figs. 26.1, 26.2, 26.3, 26.4, 26.5, 26.6, 26.7, 26.8, 26.9,
26.10, 26.11, 26.12, 26.13, 26.14, 26.15, 26.16, 26.17, 26.18,
26.19, 26.20, and 26.21 for illustrations of lymphoma.
26 Lymphoma of Bone 393

Fig. 26.1 Non-Hodgkin lymphoma: Right hip X-ray lateral view, in

the proximal femur numerous small poorly defined radiolucencies are
present within the diametaphyseal region (arrows), the overall distribu-
tion of which is poorly marginated and the features of which are char-
acteristic of a permeative or “moth-eaten” appearance. This finding is
seen in approximately 75 % of cases of bone lymphoma
394 S.F. Bonar

a b

c d

Fig. 26.2 (a–e) Non-Hodgkin lymphoma: Lateral X-ray of the right
femur shows minimal changes only (a). On closer inspection (b) a sub-
tle early periosteal reaction is evident, highlighted by the solid black
arrows. The T1-weighted axial MR image in this case (c) shows the
presence of a large soft tissue mass practically encircling the femur in
which the cortex appears largely intact with an abnormal signal noted
within the marrow. The post-contrast fat-suppressed T1-weighted sagit-
tal image (d) shows extensive involvement of the femur with a very
large soft tissue mass occupying much of the length of the thigh. The
cortex is largely intact. The FDG PET scan (e) shows markedly
increased activity predominating in the soft tissue component in par-
ticular. This combination of findings is very suggestive of lymphoma
26 Lymphoma of Bone 395

Fig. 26.2 (continued)

396 S.F. Bonar

Fig. 26.3 (a, b) Non-Hodgkin

lymphoma: In the AP X-ray of a b
the distal femur (a), a poorly
marginated area of mixed
lucency and sclerosis is noted
with a subtle laminated periosteal
reaction on the medial cortex.
The lateral X-ray (b) highlights
the poorly defined nature of the
lesion with a moth-eaten
appearance proximally affecting
the anterior cortex in particular
and mixed lucency and sclerosis
in the distal femur

a b

Fig. 26.4 (a, b) Non-Hodgkin

lymphoma: In this X-ray
extensive diffuse sclerosis of the
distal right femur is noted.
Coronal T1-weighted MRI
image (b) shows low signal
throughout the marrow of the
femur in keeping with diffuse
replacement and contrasting
with the normal marrow fat
signal in the tibia. In addition,
medial femoral cortical breach
and a large soft tissue mass are
evident
26 Lymphoma of Bone 397

Fig. 26.5 Non-Hodgkin lymphoma: This X-ray in a child with lym-

phoblastic lymphoma shows the presence of extensive diffuse osteo-
sclerosis of the tibia contrasting with the normal accompanying fibula
398
a b
Fig. 26.6 (a–c) Non-Hodgkin lymphoma: The left femoral shaft is
unremarkable on this AP X-ray with a posterior periosteal reaction
evident on the lateral view. The coronal post-contrast fat-suppressed
T1-weighted MRI (b) shows extensive abnormal marrow signal, medial
Fig. 26.7 (a–e) Non-Hodgkin lymphoma (multifocal): Axial fat-sup-
pressed T2-weighted left hip MRI image shows an acetabular homo-
geneous T2 hyperintense lesion replacing the marrow, with a medial
soft tissue mass and left external iliac adenopathy (labeled LN)
(Fig. 26.7a). In the axial fat-suppressed T2-weighted left hip MRI
image (Fig. 26.7b), a homogeneous T2 hyperintense acetabular lesion
with anterior, medial, and posterior extraosseous soft tissue extension
is noted. The coronal post-contrast fat-suppressed T1-weighted pelvis
MRI image shows multiple homogeneously enhancing lesions in the
left acetabulum and right femoral neck. The right femoral neck lesion
S.F. Bonar
cortical infiltration and enhancement, and an enhancing periosteal reac-
tion. In the axial CT (c) focal permeation and destruction of the cortex
with an early periosteal reaction is evident
is contained in the medullary cavity, well defined with a narrow zone
of transition (Fig. 26.7c). An axial ADC map of the pelvis (Fig. 26.7d)
shows low signal in the left acetabulum consistent with restricted dif-
fusion due to lymphoma. (Note that cerebral lymphoma can demon-
strate restricted diffusion, and this feature is used by neuroradiologists
to aid in the differential diagnosis of a periventricular mass. There
may be potential for the use of this functional sequence to aid in diag-
nosis of lymphoma of the bone.) This axial pelvis CT (bone window)
demonstrates a lytic left acetabular lesion with posterior cortical
breach (Fig. 26.7e)
26 Lymphoma of Bone 399

a b

c d

e
400 S.F. Bonar

Fig. 26.8 (a, b) Non-Hodgkin

lymphoma: A lateral CT image a b
of the knee (a) shows a lesion in
the tibia with a mixed
appearance with a poorly
defined somewhat irregular
sclerotic component in the
proximal tibial metaphysis and a
lucent lesion which replaces the
fatty marrow more inferiorly.
The corresponding T1-weighted
MRI image shows low signal
intensity corresponding to the
area of sclerosis and highlights
the extent of involvement by the
lesion with the inferior
component more conspicuous
on MRI (b)
26 Lymphoma of Bone
a b
Fig. 26.9 (a–f) Osseous Hodgkin disease (multifocal): In this patient
two separate foci of histologically proven Hodgkin disease are present
without accompanying nodal involvement. The AP pelvis X-ray shows a
poorly defined lucent lesion in the left femoral neck (a). Coronal
T1-weighted MRI image of the left hip shows a heterogeneous
low-signal-intensity lesion occupying much of the femoral head and neck
(b). In (c) a coronal PD MRI, image of the left hip shows a small
subchondral fracture which corresponds to the small subchondral fracture
401
seen in the gross photograph (Fig. 26.12). This lesion had a maximum
SUV of 13.63 on FDG PET. Sagittal CT scan of the skull in the same
patient shows a lytic lesion of the clivus with cortical breach (d). The
axial CT scan of the skull shows extensive clival destruction with poste-
rior cortical breach and extraosseous tumor (e), and an axial CT PET of
the skull shows a clival lesion with increased activity (maximum SUV of
15.41) (f)
402 S.F. Bonar

Fig. 26.9 (continued)

26 Lymphoma of Bone 403

Fig. 26.11 Non-Hodgkin lymphoma: Gross specimen from a fore-

quarter amputation specimen in which a large pale tumor mass is pres-
ent involving the glenoid and extending into the soft tissues

Fig. 26.10 Non-Hodgkin lymphoma: This 67-year-old female pre-

sented with increasing swelling and recent pain in her right arm. Marked
enlargement of the arm is noted

Fig. 26.12 Osseous Hodgkin disease (multifocal): In this femoral

head and neck, irregular areas of fleshy pale gray tissue are seen (solid
black arrows), irregularly distributed within the subcapital region and
in the region of the femoral neck. Within the subchondral zone a small
narrow wedge-shaped area of pallor is present which histologically cor-
responded to a small subchondral fracture (open arrow). The patient
had complained of hip pain, likely reflecting the effects of the fracture.
The fleshy areas reflect osseous Hodgkin lymphoma, which in this case
also affected the clivus without nodal involvement, representing a very
rare case of osseous Hodgkin disease
404 S.F. Bonar

a b

Fig. 26.13 (a–c) Non-Hodgkin lymphoma: At low power lymphoma
characteristically has a diffuse growth pattern which is permeative in
nature extending between and around host trabeculae which are largely
intact (a). Focal mild remodeling of the bony trabeculae is evident with
some new bone formation (solid arrow) and focal bone resorption
(open arrow). Lymphomatous tissue extends into and permeates
through the cortex via the Haversian system (b). These smaller areas of
resorption contribute to the permeative appearance seen on imaging. In
(c) more extensive cortical permeation with resorption and very early
soft tissue extension is present with tumor abutting the periosteum
(solid arrow). Periosteal reactive new bone formation is seen (open
arrow)
26 Lymphoma of Bone 405

a b

Fig. 26.14 (a–b) Non-Hodgkin lymphoma: Crush artifact is very
common in all small round blue cell tumors, particularly in lymphoma.
In this case, accompanying prominent fibrosis is present; scattered
islands of residual destroyed bone are included (a). Accurate assess-
ment of the cell morphology is practically impossible. This H&E-
stained smear from the distorted crushed tissue in Fig. 26.5a shows that
even in such circumstances, smears may yield features which allow
interpretation of morphology (b). In this instance there is a population
of atypical lymphoid cells present with some variability in cell size and
shape and scattered irregular nuclear borders with clumped chromatin.
Cytoplasm is poorly defined
406 S.F. Bonar

a b

Fig. 26.15 (a–c) Diffuse large B-cell lymphoma: Although crush arti-
fact is prevalent with smearing of nuclear chromatin, residual irregular
variably sized and shaped cells are present in the background in which
nuclear irregularities and convolutions are identifiable (a). An air-dried
MGG-stained intraoperative smear from the crushed specimen (b) elu-
cidates the cellularity and presence of an atypical population of lym-
phoid cells with clearly identifiable nuclear irregularities and clumped
chromatin. Lymphoglandular bodies are visible in the background. The
likely diagnosis of lymphoma can be suggested and material retrieved
for flow cytometry, preferably by aspiration. In the H&E-stained smear
from the same case (c), cells in which nuclei have a more rounded
appearance with prominent nucleoli are present. Apoptotic cells are
present, and the features suggest an immunoblastic form of diffuse
large B-cell lymphoma
26 Lymphoma of Bone 407

a b

c d

Fig. 26.16 (a–d) Diffuse large B-cell lymphoma is often characterized
by a diffuse growth pattern of sheets of atypical lymphoid cells with vari-
ability in shape and size, irregular nuclear borders, and, in some cells,
prominent nucleoli. Multiple nucleoli may be seen. Scattered mitoses are
visible. The chromatin has a clumped appearance (a). In another case
large multilobated vesicular nuclei with prominent nucleoli are visible.
An admixed reactive lymphocytic infiltrate is seen together with an
occasional eosinophil. Some of the lymphoid cells which are present
prompt consideration of lacunar cells of Hodgkin lymphoma; however,
the cells were CD20 positive and were negative for CD30 and CD15 (b).
In another example the majority of the component cells have smooth
nuclear borders, vesicular nuclei, and prominent nucleoli. Scattered mul-
tilobated and indented cells are noted (open arrow) (c). CD20 is clearly
demonstrable in all cases of diffuse large B-cell lymphoma (d)
408 S.F. Bonar

a b

Fig. 26.17 (a, b) Diffuse large B-cell lymphoma: Widespread necrosis may be present making interpretation challenging (a). In such cases, reten-
tion of immunoreactivity may be identified, illustrated in this case by membrane positivity for CD20 within the necrotic cells (b)

a b

Fig. 26.18 (a, b) Diffuse large B-cell lymphoma: Cytoplasmic clear- cells prompting consideration of the possibility of metastatic poorly
ing can be seen in lymphoma which in some cases may mimic carci- differentiated carcinoma. Smearing artifact may mimic neuroendocrine
noma (a). Stromal fibrosis may result in isolation of groups of tumor carcinoma (b)
26 Lymphoma of Bone 409

a b

Fig. 26.19 (a, b) Diffuse large B-cell lymphoma: In some cases, an irregular nuclei, some with prominent nucleoli (arrows) (a). Reactive T
accompanying chronic inflammatory infiltrate, commonly T cells, may cells are decorated by CD3, and neoplastic lymphoid cells are visible in
obscure the background atypical cells which are visible focally as the background (b)

a b

c d

Fig. 26.20 (a–d) Lymphoblastic lymphoma: Intermediate-sized atypi- positivity for FLI1 (c) and membrane staining for CD99/MIC2 (d) were
cal lymphoid cells are present with scattered isolated skeletal muscle present, emphasizing the importance of differentiating this from Ewing
fibers (a). Tumor cells show strong nuclear positivity for TDT, confirm- tumor in which TdT will be negative
ing the diagnosis of lymphoblastic lymphoma (b). In this case, nuclear
410 S.F. Bonar

a b

Fig. 26.21 (a–c) Osseous Hodgkin lymphoma: Scattered Reed- (a). The Reed-Sternberg variant cells show positivity for CD30 (b) and
Sternberg variants are present (open arrows) lying in a background of a for CD15 (c), confirming the diagnosis of Hodgkin lymphoma
polymorphous cellular infiltrate including large numbers of eosinophils
26 Lymphoma of Bone
Recommended Reading
Alencar A, et al. Primary bone lymphoma: the University of Miami
experience. Leuk Lymphoma. 2010;51:39–49.
Bhagavathi S. Primary bone lymphoma. Arch Pathol Lab Med.
2009;133:1868–71.
Bhagavathi S, et al. Primary diffuse large B cell lymphoma: clinico-
pathologic study of twenty one cases in review of literature. Am J
Surg Pathol. 2009;33:1463–9.
Demircay E, et al. Malignant lymphoma of bone: a review of 119
patients. Clin Orthop Relat Res. 2013;471:2684–90.
Ford DR, et al. Primary bone lymphoma. Treatment and outcome. Clin
Oncol. 2007;19:50–5.
Heyning FH, et al. Primary non-Hodgkin’s lymphoma of bone, a clinico-
pathological investigation of sixty cases. Leukemia. 1999;13:2094–8.
Heyning FH, et al. Primary lymphoma of bone: extranodal lymphoma
with favourable survival independent of germinal centre, post ger-
minal centre or indeterminate phenotype. J Clin Pathol. 2009;62:
820–4.
Heyning FH, et al. Array based comparative genomic hybridisation
analysis reveals recurrent chromosomal alterations in primary dif-
fuse large B cell lymphoma of bone. J Clin Pathol. 2010;63:
1095–110.
Hogendoorn PCW, Kluin PM. Primary non-Hodgkin lymphoma of
bone in haemopatopoietic neoplasms. In: WHO, editor. Classification
of tumours of soft tissue and bone. 2013. p. 316–8.
Horsman JM, et al. Primary bone lymphoma. A retrospect analysis. Int
J Oncol. 2006;28:1571–5.
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Krishnan A, et al. Primary bone lymphoma: radiographic – MR imag-
ing correlation. Radiographics. 2003;23:1371–87.
Li S, Siegal GP. Small cell tumours of bone. Adv Anat Pathol. 2010;
17:1–11.
Lowry L, et al. Reduced dose radiotherapy for local control in non-
Hodgkin’s lymphoma; randomised phase three trial. Radiother
Oncol. 2011;100:86–92.
Maruyama D, et al. Primary bone lymphoma: a new and detailed char-
acterisation of twenty-eight patients in a single institution study. Jpn
J Clin Oncol. 2007;37:216–23.
Mulligan ME, et al. Imaging features of primary bone lymphoma. Am
J Roentgenol. 1999;173:1691–7.
Ostrowski ML, et al. Malignant lymphoma of bone. Cancer. 1986;58:
2646–55.
Ostrowski ML, et al. Osseous Hodgkin disease. Cancer. 1999;85:
1166–78.
Pellegrini C, et al. Primary bone lymphoma, evaluation of chemo-
immunotherapy as frontline treatment in twenty one patients. Clin
Lymphoma Myeloma Leuk. 2011;11:321–5.
Ramadan KM, et al. A clinicopathological retrospective study of 131
patients with primary bone lymphoma; a population based study of
successively treated cohorts from the British Columbia Cancer
Agency. Ann Oncol. 2007;18:129–35.
Unni KK, Inwards CW. Malignant lymphoma of bone. In: Dahlins bone
tumours. 6th ed. Lippincott Williams and Wilkins; Philadelphia.
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 Myeloma
27
Michael J. Klein

Abstract
Myeloma is a malignant tumor of plasma cell lineage; these cells proliferate and infiltrate
the bone marrow, displacing the normal marrow and initiating secondary changes in the
surrounding bone. Myeloma may be solitary at the outset (plasmacytoma or solitary
myeloma) or it may present systemically (multiple myeloma, myelomatosis). There is a
male predominance seen in most clinical series. Myeloma is a disease of older adults; most
patients are in the sixth and seventh decades of life. Myeloma is most frequently in the
distribution of red marrow. The axial skeleton is most frequently involved. Radiologically,
myeloma may present as a solitary radiolucent lesion or multiple punched-out lesions with-
out reactive or sclerotic borders. Histologically, punched-out or space-occupying lesions
are comprised of cells having terminal plasma cell differentiation. Treatment options for
multiple myeloma range from alkylating agents in combination with steroids to highly tai-
lored combination drug regimens with or without marrow transplantation.

Definition monoclonal. This means that the variable region of the

• A malignant tumor of plasma cell lineage; these cells pro-
liferate and infiltrate the bone marrow, displacing the nor-
mal marrow and initiating secondary changes in the
surrounding bone.
• Myeloma may be solitary at the outset (plasmacytoma or
solitary myeloma) or it may present systemically (multi-
ple myeloma, myelomatosis).
• Since one of the differentiating clinical features of plasma
cells is the production of immunoglobulins, unless a par-
ticular myeloma is extremely undifferentiated, it usually
produces immunoglobulins like normal plasma cells.
However, normal plasma cells produce immunoglobulins
as antibodies in response to specific antigenic stimuli. In
myeloma, because the tumor originally arises as an onco-
genic event in a single cell, the malignant plasma cells are
M.J. Klein, MD
• Multiple myeloma is distinguished from solitary myeloma
Department of Pathology and Laboratory Medicine,
Hospital for Special Surgery, New York, NY, USA
e-mail: kleinm@hss.edu
immunoglobulin molecule that each malignant cell pro-
duces is chemically and structurally identical. As a conse-
quence, the immunoglobulins are of a single class type and
have identical charge, shape, molecular weight, and flow
resistance, producing a dense and narrow band on a serum
protein electrophoresis, a so-called monoclonal gammop-
athy. When immunoelectrophoresis is performed, the type
of heavy chains and light chains can be determined, and in
a large population of myeloma patients, the type of heavy
and light chains produced by the tumors is proportionate
to the frequency of the immunoglobulin amounts in a nor-
mal population. Thus, IgG-producing myelomas are more
common than IgA myelomas, and IgA myelomas are more
common than IgD and IgE myelomas. Normal immuno-
globulins in myelomas are either hypermetabolized or
decreased in production as the tumoral plasma cells
become more dominant; and there is often compensatory
hypoglobulinemia and altered serum immunity.
which requires the presence of a histologically demon-
strated plasmacytoma or greater than 10 % plasma cells in

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 413
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_27, © Springer-Verlag London 2015
414
a bone marrow examination combined with monoclonal
paraprotein in the serum or urine and organ dysfunction
related to myeloma.
Synonyms
• Multiple myeloma
• Myelomatosis
• Plasma cell myeloma
• Solitary myeloma
• Plasmacytoma
• Kahler’s disease
Etiology
• Myeloma is presumed to arise from the malignant trans-
formation of a single plasma cell clone, but the cause of
the transformation is not known.
• Infection, genetic predisposition, and various environ-
mental factors including radiation and chemical exposure
have been implicated but not proven.
• While the tumor may grow in perioral soft tissues and
parenchymal organs, it usually presents either as a solitary
osseous lesion (plasmacytoma) or multiple punched-out
bone lesions or diffuse marrow infiltration of the skeleton.
• If it is regarded as a primary bone tumor (rather than as a
marrow tumor), myeloma easily outnumbers all other pri-
mary malignant tumors added together.
M.J. Klein
Clinical Features
Epidemiology
• Myeloma has an incidence of 3–4/100,000 making it
about four times more common than all primary malig-
nant bone tumors combined.
Sex
• There is a male predominance seen in most clinical series.
Age
• Myeloma is a disease of older adults; most patients are in
the sixth and seventh decades of life.
• Some patients have a monoclonal immunoglobulin for
many years prior to developing clinical myeloma.
• Patients with solitary myeloma may have their disease
localized for years although it usually eventuates in sys-
temic disease.
• In solitary myeloma, there is usually no monoclonal
immunoglobulin detectable.
• The type of immunoglobulin produced by the malignant
clone of plasma cells parallels the type and distribution of
normal plasma cells; i.e., IgG is the most frequent and IgE
is the least frequent.
• Malignant plasma cells may also overexpress the light-
chain portions of immunoglobulins, resulting in Bence
Jones proteinuria.
27 Myeloma
Sites of involvement
• Myeloma is most frequently found in the distribution of
red marrow.
• The axial skeleton is most frequently involved.
• The proximal appendicular skeleton is also involved.
• Parenchymal organs, spleen, and lymph nodes may be
involved, but it is usual for the bones to be involved
first.
Clinical Symptoms and Signs
• The most common presentation is bone pain, which is
often back pain of relatively short duration.
• In many cases, the disease is diagnosed serendipitously
by nonspecific laboratory findings.
• Patients may have weakness, weight loss, and even nausea.
• Patients may present with recurrent infections (e.g., pneu-
monia) secondary to hypogammaglobulinemia.
415
• Laboratory findings may include anemia of chronic dis-
ease, leukocytopenia, and thrombocytopenia. Most
patients have monoclonal immunoglobulins on serum
protein electrophoresis, and many have monoclonal light
chains in their urine.
• If the concentration of monoclonal protein is sufficient,
patients may have rouleaux on peripheral blood smears
and interference with renal function, which may be asso-
ciated with hypercalcemia and hyperuricemia.
• In very rare cases, myeloma may present as a peripheral
polyneuropathy. There is a statistically higher incidence
of this presentation with myelomas that are associated
with osteosclerosis. The combination of polyneuropathy,
organomegaly, endocrinopathy, myeloma monoclonal
gammopathy, and sclerosing bone lesions defines the so-
called POEMS syndrome; patients with this combination
tend to have a shorter survival than those with usual
myeloma.
416
Image Diagnosis
Radiographic Features
• Myeloma most often presents on imaging as diffuse
osteopenia.
• Myeloma may present as a solitary radiolucent lesion or
multiple punched-out lesions without reactive or sclerotic
borders.
• In less than 2 % of the cases, myeloma is associated with
osteosclerosis.
• Patients may present with pathologic fractures of periph-
eral bones or compression vertebral fractures.
• Unless there are fractures, radionuclide scans are usually
negative.
CT Features
• CT is more sensitive than conventional radiographs and
can demonstrate early bone destruction before it becomes
visible on conventional radiographs.
• CT demonstrates non-displaced fractures earlier than con-
ventional radiography.
• CT with many detectors is useful in the assessment of loss
of bone and fracture risk.
MRI Features
• Useful for evaluating small lesions that are not visible
with radionuclide scans.
• About 30–35 % of patients are understaged if radiographs
are used instead of MRI.
• While there are no signal-specific features, the lesions are
usually hypointense to normal fat on T1-weighted images.
Although myeloma is usually bright on T2-weighted
images, it is difficult to distinguish from the bright T2 signal
of fat. STIR and other fat suppression techniques are very
sensitive in demonstrating marrow replacement by myeloma.
• MRI is also useful to detect extension of lesions into soft
tissue.
Image Differential Diagnosis
Metastatic Carcinoma
• Patients are in the same age range.
• Radiolucent lesions are less geographic and usually do
not appear “punched out.”
• Solitary osseous metastasis and solitary myeloma may
appear identical; less than half of solitary myeloma
patients have monoclonal gammopathies, but this is a use-
ful laboratory finding when present.
M.J. Klein
• Patients usually have a history of a primary tumor prior to
presenting with osseous metastasis.
Lymphoma
• May be solitary or affect multiple bones.
• Usually radiolucent but presents as a sclerotic lesion
about 10 % of the time, often in the vertebrae (“ivory
vertebra”).
• Most of the time, there is associated lymphadenopathy
because most cases of lymphoma involving the bone are
stage 4 diseases.
• The degree of bone destruction is usually disproportion-
ate to the relatively mild clinical symptoms.
• Individual lesions are often visible on bone scans.
Langerhans Cell Histiocytosis
• Usually destructive but there is often a visible periosteal
reaction.
• A lesion may be punched out but usually has a beveled
edge rather than being uniformly radiolucent.
• Very rarely affects patients in the same age group as
myeloma.
Pathology
Gross Features
• Lesions resemble hematopoietic marrow in that they are
brown and gelatinous, but they are present in bone defects
or replace normal marrow.
• The bone may be sclerotic or have mixed destructive and
sclerotic features.
• Diffuse marrow involvement appears grossly as osteopo-
rotic bone with red marrow.
Histologic Features
• Punched-out or space-occupying lesions are com-
prised of cells having terminal plasma cell differentia-
tion: the cells are pear shaped with basophilic
cytoplasm having eccentric nuclei with their chroma-
tin showing peripheral clumping and clearing (clock-
face nuclei). In addition, some of the nuclei are
hyperchromatic, many will have large nucleoli, and
some will be multinucleated.
• In bones having diffuse osteoporosis or even with no dis-
cernible radiographic abnormalities, space-occupying
lesions consist of sheets of plasma cells. A myeloma
patient without discrete destructive bone lesions shows at
least 10 % plasma cells, often with atypical nuclear fea-
tures in a random marrow aspirate.
27 Myeloma
• The presence of increased circulating paraproteins often
makes the background look hypereosinophilic in
hematoxylin-eosin slides. Very often, erythrocytes in the
section demonstrate rouleaux in fixed paraffin section.
• The adjacent bone often demonstrates increased osteo-
clastic activity without significant osteoblast activity at
the border of lesions.
• Occasionally, there are large intranuclear eosinophilic
inclusions demonstrable in IgA myeloma, one of the few
histologic features pointing toward a particular monoclo-
nal differentiation.
• There may be amyloid stromal deposits in foci of tumor
whether or not the patient has systemic amyloidosis.
• In less well-differentiated lesions, plasma cell differentia-
tion may be demonstrated by immunohistochemistry.
Plasma cells show strong membrane staining with CD138
and EMA and strong nuclear staining with plasma cell tran-
scription factor MUM1, and sometimes their monoclonal-
ity may be differentiated with RNA amplification staining
for kappa or lambda light chains, while staining with heavy-
chain or whole-immunoglobulin antibodies is less reliable.
Pathologic Differential Diagnosis
Infections
• Chronic osteomyelitis may demonstrate entire fields of
plasma cells histologically, but this is seldom a diagnostic
problem because there are other signs and symptoms of
infection and because the cellular proliferation is not
monoclonal. A large aggregate of plasma cells in a space-
occupying bone lesion in the first and second decades is
almost always an infection and almost never myeloma.
Lymphoma and Leukemia
• Lymphoma and leukemia are the other round cell tumors
in adults. The morphology of these is usually easily dif-
ferentiable from differentiated plasma cells, though lym-
phomas may be plasmacytoid and anaplastic myelomas
may look lymphoid. Leukemia, a marrow-replacing
tumor, seldom presents with space-occupying, bone-
417
destroying lesions in the absence of granulocytic sarco-
mas. While these and almost all lymphomas are positive
for CD45, tumors of the granulocytic series stain with
myeloperoxidase.
Prognosis
• Survival in multiple myeloma depends upon the clinical
stage and other abnormalities such as renal insufficiency,
degree of tumor proliferative activity, peculiar karyotypic
abnormalities, chromosomal deletions, and other factors.
• Although there have been significant advances in treat-
ment strategies, the average overall survival rate is about
3 years.
• Patients with solitary myeloma usually progress clinically
to multiple myeloma, and their 10-year survival is about
50 %.
Treatment
• Treatment options for multiple myeloma range from
alkylating agents in combination with steroids to highly
tailored combination drug regimens with or without mar-
row transplantation (the scope of therapies is beyond the
scope of this text, but some of the selected references are
useful starting places).
• Individual lesions of the bone are highly radiosensitive,
and local radiation therapy is particularly useful in the
treatment of solitary bone lesions.
• Anti-RANKL antibodies and bisphosphonates have been
used with some success in arresting the progress of oste-
olysis but do not necessarily alter the overall progress of
disease.
Images
See Figs. 27.1, 27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9,
27.10 and 27.11 for illustrations of myeloma.
418
Fig. 27.1 Multiple myeloma usually presents radiographically with
diffuse osteoporosis rather than with discrete lesions of the bone. This
patient presented with sudden and severe lower back pain. The AP and
lateral radiographs demonstrate a compression fracture of the L4 verte-
bral body in a background of diffuse skeletal radiolucency without dis-
crete lesions. Clinical workup revealed a monoclonal immunoglobulin.
The photomicrographs are from a hematoxylin-eosin-stained cell block
Fig. 27.2 The more familiar presentation of myeloma but less typical
clinically is for discrete, punched-out lesions of various sizes (left). The
biopsy (H and E, 500×) demonstrates sheets of cells with plasmacytoid
M.J. Klein
taken from an iliac crest marrow aspirate; the upper photograph (787×)
demonstrates diffuse plasmacytosis in which there is diffuse nuclear
enlargement with coarse, cartwheel distribution of chromatin; there are
a few inclusion-like nucleoli. The lower photograph shows a very
unusual trinucleated plasma cell which would be very atypical for a
benign plasma cell proliferation
features (very large, eccentric nuclei, basophilic cytoplasm, peripher-
ally condensed chromatin in enlarged nuclei containing prominent
nucleoli)
27 Myeloma 419

Fig. 27.3 Myeloma involving the head and shaft of the humerus. lage; they are well circumscribed, blue, and contain no pink osseous
There are multiple discrete punched-out lesions, and some involve the tissue. There is no discernible peripheral reaction (Hematoxylin-eosin
endosteal cortex with scalloping radiolucency. The whole mount sec- 4×)
tion shows some of these lesions just below the humeral articular carti-
420 M.J. Klein

Fig. 27.4 Myeloma with involvement of the proximal humerus. bone scan, indicating no reaction to the tumor. This is characteristic for
Although there is a rather large destructive lesion below the humeral myeloma in the absence of a fracture
head extending to the diaphysis, there is no increased uptake on the
27 Myeloma 421

Fig. 27.5 Myeloma involving the femoral head with secondary frac- Note that the marrow adipose tissue is missing (6×, hematoxylin-eosin).
ture of the femoral neck. Grossly the tumor mass shows peripheral Higher magnifications, top right, shows an atypical plasmacytic infil-
hemorrhage at the distal margin. At low-power magnification, most of trate on both sides of a bone trabecula. At bottom right, there is wide-
the marrow is infiltrated, and the trabeculae become sparse distally. spread osteoclastic resorption at the bone-tumor interface

Fig. 27.6 Typical advanced multiple myeloma with large and small punched-out lesions of the humeri and femurs, one large enough to have
caused a pathologic fracture of the left femoral shaft
422
Fig. 27.7 Solitary myeloma (plasmacytoma) of the proximal left
femur. Patient presented with localized hip pain but had no other symp-
toms and there was no paraprotein. The lesion was resected, showing a
Fig. 27.8 Multiple myeloma, laboratory, immunologic, and molecular
findings. Serum immunofixation demonstrates a monoclonal immuno-
globulin of IgA lambda type. Top, middle, the plasma cells of this
tumor, like almost all plasma cells, demonstrate membrane staining
with CD138. Middle, bottom is a colorimetric in situ hybridization for
RNA encoding for lambda light chains, which densely stains the cyto-
M.J. Klein
gelatinous tumor mass centered in the intertrochanteric region and
femoral neck that histologically is identical to multiple myeloma
plasm of the malignant plasma cells. Upper right, plasma cells in this
section float free blood in an area of the biopsy with hemorrhage. Note
visible mitotic activity and nuclear inclusions seen both here and in the
lower left panel, typical for IgA myeloma. Photograph at the lower
right is taken with polarization contrast microscopy, to clearly demon-
strate the plasmacytoid morphology
27 Myeloma 423

Fig. 27.9 Multiple myeloma with sclerosis. Note lesions of the pelvis, of compact bone where there should be cancellous bone, and some of
sacrum, and femurs. The patient had presented 2 years prior with a the Haversian canals have small amounts of internal tissue. At higher
peripheral neuropathy and was later noted to have an IgG monoclonal magnification (right), atypical plasma cells are within fibrous tissue in
paraprotein. Biopsy of the iliac lesion (center) demonstrates aggregates one of these Haversian canals

Fig. 27.10 Myeloma with an amyloid extracellular matrix that has cations, but these are due to calcifications of amyloid and to reactive
secondary ossification. The lesion of the right humerus superficially bits of bone. The photomicrograph at the right demonstrates both new
resembles a cartilage tumor because of the overlapping stippled calcifi- bone formation and aggregates of amyloid separating the plasma cells
424
Fig. 27.11 Multiple myeloma. Lateral radiographic view of a skull.
Multiple lytic, “punched-out”, lesions
Recommended Reading
Cavo M, Rajkumar SV, Palumbo A, Moreau P, et al. International
Myeloma Working Group consensus approach to the treatment of
multiple myeloma patients who are candidates for autologous stem
cell transplantation. Blood. 2011;117(23):6063–73.
Dimpoulos MA, Moulopoulos LA, Maniatis A, et al. Solitary plasma-
cytoma of bone and asymptomatic multiple myeloma. Blood.
2004;96:2037–44.
Dispenzieri A. POEMS syndrome: update on diagnosis, risk-
stratification, and management. Am J Hematol. 2011;86:591–601.
M.J. Klein
Durie BGM. The epidemiology of multiple myeloma. Semin Hematol.
2001;38:1–5.
Durie BGM, Salmon SE. Myeloma management guidelines: a consen-
sus report from the Scientific Advisors of the International Myeloma
Foundation. Int J Hematol. 2003;4:379–98.
Fonseca R, Monge J. Myeloma: classification and risk assessment.
Semin Oncol. 2013;40(5):554–66.
Fonseca R, Monge J, Dimopoulos MA. Staging and prognostication of
multiple myeloma. Expert Rev Hematol. 2014;7(1):21–31.
Jasielec JK, Jakubowiak AJ. Current approaches to the initial treatment
of symptomatic multiple myeloma. Int J Hematol Oncol. 2013;
Feb;2(1). doi:10.2217/ijh.13.3.
Kaya H, Peressini B, Jawed I, et al. Impact of age, race and decade of
treatment on overall survival in a critical population of 40,000 mul-
tiple myeloma patients. Int J Hematol. 2012;95:64–70.
Kumar SK, Dispenzieri A, Lacy MQ, et al. Continued improvement in
survival in multiple myeloma: changes in early mortality and out-
comes in older patients. Leukemia. 2014;28(5):1122–8. doi:10.1038/
leu.2013.313.
Kyle RA, Gertz MA, Witzig TE, et al. Review of 1027 patients with
newly diagnosed multiple myeloma. Mayo Clin Proc. 2003;
78:21–33.
Lorsbach R, Kluin PM. Plasma cell myeloma. In: Fletcher CDM,
Bridge JA, Hogendoorn PCW, Mertens F, editors. WHO classifica-
tion of tumors of soft tissue and bone. Lyon: International Agency
for Research on Cancer; 2013a. p. 312–4.
Lorsbach R, Kluin PM. Solitary plasmacytoma of bone. In: Fletcher
CDM, Bridge JA, Hogendoorn PCW, Mertens F, editors. WHO clas-
sification of tumors of soft tissue and bone. Lyon: International
Agency for Research on Cancer; 2013b. p. 315.
McCarthy PL, Einsele H, Attal M, Giralt S. The emerging role of con-
solidation and maintenance therapy for transplant-eligible multiple
myeloma patients. Expert Rev Hematol. 2014;7(1):55–66.
McKenna RW, Kyle RA, Kuehl WM. Plasma cell neoplasms. In:
Swerdlow SH, Campo E, Harris NL, editors. WHO classification of
tumours of haematopoietic and lymphoid tissue. Lyon: International
Agency for Research on Cancer; 2008. p. 200–13.
Soutar R, Lucraft H, Jackson G, et al. Guidelines on the diagnosis and
management of solitary plasmacytoma of bone and solitary extra-
medullary plasmacytoma. Br J Haematol. 2004;124:717–26.
 Part VI
Fibrous Tumors
 Desmoplastic Fibroma of Bone
28
Ricardo K. Kalil

Abstract
Desmoplastic fibroma of bone is an intraosseous, locally aggressive neoplasm, constituted
by spindle cells and abundant collagen production. Beta-catenin is usually positive in the
cytoplasm of neoplastic cells. It corresponds to less than 0.1 % of primary bone neoplasms.
Its main incidence is in the second and third decade of life. Males correspond to more than
70 % of the cases. Most cases occur in the jaw; metaphysis of long bones, especially the
distal end of the radius; scapula; and pelvis. Radiographs show a lytic, well-defined lesion,
with no peripheral sclerosis or periosteal reaction. Soft tissue expansion of the lesion may
occur. Wide en bloc resection is the treatment of choice.

Definition Epidemiology

• An intraosseous, locally aggressive neoplasm, constituted • Corresponds to less than 0.1 % of primary bone
by spindle cells and abundant collagen production neoplasms

Synonyms Age

• Fibromatosis of bone • Can be seen at any age, but its main incidence is in the
• Aggressive fibromatosis of bone second and third decades of life
• Desmoid tumor of bone

Sex
Etiology
• Males correspond to more than 70 % of the cases.
• Unknown

R.K. Kalil, MD
Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina
Department of Surgical Pathology, A.C. Camargo Cancer Center,
São Paulo, SP, Brazil
e-mail: rkkalil@gmail.com

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 427
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_28, © Springer-Verlag London 2015
428 R.K. Kalil

Sites of Involvement Image Diagnosis

• Any bone can be involved. Radiographic Features

• Most cases occur in the jaw; metaphysis of long bones,
especially the distal end of the radius; scapula; and
pelvis.
Clinical Symptoms and Signs
• Radiographs show a lytic, usually well-defined lobulated
lesion, with no peripheral sclerosis or periosteal reaction.
The bone can be slightly expanded, and with tumor
growth, the cortex can be destroyed with soft tissue
expansion of the lesion.

• Local pain and/or the presence of a mass is the usual ini- CT Features
tial symptom.
• Pathological fracture occurs in between 12 and 20 % of • CT confirms the absence of bone production by the tumor
the cases at presentation. tissue.
28 Desmoplastic Fibroma of Bone 429

MRI Features tive bone; MRI shows heterogeneous, predominantly high

intensity signal on T2-weighted images.
• MRI imaging usually presents iso- or hypointense signal
relative to the adjacent muscle on T1- and a characteristic Fibrous Dysplasia
low signal on T2-weighted images. • It may be difficult to differentiate FD cases with scarce
• CT and MRI help define the soft tissue extension of the osteoid production.
lesion.
Low-Grade Central Osteosarcoma
• Usually presents blurred borders due to permeation into
Image Differential Diagnosis the host bone; variable bone production identified by
radiographs, CT, or MRI
Chondromyxoid Fibroma
• CMF has a better defined border inside the bone; expan- Fibrosarcoma of Bone
sion to soft parts shows a thin mineralized shell of reac- • Has blurred borders due to permeative pattern; rarely
expands the host bone

a b

Fig. 28.1 (a) Macrophotography of a desmoplastic fibroma of the lesion in (a). Lytic lesion, devoid of mineral deposits, and partial reac-
radius. Whitish, firm elastic metaphyseal lesion, with cortex destruction tive sclerosis in the proximal lateral bone margin of the lesion
and soft tissue involvement. (b) Specimen radiography of the same
430
a b
Fig. 28.2 (a) A desmoplastic fibroma of the tarsus. Lesion destroys
the tarsal bones and involves adjacent soft parts. (b) Specimen radiog-
raphy of lesion in (a). Lytic tarsal lesion involving all the short bones
Pathology
Gross Features
• The cut surface is white and firm, with a whorled pattern
and clear, scalloped margins.
Histological Features
• More commonly, desmoplastic fibroma has a general low
cellularity and abundant collagen matrix, with occasional
permeation of neighboring tissues.
• Cells are spindle and arranged in a whorled fashion
or in long fascicles, similar to what happens in soft
tissue desmoplastic fibroma. Nuclei look active and
may show minimal atypia, and mitoses are absent or
rare.
• Long, dilated vascular channels are commonly seen.
• Thick, undulating collagen fibers resembling keloid may
be focally seen.
R.K. Kalil
and involving the soft tissue. Some residual trabecular bone is seen
amid the lesional tissue. There is no reactive bone
• Reactive bone trabeculae may be focally present in a frac-
tured or recurrent tumor, raising a differential diagnosis
with fibrous dysplasia.
Pathology Differential Diagnosis
Fibrous Dysplasia
• Presents a variable production of curvilinear immature
bone trabeculae regularly disposed inside a slightly
whorled and loose collagenic stroma; cellularity is low, it
is regularly distributed, and cells are always typical; mito-
ses are absent.
Low-Grade Central Osteosarcoma
• Has a permeative pattern; contains neoplastic bone tra-
beculae; cells are elongated, and although mitoses may be
rare, nuclei have a slight atypical appearance. Positive for
CDK4 and MDM2
28 Desmoplastic Fibroma of Bone 431

a b

Fig. 28.3 (a) A desmoplastic fibroma of the distal metaphysis of a lesion in Fig. 28.3a. Lytic metaphyseal lesion, with very slight marginal
femur. Medullar, cortical, and adjacent soft tissue involvement by the sclerosis and a more pronounced periosteal reaction, possibly due to
lesion. Secondary cyst formation is seen. (b) Specimen radiography of fracture

Fibrosarcoma of Bone Genetics

• Has a permeative pattern; more cellular and atypical than
desmoplastic fibroma with a herringbone arrangement; • Rearrangement involving chromosomes 11 and 19 was
occasional mitoses are seen, typical and atypical. reported.

Ancillary Techniques Prognosis

• MDM2 and CDK4 are negative in desmoplastic fibroma
and can differentiate it from low-grade osteosarcoma
which will show positivity for these markers.
• Beta-catenin is usually positive in the cytoplasm of
neoplastic cells.
• Desmoplastic fibroma is a locally aggressive tumor, and if
allowed to grow, it will destroy the bone cortex and
expand into neighboring soft tissue.
• It has no metastatic potential.
• Complete excision can be curative.
• Curettage or incomplete resection is almost always related
to recurrence.
432 R.K. Kalil

a b

Fig. 28.4 (a) Desmoplastic fibroma affecting the proximal epiphysis epiphysio-metaphyseal lesion, with no mineral deposits, some medul-
and metaphysis of a humerus. Shoulder joint and adjacent soft tissues lary reactive bone, and imprecise external limits
are involved. (b) Specimen radiography of lesion in (a). Destructive

Treatment Images

• Wide en bloc resection is the treatment of choice to avoid See Figs. 28.1, 28.2, 28.3, 28.4, 28.5, 28.6, 28.7, 28.8,
recurrence. 28.9, and 28.10 for illustrations of desmoplastic fibroma of
bone.
28 Desmoplastic Fibroma of Bone 433

Fig. 28.5 Medium-power microphotography. Cellularity is variable Fig. 28.8 Medium-power microphotography. Thick collagen fibers
and collagen production not pronounced in this field may be pronounced in some cases

Fig. 28.6 Medium-power microphotography. Spindle cell prolifera- Fig. 28.9 High-power microphotography. A few cases may present
tion, plump nuclei, no atypia, and moderate collagen production mitotic activity. Atypical mitoses are not seen

Fig. 28.7 Low-power microphotography. Area with some thick colla- Fig. 28.10 Low-power view of the peripheral area of a lesion.
gen fibers is seen adjacent to more cellular area with less collagen Residual, partially destroyed bone trabeculae are seen amid spindle cell
proliferation. Cellular nuclei are more elongated, with some atypia
434 R.K. Kalil

Recommended Reading immunohistochemical study including beta-catenin expression and

mutational analysis for beta-catenin. Hum Pathol.
2005;36(9):1025–30.
Bahk WJ, Kang YK, Lee AH, Mirra JM. Desmoid tumor of bone with
Inwards CY, Unni KK, Beabout JW, Sim FH. Desmoplastic fibroma of
enchondromatous nodules, mistaken for chondrosarcoma. Skelet
bone. Cancer. 1991;68(9):1978–83.
Radiol. 2003;32(4):223–6.
Itami Y, Akamatsu Y, Inoue T. Radiographic and histopathological
Bertoni F, Calderoni P, Bacchini P, Campanacci M. Desmoplastic
appearance of desmoplastic fibroma. Rinsho Geka.
fibroma of bone. A report of six cases. J Bone Joint Surg (Br).
1964;19:207–11.
1984;66(2):265–8.
Lagacé R, Delage C, Bouchard HL, Seemayer TA. Desmoplastic
Crim JR, Gold RH, Mirra JM, Eckardt JJ, Bassett LW. Desmoplastic
fibroma of bone. An ultrastructural study. Am J Surg Pathol.
fibroma of bone: radiographic analysis. Radiology.
1979;3(5):423–30.
1989;172(3):827–32.
Taconis WK, Schütte HE, van der Heul RO. Desmoplastic fibroma of
Dahlin DC, Hoover NW. Desmoplastic fibroma of bone. Report of two
bone: a report of 18 cases. Skelet Radiol. 1994;23(4):283–8.
cases. JAMA. 1964;188:685–7.
Trombetta D, Macchia G, Mandahl N, Nord KH, Mertens F. Molecular
Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F. WHO clas-
genetic characterization of the 11q13 breakpoint in a desmoplastic
sification of tumors of soft tissue and bone. Lyon: IARC; 2013.
fibroma of bone. Cancer Genet. 2012;205(7-8):410–3.
p. 302–4.
Unni KK, Inwards C. Dahlin’s bone tumors. 6th ed. Philadelphia:
Frick MA, Sundaram M, Unni KK, Inwards CY, Fabbri N, Trentani F,
Lippincott Williams & Wilkins; 2010. p. 179–83.
Baccini P, Bertoni F. Imaging findings in desmoplastic fibroma of
Vanhoenacker FM, Hauben E, De Beuckeleer LH, Willemen D, Van
bone: distinctive T2 characteristics. AJR Am J Roentgenol.
Marck E, De Schepper AM. Desmoplastic fibroma of bone: MRI
2005;184(6):1762–7.
features. Skelet Radiol. 2000;29(3):171–5.
Gebhardt MC, Campbell CJ, Schiller AL, Mankin HJ. Desmoplastic
Yoshida A, Ushiku T, Motoi T, Shibata T, Beppu Y, Fukayama M,
fibroma of bone. A report of eight cases and review of the literature.
Tsuda H. Immunohistochemical analysis of MDM2 and CDK4 dis-
J Bone Joint Surg Am. 1985;67(5):732–47.
tinguishes low-grade osteosarcoma from benign mimics. Mod
Hauben EI, Jundt G, Cleton-Jansen AM, Yavas A, Kroon HM, Van
Pathol. 2010;23(9):1279–88.
Marck E, Hogendoorn PC. Desmoplastic fibroma of bone: an
 Fibrosarcoma of Bone
29
Ricardo K. Kalil

Abstract
Fibrosarcoma of bone is a malignant spindle cell tumor characterized by a herringbone or
fascicular disposition of atypical, monomorphic fibroblasts and is always negative for any
specific marker, which makes this tumor a diagnosis of exclusion. It can be primary or, less
frequently, secondary to radiation or other pathologic conditions. It represents from 2 % to
4 % of primary bone tumors and is reported to occur from the second to the seventh decades
of life. Fibrosarcoma has a preference for the metaphyses of long bones, especially the
distal femur. The more important prognostic feature is histological grade. Wide resection or
amputation is the indicated treatment.

Definition Epidemiology

• A malignant spindle cell tumor of the bone, characterized • Represents from 2 % to 4 % of primary bone tumors
by a herringbone or fascicular disposition of atypical,
monomorphic fibroblasts.
• It can be primary or, less frequently, secondary to radia- Sex
tion or other pathologic conditions.
• There is no clear gender predominance.

Etiology
• There are no known causes.
• Fibrosarcoma may appear secondarily on numerous con-
ditions like fibrous dysplasia, Paget’s disease, Ollier dis-
ease, osteochondromatosis, giant cell tumor, bone infarct,
dedifferentiated chondrosarcoma, dedifferentiated paros-
teal osteosarcoma, and others.
Age
• It is reported to occur from the second to the seventh
decades of life.
• These historical figures, however, can be challenged by the
recent introduction of ancillary techniques that exclude
cases morphologically similar to fibrosarcoma but which
can now be classified under other neoplastic categories.

R.K. Kalil, MD
Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina
Department of Pathology, A.C. Camargo Cancer Center,
São Paulo, SP, Brazil
e-mail: rkkalil@gmail.com

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 435
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_29, © Springer-Verlag London 2015
436
Sites of Involvement
• Just as for osteosarcoma, fibrosarcoma has a preference
for the metaphyses of long bones, especially the distal
femur, with the proximal femur, distal humerus, proximal
tibia, and pelvis following in frequency.
Clinical Symptoms and Signs
• Local pain and/or the presence of a mass is the usual ini-
tial symptom of primary fibrosarcoma of the bone.
• Limitation of motion of a neighboring joint and patho-
logical fracture can occur in some cases at presentation.
Image Diagnosis
Radiographic and CT Features
• Imaging methods show a metaphyseal eccentric lytic
lesion, with a predominantly permeative pattern, without
R.K. Kalil
peripheral or periosteal bone reaction even after cortical
permeation and soft tissue extension.
• There is no sign of mineral deposits or of bone production
by the tumor.
• Geographical, permeative, or “moth-eaten” patterns can
probably be related to different histological grades.
• MRI, and bone scan do not contribute with further data
for the diagnosis.
Image Differential Diagnosis
Fibroblastic Osteosarcoma and Low-Grade
Central Osteosarcoma
• These tumors present very scarce or variable bone pro-
duction that when and if identified by imaging methods
can suggest the correct diagnosis.
Desmoplastic Fibroma of Bone
• Fibrosarcoma shows indistinct borders due to tumor per-
meation, and expansion of the cortices is unusual.
29 Fibrosarcoma of Bone
Malignant Lymphoma of Bone
• In long bones, it is preferentially situated in the diaphysis.
Both lesions can share the “moth-eaten” pattern; other
infiltration patterns are more suggestive of fibrosarcoma.
Undifferentiated Pleomorphic
Sarcoma/MFH
• Has no imaging differences in relation to high-grade
fibrosarcoma
Pathology
Gross Features
• Fibrosarcoma presents a white and firm cut surface, with
a trabeculated pattern and circumscribed margins.
• Higher-grade tumors present a more fleshy appearance
and focal friable necrotic or hemorrhagic areas.
• Margins tend to be indistinct.
Histological Features
• Fibrosarcoma is composed by a uniform spindle cell pop-
ulation arranged in “herringbone” or fascicular pattern.
• Collagen production is variable and related to tumor grade,
high-grade lesions scarcely showing collagen matrix.
• By definition, there can be no other kind of matrix pro-
duction except pure collagen to categorize a neoplasia as
fibrosarcoma.
• High-grade lesions also present more frequent mitotic and
atypical nuclei as well as occasional areas of necrosis.
Pathology Differential Diagnosis
Fibrous Dysplasia
• If the sample does not include immature bone trabeculae,
it may be difficult to separate, on exclusively histological
grounds, from well-differentiated fibrosarcoma.
• Attention to infiltrated margins on histology and radio-
logical signs of aggressiveness can help in the diagnosis.
Fibroblastic Osteosarcoma
• Always contains neoplastic bone trabeculae that must be
sought extensively in these predominantly fibroblastic tumors
Desmoplastic Fibroma of Bone
• Has elongated strands of well-differentiated active-
appearing spindle cells and is seldom permeative, less
cellular, and less atypical than fibrosarcoma; mitoses,
when present, are always typical.
437
Leiomyosarcoma of Bone
• Spindle cell bundles are disposed at cross angles and pres-
ent a “schoolfish” pattern different from the herring bone
predominant pattern of fibrosarcoma; nuclei are elongated
and blunt ended (cigar-shaped).
• Positive for smooth muscle markers and keratin.
Synovial Sarcoma, Monophasic
• Spindle cells are densely arranged in vague fascicles (so
dense that no matter how thin the histological section,
these areas will always have a thick appearance).
• Mast cells are an almost constant finding and may be
abundant.
• Calcification or ossification areas may also be extensive.
• Immunohistochemical techniques may be necessary to
rule out this diagnosis: epithelial markers and CD99.
• Translocation t(X;18)(p11:q11) is found exclusively
in SS.
• RT-PCR detection of SYT-SSX1/2 fusion transcripts is
diagnostic of SS.
Myxofibrosarcoma
• Shows frequent areas of myxoid matrix alongside areas of
more dense, collagenic matrix
• Intratumoral heterogeneity of low-grade and high-grade
juxtaposed areas
• Scattered positivity for SMA marker
Undifferentiated Pleomorphic Sarcoma/MFH
• This is always a high-grade and pleomorphic lesion.
Ancillary Techniques
• Fibrosarcoma is always negative for any specific marker,
which makes this tumor a diagnosis of exclusion.
Genetics
• A number of apparently specific mutations in KIAA1432,
CA9, TLN1, and MELK were found in a limited number
of sarcomas, which includes fibrosarcoma, MFH, and
Ewing family of tumors.
Prognosis
• The more important prognostic feature is histological
grade.
• Five-year survival rate varies accordingly from 83 to
34 %.
• Ten-year survival rates can be as low as 28 %.
438 R.K. Kalil

• Metastases, when present, usually spread to the lungs and • There is no data in the literature regarding chemotherapy
other bones. as a standard treatment procedure.
• Local recurrence is related to a poor long-term prognosis.

Images
Treatment
See Figs. 29.1, 29.2, 29.3, 29.4, 29.5, and 29.6 for illustra-
• Wide resection or amputation is the usually the indicated tions of malignant fibrosarcoma of the bone.
treatment.

a b

Fig. 29.1 (a) Macrophotography of a fibrosarcoma in the proximal rhagic central areas. (b) Radiograph of the specimen in the previous
end of the tibia. Lesion involves the entire width of the bone as well as picture depicting soft tissue lesion devoid of any bone or mineral
the adjacent soft parts. Pink-whitish tissue with necrotic and hemor- deposits
29 Fibrosarcoma of Bone 439

Fig. 29.2 Macrophotography of a fibrosarcoma of the maxilla, an

infrequent site
Fig. 29.4 Low-power microphotography. Grade 3 fibrosarcoma

Fig. 29.5 High-power view of the same case as Fig. 29.4

Fig. 29.3 Radiograph of a fibrosarcoma in the posterior vertebral ele-

ments, another rare site

Fig. 29.6 Immunohistochemistry positivity for vimentin. No other

marker was positive
440 R.K. Kalil

Recommended Reading Knuutila S. Frequent deletion of CDKN2A and recurrent coamplifi-

cation of KIT, PDGFRA, and KDR in fibrosarcoma of bone–an
array comparative genomic hybridization study. Genes
Antonescu CR, Erlandson RA, Huvos AG. Primary fibrosarcoma and
Chromosomes Cancer. 2010;49(2):132–43.
malignant fibrous histiocytoma of bone – a comparative ultrastruc-
Papagelopoulos PJ, Galanis EC, Trantafyllidis P, Boscainos PJ, Sim
tural study: evidence of a spectrum of fibroblastic differentiation.
FH, Unni KK. Clinicopathologic features, diagnosis, and treatment
Ultrastruct Pathol. 2000;24(2):83–91.
of fibrosarcoma of bone. Am J Orthop. 2002;31(5):253–7.
Bertoni F, Capanna R, Calderoni P, Patrizia B, Campanacci M. Primary
Romeo S, Bovée JV, Kroon HM, Tirabosco R, Natali C, Zanatta L,
central (medullary) fibrosarcoma of bone. Semin Diagn Pathol.
Sciot R, Mertens F, Athanasou N, Alberghini M, Szuhai K,
1984;1(3):185–98.
Hogendoorn PC, Dei Tos AP. Malignant fibrous histiocytoma and
Dahlin DC, Ivins JC. Fibrosarcoma of bone. A study of 114 cases.
fibrosarcoma of bone: a re-assessment in the light of currently
Cancer. 1969;23(1):35–41.
employed morphological, immunohistochemical and molecular
Eyre-Brook AL, Price CH. Fibrosarcoma of bone. Review of fifty con-
approaches. Virchows Arch. 2012;461(5):561–70.
secutive cases from the Bristol Bone Tumour Registry. J Bone Joint
Sarhadi VK, Lahti L, Scheinin I, Ellonen P, Kettunen E, Serra M,
Surg Br. 1969;51(1):20–37.
Scotlandi K, Picci P, Knuutila S. Copy number alterations and
Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F. WHO clas-
neoplasia-specific mutations in MELK, PDCD1LG2, TLN1, and
sification of tumors of soft tissue and bone. Lyon: IARC; 2013.
PAX5 at 9p in different neoplasias. Genes Chromosomes Cancer.
p. 302–4.
2014;53(7):579–88.
Huvos AG, Higinbotham NL. Primary fibrosarcoma of bone. A clinico-
Taconis WK, van Rijssel TG. Fibrosarcoma of long bones: a study of
pathologic study of 130 patients. Cancer. 1975;35(3):837–47.
the significance of areas of malignant fibrous histiocytoma. J Bone
McLeod JJ, Dahlin DC, Ivins JC. Fibrosarcoma of bone. Am J Surg.
Joint Surg Br. 1985;67:111–6.
1957;94(3):431–7.
Unni KK, Inwards C. Dahlin’s bone tumors. 6th ed. Philadelphia:
Niini T, López-Guerrero JA, Ninomiya S, Guled M, Hattinger CM,
Lippincott Williams & Wilkins; 2010. p. 179–83.
Michelacci F, Böhling T, Llombart-Bosch A, Picci P, Serra M,
 Part VII
Fibrohistiocytic Tumors
 Benign Fibrous Histiocytoma
of Bone 30
Ricardo K. Kalil

Abstract
Benign fibrous histiocytoma of bone is a benign primary bone neoplasia characterized by
a mixture of fibroblasts disposed in a predominant storiform fashion, a variable amount of
osteoclast-type giant cells, foamy macrophages, hemosiderin, and chronic inflammatory
infiltrate, a histologic picture indistinguishable from non-ossifying fibroma, from which it
distinguishes itself by its neoplastic growth potential and on clinico-radiological grounds.
It is more frequent in young adults, affecting mainly the spine and long bones, especially
the femur and tibia. Curettage or simple resection is usually curative, having a good
prognosis.

Definition Etiology

• A benign primary bone neoplasia characterized by a mix- • Unknown

ture of fibroblasts disposed in a predominant storiform
fashion, a variable amount of osteoclast-type giant cells,
foamy macrophages, hemosiderin, and chronic inflamma- Epidemiology
tory infiltrate.
• The histologic picture is indistinguishable from that of • Very low incidence
non-ossifying fibroma, from which it distinguishes itself
by its neoplastic growth potential and on clinico-
radiological grounds. Sex

• Females more frequent than males

Synonyms

• Fibroxanthoma Age
• Xanthogranuloma
• More frequent between the third and the fifth decades but
has a very large age span incidence

R.K. Kalil, MD
Laboratory of Orthopaedic Pathology,
Buenos Aires, Argentina
Department of Pathology, A.C. Camargo Cancer Center,
São Paulo, SP, Brazil
e-mail: rkkalil@gmail.com

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 443
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_30, © Springer-Verlag London 2015
444
Sites of Involvement
• The spine and long bones, especially the femur and tibia,
preferably in a non-metaphyseal location, are the more
common sites involved.
• Small long bones of the feet follow in frequency.
• Any other bone may be involved.
Clinical Symptoms and Signs
• Local pain that may be of long duration is commoner in
benign fibrous histiocytoma (BFH) than in its histologi-
cally similar counterpart, NOF.
• Patients may be asymptomatic, the lesion being discov-
ered incidentally.
• Pathological fracture is exceptional.
R.K. Kalil
Image Diagnosis
Radiographic Features
• Radiographs show a medullar, central, or slightly eccen-
tric well-defined radiolucent lesion.
• Dense pseudoseptation may be seen.
• Most lesions have sclerotic margins but a few of them
may have irregular margins suggestive of aggressiveness.
CT Features
• CT confirms absence of bone production, emphasizing
the pseudoseptation and sclerotic margins.
MRI Features
• MRI shows an isointense signal related to muscle on T1-
and varying degrees of high signal intensity on
T2-weighted images.
• Bone scintigraphy may show moderately increased uptake.
30 Benign Fibrous Histiocytoma of Bone
Image Differential Diagnosis
Non-ossifying Fibroma
• Their radiographic characteristics may be indistinguish-
able, but NOF has a clear preference for the metaphysis of
long bones, especially the distal femur of younger patients
than BFH.
Giant Cell Tumor of Bone
• When in the end of a long bone, these two lesions may be
indistinguishable by image methods, but GCT is more
aggressive and can present earlier expansion to soft tis-
sue; GCT also presents less or no sclerotic margins.
Chondromyxoid Fibroma
• Can present very similar radiographic characteristics. By
MRI, the chondroid component may be responsible for a
high-intensity signal on T2.
Pathology
Gross Features
• BFH cut surface shows a well-delimited medullar lesion.
• The tumor tissue is firm, elastic, tan to whitish with yel-
lowish areas.
• Fractured lesions may show hemorrhagic or necrotic areas.
Histological Features
• Histologically, BFH shows a mixture of spindle cells dis-
posed in a predominant storiform fashion, a variable
amount of osteoclast-type giant cells, foamy macrophages,
hemosiderin, and chronic inflammatory infiltrate.
• At higher power, the spindle cells’ nuclei are bland and
with rare mitoses.
• Multinucleated giant cells are scattered throughout the
lesion.
• Hemosiderin-laden cells are abundant in the stroma.
• Collections of foamy histiocytes are also frequently seen.
• Diffuse areas of mononuclear inflammatory infiltrate may
also be present.
445
Pathology Differential Diagnosis
Non-ossifying Fibroma
• Presents similar histologic findings as BFH, being distin-
guishable from it only on clinical grounds. NOF affects a
younger population and is less bound to produce symp-
toms than BFH and is almost always located eccentrically
or cortically in the metaphysis of a long bone.
Giant Cell Tumor of Bone
• When in the end of a bone, BFH can present this differential
diagnosis. GCT is a more aggressive lesion and expands more
easily to soft tissue. It has less or no sclerotic borders and
more hemorrhagic or necrotic areas, giant cells are more
abundant and with larger number of nuclei, stromal cells may
only focally present a storiform arrangement, their nuclei are
more active, and mitosis may be more easily found.
Malignant Fibrous Histiocytoma
• Has the same cellular elements than BFH but pres-
ents always a high-grade malignant histological
picture, with frequent cellular and nuclear atypias
and numerous atypical mitoses either in the spindle
cells or the giant cells.
Prognosis
• Excellent, although it may rarely recur if not completely
excised.
• Differently from NOF, whose growth potential is limited
and can even involute in time, BFH has the growth poten-
tial of a benign neoplasm.
Treatment
Thorough curettage or simple resection may be curative.
Images
See Figs. 30.1, 30.2, 30.3, 30.4, 30.5, 30.6, 30.7, 30.8, and
30.9 for illustrations of benign fibrohystiocytoma.
446 R.K. Kalil

Fig. 30.1 Macrophotography of a BFH of a scapula. Yellowish pre-

dominant color denotes rich lipid content
30 Benign Fibrous Histiocytoma of Bone 447

a b

Fig. 30.2 (a) Predominant whitish color in this BFH of a fibula denotes its predominant fibrous structure.(b) Specimen radiography of the same
lesion as (a). Lytic lesion, without clear borders and a central area of mineral deposit

Fig. 30.3 Low-power microphotography. Spindle cell proliferation in Fig. 30.4 Medium-power microphotography. Diffuse infiltration of
haphazard, cartwheel fashion spindle cell stroma by mononuclear inflammatory cells
448 R.K. Kalil

Fig. 30.5 Medium-power microphotography. Focus of inflammatory Fig. 30.8 Areas rich in multinucleated giant cells are almost always
cells and foamy histiocytes seen, especially next to hemorrhagic foci

Fig. 30.6 Medium-power microphotography. Hemosiderin-laden his- Fig. 30.9 At the periphery, a mixture of spindle cells, foamy histio-
tiocytes are focally seen cytes, and other inflammatory cells is seen amid mature bone trabecu-
lae. There is no evidence of aggressiveness to the bone trabeculae by
the tumor cells

Fig. 30.7 Exceptionally, a few atypical cells may be focally seen scat-
tered in the stroma
30 Benign Fibrous Histiocytoma of Bone 449

Recommended Reading Destouet JM, Kyriakos M, Gilula LA. Fibrous histiocytoma (fibroxan-
thoma) of a cervical vertebra. A report with a review of the litera-
ture. Skeletal Radiol. 1980;5(4):241–6.
Bertoni F, Calderoni P, Bacchini P, Sudanese A, Baldini N, Present D,
Grohs JG, Nicolakis M, Kainberger F, Lang S, Kotz R. Benign fibrous
Campanacci M. Benign fibrous histiocytoma of bone. J Bone Joint
histiocytoma of bone: a report of ten cases and review of literature.
Surg Am. 1986;68(8):1225–30.
Wien Klin Wochenschr. 2002;114(1–2):56–63.
Ceroni D, Dayer R, De Coulon G, Kaelin A. Benign fibrous histiocy-
Macdonald D, Fornasier V, Holtby R. Benign fibrohistiocytoma (xan-
toma of bone in a paediatric population: a report of 6 cases.
thomatous variant) of the acromion. A case report and review of the
Musculoskelet Surg. 2011;95(2):107–14.
literature. Arch Pathol Lab Med. 2002;126(5):599–601.
Dahlin DC. General aspects and data on 6,221 cases. In: Bone tumors.
Nielsen GP, Kyriakos M. In: Fletcher CDM, Bridge JA, Hogendoorn
3rd ed. Springfield: Charles C Thomas; 1978. p. 116–36.
PCW, Mertens F, editors. WHO classification of tumors of soft tis-
Demiralp B, Kose O, Oguz E, Sanal T, Ozcan A, Sehirlioglu A. Benign
sue and bone. Lyon: IARC; 2013. p. 302–4.
fibrous histiocytoma of the lumbar vertebrae. Skeletal Radiol.
Unni KK, Inwards C. Dahlin’s bone tumors. 6th ed. Philadelphia:
2009;38(2):187–91.
Lippincott Williams & Wilkins; 2010. p. 179–83.
 Malignant Fibrous Histiocytoma
of Bone 31
Ricardo K. Kalil

Abstract
Malignant fibrous histiocytoma of bone is a malignant high-grade neoplasia characterized
by a mixture of atypical fibroblasts and pleomorphic undifferentiated cells disposed in a
predominant storiform fashion. Up to 28 % of cases appear secondarily in a number of bone
conditions such as irradiated bone, Paget disease, bone infarct, prosthetic surgery, and the
hereditary condition known as diaphyseal medullary stenosis – Hardcastle syndrome. It
corresponds to 2 % of primary malignant bone tumors. It is more frequent after the fifth
decade of life; occurs mainly in the metaphysis or diaphysis of long bones, especially
around the knee; and is radiographically aggressive. Secondary MFH is reported to have a
worse prognosis and necessitates the same treatment as for conventional osteosarcoma.

• In up to 28 % of cases, MFH can appear secondarily in a

Definition
• A malignant high-grade primary bone neoplasia charac-
terized by a mixture of atypical fibroblasts and pleomor-
phic undifferentiated cells disposed in a predominant
storiform fashion
number of bone conditions such as irradiated bone, Paget
disease, bone infarct, prosthetic surgery, and the heredi-
tary condition known as diaphyseal medullary stenosis;
Rarely, it is seen associated to a diaphyseal dysplasia in
Hardcastle syndrome.

Synonyms Epidemiology
• Undifferentiated high-grade pleomorphic sarcoma of bone • Corresponds to 2 % of primary malignant bone tumors

Etiology
Sex
• Primary MFH has no known causes.
• Affects slightly more males than females

Age
R.K. Kalil, MD
Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina
• More frequent after the fifth decade of life but has a wide
Department of Pathology, A.C. Camargo Cancer Center,
São Paulo, SP, Brazil age incidence, from the second to the eighth decade
e-mail: rkkalil@gmail.com • Less frequent under 20 years of age

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 451
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_31, © Springer-Verlag London 2015
452
Sites of Involvement
• Metaphysis or diaphysis of long bones, especially around
the knee.
• Femur, tibia, and humerus are, in this order, the more fre-
quent locations.
• Pelvis, especially the ilium, follows in frequency.
• About any other bone can be more rarely affected.
Clinical Symptoms and Signs
• Local pain and/or the presence of a mass is the initial
symptom that can present as early as 1 week to several
months.
• Pathologic fracture may occur.
R.K. Kalil
• As this tumor is frequently associated to a preceding disease,
there may be symptoms related to the primary condition.
Image Diagnosis
Radiographic and CT Features
• Radiographic and CT findings correspond to a high-grade
malignant lesion usually located in the metaphysis or
diaphysis of a long bone.
• Lytic, with no mineral deposits or ossification, poorly cir-
cumscribed, with early cortical destruction and extension
to soft parts.
31 Malignant Fibrous Histiocytoma of Bone
• Periosteal reaction is unusual.
• Evidence of a preceding disorder may be seen.
MRI Features
• MRI shows a lesion hypo- or isointense to muscle on
T1-weighted images, high signal intensity on T2, and con-
trast enhancement, especially at the periphery of the tumor.
Bone Scan
• Bone scan demonstrates a hot lesion.
Image Differential Diagnosis
Osteosarcoma, in Young Patients
• In the absence of discernible mineralized tissue, it may be
impossible to differentiate by image methods.
• All the following tumors may also present very similar
imaging features when a single lesion is considered:
Fibrosarcoma, high grade
Leiomyosarcoma, high grade
Angiosarcoma
Malignant primary lymphoma of the bone
Metastatic carcinoma
Myeloma
• Signals of a preexisting lesion can suggest the diagnosis
of MFH.
• Presence of multiple lesions can suggest metastasis or
myeloma, which have to be screened clinically.
Pathology
Gross Features
• Usually a large lesion with undefined limits either intra-
medullary or in its eventual soft tissue extension.
• Its cut surface varies from white and fibrous (collagen produc-
ing areas) to soft (cellular areas) to tan and yellowish (lipid-
laden areas) to hemorrhagic and friable (necrotic areas).
Histological Features
• Histologically, MFH is characterized by a mixed popula-
tion of spindle cells, histiocytic-like cells, multinucleated
453
giant cells, all of which, including the giant cells, may be
very atypical, and a chronic inflammatory infiltrate.
• Specific kinds of cells may predominate in certain areas.
• Spindle cell areas present a storiform or cartwheel pattern.
• Histiocytic-like cells may predominate, with large clear
cytoplasm and atypical nuclei.
• Atypical mitoses are frequent.
• Some areas may be richly vascularized, sometimes in a
hemangiopericytoma-like pattern.
• Foci of inflammatory infiltration are a common finding.
• Giant multinucleated very bizarre cells are seen and may
be abundant.
• Areas with a myxoid background may be seen.
• In certain tumors, the presence of intercellular hyalinized col-
lagen matrix may be impossible to tell from osteoid. Extensive
sampling may be necessary to rule out this possibility.
Pathology Differential Diagnosis
Osteosarcoma
• Always contains neoplastic bone trabeculae that must be
sought extensively; may present nuclear positivity with
SATB2.
Fibrosarcoma, High Grade
• Absolute predominance of spindle cell population
Both differential diagnosis cited above may not be of clin-
ical importance, since these tumors will probably be treated
the same way.
Liposarcoma, Pleomorphic Type
• Because of the foamy aspect of some neoplastic cells
Leiomyosarcoma, High Grade
• Immunohistochemical methods may be necessary in dif-
ficult cases.
Metastatic Sarcomatoid Carcinoma
• Clinical and immunohistochemical methods may identify
a renal tumor and characteristic immunophenotype.
Malignant Lymphoma with Fibrosis
• Look for eventual multicentricity.
• Spindle cells are not atypical.
Giant Cell Tumor of Bone
• Epiphyseal location.
• Spindle cell areas may be abundant but do not have atypi-
cal features.
454
Ancillary Techniques
• MFH lacks specific immunohistochemical markers,
which makes this tumor a diagnosis of exclusion.
• Ultrastructurally, it appears that the predominant cells in
MFH are fibroblasts or modified fibroblasts, suggesting
identification with fibrosarcoma.
Genetics
• MFHs show very complex karyotypes with no identifi-
able particular aberration so far.
Prognosis
• MFH is always high grade.
• Metastases present early and usually to the lungs.
Fig. 31.1 Macrophotography of MFH of femur. Yellowish-red, soft,
and friable viable and necrotic tumor tissue occupying the diaphysis
and protruding into the anterior soft parts
R.K. Kalil
• Local recurrence is related to a poor prognosis.
• Adequate treatment can achieve a 5-year disease-free sur-
vival in more than 50 % of patients.
• Secondary MFH is reported to have a worse prognosis.
• High tumor necrosis index posttreatment, younger age at
presentation, and adequate surgical margins are related to
a more frequent favorable prognosis.
Treatment
• The same as for conventional osteosarcoma
Images
See Figs. 31.1, 31.2, 31.3, 31.4, 31.5, 31.6, 31.7, 31.8, and
31.9 for illustrations of malignant fibrous histiocytoma of the
bone.
Fig. 31.2 Specimen radiography. Undefined lucent lesion permeating
diffusely the femoral shaft, with no clear limits
31 Malignant Fibrous Histiocytoma of Bone 455

Fig. 31.4 MFH of the distal end of a femur. The lesion is extensively
necrotic

Fig. 31.3 MFH of a humeral metaphysis. Whitish-red soft tissue

extruding through permeated cortex. Limits of the lesion are not clear
456 R.K. Kalil

Fig. 31.6 Medium-power microscopic view – highly atypical spindle

cells, admixed with some inflammatory cells

Fig. 31.5 MFH involving the whole shaft of a humerus. Amputation

specimen after chemotherapy. Extensive degenerative and cystic
changes
Fig. 31.7 Medium-power microscopic view – extremely large nuclei
in multinucleated cells. Atypical mitoses are frequent
31 Malignant Fibrous Histiocytoma of Bone 457

Fig. 31.8 High-power microscopic view – another field with highly

pleomorphic and hyperchromatic cells

Fig. 31.9 Panoramic microscopic view. Tumor tissue is seen penetrat-

ing and enlarging cortical haversian canals
458 R.K. Kalil

Recommended Reading and secondary malignant fibrous histiocytoma of bone. Skeletal

Radiol. 2010;39(8):791–8.
Martinez-Tello FJ, Navas-Palacios JJ, Calvo-Asensio M, Loizaga-
Antonescu CR, Erlandson RA, Huvos AG. Primary fibrosarcoma and
Iriondo JM. Malignant fibrous histiocytoma of bone. A clinico-
malignant fibrous histiocytoma of bone – a comparative ultrastruc-
pathological and electronmicroscopical study. Pathol Res Pract.
tural study: evidence of a spectrum of fibroblastic differentiation.
1981;173(1–2):141–58.
Ultrastruct Pathol. 2000;24(2):83–91.
McCarthy EF, Matsuno T, Dorfman HD. Malignant fibrous histiocy-
Bertoni F, De Santis E, Laus M, Bravo JS. Malignant fibrous histiocy-
toma of bone: a study of 35 cases. Hum Pathol. 1979;10(1):
toma of bone. Ital J Orthop Traumatol. 1978;4(3):369–78.
57–70.
Capanna R, Bertoni F, Bacchini P, Bacci G, Guerra A, Campanacci
Mertens F, Romeo S, Bovée JV, Tirabosco R, Athanasou N, Alberghini
M. Malignant fibrous histiocytoma of bone. The experience at
M, Hogendoorn PC, Dei Tos AP, Sciot R, Domanski HA, Aström K,
the Rizzoli Institute: report of 90 cases. Cancer. 1984;54(1):
Mandahl N, Debiec-Rychter M. Reclassification and subtyping of
177–87.
so-called malignant fibrous histiocytoma of bone: comparison with
Dahlin DC, Ivins JC. Fibrosarcoma of bone. A study of 114 cases.
cytogenetic features. Clin Sarcoma Res. 2011;1(1):10.
Cancer. 1969;23(1):35–41.
Nishida J, Sim FH, Wenger DE, Unni KK. Malignant fibrous histiocy-
Dahlin DC, Unni KK, Matsuno T. Malignant (fibrous) histiocytoma of
toma of bone. A clinicopathologic study of 81 patients. Cancer.
bone–fact or fancy? Cancer. 1977;39(4):1508–16.
1997;79(3):482–93.
Eyre-Brook AL, Price CH. Fibrosarcoma of bone. Review of fifty con-
Romeo S, Bovée JV, Kroon HM, Tirabosco R, Natali C, Zanatta L,
secutive cases from the Bristol Bone Tumour Registry. J Bone Joint
Sciot R, Mertens F, Athanasou N, Alberghini M, Szuhai K,
Surg Br. 1969;51(1):20–37.
Hogendoorn PC, Dei Tos AP. Malignant fibrous histiocytoma and
Feldman F, Lattes R. Primary malignant fibrous histiocytoma (fibrous
fibrosarcoma of bone: a re-assessment in the light of currently
xanthoma) of bone. Skeletal Radiol. 1977;1:145–60.
employed morphological, immunohistochemical and molecular
Feldman F, Norman D. Intra- and extraosseous malignant histiocy-
approaches. Virchows Arch. 2012;461(5):561–70.
toma (malignant fibrous xanthoma). Radiology. 1972;104(3):
Spanier SS, Enneking WF, Enriquez P. Primary malignant fibrous his-
497–508.
tiocytoma of bone. Cancer. 1975;36(6):2084–98.
Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F. WHO clas-
Taconis WK, van Rijssel TG. Fibrosarcoma of long bones: a study of
sification of tumors of soft tissue and bone. Lyon: IARC; 2013.
the significance of areas of malignant fibrous histiocytoma. J Bone
p. 302–4.
Joint Surg Br. 1985;67:111–6.
Hardcastle P, Nade S, Arnold W. Hereditary bone dysplasia with malig-
Tarkkanen M, Larramendy ML, Böhling T, Serra M, Hattinger CM,
nant change. Report of three families. J Bone Joint Surg Am.
Kivioja A, Elomaa I, Picci P, Knuutila S. Malignant fibrous histio-
1986;68(7):1079–89.
cytoma of bone: analysis of genomic imbalances by comparative
Huvos AG. Primary malignant fibrous histiocytoma of bone; clinico-
genomic hybridisation and C-MYC expression by immunohisto-
pathologic study of 18 patients. N Y State J Med.
chemistry. Eur J Cancer. 2006;42(8):1172–80.
1976;76(4):552–9.
Unni KK, Inwards C. Dahlin’s bone tumors. 6th ed. Philadelphia:
Koplas MC, Lefkowitz RA, Bauer TW, Joyce MJ, Ilaslan H, Landa J,
Lippincott Williams & Wilkins; 2010. p. 179–83.
Sundaram M. Imaging findings, prevalence and outcome of de novo
 Part VIII
Vascular Tumors
 Hemangioma
32
Liliana G. Olvi, Maria L. Gonzalez,
and Eduardo Santini-Araujo

Abstract
Hemangioma of the bone is a very common benign tumor consisting of newly formed thin-
walled capillary of small or large caliber. Its variants include multiple primary bone heman-
giomas, diffuse cystic angiomatosis, multifocal and with frequent visceral and/or soft tissue
involvement, and massive osteolysis (Gorham’s disease). It is usually asymptomatic and is
more frequent in adult women. Vertebral bodies are the most common locations, followed
by craniofacial bones and metaphyses of long bones. Imaging of hemangioma is character-
ized by coarse trabeculations. Asymptomatic lesions may not require treatment. Prognosis
is excellent.

Definition • Diffuse cystic angiomatosis, multifocal and with frequent

visceral involvement especially the spleen, and angioma-
• Benign tumor consisting of newly formed capillary of tous lesions in soft tissues
small or large caliber • Massive osteolysis (“disappearing bone disease,” “phan-
tom bone,” or Gorham’s disease)

Variants
Etiology
• Multiple primary bone hemangiomas, morphologically
similar to solitary hemangiomas • Unknown
• Is a benign proliferation of neoplastic endothelial cells

L.G. Olvi, MD
Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina
M.L. Gonzalez, MD
Laboratory of Orthopaedic Pathology, University
of Buenos Aires, Buenos Aires, Argentina
E. Santini-Araujo, MD (*)
Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina
Department of Pathology, School of Medicine,
Buenos Aires, Argentina
School of Dentistry, University of Buenos Aires,
Buenos Aires, Argentina
Central Army Hospital, Buenos Aires, Argentina
e-mail: santiniaraujo@laborpat.com.ar
Clinical Features
Epidemiology
• Very common benign tumor.
• Autopsy studies have found an incidence in vertebral bod-
ies of about 12 % in an adult population.
• Clinically symptomatic tumors are infrequent, around
less than 1 % of primary bone tumors.
Sex
• More frequent in women. Male/female ratio of 3:2.

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 461
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_32, © Springer-Verlag London 2015
462 L.G. Olvi et al.

Age Image Differential Diagnosis

• Adults are mostly affected.
• Peak of incidence in the fifth decade.
• Cases are reported from the first to the eighth decades of life.
Sites of Involvement
Maffucci Syndrome
• Non-osseous hemangiomas of this syndrome frequently
present calcified thrombosis in soft tissues, as part
of Maffucci syndrome which includes skeletal
chondromatosis.

• Vertebral bodies are the most common locations.

• Second in frequency are craniofacial bones. Pathology
• Followed by metaphysis of long bones.
• Multifocal locations are frequent in multiple primary Gross Features
bone hemangiomas and diffuse cystic angiomatosis.
• Well-demarcated, dark red-bluish spongy mass
• May show honeycomb appearance
Clinical Symptoms and Signs • Coarse trabeculations
• Scattered blood-filled cavities
• Most hemangiomas, especially in spine, are incidentally
discovered in roentgenograms for other reasons.
• Large vertebral hemangiomas may cause back pain and Histological Features
neurological symptoms due to compression of spinal cord
or nerve roots and pathological fractures. • Capillary and cavernomatous hemangiomas present thin-
walled blood-filled vessels.
• Tumoral vessels show a single layer of flat bland endothe-
Image Diagnosis lial cells.
• Tumoral vessels infiltrate the marrow and surround native
Radiographic Features trabeculae.
• Sometimes vessels are not filled with red blood cells.
• Well-demarcated lesions. • In some cases it is possible to find sclerotic bone
• Lytic and radiolucent lesion that frequently presents trabeculae.
coarse trabeculations or striations (“corduroy” appear-
ance), especially in vertebral bodies.
• In calvarium, hemangiomas are expansile lesions that produce Ancillary Techniques
reactive bone formation with a “sunburst” or “sunray” pattern.
• May present a honeycombed pattern. • Immunohistochemically, endothelial cells stain positive
• In long bones, the images may have a nonspecific appearance. with antibodies for factor VIII, Ulex europaeus, lectin,
CD 31, CD 34, FLI 1, and ERG.

CT Features
• Well-defined lytic lesion.
• The X-ray striations are seen in CT like round sclerotic
bone foci mixed with fat marrow (“polka dot” pattern).
Genetics
Somatic mutations in exon 17 of the TEK gene were detected in EH
along with other vascular tumors and vascular malformations.
Pathologic Differential Diagnosis

MRI Features Epithelioid Hemangioma

• Vessels present epithelioid endothelial cells with polyhe-
• Clinically indolent lesions contain fat and sclerotic dral shape.
trabeculations. • These epithelioid endothelial cells have a densely eosino-
• Symptomatic tumors commonly present loss of fat and philic cytoplasm.
low signal on T1-weighted images and high signal on
T2-weighted images. Epithelioid Hemangioendothelioma
• The fatty component of the lesion is an important clue, • Endothelial cells are distributed in clusters in a fibrous
because malignant tumors do not present this component. hyaline and myxoid matrix.
32 Hemangioma 463

Prognosis Images

• Excellent, with low rate of local recurrence See Figs. 32.1, 32.2, 32.3, 32.4, 32.5, 32.6, 32.7, 32.8, 32.9,
32.10, 32.11, 32.12, 32.13, 32.14, 32.15, 32.16, 32.17, 32.18,
32.19, 32.20, 32.21, and 32.22 for illustrations of hemangiomas.
Treatment

• Incidental and asymptomatic lesions do not require treatment.

• Severe hemorrhage may occur during surgical treatment,
especially in jawbones.
464 L.G. Olvi et al.

Fig. 32.1 Vertebral a b

hemangioma. Roentgenogram
(a), axial (b) and sagittal (c) CT,
and MRI (d) show a lesion
occupying the body of T2
vertebra, with intensification of
vertical trabeculae in an
otherwise lytic lesion. Cortex is
preserved

c d
32 Hemangioma 465

Fig. 32.2 Vertebral hemangioma. Roentgenogram (a) and CT (b)

show characteristic vertical trabeculation and dotted image on axial CT
466 L.G. Olvi et al.

a b

Fig. 32.3 Small vertebral hemangioma. Roentgenogram, (a) CT (b), and MRI (c) showing a small hemangioma in the vertebral body, next to the
left pedicle
32 Hemangioma 467

Fig. 32.4 Vertebral hemangioma. Axial CT image showing a heman-

gioma involving part of the vertebral body. The contour of the vertebra
is preserved

Fig. 32.5 Sagittal CT image of fractured vertebra with a hemangioma

468 L.G. Olvi et al.

Fig. 32.8 Roentgenogram (a) and CT (b) of a hemangioma of a rib

Fig. 32.6 Roentgenogram showing a hemangioma in the neck of the

femur

Fig. 32.9 Roentgenogram of a hemangioma in the skull. Differential

Fig. 32.7 Roentgenogram showing a hemangioma of the ischium diagnosis with eosinophilic granuloma
32 Hemangioma 469

Fig. 32.10 AP (a) and lateral

(b) radiographic view of a a b
cortical hemangioma in the
metaphysis of a tibia
470 L.G. Olvi et al.

Fig. 32.11 CT sagittal view of a cortical hemangioma of the femoral

diaphysis

Fig. 32.12 Cortical

hemangioma of the tibia.
(a) Radiograph shows a dense
reactive sclerosis obscuring the
lesion. Differential diagnosis
with osteoid osteoma. (b) CT
showing a large heterogeneous
cortical lesion
32 Hemangioma 471

Fig. 32.13 Roentgenogram (a) a b

and CT (b) of leg and foot.
Angiomatosis lesions involving
the tibia, fibula, and short bones
of the foot
472 L.G. Olvi et al.

Fig. 32.14 (a–d) Radiographs

of a femur demonstrating several
a b
cortical and medullary
hemangiomas

c d
32 Hemangioma 473

a b

Fig. 32.15 (a, b) Radiographs of cystic angiomatosis of the humerus with pathological fracture

a b

c d

Fig. 32.16 (a–d) Microphotographs of classical hemangioma of the bone in different magnifications. Large vessels with thin walls and flattened
endothelial lining
474 L.G. Olvi et al.

Fig. 32.17 Microphotograph of a sclerosing hemangioma. Large ves-

sel proliferation alternating with thick mature bone trabeculae

Fig. 32.18 (a) Radiograph and (b) CT of a hemangioma of the clavi-

cle with a “sunburst” appearance, similar to calvarial hemangiomas
32 Hemangioma 475

a b c

Fig. 32.19 Cystic angiomatosis, osteoblastic variant. Differential diagnosis must be made with osteoblastic metastasis, sclerosing myeloma,
lymphoma, mastocytosis, and osteopoikilosis. (a) X-ray, (d) CT, and (a, b) MRI show several sclerotic lesions affecting several vertebrae
476 L.G. Olvi et al.

a b

c d

Fig. 32.20 Same case as previous figures. (a) X-ray, (b) CT, and (c) MRI of the pelvis revealing similar lesions. (d) X-ray of the humerus dem-
onstrating lesion in the proximal metaphysis

a b

Fig. 32.21 (a, b) Same case as previous figures. Microphotographs depicting large blood vessel proliferation, dense medullar fibrosis, and bone
sclerosis
32 Hemangioma 477

a b

Fig. 32.22 (a, b) Microphotographs of another case. Diffuse mature vascular proliferation amid dense mature bone trabeculae

Ross JS, Masaryk TJ, Modic MT, et al. Vertebral hemangiomas: MR

Recommended Reading
Dorfman HD, Czerniak B. Vascular lesions. In: Dorfman HD, Czerniak
B, editors. Bone tumors. Mosby: St Louis. 1998; p. 729–814.
Kenan S, Abdelwahab IF, et al. Hemangiomas of the long tubular bone.
Clin Orthop. 1992;280:256–60.
Nielsen GP, Rosenberg AE. Diagnostic pathology bone. 1st ed. Salt
Lake City: Amirsys; 2013.
imaging. Radiology. 1987;165:165–9.
Wenger DE, Wold LE. Benign vascular lesions of bone: radiologic and
pathologic features. Skeletal Radiol. 2000;29(2):63–74.
Wold LE, McLeod RA, Sim FH. Atlas of orthopedic pathology.
Philadelphia: Saunders; 1990.
 Epithelioid Hemangioma
33
Ricardo K. Kalil

Abstract
Epithelioid hemangioma is a special type of hemangioma characterized by a benign
although locally aggressive behavior, composed by proliferated small-caliber blood vessels
lined by plump endothelial cells with an epithelioid morphology. It is rare in bone, where it
grows in a more solid fashion than its soft tissue counterpart. It is seen more often between
20 and 60 years of age. Long bones of the extremities are preferably affected and may be
multifocal. EH is usually painful. Regional lymph node metastases and soft tissue extension
of the tumor do not mean altered aggressiveness. Besides endothelial markers, epithelial
markers are positive. It has a 10 % recurrence risk.

Definition Sex

• A special type of hemangioma characterized by a benign • Sexes appear to be equally affected.

although locally aggressive behavior, composed by a pro-
liferation of small-caliber blood vessels lined by plump
endothelial cells with an epithelioid morphology. It is rare
in bone, where it grows in a more solid fashion than its
soft tissue counterpart.
Epidemiology
• It is a rare tumor in bone.
Sites of Involvement
• Long bones of the extremities are preferably affected. The
feet, pelvis, ribs, vertebrae, and hands follow in
frequency.
• May be multifocal (20–25 %), affecting different foci in
the same bone or, more rarely, several bones of the same
anatomical area as well as soft parts.

Age Signs and Symptoms

• Can affect any age group but is seen more often between • Different from classical hemangiomas, EHs are usually
20 and 60 years of age painful and swelling may be present.
• May be asymptomatic.

R.K. Kalil, MD
Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina
Department of Pathology, A.C. Camargo Cancer Center,
São Paulo, SP, Brazil
e-mail: rkkalil@gmail.com

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 479
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_33, © Springer-Verlag London 2015
480
Image Diagnosis
Radiographic Features
• Radiographs show an expanded bone with cortical
erosion.
• Internal trabeculations may be seen.
CT Features
• Expansile, septated, lytic lesion that may present soft tis-
sue extension.
• Trabeculations are more readily seen with this image
method.
• Lesions and their well-limited contour, inside and outside
the bone, are enhanced by contrast injection.
MRI Features
• On MRI, EH has a usually low signal intensity on
T1-weighted and high signal intensity on T2-weighted
image.
• Its limits, inside and outside the bone, are clearly
demarcated.
Imaging Differential Diagnosis
Angiosarcoma and Hemangioendothelioma
• Are radiographically less delimited lesions
Cystic Angiomatosis
• Presents multiple widespread skeletal and visceral lesions.
Soft tissue lesions usually contain phleboliths.
Pathology
Gross Features
• Radiography of the specimen is helpful to localize multi-
ple lesions and orient sectioning.
• The cut surface shows a well-delimited lesion, mostly
hemorrhagic and soft, with spongy areas alternating with
sometimes more solid areas.
• Cortical destruction and soft tissue tumor may be appar-
ent but the limits are usually clear.
R.K. Kalil
Microscopic Features
• EH is composed of lobules of neoplastic blood vessels pre-
senting a kind of zonation phenomenon, where the vessels
found at the periphery of the lobules are hypocellular, with
flattened endothelium, that gradually turns more cellular
towards the center of the lobules. The cells get plumper,
with epithelioid features, abundant eosinophilic cytoplasm,
sometimes resembling the so-called “tombstone-like”
aspect; the foci of solid epithelioid cell proliferation,
devoid of evident vascular lumina, may be seen in the cen-
ter, leading to a differential diagnosis with EHE. The nuclei
of these cells are typically round or oval, sometimes lobu-
lated, and occasional nucleoli may be seen. Mitoses occur
in an average of 1/10 high-power fields and atypical mito-
ses are not seen. The stroma is loose, with frequent eosino-
phils and a few other mononuclear inflammatory cells.
• Less frequent features are intracytoplasmic vacuoles,
occasionally containing red cell fragments, osteoclast-
like giant cells, necrosis, dense inflammatory foci, and
new bone formation.
• Host bone trabeculae may be seen entrapped between the
neoplastic lobules.
• The tumor expands the bone by growth pressure of its push-
ing borders and erodes but does not infiltrate the cortex.
Pathology Differential Diagnosis
Epithelioid Hemangioendothelioma
• These tumors usually present chords and small groups of
cells in a myxohyaline or chondroid matrix, which is not
seen in EH.
• Presents translocation t(1;3)(p36.3;q23-25) resulting in
the WWTR1-CAMTA1 fusion, not found in EH.
Angiosarcoma
• Presents large irregularly anastomosing vascular chan-
nels, intense cellular atypia, and high mitotic activity
Ancillary Methods
Immunohistochemistry
• Endothelial markers (CD34, CD31, Fli1, vW, and ERG)
are expressed by the tumor cells.
• Epithelial markers are frequently positive in the neoplas-
tic epithelioid cells.
33 Epithelioid Hemangioma 481

Ultrastructure • Radiation therapy has also been used in incompletely

resected tumors, usually as a complement to surgery. The
• Weibel-Palade bodies may be seen, characterizing endo- risk of secondary radiation effects has to be evaluated
thelial cells. against the risk of an observation attitude.

Prognosis Images

• Presents a 10 % recurrence risk. See Figs. 33.1, 33.2, 33.3, 33.4, 33.5, 33.6, and 33.7 for
• EH is a benign tumor and wide metastatic spread and illustrations of epithelioid hemangioma.
death from disease does not occur.
• Regional lymph node metastases and soft tissue extension
of the tumor do not mean altered aggressiveness.

Treatment

• Thorough curettage or en bloc surgical resection is the

preferred choice of treatment.
• Preoperative embolization has been used.
482 R.K. Kalil

a b

Fig. 33.1 (a) Macrophotography and (b) specimen radiograph of an epithelioid hemangioma of the distal femur with pathological fracture. The
lesion has a hemorrhagic pattern and expands to soft tissue
33 Epithelioid Hemangioma 483

a b

e
d

Fig. 33.2 Multifocal EH. (a and b) Radiographs showing lesions in vertebrae and a rib. (c and d) MRI and CT of a vertebral lesion. (e) CT-guided
needle biopsy of the rib lesion
484 R.K. Kalil

Fig. 33.3 Low-power microscopic view of EH. Endothelium is more

flattened at the periphery, left, and more epithelioid towards the center
of the lesion Fig. 33.6 High-power microscopic image. Large, epithelioid cells,
with eosinophilic cytoplasm with occasional intracytoplasmic vacuoles
and round to oval, sometimes lobulated, nuclei

Fig. 33.4 Medium-power view: irregular blood vessels lined by epi-

thelioid endothelial cells
Fig. 33.7 Immunohistochemistry. CD34-positive epithelioid cells

Fig. 33.5 Higher power of a more compacted cellular area

33 Epithelioid Hemangioma 485

Recommended Reading 21948309, PubMed Central PMCID: PMC3314752, Epub 2011

Sep 24.
Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F, editors. WHO
Boyaci B, Hornicek FJ, Nielsen GP, DeLaney TF, Pedlow Jr FX,
classification of tumors of soft tissue and bone. 4th ed. Lyon: IARC
Mansfield FL, Carrier CS, Harms J, Schwab JH. Epithelioid heman-
Press; 2013.
gioma of the spine: a case series of six patients and review of the
Hart JL, Edgar MA, Gardner JM. Vascular tumors of bone. Semin
literature. Spine J. 2013;13(12):e7–13.
Diagn Pathol. 2014;31:30–8.
Errani C, Vanel D, Gambarotti M, Alberghini M, Picci P, Faldini C.
Sirikulchayanonta V, Jinawath A, Jaovisidha S. Epithelioid hemangi-
Vascular bone tumors: a proposal of a classification based on clini-
oma involving three contiguous bones: a case report with a review
copathological, radiographic and genetic features. Skeletal Radiol.
of the literature. Korean J Radiol. 2010;11(6):692–6.
2012a;41(12):1495–507.
Verbeke SL, Bovée JV. Primary vascular tumors of bone: a spectrum of
Errani C, Zhang L, Panicek DM, Healey JH, Antonescu CR.
entities? Int J Clin Exp Pathol. 2011;4(6):541–51.
Epithelioid hemangioma of bone and soft tissue: a reappraisal of a
Ye C, Pan L, Huang Y, Ye R, Han A, Li S, Li X, Wang S. Somatic muta-
controversial entity. Clin Orthop Relat Res. 2012b;470(5):
tions in exon 17 of the TEK gene in vascular tumors and vascular
1498–506. doi:10.1007/s11999-011-2070-0. PubMed PMID:
malformations. J Vasc Surg. 2011;54(6):1760–8.
 Glomus Tumor
34
Ricardo K. Kalil

Abstract
Glomus tumor is a rare benign neoplasm composed of cells derived from the smooth muscle
cells that surround blood vessels in the glomus body. It can be multiple – glomangiomato-
sis. Most cases occur in the fingers, usually in a subungueal location. Feet are also a fre-
quent site. Excruciating pain is the hallmark of this tumor. Radiographs show a lucent,
well-defined nodular depression in the extremity of the distal phalanx. Tumor cells are
round in glomus tumor but may be elongated, in glomangiomyoma. They are positive for
smooth muscle markers. Marginal resection or curettage is curative for benign tumors.
Malignant glomus tumors require multimodality cancer treatment.

Definition • Glomangiomyoma
• Symplastic glomus tumor
• A rare benign neoplasm composed of cells derived from
the smooth muscle cells of the glomus body.
• Glomus bodies are small, specialized cellular structures Etiology
composed of an arteriovenous shunt surrounded by cells
with a smooth muscle cell phenotype and nervous struc- • Unknown.
tures. They function as body thermoregulators and are • The lesion originates in the cells that surround blood ves-
mainly localized in the body extremities, hands and feet, sels in glomus bodies.
especially the ends of fingers and toes.
• It should not be confused with the carotid body, which is
a chemoreceptor and has other functions. Epidemiology

• It is a rare tumor, most often seen eroding bone from the

Synonyms soft tissue. Intraosseous glomus tumors account for about
20 cases described in the literature.
• Glomangioma

Age
Variants
• Can be seen from the third to the seventh decade and its
• Glomangiomatosis
main incidence is in the fourth decade of life.
R.K. Kalil, MD
Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina
Department of Pathology, A.C. Camargo Cancer Center,
Sex
São Paulo, SP, Brazil
e-mail: rkkalil@gmail.com • There is a slight female predominance.

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 487
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_34, © Springer-Verlag London 2015
488
Sites of Involvement
• Most cases occur in the hands, especially in the extremity
of the fingers, usually in a subungueal location.
• Feet are also a frequent site.
• The spine is another site where it can be seen.
Clinical Symptoms and Signs
• Excruciating pain is the hallmark of this tumor.
• Tenderness and high sensitivity to cold temperature also
are present, in superficial locations.
Image Diagnosis
Radiographic Features
• Radiographs show a lucent, usually well-defined nodular
depression in the extremity of the distal phalanx, usually
without periosteal reaction.
CT Features
• The tumor shows a well-circumscribed lytic lesion with little
peripheral sclerosis and absence of periosteal reaction.
• Glomangiomatosis presents an image similar to
angiomatosis.
MRI Features
• MRI presents low intensity signal on T1- and high inten-
sity signal on T2-weighted images and striking enhance-
ment with gadolinium injection.
Imaging Differential Diagnosis
Epidermoid Inclusion Cyst
• May have a similar image as glomus tumor in the fingers
but has a different clinical presentation
Enchondroma
• Usually presents scattered calcifications
Metastasis, Myeloma, Lymphoma or Osteoid
Osteoma
• Vertebral lesions may suggest these tumors, since intraos-
seous glomus tumor is exceedingly rare and usually is not
considered in the diagnosis.
R.K. Kalil
Pathology
Gross Features
• Grossly, glomus tumors are well-circumscribed small
tumors. The cut surface shows a smooth, tan to dark red,
and soft lesion. It usually measures less than 1 cm in
diameter.
• In glomangiomatosis, the appearance of regional multiple
nodules may suggest isolated tumors, but they are all
probably interconnected in an inconspicuous way.
Histological Features
• Glomus tumors consist of numerous small vascular chan-
nels surrounded by clusters of round cells with eosino-
philic cytoplasm, well-defined cell membranes, and small
nuclei with no atypia.
• Glomangiomas contain larger and more numerous vascu-
lar spaces relative to the cellular component.
• Multiple tumors (glomangiomatosis) resemble angioma-
tosis in its way of spread and may be more cellular.
• Glomangiomyomas present more elongated cells, resem-
bling short smooth muscle fibers.
• Malignant glomus tumors are rare and in some cases may
be difficult to establish its aggressive nature based on his-
tology alone. Aside from the obviously malignant cases,
with clear pleomorphism, atypias and atypical mitoses,
cases with less than optimal criteria for malignancy
should be named “glomus tumor with uncertain malig-
nant potential.”
• Symplastic glomus tumors are benign lesions that present
marked nuclear atypia and no other pathological or clini-
cal malignant feature.
Ancillary Methods
Immunohistochemistry
• Glomus tumor cells are strongly positive for vimentin and
smooth muscle actin.
Genetics
• MIR143-NOTCH fusions were identified in benign and
malignant glomus tumors but not in multiple NF1-
associated glomus tumors.
• NF1 biallelic inactivation secondary to mitotic recombi-
nation of chromosome arm 17q was reported in multiple
NF1-associated glomus tumors.
34 Glomus Tumor 489

• Glomangioma-related gene was localized to chromosome Treatment

1p21-22.
• Paraganglioma, which has also been called glomus tumor
in the recent literature, originates in the APUD cell sys-
tem and whose underlying defect was mapped to chromo-
some 11p23 is a different tumor and is not discussed here.
Prognosis
• Marginal resection or curettage is curative for benign
tumors.
• Radiosurgery has also been used.
• Sclerotherapy was reported to treat recurrent glomus
tumors.
• Malignant tumors require multimodality cancer
treatment.

• Excellent for benign solitary glomus tumor.

• It has no metastatic potential. Images
• Complete excision is curative.
• Incomplete curettage or resection may result in See Figs. 34.1, 34.2, 34.3, 34.4, 34.5, 34.6, 34.7, 34.8, 34.9,
recurrence. and 34.10 for illustrations of glomus tumor.
• Glomangiomatosis may require more extensive surgery to
avoid recurrence.
• Malignant glomus tumors are locally aggressive and,
when metastasize, the prognosis is dismal.
490 R.K. Kalil

Fig. 34.1 Glomus tumor of a finger. Macrophotography showing a

well-delimited dark brown nodule

Fig. 34.3 Panoramic microscopic view of a glomus tumor. Tumor

cells proliferate around small vascular channels

Fig. 34.2 Glomus tumor of a finger. Macrophotography of the cut sur-

face of another tumor showing partial enclosure by a fibrous pseudo-
capsule and a smooth tan-white surface
34 Glomus Tumor 491

a b

Fig. 34.4 Medium- and high-power view of a glomus tumor. Cells proliferate around compressed vascular lumina (a). Cells present eosinophilic
cytoplasm, round nuclei, and well-delimited cell membranes (b)

Fig. 34.5 Low-power microscopic view of glomangioma. In this pic- Fig. 34.6 Medium-power microscopic view of a glomus tumor depict-
ture vascular channels predominate over cellular areas ing somewhat more elongated cells. Possible glomangiomyoma
492 R.K. Kalil

a b

Fig. 34.7 (a and b) Medium-power microphotographs of a glomus tumor of uncertain malignant potential involving soft tissue and bones of the
ankle. There is marked cellular and vascular proliferation but does not present all the cytologic criteria of malignancy

a b

Fig. 34.8 (a and b) Immunohistochemistry stain of two different glomus tumors. Strong staining with SMA
34 Glomus Tumor 493

Fig. 34.9 Glomus tumor at the

end of a distal phalanx. (a) X-ray a b
shows a well-delimited lytic
lesion in its most typical location.
(b) Panoramic microscopic view
shows a well-circumscribed
cellular lesion, with clefts
corresponding to lumina of blood
vessels and pink hyaline areas

a b

Fig. 34.10 Glomus tumor at the proximal end of a first phalanx. (a) Bone scan shows a hot spot. (b) X-ray shows a lytic lesion thinning the overly-
ing cortex, with very little expansion of the cortex laterally and a slight peripheral sclerosis
494 R.K. Kalil

Recommended Reading Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F. WHO classifica-
tion of tumors of soft tissue and bone. Lyon: IARC; 2013. p. 302–4.
Mosquera JM, Sboner A, Zhang L, Chen CL, Sung YS, Chen HW,
Blume-Peytavi U, Adler YD, Geilen CC, Ahmad W, Christiano A,
Agaram NP, Briskin D, Basha BM, Singer S, Rubin MA, Tuschl T,
Goerdt S, Orfanos CE. Multiple familial cutaneous glomangioma: a
Antonescu CR. Novel MIR143-NOTCH fusions in benign and
pedigree of 4 generations and critical analysis of histologic and
malignant glomus tumors. Genes Chromosomes Cancer.
genetic differences of glomus tumors. J Am Acad Dermatol.
2013;52(11):1075–87.
2000;42(4):633–9.
Murphey MD, Fairbairn KJ, Parman LM, Baxter KG, Parsa MB, Smith
Boon LM, Brouillard P, Irrthum A, Karttunen L, Warman ML, Rudolph
WS. From the archives of the AFIP. Musculoskeletal angiomatous
R, Mulliken JB, Olsen BR, Vikkula M. A gene for inherited cutane-
lesions: radiologic-pathologic correlation. Radiographics.
ous venous anomalies (“glomangiomas”) localizes to chromosome
1995;15(4):893–917.
1p21-22. Am J Hum Genet. 1999;65(1):125–33.
Nielsen GP, Rosenberg AE. Diagnostic pathology – bone. Philadelphia:
Brems H, Park C, Maertens O, Pemov A, Messiaen L, Upadhyaya M,
Amirsys; 2013. p. 3.2–3.3.
Claes K, Beert E, Peeters K, Mautner V, Sloan JL, Yao L, Lee CC,
Stewart DR, Pemov A, Van Loo P, Beert E, Brems H, Sciot R, Claes K,
Sciot R, De Smet L, Legius E, Stewart DR. Glomus tumors in neu-
Pak E, Dutra A, Lee CC, Legius E. Mitotic recombination of chro-
rofibromatosis type 1: genetic, functional, and clinical evidence of a
mosome arm 17q as a cause of loss of heterozygosity of NF1 in
novel association. Cancer Res. 2009;69(18):7393–401.
neurofibromatosis type 1-associated glomus tumors. Genes
Brouillard P, Boon LM, Mulliken JB, Enjolras O, Ghassibé M, Warman
Chromosomes Cancer. 2012;51(5):429–37.
ML, Tan OT, Olsen BR, Vikkula M. Mutations in a novel factor,
Unni KK, Inwards C. Dahlin’s bone tumors. 6th ed. Philadelphia:
glomulin, are responsible for glomuvenous malformations (“glo-
Lippincott Williams & Wilkins; 2010. p. 179–83.
mangiomas”). Am J Hum Genet. 2002;70(4):866–74.
Wenger DE, Wold LE. Benign vascular lesions of bone: radiologic and
Choi JJ, Murphey MD. Angiomatous skeletal lesions. Semin
pathologic features. Skeletal Radiol. 2000;29(2):63–74.
Musculoskelet Radiol. 2000;4(1):103–12.
 Epithelioid Hemangioendothelioma
35
Ricardo K. Kalil

Abstract
Epithelioid hemangioendothelioma is a rare, low- to intermediate-grade malignant neo-
plasm, characterized by small cords or nests of epithelioid cells with endothelial differentia-
tion set on a myxohyaline or chondroid background. Bones of the extremities respond for
at least half the cases. More than half of osseous tumors are multifocal. Pain and swelling
are usually present. Intracytoplasmic vacuoles sometimes containing erythrocytic material
are characteristic (“blister cells”). Marked cellular atypia, high mitotic rate, extensive cell
spindling, and necrosis usually correlate to more aggressive tumors. WWTR1-CAMTA1
gene fusion is considered specific for EHE. Wide en bloc surgical resection is the preferred
choice of treatment.

Definition Age

• Epithelioid hemangioendothelioma (EHE) is a rare, low- • Can affect any age group but is seen more or less evenly
to intermediate-grade malignant neoplasm, characterized between 10 and 60 years of age.
by epithelioid cells with endothelial differentiation set on
a myxohyaline or chondroid background.
Sex

Epidemiology • Sexes appear to be equally affected.

• It is a very rare tumor, but there is not a reference study on

its real incidence. Sites of Involvement

• Bones of the extremities respond for at least half the

cases. The pelvis, ribs, and vertebrae follow in
frequency.
• More than half of osseous tumors are multifocal and
involve one or more bones within a localized anatomical
region, like the foot and/or ankle.

R.K. Kalil, MD
Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina Signs and Symptoms
Department of Pathology, A.C. Camargo Cancer Center,
São Paulo, SP, Brazil • Pain and swelling are usually present.
e-mail: rkkalil@gmail.com • May be asymptomatic.

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 495
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_35, © Springer-Verlag London 2015
496
Image Diagnosis
Radiographic and CT Features
• Radiographs and CT show lytic lesions, rarely with min-
eral deposits. Lesions are more commonly multiple than
single. Margins may be well defined or poorly circum-
scribed; cortical erosion and soft tissue invasion may
also be seen. Usually, there is no periosteal reaction
except with pathologic fracture. Joint involvement is
common. Contrast injection reveals homogeneous
enhancement.
MRI Features
• On MRI, EHE shows no specific picture, presenting
usually low to intermediate signal intensity on
T1-weighted and high signal intensity on T2-weighted
images and homogeneous enhancement after gadolin-
ium injection.
Imaging Differential Diagnosis
Angiosarcoma
• Is a radiographically similar lesion, very difficult to tell
apart
Cystic Angiomatosis
• Presents multiple widespread skeletal and visceral lesions.
Soft tissue lesions usually contain phleboliths.
Metastatic Carcinoma
• May present as lytic lesions but is a disease of older
people. It may be diffusely or irregularly distributed in
the skeleton more than the locoregional distribution of
EHE.
• History or investigation for a primary disease helps in the
differential.
Primary Lymphoma of Bone
• Aggressive lytic lesions, with a permeative pattern. More
common in the diaphysis of long bones, pelvis, vertebrae,
and scapula
R.K. Kalil
Osteomyelitis
• A serpiginous lytic pattern is more specific for infection.
Sequestrum, when present, is also characteristic of osteo-
myelitis. Has a regular surrounding enhancement due to
inflammatory changes.
Multiple Myeloma
• Presents “punched-out” lytic lesions mainly in the skull
and axial skeleton. Diffuse osteopenia may be present.
Affects mostly older patients, over 40 years of age.
Langerhans Cell Histiocytosis
• May be mono- or polyostotic and sometimes looks
aggressive by x-rays. It is most often seen in the first two
decades of life.
• Other bone tumor differential may be considered in a soli-
tary EHE – fibrous dysplasia, Ewing’s sarcoma, osteosar-
coma, and undifferentiated pleomorphic sarcoma.
Pathology
Gross Features
• Radiography of the specimen is helpful to localize multi-
ple lesions and orient sectioning.
• The cut surface shows more or less rounded lesions, solid,
with a gray to tan color and rubbery consistency. Large
lesions may be hemorrhagic.
• Cortical destruction and soft tissue invasion may be seen
in aggressive cases.
Microscopic Features
• EHE is composed of cords, nests, and/or isolated cells set
in a myxoid, hyaline, or, less frequently, chondroid or
sclerotic matrix that may present foci of mineralization
resembling osteoid. Cells are usually large and epithelioid
but may be spindled. Cytoplasm is large, eosinophilic,
and with frequent round vacuoles of variable size, proba-
ble primitive lumina that, when showing erythrocytic
material content, are characteristic of EHE (“blister
cells”). Nuclei are vesicular, with nucleoli and mildly
atypical. Frequent folded or “dumbbell-shaped” nuclei
are seen. Well-formed vascular channels are usually not
seen.
35  Epithelioid Hemangioendothelioma
• The presence of stromal neutrophils is a useful diagnostic
clue.
• Marked nuclear atypia, high mitotic rate, extensive cell
spindling, and necrosis are worrisome histological find-
ings, correlated to more aggressive tumors.
Pathological Differential Diagnosis
 pithelioid Hemangioma and Epithelioid
E ing that they represent local spread or skip metastasis
Angiosarcoma
• These tumors usually display areas of vascular channel
formation and do not present myxohyaline or chondroid
matrix, contrary to what is seen in EHE.
 hordoma, Metastatic Carcinoma,
C indolent to an aggressive course.
Myoepithelial, and Chondroid Neoplasms
• Myxoid or chondroid background associated to cords of
epithelioid, vacuolated cells may raise this differential
diagnosis. Immunohistochemical investigation may be
needed to properly identify these tumors.
Osteogenic Tumors
• As EHE in bones may present mineralization of the
matrix, this differential may be considered.
Ancillary Methods
Immunohistochemistry
• Endothelial markers (CD34, CD31, Fli1, vW, and ERG)
are expressed by the tumor cells.
• Lymphangiocystic marker D2-40 may be positive.
• Epithelial markers are positive in about 1/3 of the cases.
Ultrastructure
• Weibel-Palade bodies may be seen, characterizing endo-
thelial cells.
Genetics
• Translocation t(1;3) (p36.3;q23-25), resulting in the
WWTR1-CAMTA1 fusion, which is considered specific
497
for EHE. Three variants were reported, resulting from
fusion of exon 3 or 4 of WWTR1 to exon 8 or 9 of
CAMTA1.
• A subset of WWTR1-CAMTA1-negative cases but pre-
senting a YAP1-TFE3 fusion was identified, character-
ized morphologically by at least focal areas of well-formed
vascular channels.
• Multiple tumors located in the same anatomical setting
have been shown to present identical breakpoints suggest-
from one original lesion as opposed to multiple primary
tumors.
Prognosis
• The behavior of EHE is highly variable, ranging from an
• Histological features alone cannot predict the prognosis,
but a worse prognosis and increased risk of metastasis
have been associated to the following features:
– Large tumors.
– Visceral involvement.
– Marked nuclear atypia.
– High mitotic rate.
– Extensive cell spindling.
– Necrosis.
• Metastatic spread and death from disease occur in about
20 % of cases.
Treatment
• Wide en bloc surgical resection is the preferred choice of
treatment.
• Radiofrequency ablation has been reported to be
successful.
• Radiation therapy has also been used for unresectable
lesions, usually as a complement to surgery.
• The role of chemotherapy is not clear.
Images
See Figs. 35.1, 35.2, 35.3, 35.4, 35.5, 35.6, 35.7, 35.8, 35.9,
35.10, 35.11, 35.12, 35.13, 35.14, 35.15, 35.16, and 35.17
for illustrations of epithelioid hemangioendothelioma.
498 R.K. Kalil

Fig. 35.1 EHE. Radiograph showing a lytic lesion involving phalan-

ges of the hallux, with cortical permeation and no reactive sclerosis

a b

Fig. 35.2 (a) EHE. Radiograph demonstrating lytic lesions over the cranial vault. (b) EHE. Same case as (a). CT demonstrating an expansive lytic
lesion involving and expanding the skull bones. There is a thin cortical shell of reactive periosteal bone
35  Epithelioid Hemangioendothelioma 499

a b

Fig. 35.3 (a) Multicentric EHE. Radiograph showing lytic lesions is some reactive sclerosis around some lesions. (c) MRI shows that the
involving the femoral head and the iliac bone around the acetabulum. lesions seen in (a, b) present intermediate-intensity signal in TSE-
(b) Same case as a. CT shows a needle biopsy being undertaken in one weighted image
of several lytic nodular lesions in the femoral head and iliac bone. There
500 R.K. Kalil

Fig. 35.4 Multicentric

EHE. MRI of the lower spine
demonstrates several lesions with
a high-intensity signal in
TSE-weighted images, involving
lumbar and sacral vertebrae
35  Epithelioid Hemangioendothelioma
a b
c
Fig. 35.5 Malignant EHE. (a) Radiograph shows a large lytic lesion in
the distal metaphysis of the femur with epiphyseal and cortical perme-
ation. Medullary limits are partially indistinct and partially sclerotic.
Absence of discernible periosteal bone reaction. (b) MPR CT does not
show any bone or mineral deposits in this solid lesion. Medullary limits
are well defined and mostly with reactive sclerosis. Cortex is destroyed
501
d
and the lesion is seen involving adjacent soft parts as well as the femo-
ral epiphysis. (c) MRI coronal view, T1-weighted image. Solid lesion
with iso-intensity to muscle. Involvement of adjacent soft tissues. (d)
MRI coronal view, T1-weighted image with contrast and fat saturation.
Enhancement of the peripheral areas of the lesion and low-signal inten-
sity in the center, possible necrotic area
502 R.K. Kalil

Fig. 35.6 (a) Macrophotography

of the same case as previous a b
figure. Peripheral areas of the
lesion are whitish, solid, and soft,
viable areas of the tumor, while
the center is fragmented,
yellowish red, and friable,
degenerative and necrotic areas.
(b) Specimen radiograph
emphasizing CT findings

Fig. 35.7 Thoracic CT of the same case as previous figures. Metastatic

spread to pleura and lungs
35  Epithelioid Hemangioendothelioma
Fig. 35.8 EHE. Medium-power microphotography. Loose prolifera-
tion of endothelial cells either isolated or in chords over a bluish, myxo-
chondroid matrix. Intracytoplasmic vacuoles, sometimes containing red
cells or their fragments, are evident
Fig. 35.9 EHE. Higher-power view of previous figure. Small nests of
endothelial cells with intracytoplasmic vacuoles are demonstrated
Fig. 35.10 EHE. Medium-power view. Cells in small chords or iso-
lated, with frequent intracytoplasmic vacuoles, sometimes containing
red cells or their fragments – “blister cells”
503
Fig. 35.11 EHE. High-power view of the same field illustrated in
Fig. 36.10
Fig. 35.12 EHE. High-power view. Endothelial cells in short chords
in a myxoid matrix
Fig. 35.13 EHE. Medium-power view of a more cellular area.
Occasional intracytoplasmic vacuoles containing red cells are seen.
Neutrophils and eosinophils scattered in the background are frequent
and sometimes focally abundant
504 R.K. Kalil

Fig. 35.16 Focal epithelioid hemangioma-like area in an

EHE. Spindle-celled and myxoid stroma, with numerous eosinophils
Fig. 35.14 EHE. Positive immunohistochemistry marking for CD31

Fig. 35.15 Rare areas of otherwise typical EHE may present a vascu-
lar arrangement of the endothelial cells reminiscent of epithelioid hem-
angioma. Abundant eosinophils
35  Epithelioid Hemangioendothelioma
a b
c d
Fig. 35.17 (a) Malignant EHE. Same case as Figs. 36.5 and 36.6.
High cellularity sample with a few vacuolated cells containing red cells.
(b) Malignant EHE. Same case as Figs. 36.5 and 36.6. Solid prolifera-
tion of epithelioid cells in rounded groups and some spindling. Frequent
mitosis. Occasional vacuolated cells. Numerous eosinophils. (c)
Recommended References
Angelini A, Mavrogenis AF, Gambarotti M, Merlino B, Picci P,
Ruggieri P. Surgical treatment and results of 62 patients with epithe-
lioid hemangioendothelioma of bone. J Surg Oncol.
2014;109(8):791–7.
Antonescu CR, Le Loarer F, Mosquera JM, Sboner A, Zhang L, Chen
CL, Chen HW, Pathan N, Krausz T, Dickson BC, Weinreb I, Rubin
MA, Hameed M, Fletcher CD. Novel YAP1-TFE3 fusion defines a
distinct subset of epithelioid hemangioendothelioma. Genes
Chromosomes Cancer. 2013;52(8):775–84.
Deyrup AT, Tighiouart M, Montag AG, Weiss SW, et al. Epithelioid
hemangioendothelioma of soft tissue: a proposal for risk stratifica-
tion based on 49 cases. Am J Surg Pathol. 2008;32(6):
924–7.
Errani C, Zhang L, Sung YS, et al. A novel WWTR1-CAMTA1 gene
fusion is a consistent abnormality in epithelioid hemangioendothe-
lioma of different anatomic sites. Genes Chromosomes Cancer.
2011;50(8):644–53.
505
Malignant EHE. The same case as Figs. 36.5 and 36.6. Solid cellular
area consisting of endothelial cells with predominant spindle shape.
Frequent mitoses. (d) Malignant EHE. The same case as Figs. 36.5 and
36.6. Solid large nests of epithelioid cells, rare vacuolization in this
field, and rare eosinophils
Errani C, Vanel D, Gambarotti M, Alberghini M, Picci P, Faldini
C. Vascular bone tumors: a proposal of a classification based on
clinicopathological, radiographic and genetic features. Skeletal
Radiol. 2012;41(12):1495–507.
Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F, editors. WHO
classification of tumors of soft tissue and bone. 4th ed. Lyon: IARC
Press; 2013.
Hart JL, Edgar MA, Gardner JM. Vascular tumors of bone. Semi Diagn
Pathol. 2014;31:30–8.
Kleer CG, Unni KK, McLeod RA. Epithelioid hemangioendothelioma
of bone. Am J Surg Pathol. 1996;20:1301–11.
Rosenthal DI, Treat ME, Mankin HJ, Rosenberg AE, Jennings
CL. Treatment of epithelioid hemangioendothelioma of bone using
a novel combined approach. Skeletal Radiol. 2001;30:219–22.
Tsuneyoshi M, Dorfman HD, Bauer TW. Epithelioid hemangioendo-
thelioma of bone: a clinicopathologic, ultrastructural, and immuno-
histochemical study. Am J Surg Pathol. 1986;10:754–64.
Weiss SW, Enzinger FM. Epithelioid hemangioendothelioma: a vascular
tumor often mistaken for a carcinoma. Cancer. 1982;50:970–81.
 Angiosarcoma
36
Ricardo K. Kalil

Abstract
Angiosarcoma is a high-grade malignant neoplasia characterized by cells with endothelial
differentiation. It is rare in bone, usually seen in adult patients, affecting bones of the
extremities, especially the femur, followed by the pelvis and axial skeleton. Most cases are
unifocal but can be multifocal. It is usually painful. Its cells express endothelial markers, its
epithelioid variant also expressing epithelial markers. Angiosarcoma is a very aggressive
neoplasia, and its eventual multifocality makes it difficult or impossible to control; the
prognosis is dismal in most cases.

Definition Epidemiology

• A high-grade malignant neoplasia with endothelial differ- • Less than 1 % of primary bone tumors
entiation, rare in bone • Usually seen in adult patients from the second to the
eighth decade
• Rare in children
Synonyms

• Hemangiosarcoma Sites of Involvement

• Bones of the extremities, especially the proximal femur,

Etiology
• Unknown.
• Some cases were associated to exposure to radiation, to
bone infarcts, and to metallic implants.
• Multipotential bone marrow-derived hematopoietic stem
cells or early endothelial progenitor cells expressing CD117,
CD34, and CD45 are involved in angiosarcoma formation.
R.K. Kalil, MD
Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina
Department of Pathology, A.C. Camargo Cancer Center,
São Paulo, SP, Brazil
e-mail: rkkalil@gmail.com
account for more than 70 % of cases. The pelvis and axial
skeleton follow in frequency.
• Most cases are unifocal (around 70 %); the rest are
multifocal affecting the same bone or multiple,
contiguous bones and may also be widespread in the
skeleton.
Clinical Symptoms and Signs
• Pain is usually the first symptom.
• A local mass may be present.

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 507
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_36, © Springer-Verlag London 2015
508
Image Diagnosis
• Radiographically, angiosarcoma usually is a completely
lytic, uni- or multilocular lesion, with medullar and
cortical permeation. Less commonly, it may be sclerotic
or mixed, lytic and sclerotic. It usually has infiltrative
margins, but these can be well defined and with no
peripheral sclerosis. Periosteal reaction is absent. Invasion
of the neighboring soft parts may also be seen.
• CT and MRI demonstrate more clearly the multifocal aspect
of the bone or bones affected. Secondary aneurysmal bone
cyst may be seen in a few cases. Reactive changes may be
seen. MRI, characteristically, demonstrates low signal inten-
sity on T1-weighted images and heterogeneously interme-
diate to high signal intensity on T2-weighted images.
• The imaging finding of multiple lesions by itself should be
sufficient to include angiosarcoma as a diagnostic possibility.
R.K. Kalil
Image Differential Diagnosis
• Metastatic carcinoma, multiple myeloma, and lym-
phoma may be difficult to differentiate by image methods
alone. See also epithelioid hemangioendothelioma.
Pathology
Gross Features
• It is useful to radiograph the specimen in order to locate
possible multiple foci as well as resection margins related
to the lesions before sectioning.
• The cut surface shows a large or multiple hemorrhagic
lesions, friable, with cortex permeation.
36 Angiosarcoma
Histopathological Features
• Angiosarcoma is histologically classified in three grades
according to cytological atypia.
• Microscopically, the tumor is composed of sheets of
atypical epithelioid cells with eosinophilic cytoplasm
where one or more vacuoles may be seen (“blister cells”).
The occasional finding of erythrocytes or its fragments in
these vacuoles is characteristic of the endothelial origin
of the tumor cells. In a minority of cases, cells may be
spindled. The nuclei are large, vesicular, and with promi-
nent nucleoli. Atypical and numerous mitotic figures are
common.
• Another tissue pattern that may be found, especially in
well-differentiated tumors, is vasoformative, with the
atypical endothelial cells lining irregular vascular
spaces.
• Inflammatory infiltrate, hemorrhage, hemosiderin depos-
its, and necrotic areas are usually seen, and the tumoral
infiltration by erythrocytes and neutrophils is considered
suggestive of endothelial tumors.
Pathology Differential Diagnosis
• Epithelioid hemangioendothelioma or epithelioid
hemangioma – These tumors do not present the numer-
ous atypical cells and atypical mitosis usually seen in an
angiosarcoma.
• Metastatic carcinoma – As angiosarcoma may stain
with epithelial markers, this differential must be consid-
ered in a biopsy sample. Endothelial markers are needed
to establish the correct diagnosis. Desmoplastic stromal
reaction is more common in metastatic carcinoma than in
angiosarcoma.
• Metastatic melanoma – Negative for endothelial mark-
ers and positive for melan-A, HMB45, and S100.
Ancillary Methods
• Angiosarcomas express endothelial markers as CD31,
CD34, von Willebrand factor, FLI1, and ERG. Epithelioid
cells of epithelioid angiosarcoma usually express epi-
thelial markers. A few cells may be positive for SMA.
Lymphangiogenic marker D2-40 may be positive in a
few cases.
509
Genetics
• Translocation t(1;14)(p21;q24) was described in one case.
• In nearly 55 % of the angiosarcomas of the bone, the reti-
noblastoma (Rb) pathway was affected, suggesting that this
pathway is involved in tumorigenesis of angiosarcoma. The
loss of CDKN2A expression was associated with a signifi-
cantly worse prognosis. No overexpression of TP53 or
MDM2 was found. Angiosarcoma of the bone showed
highly active TGF-β signaling with immunoreactivity for
phospho-Smad2 and PAI-1. PIK3CA hotspot mutations
were absent. The PI3K/Akt pathway is activated in both
angiosarcomas of the bone and soft tissue, however, with a
different cause; contrary to its soft tissue counterpart, PTEN
expression is decreased in angiosarcoma of the bone.
Prognosis
• Angiosarcoma is a very aggressive neoplasia, and its even-
tual multifocality makes it difficult or impossible to control.
• One- and five-year survival rates average 55 % and 33 %,
respectively.
• Pathologic characteristics of worse prognosis are:
– Tumors larger than 10 cm
– Presence of macronucleolus
– Three of more mitoses per 10 HPF
– Fewer than five eosinophilic granulocytes per 10 HPF
– D2-40 positivity by immunohistochemistry
– Loss of CDKN2A expression
Treatment
• Early diagnosis and surgical resection may offer the best
hope of cure, but in the large majority, especially in
advanced cases, the prognosis is dismal.
• Radiation for close surgical margins or worrisome patho-
logic features can result in long-term survival.
• The effectiveness of adjuvant chemotherapy is unknown,
but there can be dramatic responses in a minority of patients.
Images
See Figs. 36.1, 36.2, 36.3, 36.4, 36.5, 36.6, 36.7, 36.8, and
36.9 for illustrations of angiosarcomas.
510 R.K. Kalil

Fig. 36.1 Radiograph showing angiosarcoma involving multiple

regional bones of the hand
36 Angiosarcoma 511

Fig. 36.2 (a) Radiograph

showing another example of a
angiosarcoma involving multiple
regional bones of the foot. (b)
The tibia was also involved in
this case

b
512 R.K. Kalil

Fig. 36.3 The same case as the previous figure. Macrophotography

shows involvement of multiple bones of the foot by a spongy brown
tissue with small cyst-like or large vascular spaces filled by blood

Fig. 36.6 Another field of the same case as the previous figure. Solid
proliferation of moderate differentiated epithelioid cells

Fig. 36.4 Microphotography showing bone involvement by a richly

vascular tissue. Dilated neoplastic vessels at the periphery of a tumoral
nodule

Fig. 36.7 Higher-power view of the previous case highlighting the

epithelioid morphology of the cells as well as moderate atypia

Fig. 36.5 Microphotography of the same field as the previous figure.

Well-differentiated angiosarcoma, in this field constituted by small vas-
cular channels lined by epithelioid endothelial cells with moderate
atypia
36 Angiosarcoma 513

Fig. 36.8 Irregular vascular channels lined by moderately atypical Fig. 36.9 Immunohistochemistry demonstrated positivity for CD34
endothelial cells in a loose, somewhat myxoid, stroma
514 R.K. Kalil

Recommended Reading McDonald DJ, Enneking WF, Sundaram M. Metal-associated

angiosarcoma of bone: report of two cases and review of the litera-
ture. Clin Orthop Relat Res. 2002;(396):206–14.
Abdelwahab IF, Klein MJ, Hermann G, et al. Angiosarcomas associ-
Mittal S, Goswami C, Kanoria N, Bhattacharya A. Post-irradiation
ated with bone infarcts. Skeletal Radiol. 1998;27:546–51.
angiosarcoma of bone. J Cancer Res Ther. 2007;3(2):96–9.
Abraham JA, Hornicek FJ, Kaufman AM, Harmon DC, Springfield DS,
Palmerini E, Maki RG, Staals EL, Alberghini M, Antonescu CR,
Raskin KA, Mankin HJ, Kirsch DG, Rosenberg AE, Nielsen GP,
Ferrari C, Ruggieri P, Mavrogenis A, Bertoni F, Cesari M, Paioli A,
Desphpande V, Suit HD, DeLaney TF, Yoon SS. Treatment and
Marchesi E, Picci P, Ferrari S. Primary angiosarcoma of Bone: a
outcome of 82 patients with angiosarcoma. Ann Surg Oncol.
retrospective analysis of 60 patients from 2 institutions. Am J Clin
2007;14(6):1953–67.
Oncol. 2014;37(6):528–34.
Errani C, Vanel D, Gambarotti M, Alberghini M, Picci P, Faldini C.
Verbeke SL, Bertoni F, Bacchini P, Sciot R, Fletcher CD, Kroon HM,
Vascular bone tumors: a proposal of a classification based on clini-
Hogendoorn PC, Bovée JV. Distinct histological features character-
copathological, radiographic and genetic features. Skeletal Radiol.
ize primary angiosarcoma of bone. Histopathology. 2011;58(2):
2012;41(12):1495–507.
254–64.
Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F, editors. WHO
Verbeke SL, Bertoni F, Bacchini P, Oosting J, Sciot R, Krenács T,
classification of tumors of soft tissue and bone. 4th ed. Lyon: IARC
Bovée JV. Active TGF-β signaling and decreased expression of
Press; 2013.
PTEN separates angiosarcoma of bone from its soft tissue counter-
Hart JL, Edgar MA, Gardner JM. Vascular tumors of bone. Semin
part. Mod Pathol. 2013;26(9):1211–21.
Diagn Pathol. 2014;31:30–8.
Liu L, Kakiuchi-Kiyota S, Arnold LL, Johansson SL, Wert D,
Cohen SM. Pathogenesis of human hemangiosarcomas and heman-
giomas. Hum Pathol. 2013;44(10):2302–11.
 Part IX
Adamantinoma
 Adamantinoma
37
Edward McCarthy

Abstract
Adamantinoma is a primary low-grade malignant bone tumor that has nests of epithelial
cells in a fibro-osseous background. Epithelial nests pattern are commonly basaloid type
but can be spindle shaped, tubular, or squamoid. Ninety-five percent of cases involve the
tibia or the fibula. On rare occasions, other long bones may be involved. Patients are mostly
in their 30s and often have symptoms of long duration. Radiologically, adamantinomas are
diaphyseal multifocal cortical-based lesions that can invade the adjacent soft tissue or the
medullary canal. It is best treated by wide resection and late metastases can occur.
Osteofibrous dysplasia-like adamantinomas are not malignant.

Definition Epidemiology

• A primary bone tumor that has nests of epithelial cells in • Adamantinoma is a very rare neoplasm.
a fibro-osseous background • Patients range from age 3 to age 72, but most are in
their 30s.

Etiology
Clinical Signs and Symptoms
• Unknown
• Patients usually complain of pain and swelling, often of
long duration.
• Approximately one-third of patients have had symptoms
Clinical Features
for longer than 5 years. One reported patient had symp-
toms for 50 years.
Sites of Involvement

• Ninety percent of cases involve the tibia or (10 %) the
fibula.
• On rare occasions, other long bones, such as the femur,
humerus, and ulna, may be involved. This neoplasm has
also been reported in the pretibial soft tissues.
E. McCarthy, MD
Department of Pathology and Orthopaedic Surgery,
Johns Hopkins Hospital, Baltimore, MD, USA
e-mail: mccarthy@jhmi.edu
Image Diagnosis
Radiologic Features
• Adamantinomas are cortical-based lesions, and 90 % of
cases involve the diaphysis (Fig. 37.1).
• Many lesions show invasion of the adjacent soft tissue or
the medullary canal (Fig. 37.2).
• Some lesions show multiloculated lytic areas surrounded
by dense reactive bone.
• Often the lesion appears multifocal and involves long seg-
ments of the tibial shaft.

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 517
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_37, © Springer-Verlag London 2015
518
MRI Features
• MRI usually shows a uniform high signal on T2-weighed
images.
Image Differential Diagnosis
• Osteofibrous dysplasia
– This disease is cortical based and does not involve the
medullary canal or adjacent soft tissue.
– Any non-matrix producing primary bone tumor.
• Metastatic carcinoma
Pathology
• Histologically, adamantinomas consist of various patterns
of epithelial cells in a fibrous and fibro-osseous stroma.
Keratin stains are positive (Fig. 37.3).
• The most common pattern is nests of basaloid epithelial
cells with peripheral palisading, a feature similar to basal
E. McCarthy
cell carcinoma of the skin. Cystic spaces of various sizes
often develop within the epithelial nests.
• Another common pattern of the epithelial cells is a spin-
dle shape – cords of elongated cells with plump nuclei are
surrounded by a more hyalinized stroma. Occasionally,
the stroma may be cellular with a gradual differentiation
to epithelial cells.
• A third epithelial pattern in adamantinoma, tubule forma-
tion, resembles glands or vascular spaces. The tubules,
present in a fibrous background, are formed by a single
layer of small cuboidal cells which line anastomosing
spaces (Fig. 37.4).
• Finally, a rare squamoid pattern of the epithelium may be
present. Clusters of cells with large eosinophilic cyto-
plasms and rounded or pyknotic nuclei are nested in the
spindle cell background.
• The epithelial cells of adamantinomas, although occa-
sionally hyperchromatic, are cytologically bland. They
lack pleomorphism, and mitotic figures are rare. These
bland features, in addition to a typical radiographic pat-
tern, distinguish adamantinoma from metastatic
carcinoma.
37 Adamantinoma 519

a b c

Fig. 37.1 (a) Plain radiograph of an adamantinoma in the anterior tibial diaphyseal cortex. (b) CT image of this area showing an intercortical
lesion with a cortical expansion. (c) MRI of this lesion showing intense signal in a T2-weighted gadolinium-enhanced image

• Adamantinoma may have areas in which the epithelial

cells are not apparent. These areas are morphologically
identical to osteofibrous dysplasia, mandating a complete
tissue sampling of an osteofibrous dysplasia-like lesion to
rule out adamantinoma.

Pathologic Differential Diagnosis

• Metastatic carcinoma
– Metastatic foci are usually pleomorphic with a high
mitotic rate.
• Differentiated adamantinoma
– Some lesions, clinically and radiographically identi-
cal to severe osteofibrous dysplasia, contain discrete
nests of epithelial cells, although they are not as
prominent as in adamantinomas. These lesions, called
differentiated adamantinomas, may represent burned
out cases of severe osteofibrous dysplasia.
Alternatively, they may represent an intermediate
stage between osteofibrous dysplasia and classic Fig. 37.2 Plain radiograph of a classic adamantinoma in a distal tibial
adamantinoma. shaft. There are intercortical lucencies as well as involvement of the
• Formerly, lesions which are now regarded as differenti- medullary canal
ated adamantinomas were grouped with classical ada-
mantinomas. Often, they were regarded as “osteofibrous conservatively. Surgery should be reserved to correct
dysplasia-like” adamantinomas. They occur in a similar deformities or stabilize pathologic fractures.
age group, and they involve long segments of the tibia. As
a result, they were often treated aggressively, similar to
adamantinoma. However, differentiated adamantinomas Treatment and Prognosis
are indolent lesions. Sometimes they are asymptomatic
and do not grow at all. Radiographically, they lack corti- • Adamantinomas are low-grade malignant neoplasms.
cal destruction and soft-tissue infiltration (Fig. 37.5). • They should be treated by wide segmental resection or
Therefore, differentiated adamantinomas may be treated amputation.
520 E. McCarthy

Fig. 37.3 Photomicrograph of a keratin stain showing keratin-positive

epithelial cells

Fig. 37.5 Plain radiograph of a differentiated adamantinoma. There is

extensive involvement of the entire shaft of the tibia. This lesion has not
changed over 10 years

Recommended Reading
Cohn BT, Brahms MA, Froimson AI. Metastasis of adamantinoma six-
Fig. 37.4 Photomicrograph showing slit-like spaces lined by basaloid
teen years after knee disarticulation. Report of a case. J Bone Joint
epithelial cells
Surg. 1986;68-A:772–6.
Czerniak B, Rojas-Corona RR, Dorfman HD. Morphologic diversity
of long bone adamantinoma. The concept of differentiated (regress-
• About 25 % of patients develop metastases after surgical ing) adamantinoma and its relationship to osteofibrous dysplasia.
Cancer. 1989;64:2319–34.
ablation.
Ishida T, Iijima F, Kikuchi F, et al. A clinicopathological and immu-
• Metastasis may occur as late as 16 years after surgery. nohistochemical study of osteofibrous dysplasia, differentiated ada-
• Osteofibrous dysplasia-like adamantinomas (differenti- mantinoma, and adamantinoma of long bones. Skelet Radiol. 1992;
ated adamantinomas) are not malignant and may be fol- 21:493–502.
Kahn LB. Adamantinoma, osteofibrous dysplasia, and differentiated
lowed closely without surgery.
adamantinoma. Skelet Radiol. 2003;32:245–58.
Keeney GL, Unni KK, Beabout JW, et al. Adamantinoma of long bones.
A clinicopathologic study of 85 cases. Cancer. 1989;64:730–7.
Mills SE, Rosai J. Adamantinoma of the pretibial soft tissue.
Clinicopathologic features, differential diagnosis, and possible
Images relationship to intraosseous disease. Am J Clin Pathol. 1985;83:
108–14.
Weiss SW, Dorfman HD. Adamantinoma of long bone. An analysis of
See Figs. 37.1, 37.2, 37.3, 37.4, and 37.5 for illustrations of nine new cases with emphasis on metastasizing lesions and fibrous
adamantinoma. dysplasia-like changes. Hum Pathol. 1977;8:141–53.
 Part X
Notochordal Tumors
 Benign Notochordal Cell Tumor
38
Yasuaki Nakashima

Abstract
Benign notochordal tumor is a benign indolent bone tumor probably derived from vestigial
notochordal rests. As it is usually asymptomatic, its true incidence is unknown but has been
found in 20 % of spines in an autopsy study. Radiographs, CT, or bone scan may appear
normal. MRI shows altered signal intensity. Histologically, it appears as sheet-like
proliferation of bland-looking cells with well-defined boundary, resembling fatty marrow at
low magnification. Foci of chordoma may be found next to the lesion, suggesting histoge-
netic relationship. It is immunohistochemically positive for S100, epithelial markers, and
brachyury. Surgery is only indicated in large lesions and for differential diagnosis.

Definition Epidemiology

• A benign tumor with notochordal differentiation. • The exact incidence is unknown.

• Twenty percent in a study for consecutive autopsy cases,
and 7.3 % at sacral/coccygeal resections performed for
Synonyms primary chordoma.
• Ecchordosis physaliphora is detected in 0.6–2.0 % in
• Giant notochordal rest. autopsy, 1.7 % by MRI.
• Notochordal hamartoma. • Male-to-female ratio ranging from 1:5 to 2:1.
• Ecchordosis physaliphora spheno-occipitalis. • Age of 7–83 (average 58–63) years.
• Intraosseous benign notochordal cell tumor.

Etiology Sites of Involvement

• The origin of benign notochordal cell tumor is undeter-
mined and controversial. It may develop from the vesti-
gial rest of notochord in early embryogenesis, or it can
occur de novo as an acquired lesion.
Y. Nakashima, MD, PhD
Laboratory of Anatomic Pathology,
Kyoto University Hospital, Kyoto, Japan
e-mail: nakashim@kuhp.kyoto-u.ac.jp
• The same distribution as seen in classic chordomas.
• In autopsy study, base of the skull, most common in
the clivus, the sacrococcygeal vertebrae, the cervical
vertebrae, and the lumbar vertebrae, in this order sparing
the thoracic spine.
• Rare extraskeletal involvement, including the lungs and
the paravertebral mediastinum.

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 523
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_38, © Springer-Verlag London 2015
524
Clinical Symptoms and Signs
• Usually asymptomatic and incidental radiographic findings
• Pain and/or numbness in the back or in the extremity,
shoulder stiffness, and, very rarely, diplopia from abdu-
cens palsy due to a retroclival prepontile lesion.
Image Diagnosis
Radiographic Features
• In the clivus or, in the cervical, lumbar, or sacrococcygeal
vertebral body
• Solitary lesion confined to the bone without extraosseous
extension
• Very rarely associated with an extraosseous mass
• Ill-defined, vague sclerosis within the vertebral body
• Diffuse prominent sclerosis presenting as ivory vertebra
• May be normal and not identified on radiography or can
show minimal sclerosis
• Decreased physiological lordosis with a lesion in the cer-
vical spine
CT Features
• May be normal or show minimal sclerosis.
• Mild to marked osteosclerosis in the vertebral body.
• Intervening residual bone architecture can be seen focally.
• Diffuse sclerosis may replace entire bone.
• Generally without cortical disruption or bone destruction.
MRI Features
• Low T1- and high T2-weighted signal intensities
• Slightly heterogeneous signal intensities in hyperintensity
area on T2-weighted images
• No significantly increased intensity in gadolinium-DTPA-
enhanced T1-weighted images
Bone Scan
• No abnormal uptake
Image Differential Diagnosis
Chordoma
• Larger (20–110 mm, mean 50.2 mm) than benign noto-
chordal tumor (6–35 mm, mean 18.8 mm) in size.
Y. Nakashima
• Osteolytic lesion, usually associated a soft tissue mass.
• In the sacrum, the extension is almost always into the pre-
sacral space.
• Irregular areas of destruction involving the midline of the
sacrum, the body of the vertebra, clivus, and retroclival
dura.
• Bone destruction and intraosseous residual bone
structures or calcification are manifested in CT.
• Heterogeneous in hyperintensity on T2-weighted images.
• Mild to avid contrast enhancement.
Enchondroma
• Relatively rare in movable spine or sacrum
• Well-circumscribed lucency in medullary cavity with
frequently regular calcification
• Different histological pattern
Intraosseous Lipoma
• Rare in the spine.
• Osteolytic lesion with centrally located calcification-like
density suggestive of infarction.
• Histological differentiation between benign notochordal
tumor and intraosseous lipoma may be difficult in H&E
stained sections, and immunostainings of keratins and
brachyury sometimes may be mandatory.
Osteonecrosis (Bone Infarct)
• Well to poorly circumscribed lucency, with peripheral
calcified shell.
• Delayed post-traumatic collapse of vertebral bodies in
Kummell’s disease.
• Histological differentiation between benign notochordal
tumor and bone infarct may be difficult in H&E stained
sections, and immunostainings of keratins and brachyury
sometimes may be mandatory.
Osteomyelitis
• Involvement of intervertebral disk is common.
• Bone scintigraphy is usually positive.
Enostosis (Bone Island, Osteoma)
• Asymptomatic incidental finding.
• In the spine, incidence is 1–15 %.
• Single or multiple, intramedullary sclerotic change with
radiation of spicule-like thorny projection into surround-
ing bone marrow.
• Osteoma is osseous protrusion in the bone surface.
Osteoid Osteoma
• Night pain relieved by NSAIDs including aspirin
• Less than 1.5 cm in diameter
• In the spine, usually involving posterior components,
sometimes accompanied with scoliosis
38 Benign Notochordal Cell Tumor
• In a medullary lesion, a radiolucent nidus surrounded by
osteosclerotic rim, with or without central calcification,
demonstrated in CT
• Different histological pattern
Plasmacytoma
• Purely osteolytic, frequently multiple punched-out
lesions
• Abnormal hematological finding including serum
M-protein
• POEMS (Crow-Fukase) syndrome; osteosclerotic
myeloma particularly in the spine and pelvis with plasma
cell dysplasia, accompanied with polyneuropathy and
endocrinopathy
• Proliferation of plasma cells in histology
Malignant Lymphoma
• Extensive involvement with permeation in the bone.
• Mixed lytic and sclerotic changes
• Positive bone scan
• Proliferation of atypical lymphoid cells in histology
Metastatic Carcinoma
• Usually osteolytic and destructive
• Osteosclerotic metastasis, for example, from prostatic car-
cinoma, breast carcinoma, and endometrial carcinoma, etc.
• Positive bone scan
• Proliferation of malignant epithelial cells in histology
Pathology
Gross Features
• Ranging from 1 to 20 (mean 6.1) mm and radiographi-
cally ranging from 6 to 35 (mean 18.8) mm.
• Can occupy the entire marrow space of the vertebral body.
• Gross appearance can be very subtle and nonspecific.
Histological Features
• Permeating the intertrabecular spaces of the vertebral
body, frequently with entrapped home marrow islands.
• Intervening bony trabeculae in the lesion are often
sclerotic.
• Without lobulation, fibrous septa, extracellular myxoid
matrix, necrosis, or a destructive growth pattern.
• Uniform, sheet-like proliferation of bland-looking tumor
cells with well-defined cell boundary, resembling fatty
marrow at low magnification.
• Centrally or peripherally placed round to oval small nuclei,
containing small nucleoli and fine nuclear chromatin.
525
• Clear to faintly eosinophilic cytoplasm with various
degree of vacuolization, mimicking mature adipocytes.
• Can have eosinophilic cytoplasm, with eosinophilic
hyaline globules.
• No mitotic figures.
• Juxtaposed to a benign notochordal tumor, foci of a
chordoma may be found, with sharp transition, sug-
gesting histogenetic relationship between these two
tumors.
• Immunohistochemically positive for S100 protein, EMA,
AE1/AE3, CAM5.2, and brachyury.
• Ecchordosis physaliphora spheno-occipitalis shows the
same morphological features as seen in benign noto-
chordal tumor.
Pathologic Differential Diagnosis
Chordoma
• Destructive growth pattern.
• Lobular architecture separated by fibrous bands.
• Syncytial cords and strands of tumor cells.
• Extracellular mucinous or myxoid matrix, vasculature,
and necrosis.
• “Physaliphorous” cells with bubbly cytoplasm.
• Low-grade nuclear atypia to rare high-grade spindle cell
sarcomatous pattern.
• “Dedifferentiation” may occur.
• Showing similar immunohistochemical profiles to benign
notochordal tumor, with positive expression for S100
protein, EMA, AE1/AE3, CAM5.2, and brachyury.
Intraosseous Lipoma
• Extremely rare in the spine.
• Bone marrow lesion occupied of fatty tissue, with cen-
trally located fat necrosis, infarction, and calcification.
• Due to anoxic change, like bone infarct, wavy folds of
surface membrane of lipocytes may focally and nonspe-
cifically simulate membranous lipodystrophy (Nasu-
Hakola disease).
• Immunohistochemically negative for keratins or brachyury.
Osteonecrosis (Bone Infarct)
• Empty lacuna in bony trabecula is frequently nonspecific
for an evidence of ischemia.
• Fat necrosis and irregular calcification in the space
between bony trabeculae.
• In the area of fat necrosis, wavy folds of surface mem-
brane of lipocytes simulating membranous lipodystrophy
(Nasu-Hakola disease) may be seen.
• Immunohistochemically negative for keratins or
brachyury.
• Secondary malignant change can occur.
526 Y. Nakashima

Prognosis conventional chordoma.

• In large lesions, treatment consisting of curettage or excision
• Biologic behavior is benign or indolent. followed by bone grafting may be indicated by clinicians,
• Development of classical chordoma from benign with suspected clinical diagnosis of other bone lesions.
notochordal tumor has been still controversial.

Images
Treatment
See Figs. 38.1, 38.2, 38.3, 38.4, 38.5, 38.6, 38.7, 38.8, and
• No need the aggressive treatment required for treating a 38.9 for illustrations of benign notochordal cell tumors.
38 Benign Notochordal Cell Tumor 527

a b

Fig. 38.1 Benign notochordal cell tumor involving the S3 of the images demonstrate low signal intensity, without significantly increased
sacrum in a 31-year-old man. Sagittal (a) and axial (b) computed tomo- intensity in gadolinium-DTPA-enhanced T1-weighted image (e).
graphic scans show a slightly sclerotic mass in midline of the S3 in the Sagittal (f) and axial (g) T2-weighted magnetic resonance images show
sacrum. Sagittal (c) and axial (d) T1-weighted magnetic resonance heterogeneously high signal intensities
528 Y. Nakashima

e f

Fig. 38.1 (continued)

38 Benign Notochordal Cell Tumor 529

Fig. 38.2 No abnormal uptake in bone isotope scan

Fig. 38.3 Low-power scanning view of a benign notochordal cell

tumor showing a relatively well-circumscribed medullary nodule con-
taining slightly sclerotic bony trabeculae (Case by courtesy of Doctor
Takehiko Yamaguchi, Tochigi, Japan)

Fig. 38.4 Benign notochordal cell tumor permeating the intertrabecu-

lar spaces with various degree of osteosclerotic change (Case by cour-
tesy of Doctor Takehiko Yamaguchi, Tochigi, Japan)
530 Y. Nakashima

Fig. 38.5 Proliferation of bland-looking tumor cells resembling fatty Fig. 38.7 Benign notochordal cell tumor (center to right) continu-
marrow between bony trabeculae (Case by courtesy of Doctor Takehiko ously merging into fatty marrow (left) (Case by courtesy of Doctor
Yamaguchi, Tochigi, Japan) Takehiko Yamaguchi, Tochigi, Japan)

Fig. 38.6 Faintly eosinophilic cytoplasm with prominent vacuoliza- Fig. 38.8 Discretely isolated small foci of giant notochordal tumor in
tion, mimicking mature adipocytes (Case by courtesy of Doctor the fatty bone marrow (Case by courtesy of Doctor Takehiko Yamaguchi,
Takehiko Yamaguchi, Tochigi, Japan) Tochigi, Japan)
38 Benign Notochordal Cell Tumor 531

a b

Fig. 38.9 Inconspicuous neoplastic cells between bony trabeculae (a) are positive for keratin (CAM5.2) in immunostaining (b)
532 Y. Nakashima

Recommended Reading MRI, CT, and tomography. AJR Am J Roentgenol. 2011;196:

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Oner AY, Akpek S, Tali T, Ucar M. Giant vertebral notochordal rest:
Adamek D, Malec M, Grabska N, Krygowska-Wajs A, Galazka K.
magnetic resonance and diffusion weighted imaging findings.
Ecchordosis physaliphora – a case report and a review of notochord-
Korean J Radiol. 2009;10:303–6.
derived lesions. Neurol Neurochir Pol. 2011;45:169–73.
Rotondo M, Natale M, Mirone G, Cirillo M, Conforti R, Scuotto A. A
Alkan O, Yildirim T, Kizilkilic O, Tan M, Cekinmez M. A case of
rare symptomatic presentation of ecchordosis physaliphora: neuro-
ecchordosis physaliphora presenting with an intratumoral hemor-
radiological and surgical management. J Neurol Neurosurg
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Psychiatry. 2007;78:647–9.
Amer HZ, Hameed M. Intraosseous benign notochordal cell tumor.
Shen J, Li CD, Yang HL, et al. Classic chordoma coexisting with benign
Arch Pathol Lab Med. 2010;134:283–8.
notochordal cell rest demonstrating different immunohistological
Cha ST, Jarrahy R, Yong WH, Eby T, Shahinian HK. A rare symptom-
expression patterns of brachyury and galectin-3. J Clin Neurosci.
atic presentation of ecchordosis physaliphora and unique endoscope-
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Smith DS, French G, Miller M. Multifocal benign notochordal cell
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Deshpande V, Nielsen GP, Rosenthal DI, Rosenberg AE. Intraosseous
Souteyrand P, Bouvier C, Zink JV, et al. Benign notochordal cell
benign notochord cell tumors (BNCT): further evidence supporting
tumour: case report. Diagn Interv Imaging. 2013;94:466–9.
a relationship to chordoma. Am J Surg Pathol. 2007;31:1573–7.
Terzi S, Mobarec S, Bandiera S, et al. Diagnosis and treatment of
Golden LD, Small JE. Benign notochordal lesions of the posterior
benign notochordal cell tumors of the spine: report of 3 cases and
clivus: retrospective review of prevalence and imaging characteris-
literature review. Spine (Phila Pa 1976). 2012;37:E1356–60.
tics. J Neuroimaging. 2013;23:314–6.
Uglialoro AD, Beebe KS, Hameed M, Benevenia J. A rare case of
Haasper C, Langer F, Rosenthal H, et al. Coccydynia due to a benign
intraosseous benign notochordal cell tumor of the coccyx.
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Orthopedics. 2009;32:445.
Iorgulescu JB, Laufer I, Hameed M, et al. Benign notochordal cell
Wang WL, Abramson JH, Ganguly A, Rosenberg AE. The surgical
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pathology of notochordal remnants in adult intervertebral disks: a
confirmed lesions. Neurosurgery. 2013;73:411–6.
report of 3 cases. Am J Surg Pathol. 2008;32:1123–9.
Kikuchi Y, Yamaguchi T, Kishi H, et al. Pulmonary tumor with noto-
Yamaguchi T, Yamato M, Saotome K. First histologically confirmed
chordal differentiation: report of 2 cases suggestive of benign noto-
case of a classic chordoma arising in a precursor benign notochordal
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and current appraisal. Skelet Radiol. 2011;40:1141–52.
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notochordal cell tumors from chordomas: radiographic features on
 Chordoma
39
Yasuaki Nakashima

Abstract
Chordoma is a rare malignant tumor with notochordal differentiation. It is most common in
40–70 years of age male patients, 50 % of cases involving sacrococcygeal bones, 20–40 %
skull base, and 10–30 % the mobile spine. Extra-axial cases have been reported.
Radiologically, it is a destructive expanding lesion in the midline of the affected segment.
Histologically, it has a lobular arrangement of cells with eosinophilic cytoplasm and intra-
cytoplasmic vacuoles showing “physaliphorous” appearance. It is immunohistochemically
positive for epithelial markers, brachyury, S100, and vimentin. It must be differentiated
mainly from chondrosarcoma, metastatic carcinoma, and myxopapillary ependymoma. It
has a slow infiltrative growth with frequent recurrences. There is a poor prognosis for dedif-
ferentiated chordoma. Surgery is the mainstay of treatment.

Definition reported, and the similarity of the anatomical distribution

of these two tumors may suggest development of classical
• A malignant tumor with notochordal differentiation. chordoma from benign notochordal cell tumors.
Etiological relationship of these two entities is, however,
still uncertain.
Etiology

• Most cases of chordoma are sporadic, and less than 10 %

of sporadic tumors displayed amplification of the tran-
scription factor T (brachyury) gene locus located in 6q27.
Autosomal dominant inheritance with duplication of
brachyury gene (T gene) may present major susceptibility
to rare familial chordoma.
• Rare occurrence of chordoma in children with tuber-
ous sclerosis suggests that TSC1 and TSC2 mutations
may etiologically contribute to development of
chordoma.
• Mutually appositional coexistence of chordoma and
benign notochordal tumor in the same vertebra was
Epidemiology
• The incidence is 0.08 per 100.000 people.
• Nearly 5 % of primary bone tumors.
• Male-to-female ratio is approximately 1.8:1 to 2:1.
• Most common in 40–70 years of age, with 95 %
being over the age of 20 years. Peak incidence in 50s
and 60s.
Sites of Involvement

• Approximately 50 % of the cases in sacrococcygeal

Y. Nakashima, MD, PhD
Laboratory of Anatomic Pathology, Kyoto University Hospital,
bones; nearly 20–40 % in skull base, most commonly in
Kyoto, Japan the clivus; and nearly 10–30 % in mobile spine, mainly in
e-mail: nakashim@kuhp.kyoto-u.ac.jp the body of cervical and lumbar vertebrae.

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 533
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_39, © Springer-Verlag London 2015
534
• In pediatric patients, frequently in the base of the skull
and the cervical spine.
• Rare examples of extra-axial chordoma in bone or soft
tissue were reported.
Clinical Symptoms and Signs
• Pain for months to years
• Low-back pain, coccydinia, perineal pain, numbness,
constipation, bladder dysfunction, and/or paresthesia of
the limbs, secondary to nerve impairment in sacrococcy-
geal lesions
• In spheno-occipital tumors, headache, neck pain, blurred
vision, diplopia, weakness, memory loss, emotional
instability, or facial nerve palsy, referable to increased
intracranial pressure and/or involvement of cranial
nerves
• Pituitary dysfunction due to destruction of the pituitary
gland
• An anterior mass in most of sacrococcygeal tumors, rarely
accompanied with posterior mass
Y. Nakashima
Image Diagnosis
Radiographic Features
• Irregular destruction of the midline of the sacrum, the ver-
tebral body, and clivus, showing osteolysis with or without
residual bony trabeculae and amorphous calcification.
• Sacral lesions almost always extend into the presacral
space.
• Destruction of the clivus and sella turcica, extension into
the petrous and sphenoid bones, and nasopharyngeal
involvement, in the spheno-occipital lesions.
• In mobile spine, later involvement of contiguous vertebral
bodies and intervertebral disks, with vertebral collapse.
• Bone or soft tissue in extra-axial location can be very
rarely affected by primary chordoma.
CT Features
• Extent of the tumor and soft tissue extension is defined
by CT.
• Peripheral amorphous calcification in most cases.
39 Chordoma
MRI Features
• Low to intermediate T1-weighted signal intensities.
• High T2-weighted signal intensities in the lobulated
areas.
• Low T2-weighted signal intensities in the septal areas.
• MRI demonstrates relationship between the tumor and
surrounding structures.
Bone Scan
• Practically no abnormal uptake in typical lesions
Image Differential Diagnosis
Giant Cell Tumor
• Purely lytic, expansile lesion without soft tissue
invasion
• Soft tissue extension limited by calcified shell
• No amorphous calcification within the lesions
• Low T1- and high T2-weighted signal intensities
• Significantly increased intensity in gadolinium-DTPA-
enhanced T1-weighted images
• Different histological pattern
Aneurysmal Bone Cyst
• Extraosseous blowout with a sclerotic rim of peripheral
ossification
• Largely cystic change with fluid-fluid levels (niveau)
formation
• Involvement of posterior components of the vertebrae
• Different histological pattern
Chondrosarcoma
• Osteolytic invasive lesion with mottled calcification.
• Differentiation between cartilaginous and chondroid neo-
plasias in the skull base has been controversial.
• Cartilaginous-like or chondroid-appearing lesions in the
midline related to clivus may be “chondroid” chordoma,
while possibility of chondrosarcoma should be consid-
ered for an eccentrically located lesion distant from mid-
line in the skull base or clivus.
• For differentiation between chondrosarcoma and “chon-
droid” chordoma, radiological and histological pattern is
frequently confusing, and immunohistochemistry may be
helpful and mandatory.
Metastatic Carcinoma
• Usually suggests a malignant quality of the lesions.
• Osteolytic and destructive change mainly located in mar-
row cavity.
• Osteoblastic or mixed lytic and blastic change.
535
• Prostatic adenocarcinoma or neuroendocrine tumor fre-
quently shows purely osteoblastic metastasis.
• Metastatic renal cell carcinoma frequently produces
purely lytic large destruction with aneurysmal bone cyst-
like change.
• Florid ossification with pathologic fracture may simulate
osteosarcoma.
• Radioisotope scintigram bone scan is positive and is use-
ful for finding multiple skeletal metastases.
• Different histological pattern.
Meningioma
• Intradural and extra-axial/extramedullary lesions with
broad dural base
• In extracranial location, most commonly seen in the
thoracic spine
• Isointensity in T1- and T2-weighted images identical to
neural elements
• Increased intensity in gadolinium-DTPA-enhanced
T1-weighted images
• Different histological pattern
Pathology
Gross Features
• Destructive intraosseous lesion and expansile soft tissue
protrusion with pushing margins.
• Soft, whitish gray to tan, firm, myxoid or gelatinous in
consistency, with lobulated appearance.
• Sometimes hemorrhagic, rarely with necrosis and/or cys-
tic change.
• Most sacrococcygeal chordomas present with an anterior
mass, rarely accompanied with posterior mass.
• Tumors at the skull base may invade the paranasal sinus,
nasal cavities, or nasopharyngeal spaces.
• Very rarely, exact gross relationship between the
extraskeletal soft tissue tumor and the sacrum is
uncertain.
Histological Features
• Lobular arrangement of cellular aggregation separated by
fibrous septa in a low magnification.
• In a tiny specimen obtained by needle biopsy, identifica-
tion of the lobulation can be difficult.
• Ribbons, chords, or reticular epithelial-like arrangement
of tumor cell, with myxoid and slightly bluish stroma, in
the cellular lobules.
• Faintly eosinophilic or clear cytoplasm with frequent
intracytoplasmic bubbly vacuoles, showing “physalipho-
rous” appearances.
536
• Usually blunt nuclear features.
• Immunohistochemically negative for D2-40 and positive
for AE1/AE3, CAM5.2, EMA, brachyury, S100 protein,
and vimentin.
• Chordomas in infants frequently show atypical histologic
feature with relentless clinical course.
• “Atypical” chordoma, as frequently seen in pediatric
patients, histologically shows higher cellularity with
sheet-like arrangement and/or spindle cell proliferation,
nuclear atypia, or pleomorphic nucleus, even demonstrat-
ing sarcomatoid appearances.
• In clival lesion, chondroid appearance can be prominent,
producing the histologic features of “chondroid”
chordoma.
• According to recent studies, differentiation between
“chondroid” chordoma and genuine chondrosarcoma in
the skull base has been controversial.
• Dedifferentiated chordoma shows synchronous or meta-
chronous coexistence of typical chordoma and anaplastic
spindle/pleomorphic cell sarcoma as seen in dedifferenti-
ated chondrosarcoma.
• In contrast to dedifferentiated chondrosarcoma, reported
examples of dedifferentiated chordoma may include post-
radiation sarcomas after radiation therapy for preexistent
chordomas.
Pathologic Differential Diagnosis
Benign Notochordal Tumor/Ecchordosis
Physaliphora Spheno-occipitalis
• Asymptomatic solitary intraosseous lesion, incidentally
found in the base of skull, most common in the clivus, the
sacrococcygeal vertebrae, the cervical vertebrae, and the
lumbar vertebrae, in this order, sparing the thoracic spine.
• Without extraosseous extension.
• Permeating the intertrabecular spaces of the vertebral
body, frequently with entrapped bone marrow islands.
• Intervening bony trabeculae in the lesion are often
sclerotic.
• Without lobulation, fibrous septa, extracellular myxoid
matrix, necrosis, or destructive growth pattern.
• Uniform, sheet-like proliferation of bland-looking tumor
cells with well-defined cell boundary, resembling fatty
marrow at low magnification.
• Centrally or peripherally placed round to oval small
nuclei, containing small nucleoli and fine nuclear
chromatin.
• Clear to faintly eosinophilic cytoplasm with various
degree of vacuolization, mimicking mature adipocytes,
without typical “physaliphorous” cellular features.
• Can have eosinophilic cytoplasm, with eosinophilic hya-
line globules.
• No mitotic figures.
Y. Nakashima
• Juxtaposed to a benign notochordal tumor, foci of a chor-
doma may be found, with sharp transition, suggesting his-
togenetic relationship between these two tumors.
• Immunohistochemically negative for D2-40, positive
for S100 protein, EMA, AE1/AE3, CAM5.2, and
brachyury.
• Ecchordosis physaliphora spheno-occipitalis affects skull
base and shows the same morphological features as seen
in benign notochordal tumor.
Meningioma
• Chordoid meningioma, clear cell meningioma, and even
rhabdoid meningioma can histologically mimic
chordoma.
• Usually accompanied by intradural, extramedullary tumor
attached to the dura.
• In the paraspinal soft tissue, post-vertebral proliferation is
frequent.
• Lobular arrangement separated by fibrous connective tis-
sue septa is unusual.
• Immunohistochemically positive for EMA and negative
for pan-cytokeratin and brachyury.
Myxopapillary Ependymoma
• Intradural tumor in the cauda equina region, arising from
the filum terminale, with rare extradural occurrence
• Without lobulation separated by fibrous septa
• Papillary structure to web-like reticular network of cuboi-
dal or flat to even spindle cells, with myxoid to mucinous
extracellular materials
• Immunohistochemically negative for keratins or
brachyury
Chondrosarcoma
• Without interlobular fibrous septum, even in tumors
showing vague lobulation.
• Can show calcification in the center of chondroid lobule-
like proliferation.
• Immunohistochemically positive for D2-40 and podo-
planin and negative for keratins and brachyury.
• Sox 9 is positive in chondrosarcoma as well as in
chordoma.
• In the skull base lesions, differentiation between chondro-
sarcoma and “chondroid” chordoma is controversial, and
immunostainings for brachyury and keratins may be
mandatory.
Giant Cell Tumor
• Diffuse proliferation of mononuclear neoplastic cells with
eosinophilic cytoplasm and ill-defined cell borders makes
“hand-in-hand” reticular arrangement.
• Large geographic necrosis is frequent.
• Xanthogranulomatous change or fibrous histiocytoma-
like proliferation can be seen.
39 Chordoma
• Multinucleate giant cell is not a histologic feature of
chordoma.
• Sometimes, cystic changes with bloody contents showing
secondary aneurysmal cyst-like change.
Aneurysmal Bone Cyst
• Intraosseous or expansile lesion protruding into soft tis-
sue, without invasion.
• Large cystic spaces containing blood.
• In the cyst wall and septal tissue between cystic spaces,
proliferation of mononuclear cells and spindle cells with
multinucleate giant cells showing granulation-like fea-
tures, frequently accompanied with bone and osteoid
formation.
• In spine, usually affects the posterior components, with
soft tissue protrusion.
• “Solid” variant of aneurysmal bone cyst shows
granulation-like histology with various degrees of ossifi-
cation and osteoid formation.
Extraskeletal Myxoid Chondrosarcoma
(“Chordoid Tumor”)
• Soft tissue sarcoma is usually affecting extra-axial loca-
tion; very unusual intraosseous variant of extraskeletal
myxoid chondrosarcoma, however, has been reported.
• Lobular and multinodular arrangement of epithelial-like
cells with clear to eosinophilic cytoplasm in the myxoid
of mucinous pool, frequently with the so-called “chor-
doid” appearance.
• Without chondrogenic features or calcification.
• Immunohistochemically negative for EMA, cytokeratins,
brachyury, or S-100 protein.
• With characteristic translocation of t(9;22)(q22;q12).
Myoepithelioma/Myoepithelial Carcinoma/
Mixed Tumor/Parachordoma
• May rarely arise in bone.
• Same histologic spectrum as seen in mixed tumor of sali-
vary gland, including ductal structure.
• Lobular pattern in low-power field, with strandular or retic-
ular arrangement of epithelial cells in myxoid background
in each lobule, may, apparently, simulate chordoma.
• Physaliphorous cellular appearance is not typical.
• May show cartilaginous or osseous matrix in the stoma.
• Immunohistochemically positive for EMA, CK8/18,
AE1/3, and S100 protein.
• Gene rearrangement of EWSR1/POU5F1 due to t(6;22)
(p21;q12), and EWSR1/PBX1 due to t(1;22)(q23;q12).
• PLAG1 gene rearrangement in benign myoepithelioma
has also been reported.
Osteosarcoma
• Usually high-grade, spindle cell or pleomorphic cell sar-
coma, with osteoid formation by neoplastic cells.
537
• Without epithelial arrangement with “physaliphorous”
cellular feature in the myxoid stroma.
• Immunohistochemically negative for EMA, keratins, or
brachyury.
• In “dedifferentiated” chordoma, histologic differentiation
of undifferentiated anaplastic sarcoma component of
fibroblastic osteosarcoma may be difficult.
Metastatic Carcinoma
• Diffusely infiltrating proliferation of nests or sheets of
carcinoma cells.
• Largely lobular arrangement separated by fibrous septa is
relatively unusual.
• Glandular arrangement with mucin production can be
seen in carcinoma, while intracytoplasmic mucin is gen-
erally negative in chordoma.
• Physaliphorous features are not typical in carcinomas.
• Immunohistochemically may be positive for EMA and
cytokeratins, but negative for brachyury.
• Specific antigens suggestive of primary site can be
available, including TTF1 (lung, thyroid), napsinA
(lung), PSA (prostate), CDX2 (large intestine),
GCDFP-15 (breast), CD10 (kidney, endometrium),
estrogen and progesterone receptors (breast, endome-
trium), CK5/6 (squamous cell carcinoma in various
organs), MITF and SOX10 (melanoma), various com-
bination of positivity with CK7 and CK20 (various
epithelial tissue), etc.
Ancillary Techniques
• Immunohistochemistry – see histological features and
pathology differential diagnosis, above.
Genetics
• Homo- or heterozygous loss of CDKN2A and CDKN2B
loci in 9p21was reported in 70 % of chordoma.
• IDH1 and IDH2 mutations are negative.
• CDKN2A and CDKN2B loci were homo- or heterozy-
gously lost in 70 % of chordoma.
• Amplification of the transcription factor T (brachyury)
gene locus located 6q27 in less than 10 % of sporadic cases.
• Autosomal dominant inheritance with duplication of
brachyury gene (T gene) in rare familial chordoma.
• TSC1 and TSC2 mutations in chordoma in children with
tuberous sclerosis.
Prognosis
• Slow but infiltrative growth.
• Frequent local recurrence after surgical resection.
• Local recurrence rate of 48 % in 5 years and 67 % in 10 years.
538
• Survival rate of 45–77 % in 5 years and 28–50 % in 10 years.
• Distant metastasis, mainly to the lungs, can occur.
• In children and young adults, relatively high incidence of
atypical chordoma with more aggressive clinical course
has been reported. Some recent studies, however, docu-
mented relatively better prognosis for adolescent patients
with a chordoma in the skull base.
• Very poor prognosis for dedifferentiated chordoma.
Treatment
• Surgery is the mainstay.
• Complete removal is frequently difficult.
a c
Fig. 39.1 Chordoma involving the sacrum of a 62-year-old man.
Anteroposterior radiograph (a) is of limited quality to demonstrate the
lesion. Axial (b) and coronal (c) computed tomographic scans show
lytic destruction of the sacrum with anterior soft tissue extension.
Sagittal (d) and axial (e) T1-weighted magnetic resonance images
Y. Nakashima
• No response to chemotherapy.
• Radiation therapy using proton beam may be indicated
for skull base lesions without surgical amenability.
• Therapeutic implication of epidermal growth factor
receptor (EGFR) antagonists is suggested because of
EGFR abnormality demonstrated in chordoma.
Images
See Figs. 39.1, 39.2, 39.3, 39.4, 39.5, 39.6, 39.7, 39.8, 39.9,
39.10, 39.11, 39.12, 39.13, 39.14, 39.15, 39.16, and 39.17
for illustrations of chordoma.
demonstrate low signal intensity. Axial (f) T2-weighted magnetic reso-
nance image shows slightly high heterogeneous signal intensities.
Sagittal (g) and axial (h) T2-weighted STIR magnetic resonance images
show high signal intensity with soft tissue mass
39 Chordoma 539

e f

g
h

Fig. 39.1 (continued)

540 Y. Nakashima

a b

c d

Fig. 39.2 Destruction of the sacrum is not clearly evident in this chor- magnetic resonance images, axial (g) and coronal (h) T2-weighted
doma in a 69-year-old man. Anteroposterior radiograph (a), axial com- STIR magnetic resonance images, axial (i) and coronal (j) positron
puted tomographic scans (b), sagittal (c) and axial (d) T1-weighted emission tomography-computed tomography, respectively
magnetic resonance images, sagittal (e) and axial (f) T2-weighted
39 Chordoma 541

e f

g h

i j

Fig. 39.2 (continued)

542 Y. Nakashima

a b

Fig. 39.3 Axial view of chordoma involving the thoracic spine, T8/T9, image shows very limited increase of signal intensity (b), and
of a 49-year-old man. Computed tomographic scan shows no significant T2-weighted magnetic resonance images shows high signal intensity
contrast enhancement (a), gadolinium-DTPA-enhanced T1-weighted (c)
39 Chordoma 543

a b

Fig. 39.4 Chordoma involving the skull base in a 70-year-old woman.
Sagittal computed tomographic scan shows lytic destruction of the cli-
vus (a). Sagittal (b) and axial (c) T1-weighted magnetic resonance
images demonstrate low signal intensity, without significantly increased
intensity in gadolinium-DTPA-enhanced T1-weighted sagittal (d),
axial (e), and coronal (f) images. Sagittal (g) and axial (h) T2-weighted
magnetic resonance images show slightly high heterogeneous signal
intensities. Coronal T2-weighted fat saturation magnetic resonance
image (i) and axial T2-weighted FLAIR magnetic resonance image also
demonstrate slightly high heterogeneous signal intensities (j)
544 Y. Nakashima

e f

g h

Fig. 39.4 (continued)

39 Chordoma 545

i j

Fig. 39.4 (continued)

546 Y. Nakashima

a c

Fig. 39.5 Chordoma extending into the paranasal sinuses in a 66-year-old woman. Sagittal (a), axial (b), and coronal (c) computed tomographic
scans show lytic destruction of the clivus with extension and invasion of the tumor into paranasal sinuses
39 Chordoma 547

a b

Fig. 39.6 Axial view of chondroid chordoma involving the skull base intensity in gadolinium-DTPA-enhanced T1-weighted image (b), and
in a 65-year-old woman. T1-weighted magnetic resonance image (a) T2-weighted image shows high signal intensity (c), suggesting chon-
shows low signal intensity, with slightly increased heterogeneous droid quality of the lesion
548 Y. Nakashima

b c

Fig. 39.7 Atypical chordoma involving cervical spine, C2, in a axis with extension to the atlas and soft tissue invasion. Chordoma in
14-year-old boy. Anteroposterior (a) and lateral (b) radiographs suggest pediatric patients can show atypical features, with relatively poor
a destructive lesion in the cervical spine. Sagittal (c), axial (d), and prognosis
coronal (e) computed tomographic scans show lytic destruction of the
39 Chordoma 549

d e

Fig. 39.7 (continued)

550 Y. Nakashima

Fig. 39.9 Lobular arrangement separated by fibrous septa in a low

magnification

b
Fig. 39.10 Ribbons or chords of tumor cells in bluish myxoid stroma

Fig. 39.8 Gross appearance of chordoma. (a) Sacrococcygeal tumor

extensively protrudes into soft tissue, with anterior mass. (b) Pale to
yellowish white in color, with hemorrhagic change

Fig. 39.11 Cellular lobules composed of eosinophilic or clear cyto-

plasm with various degree of vacuolization
39 Chordoma 551

Fig. 39.12 Strands of epithelial-like cells with reticular arrangement Fig. 39.13 Eosinophilic epithelioid sheet of cells with numerous vacuoles

a b

Fig. 39.14 (a) Bubbly cells in myxoid bluish background producing a “physaliphorous cell” appearance. Neoplastic cells in the same area are
positive for keratin (AE1/3) (b) and for brachyury (c) in immunostaining
552 Y. Nakashima

b Fig. 39.16 Atypical chordoma. Monotonous proliferation of round

mononuclear cells with clear to vacuolated cytoplasm

Fig. 39.15 Atypical chordoma in cervical spine of 14-year-old boy.

(a) Lobular pattern of highly cellular aggregation divided by fibrous
tissue. (b) Immunostaining for keratin (CAM5.2) is positive in cellular
lobules
Fig. 39.17 Atypical chordoma showing nuclear atypia with easily dis-
cernible nucleoli
39 Chordoma 553

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DJ. Chordoma and chondroid neoplasms of the spheno-occiput. An
Chordoma and chondrosarcoma: similar, but quite different, skull
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logic implications. Cancer. 1993;72:2943–9.
Bjornsson J, Wold LE, Ebersold MJ, Laws ER. Chordoma of the mobile
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spine. A clinicopathologic analysis of 40 patients. Cancer.
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Bloch OG, Jian BJ, Yang I, et al. A systematic review of intracranial
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Oakley GJ, Fuhrer K, Seethala RR. Brachyury, SOX-9, and podoplanin,
Cho YH, Kim JH, Khang SK, Lee JK, Kim CJ. Chordomas and chondro-
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Cho HY, Lee M, Takei H, Dancer J, Ro JY, Zhai QJ. Immunohistochemical
Presneau N, Shalaby A, Ye H, et al. Role of the transcription factor T
comparison of chordoma with chondrosarcoma, myxopapillary
(brachyury) in the pathogenesis of sporadic chordoma: a genetic
ependymoma, and chordoid meningioma. Appl Immunohistochem
and functional-based study. J Pathol. 2011;223:327–35.
Mol Morphol. 2009;17:131–8.
Ridenour 3rd RV, Ahrens WA, Folpe AL, Miller DV. Clinical and histo-
Coffin CM, Swanson PE, Wick MR, Dehner LP. Chordoma in child-
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variant of chordoma. A morphologic and immunohistochemical
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study. Am J Clin Pathol. 1994;101:36–41.
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Rosenberg AE, Nielsen GP, Keel SB, et al. Chondrosarcoma of the base
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Fuchs B, Dickey ID, Yaszemski MJ, Inwards CY, Sim FH. Operative
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childhood chordoma associated with tuberous sclerosis complex
 Part XI
Leiomyosarcoma
 Leiomyosarcoma of Bone
40
Ricardo K. Kalil

Abstract
Leiomyosarcoma is a rare malignant intraosseous neoplasm, constituted by spindle cells showing
smooth muscle differentiation and devoid of matrix production. More common in long bones of
adults, especially the femur and tibia, craniofacial bones and the spine are other preferred sites. It
is radiologically osteolytic and permeative. It is histologically similar to its soft tissue counterpart,
with long and interwoven bundles of spindle cells with eosinophilic cytoplasm and characteristic
blunt-ended nuclei. It is positive for smooth muscle immunohistochemical markers. Histologic
grade correlates with prognosis. Surgical resection and chemotherapy are indicated.

Definition Age

• A rare malignant intraosseous neoplasm, constituted by • More common in adults

spindle cells showing smooth muscle differentiation and
devoid of matrix production
Sites of Involvement

Etiology • Most cases occur in long bones, especially the distal metaph-
ysis of femur and the proximal metaphysis of the tibia.
• Mostly unknown. • Craniofacial bones and the spine are other reported sites of
• Some cases secondary to radiation therapy or associated occurrence.
to EBV infection were reported.

Clinical Symptoms and Signs

Epidemiology
• Pain is the most frequent first symptom.
Sex • Pathological fracture may occur.

• There is a slight male predominance.

Image Diagnosis

Radiographic Features
R.K. Kalil, MD
Laboratory of Orthopaedic Pathology,
Buenos Aires, Argentina • Radiographs show a purely osteolytic mass centered in
the medullary cavity with ill-defined margins. Cortical
Department of Pathology, A.C. Camargo Cancer Center,
São Paulo, SP, Brazil permeation and periosteal reaction suggestive of an
e-mail: rkkalil@gmail.com aggressive lesion may be seen.

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 557
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_40, © Springer-Verlag London 2015
558 R.K. Kalil

CT and MRI Features Pathology Differential Diagnosis

• CT and MRI disclose an unusual high preference for this
neoplasia to grow in length relative to a much less medio-
lateral expansion.
• MR images of the tumor are iso- or hypointense relative
to the muscle on T1-weighted images, and iso- or hypoin-
tense areas relative to fat on T2-weighted SE images.
Imaging Differential Diagnosis
• Metastasis from primary leiomyosarcoma from other sites
must be ruled out, especially from the uterus and bowel.
Ancillary Techniques
• Immunohistochemical techniques demonstrate positivity
for muscle markers: desmin, h-caldesmon, and smooth
muscle actin.

Lymphoma of Bone Genetics

• May present similar imaging features • Genomic losses and absence of phosphorylated RB, simi-
Other primary and secondary malignancies with lytic but lar to soft tissue leiomyosarcoma
otherwise nonspecific images may be considered in individ-
ual cases.

Prognosis
Pathology
• Histologic grade correlates directly with recurrence and
Gross Features metastatic rates.
• Prognosis may be better than for other primary bone sar-
• The cut surface of the tumor is fleshy and gray pinkish white, comas of the same grade in nonmetastatic patients.
with areas of necrosis, with well or poorly defined margins.

Treatment
Histological Features
• Surgical resection and chemotherapy
• Long and interwoven bundles of spindle cells with eosino-
philic cytoplasm and characteristic blunt-ended nuclei, with
variable pleomorphism, similar to its soft tissue counterpart. Images
• Osteoid is always absent.
• Epithelioid, myxoid, and pleomorphic variants have been See Figs. 40.1, 40.2, 40.3, 40.4, and 40.5 for illustrations of
reported. leiomyosarcoma of the bone.
40 Leiomyosarcoma of Bone 559

a b

Fig. 40.3 High-power microscopic view. Spindle cells with hyperchro-

matic nuclei, sometimes showing blunt ends. Atypical mitoses are frequent

Fig. 40.1 Leiomyosarcoma of the metaphysis and diaphysis of a

femur. Specimen photography and radiography. The lesion involved
metallic implants from a previous surgical procedure. (a) Whitish-pink
firm and elastic lesion occupying the marrow space in a mostly longitu-
dinal fashion, permeating the cortex and involving adjacent soft tissue.
(b) Absence of mineral deposits in tumor tissue

Fig. 40.4 Medium-power microscopic view of a leiomyosarcoma of a

higher grade than the previous figure. Immunohistochemistry may be
needed to properly identify the neoplasia

Fig. 40.2 Low-power microscopic view. Long and interwoven bundles

of spindle cells

Fig. 40.5 Immunohistochemistry – SMA positive in neoplastic cells

560
Recommended Reading
Antonescu CR, Erlandson RA, Huvos AG. Primary leiomyosarcoma of
bone: a clinicopathologic, immunohistochemical, and ultrastruc-
tural study of 33 patients and a literature review. Am J Surg Pathol.
1997;21(11):1281–94.
Berlin O, Angervall L, Kindblom LG, Berlin IC, Stener B. Primary
leiomyosarcoma of bone. A clinical, radiographic, pathologic-
anatomic, and prognostic study of 16 cases. Skelet Radiol. 1987;
16(5):364–76.
Brewer P, Sumathi V, Grimer RJ, Carter SR, Tillman RM, Abudu A,
Jeys L. Primary leiomyosarcoma of bone: analysis of prognosis.
Sarcoma. 2012;2012:636849.
Davies AM, Sundaram M, James SJ. Imaging of bone tumors and tumor-
like lesions. Berlin/Heidelberg: Springer-Verlag; 2009. p. 393–9.
R.K. Kalil
Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F. WHO classi-
fication of tumors of soft tissue and bone. Lyon: IARC; 2013.
p. 302–4.
Jeanrot C, Ouaknine M, Anract P, Carlioz A, Forest M, Tomeno
B. Primary leiomyosarcoma of bone. Report of 5 anatomo-clinical
cases and review of the literature. Rev Chir Orthop Reparatrice
Appar Mot. 2000;86(1):63–73.
Myers JL, Arocho J, Bernreuter W, Dunham W, Mazur
MT. Leiomyosarcoma of bone. A clinicopathologic, immunohisto-
chemical, and ultrastructural study of five cases. Cancer. 1991;67(4):
1051–6.
Unni KK, Inwards C. Dahlin’s bone tumors. 6th ed. Philadelphia:
Lippincott Williams & Wilkins; 2010. p. 179–83.
Young CL, Wold LE, McLeod RA, Sim FH. Primary leiomyosarcoma
of bone. Orthopedics. 1988;11(4):615–8.
 Part XII
Adipocytic Tumors
 Lipoma of Bone
41
Ricardo K. Kalil

Abstract
Lipoma is a rare benign intraosseous neoplasm, constituted by adipose cells that can also
arise on the surface of bone. It corresponds to less than 0.1 % of primary bone neoplasms,
and 15 % of them are surface tumors. Main incidence is in the fifth decade of life. Most
cases occur in the calcaneus and in the metaphysis of long bones. Surface tumors are seen
over the diaphysis of long bones of the extremities. Lipomas are mostly asymptomatic.
Radiographs show a lucent, well-defined intramedullary lesion, CT and MRI showing fea-
tures similar to subcutaneous fat. Mineralized foci may be found inside the tumor. Non-
evolutive tumors do not deserve treatment.

Definition Sex

• A rare benign intraosseous neoplasm, constituted by adi- • There is a slight male predominance (4:3).
pose cells that can also arise on the surface of bone

Sites of Involvement
Etiology
• Most cases occur in the calcaneus and in the metaphysis
• Unknown. of long bones, especially the proximal femur.
• Flat bones are occasionally affected.
• Surface tumors may be seen over the diaphysis of long
Epidemiology tubular bones of the extremities.

• Corresponds to less than 0.1 % of primary bone neo-

plasms, and 15 % of them are surface tumors. Clinical Symptoms and Signs

• Lipomas are mostly asymptomatic but may present local

Age aching pain and/or the presence of a mass.
• Pathological fracture is rare.
• Can be seen at any age, but its main incidence is in the
fifth decade of life.
Image Diagnosis
R.K. Kalil, MD
Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina Radiographic Features
Department of Pathology, A.C. Camargo Cancer Center,
São Paulo, SP, Brazil • Radiographs show a lucent, usually well-defined intramed-
e-mail: rkkalil@gmail.com ullary lesion, with or without some trabeculation and a thin

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 563
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_41, © Springer-Verlag London 2015
564
marginal sclerosis. Expansion of the bone is slight and
infrequent, except in small or thin bones. Parosteal lesions
may produce a solid periosteal reaction. Dense foci of calci-
fication may be seen in a third of the cases and more fre-
quently in the os calcis, where it is, characteristically,
centrally located.
CT and MRI
• The tumor shows features similar to subcutaneous fat and
may demonstrate the presence of intralesional cysts. MRI
presents high intensity signal on T1- and T2-weighted
images and low signal on STIR or fat-suppressed
T2-weighted sequences.
Image Differential Diagnosis
Chondromyxoid Fibroma
• It may expand to soft parts where it shows a thin mineral-
ized shell of reactive bone; MRI shows heterogeneous, pre-
dominantly high intensity signal on T2-weighted images.
Bone Infarct
• Calcifications have different pattern, the so-called “chim-
ney smoke” pattern.
Enchondroma
• Calcifications also have a different, more scattered, pat-
tern. Low to intermediate intensity signal on T1-weighted
images on MRI.
Osteochondroma
• May be difficult to distinguish from parosteal lipoma on
radiographs. CT and MRI will show absence of cortical and
medullary continuity, besides evidence of its fatty nature.
Simple Bone Cyst
• It may mimic lipoma on radiographs, when calcification
is not present.
Osteoporosis
• It may present areas devoid of bone trabeculae that may be
confused with a lipoma, when no clear limits can be devised
Pathology
Gross Features
• The cut surface shows a well-defined, yellow, and soft
lesion, with a marginal sclerosis. It usually measures less
than 5 cm in diameter.
R.K. Kalil
• Parosteal tumors may be large, up to 10 cm in diameter.
• Dense mineralized foci may be found inside the tumor in
older lesions.
Histological Features
• Lipomas consist of lobules of well-differentiated adipo-
cytes that may surround small bone trabeculae.
• Brown fat areas may be seen rarely.
• Fat necrosis and/or cyst formation may occur, along with
foamy macrophages and fibrosis.
• Central areas of amorphous calcification may be present,
more characteristically in the os calcis.
• Ossifying lipomas present a more abundant and diffuse
bony trabeculation.
• Parosteal lipomas consist of white fat with a periosteal
cover. Hyaline cartilage with endochondral ossification or
reactive bone formation may be found at the tumor limit
with the bone cortex.
Pathology Differential Diagnosis
Normal Fat Marrow
• Lipoma presents pushing borders that may be easily over-
looked and only scarce or no bone trabeculae.
Genetics
• The same translocation t(3;12)(q28;q14) and fusion tran-
script HMGA2-LPP seen in soft tissue lipoma has been
identified in parosteal lipoma.
Prognosis
• Excellent.
• It has no metastatic potential.
• Complete excision is curative.
• Curettage or incomplete resection may rarely result in
recurrence.
Treatment
• Marginal resection or curettage is curative.
• Non-evolutive or regressive tumors may not deserve
treatment.
Images
See Figs. 41.1, 41.2, 41.3, 41.4, and 41.5 for illustrations of
lipoma of the bone.
41 Lipoma of Bone 565

Fig. 41.1 (a) Radiograph of a a b

lipoma in the proximal end of the
fibula with some central areas of
calcification. (b) MPR CT of
same case. Coronal view. (c)
MRI T1-weighted image, coronal
view. Lesion signal intensity is
similar to normal adipose bone
marrow. (d) MRI DP fat-
saturated image, coronal view.
Lesion presents the same signal
as normal adipose bone marrow.
(e) Specimen cut surface with
characteristic yellowish color

c d
566 R.K. Kalil

Fig. 41.1 (continued)

a b c

Fig. 41.2 (a–c) Radiograph and CT of a case of multiple lipomas: in a characteristic calcaneal location and in the lower tibia
41 Lipoma of Bone 567

Fig. 41.5 Microphotography of a surface lipoma. Same histology as

classical lipomas of soft parts
Fig. 41.3 Bilateral calcaneal lipomas with central mineral calcifica-
tions, a common finding

a b

Fig. 41.4 (a, b) MRI T1-weighted image and macrophotography of a

parosteal lipoma
568 R.K. Kalil

Recommended Reading Milgram JW. Malignant transformation in bone lipomas. Skelet Radiol.
1990;19:347–52.
Nielsen GP, Rosenberg AE. Diagnostic pathology – bone. Philadelphia:
Bridge JA, DeBoer J, Walker CW, et al. Translocation t(3;12)(q28;q14)
Amirsys; 2013. p. 3.2–3.3.
in parosteal lipoma. Gene Chromosome Cancer. 1995;12:70–2.
Palczewski P, Swiątkowski J, Gołębiowski M, Błasińska-Przerwa
Campbell RSD, Grainger AJ, Mangham DC, et al. Intraosseous lipoma:
K. Intraosseous lipomas: a report of six cases and a review of litera-
report of 35 new cases and a review of the literature. Skelet Radiol.
ture. Pol J Radiol. 2011;76(4):52–9.
2003;32:209–22.
Schajowicz F. Tumors and tumorlike lesions of bone: pathology, radiol-
Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F. WHO clas-
ogy and treatment. 2nd ed. Berlin: Springer-Verlag; 1994.
sification of tumors of soft tissue and bone. Lyon: IARC; 2013.
Unni KK, Inwards C. Dahlin’s bone tumors. 6th ed. Philadelphia:
p. 302–4.
Lippincott Williams & Wilkins; 2010. p. 179–83.
Milgram JW. Intraosseous lipomas. A clinicopathologic study of 66
cases. Clin Orthop. 1988;231:277–302.
 Liposarcoma of Bone
42
Ricardo K. Kalil

Abstract
Liposarcoma is an exceedingly rare malignant intraosseous neoplasm, constituted by
adipose cells, that can also arise on the surface of the bone. The long bones of extremities
are usually affected. The nonspecific image findings of liposarcoma in bone can be seen in
various other benign and malignant bone lesions. Histologically, it is similar to soft tissue
variants of liposarcomas. Immunohistochemically, MDM2/CDK4 is usually positive.
Well-differentiated and myxoid liposarcomas, the two most common types, have a more
favorable prognosis than the other histological types. Treatment includes wide resection or
amputation.

Definition Sex

• An exceedingly rare malignant intraosseous neoplasm, • There is a slight male predominance.

constituted by adipose cells, which can also arise on the
surface of bone.
Sites of Involvement

Etiology • Almost all cases reported are in the long bones, especially
femur and tibia.
• Unknown.
• It may arise from preexisting lipomas.
Clinical Symptoms and Signs

Epidemiology • Pain and the presence of a mass are the usual symptoms.
• Pathological fracture may occur.
• Liposarcoma of bone is an exceedingly rare tumor.

Image Diagnosis
Age
• Radiographs show a lucent mass that may or may not pres-
• It can be seen at any age but is more common in adults. ent well-defined margins, including cortical permeation.
• CT and MRI of the tumor show features characteristic of
fat tissue.
R.K. Kalil, MD
Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina
Department of Pathology, A.C. Camargo Cancer Center,
São Paulo, SP, Brazil
e-mail: rkkalil@gmail.com

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 569
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_42, © Springer-Verlag London 2015
570
Image Differential Diagnosis
• The nonspecific image findings of liposarcoma in bone
can be seen in various other benign and malignant bone
lesions.
Pathology
Gross Features
• The cut surface shows a lobulated, yellow to white, and
soft or firm lesion, with well- or poorly defined margins.
It is usually a large lesion.
• Some lesions may present myxoid, mucinous features.
Histological Features
• Similar to soft tissue variants of liposarcomas:
– Atypical lipomatous tumor/well-differentiated
liposarcoma.
Neoplastic tissue is very similar to normal fat.
Atypical nuclei may be seen mostly in or near the spin-
dle cell septae that traverse the neoplasia. A few lipo-
blasts are also seen.
– Dedifferentiated liposarcoma
Abrupt transition from low-grade lipogenic area to
high-grade non-lipogenic morphology within a well-
differentiated liposarcoma is seen. May have heterolo-
gous elements.
– Myxoid liposarcoma
It may be constituted by two neoplastic tissue pat-
terns, a richly arborizing vascularized myxoid pattern
and a round cell pattern. Patterns may be seen alone or
in variable mixture in a particular tumor.
– Pleomorphic liposarcoma
Highly anaplastic fat cells characterize this variant.
Pathology Differential Diagnosis
Lipoma
• It may be difficult to differentiate from well-differentiated
liposarcoma in a limited sample.
R.K. Kalil
Ancillary Techniques
• MDM2/CDK4 are usually positive together or individually
in liposarcomas. Pleomorphic liposarcomas differ from the
dedifferentiated variant by expressing only one marker.
Genetics
• Supranumerary ring or long marker chromosomes in
well-differentiated liposarcomas.
• Translocation t(12;16) is common in myxoid/round
liposarcoma. Fusion of DDIT3 (CHOP) and FUS (TLS)
genes. Translocation t(21;22) rarely.
• Amplification of 12q14.2–21.2 includes the HMGA2 and
MDM2 gene regions.
• Various aberrations of 12q13–15 were described in
lipomas.
• Pleomorphic liposarcomas present complex karyotypes.
• Amplification of 1q21.2–31.2 was described in a paros-
teal liposarcoma.
• Abnormalities in the AKT genes were found to correlate
with clinicopathological profile of tumors.
Prognosis
• Well-differentiated and myxoid liposarcoma, the two
most common types, have a more favorable prognosis
than the other histological types.
Treatment
• Wide resection or amputation
Images
See Figs. 42.1, 42.2, 42.3, 42.4, 42.5, 42.6, and 42.7 for
illustrations of liposarcoma of bone.
42 Liposarcoma of Bone 571

a b

Fig. 42.3 Low-power microscopic view of well-differentiated

liposarcoma

Fig. 42.1 (a, b) Radiographs of a liposarcoma of the femur.

Uncharacteristic lucent mass in the medullary compartment with some
endosteal scalloping and undefined limits

Fig. 42.4 Medium-power microscopic view of well-differentiated

liposarcoma. Atypical cells are more easily found in the spindle cells
septae of the lesion

Fig. 42.2 CT scan of surface liposarcoma of the proximal femur. Well-

circumscribed lucent lesion distorting the host bone external shape
572 R.K. Kalil

Fig. 42.5 High-power microscopic view of well-differentiated lipo- Fig. 42.7 Medium-power microscopic view of pleomorphic
sarcoma. There may be only a few atypical cell nuclei. Multivacuolated liposarcoma
adipocytes and lipoblasts are also seen

Fig. 42.6 High-power microscopic view of well-differentiated lipo-

sarcoma. Multiple atypical nuclei in adipocyte
42 Liposarcoma of Bone 573

Recommended Reading Milgram JW. Malignant transformation in bone lipomas. Skelet Radiol.
1990;19(5):347–52.
Murphey MD, Arcara LK, Fanburg-Smith J. From the archives of the
Dei Tos AP, Doglioni C, Piccinin S, Sciot R, Furlanetto A, Boiocchi M,
AFIP: imaging of musculoskeletal liposarcoma with radiologic-
Dal Cin P, Maestro R, Fletcher CD, Tallini G. Coordinated expres-
pathologic correlation. Radiographics. 2005;25(5):1371–95.
sion and amplification of the MDM2, CDK4, and HMGI-C genes in
Nielsen GP, Rosenberg AE. Diagnostic pathology – bone. Philadelphia:
atypical lipomatous tumours. J Pathol. 2000;190(5):531–6.
Amirsys; 2013. p. 3.2–3.3.
Dobashi Y, Sato E, Oda Y, Inazawa J, Ooi A. Significance of Akt
Schwartz A, Shuster M, Becker SM, Amboy P. Liposarcoma of bone.
activation and AKT gene increases in soft tissue tumors. Hum
Report of a case and review of the literature. J Bone Joint Surg Am.
Pathol. 2014;45(1):127–36.
1970;52(1):171–7.
Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F. WHO
Torigoe T, Matsumoto T, Terakado A, Takase M, Yamasaki S,
classification of tumors of soft tissue and bone. Lyon: IARC; 2013.
Kurosawa H. Primary pleomorphic liposarcoma of bone: MRI
p. 302–4.
findings and review of the literature. Skelet Radiol. 2006;35(7):
Kenan S, Klein M, Lewis MM. Juxtacortical liposarcoma. A case report
536–8.
and review of the literature. Clin Orthop Relat Res. 1989;243:
Torok G, Meller Y, Maor E. Primary liposarcoma of bone. Case report
225–9.
and review of the literature. Bull Hosp Jt Dis Orthop Inst. 1983;
Mariño-Enríquez A, Hornick JL, Dal Cin P, Cibas ES, Qian X.
43(1):28–37.
Dedifferentiated liposarcoma and pleomorphic liposarcoma: a com-
Unni KK, Inwards C. Dahlin’s bone tumors. 6th ed. Philadelphia:
parative study of cytomorphology and MDM2/CDK4 expression on
Lippincott Williams & Wilkins; 2010. p. 179–83.
fine-needle aspiration. Cancer Cytopathol. 2014;122(2):128–37.
 Part XIII
Neurogenic Tumors
 Schwannoma of Bone
43
Ricardo K. Kalil

Abstract
Schwannoma is a rare benign intraosseous neoplasm, originating in Schwann cells of the
nerve fibers and usually originates in sensitive nerves. It corresponds to less than 1 % of
primary benign bone neoplasms. Most cases occur in the mandible; the sacrum is also a
preferred site. Schwannomas are, generally, asymptomatic. Radiographs show a lucent,
usually well-defined intramedullary lesion. The tumor is very well delimited, composed by
spindle cells with wavy nuclei, with focal palisading arrangement. Immunohistochemistry
shows positivity for S100 protein. Once relationship to neurofibromatosis is excluded,
prognosis is excellent. Marginal resection or curettage is curative.

Definition Epidemiology

• A rare benign intraosseous neoplasm, originating in • Corresponds to less than 1 % of primary benign bone
Schwann cells of the nerve fibers. neoplasms

Synonyms Age

• Neurilemmoma • Excepting the first decade, all other age groups may be
• Neurinoma evenly affected.
• Conventional schwannoma
• Sporadic schwannoma
Sex

Etiology • There is no sex preference.

• Unknown
• Usually originates in sensitive nerves Sites of Involvement
• May be associated to Carney complex or neurofibromatosis
• Most cases occur in the mandible; the sacrum is also a
preferred site.
R.K. Kalil, MD
Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina • Other sites where this tumor was reported include the
long bones, vertebra, rib, fibula, and flat bones.
Department of Pathology, A.C. Camargo Cancer Center,
São Paulo, SP, Brazil
e-mail: rkkalil@gmail.com

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 577
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_43, © Springer-Verlag London 2015
578
Clinical Symptoms and Signs
• Schwannomas are, generally, asymptomatic, but exces-
sive growth may cause local aching pain and/or the pres-
ence of a mass.
Image Diagnosis
• Radiographs show a lucent, usually well-defined intra-
medullary lesion, with or without some trabeculation and
a thin marginal sclerosis. Expansion of the bone is slight
and infrequent, except in small or thin bones.
Image Differential Diagnosis
• Given its rarity, schwannoma is not usually included in
the differential diagnosis of bone lesions.
• Relationship to known nerve tracts may suggest the
diagnosis.
Pathology
Gross Features
• The tumor is solid, lobular, and well circumscribed, and
its cut surface is yellowish-white, smooth and solid and
frequently with myxoid appearing areas and sometimes
with small cystic cavities.
Histological Features
• The tumor is very well delimited, composed by spindle
cells with wavy nuclei that when presenting a palisading
arrangement – Verocay bodies – the diagnosis is suggested.
Verocay bodies may not be so well formed in bone schwan-
nomas as in soft tissue lesions. Low (Antoni B) and/or high
density areas (Antoni A) may be seen. At least some blood
vessels will present with thick hyaline walls.
R.K. Kalil
Pathology Differential Diagnosis
Neurofibromatosis
• Must be clinically and radiographically excluded
Malignancy
• May be suggested by bizarre nuclei, common in
degenerative or “old” schwannomas, but mitoses are not
seen and the tumor present clear limits.
Ancillary Techniques
• Immunohistochemistry shows nuclear and cytoplasmic
positivity for S100 protein.
Genetics
• Soft tissue schwannomas commonly present partial or
complete loss of chromosome 22, a feature not yet
reported in bone lesions.
Prognosis
• Once relationship to neurofibromatosis is excluded, prog-
nosis is excellent.
• It has no metastatic potential.
Treatment
• Marginal resection or curettage is curative.
Images
See Figs. 43.1, 43.2, 43.3, 43.4, 43.5, and 43.6 for
illustrations of schwannoma of bone.
43 Schwannoma of Bone 579

Fig. 43.1 Schwannoma of mandible. Panoramic radiograph showing a

large lytic lesion at left

a b

Fig. 43.2 Periosteal schwannoma of femur. (a) Radiograph shows a translucent external indentation in the cortical metaphysis at left. (b) CT scan
shows a lucent periosteal nodule producing a well-delimited depression in the subjacent cortex
580 R.K. Kalil

Fig. 43.3 Medium-power microscopic view of a schwannoma with Fig. 43.5 Medium-power microscopic view. Dense proliferation of
more crowded spindle cell areas (Antoni A) and a looser central area spindle cells with long and wavy nuclei. Blood vessel with thick hyaline
(Antoni B) wall is also seen

Fig. 43.4 Medium-power microscopic view. Suggestive palisading of Fig. 43.6 Higher-power microscopic view a schwannoma with degen-
the nuclei of the spindle cells, at left, and large congestive blood vessels erative changes. Cells contain large, somewhat pleomorphic nuclei,
with thick hyaline walls with vacuolization and occasional hyperchromasia
43 Schwannoma of Bone
Recommended Reading
de la Monte SM, Dorfman HD, Chandra R, Malawer M. Intraosseous
schwannoma: histologic features, ultrastructure, and review of the
literature. Hum Pathol. 1984;15(6):551–8.
Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F. WHO
classification of tumors of soft tissue and bone. Lyon: IARC; 2013.
p. 170–2.
581
Ida CM, Scheithauer BW, Yapicier O, Carney JA, Wenger DE,
Inwards CY, Bertoni F, Spinner RJ, Unni KK. Primary schwannoma
of the bone: a clinicopathologic and radiologic study of 17 cases.
Am J Surg Pathol. 2011;35(7):989–97.
Tian YW, Zhang LY, Liu ZQ. Giant intraosseous schwannoma of
scapula: a rare case report and review of the literature. Diagn
Pathol. 2014;9:31. doi:10.1186/1746-1596-9-31.
Unni KK, Inwards C. Dahlin’s bone tumors. 6th ed. Philadelphia:
Lippincott Williams & Wilkins; 2010. p. 295–7.
 Neurofibroma of Bone
44
Ricardo K. Kalil

Abstract
Neurofibroma (NF) is a benign neoplasm originated in nerve fascicles and containing
Schwann cells, fibroblasts, mast cells, axons, and variable collagen matrix, exceedingly rare
in the bone. NF originates in peripheral nerves at the periosteum, cortex, or vascular mar-
row. Most cases occur in the head and neck, especially the maxilla. Radiologically, neuro-
fibroma is a radiolucent well-circumscribed lesion. Relationship to known nerve tracts may
suggest the diagnosis. The tumor is not well circumscribed, and its short spindle cells have
long wavy nuclei, with partial positivity for S100. Allelic loss of the NF1 gene region of
17q in Schwann cells is found. Wide resection is recommended to avoid recurrence.

Definition Sites of Involvement

• A benign neoplasm originated in nerve fascicles and • Most cases occur in the head and neck, especially the
containing Schwann cells, fibroblasts, mast cells, axons, maxilla; tibia, femur, vertebra, clavicle, and skull cases
and variable collagen matrix, exceedingly rare in the bone. were also reported.

Etiology Clinical Symptoms and Signs

• Inactivation of the NF1 gene. • Local aching pain and/or the presence of a mass
• NF originates in peripheral nerves at the periosteum, cor-
tex, or vascular marrow. In the maxilla, they probably
originate in inferior alveolar nerve. Image Diagnosis

• Radiologically, neurofibroma is a radiolucent well-

Epidemiology circumscribed lesion.
• Relationship to known nerve tracts may suggest the diag-
• Exceedingly rare. A 2010 review disclosed 40 cases of nosis of a neural lesion.
possible sporadic cases of neurofibroma originating in
bone, excluding cases where neurofibromatosis had been
diagnosed. Image Differential Diagnosis

R.K. Kalil, MD • Given its rarity, solitary neurofibroma is not usually

Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina included in the differential diagnosis of bone lesions.
Department of Pathology, A.C. Camargo Cancer Center,
São Paulo, SP, Brazil
e-mail: rkkalil@gmail.com

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 583
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_44, © Springer-Verlag London 2015
584 R.K. Kalil

Pathology • Malignant tumors have hypercellular areas where nuclei

are uniformly hyperchromatic and at least three times the
Gross Features size of nuclei of benign neurofibroma.

• The tumor is solid, non-encapsulated. Its cut surface may

be fasciculated and is usually firm, uniformly Ancillary Techniques
gray-pinkish-white.
• Immunohistochemistry shows partial nuclear and cyto-
plasmic positivity for S100 protein.
Histological Features
Genetics
• The tumor is not well circumscribed and is composed by • Allelic loss of the NF1 gene region of 17q in Schwann
short spindle cells with oval or long and wavy nuclei cells
included in a collagenic or myxoid matrix. Collagen
fibers may be abundant and thick.
Prognosis

Pathology Differential Diagnosis • Recurrence may occur.

• Progression of solitary neurofibroma to MPNST may
Neurofibromatosis must be clinically and radiographically occur but much less frequently than the 5–10 % rate seen
excluded. in NF1 patients.

Schwannoma
• It also arises from a nerve but is usually very well delim- Treatment
ited, whereas neurofibroma involves the nerve and usually
do not have clear limits. • Wide resection is recommended to avoid recurrence.
• The histological identification of Verocay bodies – nuclear
palisading – is characteristic of schwannoma that also con-
tains hyalinized vessel walls and scarce or no collagen. Images

Malignant Peripheral Nerve Sheath Tumor See Figs. 44.1 and 44.2 for illustrations of neurofibroma of
(MPNST) the bone.
• Atypical neurofibroma with hyperchromatic, pleomor-
phic smudgy nuclei and some mitotic activity may sug-
gest malignancy.
44 Neurofibroma of Bone 585

Fig. 44.2 Medium-power microscopic view of neurofibroma. Slender

Fig. 44.1 CT scan image. Needle biopsy of neurofibroma. Lytic, short spindle cells with long and wavy nuclei included in a collagenic
expanding, well-delimited mass in the sacrum matrix
586 R.K. Kalil

Recommended Reading Pontes HA, Pontes FS, Cruz e Silva BT, Fonseca FP, Carneiro Jr JT,
Paiva HB, Pinto Ddos Jr S. Solitary neurofibroma of the temporal
bone. J Craniofac Surg. 2010;21(6):1984–7. doi:10.1097/
Fawcett KJ, Dahlin DC. Neurilemmoma of bone. Am J Clin Pathol.
SCS.0b013e3181f503be. PubMed PMID: 21119477.
1967;47(6):759–66.
Unni KK, Inwards C. Dahlin’s bone tumors. 6th ed. Philadelphia:
Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F. WHO clas-
Lippincott Williams & Wilkins; 2010. p. 295.
sification of tumors of soft tissue and bone. Lyon: IARC; 2013.
Yamaguchi R, Yoshida T, Nakazato Y, Yoshimoto Y. Solitary
p. 174–6.
intraosseous neurofibroma of the frontal bone. Case report.
Huang GS, Lee CH, Lee HS, Chang WC, Juan CJ, Chen CY. Solitary
Neurol Med Chir (Tokyo). 2010;50(8):683–6. PubMed PMID:
intraosseous neurofibroma of the tibia. Skelet Radiol.
20805655.
2005;34(5):303–6. Epub 2004 Nov 13, PubMed PMID: 15838705.
 Part XIV
Phosphaturic Mesenchymal Tumor
 Phosphaturic Mesenchymal Tumor
45
Ricardo K. Kalil

Abstract
Phosphaturic mesenchymal tumor is a neoplasm that produces a phosphaturic substance,
fibroblast growth factor-23 (FGF23), causing systemic phosphate depletion and leading to
oncogenic osteomalacia. Sites of occurrence are the soft tissue and bone, almost half of the
cases in the lower extremities. A long history of osteomalacia, bone pain, and fractures is
usually present. Renal phosphate wasting and elevated serum levels of FGF23 are found.
Radiologically, the tumor may present a varied appearance. Histologically, three variants are
seen: osteoblastoma-like, non-ossifying fibroma-like, and mixed connective tissue variant
(PMTMCT), the commonest. This is characterized by a hemangiopericytoma-like tissue pat-
tern and areas of matrix with peculiar calcifications. FGF23 may be identified within PMT
cells by RT-PCR and immunohistochemistry. Osteomalacia may be cured once the tumor is
discovered and resected. Exceptional cases of malignant PMTs may behave aggressively.

Definition tion from the proximal tubules and intestine. It is also an

• Phosphaturic mesenchymal tumor (PMT) is a neoplasm
that produces a phosphaturic substance causing systemic
phosphate depletion that usually leads to a tumor-induced
osteomalacia, oncogenic osteomalacia (OO).
• Oncogenic osteomalacia (OO) is a special and rare metabolic
bone disorder that is caused by the presence of this neoplasm.
Etiology
• Etiology of the tumor is unknown.
• PMTs secrete a circulating phosphaturic factor, a “phos-
phatonin,” identified as fibroblast growth factor-23
(FGF23).
• This growth factor exerts its effect as regulator of phos-
phate metabolism through inhibition of phosphate resorp-
R.K. Kalil, MD
Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina
Department of Pathology, A.C. Camargo Cancer Center,
São Paulo, SP, Brazil
e-mail: rkkalil@gmail.com
antagonist to vitamin D, explaining the resistance to vita-
min D in these patients.
• PHEX, DMP1, and FGF23, substances recently found to
be produced by osteocytes, appear to coordinate mineral-
ization and systemic phosphate homeostasis through its
action in the bone–kidney phosphoregulatory axis, with
an impact on multiple tissues, including regulation of kid-
ney function in terms of phosphate uptake. Normal
homeostasis is maintained by a kind of feedback mecha-
nism between these “hormones.” Thus, FGF23 may be
degraded by PHEX, a membrane-bound endopeptidase,
to maintain it at normal levels. PHEX is mutated in
X-linked hypophosphatemic rickets; and it has been sug-
gested that OO-associated mesenchymal tumors may pro-
duce enough FGF23 to overwhelm native PHEX levels.
Epidemiology
• PMT is a very rare tumor.
• Reported patients were as young as 3 years and as old as
73 years, but most were middle-aged adults.
• It does not appear to have sex predilection.

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 589
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_45, © Springer-Verlag London 2015
590
Sites of Involvement
• Soft tissue and bone, almost half of the cases in the lower
extremities.
• In bone, localizations in femur, sacrum, phalanx, meta-
carpal, ilium, vertebra, mandible, tibia, humerus, acetabu-
lum, and skull were described.
• A few of them occur in the craniofacial sinuses and the spine.
• The thoracic wall is also a site of occurrence.
• Exceptionally rare instances of multiple tumors have been
reported.
• Oncogenic osteomalacia can very rarely be seen as a para-
neoplastic manifestation associated to other tumors, like
prostate cancer and skin nevi.
Clinical Symptoms and Signs
• A long history of osteomalacia is usually present.
• Bone pain and fractures are characteristically frequent.
• Fractures may be so numerous as to induce body, espe-
cially thoracic, deformities that may lead to serious respi-
ratory difficulties.
• Generalized muscle weakness.
• Renal phosphate wasting.
• Hypophosphatemia.
• Normal or slightly decreased calcemia.
• Variably elevated serum alkaline phosphatase.
• Decreased serum 1,25-dihydroxyvitamin D3 levels.
• Elevated parathormone concentrations in half of the patients.
• Elevated serum levels of FGF23.
• Resistance to vitamin D supplementation.
• Tumors can be found before or long after osteomalacia
symptoms appear.
Image Diagnosis
Radiographic Features
• Osteopenia – A long history of osteomalacia is usually
present, and although a tumor may be suspected and
searched for from the beginning, it may be hard to locate,
or it may only be disclosed many years later, even with
modern image methods.
• Widespread cortical lucent areas.
• The tumor itself may present a varied appearance, mainly
lytic, with or without areas of mineral deposits.
• Rare malignant examples of PMT are lytic, with blurred
borders and cortical destruction.
• When in the soft tissue, the tumor may be initially unde-
tectable by radiographs. Later on, it may present areas of
mineral deposits, sometimes peripherally, in a roughly
“myositis ossificans fashion.”
R.K. Kalil
MRI Features
• MRI shows a lesion with high signal on T1-weighted
images, owed mainly to its high vascularization.
Bone Scan
• Bone scan shows increased uptake corresponding to the
lucent areas.
Image Differential Diagnosis
Osteomalacia/Rickets-Related DD
• A neuromyopathy or a genetic disease may be the first
clinical diagnostic hypothesis in the case that no tumor is
initially found.
• Uncommon inborn errors of metabolism such as autosomal
dominant hypophosphatemic rickets and X-linked hypo-
phosphatemic rickets. See ancillary techniques, below.
• Osteomalacia due to other uncommon processes such as
chronic renal disease primary hyperparathyroidism and
chemotherapy side effects.
Tumor-Related DD
• A variety of primary benign and malignant bone tumors
can be considered.
• Myositis ossificans, in soft parts.
Pathology
Gross Features
• Nonspecific soft tissue mass, heterogeneous appearance
• Brown to white to yellowish color
• May have mineralized areas, sometimes surrounding a
cystic area, resembling the zonation phenomenon of myo-
sitis ossificans when in soft tissue
Histological Features
• Depending on the kind of predominant tissue in the sam-
ples, it can present histological variants like:
– Osteoblastoma-like variant
– Non-ossifying fibroma-like variant
– Mixed connective tissue variant (PMTMCT), the
commonest
• Histological diagnosis of PMTMCT is based in these
main features:
– Characteristic matrix with peculiar calcifications – an
unusual “smudgy” matrix that calcifies in a character-
45 Phosphaturic Mesenchymal Tumor
istic flocculent fashion and sometimes may resemble
primitive cartilage or chondroid.
– This peculiar matrix appears to be produced by a
highly vascular proliferation of bland, spindled to stel-
late cells, the probable neoplastic cells.
– Hemangiopericytoma-like pattern – the vasculature of
PMTMCT may be prominent and may present numer-
ous arborizing capillaries in a high proliferation of
bland, spindled to stellate cells.
– Areas of fibrohistiocytic reaction may also be seen.
– Areas of aneurysmal bone cyst-like changes may be
present.
– There may be a peripheral zone of metaplastic bone
with central cystic areas, resembling the zonation phe-
nomenon of myositis ossificans, in paracortical soft
tissue tumors.
– Osteoclasts may be seen near these calcified areas.
– A rare chondromyxoid fibroma-like variant has been
described.
• The rare malignant tumors usually present with histologi-
cal high-grade sarcoma features.
Pathology Differential Diagnosis
Lesions with hemangiopericytoma-like tissue pattern, giant
cell tumor of bone and soft tissue, chondroma of soft parts,
and myositis ossificans
• All can, in a biopsy sample, present a differential diagnos-
tic problem, but they lack the distinctive elements that
characterize PMTMCT.
Primary Malignant Bone Sarcomas
• Malignant cases can elicit a difficult differential diagnosis
with mesenchymal chondrosarcoma because of the HPC-
like spindle cell areas and chondroid-like matrix, as well
as with osteosarcoma and conventional chondrosarcoma
because of the osteoid-like and/or chondroid-like areas.
Attention to the ensemble of characteristic histologic ele-
ments can allow the distinction.
Ancillary Techniques
• FGF23 may be identified within PMT cells by both RT-
PCR of the tumor tissue and immunohistochemistry, fur-
ther confirming its role in tumor-induced osteomalacia.
However, FGF23 expression is not pathognomonic of
PMT, as it has also been demonstrated in a few examples
of other bone tumors, e.g., aneurysmal bone cyst and
fibromyxoid chondroma.
• Serum levels of FGF23 may be measured and present
very high levels.
591
• If no tumor is found, the demonstration of a FGF23 muta-
tion by DNA sequencing from peripheral blood lympho-
cytes provides a definitive diagnosis of hypophosphatemic
rickets and excludes PMT.
• Transmission electron microscopy features found in the
few cases studied include: a well-developed RER, altered
mitochondria, and electrondense membrane-bound
neurosecretory-like granules. An intercellular mucoid or
myxoid matrix is also described.
Genetics
• Abnormal and different karyotypes were obtained from
phosphaturic mesenchymal tumor of mixed connective
tissue type in two cases.
Prognosis
• OO may be cured once the tumor is discovered and
resected.
• Until the tumor is found, the patient may have suffered
many fractures as well as severe permanent deformities
caused by weakened bones, or even death.
• Although deformities remain, fractures heal, and the bone
consistency gets back to normal.
• Serum levels of FGF23 and phosphate and urinary
phosphate get back to normal levels after the tumor
resection and serve to monitor the completeness of the
resection of the tumor as well as to the early detection
of recurrences.
• Exceptional cases of malignant PMTs may behave aggres-
sively and recur after resection, metastasize, and lead to
death. Most of them, however, are benign.
Treatment
• Surgical excision is the treatment of choice.
• Until a tumor is found, patients have been treated with
phosphate salts and vitamin D.
• There are no data related to treatment of malignant PMT,
except sound oncologic surgery.
Images
See Figs. 45.1, 45.2, 45.3, 45.4, 45.5, 45.6, 45.7, 45.8, 45.9,
45.10, 45.11, 45.12, 45.13, 45.14, 45.15, 45.16, 45.17, 45.18,
45.19, and 45.20 for illustrations of phosphaturic mesenchy-
mal tumor.
592 R.K. Kalil

Fig. 45.2 MRI axial view of same case in Fig. 45.1

Fig. 45.1 Benign PMT. MRI showing a high signal intensity juxtacor-
tical heterogeneous mass in the left femur in a coronal view

Fig. 45.3 Benign PMT. CT shows an ovoid lesion attached to the

internal wall of the rib cage. There is no mineralized area
45 Phosphaturic Mesenchymal Tumor 593

a b

Fig. 45.4 Same case as in Fig. 45.1. Radiographs show diffuse, intense osteopenia, a deformed pelvis, and insufficiency fractures of both femurs
(a) and intense deformities of the spine and the rib cage (b). Bone consistency got back to normal, and fractures healed after removal of tumor

Fig. 45.6 Another slab section of the same case as in Fig. 45.2. White,
fish-flesh-like areas denounce cellular areas of lesion. Hemorrhagic and
b tan soft areas are also seen

Fig. 45.5 Same case as in Fig. 45.1. The specimen contained cysts
surrounded by tan soft tissue with white areas of ossification (a). (b) A
whole specimen histological mount; cellular areas are seen around the Fig. 45.7 PMTMCT – peripheral ossification is seen between a fibrous
cysts with peripheral ossification capsule and cellular area of the tumor
594 R.K. Kalil

Fig. 45.8 PMTMCT – richly vascularized tumor tissue, Fig. 45.11 PMTMCT – low-power view of area with peculiar calcifi-
hemangiopericytoma-like pattern cations, an unusual “smudgy” matrix that calcifies in a characteristic
flocculent fashion

Fig. 45.9 PMTMCT – numerous capillaries in a high proliferation of

bland, spindled to stellate cells Fig. 45.12 PMTMCT – higher-power view of focus of flocculent
calcifications

Fig. 45.10 PMTMCT – area with background resembling chondroid

matrix Fig. 45.13 PMTMCT – another area with so-called “smudgy” matrix
45 Phosphaturic Mesenchymal Tumor 595

Fig. 45.14 PMTMCT – tumor cells present strong immunohistochem-

ical affinity for FGF23

Fig. 45.16 Same case as in the previous figure. MRI showing focus of
recurrence 3 years after initial treatment. Osteopenia and related symp-
toms, that have disappeared after the first excision, also returned

Fig. 45.17 Same case as in the previous figure. Thorax CT shows

Fig. 45.15 Malignant PMT. Radiograph showing a lytic epiphyso- metastatic nodules
metaphyseal lesion in the distal end of a femur. Permeative undefined
borders. There is cortical permeation and involvement of soft tissue
596 R.K. Kalil

Fig. 45.18 Malignant PMT – recurrent tumor. Histological section Fig. 45.20 Malignant PMT – original tumor showed bland, although
with high cellular proliferation of somewhat spindled cells, moderate cellular histomorphology, and numerous multinucleated giant cells
cellular atypia. Mitoses were infrequent

Fig. 45.19 Malignant PMT – histological section of chondroid-like

area and matrix calcification. Same case as in the previous figure
45 Phosphaturic Mesenchymal Tumor
Recommended Reading
Bahrami A, Weiss SW, Montgomery WE, Horvai AE, Jin YL, Inwards
CY, Folpe AL. RT-PCR analysis for FGF23 using paraffin sections
in the diagnosis of phosphaturic mesenchymal tumors with and
without known tumor induced osteomalacia. Am J Surg Pathol.
2009;33:1348–54.
Folpe AL, Fanburg-Smith JC, Billings SD, Bisceglia M, Bertoni F, Cho
JY, Econs MJ, Inwards CW, De Beur SMJ, Mentzel T, Montgomery
E, Michal M, Miettinen M, Mills SE, Reith JD, O’Connell JX,
Rosenberg AE, Rubin BP, Sweet DE, Vinh TN, Wold LE, Wehrli
BM, White KE, Zaino RJ, Weiss SW. Most osteomalacia-associated
mesenchymal tumors are a single histopathologic entity. An analy-
sis of 32 cases and a comprehensive review of the literature. Am J
Surg Pathol. 2004;28(1):1–30.
Graham R, Krishnamurthy S, Oliveira A, Inwards C, Folpe AL. Frequent
expression of fibroblast growth factor-23 (FGF23) mRNA in aneu-
rysmal bone cysts and chondromyxoid fibromas. J Clin Pathol.
2012a;65(10):907–9.
Graham RP, Hodge JC, Folpe AL, Oliveira AM, Meyer KJ, Jenkins RB,
Sim FH, Sukov WR. A cytogenetic analysis of 2 cases of phospha-
597
turic mesenchymal tumor of mixed connective tissue type. Hum
Pathol. 2012b;43(8):1334–8.
Jiang Y, Xia WB, Xing XP, Silva BC, Li M, Wang O, Zhang HB, Li F,
Jing HL, Zhong DR, Jin J, Gao P, Zhou L, Qi F, Yu W, Bilezikian JP,
Meng XW. Tumor-induced osteomalacia: an important cause of
adult-onset hypophosphatemic osteomalacia in China: report of 39
cases and review of the literature. J Bone Miner Res.
2012;27(9):1967–75.
Noble BS. The osteocyte lineage. Arch Biochem Biophys.
2008;473(2):106–11.
Park YK, Unni KK, Beabout JW, et al. Oncogenic osteomalacia: a clini-
copathologic. Study of 17 bone lesions. J Korean Med Sci.
1994;9:289–98.
Peterson NR, Summerlin DJ, Cordes SR. Multiple phosphaturic mesen-
chymal tumors associated with oncogenic osteomalacia: case report
and review of the literature. Ear Nose Throat J. 2010;89(6):E11–5.
Sundaram M, McCarthy EF. Oncogenic osteomalacia. Skelet Radiol.
2000;29(3):117–24.
Weidner N. Review and update: oncogenic osteomalacia-rickets. Ultrast
Pathol. 1991;15:317–33.
Weidner N, Santa CD. Phosphaturic mesenchymal tumors – a polymorphous
group causing osteomalacia or rickets. Cancer. 1987;59:1442–54.
 Part XV
Metastatic Carcinoma Involving Bone
 Metastatic Bone Carcinoma
46
Patrizia Bacchini and Franco Bertoni

Abstract
A growth of malignant cells in the bone originating from a primary tumor elsewhere. The
lung, the liver, and the skeleton are the most involved sites of a metastatic process. It is
found most frequently in the older population. Rare in the pediatric age. The bones most
frequently involved by metastatic tumors are the skull, spine, rib, pelvis, humerus, and
femur (there is a known predilection for areas containing red marrow). Single or multiple
lesions can be found. These include sclerotic or lytic or the presence of both types (sclerotic
and lytic). Radiologically single or multiple lesions can be found. These include sclerotic or
lytic or the presence of both types (sclerotic and lytic). Most common primary carcinomas
that metastasize in bone are: breast, prostate, lung, kidney, and gastrointestinal carcinomas.
Ancillary technique, especially immunohistochemistry, is useful to diagnose the primary
lesion. The combination of surgical procedures and radiation and/or other therapies can be
of value when managing metastatic carcinomas involving the bones.

Definition • It is a frequent problem to diagnose when there is a sole

skeletal lesion without knowledge of the primary tumor.
• It is a growth of malignant cells in the bone originating
from a primary tumor elsewhere.
• It is one of the most common consequences from a pri- Etiology
mary malignant tumor in extra-osseous location and occa-
sionally from primary sarcoma in bone. • The cause is undefined.

Epidemiology

• Of the various tumors affecting the bone, metastatic carci-

noma is the most common type. It is much more common
P. Bacchini, MD
than primary bone tumors (25:1).
Department of Surgical Pathology,
Private Hospital Villa Erbosa, Bologna, Italy • The most frequent primary sites are the lung, breast, pros-
tate, kidney, thyroid, pancreas, and liver.
F. Bertoni, MD (*)
Department of Surgical Pathology, University of Bologna, • Other primary tumors are lymphoma, melanoma, neuro-
Bologna, Italy endocrine carcinoma, and sarcoma.
Surgical Pathology Department, Istituto Rizzoli, Bologna, Italy • The lung, the liver, and the skeleton are the most involved
sites of a metastatic process.
Department of Surgical Pathology, Villa Erbosa Hospital,
Bologna, Italy • It is found most frequently in the older population. Rare
e-mail: proffrancobertoni@gmail.com in the pediatric age.

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 601
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_46, © Springer-Verlag London 2015
602
Sites of Involvement
• The bones most frequently involved by metastatic
tumors are the skull, spine, rib, pelvis, humerus, and
femur (there is a known predilection for areas contain-
ing red marrow).
• Metastases distal to the knee and the elbow are rarely
found. Very rarely metastases involve the small bones of
the hands and feet. Acral metastases are most frequently
related to lung carcinoma, but other carcinoma may do it.
• The metaphysis tends to be the site of metastatic deposits
in the long bones.
• A primary sarcoma in bone may be mimicked by a single
metastasis of carcinoma in the long bones.
Symptoms
• Pain is the most frequent symptom, accompanied or not
by swelling.
• Abrupt and severe pain is frequently related to a patho-
logic fracture or result from the pressure exerted on
nearby structures.
• There may or may not be accompanying systemic
symptoms.
Image Diagnosis
• Radiographically, single or multiple lesions can be found.
These include sclerotic or lytic or the presence of both
types (sclerotic and lytic).
• Typical lytic metastases include the renal cell carcinoma,
lung carcinoma, and thyroid carcinoma. Lung carcinoma
has peculiarities such as:
– High percentage of solitary bone metastasis at
presentation
– May have an unusual radiographic presentation (intra-
cortical or subperiosteal)
– Involves unusual sites (acral metastases)
– Bilateral symmetrical metastasis in unusual sites
(patella)
• The most typical sclerotic metastases arise from the pros-
tate, breast, and neuroendocrine carcinomas.
• Radioisotopic bone scan: is very sensitive, more than
plain radiographs.
• Metastases are hot on bone scan when associated with
osteoblastic activity, and involvement of multiple skeletal
sites may be observed.
• CT/PET is very sensitive for detecting bone metastases,
and the occult primary tumor may also be observed. CT
reveals the cortical bone destruction.
P. Bacchini and F. Bertoni
• MRI: More extensive disease may be observed than that
which is seen clinically, particularly when the bones are
involved; MRI, in particular, shows the amount of soft tis-
sue invasion.
Pathology
Gross Features
• No gross diagnostic characteristics are observed.
• The lesions can range from dense fibrotic/desmoplastic to
very soft, destructive, necrotic lesions.
• The color can range from reddish-brown, fleshy tannish-
gray, or red (characteristic of a renal cell carcinoma) to
inky-black (characteristic of metastatic melanoma).
Histologic Features
• When there is a known primary tumor, a biopsy or fine-
needle aspiration (FNA) may confirm the diagnosis.
• However, when the sole sign of carcinoma is that exist-
ing in a bone lesion, search for the primary neoplasm is
necessary. This situation is more frequent in carcinoma
of the kidney, lung, breast, pancreas, thyroid, and colon,
but solitary skeletal metastasis can be present in any type
of carcinoma, malignant melanoma, lymphoma, and
sarcoma.
• The majority of metastatic adenocarcinomas and squa-
mous cell carcinomas are demonstrated morphologically.
The metastasis generally has the same characteristics as
the primary lesion.
• The most common metastases are: adenocarcinomas and
squamous cell carcinomas; however, sarcomatoid renal
cell carcinomas have the same characteristics as primary
sarcomas of bone.
• Osteoblastic metastases are characterized by abundant
reactive woven bone; this bone is lined by plump osteo-
blasts. The differential diagnosis with an osteosarcoma is
that in an osteosarcoma the tumor cells are directly
opposed to woven bone.
• Secondary changes include: hemorrhages, fibrosis and
osteoclast-like giant cell reactions. Sometimes, the
stromal reaction is prominent, and only few neoplas-
tic cells are recognizable, well identified in cytokeratin
immunostain.
• The most common metastatic lesions in children are: neu-
roblastomas, rhabdomyosarcomas, and clear cell sarcoma
of the kidney. Primary bone sarcomas such as osteosar-
coma and Ewing sarcoma may spread to other osseous
sites.
46 Metastatic Bone Carcinoma
• In metastatic carcinomas of the thyroid and hepatocellular
carcinomas, the primary site can generally be easily iden-
tified on histology.
• However, in the case of undifferentiated adenocarcinoma
or squamous cell carcinoma, immunoperoxidase staining
is important; this is also necessary in metastatic sarcoma-
toid carcinoma (which can resemble a primary bone
sarcoma).
Pathological Differential Diagnosis
• Osteosarcoma: Osteoblastic metastasis, like prostatic
metastasis, may mimic osteosarcoma resulting in a wrong
diagnosis. Osteosarcomas can be positive for keratin and
epithelial membrane antigen (EMA) but are negative for
prostate-specific antigen (PSA) and prostatic acid phos-
phatase (PSAP).
• All vascular tumors are positive for the following endo-
thelial cell markers: CD31, CD34, factor VIII, and Erg.
However, epithelioid vascular tumors, epithelioid heman-
giomas, epithelioid hemangioendotheliomas, and epithe-
lioid angiosarcomas can also be positive for keratin.
• Many sarcomatoid carcinomas do not demonstrate epi-
thelial differentiation, and, in some cases, the sarcomas
may be positive for cytokeratin. Therefore, in adults, in
the case of a presumed sarcoma, it is imperative to rule
out sarcomatoid carcinomas before definitive surgery.
Ancillary Techniques
• Renal cell carcinoma: Low-molecular-weight keratins are
commonly positive. Renal cell carcinoma markers and
CD10 are generally positive. CK 7 and CK 20 are gener-
ally negative, and Pax 2 and Pax 8 are generally positive.
• Lung adenocarcinoma: The majority are keratin 7 posi-
tive and keratin 20 negative. The majority are TTF1 posi-
tive and napsin positive. The lung squamous cells
carcinoma is almost always p63 and CK5 positive; small
lung carcinoma in addition to almost always being TTF1
positive is almost always positive for synaptophysin.
• Thyroid: Tumors of this gland are generally thyreoglobu-
lin and TTF1 positive.
• Prostate: In the prostate, the majority of tumors are kera-
tin 7 and keratin 20 negative, PSA positive, and PSAP
positive.
603
• Breast: In the breast, estrogen and progesterone receptors
may be positive.
• Epithelioid vascular tumors, osteosarcomas, and adaman-
tinomas are CK-positive bone tumors.
• When a bone lesion in the adulthood has radiographic
aggressive features and there is no knowledge of a pri-
mary malignant tumor elsewhere, the hint of algorithm
including both CK 7 and 20 may be useful for identifica-
tion of primary site of a carcinoma. The various combina-
tions of positive or negative markers would be a useful
diagnostic aid.
Genetics
• Real-time PCR may be used to locate primary sites.
• The DNA and RNA degradation following decalcification
creates difficulties in applying molecular tests.
Prognosis
• A number of metastatic carcinomas of the breast occa-
sionally respond to treatment.
• In order to choose the appropriate hormonal therapy, the
identification of metastatic prostatic adenocarcinoma is
important.
• However, the prognosis is usually poor when dealing with
metastases originating from the lung or the kidney. This is
especially true in patients who present with metastatic
bone disease.
Treatment
• Both medical (hormonal) and surgical therapy are used in
patients with metastatic prostate or breast carcinomas.
• Radioactive iodine can be used to treat metastatic carcino-
mas originating in the thyroid.
• The combination of surgical procedures and radiation
and/or other therapies can be of value when managing
metastatic carcinomas involving the bones.
Images
• See Figs. 46.1, 46.2, 46.3, 46.4, 46.5, 46.6, 46.7, 46.8¸
46.9, 46.10, 46.11, 46.12, 46.13, 46.14, and 46.15 for
illustrations of these tumors.
604 P. Bacchini and F. Bertoni

Fig. 46.1 Plain radiograph of the proximal humerus. Purely lytic

lesion, destroying the cancellous bone. This represents a completely
lytic osseous metastasis in women with a follicular carcinoma of the
thyroid

Fig. 46.2 Plain radiograph of

the surgical specimen: The lesion
is entirely lytic with pathologic
fracture. The gross image shows
a solid homogeneous
parenchymatous brown lesion,
with focal hemorrhage
46 Metastatic Bone Carcinoma 605

Fig. 46.3 Follicular adenocarcinoma of the thyroid infiltrating the

cancellous bone. Follicular structures containing pink eosinophilic col-
loid material are present

Fig. 46.4 Plain radiograph shows a large lucent lesion on the distal
metaphysis of the femur

Fig. 46.5 Gross image shows a hemorrhagic lytic destructive lesion along with radiograph of the surgical specimen. The expansile red tumor
destroys the cancellous bone and focally involves the cortical bone
606 P. Bacchini and F. Bertoni

Fig. 46.6 The histology shows metastatic renal cell carcinoma, clear Fig. 46.9 A low-power photograph with inset: the neoplatic cells are
cell type. There is preexisting residual cancellous bone embedded in a not easily visualized on this image, overwhelmed by desmoplastic
mainly clear and focally eosinophilic malignant cell proliferation stroma and abundant reactive bone

Fig. 46.7 Axial CT shows a small osteoblastic metastasis (primary in

the breast) to the posterior iliac spinous process

CK+

Fig. 46.10 Immunohistochemistry shows cytokeratin positivity (same

patient as Fig. 46.9)

Fig. 46.8 A fine-needle CT-guided biopsy was performed

46 Metastatic Bone Carcinoma 607

Estrogen receptors+
Fig. 46.13 Thick seams of bone are seen embedding metastatic ade-
nocarcinoma confirming the diagnosis (same patient as Fig. 46.12)

Fig. 46.11 Estrogen receptor positive (same patient as Fig. 46.10)

Fig. 46.14 Plain radiograph shows cortical lucency with ill-defined

margins in the femoral diaphysis of a 60-year-old man with lung
adenocarcinoma

Fig. 46.12 Cross section of a resected proximal femur in patient with

blastic osseous metastatic adenocarcinoma of the prostate
608 P. Bacchini and F. Bertoni

Recommended Reading
Dorfman HD, Czerniak B. One tumors. St. Louis: Mosby; 1998.
p. 1009–40.
Nielsen GP, et al. Diagnostic pathology. Bone: metastatic tumors 14.
Philadelphia: Amirsys; 2013. p. 2–7.
Sim FH. Diagnostic and management of metastatic bone disease.
Multidisciplinary approach. New York: Raven Press; 1988.
Unni KK, Inwards CY. Dahlin’s bone tumors. 6th ed. Philadelphia:
Kluwer/Lippincott; 2010. p. 305–10.
Varadhachary GR, Abbruzzese JL, Lenzi R. Diagnostic strategies for
unknown primary cancer. Cancer. 2004;100:1776–85.

Fig. 46.15 The needle biopsy confirms the bone infiltration by a meta-
static adenocarcinoma (same patient as Fig. 46.14)
 Part XVI
Tumorlike Lesions and Other Conditions That
Simulate Primary Bone Tumors
 Simple Bone Cyst
47
Liliana G. Olvi, Gustavo M. Lembo, Osvaldo Velan,
and Eduardo Santini-Araujo

Abstract
It is an intramedullary, usually unilocular cystic cavity filled with serous or serosanguine-
ous fluid and lined by a membrane of variable thickness, with greater incidence in males
than females (2/3:1). The first two decades of life account for 80 % of cases and has a
predilection for proximal humerus (50 %), proximal femur (25 %), and proximal tibia.
Radiologically, it is well outlined centrally and symmetrically located metaphysiodiaphy-
seal lucency, expanding, thinning, and scalloping the cortices. The lesion is not wider
than the epiphyseal plate. Histologically the inner lining of the cyst consists of connective
tissue with foci of immature bone trabeculae. The bone marrow spaces are rich in dilated
hyperemic capillaries. Fibrinous deposits are often seen. Treatment: multiple needle aspi-
ration of the fluid of the cyst and injection of methylprednisolone, promoting healing of
the lesion.

Definition Synonyms

• An intramedullary, usually unilocular cystic cavity filled • Solitary bone cyst

with serous or serosanguineous fluid and lined by a mem- • Unicameral bone cyst
brane of variable thickness.

Etiology

• Unknown.
L.G. Olvi, MD • Several causes have been suggested, the main one being
Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina disturbance in growth at the epiphyseal plate.
G.M. Lembo, MD
Department of Pathology, Centenary Hospital Rosario
Santa Fe Argentina, Rosario, Santa Fe, Argentina Clinical Features
O. Velan, MD
Department of Radiology, Italian Hospital of Buenos Aires, Epidemiology
Buenos Aires, Argentina
E. Santini-Araujo, MD, PhD (*) Sex
Department of Pathology, School of Medicine • Greater incidence in males than females (2/3:1)
and School of Dentistry, University of Buenos Aires,
Buenos Aires, Argentina
Age
Central Army Hospital, Buenos Aires, Argentina
• The first two decades of life account for 80 % of cases.
Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina Patients with growth plate still open.
e-mail: santiniaraujo@laborpat.com.ar

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 611
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_47, © Springer-Verlag London 2015
612
Sites of Involvement
• Predilection for proximal humerus (50 %), proximal
femur (25 %), and proximal tibia.
• The ilium, calcaneus, and talus are often affected in older
patients.
Clinical Symptoms and Signs
• The majority are asymptomatic.
• Generally discovered after a pathological fracture or, inci-
dentally, after a roentgenologic examination for other
reasons.
• Some patients may experience mild pain or limitation of
motion.
• Swelling in the affected region is infrequent.
• In some patients it may regress spontaneously.
Image Diagnosis
Radiographic Features
• Well outlined centrally and symmetrically located meta-
physiodiaphyseal lucency, expanding, thinning, and scal-
loping the cortices.
• Not wider than the epiphyseal plate.
• It usually abuts but rarely transgresses the growth plate.
Epiphyseal involvement is uncommon.
• The lesion originally arises in metaphysis and extends
progressively into the diaphysis.
• The cyst has its greatest diameter near the epiphyseal
plate and its conic end in the shaft with a sharp margin
with trabeculation.
• In long bones, growth may result in the cyst moving
away from the plate and finishing centered in the
diaphysis. Cysts located near the plate are called
“active” and “inactive” or “latent” those separated –
for the skeletal growth – from the plate by normal can-
cellous bone.
• A multilocular or trabeculated appearance may be seen
due to prominent endosteal bony ridges in the inner corti-
cal wall.
• In cysts complicated with fracture, it is frequent to observe
one or more fragments of cortex floating in the fluid –
“fallen fragment” sign – that moves with the change of
patient position.
• Periosteal reaction is absent except at sites of fracture.
L.G. Olvi et al.
CT Features
• Well-demarcated lesion.
• True septation is unusual.
MRI Features
• Usually confirms the cystic nature and its fluid content with-
out solid components that can be bloody in fractured lesions.
Bone Scan
• Peripheral uptake or normal
Image Differential Diagnosis
Aneurysmal Bone Cyst
• SBC is never wider than the epiphysis plate.
• ABC is a lytic lesion, more expanded than SBC with fluid-
fluid levels in CT and MRI, better seen using contrast.
• Area of lucency situated eccentrically in the medullary
cavity in the metaphysis of a long bone.
• Most ABCs are completely lytic, but a few contain traces
of mineral.
• Frequently presents a multiloculated appearance.
• Later on, “ballooned” or “aneurysmal” cystic expansion
of the affected bone – “blow out” – is evident. Usually
forms a thin sclerotic rim of ossification due to periosteal
new bone formation.
• In ABC, the cortex is eccentrically expanded, feature that
is never seen in SBC.
• ABC may cross joints and involve an adjacent bone.
• CT and MRI highlight the internal septation, the cystic
nature, and the fluid-fluid levels.
Fibrous Dysplasia
• Intramedullary centered, elongated lesions arising in the
metaphysis or diaphysis of the long bones.
• Well-circumscribed areas of rarefaction, commonly bordered
by a sclerotic rim, frequently so thick that appears as a rind.
• The upper or lower limit frequently shows a triangular-
shaped image.
• The lesion has a ground glass-like or lytic appearance.
• The lesions may expand the affected bone – but with
sharp circumscription.
• Bone deformity – bowing – usually affects weight-bearing
long bones such as the femur, “shepherd’s crook defor-
mity,” and tibia.
47 Simple Bone Cyst
Pathology
Gross Features
• Well-delimited unicameral cavity filled with a clear
citrine or serosanguineous fluid.
• Bleeding is due to prior pathologic fracture.
• The inner wall presents bony ridges and depressed zones
lined by a thin smooth grayish-white to reddish-brown
membrane.
• Cortical bone expansion.
Histological Features
• The inner lining of the cyst consist of connective tissue
with foci of immature bone trabeculae.
• Scattered giant cells, hemosiderin pigment, and foamy
histiocytes are seen.
• Fibrinous deposits are often seen – probably from previ-
ous hemorrhages. Some of these deposits are mineralized,
resembling cementum.
• In some cases an active osteoblastic bone apposition is
seen on the surface of this cementum-like material.
• The bone marrow spaces are rich in dilated hyperemic
capillaries.
• Occasionally, histological features of fracture callus may
be prominent.
Pathologic Differential Diagnosis
Aneurysmal Bone Cyst
• Grossly SBC is an unicameral cyst with endosteal crests,
but true septation is unusual and related to pathologic
fracture repairing.
• A previous pathologic fracture may produce a thick mem-
brane due to fibroblast proliferation, with osteoclast-like giant
cells and reactive immature bone trabeculae mimicking ABC.
• Cementum-like material is never seen in ABC.
Fibrous Dysplasia
• In small biopsies, some SBCs with prominent cementum-
like material may mimic FD.
• Irregular curvilinear immature trabeculae in a bland spin-
dle cell’s fibrous component.
• Rounded cementum-like bodies.
613
• Foam cells, multinucleated cells, myxoid, or secondary
aneurysmal bone cyst change may occur.
• Cartilage may be rarely present in solitary lesions and
more frequently in multiple lesions.
• Extensive myxoid changes in some cases.
Ancillary Techniques
Genetics
• Cytogenetically, simple bone cysts lack any consistent
genetic alteration. Translocation (16;20) (p11.2;q13) has
been reported as the sole cytogenetic rearrangement in
another one.
• A recurrent case demonstrated tp53 mutations.
• Another simple bone cyst of the distal humerus with at
(7;12) (q21;q24.3) in a patient with hypophosphatemic
rickets was also reported.
Prognosis
• Recurrence is reported at 10–20 % of patients, especially
in younger subjects.
• Spontaneous healing after fracture has been described.
Treatment
• Multiple needle aspiration of the fluid of the cyst and
injection of methylprednisolone, promoting healing of the
lesion.
• Aspiration of the cyst content followed by percutaneous
bone marrow autotransplantation.
• Curettage and bone grafting in cases of loss of bone struc-
tural integrity.
• Infrequently may be resected.
Images
See Figs. 47.1, 47.2, 47.3, 47.4, 47.5, 47.6, 47.7, 47.8, 47.9,
47.10, 47.11, 47.12, 47.13, 47.14, 47.15, 47.16, 47.17, 47.18,
47.19, 47.20, 47.21, 47.22, 47.23, 47.24, 47.25, 47.26, 47.27,
47.28, 47.29, 47.30, 47.31, 47.32, 47.33, and 47.34 for illus-
trations of simple bone cysts.
614 L.G. Olvi et al.

Fig. 47.1 Simple bone cyst in its most common site. Well outlined
centrally and symmetrically located metaphysiodiaphyseal lucency.
The cortices are expanded and thinned. The lesion is not wider than the
epiphyseal plate. Cysts located near the plate are called “active”

Fig. 47.2 Simple bone cyst located in the diaphysis of humerus. In

long bones, growth may result in the cyst moving away from the plate
and finishing located in the diaphysis. This kind of cyst is called “latent”
or “inactive”
47 Simple Bone Cyst 615

Fig. 47.3 SBC showing a multilocular appearance due to prominent

endosteal bony ridges in the inner cortical wall

Fig. 47.5 “Active” SBC with a large extension to the diaphysis. The
cyst shows a conic end in the shaft, with a sharp margin with
trabeculation

Fig. 47.4 A diaphyseal location in humerus. The sclerotic area is

probably the result of a previous fracture
616 L.G. Olvi et al.

Fig. 47.7 SBC in the second most common site, the upper end of
femur. This cyst is located in the femoral neck

Fig. 47.6 SBC with trabeculations in the metaphyseal area and a

prominent extension in diaphysis
47 Simple Bone Cyst 617

a b

Fig. 47.8 (a) SBC located in the intertrochanteric area of the upper and its fluid content. (c) CT scan, well-delimited lesion that thinned the
end of femur. Periosteal reaction is always absent in SBC except at the cortex. True septation is unusual and may be present after fractures
sites of fracture. (b) MRI usually confirms the cystic unicameral nature
618 L.G. Olvi et al.

a b

Fig. 47.9 (a and b) Two patients with solitary bone cyst affecting the upper end of the femur. In the two cases the cysts present well-delimited
margins and trabeculations or pseudoseptations. The lesions are centrally located and do not expand the cortex
47 Simple Bone Cyst 619

a b

Fig. 47.10 (a, b) Anteroposterior and lateral X-ray showing an SBC of the upper end of the tibia, with an eccentrical location
620 L.G. Olvi et al.

Fig. 47.11 SBC in distal metaphysis of a tibia, adjacent to the physis

a b

Fig. 47.12 (a) SBC in the ilium. This location is affected more often in older patients. (b) CT scan shows a lytic lesion showing a pseudosepta-
tion. (c) MRI shows a cystic unicameral lesion with fluid content
47 Simple Bone Cyst 621

Fig. 47.13 Typical aspect of an SBC arising in the calcaneus. In this

site lipoma of bone is the most common image differential diagnosis

a b

Fig. 47.14 (a, b) Typical roentgenogram and CT of an SBC of the calcaneus

622 L.G. Olvi et al.

a b

Fig. 47.15 (a–c) SBC arising in the calcaneus with typical MRI pattern in T1- and T2-weighted images
47 Simple Bone Cyst 623

Fig. 47.16 Infrequent multiple locations of an SBC in both calcanei of Fig. 47.17 SBC located in the upper metaphysis of the fibula
the patient
624 L.G. Olvi et al.

a b

Fig. 47.18 (a, b) Anteroposterior and lateral X-rays showing an SBC in diaphyseal location. In small-diameter long bones, the cyst tends to
expand the cortex

Fig. 47.19 Infrequent location of an SBC in the lower metaphysis of

the ulna
47 Simple Bone Cyst 625

a b

Fig. 47.20 (a) Typical image of an SBC arising in the upper metaphysis of the humerus. (b) X-ray showing a pathologic fracture of the cyst
6 months after the previous image
626 L.G. Olvi et al.

Fig. 47.21 Pathologic fracture in a “latent” SBC located in the shaft of

the humerus
Fig. 47.22 Pathological fracture in an SBC of the upper end of the
femur. One can observe fragments of cortex floating in the fluid –
“fallen fragment” sign
47 Simple Bone Cyst 627

Fig. 47.23 SBC with pathological fracture showing a fragment of the

cortex with the so-called rack sign

Fig. 47.25 Fracture in an SBC located in the lower metaphysis of the

radius. The X-ray shows the typical “fallen fragment” sign

a b

Fig. 47.24 (a) Fracture

associated with an SBC located
in the upper end of the humerus.
(b) Bone scan shows a hot signal
due to fracture
628 L.G. Olvi et al.

a b

Fig. 47.26 (a, b) X-ray and MRI showing a rare example of SBC with epiphyseal involvement
47 Simple Bone Cyst 629

a b

Fig. 47.27 (a, b) Roentgenogram and MRI of other unusual case of epiphyseal involvement
630 L.G. Olvi et al.

Fig. 47.28 Microphotograph at low magnification showing the inner Fig. 47.29 At higher magnification, the wall of the cyst is usually thin
lining of the cyst that consists of connective tissue with immature tra- and with a rich vascularization
beculae. It is possible to see dilated hyperemic capillaries in the fibrous
tissue
47 Simple Bone Cyst 631

Fig. 47.32 Deposition of hemosiderin due to ancient hemorrhages

Fig. 47.30 Fibrinous deposits are often seen in SBC

Fig. 47.33 Fibrous membrane with foam cells (xanthoma cells) and
cholesterol crystals surrounded by foreign body giant cells

a b

Fig. 47.31 (a, b) Peripheral areas of bone marrow spaces show numerous dilated hyperemic capillaries
632 L.G. Olvi et al.

a c

Fig. 47.34 (a–d) Treatment of SBC with multiple needle aspiration of the fluid and injection of methylprednisolone
47 Simple Bone Cyst 633

Recommended Reading Margau R, Babyn P, Cole W, et al. MR imaging of simple bone cysts in
children: not so simple. Pediatr Radiol. 2000;30:551–7.
Ottolenghi CF, Schajowicz F, Raffa J. Le quiste osseux essential uni-
Ambacher T, Maurer F, Weise K. Spontaneous healing of a juvenile
loculaire. Etude Clinique et anatomo-pathologique de 123 cas. Rev
bone cyst of the tibia after pathological fracture. Unfallchirurg.
Orthop. 1969;55:287–303.
1999;102:972–4.
Richkind KE, Mortimer E, Mowery-Rushton P, et al. Translocation
Capanna R, Dal Monte A, Gitelis S, et al. The natural history of uni-
(16;20)(p11.2;q13). Sole cytogenetic abnormality in a unicameral
cameral bone cyst after steroid injection. Clin Orthop Relat Res.
bone cyst. Cancer Genet Cytogenet. 2002;137:153–5.
1982;166:204–11.
Sakai Junior N, Pereira MF, Kalil RK. A simple bone cyst of the distal
Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F. WHO clas-
humerus with a t(7;12)(q21;q24.3) in a patient with hypophospha-
sification of tumours of soft tissue and bone. 4th ed. Lyon: IARC
temic rickets. Cancer Genet. 2012;205(10):541–3.
Press; 2013.
Vasilev V, Andreeff I, Sokolov T, Vidinov N. Clinical-morphological
Glowacki M, Ignys-O Byrne A, Ignys l, et al. Evaluation of volume and
and electron-microscopic studies of the growth plate in solitary
solitary bone cyst remodeling using conventional radiological
bone cysts. Arch Orthop Trauma Surg. 1987;106(4):232–7.
examination. Skelet Radiol. 2010;39:251–9.
Vayego-Lourenco SA. TP53 mutations in a recurrent unicameral bone
Glowacki M, Ignys-O Byrne A, Ignys l, et al. Limb shortening in the
cyst. Cancer Genet Cytogenet. 2001;124:175–6.
course of solitary bone cyst treatment – a comparative study. Skelet
Vayego SA, De Conti OJ, Varella-Garcia M. Complex cytogenetic rear-
Radiol. 2011;40:173–9.
rangement in a case of unicameral bone cyst. Cancer Genet
Jaffe HL, Lichtenstein L. Solitary unicameral bone cyst. Arch Surg.
Cytogenet. 1996;86:46–9.
1942;44:1004–25.
 Aneurysmal Bone Cyst
48
Liliana G. Olvi, Gustavo M. Lembo, Osvaldo Velan,
and Eduardo Santini-Araujo

Abstract
Aneurysmal bone cyst is an intramedullary eccentric metaphyseal and rapid expansible
benign lytic lesion with multiloculated blood-filled cystic cavities, lined by membranes of
different thickness and composed of spindle cells, osteoid trabeculae, and osteoclastic-type
giant cells. Primary ABC: When ABC arises “de novo” in bone − 70 % of cases. In these
cases, a definite preexisting lesion cannot be demonstrated. Secondary ABC: Areas similar
to primary ABC are found in various benign and malignant conditions. Male/female ratio is
equal. The second followed by the first decade of life accounts for 80 % of cases.
Roentgenographically, it is an area of lucency situated eccentrically in the medullary cavity
in the metaphysis of a long bone. MRI confirms the entirely cystic nature, the internal septa-
tions, and its fluid-fluid levels. Treatment includes excision or curettage and bone grafting.

Definition Variants

• Aneurysmal bone cyst is an intramedullary eccentric
metaphyseal and rapid expansible benign lytic lesion with
multiloculated blood-filled cystic cavities, lined by mem-
branes of different thickness and composed of spindle
cells, osteoid trabeculae, and osteoclastic-type giant cells.
L.G. Olvi, MD
Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina
G.M. Lembo, MD
Department of Pathology, Centenary Hospital Rosario
Santa Fe Argentina, Rosario, Santa Fe, Argentina
O. Velan, MD
Department of Radiology, Italian Hospital of Buenos Aires,
Buenos Aires, Argentina
E. Santini-Araujo, MD, PhD (*)
Department of Pathology, School of Medicine and
School of Dentistry, University of Buenos Aires,
Buenos Aires, Argentina
Central Army Hospital, Buenos Aires, Argentina
Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina
e-mail: santiniaraujo@laborpat.com.ar
• Primary ABC: When ABC arises “de novo” in bone –
70 % of cases. In these cases, a definite preexisting lesion
cannot be demonstrated.
• Secondary ABC: Areas similar to primary ABC are found
in various benign and malignant conditions. Secondary
ABC corresponds to about 30 % of all ABCs. In some
cases, secondary ABC represents a minor component of
the lesion. However, the secondary cystic area may pre-
dominate over the precursor lesion.
Synonims
• Multicameral hematic bone cyst.
Etiology
• Unknown.
• A neoplastic nature was suggested for this lesion, based
on recent molecular and cytogenetic findings of clonal
alterations.

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 635
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_48, © Springer-Verlag London 2015
636
Clinical Features
Epidemiology
Sex
• Male/female ratio is equal.
Age
• The second followed by the first decade of life accounts
for 80 % of cases. It is less frequent under the age of
5 years. The condition may affect any age group.
Sites of Involvement
• Metaphysis of long bones. Predilection for distal femur,
proximal tibia, proximal femur, and proximal humerus.
• When in the spine, also a frequent location, it is usually
the posterior elements that are involved.
• Less frequently affects bones of hands and feet, craniofa-
cial bones, scapula, and pelvis.
• ABC may rarely arise in epiphysis and diaphysis and, less
commonly yet, in cortical and periosteal locations.
Clinical Symptoms and Signs
• Pain and swelling.
• Some cases expand at an alarming rate and may suggest
the possibility of a malignant neoplasia. However, malig-
nant lesions usually do not grow so fast.
• In vertebra: neurological signs – paresthesias and numb-
ness of the extremities, due to progressive cord or emerg-
ing nerve compression.
Image Diagnosis
Radiographic Features
• Area of lucency situated eccentrically in the medullary
cavity in the metaphysis of a long bone.
• Most ABCs are completely lytic, but a few contain traces
of mineral.
• A thin shell of cortical or periosteal bone is usually seen
at the external contour of the lesion.
• Frequently presents a multiloculated appearance.
• Less commonly, the lesion is centrally situated.
• Later on, “blow out,” “ballooning,” or “aneurysmal” cys-
tic expansion of the affected bone is evident. The lesion
involves the cortex and destroys it, bulging out into soft
tissues. It usually forms a thin sclerotic rim of ossification
due to periosteal new bone formation.
• ABC may cross joints and involve an adjacent bone.
L.G. Olvi et al.
• When in spine, it commonly affects more than one verte-
bral segment.
• In some ABCs that grow at an alarming rate, images may
suggest a malignant lesion.
CT Features
• Cystic and radiolucent.
• CT scan highlights the calcified rim at the periphery.
• CT may show internal septation and multiple fluid-fluid
levels – a result of the so-called hematocrit effect that is
seen because of the separation of serum and blood prod-
ucts within the lesion, which can be emphasized using
contrast. For this effect to be apparent, the patient must
remain in position for about 10 min to allow precipitation
of the denser elements.
MRI Features
• Confirm the entirely cystic nature, the internal septations,
and its fluid-fluid levels.
• Both CT and MRI help to highlight the eventual presence
of an underlying lesion.
Bone Scan
• Shows a hot spot
Image Differential Diagnosis
Simple Bone Cyst (SBC)
• SBC is a unicameral lesion that is centrally and symmetri-
cally located.
• Exceptionally, after fracture healing, may present
septation.
• The eccentrical expansion of the cortex is a feature that
practically is never seen in SBC.
• SBC never presents fluid-fluid levels in CT and MRI,
except in fractured cases where a level may be seen as a
result of hemorrhage.
Giant Cell Tumor (GCT)
• When ABC arises in an epiphysis and especially when the
GCT presents secondary cyst, present a difficult differen-
tial diagnosis.
Telangiectatic Osteosarcoma (TOS)
• Images overlap and may be totally similar.
• TOS shows a purely lytic lesion on X-rays. Any appre-
ciable sclerosis rules out a diagnosis of TOS.
48 Aneurysmal Bone Cyst
Osteoblastoma
• When in the spine, this may be a possible differential
diagnosis.
• Osteoblastoma is commonly a more mineralized lesion.
Hydatid Cyst of the Bone
• X-ray shows a lytic, cystic lesion.
• CT scan and MRI show a multicameral cystic lesion.
Pathology
Gross Features
• In resected specimens, multiple unclotted blood-filled
spaces are seen separated by septae of various thick-
nesses. Cortical bone expansion is usually present.
• The presence of more solid areas determines that the pos-
sibility of an underlying primary lesion must be ruled out.
• When the lesion is treated by curettage, fragments of red-
brown granular material are seen. One striking feature is
the disparity between the size of the lesion on roentgeno-
grams and the amount of tissue received for examination.
Histological Features
• Cavernous spaces filled with blood.
• A periosteal new bone formation makes up the external
contour and limits the lesion with the soft tissues.
• When ABC is treated by resection, the cyst is well pre-
served. When the lesion is curetted, the spaces
collapse.
• The walls of these spaces lack the normal features of
blood vessels. These walls lack an endothelial lining.
• Septae separating spaces contain loosely arranged spindle
cells with plump nuclei. The appearance is “loose”
because of capillary proliferation and edema.
• The spindle cells have plump nuclei but without
hyperchromasia.
• Spindle cells may show brisk mitotic activity but without
atypical mitotic figures and without cytological atypia.
• Immature bone trabeculae with prominent osteoblastic
activity are easily found. Sometimes these trabeculae
present an intensely calcified matrix known as “blue
bone.” This last feature – “blue bone” – besides not always
present, must be considered a very specific pattern of
ABC.
• The septae contain also multinucleated giant cells, usu-
ally scattered through the lesion or in clusters or sheets.
• Necrosis is infrequent, except in cases of pathologic
fractures.
• Lace-like or powdery calcifications with a basophilic
appearance, peculiar chondroid-like zones, and parallel
637
seams of fibrillary osteoid beneath the lining of the
septum are typical and relatively specific features
of ABC.
• ABCs may have some solid area that may be prominent
and where cystic spaces and septae may not be identi-
fied. The term “solid ABC” has been adopted for these
cases.
• Lesions similar to ABC may arise also in soft tissues.
These lesions are called “extraskeletal ABCs.”
• Secondary ABC is associated with other benign and also
malignant lesions such as:
– Giant cell tumor
– Chondroblastoma
– Osteoblastoma
– Fibrous dysplasia
– Metaphyseal fibrous defect
– Chondromyxoid fibroma
– Benign fibrous histiocytoma
– Osteosarcoma
Pathologic Differential Diagnosis
Simple Bone Cyst
• Grossly SBC is a unicameral cyst with endosteal crests,
but true septation is unusual and related with pathologic
fracture repairing.
• The overlying cortex is thinned, lined on its inner surface
by a thin fibrous membrane rich in dilated capillaries and
newly formed immature trabeculae.
• Aggregates of fibrin, probably from previous hemor-
rhages, are present. Some of these are partially mineral-
ized and secondarily ossified.
• A previous pathologic fracture may produce a thick mem-
brane with fibroblastic proliferation, osteoclast-like giant
cells, and reactive immature bone trabeculae mimicking
ABC.
Hydatid Cyst of the Bone
• The cyst wall has an inner, nucleated, germinative layer
and an outer, nonnucleated layer.
• The outer nonnucleated layer is quite distinctive and has
innumerable PAS-positive laminations.
• Scolices of the head of the worm are seen and, by a closer
look, the hooks can be identified.
Giant Cell Tumor
• Small foci of cystic changes are common in GCT – the
most common bone neoplasm associated with secondary
ABC.
• Rarely the ABC-like areas are dominant.
• In such cases one must take in account the location and
X-ray appearance of the lesion as well as the clinical
data.
638
• In GCT the mononucleated cells have similar nuclei to the
nuclei of giant cell and do not show a consistent fibrous
stroma.
Telangiectatic Osteosarcoma
• Grossly this tumor has been compared to a bag of blood.
• ABC and TOS may be similar at low-power appearance.
Misdiagnosis could be made in both directions.
• In TOS, two microscopical patterns may be seen:
1. Commonly, bloody spaces and septae, as in
ABC. However, the cells that line the septa are cyto-
logically malignant.
2. Rarely, only very pleomorphic cells appear in a bloody
background without any pattern.
• Osteoid production is minimal and, in rare instances, no
osteoid is found.
Giant Cell Reparative Granuloma
• The differential is with solid ABC.
• GCRG arises in small bones of the hands and feet or jaws.
• GCRG lacks the cytogenetic abnormalities present in ABC.
Ancillary Techniques
Genetics
• Translocation t(16;17), which determines CDH11-USP6
gene fusion transcript, can be demonstrated by FISH.
• A subset of cases with apparent classical histological and
imaging features of MO presented with clonal USP6 rear-
rangements. They represent, probably, early phases of
soft tissue ABC.
L.G. Olvi et al.
Prognosis
• Excellent, in primary ABC.
• Recurrences are rare.
• In some cases, incomplete removal may be followed by
regression of the lesion.
• There are rare reports of possible malignant transforma-
tion. It is not clear if the lesions represent secondary ABC
in preexisting sarcomas.
Treatment
• Excision or curettage and bone grafting.
• Surgical adjuvant treatment with chemical cautery.
• Preoperative embolization may be performed in large
lesions.
• In expandable bones, like the fibula or rib, wide resection
may be done.
• Radiation is not recommended due to potential malignant
transformation.
Images
See Figs. 48.1, 48.2, 48.3, 48.4, 48.5, 48.6, 48.7, 48.8, 48.9,
48.10, 48.11, 48.12, 48.13, 48.14, 48.15, 48.16, 48.17, 48.18,
48.19, 48.20, 48.21, 48.22, 48.23, 48.24, 48.25, 48.26, 48.27,
48.28, 48.29, 48.30, 48.31, 48.32, 48.33, 48.34, 48.35, 48.36,
48.37, 48.38, 48.39, 48.40, 48.41, 48.42, 48.43, 48.44, 48.45,
48.46, 48.47, 48.48, 48.49, 48.50, 48.51, 48.52, 48.53, and
48.54 for illustrations of aneurysmal bone cyst.
48 Aneurysmal Bone Cyst 639

Fig. 48.1 (a, b) ABC in the

upper metaphysis of a humerus. a b
Lytic, rapidly expansible lesion

a b

Fig. 48.2 (a, b) Two months

follow-up shows a rapid
ballooned expansion of the lower
femoral metaphysis affected by
an ABC
640 L.G. Olvi et al.

a b

c d

Fig. 48.3 Secondary ABC may affect other lesions. Example: (a–d) chondroblastoma of long evolution with soft tissue involvement and minimal
secondary ABC
48 Aneurysmal Bone Cyst 641

a b

c d

Fig. 48.4 (a–d) Secondary ABC in conventional central osteosarcoma in the upper metaphysis of a humerus
642 L.G. Olvi et al.

a b c

Fig. 48.5 (a–c) Secondary ABC developed after surgical treatment of a femoral shaft fracture

Fig. 48.6 (a–d) Secondary ABC in a pre-existent GCT, with minor

cystic component arising in lower epiphysis of femur
48 Aneurysmal Bone Cyst 643

Fig. 48.6 (continued)

644 L.G. Olvi et al.

c d

Fig. 48.6 (continued)

48 Aneurysmal Bone Cyst 645

Fig. 48.7 (a–c) Secondary

ABC, predominantly cystic, a b
arising in giant cell tumor located
in the lower epiphysis of the
femur

c
646 L.G. Olvi et al.

a b c

Fig. 48.8 (a, b) Anteroposterior and lateral roentgenographic lytic image of ABC in the lower metaphysis of the femur. Most ABCs are com-
pletely lytic, but a few contain traces of mineral. (c) MRI shows the internal septation with multiple fluid-fluid levels
48 Aneurysmal Bone Cyst 647

Fig. 48.9 Less commonly, the lesion is centrically situated

648 L.G. Olvi et al.

Fig. 48.10 (a) ABC in

epiphyseal location. (b, c) a b
Coronal and axial MRI showing
the typical fluid-fluid levels

c
48 Aneurysmal Bone Cyst 649

Fig. 48.11 (a) Radiograph

shows an expansible lesion on a b
lower epiphysis of the tibia
corresponding to ABC. (b) Axial
MRI shows the multicameral
feature of the lesion with
fluid-fluid levels

a b

Fig. 48.12 (a) ABC in a fibula diaphysis. (b) Gross section of the surgical specimen with multiple unclotted blood-filled spaces separated by
septae of different thicknesses
650 L.G. Olvi et al.

Fig. 48.13 (a) Intracortical

diaphyseal ABC of a femur. a b
X-ray shows an intracortical
lucency with a shell of cortical
bone at the external contour of
the lesion. (b) Axial CT scan
shows a cystic radiolucent lesion
arising in the cortex of the femur
48 Aneurysmal Bone Cyst 651

a b

c d

Fig. 48.14 (a) Subperiosteal location of ABC in the shaft of a femur. (b, c) Coronal and axial MRI views show the precise location of the lesion
and the typical fluid-fluid levels. (d) Core needle biopsy guided by CT
652 L.G. Olvi et al.

Fig. 48.15 (a, b)

Anteroposterior radiograph a b
showing early ABC situated
eccentrically in the medullary
cavity on the lower metaphysis
of the femur

a b

Fig. 48.16 (a) Late ballooning or expansion of the affected bone. The of calcification and periosteal new bone formation. (b) CT scan high-
lesion tends to involve the cortex and may destroy it completely and lights the calcified rim at the periphery
bulge out into the soft tissue where it usually forms a thin sclerotic rim
48 Aneurysmal Bone Cyst 653

Fig. 48.17 (a, b)

Anteroposterior X-ray showing a a b
growing lesion that involves the
meta-diaphysis of the tibia. The
lesion presents a multiloculated
appearance

a b

Fig. 48.18 (a) Roentgenogram

showing an ABC in distal
metaphysis of the tibia. (b) MRI
shows the so-called hematocrit
effect
654 L.G. Olvi et al.

a b c

Fig. 48.19 (a) ABC affecting the upper metaphysis of the fibula. (b) Typical gross appearance of multicameral hemorrhagic cyst. (c) X-ray of
slab of the gross specimen

a b

Fig. 48.20 (a) ABC located in the tarsal region. (b) Typical multicameral cystic lesion in MRI. (c) Gross appearance of the surgical specimen
with blood-filled cystic areas and septae of different sizes
48 Aneurysmal Bone Cyst 655

a b

Fig. 48.21 (a) ABC in the fourth metatarsal bone. (b) Evolution: 4 months later
656 L.G. Olvi et al.

a b

Fig. 48.22 (a) ABC in the upper end of the humerus with a great expansion of the cortex. (b) MRI shows a typical multicameral appearance of
the lesion. (c) Gross specimen showing complete septae. Some cavities are filled with nonclotted blood
48 Aneurysmal Bone Cyst 657

Fig. 48.24 Lateral X-ray of the cervical spine showing a destructive

lesion corresponding to an ABC in the posterior elements of a vertebra
c

Fig. 48.23 (a) Ballooned destructive lesion in the iliopubic area of the
right pelvis. (b) CT shows a well-delimitated lesion surrounded by a
thin periosteal bone shell. (c) MRI showing fluid-fluid levels

Fig. 48.25 Commonly (like in osteoblastoma) more than one vertebral

segment are affected
658 L.G. Olvi et al.

Fig. 48.26 (a, b) X-ray and CT scan showing another example of

ABC involving more than one vertebra
48 Aneurysmal Bone Cyst 659

a b

Fig. 48.27 (a–c) Roentgenogram and MRI showing the most common location of ABC in the dorsal elements
660 L.G. Olvi et al.

Fig. 48.28 (a, b) Anteroposterior X-ray and CT scan. ABC of the fifth
lumbar vertebra showing the involvement of the vertebral body. The
diagnosis was performed with a core needle biopsy
48 Aneurysmal Bone Cyst 661

a b

Fig. 48.29 (a, b) Sagittal MRI showing in T1- and T2-weighted images an uncommon case of ABC with great involvement of vertebral body and
spinal cord compression. (c) Axial CT image showing the great involvement of posterior elements and vertebral body
662 L.G. Olvi et al.

Fig. 48.30 Infrequent location of ABC in patella

Fig. 48.31 ABC arising in the lateral end of the clavicle: (a) roent-
genograph, (b) gross surgical specimen, (c) radiograph of the specimen,
and (d) histopathology image at low magnification
48 Aneurysmal Bone Cyst 663

a b

Fig. 48.32 (a) ABC located in the jaw showing a lytic nonspecific image. (b, c) Coronal and axial CT showing an expansible lytic lesion bulging
out into the soft tissue with a thin calcified rim of periosteal new bone formation
664 L.G. Olvi et al.

a b

c1 c2

d1 d2

Fig. 48.33 Image differential diagnosis. (a) Simple bone cyst. (b) Telangiectatic osteosarcoma. (c1–c2) Giant cell tumor of the bone. (d1, d2)
Osteoblastoma (when in a vertebra)
48 Aneurysmal Bone Cyst 665

Fig. 48.34 Grossly, the blood-filled spaces are seen separated by septae of various thicknesses
666 L.G. Olvi et al.

Fig. 48.35 ABC treated by curettage. Fragments of red-brown

material

Fig. 48.37 (a) Microphotograph at low magnification of a core needle

biopsy of ABC showing the most striking features of the lesion. (b) At
higher magnification, blood-filled cavities are seen lined by fibrovascu-
lar septae containing multinucleated giant cells of osteoclastic type. It is
possible to see fibrillary osteoid

Fig. 48.36 (a) Histologically, the essential feature is cavernomatous

spaces filled with blood. Under low-power magnification the spaces are
separated by septae and contain blood or are empty. (b) At the left,
periosteal bone reaction. Powdery calcification at the middle of the
image and a typical microscopy of the wall of ABC
48 Aneurysmal Bone Cyst 667

Fig. 48.40 It is frequent to find immature bone trabeculae in this spin-

dle cell stroma
b

Fig. 48.38 (a, b) The walls of the cyst lack features of blood vessels
and lack an endothelial lining

Fig. 48.39 Septae separating spaces contain loosely arranged spindle

cells
Fig. 48.41 The multinucleated giant cell is a common component of
ABC. They are separated by a fibrovascular stroma
668 L.G. Olvi et al.

a b

c d

Fig. 48.42 (a) Microphotograph of ABC at low magnification: the relatively specific of ABC. (b) Fibrillary osteoid at high magnification.
membranes show the chondroid-like blue bone areas and fibrillary oste- (c) Areas of blue bone. (d) Chondroid areas
oid beneath the lining of the septum. All these features are typical and
48 Aneurysmal Bone Cyst 669

b c

Fig. 48.43 (a) Solid ABC. Lytic and expanded lesion arising in a rib. (b) Gross appearance of the lesion showing few blood-filled spaces. (c)
Microphotograph at low magnification of the lesion
670 L.G. Olvi et al.

a b

Fig. 48.44 (a) Soft tissue ABC. Gross specimen. (b) Microphotograph at low magnification
48 Aneurysmal Bone Cyst
a b
d e
Fig. 48.45 Some ABCs that may grow at an alarming rate and the
X-ray features may suggest a malignant lesion. (a) A 9-year-old girl
showing a metaphyseal lytic lesion with the differential diagnosis with
SBC or fibrous dysplasia. (b) With a fine needle biopsy, a diagnosis of
SBC was performed. Six months later the patient developed a large
671
c
f
destructive lesion bulging out into the soft tissue with a periosteal reac-
tion (Codman’s triangle). Core needle biopsy confirmed the diagnosis
of ABC. (c) The lesion was diagnosed in 1990. The patient was treated
by embolization. (c–f) We can see the follow-up after treatment from
1991 to 1996
672 L.G. Olvi et al.

Fig. 48.46 (a) ABC of the

scapula. Radiograph showed a a b
large radiolucent lesion involving
the scapula. (b) Gross specimen
showing the cavities of the
aneurysmal bone cyst

a b

Fig. 48.47 (a) Roentgenogram

showing an extensive and
expansive diaphyseal lesion in
the femoral shaft. (b) CT shows a
periosteal lesion, which was
diagnosed with a core needle
biopsy as an aneurysmal bone
cyst
48 Aneurysmal Bone Cyst 673

Fig. 48.48 Radiograph showed a large radiolucent lesion involving

the entire iliac bone. The patient had a primary aneurysmal bone cyst
674 L.G. Olvi et al.

a b

Fig. 48.49 (a–c) Infrequent location of ABC involving the sphenoid and the left cavernous sinus. It is possible to see the fluid-fluid levels of the
lesion that destroyed the sphenoid and involved the temporal bone and Turkish saddle
48 Aneurysmal Bone Cyst 675

Fig. 48.50 (a) Solitary bone

cyst is one of the most relevant a b
histological differential
diagnosis. This X-ray shows a
ballooned lytic lesion arising
in the diaphysis of the fibula.
(b) The lesion was diagnosed as
a benign cystic lesion by a fine
needle biopsy and was resected.
The gross specimen shows a
unicameral cavity. The inner
wall shows bone ridges that
radiologically simulate
trabeculation and compartments
676 L.G. Olvi et al.

a b

c d

e f

Fig. 48.51 (a) Lytic lesion arising in the metaphysis of the tibia. (b)
MRI shows intraosseous lesion and an important soft tissue involve-
ment as well as fluid-fluid levels. (c) Intramedullary lesion with a rele-
vant extraosseous extension. The surface section shows numerous
cystic cavities. (d) Microphotograph showing an inner nucleated germi-
native layer and an outer, nonnucleated layer. (e) The outer nonnucle-
ated layer is quite distinctive and has innumerable lamination, PAS
positive. (f) The presence of scolex with the other histological findings
made the diagnosis of hydatid cyst of the bone
48 Aneurysmal Bone Cyst 677

a b

c d

Fig. 48.52 (a) Roentgenogram shows a lytic epiphyseal lesion with appearance of giant cell tumor, with secondary aneurysmal bone cyst.
extension to the metaphysis of bone. (b) MRI shows a multicameral Giant cell tumor is probably the most common bone neoplasm associ-
minor cystic component. (c) Resection specimen with numerous cystic ated with secondary aneurysmal bone cyst
blood-filled spaces. (d) Histopathologic study shows areas of typical
678 L.G. Olvi et al.

Fig. 48.53 (a) Lytic eccentrical

metaphyseal lesion in the lower a b
metaphysis of the femur. (b) MRI
shows a lytic lesion with
multicameral cavities showing
characteristic fluid-fluid levels.
(c) Gross specimen looks as a
true bag of blood. (d) At low
magnification the lesion
simulates an aneurysmal bone
cyst with spaces separated by
septae. (e) However, at higher
magnification, the cells that line
the septae are cytologically
malignant and confirm the
diagnosis of telangiectatic
osteosarcoma. Rarely, only
pleomorphic cells appear in a
bloody background without any
pattern. (f) Osteoid production c
may be minimal and in rare
instances no osteoid is seen
48 Aneurysmal Bone Cyst 679

e f

Fig. 48.53 (continued)

680 L.G. Olvi et al.

c d

Fig. 48.54 Lower shaft of femur. (a) Metaphyseal lesion with soft tis- magnification the lesion simulates an aneurysmal bone cyst. But the
sue involvement and characteristic Codman’s triangle and a “sunburst” aneurysmatic pattern corresponds to a secondary cystic change in a cen-
pattern reaction. (b) MRI demonstrates in the soft tissue involvement of tral conventional osteosarcoma. (d) Microphotograph at higher magni-
the lesion, multiple cystic lesions with fluid-fluid levels. (c) At lower fication showing typical areas of osteosarcoma
48 Aneurysmal Bone Cyst 681

Recommended Reading Oliveira AM, Hsi BL, Weremowicz S, Rosenberg AE, Dal Cin
P, Nora J, Bridge JA, Perez-Atayde AR, Fletcher JA. USP6
(Tre2) fusion oncogenes in aneurysmal bone cyst. Cancer Res.
Bertoni F, Bacchini P, Capanna R, Ruggieri P, Biagini R, Ferruzi A,
2004;64:192–202.
Bertelli G, Picci P, Campanacci M. Solid variant of aneurysmal
Pan S, Bridge J, Siiegal, et al. Hum Pathol. 2012;43:952–7.
bone cyst. Cancer. 1993;71:729–34.
Sukov WRD, Franco MF, Erickson-Johnson M, Chou MM, Unni
Jaffe HL. Aneurysmal bone cyst. Bull Hosp Joint Dis. 1950;11:3–13.
KK, Wenger DE, Wang X, Oliveira AM. Frequency of USP6
Jaffe HL, Lichtenstein L. Solitary unicameral bone cyst. Arch Surg.
rearrangements in myositis ossificans, brown tumor, and cherubism:
1942;44:1004–25.
molecular cytogenetic evidence that a subset of “myositis ossifi-
Kransdorf MJ, Sweet DE. Aneurysmal bone cyst: concept, contro-
cans-like lesions” are the early phases in the formation of soft-tissue
versy, clinical presentation and imaging. AJR Am J Roentgenol.
aneurysmal cyst. Skeletal Radiol. 2008;37(4):321–7.
1995;164:573–80.
Vergel DeDios AM, Bond JR, Shives TC, McLeod RA, Unni KK.
Lichtenstein L. Aneurysmal bone cyst. A pathological entity commonly
Aneurysmal bone cyst. A clinicopathologic study of 238 cases.
mistaken for giant cell tumor and occasionally for hemangioma and
Cancer. 1992;69:2921–31.
osteogenic sarcoma. Cancer. 1950;3:279–89.
Martinez V, Sissons HA. Aneurysmal bone cyst. A review of 123
cases including primary lesions and those secondary to other bone
pathology. Cancer. 1988;61:2291–304.
 Juxta-articular Bone Cyst
49
Liliana G. Olvi, Gustavo M. Lembo, Osvaldo Velan,
and Eduardo Santini-Araujo

Abstract
Juxta-articular bone cyst is an intraosseous nonneoplastic subchondral cystic lesion not
related to joint pathology – especially osteoarthritis. The lesion contains mucoid fluid and
is lined by fibrous tissue with myxoid change. If the joint presents osteoarthritis, the lesion
is defined as a degenerative subchondral pseudocyst. Male predominance. Adults, more
frequently – 80 % – between the third and sixth decade of life. Predilection for bones adja-
cent to hip, knee, ankle, wrist, and shoulder joints. Roentgenograms show a well-outlined
oval or round osteolytic radiolucent lesion, frequently located eccentrically, in close rela-
tionship to the subchondral layer in the epiphysis of a long tubular bone. Histologically the
cyst is surrounded by a connective tissue membrane with scarce number of fibroblasts and
parallel fascicles of collagen fibers and lacks an evident synovial layer. Foci of myxoid
transformation in the connective membrane. Stellate cells and abundant mucoid substance.
Painful cysts are treated with curettage and bone grafting.

Definition • If the joint presents osteoarthritis, the lesion is defined as

a degenerative subchondral pseudocyst.
• Juxta-articular bone cyst is an intraosseous nonneoplastic
subchondral cystic lesion not related to joint pathology –
especially osteoarthritis. The lesion contains mucoid fluid
and is lined by fibrous tissue with myxoid change. Synonyms

L.G. Olvi, MD
Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina
G.M. Lembo, MD
Department of Pathology, Centenary Hospital Rosario Santa Fe
Argentina, Rosario, Santa Fe, Argentina
O. Velan, MD
Department of Radiology, Italian Hospital of Buenos Aires,
Buenos Aires, Argentina
E. Santini-Araujo, MD, PhD (*)
Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina
Department of Pathology, School of Medicine, School of Dentistry,
University of Buenos Aires, Buenos Aires, Argentina
Central Army Hospital, Buenos Aires, Argentina
e-mail: santiniaraujo@laborpat.com.ar
• Intraosseous ganglion
• Intraosseous mucoid cyst
Etiology
• Probably, intraosseous juxta-articular bone cyst shares a
common pathogenesis with the soft tissue ganglion:
mucoid degeneration of connective tissue.
• In a great number of cases, the cyst is primarily intraosse-
ous, located in the subchondral region. Others are origi-
nated by penetration of a soft tissue ganglion into the
underlying cortex.

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 683
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_49, © Springer-Verlag London 2015
684 L.G. Olvi et al.

Clinical Features • Low signal in the peripheral sclerotic margin

• Edema in the peripheral bone marrow
Epidemiology

Sex Bone Scan

• Male predominance
• Occasionally shows a hot spot
Age
• Adults, more frequently – 80 % – between third and sixth
decade of life Image Differential Diagnosis

Sites of Involvement Chondroblastoma

• Similar sites
• Predilection for bones adjacent to hip, knee, ankle, wrist, • More conspicuous expansion and thinning of the
and shoulder joints cortex
• Presents stippled calcifications
Clinical Symptoms and Signs
Chondroma
• Pain (approximately 60 % of patients) referred to a joint, • Absence of sclerotic peripheral margin
often increasing with effort and exercise • Commonly presents ring-like and stippled mineraliza-
• Frequently a totally asymptomatic silent condition inci- tion that can be traced circumferentially as a continu-
dentally discovered after a radiological examination for ous line
other reasons
Aneurysmal Bone Cyst
• Rarely in an epiphysis.
Image Diagnosis • Without peripheral sclerotic rim.
• CT and MRI show fluid-fluid levels, which can be empha-
Radiographic Features sized by contrast.

• Roentgenograms show a well-outlined oval or round Osteoarthritis

osteolytic radiolucent lesion, frequently located eccentri- • Reduced joint lumina
cally, in close relationship to the subchondral layer in the • Presence of several smaller pseudocysts in the pressure
epiphysis of a long tubular bone. zone
• Some cysts may expand the cortex. • Numerous joint communications due to loss of articular
• The lesion is outlined by a sclerotic rim. cartilage
• The cyst may be unicameral or multiloculated – in larger cysts.
• In later stages, the X-ray may show communication
between intraosseous cyst and the adjacent joint. Pigmented Villonodular Synovitis
• Usually, the size is between 1 and 2 cm, rarely attaining a • Intraosseous penetration may occur.
diameter of up to 5 cm. • Lesions are frequently located in both bony ends of the
• Degenerative changes in the related joint are not observed. affected joint.

CT Features Pathology
• Lytic lesion with peripheral sclerotic rim. In some cases, The gross and histological features of intraosseous cyst and
CT shows better the communication between intraosse- the classic soft tissue ganglion, frequently observed in juxta-
ous cyst and the adjacent joint. articular connective tissue, are similar.

MRI Features
Gross Features
• Confirms the fluid content of the lesion, with low signal
intensity on T1-weighted images and high signal on • Uni- or multilocular cyst.
T2-weighted images • Lined by a fibrous membrane of variable thickness.
49 Juxta-articular Bone Cyst 685

• Filled with a mucoid jelly-like material – whitish or Chondrosarcoma

yellowish. • Some chondrosarcomas may show areas of extensive
• In a small percentage of cases, it is possible to find identical myxoid change, difficult to recognize specially in fine
cysts in the connective tissue adjacent to the bone cyst, some- needle biopsies.
times clearly penetrating through the interrupted cortex. • Roentgenographic features are of great help.

Histological Features
Prognosis
• The cyst is surrounded by a connective tissue membrane
with scarce number of fibroblasts and parallel fascicles of
• Excellent.
collagen fibers.
• Recurrences are rare.
• Lacks an evident synovial layer.
• Foci of myxoid transformation in the connective
membrane.
• These foci represent new cyst formation.
Treatment
• Stellate cells and abundant mucoid substance.
• Round cells with abundant vacuolar mucoid cytoplasm –
• Small and asymptomatic juxta-articular cysts do not need
muciphages – with PAS-positive material.
treatment, only follow-up.
• Similar cells are floating in cystic cavities.
• Painful cysts are treated with curettage and bone
• Small number of inflammatory cells and histiocytes may
grafting.
be present.
• In patients with extraosseous ganglion associated with
• Peripheral cancellous bone shows new bone formation
intraosseous component, excision of the soft tissue gan-
originating a sclerotic rim. It is possible to find areas of
glion and curettage of the intraosseous component is
cortical osteoclastic resorption.
recommended.
• In small and painful lesions, needle biopsy may convert
Pathologic Differential Diagnosis them to asymptomatic.

Osteoarthritis Subchondral Pseudocyst

• Microscopic findings of necrotic bone, cartilage debris,
and foci of cartilaginous metaplasia are absent in juxta- Images
articular cysts but are common features of osteoarthritic
pseudocysts. See Figs. 49.1, 49.2, 49.3, 49.4, 49.5, 49.6, 49.7, 49.8, 49.9,
49.10, 49.11, 49.12, 49.13, 49.14, 49.15, 49.16, 49.17, 49.18,
Chondromyxoid Fibroma 49.19, 49.20, 49.21, 49.22, and 49.23 for illustrations of
• Myxoid areas may be found in a scenario otherwise typi- juxta-articular bone cysts.
cal of CMF with spindle cells, multinucleated giant cells,
and myxochondroid lobules.
686 L.G. Olvi et al.

Fig. 49.1 JBC in the femoral neck. X-ray shows a well-delimited oval
osteolytic radiolucent small lesion outlined by a sclerotic rim

a b

Fig. 49.2 (a, b) JBC arising in the femoral neck. Bone scan occasionally shows a hot spot
49 Juxta-articular Bone Cyst 687

a b

Fig. 49.3 (a) JBC located in the femoral head. (b) CT scan evidencing a lytic lesion with a peripheral sclerotic rim. (c) The diagnosis was made
by core needle biopsy

a b

Fig. 49.4 (a) X-ray and (b) CT show a large JBC arising in the femoral head
688 L.G. Olvi et al.

a b

Fig. 49.5 (a) Roentgenogram and (b) CT scan of a JBC arising in the acetabulum, not related to joint osteoarthritic pathology

Fig. 49.6 Typical JBC located in the acetabulum

49 Juxta-articular Bone Cyst 689

a b

Fig. 49.7 (a) Humerus epiphyseal location of a JBC. (b) MRI confirms the fluid content of the lesion, low signal in the peripheral sclerotic margin
and edema in the peripheral bone marrow
690 L.G. Olvi et al.

Fig. 49.8 (a) X-ray and (b) MRI showing a JBC in the glenoid of the scapula
49 Juxta-articular Bone Cyst 691

a b

Fig. 49.9 (a) X-ray and (b) CT showing a typical JBC arising in the lunate bone

Fig. 49.10 (a) Roentgenogram of a JBC in a lunate bone. (b) CT

shows the communication between intraosseous cyst and the adjacent
joint
692 L.G. Olvi et al.

a b

Fig. 49.11 (a) X-ray and (b) MRI showing the characteristic findings of an intraosseous mucoid cyst in a lunate bone

Fig. 49.12 X-ray showing a scaphoid with a multiloculated JBC

49 Juxta-articular Bone Cyst 693

a b

c d

Fig. 49.13 (a, b) Anteroposterior and lateral roentgenograms show a JBC in the femoral epiphysis. (c) CT scan with the typical image of the
lesion. (d) Core needle biopsy of the cyst
694 L.G. Olvi et al.

Fig. 49.14 (a, b) Centrally

located JBC in tibial epiphysis a b

a b

Fig. 49.15 (a, b) Peripheral JBC in the upper epiphysis of the tibia
49 Juxta-articular Bone Cyst 695

Fig. 49.16 (a) X-ray

and (b) MRI of a typical a b
intraosseous mucoid cyst
located in the tibial
epiphysis

Fig. 49.17 JBC in a lower epiphysis of the tibia. The differential

radiographic diagnosis is with giant cell tumor of the bone
696 L.G. Olvi et al.

a b

c d

Fig. 49.18 (a, b) JBC in the lower epiphysis of the tibia. Marginal intra-medullary sclerotic margin help to differentiate from GCT. (c) Prominent
endosteal bony ridge is seen. (d) Core needle biopsy of the lesion
49 Juxta-articular Bone Cyst 697

a b

Fig. 49.19 (a) JBC located in astragalus. (b) Typical image in CT. (c) Hot spot in bone scan
698 L.G. Olvi et al.

a b

Fig. 49.20 (a) X-ray shows a JBC arising in the lateral epiphysis of the clavicle. (b) Gross image of surgical specimen. Large multilocular cyst
with other apparently separated smaller cysts. (c) X-ray of a slab of the surgical specimen

Fig. 49.21 Microphotograph at low magnification showing a multi-
loculated cyst
Fig. 49.22 At higher magnification the cyst is surrounded by a con-
nective tissue membrane with scarce number of fibroblasts. It is possi-
ble to see areas of myxoid transformation in the connective tissue
membrane. Peripheral cancellous bone shows new bone formation
originating a sclerotic rim
49 Juxta-articular Bone Cyst 699

Recommended Reading
Bauer TW, Dorfman HD. Intraosseous ganglion: a clinicopathological
study of 11 cases. Am J Surg Pathol. 1982;6(3):207–13.
Campanacci M, Cerveletti C. Cisti mucose periostee e intraossee. Chir
Organi Mov. 1971;60(III):221–32.
Kambolis C, Bullough PG, Jaffe HI. Ganglionic cystic defects of bone.
J Bone Joint Surg. 1973;55A:496–505.
Pope TL, Fechner RE, Keats TE. Intra-osseous ganglion. Report of four
cases and review of the literature. Skelet Radiol. 1989;18:185–7.
Schajowicz F, Clavel Sainz M, Slullitel JA. Juxtaarticular bone cysts
(intra-osseous ganglia): a clinicopathological study of eighty-eight
cases. J Bone Joint Surg (Br). 1979;61:107–16.
Sim FH, Dahlin DC. Ganglion cysts of bone. Proc Staff Meet Mayo
Clin. 1971;46:484–8.

Fig. 49.23 Myxoid areas at higher magnification. Lacks an evident

synovial layer
 Epidermoid Bone Cyst
50
Liliana G. Olvi, Maria L. Gonzalez, Osvaldo Velan,
and Eduardo Santini-Araujo

Abstract
Epidermoid bone cyst is an intramedullary, unilocular cyst lined by squamous epithelium
containing keratin, with greater incidence in males. Acral lesions – common in manual
workers – present from the third to sixth decade of life. Skull lesions are more frequent in
the first decade. Excluding the epithelium-lined cyst of jaws, epidermoid cysts are located
almost exclusively in the distal phalanges, followed by the skull – frontal and parietal
region. Roentgenographically, it is a well-defined round osteolytic lesion. The inner lining
of the cyst consists of squamous malpighian epithelium with a granulosa layer covered by
laminated masses of keratin that fill the cavity. Treatment includes curettage or excision of
the phalanx lesion or skull cysts.

Definition Etiology

• An intramedullary, unilocular cyst lined by squamous • Developmental origin is postulated in skull locations.
epithelium containing keratin • Traumatic etiology is postulated in the phalanges.

Synonyms Clinical Features

• Epidermoid inclusion cyst Epidemiology

Sex
• Greater incidence in males

L.G. Olvi, MD
Age
Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina
• Acral lesions – common in manual workers – from the
M.L. Gonzalez, MD
third to sixth decade of life.
Laboratory of Orthopaedic Pathology, University of Buenos Aires,
Buenos Aires, Argentina • Skull lesions are more frequent in the first decade.
O. Velan, MD
Department of Radiology, Italian Hospital of Buenos Aires,
Buenos Aires, Argentina Sites of Involvement
E. Santini-Araujo, MD, PhD (*)
Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina • Excluding the epithelium-lined cyst of jaws, epidermoid
Department of Pathology, School of Medicine, School of Dentistry, cysts are located almost exclusively in the distal phalan-
University of Buenos Aires, Buenos Aires, Argentina ges, followed by the skull – the frontal and parietal
Central Army Hospital, Buenos Aires, Argentina region.
e-mail: santiniaraujo@laborpat.com.ar • Multiple lesions are rare.

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 701
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_50, © Springer-Verlag London 2015
702 L.G. Olvi et al.

Clinical Symptoms and Signs Giant Cell Granuloma

• In distal phalanges, they have very similar radiologic
• Asymptomatic or with intermittent pain. features.
• Increase in finger size.
• Curving of the nail. Osteomyelitis
• In rare cases, pathologic fracture. • Lesion borders are less clear and present imaging and
• Squamous cysts involving the skull are asymptomatic or clinical signs of inflammation, like edema and pain.
produce palpable painless swelling. Expanded lesions
may produce neurological symptoms.
Pathology

Image Diagnosis Gross Features

Radiographic Features • Well-delimitated unilocular cavity of 1–2 cm of diameter.

The inner membrane is 1–5 mm thick. The cyst is filled
• Well-defined round osteolytic lesion. with a whitish-yellow substance – keratinous debris.
• Absence of trabecular pattern. • A peripheral granulomatous reaction may occur.
• In growing lesions, the cortex is expanded and thinned or
sclerotic.
• Fractures may be observed in the phalanges. Histological Features
• Healing of the fracture may modify the roentgenographic
appearance. • The inner lining of the cyst consists of squamous malpi-
ghian epithelium with a granulosa layer covered by lami-
nated masses of keratin that fill the cavity.
CT Features • The epithelium is thin, composed by few cellular layers.
• The epithelium is separated from the cortex by connective
• Well-demarcated lytic lesion tissue with moderate inflammatory reaction.
• The cortex may be thinned by osteoclastic endosteal
reabsorption.
MRI Features • In some cases, the cortex is destroyed and the cyst makes
contact with the dermis.
• Hypointense in T1-weighted images. Hyperintense in • In such cases, foreign-body giant cell granulomas with
T2-weighted images cholesterol crystals surrounding keratin fragments may
appear.

Image Differential Diagnosis

Pathologic Differential Diagnosis
Chondroma: In the Phalanges
• Most chondromas present characteristic spotty calcifications. Enchondroma
• The diagnosis is difficult in noncalcified chondromas. • Easily differentiated grossly and histopathologically

Intraosseous Glomus Tumor in the Phalanges Giant Cell Granuloma

• A clinically painful lesion. • Some epidermoid cyst may disrupt the cortex, producing
• Radiologically, they are identical. giant cell granulomas associated to keratin fragments.

Eosinophilic Granuloma
• In skull cysts, the differential may be difficult but the Prognosis
peripheral sclerosis in epidermoid cyst may be helpful in
the differential with acute eosinophilic granuloma. • Excellent
50 Epidermoid Bone Cyst 703

Treatment Images

• Curettage or excision of the phalanx lesion See Figs. 50.1, 50.2, 50.3, 50.4, 50.5, 50.6, 50.7, 50.8, and
• Amputation in advanced phalanx cysts with advanced 50.9 for illustrations of epidermoid bone cysts.
involvement
• In skull cysts: curettage or excision
704 L.G. Olvi et al.

a b

Fig. 50.1 (a, b) Intraosseous phalangeal epidermoid cyst. The anteroposterior and lateral radiographs showing the characteristic osteolytic lesion

Fig. 50.3 In growing lesions, the cortex is expanded and thinned.

Fig. 50.2 Well-defined round osteolytic lesion in a most common Fractures may be observed in the phalanges
location
50 Epidermoid Bone Cyst 705

Fig. 50.4 Epidermoid bone cyst in the terminal phalanx of the hallux.
The lesion destroyed the cortex
706 L.G. Olvi et al.

a c

Fig. 50.5 (a, b) Anteroposterior and lateral view of a parietal bone showing a well-defined round osteolytic lesion with absence of trabecular
pattern. (c) CT scan shoes a well demarcated lytic lesion with a sclerotic rim. Well-demarcated lytic lesion
50 Epidermoid Bone Cyst 707

Fig. 50.6 Lateral X-ray showing a well-demarcated lytic lesion sur- Fig. 50.8 Microphotograph with the squamous epithelial lining and
rounded by a thin sclerotic rim keratinization

Fig. 50.7 Microphotograph at lower magnification demonstrates the Fig. 50.9 At higher magnification, the microphotograph shows the
peripheral cortical bone rim and the wall of flattened, stratified squa- inner lining of the cyst consisting of squamous malpighian epithelium
mous epithelium with granular layer with a granulosa layer covered by laminated masses of keratin that fill
the cavity
708 L.G. Olvi et al.

Recommended Reading Patel K, et al. Epidermal inclusion cyst of phalanx: a case report and
review of the literature. Skeletal Radiol. 2006;35(11):861–3.
Roth SI. Squamous cysts involving the skull and distal phalanges. J
Capanna R, Dal Monte A, Gitelis S, et al. The natural history of uni-
Bone Joint Surg. 1964;46A:1442–50.
cameral bone cyst after steroid injection. Clin Orthop Relat Res.
Schajowicz F, Aiello C, Slullitel I. Cystic and pseudocystic lesions of
1982;166:204–11.
the terminal phalanx with special reference to epidermoid cysts.
Dahlin DC. Bone tumors, 3rd ed. Springfield: Thomas. 1978.
Clin Orthop. 1970;68:84–92.
Fisher ER, et al. Epidermal cyst in bone. Cancer. 1958;11(3):643–8.
 Metaphyseal Fibrous Defect
51
Liliana G. Olvi and Eduardo Santini-Araujo

Abstract
A benign nonneoplastic bone lesion, composed of fibrous tissue with a whorled pattern, with
multinucleated giant cells, hemosiderin pigment and lipid-bearing histiocytes and inflamma-
tory elements. It is one of the most frequent tumorlike lesions of bone and is more frequent in
males (60 %) than in females (40 %). It has the highest incidence in the second decade (67 %)
followed by the first decade (20 %), and it is most common in the lower metaphysis of the
femur and the upper metaphysis of the tibia – both locations comprise 80 % of cases. The
radiographic appearance is characteristic and usually diagnostic. It is a radiolucent, eccentrical,
elongated lesion in the metaphysis of long bones, juxtaposed to the endosteal surface of one
cortex. The long axis of the lesion is usually parallel to that of the host bone. Frequently, lesions
can be confidently diagnosed based on radiographic features and puncture needle or surgical
biopsy. Surgical treatment is not necessary and may be followed by X-rays.

Definition Synonyms

• A benign nonneoplastic bone lesion, composed of fibrous • Nonossifying fibroma

tissue with a whorled pattern, with multinucleated giant
cells, hemosiderin pigment, and lipid-bearing histiocytes
and inflammatory elements. Etiology
• Smaller subperiosteal or cortical elongated lesions called
“cortical fibrous defect” are similar lesions. • Unknown.
• Jaffe-Campanacci syndrome: multiple nonossifying • The presence, in some patients, of multiple foci, the self-
fibromas in different bones and café au lait spots on the limited growth potential, and the possibility of spontane-
skin. ous regression favor the nonneoplastic nature and the
possibility of a hyperplastic histiocytic origin, probably
related to an intraosseous hemorrhage. Another proposed
hypothesis is an exaggerated resorption during metaphy-
seal remodeling in sites of tendon insertions.
L.G. Olvi, MD
Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina • Clonality was not demonstrated.
E. Santini-Araujo, MD, PhD (*)
Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina
Department of Pathology, School of Medicine and School of
Clinical Features
Dentistry, University of Buenos Aires,
Buenos Aires, Argentina Epidemiology
Central Army Hospital, Buenos Aires, Argentina
e-mail: santiniaraujo@laborpat.com.ar • One of the most frequent tumorlike lesions of the bone

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 709
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_51, © Springer-Verlag London 2015
710
Sex
• More frequent in males (60 %) than in females (40 %)
Age
• Highest incidence in the second decade (67 %) followed
by the first decade (20 %)
Sites of Involvement
• Most common in the lower metaphysis of the femur
and the upper metaphysis of the tibia – both locations
comprise 80 % of cases. Lower metaphyses of the tibia
and fibula and distal radius are commonly involved
sites.
• Long bones of the upper extremities and short or flat
bones are rarely involved.
• Infrequently, some patients have multiple lesions in one
or more bones.
Clinical Symptoms and Signs
• Usually asymptomatic. Many lesions may never be
diagnosed.
• Incidental radiographic finding − 35 % of patients – after
a roentgenologic examination for other reasons.
• Pain − 40 % of patients. More common in large lesions,
probably related to microfractures.
• Slight swelling in bones near the skin, like the distal
metaphysis of the tibia.
• Pathologic fracture − 15 % of patients – may be the first
clinical sign.
Image Diagnosis
Radiographic Features
• The radiographic appearance is characteristic and usually
diagnostic.
• Radiolucent, eccentrically elongated lesion in the metaph-
ysis of long bones, juxtaposed to the endosteal surface of
one cortex.
• The long axis of the lesion is usually parallel to that of the
host bone.
• The area of the lesion closest to the epiphysis is usually
wider than the distal portion.
• As the long bone grows, the lesion becomes separated
from the epiphyseal plate, moving toward the
diaphysis.
• Lesions tend to thin and slightly expand one cortical
surface.
L.G. Olvi and E. Santini-Araujo
• The inner border is well defined and slightly sclerotic,
suggestive of a nonaggressive lesion, producing a scal-
loped margin.
• Some lesions are transversed by trabeculae, giving them a
multilocular appearance. These trabeculae are incom-
plete, and the radiographic pseudo-septated pattern is pro-
duced by crests on the sclerotic inner margin of the lesion.
• No periosteal reaction is present.
• In large lesions, the entire width of the bone may be involved.
• In small bones, the fibula, ulna, and radius, the lesion
occasionally occupies the whole diameter of the host bone.
• Multiple lesions are infrequently present.
• Older lesions may be diaphyseal and the sclerosis
increases with healing.
• Smaller subperiosteal or cortical elongated lesions are
called “cortical fibrous defect.” The lesion is limited by an
underlying thickened cortex and does not involve the med-
ullary cavity. All intermediate stages between small cortical
or subperiosteal lesions with slight excavation of the cor-
tex – fibrous cortical defect – and the large intramedullary
lesions are different manifestations of the same condition.
• Sometimes in pathologic fractures associated to MFD, the
lesion may be masked by the fracture.
CT Features
• Lytic lesion with sclerotic margin
• Useful to show medullary extension and cortical erosion
and disruption
MRI Features
• Low and heterogeneous signal on T1- and T2-weighted
images.
• Scalloped well-delimited contour.
• Dark line of sclerotic bone limits the intramedullary mar-
gin of the lesion.
• Peripheral intramedullary edema in T2-weighted images
suggests microfractures or occult fracture.
Bone Scan
• Low signal
Image Differential Diagnosis
Periosteal Desmoid
• Radiologically similar to cortical fibrous defect
• Different histological pattern
51 Metaphyseal Fibrous Defect
Benign Fibrous Histiocytoma
• Radiolucent with sclerotic margins
• Epiphyseal and diaphyseal location
• Intramedullary location
Giant Cell Tumor
• Epiphyseal lesion involving the metaphysis in its
evolution.
• Peak of incidence in the third decade of life.
• More frequent in females.
• Inner border of the lesion is lytic.
• Extremely rare with sclerotic rim.
Fibrous Dysplasia
• Intramedullary centered.
• Well-circumscribed areas of rarefaction, commonly bor-
dered by a sclerotic rim, frequently so thick that appears
as a rind.
• The upper or lower limit frequently shows a triangular
shape.
• The lesion has a ground glass-like or lytic appearance.
• Does not show trabeculation.
Simple Bone Cyst
• Well outlined; centrally and symmetrically located
metaphysio-diaphyseal lucency; expanding, thinning, and
scalloping the cortices.
• Not wider than the epiphyseal plate.
• The cyst has its greatest diameter near the epiphyseal
plate and its conic end in the shaft.
• MRI usually confirms the cystic nature and its fluid con-
tent without solid components and with a sharp margin
with trabeculation.
Pathology
Gross Features
• Frequently, the diagnostic material is obtained by core
needle biopsy.
• Small fragments when in curettage-treated lesions.
• Rarely, specimens are sent intact, treated with complete
excision or resection.
• Usually with a diameter of 2–4 cm, rarely more than
7 cm.
• Gross appearance varies considerably in different areas of
the same lesion: zones of grayish-white color alternating
with yellow or reddish-brown color.
• Soft consistency with occasional friable areas.
• In surgical excision specimens, the lesion slightly expands
and thins the cortex that usually remains intact and infre-
quently may present resorption.
711
• The lesion is well demarcated from the surrounding med-
ullary bone.
• Cystic hemorrhagic changes may be seen.
Histological Features
• Histologically, at low magnification, the lesion varies
from area to area. Grayish-white macroscopic regions
correspond to fibrous tissue, yellow areas to lipid-laden
histiocytes, and brown areas to hemosiderin-laden
histiocytes.
• Fibrous tissue presents a characteristic whorled, stori-
form, or cartwheel pattern, with varying amount of colla-
gen fibers and bland fibroblasts. Nuclei are plump and
uniform, without hyperchromasia. The nuclei of spindle
cells and histiocytes are regular.
• Moderate number of typical mitosis may be present.
• Areas of lipid-bearing histiocytes with small dark nuclei
and clear granular cytoplasm – xanthoma cells – and
hemosiderin pigment-loaded histiocytes are seen.
• Variable number of multinucleated giant cells scattered
throughout the lesion in clusters.
• Inflammatory elements – lymphocytes and plasmacytes –
are another characteristic finding.
• Lack of new bone formation except in the margins of the
lesion. The presence of new bone formation without
pathologic fracture is extremely rare.
• Presence of osteoclasts at the inner border of the cortex.
• Areas of secondary aneurysmal bone cyst may be present.
• Areas of necrosis are extremely unusual. In cases of
pathologic fracture, the lesion may be totally necrotic.
• Histologically and ultrastructurally, metaphyseal fibrous
defect and cortical fibrous defect are similar.
• In older lesions, collagenous fibrous tissue predominates,
with scarce areas of histiocytes with phagocytosis of lip-
ids and hemosiderin and few multinucleated giant cells.
Reactive bone formation is frequently seen.
• The association with pathologic fracture elicits periosteal
and endosteal new bone formation and areas of necrosis.
Pathologic Differential Diagnosis
Periosteal Desmoid
• Although roentgenographically similar to the cortical
fibrous defect, histologically it differs and is included in
the group of desmoplastic fibromas, periosteal type.
Fibrous Dysplasia
• Irregular curvilinear immature trabeculae in a bland spin-
dle cell fibrous component.
• Rounded cementum-like corps bodies.
712
• Foam cells, multinucleated cells, and myxoid or second-
ary aneurysmal bone cyst change may occur.
• Cartilage may rarely be present in solitary lesions and
more frequently in multiple lesions.
• Extensive myxoid change in some cases.
• Metaphyseal fibrous defect lacks metaplastic bone forma-
tion that is only seen at the periphery.
Osteofibrous Dysplasia
• Immature curvilinear bone trabeculae rimmed by plump
osteoblasts
• Spindle cells in a dense collagenous stroma
• Expression of cytokeratins in myofibroblastic cells
Giant Cell Tumor
• In MFD, the multinucleated giant cells are generally scat-
tered in the lesion and arranged in clusters.
• Contain fewer nuclei than the giant cells of GCT.
• The spindle nature of the stromal cells is characteristic,
with pointed-ended nuclei. GCT mononuclear cells are
oval and not spindled, and their nuclei are typically simi-
lar to the nuclei of the multinucleated giant cells.
Solid Aneurysmal Bone Cyst
• More intralesional reactive bone
• Less storiform pattern of spindle cells
Benign Fibrous Histiocytoma
• Histologically indistinguishable lesion.
• MFD and BFH share microscopic features like:
– Spindle cells in a storiform arrangement.
– Histiocytes with phagocytic activity of lipids and
hemosiderin.
– Multinucleated giant cells.
– The diagnosis of BFH is based on clinical and site
where MFD is rare.
– BFH is a very infrequent lesion.
– Occurs in adults.
– Slightly more frequent incidence in females.
– Pain is a frequent symptom.
– In long bones, it is frequently seen in the epiphysis and
diaphysis.
– Does not arise in the metaphysis.
– Most common sites: femur and tibia − 50 %. Less
common in pelvic bones.
Malignant Fibrous Histiocytoma
• Rarely, MFDs are more cellular and with brisk mitotic
activity.
• Nuclear pleomorphism and atypical mitosis are never
seen in MFD.
L.G. Olvi and E. Santini-Araujo
• The characteristic radiographic pattern of MFD is never
seen in malignancies.
Osteosarcoma
• In pathologic fracture the reactive bone formation may be
misinterpreted.
• Prominent periosteal new bone formation may be
present.
• At low magnification, the orderly arrangement of the peri-
osteal new bone formation militates against the diagnosis
of OS. This is a clue to make an accurate diagnosis.
• Contrarily, the brisk mitotic activity and the osteoid pro-
duction may result in a mistaken overdiagnosis of
malignancy.
Prognosis
• Benign lesion that often regresses spontaneously.
• Lesions may disappear or become sclerotic.
• Large lesions may be associated with pathologic fractures,
most commonly in the lower metaphysis of the tibia.
• MFDs are almost never seen in older patients, probably
because the lesions are spontaneously healed.
• Rarely recurs after surgical treatment.
• Malignant transformation is definitively infrequent.
Treatment
• With an accurate diagnosis and no threat of pathologic
fracture: observation.
• Frequently, lesions can be confidently diagnosed based on
radiographic features and puncture needle or surgical
biopsy. Surgical treatment is not necessary and may be
followed by X-rays.
• Trocar biopsy and surgical biopsy may increase the risk
of fracture.
• Treatment is indicated in large painful lesions or when
risk of pathologic fracture exists – lesion occupying more
than 50 % of the bone diameter.
• Curettage or excision, followed by bone grafting.
• In cases of pathologic fracture, it is better to allow spon-
taneous healing prior to surgical treatment.
Images
See Figs. 51.1, 51.2, 51.3, 51.4, 51.5, 51.6, 51.7, 51.8, 51.9,
51.10, 51.11, 51.12, 51.13, 51.14, 51.15, 51.16, 51.17, 51.18,
51.19, 51.20, 51.21 and 51.22, 51.23, 51.24, 51.25, and
51.26 for illustrations of metaphyseal fibrous defect.
51 Metaphyseal Fibrous Defect 713

Fig. 51.1 Metaphyseal fibrous

a b
defect (MFD) of the distal femur.
(a, b) Anteroposterior and lateral
X-ray showing a large
radiolucent lesion, with
well-defined sclerotic border. (c)
Axial CT scan showing the
defect with posterior disruption
of the cortex

c
714 L.G. Olvi and E. Santini-Araujo

Fig. 51.2 (a, b) Anteroposterior

and lateral X-ray showing a b
radiolucent, eccentrically lesion
in the distal metaphysis of the
femur, juxtaposed to the
endosteal surface of one cortex

a b

Fig. 51.3 (a, b) MFD.

Roentgenographic
anteroposterior and oblique view.
Lytic, eccentric elongated lesion
in the distal femur; the long axis
of the lesion is parallel to the
host bone
51 Metaphyseal Fibrous Defect 715

Fig. 51.4 (a, b) MFD in the

a b
posterior aspect of the femur.
Anteroposterior and lateral
radiographs showing a large
lesion with the characteristic
pattern

a b

Fig. 51.5 X-ray anteroposterior

view. (a) Male, 11 years old, with
a small fibrous defect in the distal
metaphysis of the femur. (b)
Same lesion, 3 years later
716 L.G. Olvi and E. Santini-Araujo

a b

Fig. 51.6 (a, b) Radiographic and computed tomographic scan image. Long evolution of MFD with sclerosis of the lesion

a b

Fig. 51.7 (a, b) Radiographic

images. Metaphyseal fibrous
defect complicated with
pathologic fracture
51 Metaphyseal Fibrous Defect 717

Fig. 51.8 MFD in the upper metaphysis of the tibia. Anteroposterior

radiograph shows radiolucent, eccentric lesion with well-defined, scle-
rotic inner border

a b

Fig. 51.9 (a, b) MFD of the

tibia. Anteroposterior and lateral
radiographs showing a lesion
with the characteristic pattern
718 L.G. Olvi and E. Santini-Araujo

Fig. 51.10 (a, b)

Anteroposterior and lateral a b
X-ray, sclerotic old lesion in the
proximal metaphysis of the tibia.
(c) Axial CT image of the lesion
clearly shows the sclerosis

c
51 Metaphyseal Fibrous Defect 719

Fig. 51.11 (a, b) MFD in the

a b
proximal tibia with pathologic
fracture shown in anteroposterior
and lateral radiographies
720 L.G. Olvi and E. Santini-Araujo

a b

c d

Fig. 51.12 (a–d) Radiographs and MRI showing MFD typical features in a lesion of the lower tibial metaphysis
51 Metaphyseal Fibrous Defect 721

Fig. 51.13 MDF. Lytic eccentric lesion. The inner border is well
defined and slightly sclerotic, suggestive of a nonaggressive lesion, pro-
ducing a scalloped margin
722 L.G. Olvi and E. Santini-Araujo

Fig. 51.14 (a, b) MFD in the

a b
distal tibia with dense sclerotic
margin

a b

Fig. 51.15 (a, b) Radiographic

and CT scan image. Long
evolution of MFD with sclerosis
of the lesion in the distal
metaphysis of the tibia
51 Metaphyseal Fibrous Defect 723

Fig. 51.16 Metaphyseal fibrous defect of the fibula that occupies the
entire width of the bone
724 L.G. Olvi and E. Santini-Araujo

Fig. 51.17 (a, b) Slightly

a b
expansile well-circumscribed
lesion of the distal fibula, with
trabeculated pattern and
expanded bone contour
51 Metaphyseal Fibrous Defect 725

Fig. 51.18 MFD in the upper third of the humerus. Infrequent

location

Fig. 51.19 MFD in the distal radius. Typical radiologic features

726 L.G. Olvi and E. Santini-Araujo

Fig. 51.20 (a, b)

a b
Anteroposterior and lateral X-ray
showing a large radiolucent
lesion involving the entire width
of the radius, expanding and
thinning the cortex
51 Metaphyseal Fibrous Defect 727

Figs. 51.21 and 51.22 Two cases with multiple metaphyseal fibrous defect

Fig. 51.24 Core needle biopsy showing the storiform pattern of MFD

Fig. 51.23 Metaphyseal fibrous defect gross specimen. Gross appear-

ance varies considerably in different areas of the same lesion: zones of
grayish white color alternating with yellow or reddish brown color
728 L.G. Olvi and E. Santini-Araujo

a b

Fig. 51.25 (a–c) Typical MFD showing high cellularity with spindle cell arranged in storiform pattern and scattered osteoclast-type giant cell
51 Metaphyseal Fibrous Defect 729

a Recommended Reading
Arata MA, Peterson HA, Dahlin DC. Pathological fractures through
non-ossifying fibromas. Review of the Mayo Clinic experience.
L Bone Joint Surg (Am). 1981;63:980–8.
Caffey J. On fibrous defects in cortical walls of growing prevalence,
natural course and diagnostic significance. Adv Pediatr.
1955;7:13–51.
Hatcher CH. The pathogenesis of localized fibrous lesions in the
metaphyses of long bones. Ann Surg. 1945;122:1016–30.
Jaffe HL, Lichtenstein L. Non-osteogenic fibroma of bone. Am J Pathol.
1942;18:205–21.
Kimmelstiel P, Rapp I. Cortical defect due to periosteal desmoids. Bull
Hosp Joint Dis. 1951;12:286–97.
Mirra JM, Gold RH, Rand F. Disseminated nonossifying fibromas in
association with café-au-lait spots (Jaffe-Campanacci Syndrome).
b Clin Orthop. 1982;168:192–205.
Ponseti IV, Friedman B. Evolution of metaphyseal fibrous defects.
J Bone Joint Surg. 1949;31A:582–5.
Schajowicz F. Tumors and tumorlike lesions of bone and joints.
New York/Heidelberg/Berlin: Springer-Verlag. 1981.
Steiner GC. Fibrous cortical defect and nonossifying fibroma of bone:
a study of the ultrastructure. Arch Pathol. 1974;97:205–10.

Fig. 51.26 (a) Areas of histiocytes with phagocytosis of lipids (foam

cells) and (b) hemosiderin
 Periosteal Desmoid
52
Liliana G. Olvi and Eduardo Santini-Araujo

Abstract
A hypocellular variant of fibrous cortical defect – localized in the posterior surface of the
distal femur.
Radiologically it is seen as an irregular lytic lesion in the cortex. Histologically it looks
like a hypocellular variant of the group of fibrous defects. Treatment: Frequently lesions can
be confidently diagnosed based on radiographic features and puncture needle or surgical
biopsy, and surgical treatment is not necessary and may be followed with X-rays.

Definition Clinical Features

• A hypocellular variant of fibrous cortical defect – local- Epidemiology

ized in the posterior surface of the distal femur
• Age overlap with fibrous cortical defect

Synonyms
Sites of Involvement
• Avulsive cortical irregularity
• Distal femur, posteromedial cortex

Etiology
• Probably related to an avulsive injury to the insertion of
the tendon of the adductor magnus muscle
Clinical Symptoms and Signs
• Usually asymptomatic or with mild pain
• Incidental radiographic finding, after a roentgenologic
examination for other reasons

L.G. Olvi, MD
Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina Image Diagnosis
E. Santini-Araujo, MD (*)
Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina Radiographic Features
Department of Pathology, School of Medicine, School of Dentistry,
University of Buenos Aires, Buenos Aires, Argentina • Irregular lytic lesion in the cortex.
Central Army Hospital, Buenos Aires, Argentina • May suggest malignancy.
e-mail: santiniaraujo@laborpat.com.ar • Site and small size are diagnostic.

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 731
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_52, © Springer-Verlag London 2015
732 L.G. Olvi and E. Santini-Araujo

Image Differential Diagnosis Prognosis

Cortical Fibrous Defect Excellent.

• Radiologically similar Unfortunately the term desmoid suggests an aggressive
prognosis that is not so.

Pathology
Treatment
Gross Features
• Frequently lesions can be confidently diagnosed based on
• Frequently the material is obtained by trocar biopsy. radiographic features and puncture needle or surgical
• Small fragments in curettage-treated lesions. biopsy, and surgical treatment is not necessary and may
be followed with X-rays.

Histological Features
Images
It looks like a hypocellular variant of the group of fibrous
defects. See Figs. 52.1, 52.2, 52.3, and 52.4 for illustrations of peri-
• Multinucleated giant cells are scarce or absent. osteal desmoid.

Pathologic Differential Diagnosis

It is extremely important to recognize the lesion clinically

and by images to not overdiagnose as a malignancy and to
avoid biopsy.
52 Periosteal Desmoid 733

Fig. 52.1 (a) Roentgenogram

showing an elongated area of a b
cortical irregularity along the
medial cortical tibia. (b) CT scan
shows an intracortical small lytic
lesion. (c) MRI, the arrow
indicates the area of cortical
erosion

c
734 L.G. Olvi and E. Santini-Araujo

Fig. 52.2 (a, b) Anteroposterior

and lateral X-ray of a periosteal a b
desmoid in the posterior cortex of
tibial metaphyseal area

Fig. 52.3 Microphotograph at higher magnification showing the irreg- Fig. 52.4 Microphotograph illustrating a desmoid hypocellular lesion
ularity of the underlying cortical bone. The lesion is composed of hypo- with abundant collagen production
cellular spindle cells
52 Periosteal Desmoid 735

Recommended Reading
Barnes Jr GR, Gwinn JL. Distal irregularities of the femur simulating
malignancy. Am J Roentgenol Radium Ther Nucl Med.
1974;122:180–5.
 Fibrous Dysplasia
53
Liliana G. Olvi and Eduardo Santini-Araujo

Abstract
Fibrous dysplasia is a benign intramedullary fibro-osseous “dysplastic” noninherited bone
lesion. The disorder may be monostotic or polyostotic. There is slight female predomi-
nance. Monostotic lesions (75 %) are more frequent in second and third decades. Polyostotic
lesions (25 %) are more frequent in the first decade. Approximately 3 % patients with poly-
ostotic lesions develop McCune–Albright syndrome associated with café-au-lait pigmenta-
tion of the skin and endocrine anomalies. Monostotic and polyostotic forms arise more
frequently in long bones (proximal femur, tibia, humerus), craniofacial bones—especially
in the jaws (the maxilla is more involved than the mandible)—and ribs. Any bone may be
affected. Roentgenologic appearances in monostotic or polyostotic form are similar.
Centered, intramedullary, elongated lesions arise in metaphysis or diaphysis of long bones.
Epiphyseal location is uncommon while the growing plates are open. The lesion has a
ground glass–like or lytic appearance. Histologically, the lesion is composed of a bland
proliferation of plump fibroblasts in a dense collagenous, well-vascularized matrix. Within
the fibrous tissue, in typical fibrous dysplasia, a variable presence of discontinuous imma-
ture woven osteoid or bone trabeculae is seen with flat or spindle-shaped osteoblasts rim-
ming. Treatment in monostotic asymptomatic lesions is observation, surgical treatment,
curettage, and grafting (auto- or allografts) or resection in cases of pathological fracture or
risk of fracture or to correct deformities.

Definition Etiology

• Benign intramedullary fibro-osseous “dysplastic” non- • At present, it is postulated that the immature bone produc-
inherited bone lesion. tion is determined by a post zygotic point mutation of the
• The disorder may be monostotic or polyostotic. GNAS1 gene, which encodes the α-subunit of the Gs
α-stimulatory protein.

L.G. Olvi, MD Clinical Features

Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina
E. Santini-Araujo, MD, PhD (*) Epidemiology
Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina
Department of Pathology, School of Medicine and School of • It is a common lesion.
Dentistry, University of Buenos Aires, Buenos Aires, Argentina • Slight female predominance.
Central Army Hospital, Buenos Aires, Argentina • Monostotic lesions (75 %): more frequent in the second
e-mail: santiniaraujo@laborpat.com.ar and third decades.

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 737
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_53, © Springer-Verlag London 2015
738
• Polyostotic lesions (25 %): more frequent in first the
decade.
• Approximately 3 % patients with polyostotic lesions
develop McCune-Albright syndrome, associated with café
au lait pigmentation of the skin and endocrine anomalies.
• Rarely, fibrous dysplasia is associated with soft tissues
myxomas, usually in intramuscular location (Mazabraud
syndrome).
Sites of Involvement
• Monostotic and polyostotic forms arise more frequently
in long bones (proximal femur, tibia, humerus) and cra-
niofacial bones – especially in the jaws (the maxilla is
more involved than the mandible) – and ribs. Any bone
may be affected.
• Monostotic disease affects a single bone usually with
one focus. Rarely, more foci may be seen in the same
bone.
• Polyostotic fibrous dysplasia is more frequently mono-
melic, polyostotic monomelic fibrous dysplasia – involv-
L.G. Olvi and E. Santini-Araujo
ing homolateral lower limbs and ilium. The more severe
cases are polymelic.
• Spine is an infrequent location, more frequently associ-
ated with the polyostotic form.
• Rib location is more frequent in older patients, probably
due to older patients having more commonly chest radi-
ography, and the lesions are incidentally discovered.
Clinical Symptoms and Signs
• Usually asymptomatic.
• Incidental radiographic finding after a roentgenological
examination for other reasons, most frequently in ribs.
• Pain may appear depending on site and extent of the lesion.
• Occasionally, localized swelling may appear, more fre-
quently in the jaws and the skull.
• Monostotic lesions may progress and enlarge, most com-
monly during skeletal growth. They tend to stabilize after
puberty, but lesions may not be quiescent in adulthood.
• Some lesions may grow during pregnancy.
53 Fibrous Dysplasia
• Some lesions may produce deformity.
• Pathologic fracture – frequently in the proximal femur –
and deformity of weight-bearing bones are commonly seen.
• Craniofacial lesions may produce asymmetry, exophthal-
mos, impingement of cranial nerves – like the optic
nerve – affection of middle ear structures, and deformity.
Chronic headache may be present.
• Polyostotic form may involve a few bones of a single
extremity or compromise more than 50 % of the skeleton.
This presentation begins early in life – before 10 years of
age – and the disease has a rapid progress.
• Limb length discrepancies.
• Polyostotic forms associated to McCune-Albright syn-
drome – which is more common in females – present
cutaneous pigmentation in the form of yellow or brown
patches frequently located on neck, back, shoulder, chest,
and pelvis. Albright macules of fibrous dysplasia have
irregular and dented borders like the coast of Maine,
whereas in neurofibromatosis, the macules are irregular
but with smooth borders resembling the coast of
California, endocrine hyperactivity; precocious sexual
development – sometimes starting as early as 3 years –
vaginal bleeding; development of breasts; hyperthyroid-
ism; frequently secondary hyperparathyroidism;
Cushing’s syndrome; acromegalia; hyperprolactinemia;
adrenal hyperplasia; early bone maturation with prema-
ture closure of the growth plates and consequent short
stature; and renal phosphate wasting – in 50 % of the
patients. Infrequently, excess FGF-23 is produced, deter-
mining osteomalacia as in the phosphaturic mesenchymal
tumor. If not detected in time, these patients may present
deformities and fractures, leading to a crippling disease.
Image Diagnosis
Radiographic Features
• Roentgenological appearances in monostotic or polyos-
totic form are similar.
• Centered, intramedullary, elongated lesions arising in
metaphysis or diaphysis of long bones. Epiphyseal loca-
tion is uncommon, while the growing plates are open.
• Well-circumscribed areas of rarefaction, commonly bor-
dered by a sclerotic rim, frequently so thick that appear as
a rind.
• The upper or lower limit frequently shows a triangular
shape.
• The lesion has a ground-glass-like or lytic appearance.
The roentgenological density varies in relation with the
intralesion amounts of fibrous or osseous tissue.
• The lesions may expand the affected bone – but have
sharp circumscription – especially in rib, pelvis, fibula,
and small tubular bones. Lesion scallops and erodes the
739
endosteal surface, thinning the cortex, sometimes expand-
ing bone and determining a newly formed cortex.
• Periosteal reaction and soft-tissue extension are extremely
infrequent, without a pathologic fracture occurring.
• Rarely some lesions produce a large expansile mass that
bulges into soft tissues. More frequent in craniofacial
skeleton. Some authors classified this case as fibrous dys-
plasia protuberans.
• Craniofacial lesions may be extremely dense, especially
the maxilla and skull base.
• Bone deformity – bowing – usually affects weight-bearing
long bones such as the femur – “shepherd’s crook defor-
mity” – and the tibia.
• In rare lesions with cartilaginous component, a
radiographic pattern of ring and spotty calcifications is
frequently present. This pattern is especially frequent in
the upper end of the femur and in polyostotic disease.
• Pathologic fracture may occur. The fracture line is often
transverse similar to what occurs in Paget’s disease fractures.
This pattern of fracture reveals that the microstructure of
bone is disturbed, like in Paget’s disease or osteopetrosis.
• Rarely secondary ABC may give an aggressive appear-
ance to the lesion that simulates a sarcoma.
CT Features
• Expansile well-circumscribed lesion.
• Soft mineralization in relation with ground grass roent-
genographic pattern.
• The density is related with the mineralization of the
lesion.
• Helpful in delimiting the involvement especially in maxil-
lary and craniofacial bones.
MRI Features
• Well-circumscribed T2-weighted lesion.
• The ground-glass pattern is seen as a soft mineralized
lesion.
• Cysts appear with fluid signal characteristics, with a
homogeneous hyperintense signal on T2-weighted images.
• Shows the scalloping on the endosteal surface of the cortex.
Bone Scan
• High signal
PET Scan
• High uptake
740
Image Differential Diagnosis
Periosteal Desmoid
• Radiologically similar to cortical fibrous defect
• Different histological pattern
Osteofibrous Dysplasia
• Cortical lesion arising in the tibia and fibula of children
• Frequently produce an anterior bowing of the affected bone
• Not a medullary lesion
Benign Fibrous Histiocytoma
• Radiolucent with sclerotic margins
• Epiphyseal and diaphyseal location
• Intramedullary location
Giant Cell Tumor
• Epiphyseal lesion involving metaphysis in its evolution.
• Highest incidence in the third decade of life.
• More frequent in females.
• Inner border of the lesion is lytic. Extremely rare to be
sclerotic.
Solitary Bone Cyst
• Well-outlined centrally and symmetrically located
metaphyseal-diaphyseal lucency, expanding, thinning,
and scalloping the cortices.
• The cyst has its greatest diameter near the epiphyseal
plate and its conic end in the shaft.
• A multilocular or trabeculated appearance may be seen due
to prominent endosteal bony ridges in the inner cortical wall.
• MRI usually confirms the cystic nature and its fluid con-
tent without solid components that can be bloody in frac-
tured lesions.
Chondroma, CHS
• Usually present spotty dense calcifications
Chondromyxoid Fibroma
• Is usually a more radiolucent lesion in comparison with FD
Eosinophilic Granuloma
• Radiolucent, eccentrically elongated lesion in the metaph-
ysis of long bones, juxtaposed to the endosteal surface of
one cortex
Metaphyseal Fibrous Defect
• In small bones or long bones of small diameter, the lesion
may occupy the whole diameter of the medullary cavity
and pose the differential with MFD.
• Radiologically, MFD is a radiolucent, eccentric lesion
juxtaposed to the endosteal surface of one cortex in con-
trast to FD, which is more centrally located in the medulla.
• As long bone grows, it becomes separated from the epiph-
yseal plate, moving toward the diaphysis.
L.G. Olvi and E. Santini-Araujo
• Lesions tend to thin and slightly expand one or both corti-
cal surfaces.
• The inner border is well defined and slightly sclerotic, sugges-
tive of a nonaggressive lesion, producing a scalloped margin.
• Infrequently, large lesions may involve the entire width of
the bone.
Desmoplastic Fibroma
• Usually associated to cortical disruption
ABC
• Area of lucency situated eccentrically in the medullary
cavity in the metaphysis of a long bone.
• Most ABCs are completely lytic, but a few contain traces
of mineral.
• Frequently presents a multiloculated appearance.
• Less commonly, the lesion may be situated centrally.
• Later on, “ballooned” or “aneurysmal” cystic expansion
of the affected bone –“blowout” – is evident. Usually
forms a thin sclerotic rim of ossification due to periosteal
new bone formation.
• CT and MRI show a cystic and radiolucent lesion, with
internal septations and multiple fluid-fluid levels. Some
FD, however, may show features of secondary ABC. In
any case, both CT and MRI help to highlight the eventual
presence of an underlying lesion.
Well-Differentiated Intramedullary
Osteosarcoma
• Lacks a sclerotic border
• Permeative margins
Pathology
Gross Features
• Frequently, the material is obtained by core needle biopsy.
• In surgical biopsies, tissue is tan-gray, dense, and fibrous.
• The number and size of immature osteoid or bone tra-
beculae present within the fibrous tissue give it a more or
less gritty quality to the cutting procedure.
• When the lesion is more mineralized, the appearance is
white to yellow.
• Sometimes the lesion may present a dense ossification,
most common in craniofacial and jaws locations.
• In surgical specimens, the lesions are intramedullar cen-
trally located and well defined, the bone contour is
expanded, and the cortex is thinned. In older lesions, an
edge of reactive sclerotic bone may be seen.
• Cyst formation is commonly present, and the cyst cavity
is filled with yellowish clear fluid. Cyst formation may be
slight or extensive.
• Secondary aneurysmal bone cyst may sometimes appear
with blood-filled multicameral cyst.
53 Fibrous Dysplasia
• Yellowish areas are related to lipid-laden histiocytes –
xanthoma cells.
• Chondroid foci, when present, are seen as bluish translu-
cent nodules. Rarely, the cartilaginous component may
predominate.
• Hemorrhages and hemosiderin pigment are found after
pathologic fractures.
Histological Features
• Histologically, the lesion is composed by a bland prolif-
eration of plump fibroblasts in a dense collagenous, well-
vascularized matrix by thin capillary vessels.
• The spindle cells present a storiform or whorled pattern
without cytological atypia, hyperchromatism, or nuclear
pleomorphism.
• Mitoses are extremely infrequent. Mitoses are seen in the pic-
ture of pathologic fractures. Atypical mitoses are not seen.
• Within the fibrous tissue, in typical fibrous dysplasia, a
variable presence of discontinuous immature woven oste-
oid or bone trabeculae is seen, with flat or spindle-shaped
osteoblast rimming.
• Bony trabeculae of different sizes are arranged in a hap-
hazard, nonfunctional fashion. They are peculiar with so-
called “Chinese characters” shapes. They are curvilinear,
in C, U, and sometimes circumferential shapes.
• In more mature lesions, trabeculae may present reversal
cement lines simulating the histological appearance of
Paget’s disease.
• The presence of a lamellar pattern in some trabeculae is
extremely infrequent.
• With silver stain for reticulin fibers or polarization micros-
copy, it is possible to see the continuity between newly
formed reticulin fibrils of the dysplastic stroma and those
that form the matrix of woven trabeculae. This corre-
sponds to a preexisting compressed network of newly
formed reticulin fibers, which later mineralize with cal-
cium granules.
• Typical fibrous dysplasia may show large areas without
bone formation. These areas have a particular storiform
pattern of the spindle cells.
• The presence of rounded ossicle-like or cementicle-like
structures resembling psammoma bodies or cementoid
bodies is frequently found in fibrous dysplasia. This fea-
ture is most commonly seen in lesions arising in the base
of the skull and sometimes is erroneously diagnosed as
meningiomas. This pattern is also seen in other sites as
long bones but rarely are a prominent component of the
lesions.
• Osteoclasts can be sometimes observed resorbing imma-
ture bony trabeculae.
• Hemorrhagic areas and hemosiderin pigment deposits are
found after pathologic fractures as well as areas of necrosis.
741
• Other cytological tissue patterns that can be observed are:
– Collections of foam cells.
– Frequent clusters of multinucleated giant cells.
– An occasional fibrous dysplasia will present extensive
areas of hypocellular myxoid matrix and may be called
myxoid fibrous dysplasia.
– Islands of cartilage may predominate in some cases of
fibrous dysplasia as round nodules that in some lesions
may resemble the structure of epiphyseal plate carti-
lage. Endochondral ossification may be observed.
Some authors have called these cases fibrocartilagi-
nous dysplasia.
– Areas of cystic degeneration with serous fluid content
may be found, sometimes surrounded by lipophages
and multinucleated giant cells.
– Secondary aneurysmal bone cyst formation may be
present in fibrous dysplasia.
• Rarely, sarcomas may be associated to fibrous dysplasia –
most commonly in polyostotic disease. Post-radiation sar-
coma in FD may be originated from radiation therapy.
Most commonly, these sarcomas are: osteosarcomas,
fibrosarcomas, and chondrosarcomas. Facial bones and
the femur are the more frequently involved bones.
Pathologic Differential Diagnosis
Osteofibrous Dysplasia
• Both entities share histological feature’s resemblance.
• OFD presents immature curvilinear bone trabeculae
rimmed by prominent plump osteoblasts.
• Spindle cells in a dense collagenous stroma.
• Spindle cells express keratin and EMA.
• OFD is a cortical lesion, localized predominantly in the
tibia of children.
Ossifying/Cementifying Fibroma
• Fibro-osseous lesion of the jaws.
• FD contacts with the cortex and merges into it. Frequently
erodes and thins the cortex.
• OCF is more clearly delimitated and separated by fibrous
tissue from the endosteal surface of the cortex.
• Images are extremely useful to make a sharp differential
diagnosis.
Metaphyseal Fibrous Defect
• Histologically, some FD present areas of foamy cells that
determine that, in small biopsy specimens, the differential
with MFD may be considered.
• In MFD, fibrous tissue presents a characteristic
whorled – storiform or cartwheel – pattern more evident
than in FD, with the presence of histiocytes and areas of
lipid-bearing histiocytes and hemosiderin pigment-
loaded histiocytes. Variable number of multinucleated
742
giant cells are scattered throughout the lesion, usually
in clusters.
• Inflammatory elements – lymphocytes and plasmacytes –
are another characteristic finding.
• Lack of new bone formation except in the margins of the
lesion. The presence of new bone formation without
pathologic fracture is extremely rare.
• The association with pathologic fracture presents perios-
teal and endosteal new bone formation and areas of
necrosis.
Desmoplastic Fibroma
• Lack of woven bone formation
• No storiform pattern
• Presence of intersecting fascicles of spindle cells
Chondrosarcoma
• Small microscopic foci of chondroid tissue may be seen
in FD, but sometimes the chondroid differentiation is
massive and the differential between chondroid tumors
must be considered.
• The chondroid areas in FD do not present cytological
atypia.
• The cartilage lobules in FD present a characteristic
encasement with endochondral ossification.
• Infiltration of bone marrow areas is never seen in FD.
Parosteal Osteosarcoma
• May be very difficult to diagnose on pure histological
grounds. Knowledge of clinical and x-ray data by the
pathologist is indispensable.
• Parosteal osteosarcoma arises in the surface of bone and
not in the medullary cavity.
Low-Grade Central Osteosarcoma
• Stromal spindle cells are more elongated and present
nuclear hyperchromasia and cellular atypia.
• More frequent mitoses.
• Lack of storiform pattern.
• Permeation of bone marrow areas encasing native lamel-
lar trabeculae.
• Tumor cells express MDM2 and CDK4 by immunohisto-
chemistry or molecular techniques.
Meningioma in the Base of Skull
• The presence of rounded ossicle-like or cementicle-like
structures resembling psammoma bodies or cementoid
bodies in FD, pattern that is especially prominent in skull
base lesions, may mimic meningiomas.
Aneurysmal Bone Cyst
• FD may suffer secondary ABC changes. This differential
is difficult to perform in small biopsies.
L.G. Olvi and E. Santini-Araujo
• The image correlation is of extreme value for the differen-
tial diagnosis.
Solid Aneurysmal Bone Cyst
• Almost all ABCs have some solid area that may be promi-
nent in some of them and where cystic spaces and septae
may not be identified. The term “solid ABC” has been
adopted for these cases.
• More intralesional reactive bone.
• Less storiform pattern of the stromal spindle cells.
Fibromyxoma of the Bone
• Many of the cases reported are examples of myxoid
fibrous dysplasia.
Paget’s Disease
• In more mature lesions, trabeculae may present reversal
lines simulating the appearance of Paget’s disease
trabeculae.
• Paget’s disease has a peculiar mosaic pattern of lamellar
bone, never seen in FD.
• The pagetic bony trabeculae show numerous cement
lines.
• The pagetic trabeculae are rimmed by prominent
osteoblasts alternating with areas of osteoclastic
resorption.
• The bone marrow spaces are richly vascularized and with
a peculiar loose and edematous fibrous tissue.
• The disease has a similar skeletal distribution to FD but
affects older people.
Ancillary Techniques
• Immunohistochemistry has no value for diagnosis.
• Spindle cells express vimentin and do not express EMA,
MDM2, or CDK4.
Genetics
Severity of manifestations of McCune-Albright syndrome
depends on the number and types of cells that harbor muta-
tion in GNAS protein. The GNAS gene provides instructions
for making one part of a protein complex called a guanine
nucleotide-binding protein, or a G protein.
Prognosis
• Monostotic lesions: excellent prognosis.
• Polyostotic have more risk of deformities and fractures.
• In large rib lesions, the patient may suffer respiratory
problems.
53 Fibrous Dysplasia
• Spontaneous malignant transformation is rare. The risk is
greater with the polyostotic variant. More frequent around
the fourth decade of life, associated to lesions treated with
radiotherapy.
Treatment
• In monostotic asymptomatic lesion: observation.
• Surgical treatment, curettage, and grafting (auto- or
allografts) or resection in cases of pathologic fracture or
risk of fracture or to correct deformities. Some patients
require the use of nail/plate fixation.
Fig. 53.1 FD of the upper third of the left femur. X-ray shows a radio-
lucent lesion with a “ground-glass” appearance
743
• Polyostotic disease: the use of bisphosphonates has been
suggested.
• Radiotherapy must be avoided due to risk of development
of post-radiation sarcoma.
Images
See Figs. 53.1, 53.2, 53.3, 53.4, 53.5, 53.6, 53.7, 53.8, 53.9,
53.10, 53.11, 53.12, 53.13, 53.14, 53.15, 53.16, 53.17, 53.18,
53.19, 53.20, 53.21, 53.22, 53.23, 53.24, 53.25, 53.26, 53.27,
53.28, 53.29, 53.30, 53.31, 53.32, 53.33, 53.34, 53.35, 53.36,
53.37, 53.38, 53.39, and 53.40 for illustrations of fibrous
dysplasia.
Fig. 53.2 FD. Radiographic features. Anteroposterior view of the
right hip shows isolated lesion in metaphyseal-diaphyseal region with a
typical “ground-glass” feature
744 L.G. Olvi and E. Santini-Araujo

Fig. 53.3
(a) FD. Anteroposterior x-ray a b
showing ringlike sclerosis
of the bone at the periphery
which is characteristic of FD.
(b) T1-weighted MRI of the
same lesion

Fig. 53.4 FD. Anteroposterior radiograph of the left hip showing an Fig. 53.5 FD. Anteroposterior radiograph of the right femur shows
involvement of the acetabular region and an expansile lesion in the intramedullary lesion with central opacities and a fracture in the femo-
proximal femur. Note the “ground-glass” density of the lesion ral neck
53 Fibrous Dysplasia 745

Fig. 53.8 FD. Anteroposterior x-ray of right humerus demonstrating

Fig. 53.6 FD. Typical fibrous dysplasia affecting the neck and shaft of expansion of bone contour with cortical thinning
the left femur showing a bowing deformity of the internal cortex due to
secondary ABC

a b c

Fig. 53.7 FD. (a) Anteroposterior x-ray of the right tibia illustrating the “ground-glass” feature. (b) MRI of the same lesion. (c) Gross specimen
746 L.G. Olvi and E. Santini-Araujo

Fig. 53.9 FD. (a, b)

Anteroposterior and lateral x-ray a b
or distal humerus. “Ground-
glass” feature
53 Fibrous Dysplasia 747

a b

Fig. 53.10 FD. (a) Anteroposterior x-ray does not evidence lesion. (b) CT shows a “ground-glass” appearance of the supraorbital region. (c)
Tc99m scan shows FD with dense uptake of the radioisotope
748 L.G. Olvi and E. Santini-Araujo

a b

d
c

Fig. 53.11 FD. (a) Lateral x-ray of the skull showing a lytic lesion. (b) CT illustrating the same lesion. (c) Gross specimen. (d) X-ray of gross
specimen
53 Fibrous Dysplasia 749

a b

Fig. 53.12 FD. (a) Lateral x-ray of the skull showing a lytic lesion. (b) CT of the same lesion. FD in flat bones is often expansile

a b

Fig. 53.13 FD. Coronal (a) and axial (b, c) CT view. Polyostotic involvement of skull bones with a “ground-glass” appearance. The lesion causes
diffuse expansion of the diploic space and obliteration of the right sphenoid sinus and nasal cavity. Hot spot with Tc99m (d)
750 L.G. Olvi and E. Santini-Araujo

Fig. 53.14 FD. “Ground-glass” feature involving the right maxilla

Fig. 53.15 FD of the rib. Rib is a common location for this lesion

a b

Fig. 53.16 FD. (a) Involvement of several ribs, large bubbly and expanded masses. (b) High uptake of radioisotope
53 Fibrous Dysplasia 751

Fig. 53.17 FD. (a, b)

Anteroposterior and lateral x-ray a b
of the proximal radius showing a
prominent “ground-glass”
expanding lesion
752 L.G. Olvi and E. Santini-Araujo

Fig. 53.18 FD. Anteroposterior and lateral x-ray of the radius.

Intramedullary lesion with a “ground-glass” appearance

Fig. 53.20 FD. IV metatarsal bone. Unusual location for

monostotic FD
a

Fig. 53.19 FD. (a, b) Anteroposterior and lateral x-ray of the radius
showing a pathologic fracture
53 Fibrous Dysplasia 753

Fig. 53.22 FD. Radiographic features of multifocal FD of the fibula

Fig. 53.21 FD. (a) Anteroposterior x-ray of the left hip showing a
well-defined lesion in the pelvis. (b) CT scan illustrates a sharply mar-
ginated lesion of FD expanding the left iliac bone
754 L.G. Olvi and E. Santini-Araujo

Fig. 53.23 FD. (a) Lateral x-ray

of the calcaneus. (b, c) Axial and
sagittal MRI of the same lesion

a b

Fig. 53.24 FD. Axial CT shows an expansile lesion of lumbar verte-

bral body. Unusual location of monostotic FD
53 Fibrous Dysplasia 755

a b

c d

Fig. 53.25 Mazabraud syndrome. (a) Humerus. Well-delimited and sites of polyostotic FD with dense uptake. (e, f and g) T1- and
“ground-glass” lesion typical of FD. (b) Diffuse involvement of the T2-weighted MRI show well-circumscribed soft-tissue mass and gross
right femur. (c) Left femur showing the “ground-glass” density of specimen of soft-tissue myxoma
FD. Note the thick ring of surrounding sclerosis. (d) Tc99 scan shows
756 L.G. Olvi and E. Santini-Araujo

e f

Fig. 53.25 (continued)

53 Fibrous Dysplasia 757

a d

Fig. 53.26 Polyostotic FD. Involvement of ribs in both sides of the posterior and lateral aspect of both sides (b right and c left), bulging
chest wall. (a) X-ray of chest wall. (b, c) Axial CT scan of FD protuber- into the pleural space. (d) Hot spot with the multiple uptake of the
ans of the ribs showing a large, heterogeneous mass arising from the radioisotope
758 L.G. Olvi and E. Santini-Araujo

a b

c d

Fig. 53.27 (a) Facial deformity in polyostotic FD. (b, c) of both femurs with “shepherd’s crook” deformity. (e) X-ray of the
Anteroposterior and lateral x-ray. Extensive involvement of skull in lower leg of the same patient showing extensive intramedullary involve-
polyostotic FD with McCune-Albright syndrome. (d) Anteroposterior ment of the tibia and fibula, with thinning and scalloping of the cortex
x-ray of the pelvis and the proximal femur showing medullary lesions
53 Fibrous Dysplasia 759

Fig. 53.27 (continued)

a b

Fig. 53.28 Polyostotic FD. (a) X-ray of the chest wall. (b) 3D-reconstructed CT scan of the chest wall showing deformity of the ribs
760 L.G. Olvi and E. Santini-Araujo

a b

Fig. 53.29 (a) X-ray and (b) CT scan show secondary aneurysmal bone cyst in association with FD, producing an aggressive appearance in the
image, with cortical destruction and soft-tissue extension
53 Fibrous Dysplasia 761

Fig. 53.31 Pathologic fracture of FD in the proximal femur

Fig. 53.30 Pathologic fracture in a patient with FD in diaphysis of the

tibia
762 L.G. Olvi and E. Santini-Araujo

a b

c d

Fig. 53.32 Sarcoma in FD. Distal femur. (a, b) Anteroposterior and lateral radiographic image, showing a large, expansive, and lytic lesion. (c)
Gross specimen. (d) X-ray of gross specimen
53 Fibrous Dysplasia 763

a b

Fig. 53.33 (a) Low-power magnification of FD showing its well-circumscribed margin of growth composed of a spindle cell stroma with numer-
ous irregular trabeculae. (b) Periphery of the lesion

Fig. 53.34 Microphotograph of core needle biopsy

764 L.G. Olvi and E. Santini-Araujo

a b

Fig. 53.35 (a–c) High magnification of dysplasia lesion composed of bony trabeculae of different size arranged in a haphazard, nonfunctional
fashion, so-called “Chinese characters” shapes

a b

Fig. 53.36 (a) Microphotograph of the woven bone with the typical curvilinear, in C, U, and sometimes circumferential shape. Note the absence
of active osteoblastic rim. (b) High-power magnification showing the fibroblastic stroma arranged in a whorling pattern
53 Fibrous Dysplasia 765

a b

Fig. 53.37 (a) Axial section of a dysplastic trabucula. (b) Presence of cementoid bodies

a b

Fig. 53.38 (a–c) Sometimes the fibroblastic stroma may present myxomatous changes
766 L.G. Olvi and E. Santini-Araujo

a b

Fig. 53.39 (a) Secondary ABC changes in FD. (b) The wall of the cyst may be composed of a fibrous component with giant cell

a b

Fig. 53.40 (a, b) Gross specimen and low-power magnification with cartilaginous component
53 Fibrous Dysplasia 767

Recommended Reading Ruggeri P, Sim FH, Bond JR, Unni KK. Malignancies in fibrous dyspla-
sia. Cancer. 1994;73:1411–24.
Sissons HA, Steiner GC, Dorfman HD. Calcified spherules in fibro-
Candelier GA, Glorieux FH, Prud’homme J, St.-Arnaud R. Increased
osseous lesions of bone. Arch Pathol Lab Med. 1993;117:284–90.
expression of the c-fos proto-oncogene in bone from patients with
Unni KK. Conditions that commonly simulate primary neoplasms of
fibrous dysplasia. N Engl J Med. 1995;332:1546–51.
bone. In: Dahlin’s bone tumors: general aspects and data on 11,087
Harris WH, Dudley HR, Barry RJ. The natural history of fibrous dys-
cases. 5th ed. Philadelphia: Lippincott-Raven; 1996. p. 369.
plasia. J Bone Joint Surg Am. 1962;44:207–33.
Weinstein LS, Shenker A, Gejman PV, Merino MJ, Friedman E, Spiegel
Jee WH, Choi KH, Choe BY, Park JM, Shinn KS. Fibrous dysplasia:
AM. Activating mutations of the stimulatory G protein in the
MR imaging characteristics with radiopathologic correlation. AJR
McCune-Albright syndrome. N Engl J Med. 1991;325:1688–95.
Am J Roentgenol. 1996;167:1523–7.
 Osteofibrous Dysplasia
54
Liliana G. Olvi, Maria L. Gonzalez,
and Eduardo Santini-Araujo

Abstract
Osteofibrous dysplasia is a benign fibro-osseous lesion occurring in the bone during child-
hood and with the tendency to arise in the anterior cortex of the tibia and less often the
fibula. It is more frequent in males and occurs more commonly in the first two decades of
life. Radiologically, the lesion shows multiple lytic lesions involving the anterior cortex of
the tibia, with peripheral sclerosis. Growing lesions affect the cortex and produce an ante-
rior bowing. The surgical treatment may be done after puberty. It consists of excision of
the lesion.

Definition Clinical Features

• Benign fibro-osseous lesion occurring in bone during Epidemiology

childhood and with the tendency to arise in the anterior
cortex of the tibia and less often the fibula Sex
• More frequent in males

Synonyms Age
• More common in the first two decades of life.
• Ossifying fibroma • Isolated cases are seen in adults.

Etiology Sites of Involvement

• Unknown • Tibial shaft, in the anterior cortex

• Cortex of the fibula

Clinical Symptoms and Signs

L.G. Olvi, MD • M.L. Gonzalez, MD
Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina
• Pain and local swelling
E. Santini-Araujo, MD, PhD (*) • Tendency to anterior bowing deformity
Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina
Department of Pathology, School of Medicine
and School of Dentistry, University of Buenos Aires,
Buenos Aires, Argentina
Central Army Hospital, Buenos Aires, Argentina
e-mail: santiniaraujo@laborpat.com.ar

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 769
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_54, © Springer-Verlag London 2015
770 L.G. Olvi et al.

Image Diagnosis • The woven bony trabeculae are rimmed by prominent

Radiographic Features
• Multiple lytic lesions involving the anterior cortex of the
tibia, with peripheral sclerosis.
• Less frequently, it may present as a single lucency arising
in the cortex.
• Growing lesions affect the cortex and produce an anterior
bowing.
MRI Features
• High intensity in T2-weighted images
osteoblasts.
• Scattered osteoclasts are seen lining the trabeculae.
• The lesion tends to mature toward the periphery, with
more mature bone trabeculae, zonation phenomenon.
Pathologic Differential Diagnosis
Adamantinoma
• Epithelial component predominates in classical
adamantinoma.
• The so-called well-differentiated adamantinoma contains
clusters of keratin-positive epithelial cells. In small biopsy
specimens, the differential may be extremely difficult.

Fibrous Dysplasia
Bone Scan • Is an intramedullary lesion.
• The immature bony trabeculae lack the osteoblastic
• Hot spot prominent rimming.

Image Differential Diagnosis Ancillary Techniques

Adamantinoma • Osteofibrous dysplasia presents keratin-positive cells.

• The image of adamantinoma is very similar to OFD. Positive for CK14 and CK19. Negative for CK8 and
CK18.
Fibrous Dysplasia
• Is an intramedullary lesion
Prognosis

Pathology • Lesions may regress spontaneously.

• Lesion may progress and grow with severe tibial bowing.
Gross Features • May recur after curettage.

• Cortical lesion.
• Gritty white-yellow cut surface. Treatment
• The periosteum is not affected.
• The cortex may be thinned. When lesion progresses to • The surgical treatment may be done after puberty.
the medullary cavity, the cortex develops a sclerotic • Excision of the lesion.
rim. • Re-excision in recurrences.

Histological Features Images

• Spindle cell proliferation with a storiform pattern with no See Figs. 54.1, 54.2, 54.3, 54.4, 54.5, 54.6, and 54.7 for illus-
cytologic atypia. trations of osteofibrous dysplasia.
54 Osteofibrous Dysplasia 771

Fig. 54.1 (a, b)

a b
OFD. Anteroposterior and lateral
radiographs show a typical case
with bowing deformity of the
tibia
772 L.G. Olvi et al.

a b

Fig. 54.2 (a, b) OFD. Plain x-ray of the tibia showing the fusiform cortical expansion of the anterior cortex. (c) CT scan shows multilocular defect
in thickened anteromedial cortex of the tibia
54 Osteofibrous Dysplasia 773

Fig. 54.3 (a, b) Plain a b

radiographs illustrating a large
and elongated lesion with
multiple cortical lucencies of the
anterior cortex of the tibia
774 L.G. Olvi et al.

Fig. 54.4 (a) Lateral x-ray

showing an expansile lucent
lesion surrounded by sclerosis
and thinning of the anterior
aspect of the tibia. (b and c)
Sagittal and axial MRI of the
lesion

a b

Fig. 54.5 OFD. Low-magnification microphotograph. The cortical

bone is eroded by the lesion. On the right, there is a shell of reactive
bone. The lesion is composed of trabeculae of woven bone surrounded
by a spindle cell proliferation
54 Osteofibrous Dysplasia 775

a b

Fig. 54.6 (a, b) Both microphotographs show trabeculae of woven bone with osteocytes within the osteoid matrix and active osteoblasts in the
surface of the trabeculae. The spindle cells are bland and monotonous in a storiform pattern

a b

c d

Fig. 54.7 (a–c) High magnification of OFD showing irregular bone trabeculae rimmed by prominent osteoblasts. Some trabeculae are focally
calcified. The stroma is fibrous and vascularized; (d) Immunohistochemistry positive for keratin (AE1AE3)
776 L.G. Olvi et al.

Recommended Reading Park YK, et al. Osteofibrous dysplasia: clinicopathologic study of 80

cases. Hum Pathol. 1993;24(12):1339–47.
Schajowicz F. Santini Araujo adamantinoma of the tibia masked
Campanacci M. Osteofibrous dysplasia of long bones: a new clinical
by fibrous dysplasia. Report of three cases. Clin Orthop.
entity. Ital J Orthop Traumatol. 1976;2:221–37.
1989;238:294–301.
Kempson RL. Ossifying fibroma of the long bones: a light and electron
microscopic study. Arch Pathol. 1966;48A:218–33.
 Myositis Ossificans
55
Liliana G. Olvi and Eduardo Santini-Araujo

Abstract
Myositis ossificans is a relatively rare benign lesion. It represents a localized self-limited
fibro-ossifying process. It occurs in muscles or other soft tissues especially tendons and
subcutaneous fat. It is predominant in males and occurs in adolescents or young adults, who
are athletically active. It may also be found in older persons. It is rare in small children.
Common sites of involvement are the lower extremity (quadriceps and gluteus muscles) and
upper extremity (brachialis muscle). The radiographic features are as follows: In the early
stage, there is light increase in soft tissue density and the mass is ill defined. At approxi-
mately fifth to sixth week, floccular radiopacities – “dotted veil” pattern – are present. At
approximately third to fourth month, the lesion is well circumscribed. There is more dense
mineralization at the periphery, and it is less mineralized at the center. There is zonation
appearance. Mature lesions are increasingly calcified smaller lesions. Frequently, it is
attached to the cortex. Histologically in early stages, there is active and immature vascular
fibroblastic proliferation and plump spindle cells. There are numerous mitotic figures. In
more mature lesions, a more organized shell of woven and parallel lamellar bone is present.
There is zonation phenomenon. Treatment depends on the evolution stage of the lesion.
Excision of mature lesions is curative.

Definition Synonym

• Relatively a rare benign lesion. Represents a localized • Heterotopic ossification

self-limited fibro-ossifying process.
• It occurs in muscles or other soft tissues especially ten-
dons and subcutaneous fat. Etiology

• May follow a recent mechanical trauma or a muscular

L.G. Olvi, MD excerption – traumatic type or nontraumatic type. The last
Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina
type is probably associated with a minor injury like a
E. Santini-Araujo, MD, PhD (*) muscular tear associated with sports activities or physical
Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina
exercises that has been forgotten. Both forms are morpho-
Department of Pathology, School of Medicine and logically identical.
School of Dentistry, University of Buenos Aires,
Buenos Aires, Argentina
• Myositis ossificans progressiva – a congenital hereditary
fatal disease.
Central Army Hospital, Buenos Aires, Argentina
e-mail: santiniaraujo@laborpat.com.ar
• Myositis ossificans circumscripta.

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 777
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_55, © Springer-Verlag London 2015
778 L.G. Olvi and E. Santini-Araujo

– Traumatic type (75 %) Sites

– Nontraumatic type (25 %):
1. Associated with systemic disease (paraplegia, teta- • Lower extremity: quadriceps and gluteus muscles
nus, etc.) • Upper extremity: brachialis muscle
2. Idiopathic (pseudo-malignant osseous tumor of soft
tissue)
Clinical Symptoms and Signs

Clinical Features • First stage – pain or tenderness, hours or days after the
injury:
Epidemiology – Rarely localized erythema in the skin over the lesion
• Second stage – circumscribed mass, a week or 2 later.
Sex • Third stage – the mass acquires a stony consistency at pal-
• Predominant in males pation, at third week.
• In some patients, white blood count, sedimentation rate,
Age and alkaline phosphatase are slightly elevated.
• Adolescents or young adults, athletically active. It may • The lesion commonly develops in as short time at a week
also be found in older persons. It is rare in small or 2. This rate of development is a diagnostic clue because
children. sarcomas infrequently grow so fast.
55 Myositis Ossificans 779

Image Diagnosis • The underlying cortex is classically discontinued, and the

metaphyseal spongiosa is continuous with the tumor
Radiographic Features spongiosa.

Early Stage Parosteal Osteosarcoma

• Slight increase in soft tissue density
• Ill-defined mass
Approximately Fifth to Sixth Week
• Floccular radiopacities – “dotted veil” pattern.
• Cortex not involved.
• Periosteal reaction may be seen in deeper lesions.
• At deeper locations and with only one X-ray projection
may have the false appearance of attachment to the bone.
Approximately Third to Fourth Month
• Well-circumscribed lesion
• More dense mineralization at the periphery
• Less mineralized at the center
• Zonation appearance
Mature Lesions
• Increasingly calcified lesion
• Smaller
• Attached to the cortex
• Early MO shows:
– X-ray: cortex not involved
– CT: cortex not involved
• Mature MO shows:
– Increasingly calcified lesion
– Smaller lesion
– Attachment to the cortex
• Parosteal osteosarcoma shows:
– Densely ossified juxtacortical round or oval mass
attached to the underlying cortex
– Absent well-formed periosteal reaction
– A frequent characteristic finding which is a radiolucent
line between the cortex and the tumor, except at its site
of attachment
– In CT and MRI, lytic areas, most commonly in the sur-
face corresponding to neoplastic cartilage
– Occasionally, cortical thickening under the tumor
– In advanced cases, cortical destruction and medullary
invasion

Pathology
CT Features
Gross Features
• Cortex not involved
• In early stages, the lesion is soft, grayish white or reddish,
and hemorrhagic, with gritty calcifications. In more
MRI Features mature lesions, the cut surface shows two different zones:
one peripheral zone, hard and with cancellous bone, and a
• In early stages, a nonhomogeneous mass appears.
central zone, soft grayish reddish with hemorrhagic areas
and cystic zones.
• Less than 5 cm in diameter.
Bone Scan • Stony consistency, mature lesion.

• Hot spot
Histological Features

Image Differential Diagnosis Central Portion or Early Stage

• Active and immature vascular fibroblastic proliferation.
Osteochondroma Plump spindle cells. Numerous mitotic figures.
• In sessile osteochondromas, sometimes the differential is • Cellular pleomorphic areas.
more difficult. • Although very active, the lesion lacks cytological atypia.
• Lower density. • Inflammatory cells, macrophages.
• Shows irregular calcification of the cartilage-capped • Acute inflammatory cells are not seen.
surface. • Multinucleated giant cells, osteoclastic type.
780
• Dilated vessels.
• Hemorrhage and fibrinous material.
• Necrosis of the proliferated tissue is absent.
Intermediate Portion
• Proliferating spindle cells with collagen deposition.
• Osteoid trabeculae and ectatic vessels
• Immature osseous trabeculae and more mature lamellar
trabeculae in a loose fibrous tissue.
• Masses of cartilage with different stages of differentiation
and endochondral ossification are occasionally present.
Peripheral Portion
• A more organized shell of woven and parallel lamellar
bone.
• In the outer layers, active osteoblasts are seen around
immature small bone trabeculae.
• The lesion is separated from the surrounding muscle by a
zone of myxoid fibrous tissue.
• The peripheral muscle shows atrophic changes and
inflammatory infiltrates.
• Mature lesion shows fatty and hematopoietic bone mar-
row between the lamellar trabeculae.
The clue and hallmark for diagnosis is the presence of this
zoning phenomenon or zoning effect.
Subungual exostosis, Nora’s lesion, florid reactive perios-
titis, and fibro-osseous pseudotumor of digits are probably
closely related lesions of the heterotopic ossification type.
Pathologic Differential Diagnosis
In Early Stage
Extraskeletal Osteosarcoma
• More common in elderly patients, fifth and sixth decades
– MO (zoning phenomenon):
Maturation
Lacks cytological atypia
– EO (“lacelike” osteoid):
Reverse zoning effect
Cellular atypia
Atypical mitosis
Infiltration in a destructive manner
Nodular Fasciitis
• In superficial soft tissue sites
• Extremely rare to see reactive bone formation
In Mature Lesions
Parosteal Osteosarcoma
• Low-grade malignant tumor.
• Extensive bone trabeculae formation with a tendency to
parallel arrangement.
L.G. Olvi and E. Santini-Araujo
• Immature woven bone in different stages of maturation
may be seen.
• Osteoblasts surrounding trabeculae are spindled –
inactive – and occasionally more hypertrophic.
• Fibrous stroma presents numerous spindle cells with little
pleomorphism, few mitosis, and moderate collagen fibers.
Similar to a low-grade fibrosarcoma.
• Foci of low-grade chondrosarcoma may be present, and
frequently, a superficial cap of low-grade chondrosar-
coma covers partially the surface of the tumor.
Fibro-osseous Pseudotumor of Digits
• MO and FOPD are practically similar lesions.
Ancillary Techniques
• In early stages, the spindle cells stain positive for smooth
muscle actin and muscle-specific actin, betraying its myo-
fibroblastic phenotype.
Genetics
• Gene rearrangement (USP6) similar to ABC has been
reported in cases of MO. Probably ABC and MO are
closely related lesions.
Prognosis
• Myositis ossificans circumscripta has an excellent prog-
nosis. Recurrence may be observed in cases treated in an
early stage.
• Malignant transformation has not been observed.
Treatment
• It depends on the evolution stage of the lesion.
• Excision of mature lesions is curative.
• Surgical procedure is indicated in patients with clinical
symptoms – pain and restriction of motion because of size
or location.
• With a histopathologic diagnosis, it is preferable to treat
the lesion after maturation and not in the early stages to
avoid recurrences.
Images
See Figs. 55.1, 55.2, 55.3, 55.4, 55.5, 55.6, 55.7, 55.8, 55.9,
55.10, 55.11, 55.12, 55.13, 55.14, 55.15, 55.16, 55.17, 55.18,
55.19, 55.20, 55.21, 55.22, 55.23, 55.24, 55.25, and 55.26 for
illustrations of myositis ossificans.
55 Myositis Ossificans 781

a b

Fig. 55.1 (a) Slight increase in soft tissue density in the upper end of the thigh that corresponds to an ill-defined mass. (b) Gross picture of the
excisional biopsy
782 L.G. Olvi and E. Santini-Araujo

Fig. 55.2 Radiographic image of a MO showing floccular

radiopacities – “dotted veil” pattern Fig. 55.3 MO. Lateral X-ray shows that the cortex is not involved
55 Myositis Ossificans 783

Fig. 55.4 MO. In deeper lesions, a periosteal reaction may appear

784 L.G. Olvi and E. Santini-Araujo

Fig. 55.5 MO located in the thigh. The bone scan shows a hot spot

Fig. 55.6 MO. X-ray and CT. More mature well-circumscribed lesion showing denser mineralization at the periphery and less mineralization at
the center. Typical “zonation” appearance
55 Myositis Ossificans 785

a b

c d

Fig. 55.7 (a–d) Cystic MO. 18yo rugby player; lesion appeared after local trauma
786 L.G. Olvi and E. Santini-Araujo

a b

c d

Fig. 55.8 (a–d) MO. Maturing of a MO lesion. The MO increased ossification became smaller and attached to the cortex
55 Myositis Ossificans 787

Fig. 55.9 MO. Early stage of MO showing an active and immature Fig. 55.12 MO. Hemorrhages, fibrinous material, and necrotic muscle
vascular fibroblastic proliferation fibers

Fig. 55.10 MO. In this early stage, typical mitotic figures are
frequent

Fig. 55.11 Early stage of MO. Loosely fibrotic proliferation intermin- Fig. 55.13 Immature osteoid trabeculae within the fibrovascular
gled with inflammatory cells, macrophages, and multinucleated giant stroma are seen in an intermediate stage
cells, osteoclastic type
788 L.G. Olvi and E. Santini-Araujo

Fig. 55.14 MO. Necrotic muscle fibers surrounded by immature reac- Fig. 55.17 At lower magnification, the central immature area appears
tive osteoid trabeculae surrounded by more mature trabeculae with a parallel arrangement

Fig. 55.15 MO. Intermediate stage around the center of the lesion: Fig. 55.18 Close-up view of the limits of the zonation phenomenon
spindle cells, deposition of collagen, ectatic vessels, and osteoid tra-
beculae are seen

Fig. 55.16 Microphotograph at low magnification showing the typical

zoning effect with an immature central area surrounded by more mature
trabeculae toward the periphery
55 Myositis Ossificans 789

Fig. 55.19 Masses of cartilage at different stages of differentiation and endochondral ossification are occasionally present

Fig. 55.20 More mature peripherally located bone areas Fig. 55.22 Peripheral zone showing atrophic changes in the skeletal
muscle

Fig. 55.21 At the surface of the lesions, layers of active osteoblasts in

a myxofibrous tissue are frequently present
790 L.G. Olvi and E. Santini-Araujo

a b

Fig. 55.23 Extraskeletal osteosarcoma. (a) Lateral X-ray showing a soft tissue mass in the popliteal region. Non-peripheral edge of mineraliza-
tion is seen. (b) Gross section of the resected specimen

Fig. 55.24 Extraskeletal osteosarcoma. Typical malignant lacelike

osteoid
55 Myositis Ossificans 791

Fig. 55.26 Areas rich in multinucleated giant cells are a frequent com-
ponent of extraskeletal osteosarcoma

Fig. 55.25 Extraskeletal osteosarcoma. Microphotograph at higher

magnification showing cellular pleomorphism, atypical mitosis, and
calcified tumoral bone trabeculae
792 L.G. Olvi and E. Santini-Araujo

Recommended Reading Rosenberg AE. Pseudosarcomas of soft tissue. Arch Pathol Lab Med.
2008;132:579–86.
Schajowicz F. Osteoma. Tumors and tumorlike lesions of bone and
ACKERMAN LV. Extra-osseous localized non-neoplastic bone and
joints. New York: Springer, 1981; p. 25–34.
cartilage formation (so-called myositis ossificans): clinical and
Sukov WRD, Franco MF, Erickson-Johnson M, Chou MM, Unni KK,
pathological confusion with malignant neoplasms. J Bone Joint
Wenger DE, Wang X, Oliveira AM. Frequency of USP6 rearrange-
Surg Am. 1958;40-A(2):279–98.
ments in myositis ossificans, brown tumor, and cherubism: molecu-
Angervall L, Stener B, Stener I, Ahrén C. Pseudomalignant osseous
lar cytogenetic evidence that a subset of “myositis ossificans-like
tumour of soft tissue. A clinical, radiological and pathological study
lesions” are the early phases in the formation of soft-tissue aneurys-
of five cases. J Bone Joint Surg Br. 1969;51(4):654–63.
mal cyst. Skelet Radiol. 2008;37(4):321–7.
de Silva MV, Reid R. Myositis ossificans and fibroosseous pseudotu-
Unni KK. Dahlin’s bone tumors. 5th ed. Philadelphia: Lippincott-
mor of digits: a clinicopathological review of 64 cases with empha-
Raven; 1996.
sis on diagnostic pitfalls. Int J Surg Pathol. 2003;11(3):187–95.
Fine G, Stout A. Osteogenic sarcoma of the extraskeletal soft tissues.
Cancer. 1956;9(5):1027–43.
Kransdorf MJ, Meis JM, Jelinek JS. Myositis ossificans: MR appear-
ance with radiologic-pathologic correlation. Am J Roentgenol.
1991;157:1243–8.
 Giant Cell Reparative Granuloma
56
Liliana G. Olvi, Maria L. Gonzalez,
and Eduardo Santini-Araujo

Abstract
Giant cell reparative granuloma is a benign, reactive intraosseous process characterized by
the presence of multinucleated giant cells, fibroblasts, and immature new bone formation in
the absence of hyperparathyroidism. The lesion arises most commonly in the craniofacial
skeleton and in small bones of the hands and feet. There is no sex predominance. Seventy-
five percent of the lesions occur in the first three decades of life with a peak in the third
decade. It is a solitary radiolucent expansive lesion located more frequently in the diaphysis
or metaphysis – with evolution, it may extend to the epiphysis after growth plate closure. It
presents a sharp margination. Histological features are as follows: Giant cells are com-
monly arranged in clusters. The giant cells are small and with few nuclei. Frequently, giant
cells are seen around hemorrhagic zones. The stroma is formed by spindle mononuclear
cells that produce collagen. Immature bone and osteoid reactive trabeculae lined by promi-
nent osteoblasts are common features.
The treatment consists of curettage and bone grafting.

Definition Synonyms

• Benign, reactive intraosseous process characterized by • Giant cell reaction of the bone
the presence of multinucleated giant cells, fibroblasts, and • Giant cell granuloma
immature new bone formation in the absence of • Giant cell lesion of the small bones
hyperparathyroidism.
• The lesion arises most commonly in the craniofacial skel-
eton and in small bones of the hands and feet. Etiology

• Unknown.
• History of trauma has been established in some cases.
L.G. Olvi, MD • M.L. Gonzalez, MD
Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina
E. Santini-Araujo, MD, PhD (*) Clinical Features
Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina
Department of Pathology, School of Medicine and School of Epidemiology
Dentistry, University of Buenos Aires, Buenos Aires, Argentina
Central Army Hospital, Buenos Aires, Argentina Sex
e-mail: santiniaraujo@laborpat.com.ar • No sex predominance

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 793
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_56, © Springer-Verlag London 2015
794 L.G. Olvi et al.

Age Enchondroma
• Seventy-five percent of the lesions occur in the first three • Intramedullary
decades of life with a peak in the third decade. • Without endosteal erosion
• Ringlike mineralization
• Spotty calcifications
Sites of Involvement
ABC
• Jaws – mandible more frequent than maxilla – and cranio- • Area of lucency situated eccentrically in the medullary
facial bones cavity in the metaphysis of a long bone.
• Small bones of the hands and feet – phalanges, metatar- • Later on, “ballooned” or “aneurysmal” cystic expansion
sals, and metacarpals of the affected bone – “blow out” – is evident. The
lesion involves the cortex and destroys it completely,
bulging out into soft tissues. Usually forms a thin scle-
Clinical Symptoms and Signs
rotic rim of ossification due to periosteal new bone
formation.
• Pain, in 50 % of patients
• CT and MRI may show internal septation and multiple
• Swelling, in 50 % of patients
fluid-fluid levels – a result of the so-called hematocrit
• Rarely symptomatic or incidentally radiographically
effect.
discovered
• Rarely presents pathologic fracture
Pathology
Image Diagnosis
Gross Features
Radiographic Features
• Small fragments obtained by puncture needle biopsy or
• Solitary radiolucent expansive lesion located more fre- fragments of curettage: friable and tan, gray, or red
quently in the diaphysis or metaphysis – with evolution, it tissue
may extend to the epiphysis after growth plate closure.
• Sharp margination.
• Fine or coarse trabeculation may be seen. Histological Features
• The cortex is commonly expanded and thinned, but it usu-
ally is intact. • Giant cells are commonly arranged in clusters. The giant
• No sclerosis edge is present. cells are small and with few nuclei. Frequently, giant cells
• Rarely, some calcifications are present. are seen around hemorrhagic zones.
• Uncommonly, the process may involve soft tissues. • Stroma formed by spindle mononuclear cells that produce
• Rarely, disruption of the cortex and periosteal reaction is seen. collagen.
• No atypical spindle or multinucleated cells are seen.
• Immature bone and osteoid reactive trabeculae lined by
CT Features prominent osteoblasts are common features.
• Low mitotic rate.
• Well-circumscribed expansile lesion • Lymphocyte infiltrations and histiocytes with hemosid-
• May show septations erin may be seen.
• Secondary aneurysmal bone cyst areas may be present.

MRI Features
Pathologic Differential Diagnosis
• Isointense signal intensity in T1- and T2-weighted images
Brown Tumor of Hyperparathyroidism
• Histologically, both lesions may be identical.
Image Differential Diagnosis • In hyperparathyroidism, the remained cancellous bone
shows an increased osteoclastic activity on its surface that
GCT may also present osteoid seams.
• Infrequent in small bones of the hands and feet and in jaw • In “brown tumor” of hyperparathyroidism, the peripheral
bones noninvolved bone trabeculae may present histological
• Epiphyseal and eccentrically located evidence of hyperparathyroidism (see “brown tumor”).
56 Giant Cell Reparative Granuloma 795

• In all cases of GCRG – in any location – it is extremely
important to perform laboratory test to discard
hyperparathyroidism.
Giant Cell Tumor
Giant Cell Reparative Granuloma
• Smaller giant cells with small number of nuclei than those
of GCT, frequently distributed around hemorrhagic zones.
• Mononuclear cells are spindle shaped.
• A more collagenous fibrogenic stroma is the main clue to
differentiate giant cell reparative granuloma from genuine
giant cell tumor.
• Less mitotic activity.
• Trabeculae of reactive woven bone or osteoid are fre-
quently present in the stroma.
• Commonly occurs in patients of the first and second decades.
Giant Cell Tumor
• Large multinucleated giant cells more evenly distributed
throughout the tumor.
• Giant cells have a great number of nuclei.
• The mononuclear cell component is round to oval.
• Nuclei of giant cells are morphologically identical to
nuclei of mononuclear cells.
• More intense mitotic activity.
• p63 is expressed in mononuclear cells in both lesions.
• Frequently arises in older patients than GCRG.
lagen fibers and bland fibroblasts, with plump uniform
nuclei without hyperchromasia.
• Areas of lipid-bearing histiocytes with small dark nuclei
and clear granular cytoplasm – xanthoma cells – and
hemosiderin pigment-loaded histiocytes.
• Variable number of multinucleated giant cells scattered
throughout the lesion, in clusters.
• Lack of new bone formation except in the margins of the
lesion.
• MFD is commonly localized in the metaphysis of long bones
and extremely rare in small bones of the hands and feet.
Fracture Callus
• Periosteal bone reaction.
• Necrotic laminar bone.
• Woven bone trabeculae permeating bone marrow spaces.
• Fibrocartilage is frequently present.
MFH
• Rarely GCRGs are more cellular and with a brisk mitotic
activity.
• Nuclear pleomorphism and atypical mitosis are never
seen in GCRG.

Osteosarcoma
Aneurysmal Bone Cyst, Solid Variant • Atypical osteoblastic cells in bone marrow spaces
• Neoplastic osteoblast lining the tumoral bone trabeculae
• Grossly, different from ABC, giant cell granulomas pres- • Hyperchromatic nuclei, cellular atypia, brisk mitotic
ent a volume of curetted tissue that corresponds and over- activity
laps with the radiographic size of the lesion.
• Histologically, especially with the solid variant, lesions
may be indistinguishable. Ancillary Techniques
• In typical ABC, it is frequent to find immature bone tra-
beculae with prominent osteoblastic activity. Sometimes, • Immunohistochemistry is not useful in the diagnosis.
these trabeculae present an intensely calcified matrix • p63 is commonly found in GCRG and in other giant cell
known as “blue bone.” This last feature, besides not always lesions.
present, must be considered a very specific pattern of ABC.
• Lacelike or powdery calcifications, peculiar chondroid-
like zones, and parallel seams of fibrillary osteoid beneath Prognosis
the lining of the septum are typical and relatively specific
features of ABC. • Good prognosis.
• USP6 gene rearrangement was not found in GCRG. • Recurrences are infrequent.
• No reported cases with malignant transformation.

Metaphyseal Fibrous Defect

Treatment
• Gross appearance varies considerably in different areas of
the same lesion: zones of grayish-white color alternating • Curettage and bone grafting
with yellow or reddish-brown color. • En bloc resection in large lesions and bone
• Fibrous tissue presents a characteristic whorled – stori- reconstruction
form or cartwheel – pattern with varying amount of col- • Curettage in recurrences
796 L.G. Olvi et al.

Images

See Figs. 56.1, 56.2, 56.3, 56.4, 56.5, and 56.6 for illustra-
tions of giant cell granuloma.

Fig. 56.1 Plain x-ray. Giant cell granuloma producing a lytic lesion in
the base of the distal phalanx
56 Giant Cell Reparative Granuloma 797

a b

c d

Fig. 56.2 (a, b) Anteroposterior and lateral x-ray of the hand. Proximal end of the first phalanx with a purely lytic well-marginated lesion. (c, d)
T1- and T2-weighted MRI of the lesion, showing a hypointense and high-intense image
798 L.G. Olvi et al.

Fig. 56.3 X-ray. Giant cell granuloma in the third phalanx with ero-
sion of the cortex

a b

Fig. 56.4 (a, b) Anteroposterior and lateral view. Giant cell granuloma forming an expansile lesion in the first phalanx
56 Giant Cell Reparative Granuloma 799

a b

Fig. 56.5 Microscopic features of giant cell granuloma. (a) Abundant multinucleated giant cell in a spindle cell stroma. (b) Hemorrhagic area is
present

a b

Fig. 56.6 (a, b) Microphotograph of giant cell reaction showing small multinucleated giant cells with reactive bone
800 L.G. Olvi et al.

Recommended Reading Lorenzo JC, Dorfman HD. Giant-cell reparative granuloma of

short tubular bones of the hands and feet. Am J Surg Pathol.
1980;4:551–63.
Ackerman LV, Spjut HJ. Tumors of bone and cartilage. Atlas of tumor
Picci P, Baldini N, Sudanese A, Boriani S, Campanacci M. Giant cell
pathology, 1st series, Fascicle 4. Washington, DC: Armed Forces
reparative granuloma and other giant cell lesions of the bones of the
Institute of Pathology; 1962. p. 282.
hands and feet. Skelet Radiol. 1986;15:415–21.
Glass TA, Mills SE, Fechner RE, Dyer R, Martin W, Armstrong
Wold LE, Dobyns JH, Swee RG, Dahlin DC. Giant cell reaction (giant
P. Giant-cell reparative granuloma of the hands and feet. Radiology.
cell reparative granuloma) of the small bones of the hands and feet.
1983;149:65–8.
Am J Surg Pathol. 1996;10:491–6.
Jaffe HL. Giant cell reparative granuloma, traumatic bone cyst and
fibrous (fibro-osseous) dysplasia of the jaw bones. Oral Surg Oral
Med Oral Pathol. 1953;6:159–75.
 Central Giant Cell Granuloma
of the Jaws 57
María L. Paparella and Rómulo L. Cabrini

Abstract
Central giant cell granuloma of the jaw is considered a nonneoplastic lesion. It is a benign
lesion but sometimes an aggressive osteolytic proliferation consisting of fibrous tissue with
osteoclast-like giant cells. The long-term prognosis is good. The histopathology findings
are indistinguishable from brown tumor of hyperparathyroidism, and determination of para-
thormone levels may be indicated, especially when multifocal lesions are present.

Definition
• It is a benign lesion but sometimes an aggressive osteo-
lytic proliferation consisting of fibrous tissue with
osteoclast-like giant cells.
Age
• Central giant cell granuloma is found in all age groups,
although more than 60 % of all cases are diagnosed in
patients under 30 years of age.

Sites of Involvement
Synonyms
• Central giant cell granuloma of the jaws has a predilection
• Central giant cell lesion for the mandible, mainly the posterior region of the man-
• Reparative giant cell granuloma dibular body – premolar and molar regions – but also in
the anterior portions of the jaws.

Clinical Features
Clinical Symptoms and Signs
Etiology
• Most cases present as asymptomatic incidental findings.
• Unknown. • Some cases, however, present swelling with pain or pares-
• Central giant cell granuloma is widely considered to be a thesia, tooth mobility and/or tooth loss, or perforation of
nonneoplastic lesion. the cortical bone plate with involvement of the oral
mucosa (mixed lesion: central and peripheral).
Epidemiology
Image Diagnosis
Sex
• The incidence is more often in women than in men (1.5:2.1).
• The radiographic findings are not specifically diagnostic.
• Central giant cell granuloma is usually expansive and
M.L. Paparella, PhD (*) • R.L. Cabrini, MD, PhD
radiolucent which may be unilocular or multilocular. Also
Department of Oral Pathology, School of Dentistry,
University of Buenos Aires, Buenos Aires, Argentina they can be mixed with opacities with scalloped and
e-mail: mluisapaparella@gmail.com mostly well-defined but non-corticated borders.

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 801
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_57, © Springer-Verlag London 2015
802
Pathology
Histopathological Features
• Microscopic examination reveals the presence of mul-
tinucleated giant cells and spindle-shaped cells –
fibroblastic and/or myofibroblastic. The multinucleated
giant cells may vary considerably in size and shape. In
some cases, the stroma is fibromyxoid, vascularized
with hemorrhagic areas, and hemosiderin deposits,
macrophages, and inflammatory cells may be promi-
nent. Focal osteoid and reactive bone formation may
be present within the lesion. Mitoses are frequently
found.
• The histopathology findings are indistinguishable
from “brown tumor” of hyperparathyroidism, and
determination of parathormone levels may be indi-
cated, especially when multifocal lesions are
present.
M.L. Paparella and R.L. Cabrini
Prognosis
• The long-term prognosis is good.
Treatment
• The treatment of choice is surgery, with enucleation and
curettage.
• In case of recurrences, more extensive surgery should be
considered.
• Administration of calcitonin, glucocorticoids, or antian-
giogenic with interferon has been applied.
Images
See Figs. 57.1, 57.2, and 57.3 for illustrations of giant cell
granuloma of the jaws.
57 Central Giant Cell Granuloma of the Jaws 803

Fig. 57.3 High-power view showing clusters of multinucleated giant

cells in a hemorrhagic fibrous stroma

Fig. 57.1 Periapical radiograph of a giant cell reparative granuloma

showing a lytic well-circumscribed lesion

Fig. 57.2 Plain Rx. Giant cell reparative granuloma in the posterior
portion of the body of the mandible
 Langerhans Cell Histiocytosis
58
Ricardo K. Kalil

Abstract
Langerhans cell histiocytosis comprises a set of conditions ranging from a localized form
represented by a solitary lesion to a disseminated multiorgan involvement and having in
common the microscopic findings of foci of proliferating Langerhans cells. Variants include
eosinophilic granuloma (localized disease), Hand–Schuller–Christian disease (dissemi-
nated form), and Letterer–Siwe disease (disseminated and fatal form).

Definition Epidemiology

• A set of conditions ranging from a localized form repre- • Corresponds to less than 1 % of bone lesions.
sented by a solitary lesion to a disseminated multiorgan • Monostotic disease is more frequent than polyostotic
involvement and having in common the microscopic find- disease.
ings of foci of proliferating Langerhans cells.
• Variants:
– Eosinophilic granuloma: localized disease Age
– Hand–Schuller–Christian disease: disseminated form
– Letterer–Siwe disease: disseminated and fatal form • Can affect any age group but is seen more frequently in
children

Synonyms
Sex
• Histiocytosis X (older nomenclature)
• Langerhans cell granulomatosis • Males are more affected than females.
• Nonlipid reticuloendotheliosis (generic term)

Sites of Involvement
Etiology
• LCH is a multisystem disease that can affect any organ
• Unknown. either in the isolated or in the disseminated forms.
• The neoplastic and immunologic natures for the condition • The bone is the site more commonly affected either in the
have been separately suggested without confirmation so far. solitary or in the multicentric form of the disease.
• Within the skeleton, the cranial vault is the preferred site,
but the mandible, the rest of the axial skeleton, and the
R.K. Kalil, MD
Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina long bones of the extremities follow closely.
• Ribs are more frequently affected in adults.
Department of Pathology, A.C. Camargo Cancer Center,
São Paulo, SP, Brazil • In this section we will focus as exclusively as possible in
e-mail: rkkalil@gmail.com the bone involvement of the disease.

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 805
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_58, © Springer-Verlag London 2015
806
Signs and Symptoms
• Pain and swelling over the area of the affected bone are
usually present.
• Neurological symptoms may result from spine
involvement.
• Mandibular lesions may cause loosening of teeth.
• Diabetes insipidus in 15–20 % of patients.
• Hepatosplenomegaly may occur.
Image Diagnosis
Radiographic and CT Features
• When the diagnosis of LCH is suspected, a complete skel-
etal survey must be done.
• Radiographs’ most common picture is of one or more
well-defined lytic lesions.
• In the cranial vault, lesions typically have a beveled or
“hole-in-hole” appearance because of the difference in
lesion diameter in the two bone tables. CT may better evi-
dence this feature. Some lesions may show a central
radiodense focus.
• Peripheral sclerosis may appear with healing.
• Vertebral involvement may produce a “vertebra plana,”
the total collapse of the vertebral body, with preservation
of the intervertebral disks, but the lesion may also be
expansile and lytic.
• Lesions of long bones usually are located intramedullary,
in the metaphysis or diaphysis.
• Periosteal reaction, when present, is usually solid, but
some long bone lesions may look so aggressive as to sug-
gest a malignant tumor, with cortical destruction and peri-
osteal reaction, especially in early lesions of small
children.
• Fluid-fluid levels and transphyseal lesion have been
described on rare occasions.
• The confluence of multiple lesions in chronic disease may
produce a geographic aspect.
• The disease may involve the supporting structure of the
teeth, producing the “floating-teeth” appearance.
MRI Features
• By MRI, lesions show a hypointense signal intensity
in T1-weighted images and hyperintense signal inten-
sity in T2-weighted images that reduces with healing.
Gadolinium injection shows enhancement of the
image.
R.K. Kalil
Image Differential Diagnosis
Ewing Sarcoma
• In long bones, it may have a radiographically similar
appearance.
Cystic Angiomatosis
• Presents multiple widespread skeletal and visceral lesions.
Soft tissue lesions usually contain phleboliths
Multiple Myeloma
• Is rarely seen before the third decade. Presents “punched-
out” lytic lesions mainly in the skull and axial skeleton.
Diffuse osteopenia may be present. Blood biochemistry
suggests the correct diagnosis.
Metastatic Carcinoma
• May present lytic lesions but is also a disease of older
patients. History or investigation for a primary disease
helps in the differential.
Primary Lymphoma of the Bone
• Aggressive lytic lesions, with a permeative pattern
Osteomyelitis
• A serpiginous lytic pattern and sequestrum, when present,
are more specific for infection. Has a regular surrounding
enhancement due to inflammatory changes.
Pathology
Gross Features
• Lesions are rarely excised but usually only biopsied or
curetted, at most.
• Tissue is soft or friable, with a gray to reddish to yellow-
ish color.
Microscopic Features
• Dense or scattered foci of mononuclear histiocytes
(Langerhans cells) are seen. Langerhans cells have light
or eosinophilic cytoplasm and oval, sometimes indented,
nuclei with nuclear grooves. Some cases may present
high mitotic activity. Mitoses are always typical.
• Giant cells are usually present in variable number.
• Infiltration by eosinophils is a very common finding,
sometimes in clusters or in large numbers, which may
suggest the diagnosis.
58 Langerhans Cell Histiocytosis
• Foamy histiocytes may be seen.
• An inconspicuous spindle cell background infiltrated by
other leukocytes and plasma cells, as well as areas of
necrosis, complements the microscopic picture.
Pathology Differential Diagnosis
Giant Cell Tumor
• When there are abundant giant cells. Affects patients after
closure of the growth cartilage
Osteomyelitis
• May present a difficult differential diagnosis. Immuno-
histochemistry techniques will make the diagnosis.
Lymphoma
• When there is a compact diffuse monomorphic prolifera-
tion of cells. Distinct immunohistochemistry profiles
Ancillary Techniques
Immunohistochemistry
• Langerhans cells are S-100 protein, CD1a, and langerin
positive. CD45 is negative.
Ultrastructure
• Intracytoplasmic Birbeck granules are unique ultrastruc-
tural findings, characteristic of LCH.
807
Prognosis
• Patients with solitary or a few isolated bone lesions have
an excellent prognosis with and, sometimes, without
treatment. Vertebra plana may resolve and the height of
the vertebra may be subsequently recovered.
• Patients with disseminated disease may have long sur-
vival, especially if they survive the first 3 years of treated
disease.
• Signs of worse prognosis and possible death of the dis-
ease are:
– Young age at diagnosis, less than 3 years of age
– Involvement of more than three bones
– Hematologic manifestations
– Hepatosplenomegaly
Treatment
• Solitary or few isolated lesions may, occasionally, resolve
spontaneously.
• Corticosteroids, administered by intralesional injection or
systemically, have been used with good results.
• Radiotherapy is also reported to present good response.
• Disseminated disease requires systemic administration of
corticosteroids and/or other chemotherapies.
Images
See Figs. 58.1, 58.2, 58.3, 58.4, 58.5, 58.6, 58.7, 58.8, 58.9,
and 58.10 for illustrations of Langerhans cell
histiocytosis.
808 R.K. Kalil

Fig. 58.1 Radiograph of a solitary Langerhans cell histiocytosis

(eosinophilic granuloma) in the femoral diaphysis of a young child.
Lytic lesion with extensive reactive sclerosis and lamellar periosteal
reaction. Radiologic differential diagnosis with Ewing sarcoma and
osteomyelitis

a b

c d
58 Langerhans Cell Histiocytosis 809

a b c

Fig. 58.3 (a) Radiograph of LCH affecting the lumbar spine. Lytic Although vertebral height is maintained, a lytic lesion extends to its
lesion in the body and pedicles of a vertebra can be seen. Vertebra shape posterior elements. (c) Same case as previous figure. MRI demonstrates
is maintained. (b) MPR CT of the same case as previous figure. better the extension of the lesion

Fig. 58.2 (a) Radiograph of the spine of another young child showing a onstrating the flattened vertebra. (c) Needle biopsy of the lesion in previ-
vertebra plana, flattening of the vertebral body, common occurrence in ous figure retrieved some hemorrhagic material. Processing of the blood
LCH of the vertebra. (b) MRI of same case of previous figure, better dem- clots disclosed small fragments sufficient for the diagnosis of LCH (d)
810 R.K. Kalil

a b

Fig. 58.4 (a) Radiograph of a skull lytic geographic lesion of LCH. radiographs. (c) CT scan of the pelvis of the same patient of (a).
(b) CT scan of the same case of (a). Characteristic beveled destruction Secondary focus of LCH
of the two cranial cortices, responsible for the “hole-in-hole” aspect of
58 Langerhans Cell Histiocytosis 811

a b

Fig. 58.5 (a) Histologic low-power view of an LCH lesion. Dense nification of previous histologic field depicting histiocyte and eosino-
proliferation of histiocytes with abundant eosinophils, surrounded by phil proliferation
fibrous tissue, can be seen even in this magnification. (b) Higher mag-

a b

Fig. 58.6 (a) Histologic low-power view of another LCH lesion, in of the histiocytes can be seen. Eosinophils and other inflammatory cells
this case with dense, almost exclusive histiocyte proliferation. (b) can also be identified among the histiocytes
Higher magnification of same case of previous figure. Indented nuclei

Fig. 58.8 Print cytology performed during needle biopsy procedure.

Fig. 58.7 Eosinophils may be abundant in some cases. Multinucleated Histiocytes, multinucleated giant cells, and occasional eosinophils seen
giant cells are also frequently seen in this case suggested the diagnosis
812 R.K. Kalil

Fig. 58.9 Immunohistochemistry: CD1a positivity in Langerhans

cells

a b

Fig. 58.10 (a) Transmission electron microscopy showing the typical folded nuclei of Langerhans cells. (b) Transmission electron microscopy
identified the pathognomic presence of Birbeck granules
58 Langerhans Cell Histiocytosis 813

Recommended Reading observations of pathological and clinical importance. J Bone Joint

Surg Am. 1964;46:76–90.
Lichtenstein L, Jaffe HL. Eosinophilic granuloma of bone: with report
Abla O, Egeler RM, Weitzman S. Langerhans cell histiocytosis: current
of a case. Am J Pathol. 1940;16(5):595–604.3.
concepts and treatments. Cancer Treat Rev. 2010;36(4):354–9.
Lieberman PH, Jones CR, Steinman RM, Erlandson RA, Smith J, Gee
Chu T, Jaffe R. The normal langerhans cell and the LCH cell. Br J
T, Huvos A, Garin-Chesa P, Filippa DA, Urmacher C, Gangi MD,
Cancer Suppl. 1994;23:S4–10.
Sperber M. Langerhans cell (eosinophilic) granulomatosis. A clini-
Hindman BW, Thomas RD, Young LW, Yu L. Langerhans cell histiocy-
copathologic study encompassing 50 years. Am J Surg Pathol.
tosis: unusual skeletal manifestations observed in thirty-four cases.
1996;20(5):519–52.
Skelet Radiol. 1998;27(4):177–81.
Mistry M. Eosinophilic granuloma of bone; case record and short
Kilpatrick SE, Wenger DE, Gilchrist GS, Shives TC, Wollan PC, Unni KK.
review of literature. Postgrad Med J. 1957;33(380):290–4.
Langerhans’ cell histiocytosis (histiocytosis X) of bone. A clinicopatho-
Price CH. Histiocytosis X: histology (review of Bristol bone tumour
logic analysis of 263 pediatric and adult cases. Cancer. 1995;
registry cases). Proc R Soc Med. 1971;64(4):336–8.
76(12):2471–84.
Stull MA, Kransdorf MJ, Devaney KO. Langerhans cell histiocytosis of
Lichtenstein L. Histiocytosis X; integration of eosinophilic granuloma
bone. Radiographics. 1992;12(4):801–23.
of bone, Letterer-Siwe disease, and Schüller-Christian disease as
Wester SM, Beabout JW, Unni KK, Dahlin DC. Langerhans’ cell granu-
related manifestations of a single nosologic entity. AMA Arch
lomatosis (histiocytosis X) of bone in adults. Am J Surg Pathol.
Pathol. 1953;56(1):84–102.
1982;6(5):413–26.
Lichtenstein L. Histiocytosis X, (eosinophilic granuloma of bone,
Letterer-Siwe disease, and Schueller-Christian disease). Further
 “Brown Tumor”
of Hyperparathyroidism 59
Liliana G. Olvi and Eduardo Santini-Araujo

Abstract
Localized destructive cyst-like areas in the skeleton, due to osteoclast resorption, in the
general frame of primary, secondary, or tertiary hyperparathyroidism. It is more frequent in
females and has the highest incidence between third and sixth decades. It is most common
in tubular bones of the extremities and maxillary bones. The lesions may involve any skel-
etal bone and may be solitary or multiple. Radiologically, lesions are osteolytic with unde-
fined margins. Histologically the bone marrow is replaced by a loose, richly vascularized,
connective tissue. The remaining cancellous bone shows an increased osteoclastic activity
on its surface. Hemorrhage and abundant hemosiderin pigment deposits are present. The
most common differential diagnosis is a giant cell tumor of the bone. Surgical treatment in
case of hyperfunctioning parathyroid – adenoma or hyperplastic glands – tends to reduce
the osteoclastic activity.

Definition Etiology

• Localized destructive cyst-like areas in the skeleton, due
to osteoclast resorption, in the general frame of primary,
secondary, or tertiary hyperparathyroidism
Synonym
• “Brown tumor”
L.G. Olvi, MD
Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina
E. Santini-Araujo, MD, PhD (*)
Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina
Department of Pathology, School of Medicine and
School of Dentistry, University of Buenos Aires,
Buenos Aires, Argentina
Central Army Hospital, Buenos Aires, Argentina
e-mail: santiniaraujo@laborpat.com.ar
• Primary hyperparathyroidism is most commonly due to
adenoma – 80 % of cases; parathyroid hyperplasia –
15–20 % of patients and, rarely, carcinoma – less than
0.5 %. Secretion of excessive amounts of parathyroid hor-
mone produces in the skeleton the so-called osteitis
fibrosa cystica generalisata – von Recklinghausen’s
disease.
• Approximately 20 % of patients develop cystic lesions.
• Secondary hyperparathyroidism, when parathyroid tissue
is exposed to chronic hypocalcemia, and tertiary hyper-
parathyroidism, due to development of autonomic para-
thyroid hyperfunction, in a background of secondary
hyperparathyroidism, may be considered as a less fre-
quent etiology.
• The receptors on the surface of the osteoblast are linked
by parathyroid hormone. The osteoblasts express receptor
of NF-kB ligand (RANKL). RANKL links to receptor
activator of NF-kB (RANK) on osteoclast precursors,
inducing osteoclast formation.

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 815
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_59, © Springer-Verlag London 2015
816 L.G. Olvi and E. Santini-Araujo

Clinical Features – Resorption of the tufts of terminal phalanges, periar-

ticular erosions, subperiosteal bone resorption – in the
Epidemiology middle and proximal phalanx shafts, most frequently
on the radial side; and in distal and proximal clavicles,
Sex with loss of the cortex, that can also be seen in the
• More frequent in females symphysis pubis, ischial tuberosity, scapula, and verte-
bral body plates
Age – Reduction of the articular line in interphalangeal and
• Highest incidence between the third and sixth decades. metacarpophalangeal joints
May appear in any patient with hyperparathyroidism – Diffuse radiolucent granular areas and regions of
increased mineralization in the skull – “salt and pep-
per” appearance
Sites of Involvement – Loss of the lamina dura surrounding the tooth roots
– Soft tissue calcifications and chondrocalcinosis
• Most common in tubular bones of the extremities and • May be associated with pathologic fractures.
maxillary bones.
• Are also frequent in the pelvis, ribs, and clavicles.
• The lesions may involve any skeletal bone. CT Features
• May be solitary or multiple.
• By CT, BT is a lytic lesion with irregular margins and soft
tissue density.
Clinical Symptoms and Signs

• Pain is the most common symptom. MRI Features

• Sometimes swelling may appear.
• Blood chemistry demonstrates increased serum levels of • Heterogeneous intensity signal.
calcium, alkaline phosphatase, and parathyroid hormone • Hypointensity signal suggests the presence of hemosid-
and low phosphate. It is extremely helpful for definitive erin deposits.
diagnosis.
•
Bone Scan

Image Diagnosis • Hot signal

Radiographic Features Image Differential Diagnosis

Giant Cell Tumor
• Radiologically, lesions are osteolytic with undefined • An epiphyseal usually eccentric lesion involving the
margins. metaphysis in its evolution.
• Lesions frequently expand the cortex and determine a thin • Any lesion that looks like a giant cell tumor but in an
shell of reactive periosteal bone formation. atypical location must be suspected of
• Lytic lesions may be trabeculated, with a multiloculated hyperparathyroidism.
appearance. • Highest incidence in the second and third decades of life,
• Lesions involve more commonly the shaft and less fre- age overlapping with hyperparathyroidism.
quently the ends of long bones or short tubular bones of • Never arises in the diaphysis.
the hands and feet. • Multiple locations are practically never seen.
• Brown tumors may be multiple.
• The following roentgenographic features may be helpful Giant Cell Granuloma
for diagnosis: • Sharp margination.
– Presence of smaller cystic lesions – cortical • Fine or coarse trabeculation may be seen.
tunneling • The cortex may be expanded and thinned but usually is
– Generalized osteopenia with cortical thinning not permeated.
59 “Brown Tumor” of Hyperparathyroidism
• Radiolucent lesion that shows, in some cases, sclerotic
margins.
Metastatic Carcinoma
• Multiple brown tumors may simulate metastatic
carcinoma.
Pathology
Gross Features
• Hemorrhages and deposits of hemosiderin, probably due to
microfractures, give the lesion its characteristic brown color.
• The material is frequently obtained by trocar biopsy. Small
fragments in open biopsies consist of reddish-brown soft
tissue with hemorrhage. Cases treated by resection produce
specimens showing hemorrhagic and large blood-filled
cystic areas – osteitis fibrosa cystica. The cortex is thinned
due to endosteal erosion and frequently distended.
Cancellous bone is destroyed. Periosteal reactive new bone
formation can be seen. Fibrous septa, sometimes ossifying,
may be observed in the lesion.
Histological Features
• The bone marrow is replaced by a loose, richly vascular-
ized, connective tissue.
• The remaining cancellous bone shows an increased osteo-
clastic activity on its surface.
• The weakening of the bone structure leads to multiple
fractures with hemorrhages and abundant hemosiderin
pigment deposits largely phagocytized by histiocytes.
• Small osteoclastic giant cells are distributed in the periphery
of hemorrhages and frequently arranged in irregular clusters.
• Fibrogenic stroma may be rich in collagen fibers and
sometimes produce septa.
• These septa may confer the lesion a lobulated pattern and
may frequently present reactive immature bone formation.
• Typical mitosis occasionally may be seen.
• The periphery of the lesion shows newly formed osteoid
and immature bone trabeculae lined by rows of active
osteoblasts.
• The preexistent lamellar bone trabeculae present active
osteoclastic resorption on its surfaces. May also present
osteoid seams.
• Peripheral noninvolved bone trabeculae may present
evidence of hyperparathyroidism such as paratrabecular
fibrosis; dissecting resorption, Uehlinger’s “dissecting
fibro-osteoclasia,” that is, osteoclastic resorption and fibro-
817
sis inside the trabeculae, producing irregular intratrabecular
spaces; and cortical “cutting cones” – osteoclastic
resorption tunneling and expanding haversian canals.
• Increased amounts of unmineralized bone or osteoid.
Pathologic Differential Diagnosis
Giant Cell Tumor
• Due to histologic similarities, the differential diagnosis
may be difficult, especially when the pathologist does not
have the necessary clinical, imagenologic, and biochemical
information. Fortunately, clinical correlation with image
diagnosis and blood chemistry helps to make an accurate
diagnosis. As BT also occurs in patients with secondary
hyperparathyroidism, a diagnosis of GCT in patients with
chronic renal failure must be done only after a careful cor-
relation with laboratory parameters of renal function.
• In brown tumor, the multinucleated giant cells are gener-
ally smaller and contain fewer nuclei than in the giant
cells of GCT.
• At low magnification, GCT usually has the appearance of
a syncytium of stromal cells, while in BT the osteoclastic-
type giant cells look distinct from the stromal cells.
• In BT, stromal mononuclear cells resemble fibroblasts.
• The nuclei of osteoclasts in BT are oval and not like the
spindled nuclei of the fibrogenic stroma.
• However, in some cases, the multinucleated giant cell
clusters may suggest the diagnosis of GCT.
• Vascular fibrogenic stroma with spindle cells is character-
istic of brown tumor.
• In GCT, the stromal mononuclear cells are oval and their nuclei
are typically similar to nuclei of the multinucleated giant cells.
• GCT mononuclear cells have a higher mitotic rate.
• Multinucleated giant cells in GCT are usually scattered
throughout the lesion. In brown tumor they tend to cluster,
frequently around hemorrhagic foci.
Solid Aneurysmal Bone Cyst
• Extremely difficult differential diagnosis in small biop-
sies or in fine needle biopsies.
• Brown tumor shows a more lobulated pattern.
• The host bone does not present the pattern seen in
hyperparathyroidism.
Giant Cell Granuloma
• Extremely difficult differential in small biopsies or in fine
needle biopsies.
• Brown tumor shows a more lobulated pattern.
• The host bone does not present the pattern seen in
hyperparathyroidism.
818 L.G. Olvi and E. Santini-Araujo

Prognosis • In some cases, surgery – curettage and grafting of the

brown tumor – is indicated.
• Is related to the etiology of the hyperparathyroidism. • Pathologic fracture requires fixation.
• Brown tumor may regress and repair with new bone
formation.
Images

Treatment See Figs. 59.1, 59.2, 59.3, 59.4, 59.5, 59.6, 59.7, 59.8, and 59.9
for illustrations of “brown tumor” of hyperparathyroidism.
• Surgical treatment in case of hyperfunctioning
parathyroid – adenoma or hyperplastic glands – tends to
reduce the osteoclastic activity.
59 “Brown Tumor” of Hyperparathyroidism 819

Fig. 59.1 Brown tumor. Well-demarcated lytic lesion involving the

proximal tibia

a b

Fig. 59.2 (a) Radiolucent lesion

seen in the diaphysis of the tibia.
(b) CT scan: the lesion erodes the
cortex and involves soft tissue
820 L.G. Olvi and E. Santini-Araujo

a b c

d e

Fig. 59.3 Hyperparathyroidism. (a–e) Radiographs, CT scan, and tiple hot spots. (h, i) Parathyroid adenoma. Gross specimen and micro-
MRI of the proximal tibia with a lytic lesion. (f) Core needle biopsy of scopic features
the seventh cervical body was done (arrow). (g) Scintigram shows mul-
59 “Brown Tumor” of Hyperparathyroidism 821

f g

Fig. 59.3 (continued)

822 L.G. Olvi and E. Santini-Araujo

Fig. 59.4 Multiple lytic lesions in the pelvis in a patient with

hyperparathyroidism

a b

Fig. 59.5 (a) Brown tumor of

the lower end of the radius. (b)
Gross specimen
59 “Brown Tumor” of Hyperparathyroidism 823

a c

Fig. 59.6 (a) HE stain showing a Howship lacuna in a mature bone trabecula. (b) Typical “cutting cone” in a mature bone trabecula. (c)
Undecalcified bone with Goldner trichrome, showing a typical “cutting cone”
824 L.G. Olvi and E. Santini-Araujo

Fig. 59.9 Characteristic histological pattern of brown tumor showing

newly formed reactive bone trabeculae

Fig. 59.7 (a) Numerous giant cells, osteoclastic type, and hemosiderin
deposits are seen in peripheral areas. (b) At higher magnification the
multinucleated giant cells are separated by loose fibrogenic stroma

Fig. 59.8 Conglomerate of multinucleated giant cells within a vascular

fibrous stroma. Small mature trabecule with osteoclastic resorption
is seen
59 “Brown Tumor” of Hyperparathyroidism 825

Recommended Reading Present D, Calderoni P, Bacchini P, Bertoni F. Brown tumor of the tibia
as an early manifestation of renal osteodystrophy. A case report.
Clin Orthop. 1988;231:303–6.
Albright FC, Reifenstein EC. The parathyroid glands and metabolic
Uehlinger E. Osteofibrosis deformans juvenilis. Virchows Arch Pathol
bone disease. Baltimore: Williams & Wilkins; 1948.
Anat. 1940;306:255.
Health H, Hodgson SF, Kennedy MA. Primary hyperparathyroidism:
Vigorita VJ, Einhorn TA, Phelps KR. Microscopic bone pathology in
incidence, morbidity and potential economic impact in a commu-
two cases of surgically treated secondary hyperparathyroidism.
nity. N Engl J Med. 1980;302:189–93.
Report of a distinct skeletal lesion. Am J Surg Pathol. 1987;11:
Hoshi M, et al. A case of multiple skeletal lesions of brown tumors,
205–9.
mimicking carcinoma metastases. Arch Orthop Trauma Surg.
2008;128(2):149–54.
 Avulsion Injury
60
Liliana G. Olvi, Maria L. Gonzalez,
and Eduardo Santini-Araujo

Abstract
Avulsion injury is considered a special type of fracture. Repetitive muscle contraction or a
violent muscle contraction may pull off a fragment of cortical and medullary bone across
the tendon insertion that has a stronger tensile strength than the bone. Common sites of
involvement are ischial tuberosity (ischial apophyseolysis), at the insertion of the hamstring
muscles; inferior pubic ramus, at the insertion of the adductor muscles; and iliac spine, at
the insertion of the rectus femoris. The radiographic picture commonly shows extensive
reactive bone proliferation and may suggest malignant neoplasms. Intense uptake of tech-
netium in bone scan. The histological pattern is similar to a repairing fracture process – end-
osteal and periosteal callus. Frequently lesions can be confidently diagnosed based on
radiographic features and puncture needle or surgical biopsy, so that surgical treatment is
not necessary and may be followed by radiographic studies.

Definition Etiology

• Avulsion injury is considered a special type of fracture. • Repetitive muscle contraction or a violent muscle con-
• Radiographically and histologically, the lesion may have traction may pull off a fragment of cortical and medullary
a pseudosarcomatous appearance. bone across the tendon insertion that has a stronger tensile
strength than the bone.

Synonyms
Clinical Features
• Cortical avulsion
• Avulsion fracture Epidemiology

• Occurs, more frequently, in active young adolescent

patients

L.G. Olvi, MD • M.L. Gonzalez, MD Sites of Involvement

Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina
E. Santini-Araujo, MD, PhD (*)
Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina
Department of Pathology, School of Medicine
and School of Dentistry, University of Buenos Aires,
Buenos Aires, Argentina
Central Army Hospital, Buenos Aires, Argentina
e-mail: santiniaraujo@laborpat.com.ar
• Most commonly in the tibial tuberosity, at the insertion of
the quadriceps (Osgood-Schlatter disease), and in the
medial distal metaphysis of the femur, at the insertion of
the adductor magnus tendon (distal femoral cortical syn-
drome or periosteal desmoid)
• Around the pelvis:

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 827
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_60, © Springer-Verlag London 2015
828
– Ischial tuberosity (ischial apophyseolysis), at the inser-
tion of the hamstring muscles
– Inferior pubic ramus, at the insertion of the adductor
muscles
– Iliac spine, at the insertion of the rectus femoris
– Femoral greater trochanter, at the insertion of the
gluteus
– Femoral lesser trochanter, at the insertion of the psoas
– Humerus, at the insertion of the pectoralis major, or
the subscapularis muscle
Clinical Symptoms and Signs
• Usually sudden and severe pain
• Slight swelling in bones near the skin
Image Diagnosis
Radiographic Features
• The radiographic picture commonly shows extensive
reactive bone proliferation and may suggest malignant
neoplasms.
• In the ischium, iliac spine, and femoral greater trochanter,
due to a violent muscle contraction or repetitive muscle
contraction, pulling off a portion of the cortex occurs, and
radiographs frequently show the apophysis loose in the
soft tissue.
• Later reactive bone formation – which in some patients
may be exuberant – appears repairing the avulsion
fracture.
Bone Scan
• Intense uptake of technetium
Image Differential Diagnosis
Bone-forming benign and malignant neoplasms, e.g., surface
osteosarcoma
• Avulsion injury has a limited growth potential and miner-
alizes early over time.
L.G. Olvi et al.
Pathology
Gross Features
• Frequently the material is obtained by core needle biopsy.
Histological Features
• The histological pattern is similar to a repairing fracture
process – endosteal and periosteal callus.
• The osteoid trabeculae are lined by typical osteoblasts.
• Reactive cartilage may be present, similar to a fracture
callus.
• Typical mitosis may be present, especially in the early
phase of evolution.
Pathologic Differential Diagnosis
Osteosarcoma
• The brisk mitotic activity and the osteoid production may
result in a mistaken overdiagnosis of malignancy.
• Atypical mitoses or cellular pleomorphisms are never
seen in an avulsion injury.
Prognosis
• Benign lesion, with excellent prognosis
Treatment
• Frequently, lesions can be confidently diagnosed based on
radiographic features and puncture needle or surgical
biopsy, so that surgical treatment is not necessary and
may be followed by radiographic studies.
Images
See Figs. 60.1, 60.2, 60.3, 60.4, and 60.5 for illustrations
of avulsion injuries.
60 Avulsion Injury 829

a b

Fig. 60.1 (a) X-ray and (b) CT scan showing an avulsion injury in the ischial tuberosity (ischial apophyseolysis), at the insertion of the hamstring
muscles. Muscle contraction pulled off a portion of the cortex and radiographs usually show the loose ischial apophysis in the soft tissue

a b

Fig. 60.2 (a and b) Roentgenogram and CT scan showing a cortical avulsion in the iliac spine, at the insertion of the rectus femoris
830 L.G. Olvi et al.

Fig. 60.3 Microphotograph at low magnification of a core needle Fig. 60.5 The histological pattern is similar to a repairing fracture pro-
biopsy of an avulsion injury cess with endosteal and periosteal callus

Fig. 60.4 Microphotograph showing peripheral muscle fibers and a

chondroid fracture callus
60 Avulsion Injury
Recommended Reading
Byers PD, Gray JC, Mostafa A, Ali SY. The healing of bone and articu-
lar cartilage. In: Glynn LE, editor. Tissue repair and regeneration.
Handbook of inflammation. Amsterdam: North Holland; 1981.
831
Hayda RA, Brighton CT, Esterhai JL. Pathophysiology of delayed
healing. Clin Orthop Relat Res. 1998;355:S31–40.
Ostrum RF, Chao EY, Bassett CA, et al. Bone injury, regeneration
and repair. In: Simon SR, editor. Orthopaedic basic science.
Chicago: American Academy of Orthopaedic Surgeons; 1994.
p. 277–323.
 Bizarre Parosteal
Osteochondromatous Proliferation 61
Liliana G. Olvi, Maria L. Gonzalez,
and Eduardo Santini-Araujo

Abstract
Osteofibrocartilaginous benign process arising in the surface of a bone, more common in
hand and foot locations. There is no sex predominance and it is more common in the second
and third decades. Near 75 % of cases are located on the surfaces of small bones of the hands
and feet, more commonly in the proximal phalanges. Radiologically it is a he terotopic well-
marginated calcified rounded mass attached to the cortical surface of the bone. The lesion
presents three components: cartilage, bone, and spindle cells. Treatment consists of excision.
Recurrence is seen in half of the patients. Malignant transformation is not reported.

Definition Clinical Features

• An osteofibrocartilaginous benign process arising in the sur- Epidemiology

face of a bone, more common in hand and foot locations
Sex
• No sex predominance
Synonym
Age
• Nora’s lesion • More common in second and third decades

Etiology Sites of Involvement

• It was considered a reactive process, probably traumatic,
but chromosomal abnormalities were described suggest-
ing the possibility of a neoplasm.
• Nearly 75 % of cases are located on the surfaces of small
bones of the hands and feet, more commonly in the proxi-
mal phalanges.
• Twenty-five percent in long bones, more frequently in the
radius or humerus.

L.G. Olvi, MD • M.L. Gonzalez, MD

Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina Clinical Symptoms and Signs
E. Santini-Araujo, MD (*)
Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina • Rapid growth
Department of Pathology, School of Medicine and School of • Swelling and tenderness
Dentistry, University of Buenos Aires, Buenos Aires, Argentina • Rarely painful
Central Army Hospital, Buenos Aires, Argentina
e-mail: santiniaraujo@laborpat.com.ar

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 833
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_61, © Springer-Verlag London 2015
834 L.G. Olvi et al.

Image Diagnosis • Cartilage may form a cap or separated lobules in a

Radiographic Features
• Heterotopic well-marginated calcified rounded mass
attached to the cortical surface of the bone.
• The cortex and spongiosa of the affected bone do not have
continuity with the lesion.
• Lesions are not in contact with the growth plate.
MRI Features
• In T2-weighted images, foci of cartilage are bright.
Image Differential Diagnosis
Osteochondroma
• In osteochondroma, the underlying cortex is classically
discontinued and the metaphyseal spongiosa is continu-
ous with the tumor spongiosa.
• BPOP arises on the surface of the affected bone.
Myositis Ossificans, Mature Lesions
• MO is, most commonly, attached to the cortex in the
diaphyseal region.
• It is limited by a more mineralized rim at its periphery,
whereas the center is more radiolucent: the “zonation
effect.”
• Absence of a broad base of attachment to the underlying
cortex.
Parosteal Osteosarcoma
• Extremely infrequent in small bones of the hands and feet
dense fibrous tissue more abundant at the periph-
ery of the lesion. It is hypercellular and with plump
nuclei. The presence of binucleated chondrocytes
is frequent. The term bizarre for this lesion refers
to the characteristic of the cartilage component.
• The bone component presents an irregular endo-
chondral ossification and a typical blue tinctorial
characteristic on H&E slides, due to dense calcifi-
cation. Immature trabeculae are lined by prominent
osteoblasts and may present cores of calcified carti-
lage in its matrix.
• The fibrous component is disposed between bony
trabeculae and in the edges of the lesion. Reactive
fibrous tissue is present covering the surface of the
cartilaginous cap.
• Below the predominantly cartilaginous surface
layer, the three components appear haphazardly
mixed.
• The lesion may present a brisk mitotic activity.
Atypical mitoses are not seen.
Pathologic Differential Diagnosis
Myositis Ossificans, Mature Lesions
• Is a more cellular lesion.
• Has a more organized shell of woven and parallel lamellar
bone.
• The lesion is separated from the surrounding muscle by a
zone of myxoid fibrous tissue.
• The peripheral muscle shows atrophic changes and
inflammatory infiltrate.
• The clue and hallmark for diagnosis of MO is the pres-
ence of a zoning phenomenon or zoning effect.

Osteochondroma, Sessile Type

Pathology • Cartilaginous cap in the surface.
• The cap has a similar aspect to that of normal growth car-
Gross Features tilage and lacks cytologic atypia.
• Endochondral ossification is present in the limit with the
• Osseous mass with a cartilaginous cap, frequently abun- underlying bone.
dant, or cartilaginous masses haphazardly distributed. • Trabeculae of endochondral ossification present calcified
Fibrous tissue is seen grossly. cartilage in their bone lamellar matrix.
• The underlying cortex is classically discontinuous, and
the metaphyseal spongiosa is continuous with the tumor
Histological Features spongiosa that contains active hematopoietic or fatty
marrow.
• The lesion presents three components: • BPOP resembles osteochondroma at low magnification
– Cartilage but presents a more irregular ossification with a blue tinc-
– Bone torial quality and a spindle cell proliferation that is never
– Spindle cells seen in osteochondroma.
61 Bizarre Parosteal Osteochondromatous Proliferation 835

Subungual Osteogenic Melanoma Genetics

• A type of melanoma with osseous and cartilaginous
metaplasia. • A variant translocation involving 1q32 and a t(1;17)
• The presence of melanoma in the underlying skin is a clue (q32;q21) are unique and recurrent findings.
for the differential diagnosis.

Chondrosarcoma
• Without clinical and radiographic correlation, the
moderate atypia in chondrocytes of the cartilaginous
component may drive to a diagnosis of surface
chondrosarcoma.
Prognosis
• Recurrence is seen in half of the patients treated.
• Malignant transformation is not reported.

Parosteal Osteosarcoma Treatment

• Extensive bone trabeculae formation with a parallel ten-
dency to arrangement. • Excision
• Immature woven bone in different stages of maturation • Re-excision in recurrences
may be seen. See Figs. 61.1, 61.2, 61.3, 61.4, 61.5, 61.6, 61.7, and 61.8
• Osteoblasts surrounding trabeculae are spindled – inac- for illustrations of BPOP.
tive – occasionally more hypertrophic.
• Fibrous stroma presents numerous spindle cells with little
pleomorphism, few mitosis, and moderate collagen fibers.
Similar to a low-grade fibrosarcoma.
• Foci of low-grade chondrosarcoma may be present and,
frequently, a superficial cap of low-grade chondrosar-
coma partially covers the surface of the tumor.
836 L.G. Olvi et al.

Fig. 61.2 Bizarre parosteal osteocartilaginous proliferation. Plain film,

anteroposterior view of the fifth metacarpal bone shows a uniform min-
eralized well circumscribed lesion in the bone surface

Fig. 61.1 Bizarre parosteal osteocartilaginous proliferation (BPOP).

Radiographic and macroscopic features. (a) Bone and cartilaginous
lesion of the metacarpal bone. (b) Well-circumscribed osteocartilagi-
nous nodule
61 Bizarre Parosteal Osteochondromatous Proliferation 837

a b

Fig. 61.3 (a) Bizarre parosteal osteocartilaginous proliferation of the middle phalanx (arrow) clearly shows the parosteal location in this radio-
graph. (b) MRI of same lesion
838 L.G. Olvi et al.

Fig. 61.4 BPOP. X-ray and MRI. Distal ulna well-circumscribed radiodensity
61 Bizarre Parosteal Osteochondromatous Proliferation 839

a b

Fig. 61.5 (a) X-ray and (b) CT scan. BPOP attached to the cortex of the fibula. (c) Gross appearance

Fig. 61.6 The tumoral mass is covered by reactive fibrous tissue. The Fig. 61.7 Endochondral ossification with woven trabecular bone,
cartilaginous component contains proliferating chondrocytes, and its rimmed by plump osteoblasts
base is mineralized and undergoes endochondral ossification
840 L.G. Olvi et al.

Recommended Reading
a
Meneses MF, Unni KK, Swee RG. Bizarre parosteal osteochondroma-
tous proliferation of bone (Nora’s disease). Am J Surg Pathol.
1993;17(7):691–7.
Nilsson M, Domanski HA, Mertens F, Mandahl N. Molecular cytoge-
netic characterization of recurrent translocation breakpoints in
bizarre parosteal osteochondromatous proliferation (Nora’s lesion).
Hum Pathol. 2004;35:1063–9.
Nora FE, Dahlin DC, Beabout JW. Bizarre parosteal osteochondroma-
tous proliferation of the hands and feet. Am J Surg Pathol.
1983;7:245–50.
Zambrano E, Nose V, Perez-Atayde AR, Gebhardt M, et al. Distinct
chromosomal rearrangements in subungual (Dupuytren) exostosis
and bizarre parosteal osteochondromatous proliferation (Nora
lesion). Am J Surg Pathol. 2004;28:1033–9.

Fig. 61.8 (a, b) The cartilaginous component shows hypercellularity

with large chondrocytes mimicking chondrosarcoma
 Fibro-osseous Pseudotumor of Digits
62
Liliana G. Olvi and Eduardo Santini-Araujo

Abstract
Fibro-osseous pseudotumor of digits (FPD) is a rare benign lesion. It is a localized self-
limited fibro-ossifying process that occurs in the proximal phalanx of digits. It is predomi-
nant in female. It occurs in adolescents or young adults, and the common sites of involvement
are the proximal phalanx and metacarpal and metatarsal region. Radiologically, the lesion
is an ill-defined and calcified soft tissue mass without zoning pattern of myositis ossificans.
Histologically, the lesion resembles myositis ossificans. Treatment is excision of mature
lesions which is curative.

Definition Clinical Features

• Rare benign lesion. It is a localized self-limited fibro- Epidemiology

ossifying process that occurs in the proximal phalanges of
digits. Sex
• Predominant in female

Synonyms Age
• Adolescents or young adults
• Florid reactive periostitis of the tubular bones of hands
and feet
• Pseudomalignant osseous tumor of the soft tissue Sites of Involvement
• Parosteal fasciitis
• Proximal phalanges
• Metacarpal and metatarsal regions

Clinical Symptoms and Signs

L.G. Olvi, MD • Pain

Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina • Localized and fusiform swelling in hands and less fre-
E. Santini-Araujo, MD, PhD (*) quently in feet
Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina
Department of Pathology, School of Medicine and School of
Dentistry, University of Buenos Aires,
Buenos Aires, Argentina
Central Army Hospital, Buenos Aires, Argentina
e-mail: santiniaraujo@laborpat.com.ar

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 841
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_62, © Springer-Verlag London 2015
842 L.G. Olvi and E. Santini-Araujo

Image Diagnosis Pathologic Differential Diagnosis

Radiographic Features Extraskeletal Osteosarcoma

• More common in elderly patients, fifth and sixth decades
• Ill-defined and calcified soft tissue mass without the zon- • Lacks cytological atypia
ing pattern of myositis ossificans. • “Lacelike” osteoid
• Mature lesions are similar to myositis ossificans, becom-
ing smaller and attached to the cortex. Parosteal Osteosarcoma
• Low-grade malignant tumor.
• Extensive bone trabeculae formation with a tendency to
Bone Scan parallel arrangement.
• Fibrous stroma presents numerous spindle cells with low-
• Hot spot grade sarcoma. Similar to a low-grade fibrosarcoma.

Image Differential Diagnosis Prognosis

Parosteal Osteosarcoma • FDP has an excellent prognosis. Recurrence may be

• Densely ossified juxtacortical round or oval mass attached observed in cases treated in an early stage.
to the underlying cortex
• Rare in hands and feet
Treatment

Pathology • It depends on the evolution stage of the lesion.

• Excision of mature lesions is curative.
• Less than 5 cm in diameter
• Stony consistency, mature lesion
Images

Histological Features See Figs. 62.1, 62.2, 62.3, and 62.4 for illustrations of fibro-
osseous pseudotumor of digits.
• The lesion resembles myositis ossificans.
• Lacks zoning phenomenon or zoning effect.
• Loosely arranged fibroblasts on a myxoid matrix with
abundant deposits of osteoid surrounded by active osteo-
blasts and multinucleated giant cells.
62 Fibro-osseous Pseudotumor of Digits 843

Fig. 62.1 (a) Roentgenograph a b

of the proximal phalanx of the
hand showing a dense soft tissue
mass with a periosteal reaction.
(b) Sagittal MRI evidences of the
soft tissue swelling and the
periosteal reactive reaction of the
phalanx

Fig. 62.2 Microphotograph showing woven osteoid bone trabeculae Fig. 62.3 Microphotograph showing a histology similar to the former
rimmed by active osteoblast. The bone marrow stroma is hypercellular, image with the presence of multinucleated giant cells, osteoclastic type
and some cells have a bizarre aspect
844 L.G. Olvi and E. Santini-Araujo

a b

c d

Fig. 62.4 (a, b) Hypothenar eminence swelling with a red area in the evidences a calcified mass in soft tissues close to the periosteal surface
skin. Note the small punctual scar lesion due to core needle biopsy that of the fifth metacarpal bone. (d) Evolution of the lesion 6 months later
was useful to make an accurate diagnosis. (c) Anteroposterior x-ray
62 Fibro-osseous Pseudotumor of Digits 845

Recommended Reading
Dupree WB, Enzinger FM. Fibro-osseous pseudotumor of the digits.
Cancer. 1986;58:2103.
McCarty EF, Ireland DC, Sprague BL, et al. Parosteal (nodular) fasciitis
of the hand. A case report. J Bone Joint Surg Am. 1976;58:714.
Spjut HJ, Dorfman HD. Florid reactive periostitis of the tubular bones
of the hands and feet. A benign lesion which may simulate osteosar-
coma. Am J Surg Pathol. 1981;5:423.
 Subungual Exostosis
63
Liliana G. Olvi, Maria L. Gonzalez, and
Eduardo Santini-Araujo

Abstract
Subungual exostosis is an osteocartilaginous benign process in a subungual or periungual
site. It is more frequent in females. Near 70 % of patients are in the second and third
decades. Anyway, the lesion may appear in a wide age range. Near 70 % of cases are located
in the nail bed of the distal phalanx of the big toe. Radiologically in an early stage, the
lesion appears as a soft tissue density without attachment to the underlying bone. Mature
lesions have calcification and a trabecular pattern and are attached to the cortex of the pha-
lanx. No continuity between the medullary cavity and the lesion is seen. Histologically a
mixture of chondroid metaplastic areas, woven bone, and spindle cell proliferation is pres-
ent. Treatment is excision.

Definition Clinical Features

• Osteocartilaginous benign process in a subungual or peri- Epidemiology

ungual site
Sex
• More frequent in females
Etiology
Age
• History of trauma or infection at the site in one third of • Near 70 % of patients in the second and third decades.
patients. Anyway, the lesion may appear in a wide age range.
• Recent genetics studies show chromosomal rearrange-
ments that suggest a neoplastic type of lesion.
Sites of Involvement

• Near 70 % of cases are located in the nail bed of the distal

phalanx of the big toe.

L.G. Olvi, MD • M.L. Gonzalez

Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina Clinical Symptoms and Signs
E. Santini-Araujo, MD, PhD (*)
Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina • Undernail painful lesion.
Department of Pathology, School of Medicine and School of • Swelling that elevates nail.
Dentistry, University of Buenos Aires, Buenos Aires, Argentina • Ulceration and infection may aggregate.
Central Army Hospital, Buenos Aires, Argentina
e-mail: santiniaraujo@laborpat.com.ar

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 847
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_63, © Springer-Verlag London 2015
848 L.G. Olvi et al.

Image Diagnosis • A more organized shell of woven and parallel lamellar

Radiographic Features
• In an early stage, the lesion appears as a soft tissue density
without attachment to the underlying bone, usually with
1 cm in diameter.
• Mature lesions have calcification and a trabecular pattern
and are attached to the cortex of the phalanx. No continu-
ity between the medullary cavity and the lesion is seen.
• No bone destruction of the phalanx is seen.
Image Differential Diagnosis
Osteochondroma
• The underlying cortex is classically discontinuous, and
the metaphyseal spongiosa is continuous with the tumor
spongiosa.
Myositis Ossificans: Mature Lesions
• Most commonly attached to the cortex in the diaphyseal
region
• Limited by a more calcified rim at its periphery whereas
the center is more radiolucent. Zonation effect
• Absence of a broad base of attachment to the underlying
cortex
bone.
• The lesion is separated from the surrounding muscle by a
zone of myxoid fibrous tissue.
• The peripheral muscle shows atrophic changes and
inflammatory infiltrates.
• The clue and hallmark for diagnosis is the presence of a
zoning phenomenon or zoning effect.
Osteochondroma: Sessile Type
• Cartilaginous cap in surface.
• The cap has a similar aspect to that of normal growth
cartilage.
• Endochondral ossification is present.
• Trabeculae of endochondral ossification present calcified
cartilage inside their bone trabecular matrix.
• The underlying cortex is classically discontinued, and the
metaphyseal spongiosa is continued with the tumor spon-
giosa that contains active hematopoietic or fatty marrow.
• Subungual exostosis presents a spindle cell proliferation
never seen in osteochondroma.
Subungual Osteogenic Melanoma
• A type of melanoma with osseous and cartilaginous
metaplasia.
• The presence of melanoma in the underlying skin is a clue
for the differential diagnosis.

Chondrosarcoma
Pathology • Without clinical and radiographic correlation, the moder-
ate atypia in chondrocytes of the cartilaginous cap may
Gross Features drive to a diagnosis of chondrosarcoma.

• Osseous mass with a well-circumscribed smooth carti-

laginous cap. Prognosis
• In ulcerated lesions, a fibrous granulation tissue is seen.
• Excellent.
• Rare recurrences.
Histological Features • Malignant transformation is not reported.

• In early phases, a mixture of chondroid metaplastic areas,

woven bone, and spindle cell proliferation is present. Treatment
• Close-up cartilaginous cap is highly cellular, showing
bizarre chondrocytes. • Excision.
• Bony trabeculae are intermingled with a loose spindle cell • Re-excision in recurrences.
proliferation.
• The absence of anaplasia and the progression to mature
bone reflect the benign nature of the lesion. Images

See Figs. 63.1, 63.2, 63.3, 63.4, and 63.5 for illustrations of
Pathologic Differential Diagnosis subungual exostosis.

Myositis Ossificans: Mature Lesions

• A more cellular lesion.
63 Subungual Exostosis 849

a b c

Fig. 63.1 (a–c) Subungual exostosis involving the distal phalanx of the great toe in 3 different patients

Fig. 63.2 Subungual exostosis of the distal phalanx of the fifth toe
850 L.G. Olvi et al.

Fig. 63.3 (a, b) Anteroposterior

a b
and lateral radiographs of the
distal phalanx of the second
finger

Fig. 63.5 Residual cartilage in endochondral ossification. The reactive

woven trabecular bone is rimmed by osteoblasts, and the intertrabecular
Fig. 63.4 Cartilage cap and the underlying bone at higher space is filled with vascular connective tissue
magnification

Recommended Reading
Evison G, Price CHG. Subungueal exostosis. Br J Radiol.
1966;39:451–5.
Landon GC, Johnson KA, Dahlin DC. Subungueal exostoses. J Bone
Joint Surg. 1979;61A:256–9.
Zambrano E, Nose V, Perez-Atayde AR, Gebhardt M, et al. Distinct
chromosomal rearrangements in subungual (Dupuytren) exostosis
and bizarre parosteal osteochondromatous proliferation (Nora
lesion). Am J Surg Pathol. 2004;28:1033–9.
 Stress Fracture
64
Liliana G. Olvi, Maria L. Gonzalez, and
Eduardo Santini-Araujo

Abstract
It occurs when bone elastic resistance is insufficient to support the stress of normal activity
and is more frequent in diaphysis of tibia, metatarsal bones ala of sacrum, and pubis rami.
Radiologically in early stages, X-rays commonly are negative. Later, an intramedullary
horizontal sclerotic zone repairs the lucent line. Diffuse periosteal bone reaction is overly-
ing the sclerotic area. Histologically, it is similar to immature fracture callus. Supportive
treatment.

Definition – Osteoporosis, osteomalacia, and also diseases with

increase in osseous density raise the risk of fracture
• Occurs when bone elastic resistance is insufficient to sup-
port the stress of normal activity
Clinical Features

Synonyms Epidemiology

• Insufficiency fracture • Repetitive stress to the bone

• Fatigue fractures

Sites of Involvement
Etiology
• More frequent in:
• Associated with: – Diaphysis of tibia
– Repetitive stress: marching – military recruits – dancing, – Metatarsal bones
jogging, hiking, sportive activities, or vigorous training – Ala of sacrum
– Pubis rami

Clinical Symptoms and Signs

L.G. Olvi, MD • M.L. Gonzalez
Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina
• Without history of relevant mechanical trauma
E. Santini-Araujo, MD, PhD (*) • Persistent pain
Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina
Department of Pathology, School of Medicine and School of
Dentistry, University of Buenos Aires, Buenos Aires, Argentina
Central Army Hospital, Buenos Aires, Argentina
e-mail: santiniaraujo@laborpat.com.ar

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 851
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_64, © Springer-Verlag London 2015
852 L.G. Olvi et al.

Image Diagnosis Pathology

Radiographic Features Gross Features

• Fracture line is infrequently seen in roentgenograms. • Fragments of cortical bone

• In early stages, X-rays commonly are negative.
• Transverse fracture: on the tension side.
• Oblique fracture: on the compression side. Bigger
damage.
• Later, an intramedullary horizontal sclerotic zone repairs
the lucent line.
• Diffuse periosteal bone reaction overlying the sclerotic
area.
• In pelvis: linear sclerosis in the sacral ala.
Histological Features
• Periosteal and endosteal active new bone formation
• Necrotic laminar bone
• Osteoid and calcified woven bone in the intertrabecular
bone marrow areas
• Histologically similar to immature fracture callus

CT Features Pathologic Differential Diagnosis

• Shows fractures not seen on radiographs Osteosarcoma

• Periosteal reaction • The differential between the two entities is one of the
• Medullary sclerosis most risky differential diagnoses in bone pathology.
Stress fracture
– Periosteal bone reaction
MRI Features – Woven bone trabeculae permeating bone marrow
spaces
• Medullary abnormal signals, mimicking infiltrative – No cellular atypia
process Osteosarcoma
– Atypical osteoblastic cells in bone marrow spaces
– Neoplastic osteoblasts lining the tumoral bone
Bone Scan trabeculae
– Hyperchromatic nuclei, cellular atypia, brisk
• The lesion is hot. mitotic activity

Image Differential Diagnosis Prognosis

It is relevant to consider that the absence of a significant his- • Excellent prognosis

tory of trauma frequently leads the clinician, orthopedic sur-
geon, radiologist, and/or pathologist to overdiagnosis it as a
neoplasm. Treatment

Osteosarcoma • Supportive treatment

• Both lesions are common in young people. • In osteoporosis-associated stress fractures: specific etio-
• Usually OS arises in the metaphysis. logic treatment

Round Cell Malignancies (Ewing’s Sarcoma)

• The diffuse periosteal reaction mimics an intramedullary Images
permeative process like round cell tumor.
See Figs. 64.1, 64.2, 64.3, 64.4, 64.5, 64.6, and 64.7 for illus-
Metastatic Carcinoma trations of stress fracture.
• More frequent in pubic sites
64 Stress Fracture 853

Fig. 64.1 (a, b) Stress fracture

in one of the most common a b
location – proximal tibia.
Anteroposterior and lateral
roentgenograms showing a
fracture line with exuberant new
bone formation in the
metaphysis. It is also possible to
see a periosteal reaction

Fig. 64.2 Fracture line is clearly seen, with a small periosteal

reaction
854 L.G. Olvi et al.

Fig. 64.3 (a, b) Stress fracture

in upper end of tibia. CT scan a b
shows periosteal reaction and
changes in the density of the
cortical bone

a b

Fig. 64.4 (a, b) Stress fracture in the middle shaft of fibula. (b) The technetium bone scan shows an intense uptake over the fibular diaphysis
64 Stress Fracture 855

Fig. 64.6 Microphotograph of a stress fracture. Fracture callus with

fibrous tissue, cartilage, and immature bone

Fig. 64.5 Stress fracture in the diaphysis of the second metatarsal

bone

Fig. 64.7 Photomicrograph showing reactive woven bone that differs

from necrotic preexisting bone
856 L.G. Olvi et al.

Recommended Reading Ostrum R, Chao EY, Bassett CA, et al. Bone injury, regeneration and
repair. In: Simon SR, editor. Orthopaedic basic science. Rosemont:
American Academy of Orthopaedic Surgeon; 1994. p. 277–323.
Cooper KL, Beabout JW, Swee RG. Insufficiency fractures of the
Sweet DE, Allman RM. Stress fracture. RPC of the month from the
sacrum. Radiology. 1985;156:15–20.
AFIP. Radiology. 1971;99:687–93.
McBryde AM. Stress fractures in athletes. J Sports Med.
1975;3:212–7.
 Bone Infarct
65
Liliana G. Olvi and Eduardo Santini-Araujo

Abstract
Bone infarct is a localized bone necrosis – meaning death of cells (osteocytes, hematopoi-
etic, and fatty marrow) in bone tissue – associated with local vascular ischemia. Femoral
head is the most common site. Humeral head follows. In early stages, x-rays are negative.
With the evolution, the area of lucency with patchy mixed lytic and sclerotic lesions in the
medullary canal follows. Histologically, in early stage, there is necrosis of fatty bone mar-
row, hematopoietic marrow, and capillary endothelial cells. Necrotic bone trabeculae show
picnotic osteocytes and later empty osteocytic lacunae. Phase of healing: granulation tissue
grows into the necrotic bone at the periphery to the necrotic area. New bone apposition by
osteoblasts over the necrotic non-resorbed trabeculae at the periphery of the lesion – “creep-
ing substitution.” Amorphous calcification is due to saponification of fat marrow. Rarely,
sarcomas may develop associated with bone infarct.

Definition Etiology

• A localized bone necrosis – meaning death of cells (osteo- • Avascular necrosis, usually idiopathic, associated with:
cytes, hematopoietic and fatty marrow) in bone tissue – – Trauma
associated with local vascular ischemia. Or:
– Non-traumatic avascular necrosis:
• Corticosteroid treatment
Synonyms • Alcohol abuse
• Decompression sickness – Caisson disease, bends
• Avascular necrosis • Sickle cell disease
• Aseptic necrosis • Coagulopathies
• Radiation injury – radiotherapy
• Autoimmune disorders, e.g., rheumatoid disease,
arteritis, systemic lupus erythematosus
• Gaucher’s disease
L.G. Olvi, MD • Pancreatitis
Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina • Gout
E. Santini-Araujo, MD, PhD (*) • “Idiopathic”
Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina
Department of Pathology, School of Medicine and School of
Dentistry, University of Buenos Aires, Buenos Aires, Argentina
Central Army Hospital, Buenos Aires, Argentina
e-mail: santiniaraujo@laborpat.com.ar

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 857
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_65, © Springer-Verlag London 2015
858 L.G. Olvi and E. Santini-Araujo

Clinical Features Pathology

Sites of Involvement Gross Features

• Femoral head is the most common site. • Early stage:

• Humeral head follows. – Area of bone necrosis has a yellow-cream appearance
• Affects the metaphyseal regions of the long bones. with a peripheral area of hyperemia separating the
necrotic from the surrounding viable tissue.
Clinical Symptoms and Signs • Phase of healing:
• Pain in femoral head location. – Central lucency area surrounded by undulating
• In other locations, without symptoms or mild pain. calcification
• Depends on the primary pathology that produces the bone – Fibrosis in bone marrow areas
infarct.
• Most of them are asymptomatic or radiological
findings. Histological Features

Early Stage
Image Diagnosis • Necrosis of fatty bone marrow, hematopoietic marrow,
and capillary endothelial cells.
Radiographic and CT Features • Necrotic bone trabeculae show picnotic osteocytes and
later empty osteocytic lacunae.
• In early stages, x-rays are negative.
• With the evolution: area of lucency with patchy mixed Healing Phase
lytic and sclerotic lesions in the medullary canal. • Granulation tissue grows into the necrotic bone at the
• Well-demarcated peripheral increase of radiodensity – periphery to the necrotic area.
sclerosis – with serpiginous margins. • Hyperemic bone marrow at the periphery. Osteoclastic
bone resorption of the necrotic trabeculae in the edge of
the interface between necrotic and viable bone.
MRI Features • Absence of osteoclasts in the necrotic area due to the
absence of blood supply.
Early stage: • New bone apposition by osteoblasts over the necrotic
• Edema of the bone marrow non-resorbed trabeculae at the periphery of the lesion –
• Irregular serpiginous margins “creeping substitution.” It is easily identified due to the
presence of arrested-type cement lines separating central
necrotic bone matrix from viable surface bone. This pro-
Bone Scan cess increases the density of the cancellous bone and the
radiodensity in images.
• The lesion is hot. • New bone immature formation de novo as in fracture end-
osteal callus is seen.
• Amorphous calcification due to saponification of fat
Image Differential Diagnosis released by disruption of necrotic adipocytes and calcium
soap formation in the fibrotic bone marrow spaces. This
Chondroid Neoplasm fact also contributes to the radiodensity in
• In chondroid neoplasm: calcification scattered over the roentgenograms.
entire lesion
• In bone infarct: calcification along the edges of the lesion
Pathologic Differential Diagnosis
Sarcomatous Change
• Secondary ABC changes may mimic the development of Over-decalcification
a sarcoma associated with bone infarct. Bone infarct has:
• Empty osteocytic lacunae
Intraosseous Lipoma • Absence of bone fatty marrow necrosis and
• MRI helps in diagnosis with fat-suppressed images. calcification
65 Bone Infarct 859

Intraosseous Lipoma • In metaphyseal infarct of long bones: faced with the onset
• Similar calcifications to bone infarcts may appear in of pain or increased lytic image, an association with sar-
intraosseous lipomas. coma should be discarded.

Aneurysmal Bone Cyst

• Bone infarcts can be associated with 2ry ABC. Treatment
• In all these Differential Diagnosis, the clinical and radio-
graphic findings’ correlation is indispensable. • In femoral head: total hip arthroplasty
• In other sites, do not require treatment

Prognosis
Images
• Good prognosis.
• Rarely, sarcomas may develop associated with bone See Figs. 65.1, 65.2, 65.3, 65.4, 65.5, 65.6, 65.7, 65.8, 65.9,
infarct. 65.10, 65.11, 65.12, 65.13, 65.14, and 65.15 for illustrations
of bone infarct.
860 L.G. Olvi and E. Santini-Araujo

a b c

Fig. 65.1 (a, b) Anteroposterior and lateral x-ray of distal femur showing an area of lucency with patchy mixed lytic and sclerotic lesion in the
medullary canal. (c, d) MRI of the same lesion simulating a chondroma
65 Bone Infarct 861

Fig. 65.2 (a, b) Anteroposterior

and lateral radiographic features a b
of an old multifocal medullary
infarct showing a well-defined
radiodense lesion

Fig. 65.3 Plain x-ray of the proximal metaphyseal femur illustrating a

well-demarcated sclerotic lesion with peripheral increase of
radiodensity
862 L.G. Olvi and E. Santini-Araujo

a b

d
c

Fig. 65.4 Bone infarct of femoral neck. (a, b) X-ray shows a well- suppression images and a low signal intensity on T1-weighted images
circumscribed lytic lesion with central mottled calcifications due to the with a “double-line sign.” (e) CT- guided core needle biopsy
necrosis of bone marrow. (c, d) There is a high signal intensity on fat
65 Bone Infarct 863

Fig. 65.5 Lower end of femur.

(a, b) In Plain x-ray, early lesions a b
may be little evident. A delicate
spot calcification is noted. (c, d)
Coronal and sagittal T1-weighted
MRI shows a well-demarcated
zone with serpiginous borders

c d
864 L.G. Olvi and E. Santini-Araujo

a c

d e

Fig. 65.6 (a, b) Well-delimitated heterogeneous lesion in the proximal intensity signal in cystic areas and sagittal T2-weighted MRI with high
end of the tibia. (c) CT scan showing the trabecular sclerosis and sec- intensity signal in the same areas
ondary cystic changes. (d, e) Coronal T1-weighted MRI showing low
65 Bone Infarct 865

Fig. 65.7 (a) Plain radiograph illustrating irregular medullar sclerosis in the proximal humerus. (b) MRI showing a large heterogeneous lesion
with secondary cystic changes
866 L.G. Olvi and E. Santini-Araujo

Fig. 65.8 Plain x-ray shows a bilateral symmetric multifocal bone infarct with the typical calcification of necrotic fat producing the “wisps of
smoke” pattern of radiodensity. The lesion was asymptomatic. It was a radiographic finding due to a ligament lesion
65 Bone Infarct 867

Fig. 65.9 Microphotograph showing necrotic trabecular bone. Note Fig. 65.11 High power magnification shows the calcium soap forma-
the absence of osteocytes in the lacunae. The bone marrow spaces show tion in the fibrotic bone marrow spaces. This fact contributes to the
amorphous calcification due to saponification of fat released by disrup- radiodensity in roentgenograms
tion of necrotic adipocytes

Fig. 65.10 High-power magnification of calcium soap formation in Fig. 65.12 Microscopic features of bone infarct showing empty lacu-
the fibrotic bone marrow spaces nae and necrosis of the fat marrow which is filled with amorphous acel-
lular debris. Note the increase in remodeling lines
868 L.G. Olvi and E. Santini-Araujo

a b

c d

Fig. 65.13 Sarcoma arising in bone infarct. (a, b) Plain x-ray of distal femur showing a large lytic lesion with dense spots of calcification mimick-
ing a chondrosarcoma. (c) MRI of same lesion. (d) Microscopy shows necrotic bone on the left and sarcoma on the right
65 Bone Infarct 869

a b

c d

Fig. 65.14 (a) Plain x-ray shows a lytic lesion in the proximal femur surgical specimen and the area of sarcoma transformation complicated
complicated with pathologic fracture. Note the spot calcification in the with fracture. (c) Microscopic features of bone infarct (on the left) and
distal area and the trabecular calcification at the top. (b) Gross speci- sarcoma transformation (on the right). (d) Typical osteosarcoma
men showing the alveolar features of bone necrosis at the top of the features
870 L.G. Olvi and E. Santini-Araujo

a b

c d

Fig. 65.15 Sarcoma arising in bone infarct. (a, b) Plain x-ray showing
typical features of multiple bone infarcts in a 56-year-old female who
received steroid therapy. (c) CT scan showing calcification of fat mar-
row. (d) CT shows a lytic image in the end of left femur. (e) T1-weighted
MRI showing the characteristic serpiginous low intensity image. (f)
Tumoral area in the epiphysis of the femur. (g) Tc 99m shows no uptake
in bone infarcts and hot spot uptake in sarcoma area. (h) Gross speci-
men showing the typical serpiginous yellow features of bone infarct.
The white tissue corresponds to sarcoma transformation. (i, j)
Microscopic features of fibrosarcoma arising in bone infarct
65 Bone Infarct 871

Fig. 65.15 (continued)

872 L.G. Olvi and E. Santini-Araujo

Fig. 65.15 (continued)

65 Bone Infarct 873

g h

i j

Fig. 65.15 (continued)

874 L.G. Olvi and E. Santini-Araujo

Recommended Reading Jones JP. Fat embolism, intravascular coagulation and osteonecrosis.
Clin Orthop. 1993;292:294–308.
Koo K, Kim R, Cho S, et al. Angiography, scintigraphy, intraosseous
Bullough PG, Kambolis CP, Marcove R, Jaffe HL. Bone infarctions not
pressure, and histologic findings in high-risk osteonecrotic femoral
associated with caisson disease. J Bone Joint Surg.
heads with negative magnetic resonance images. Clin Orthop.
1965;47A:477–91.
1994;308:127–8.
Franchi A, Bullough. Secondary avascular necrosis in coxarthrosis: a
McCarthy EF. Aseptic necrosis of b one. An historic perspective. Clin
morphologic study. J Rheumatol. 1992;19:1263–8.
Orthop Relat Res. 1982;168:216–21.
Furey JG, Ferrer-Torells M, Reagan JW. Fibrosarcoma arising at the
Thompson GH, Salter RB. Legg-Calve-Perthes disease. Current con-
site of bone infarcts: a report of two cases. J Bone Joint Surg.
cepts and controversies. Orthop Clin N Am. 1987;18:617–35.
1960;42A:802–10.
Hungerford DS. Pathogenetic considerations in ischemic necrosis of
bone. Can J Surg. 1981;24:583–7, 590.
 Paget’s Disease of Bone and Sarcoma
Complicating Paget’s Disease 66
Liliana G. Olvi, Maria L. Gonzalez,
and Eduardo Santini-Araujo

Abstract
Paget’s disease is a chronic disease of bone due to a hyperactivity of osteoclasts and osteo-
blasts resulting in abnormal bone remodeling. Lesions may be monostotic or polyostotic. It
is most common in Northern European – Anglo-Saxon, New Zealanders, and Australians –
people. It is more frequent in males than females, 2:1. It is more frequent after the fourth
decade. The innominate bone and femur are the most common locations, followed by the
lumbar spine, skull, and tibia. Radiologically, in the early stage, the lesion is sharply mar-
ginated, lytic, and radiolucent. In the skull it is called osteoporosis circumscripta.
The transition between the lesion and the normal cortex is sharp and wedge shaped like a
“blade of grass” or a “flame.” In the middle stage the roentgenologic appearance also
changes, and radiolucency and radiodensity reflect the histopathological picture.
The cancellous bone presents thicker, irregular, and coarser trabeculae, thickening of the
cortex, and bone expansion with increase in bone diameter. The late stage shows increased
density, with bone thickening. Bowing bone deformity – more common in the femur and
tibia – is due to the altered mechanical properties of pagetic bones. Fractures are also seen
in pagetic bones. In the spine, affected vertebral body increases all diameters. This fact is
evident in anteroposterior and lateral X-rays. Histologically the osteolytic stage shows very
active osteoclastic resorption removing normal lamellar bone and immature woven bone
formation by active osteoblasts. The osteoblastic stage is characterized by wide bone tra-
beculae with the characteristic “mosaic pattern” due to numerous reversal-type cement
lines. Treatment includes the use of calcitonin and bisphosphonates to reduce symptoms by
reducing bone turnover and surgery in pathologic fractures. Sarcoma complicating Paget’s
disease may be found in approximately 1 % of patients with Paget’s.
There is a slight predominance of men and the ages most often range from 50 to 70 years.
The most frequent sites are the femur, humerus, pelvis, and tibia. The most common tumor
type is osteosarcoma, followed by fibrosarcoma. Other less frequent varieties are chondro-
sarcoma, malignant fibrous histiocytoma, and lymphoma. Sarcomas associated with Paget’s
disease are treated with surgical resection, amputation, or disarticulation. Radiotherapy and
chemotherapy are indicated.

E. Santini-Araujo, MD, PhD (*)

L.G. Olvi, MD • M.L. Gonzalez, MD Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina
Laboratory of Orthopaedic Pathology,
Buenos Aires, Argentina Department of Pathology, School of Medicine and School of
Dentistry, University of Buenos Aires, Buenos Aires, Argentina
Central Army Hospital, Buenos Aires, Argentina
e-mail: santiniaraujo@laborpat.com.ar

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 875
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_66, © Springer-Verlag London 2015
876
Definition
• Chronic disease of bone due to a hyperactivity of osteo-
clasts and osteoblasts resulting in abnormal bone
remodeling
Synonyms
• Osteitis fibrosa deformans
Etiology
• The etiology of Paget’s disease of the bone is still not
completely understood.
• The disease consists of a localized disorder of bone
remodeling that presents areas of very active turnover,
with focus on active resorption and bone synthesis, abso-
lutely uncontrolled.
• In an early phase, an increased number of osteoclasts pro-
duce a markedly increased localized bone resorption.
These osteoclasts are different from normal osteoclasts
because they are larger in size and with an increased num-
ber of nuclei. Nuclei of Paget’s osteoclasts commonly
present nucleoli-like inclusions that, ultrastructurally,
represent paramyxovirus-like inclusions that appear in
about 43 % of patients. This finding postulates the possi-
bility that a viral infection – measles and canine distem-
per virus – might trigger the disease.
• In a progressive phase, the lesion shows an increase in
bone formation with a disrupted pattern. Not only with
shape and size changes but also the load-bearing capacity
of bones is altered.
• Gene mutations are involved in Paget’s disease and also in
hyperphosphatasia.
• In Paget’s disease a mutation was found, involving p62/
sequestosome1 (SQSTM1). Patients presenting SQSTM1
mutations develop more serious disease.
• Anyway, gene mutation present or not, the osteoclasts in
Paget’s disease are more numerous, with more nuclei and
with a resorption capacity greater than those of the nor-
mal bone. The mutation probably induces changes of the
normal RANKL (receptor activator of nuclear factor kap-
paB ligand) activation mechanism.
• Other possible factors are virus infection and unknown
environmental factors.
• The possible presence of paramyxovirus in some experi-
mental models with transgenic mice developing lesions
resembling Paget’s disease may suggest an etiologic
relationship.
L.G. Olvi et al.
Clinical Features
Epidemiology
• Most common in Northern European – Anglo-Saxon,
New Zealanders, and Australians – people. More than
30 % in the European population. Infrequent in Blacks
and Asians.
• Monostotic lesions are more frequent than polyostotic ones.
Sex
• More frequent in males than females, 2:1
Age
• More frequent after the fourth decade
Sites of Involvement
• The innominate bone and femur are the most common
locations, followed by the lumbar spine, skull, and tibia.
• Any bone may be involved.
• Less frequently, lesions may be polyostotic and, in some
patients, generalized.
Clinical Symptoms and Signs
• Often asymptomatic. Incidental radiographic finding in
some patients, after a roentgenologic examination or bone
scan for other reasons.
• Pain is present in 40 % of patients and is diffuse in the
affected bone. Increased pain raises suspicion of devel-
oping a sarcoma or the presence of metastatic
carcinoma.
• Periosteal tenderness and warmth in affected bones.
• Bone deformity in more than 25 % of patients – bowing
of long bones.
• Pathologic fractures may occur, frequently with minimal
trauma. More common in the femur and tibia.
• Secondary arthritis.
• Vertebral deformity with spinal stenosis.
• In the skull, involvement may produce headache, deaf-
ness, and other neural compression symptoms.
• In affected jaws, the teeth may be ill fitted and develop
problems of occlusion and chewing.
• Heart failure in some patients with large or multiple
locations, due to the high vascularization of bone mar-
row spaces that causes important changes in cardiovas-
cular function due to circulatory overload. This is
particularly frequent in patients with diminished cardiac
function.
66 Paget’s Disease of Bone and Sarcoma Complicating Paget’s Disease
• Elevated serum alkaline phosphatase – 25 times the nor-
mal level – is the most relevant biochemical abnormality.
Its activity is related with the extension of the monostotic
lesion, the number of bones involved in polyostotic
lesions, and its histological activity.
• Acid phosphatase may be found slightly increased.
• Urinary hydroxyproline levels can be elevated.
• Procollagen type I amino-terminal and carboxy-terminal
propeptide levels may increase in appositional phases of
the disease.
• Calcium and phosphorus levels may be normal.
• Serum calcium levels increase in patients with prolonged
periods of bed rest.
• In cases of sarcoma complicating Paget’s disease, the
symptoms are rapidly progressive, and increasing pain
appears in the affected area.
• Sarcoma complicating Paget’s disease may be found in
approximately 1 % of patients with Paget’s.
• There is a slight predominance of men, and the ages most
often range from 50 to 70 years.
• The alkaline phosphatase level usually rises abruptly
above the already high values of uncomplicated Paget’s
disease.
• The most frequent sites are the femur, humerus, pelvis,
and tibia.
• Pathologic fracture is a frequent finding.
• The most common tumor type is osteosarcoma, followed
by fibrosarcoma. Other less frequent varieties are chondro-
sarcoma, malignant fibrous histiocytoma, and lymphoma.
• Most sarcomas occur in polyostotic Paget’s disease.
Image Diagnosis
Radiographic Features
• Roentgenologic appearance in monostotic or polyostotic
forms is similar.
• The most frequent sites are the lumbar spine, pelvis, skull,
femur, and tibia.
• The images in Paget’s lesions correlate with and overlap
the stages of the disease and its histopathology.
Early Stage
• Sharply marginated, lytic, radiolucent lesions. In the skull
it is called osteoporosis circumscripta.
• In long bones, the radiolucent lesion first arises at one end
of the affected bone and extends proximally or distally.
• The transition between the lesion and the normal cortex is
sharp and wedge shaped like a “blade of grass” or a
“flame,” with normal bone in the noninvolved area, which
877
is a very characteristic and almost pathognomonic radio-
graphic feature of Paget’s disease.
• In this early phase, the cortex is involved, remodeled, and
frequently ill defined. The bone may increase in diameter.
Epiphysis involvement can lead to joint incongruity and
development, in more advanced stages, of secondary
arthritis.
Middle Stage
• When osteoclastic resorption and osteoblastic apposition
change and are balanced, the roentgenologic appearance
also changes, and radiolucency and radiodensity reflect
the histopathological picture.
• The boundary between the medulla and the cortex tends
to disappear with the altered bone trabeculation.
• Irregular periosteal and endosteal surfaces.
• The cancellous bone presents thicker, irregular, and
coarser trabeculae.
• Thickening of the cortex and bone expansion with
increase in bone diameter.
• Transition between normal and pagetic bone is commonly
abrupt.
Late: “Burnt-Out” Stage
• Increased density with bone thickening.
• Thickening of skull bones with “cotton-wool” appearance.
• Bowing bone deformity – more common in the femur and
tibia – due to the altered mechanical properties of pagetic
bones.
• In the spine, affected vertebral body increases all diame-
ters. This fact is evident in anteroposterior and lateral
X-rays and is also compared with the not involved, above
and below, vertebral bodies.
• In affected vertebral bodies, the bone trabeculae are
coarse.
• Vertebral body may show a peripheral radiodensity –
“picture frame” or “window frame” pattern.
• In the ilium, sclerosis of the innominate line is
characteristic.
• Transversal fractures are common in long bones with the
characteristic pattern of “banana” or “piece of chalk”
fracture. This feature is produced as a consequence of
pathologic remodeling of bone structure that fails to sup-
port the directional propagation of forces. Does not break
in a spiral fashion.
• Fractures may be associated with an important callus
fracture.
• Paget’s disease is often a lesion of slow evolution and dif-
ferent radiographic patterns corresponding to different
stages that can be observed in the same affected bone
radiography.
878 L.G. Olvi et al.

Paget’s Sarcoma Other Differential Diagnosis

• The affected bone shows typical roentgenographic fea- • Vertebral hemangioma
tures of Paget’s disease. • Chronic osteomyelitis
• Frequent destruction of the cortex and involvement of • Metastatic carcinoma
surrounding soft tissues. • Hyperparathyroidism
• Lytic or sclerotic bone destruction. The radiographic • Fibrous dysplasia
appearances depend largely on the histological type of the
tumor.
• Pathologic fracture through the sarcomatous area was a Pathology
frequent finding −20 % of patients.
• The humerus is a frequent location of this complication. Gross Features
• Sarcoma associated with Paget’s disease must be sus-
pected in all pagetic bones that change its X-ray sclerotic • Frequently the material is obtained by core needle biopsy.
patterns for a lytic pattern. • Distorted and hyperemic appearance of the bone surgical
specimen.
• Thickening of skull bones may determine involvement of
CT Features cranial nerve’s foramina with nerve loss.

• Very useful in demonstrating sarcomatous change or met-

Histological Features
astatic carcinoma in affected bones
Osteolytic Stage
• The normal bone marrow is replaced by a very important
MRI Features vascular proliferation in a loose edematous fibrous
tissue – no inflammatory infiltrate is seen. This feature
• Useful to demonstrate soft tissue involvement by Paget’s
appears before the appearance of osteoclasts that may be
sarcomas
scarce or abundant.
• Very active osteoclastic resorption removing the normal
lamellar bone.
Bone Scan • Immature woven bone formation by active osteoblasts
with prominent Golgi apparatus.
• Increased uptake.
• Useful in demonstrating polyostotic disease.
Osteoblastic Stage
• Late stages, with no histopathologic activity, may not
• Wide bone trabeculae with the characteristic “mosaic pat-
show uptake.
tern” due to numerous reversal-type cement lines. Almost
all bone matrix is of lamellar architecture.
• Thin trabeculae may be present.
Image Differential Diagnosis • The disease is basically a disease of uncoupled active
bone remodeling. This is responsible for the “mosaic,”
Osteofibrous Dysplasia
“jigsaw puzzle,” or “patchwork” patterns of the bony
• Cortical lesion arising in the tibia and fibula.
trabeculae that appear after the osteoclastic resorption –
• Frequently produces an anterior bowing of the affected
with its Howship lacunae – and osteoblast activity
bone.
become evident. Osteoblast activity fills the resorbed
• Not a medullary lesion.
surfaces. In this process cement lines appear when
• OFD is a cortical lesion localized predominantly in the
osteoclastic activity stops and appositional osteoblastic
tibia in children.
activity begins. These cement lines are scalloped
• Infrequently, in large lesions the entire width of the bone
because they represent the previous resorptive osteo-
is involved.
clastic activity and are called reversal lines. The other
type of cement lines, termed arrest lines, occurs when
Lymphoma of Bone osteoblastic activity produces apposition of the bone
• Uniform increase of bone density – most frequently in over the same trabecula. Osteoblasts present a promi-
involved pelvis or vertebral bodies – may suggest the nent Golgi apparatus. A clue to differentiate reversal
diagnosis of lymphoma from arrested lines is by using polarization in order to
66 Paget’s Disease of Bone and Sarcoma Complicating Paget’s Disease
observe the orientation of collagen lamellae. With this
procedure, it is possible to see that collagen lamellae
are continuous on either side of the arrested line. On the
contrary, lamellae are not continuous on either side of
reversal lines. This haphazard remodeling determines a
bone structure with great deficit in weight-bearing
capacity. This structural weakness determines the pres-
ence of cracks, bending deformities, and pathologic
fractures.
• Osteoclasts are larger and with a greater number of nuclei
than normal osteoclasts. Their nuclei contain prominent
nucleoli. Sometimes it is possible to see, in H-E sections,
intranuclear eosinophilic inclusions. Electron micro-
scopic studies revealed that they are microtubular inclu-
sions associated with myxoma virus, found in about 43 %
of patients affected by Paget’s disease.
• Bone marrow spaces show a high increase of vascular
vessels in a loose fibrous connective tissue.
Late Stage
• More evident “mosaic pattern” with wavy cement lines.
This pattern in inactive lesions may be the only clue to
diagnosis.
• Polarized light microscopy is useful to study the lamellar
structure of the trabeculae.
• More quiescent bone remodeling.
• Narrowing of blood vessels and fibrosis.
• Normalization of the bone marrow is seen in this stage.
Paget’s Sarcoma
Gross Features
• Surgical specimens show a destructive lesion in pagetic
bone, usually with soft tissue extension.
• Whitish-brown tissue with ossification in cases of
osteosarcoma.
Histological Features
• Extremely cellular pleomorphic and atypical tumors, with
more anaplasia than the conventional same type of sar-
coma arising in non-pagetic patients.
• The most common tumor type is osteosarcoma, followed
by fibrosarcoma. Other less frequent varieties are chon-
drosarcoma, malignant fibrous histiocytoma, and
lymphoma.
• The histological features of the osteosarcoma associated
with Paget’s disease are characteristic, with large num-
bers of osteoclast-like giant cells, alternating with atypi-
cal osteoblasts, thus exaggerating the anarchic remodeling
process of Paget’s disease.
879
• The neighboring areas of the pagetic bone show an
increased number of osteoclasts.
• In a few number of cases, it is possible to find, in the
fibrous marrow of the vicinity of the sarcoma – especially
with fibrosarcomas – an increase in the number and activ-
ity of the more anaplastic fibroblasts.
• Not all tumors associated with Paget’s disease are
highly malignant. Although extremely infrequent, a
giant cell tumor with no histological signs of malig-
nancy may arise in a pagetic bone. The differential
diagnosis in this instance is with a giant cell-rich
osteosarcoma.
Pathologic Differential Diagnosis
Fibrous Dysplasia
• More frequent in polyostotic forms.
• Histologically, the lesion is composed by a bland prolif-
eration of plump fibroblasts in a dense collagenous well-
vascularized matrix.
• The spindle cells present a storiform or whorled pattern
without cytologic atypia, hyperchromatism, or nuclear
pleomorphism.
• Within the fibrous tissue, there is a variable presence of
discontinuous immature woven osteoid or bone trabecu-
lae lacking osteoblastic rimming.
• At high-power magnification, it is possible to see flat or
spindle-shaped osteoblasts rimming immature trabeculae,
in typical fibrous dysplasia.
• Bony trabeculae of different sizes are arranged in a
haphazard, nonfunctional fashion. They have peculiar
shapes, the so-called Chinese characters. They are cur-
vilinear, in C and U and sometimes circumferential
shapes.
• In more mature lesions, trabeculae may present reversal
cement lines simulating the appearance of Paget’s disease
trabeculae.
• Paget’s disease bone has coarser bone trabeculae, with
active osteoclastic bone resorption. Bone matrix in Paget’s
is lamellar, different from what one sees in FD. FD bone
trabeculae are more curved, thinner and immature, being
totally formed by woven bone.
• Paget’s disease has a peculiar mosaic pattern of lamellar
bone, never seen in FD.
• The pagetic trabeculae are rimmed by prominent osteo-
blasts alternating with areas of osteoclastic reabsorption.
• The bone marrow spaces are richly vascularized and with
a peculiar loose and edematous fibrous tissue.
• The disease has a similar skeletal distribution to FD, but
affects older people.
880
Osteofibrous Dysplasia
• FD and OFD may share similar histological features.
• OFD presents immature curvilinear bone trabeculae
rimmed by prominent plump osteoblasts.
• Spindle cells in a dense collagenous stroma.
• Spindle cells expressing keratin and EMA.
• OFD is a cortical lesion localized predominantly in the
tibia of children.
Hyperparathyroidism
• In the early stages of pagetic lesions, the differential with
hyperparathyroidism is very important to consider.
• In Paget’s disease, the osteoclasts are larger and with a
greater number of nuclei – sometimes more than 20
nuclei – than normal osteoclasts.
• The osteoclastic activity in Paget’s disease almost never pro-
duces “tunneling resorption” in the cortex or “cutting cones.”
• In hyperparathyroidism, the fibrosis is prominently para-
trabecular, similar to the marrow fibrosis of Paget’s.
• In hyperparathyroidism, the vascularity of the bone mar-
row is unchanged.
• In the early phases of Paget’s disease that may be con-
fused with hyperparathyroidism, the vascularity is mark-
edly enhanced.
• The differential diagnosis may be sometimes very difficult
and requires complete laboratory and radiographic studies.
• In hyperparathyroidism due to primary parathyroid dis-
ease or parathyroid abnormalities due to renal failure,
blood biochemistry shows hypercalcemia, hyperphospha-
temia, and an increase of parathyroid hormone.
Chronic Osteomyelitis
• Present bone marrow fibrosis and different type of bone
remodeling, without “mosaic” pattern.
• Inflammatory bone marrow space infiltration by lympho-
cytes and plasma cells
Metastatic Carcinoma
• In some metastatic carcinomas – usually breast
carcinoma – desmoplastic stromal reaction may occur in
bone marrow areas.
• The presence of atypical cells and immunohistochemistry –
cytokeratins and other antibodies – may be helpful to
establish a differential diagnosis.
L.G. Olvi et al.
• The possibility of metastasis must be considered in any
patient with a known primary carcinoma.
Ancillary Techniques
• Reticulin stain, and polarization highlight the mosaic pat-
tern and the disruption of the lamellar structure of the
bone.
Prognosis
• The prognosis of Paget’s sarcoma is poor.
• Particularly bad in tumors not amenable to surgical treat-
ment, with pathologic fractures, in multicentric lesions and
in cases with histological anaplasia and pleomorphism.
Treatment
• Calcitonin and bisphosphonates are used to reduce symp-
toms by reducing bone turnover.
• Some recent publications suggest that bisphosphonate
therapy has no clinical advantages in relation to analge-
sics or anti-inflammatories to reduce symptoms.
• Surgical treatment in pathologic fractures.
• Surgical treatment – osteotomy – in severe deformities. It
should be noted that this type of treatment can be difficult
given the mechanical properties as well as the active bone
remodeling of Paget’s disease.
• Arthroplasty in severe joint disease.
• Sarcomas associated with Paget’s disease are treated with
surgical resection, amputation, or disarticulation.
Radiotherapy and chemotherapy are indicated.
Images
See Figs. 66.1, 66.2, 66.3, 66.4, 66.5, 66.6, 66.7, 66.8, 66.9,
66.10, 66.11, 66.12, 66.13, 66.14, 66.15, 66.16, 66.17, 66.18,
66.19, 66.20, 66.21, and 66.22 for illustrations of Paget’s dis-
ease of the bone.
66 Paget’s Disease of Bone and Sarcoma Complicating Paget’s Disease 881

Fig. 66.2 Paget’s disease of the mandible with typical periapical

dentinal hyperplasia

Fig. 66.1 Paget’s disease of the skull. Radiographic features present-

ing large ill-defined lytic area with cotton-wool-like opacities
882 L.G. Olvi et al.

a b

Fig. 66.3 (a, b) Paget’s disease of the vertebra. Anteroposterior and lateral X-rays show enlargement of the vertebral body with coarsening of the
trabecular pattern and sclerotic margins, with the typical “picture frame” pattern

Fig. 66.4 Paget’s disease involving the left pelvis with expansion of
the bone
66 Paget’s Disease of Bone and Sarcoma Complicating Paget’s Disease 883

Fig. 66.5 Radiograph showing Paget’s disease of the diaphyso-

metaphyseal femur, with increased thickening of the cortex and medul-
lary bone

a b c

Fig. 66.6 (a, b) Anteroposterior and lateral radiographs: Paget’s disease of the distal femur. (c) MRI: Different trabeculation as compared to the
non-affected bone of the tibia
884 L.G. Olvi et al.

a b c

Fig. 66.7 Paget’s disease. (a, b) X-ray and (c) MRI of the patella

a b

Fig. 66.8 (a, b) Extensive

Paget’s disease involving the
tibia, with anterior bowing
deformity and coarse trabecular
pattern; there is lack of the
corticomedullary demarcation,
complicated with transverse
fracture
66 Paget’s Disease of Bone and Sarcoma Complicating Paget’s Disease 885

Fig. 66.9 (a, b) Paget’s disease.

Well-defined radiolucent defect a b
in the tibia and proximal and
distal margins showing a
flame-shaped pattern
886 L.G. Olvi et al.

Fig. 66.10 (a) Lateral X-ray

with Paget’s disease of the a b
tibia. It is possible to appreciate
some bowing; (b) High uptake
of Tc99 in old stage lesion

a b

Fig. 66.11 (a, b) Paget’s

disease of the proximal fibula
66 Paget’s Disease of Bone and Sarcoma Complicating Paget’s Disease 887

a b

Fig. 66.12 (a) Radiograph of the left calcaneus with monostotic Paget’s disease. (b) Scintigram shows increased Tc-99m uptake

Fig. 66.13 Paget’s disease of proximal humerus

Fig. 66.14 Paget’s disease of the distal radius

888 L.G. Olvi et al.

Fig. 66.16 Extensive Paget’s disease of the pelvis and femur with an
increased radiodensity and expansion of the bone

Fig. 66.15 Radiograph of the right hand shows monostotic Paget’s

disease affecting the first phalanx of the 4th digit
66 Paget’s Disease of Bone and Sarcoma Complicating Paget’s Disease 889

a b

Fig. 66.17 (a, b) The femur affected by a polyostotic Paget’s disease, with multiple foci of uptake in the scintigram
890 L.G. Olvi et al.

a b

Fig. 66.18 (a, b) Microscopic features at low and high magnification resorption. The bone marrow is fibrous and hyperemic. (c)
showing the typical “mosaic” structure of the trabeculae, due to the Ultrastructurally, nuclei of Paget’s osteoclasts commonly present para-
anarchic bone formation, and rimming by osteoblast and osteoclastic myxovirus-like inclusions
66 Paget’s Disease of Bone and Sarcoma Complicating Paget’s Disease 891

a b

Fig. 66.19 (a) Paget’s sarcoma of the skull. X-ray shows large lytic area at the occipital bone. (b) CT scan shows bone destruction with extension
into soft tissue of the occipital area, presenting sclerosis of the cranial bones. (c) Microscopy showing a fibrosarcoma arising in a Paget’s disease

a b

Fig. 66.20 (a, b) Paget’s sarcoma of the mandible

892 L.G. Olvi et al.

a b

c d

Fig. 66.21 (a) Osteosarcoma developing in Paget’s disease of infiltration of malignant bone trabeculae. (d) Another area of the
the pelvis. (b) CT scan shows a large soft tissue component. (c) The same case showing numerous multinucleated giant cells. (e) Tumoral
microphotograph illustrates pagetic trabeculae with scaffolding osteoid trabeculae lined by atypical osteoblasts alternated with
apposition of tumoral bone separated by the bone marrow with multinucleated giant cells
66 Paget’s Disease of Bone and Sarcoma Complicating Paget’s Disease 893

a b

Fig. 66.22 (a) Large lytic defect in the ilium corresponding to a giant cell tumor developing in a Paget’s disease. (b) Gross specimen.
(c) Microscopic features
894 L.G. Olvi et al.

Recommended Reading Schajowicz F, Santini Araujo E, Berenstein M. Sarcoma complicating

Paget’s diseases of bone. A clinicopathological study of 62 cases.
J Bone Joint Surg Br. 1993;65(3):299–307.
Altman RD. Paget’s disease of bone. In: Coe FL, Favus MJ, editors. Disorders
Schajowicz F, Velan O, Santini Araujo E, Plantalech L, Fongi E, et al.
of bone and mineral metabolism. New York: Raven; 1992. p. 1027–64.
Metastases of carcinoma in the pagetic bone. A report of two cases.
Paget J. On a form of chronic inflammation of bones (osteitis defor-
Clin Orthop. 1988;228:290–6.
mans). Med Chir Trans. 1877;60:37–63.
von Albertini A. Über Sarkombildung auf dem Boden der Ostitis defor-
Roberts MC, Kressel HY, Fallon MD, et al. Paget disease: MR imaging
mans Paget. Virchows Arch. 1928;268:259.
findings. Radiology. 1989;173:341–5.
 Gaucher Disease
67
Michael J. Klein

Abstract
Gaucher disease is an autosomal recessive inherited disorder of glycolipid metabolism in which
the failure to metabolize a glucocerebroside results in its storage in the macrophages of the
reticuloendothelial system with secondary end-organ effects. Three clinical types exist based
upon the severity of CNS involvement. Severity of the bone disease does not necessarily cor-
relate with that of other viscera. Bone modeling deformities, osteopenia, and avascular necrosis
of bone may occur. Histologic hallmark is the presence of large macrophages containing pale
eosinophilic, cytoplasm having the appearance of crinkled tissue paper. Gaucher cells are PAS
positive, diastase resistant, and stain weakly with Sudan black. Prognosis depends on disease
type. Enzyme replacement therapy improves life quality for patients with type I disease.

Definition activity is normal but there is deficiency of saposin C, a

• An inherited disorder of glycolipid metabolism in which
the failure to metabolize glucosylceramide (glucocere-
broside) results in the storage of this glycolipid in the
macrophages of the reticuloendothelial system with atten-
dant secondary end-organ effects.
Synonyms
• Glucocerebroside storage disorder
• Glucosylceramidase deficiency
• Acid beta-glucosidase deficiency
cofactor for glucocerebroside. The accumulation results
in secondary complications of those organs containing
histiocytes.
• The liver, spleen, and bone marrow are usually
affected, resulting in hepatomegaly, splenomegaly,
and bone modeling deformities in addition to an
increased propensity for bone infarcts and aseptic
necrosis of bone ends. In some types, the central ner-
vous system is involved, and life span is significantly
shortened.
• While the accumulation of glucosylceramide alone is not
responsible for the clinical severity of the disease, the pri-
mary enzyme defect underlies its pathogenesis.

Etiology
Clinical Features
• When the lysosomal enzyme activity of glucocerebrosi-
dase is defective, glucocerebroside accumulates in tis- Epidemiology
sue macrophages. Occasionally, glucocerebrosidase
• Inherited in an autosomal recessive manner
M.J. Klein, MD
Department of Pathology and Laboratory Medicine, Sex
Hospital for Special Surgery, New York, NY, USA • Sex incidence is equal.
e-mail: kleinm@hss.edu

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 895
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_67, © Springer-Verlag London 2015
896
Age
• The three clinical types based upon the severity of CNS
involvement are as follows:
– Type I, without CNS involvement, may present from
childhood to late adulthood and is compatible with a
normal life span.
– Type II, with severe CNS involvement, presents in
infancy, and patients usually die in infancy.
– Type III, with less severe CNS involvement, presents
in childhood, and the patient’s life span is usually two
to four decades.
Sites of Involvement
• Since it is a systemic disorder, any bone with a marrow
compartment can be affected.
• While there is histological evidence of the process any-
where there is marrow, the bones may show modeling
deformities, particularly in those bones having the most
active growth when the disease is manifested.
Consequently, the distal femur and proximal tibia are
often clinically affected.
• Convex ends of bone having end-arterial circulations are
prone to secondary avascular necrosis.
• Bone infarcts usually affect the medullary cavities of the
long bones and spare the overlying cortices.
• Tumorlike accumulations of Gaucher histiocytes
(“Gaucheromas”) as isolated or multiple lesions within
the bones.
Clinical Symptoms and Signs
• Hepatosplenomegaly with anemia and thrombocytopenia
in type I disease. Bone involvement is also seen in type III
disease.
• Severity of the bone disease does not necessarily correlate
with that of other viscera and bone marrow.
• Bone modeling deformities during skeletal growth.
• Osteopenia as a result of expansion of the marrow com-
partment with increased incidence of secondary fractures,
especially compression vertebral fractures.
• Bone crises, or acute pain similar to that seen in sickle cell
disease, may simulate infections.
• Avascular necrosis of bone ends may result in decreased
mobility and joint collapse.
M.J. Klein
Image Diagnosis
Radiographic Features
• Cortical atrophy and scalloping with generalized radiolu-
cency sparing bone ends
• Modeling deformities of long bones with diaphyseal
expansion with diminished concavity of metaphyses
(Erlenmeyer flask deformity)
• Areas of irregular radiodensity and radiolucency of bone
shafts secondary to infarcts
• Reactive periostitis with ossification leading to a “bone
within bone” form
• Vertebra plana secondary to collapse, with secondary spi-
nal deformities
• Epiphyseal osteonecrosis with radiodensity and subse-
quent collapse of femoral and humeral heads, distal
femur, and tibial plateau
MRI Features
• May demonstrate fluid collections beneath periosteum.
• May reveal the extent of marrow replacement.
• Can indicate the amount of infarction and the presence of
fibrosis.
• Signal changes can be used to demonstrate responses to
therapy.
Image Differential Diagnosis
Niemann-Pick Disease
• Erlenmeyer flask deformities may be present.
• Usually severe mental retardation.
• Avascular necrosis less common.
Thalassemia
• The skull often has hair-on-end appearance.
• Hepatosplenomegaly from extramedullary hematopoiesis.
• Avascular necrosis is less common.
• Modeling deformities less common.
Legg-Calvé-Perthes Disease
• Avascular necrosis of femoral heads in children.
• Usually unilateral, and the epiphyses have different sizes
on affected and unaffected sides.
67 Gaucher Disease
• Sclerosis with or without collapse of epiphysis.
• Other bone signs of Gaucher not present.
Hurler Syndrome
• Bones of the extremities are short.
• Anterior inferior “beak” of vertebral bodies.
• Pelvis may be hypoplastic.
• Hepatosplenomegaly.
• Mental retardation.
Morquio Syndrome
• Vertebra plana.
• Vertebral bodies are ovoid and have a central anterior
“beak.”
• “Wineglass”-shaped pelvis.
Myeloma
• Generalized osteopenia.
• Bone destruction may have adjacent soft tissue mass.
• If there is no associated fracture, often silent on radionu-
clide scans.
• Older age presentation than Gaucher patients.
Pathology
Gross Features
• In large specimens, the compact bone is thin, and the
medullary space is expanded.
• Bone infarcts appear as other bone infarcts; there is no
hemorrhagic stage. The specific appearance reflects their
age rather than their etiology.
• Osteonecrosis of bone ends appears grossly similar to
osteonecrosis of other etiology. Secondary changes
including partial or total collapse with degenerative
joint disease are dependent upon the stage of the
necrosis.
Histological Features
• The hallmark is the presence of large storage macro-
phages, up to 80 μ in diameter containing pale eosino-
philic, striate cytoplasm having the appearance of crinkled
tissue paper.
• Macrophages may be present singly, in groups, or in sheets;
they are often mixed with hematopoietic elements.
897
• Cytoplasm of Gaucher cells is PAS positive, diastase
resistant, and stains weakly with Sudan black.
• There may be associated infarction of the marrow.
• The cortex is usually thin and atrophic.
• In avascular necrosis of the bone ends, the necrotic area
appears the same as with other causes of osteonecrosis,
but often Gaucher cells may be seen in the marrow spaces
that are still viable.
Pathologic Differential Diagnosis
Other Storage Disorders
• Niemann-Pick disease and mucopolysaccharidoses have
large macrophages, but the cytoplasm is vacuolated or
foamy rather than striate and crinkled.
• Erdheim-Chester disease and xanthomatosis contain mul-
tivacuolated histiocytes containing lipid; the PAS stains
are negative.
• Certain hematopoietic diseases with high cell turnover may
contain cells identical to Gaucher histiocytes. These are
probably derived from destruction of cells with increased
quantities of cell membranes released that may temporarily
overwhelm normal levels of glucocerebrosidase.
Ancillary Techniques
Genetics
• The gene encoding glucocerebrosidase has been located
on chromosome 1q21; approximately 100 mutations have
been documented.
• The correlation of genotype with phenotypic severity is
inconstant, even in identical twins.
Prognosis
• Type I Gaucher disease is compatible with a normal life
span. However, the skeletal manifestations may be disabling,
resulting in a diminished quality of life. Patients may have
growth impairment, and there is a significantly increased risk
of multiple myeloma, leukemia, and lymphoma.
• Type II Gaucher disease eventuates in death, usually in
the first 2 years of life.
• Type III Gaucher disease is more slowly progressive, with
death usually in the third decade of life.
898 M.J. Klein

Treatment • Splenectomy has fallen into disfavor because it is thought

to accelerate the progress of lesions elsewhere.
• Enzyme replacement therapy improves life quality and has
reduced complications for patients with type I disease.
Unfortunately, because the enzyme does not traverse the Images
blood-brain barrier, it is not effective in the other types.
• Supportive therapy is a mainstay of care, particularly for See Figs. 67.1, 67.2, 67.3, 67.4, 67.5, 67.6, 67.7, and 67.8 for
pain and Gaucher crises. images of Gaucher disease.
67 Gaucher Disease 899

Fig. 67.2 Gaucher disease causing modeling deformity and cortical

Fig. 67.1 Gaucher disease involving the humerus. Note the radiolu- thinning of the femur. There is overall radiolucency of the femur, and
cency with cortical scalloping involving the distal diaphysis; the tra- the normal tapering cortical flare is widened, giving rise to the so-called
becular pattern of the distal end is spared Erlenmeyer flask deformity
900 M.J. Klein

Fig. 67.3 Gaucher disease, leg. There are areas of radiodensity and
space-occupying radiolucency secondary to deposits of Gaucher histio-
cytes with extreme attenuation of the tibial and fibular cortex leading to
pathologic fracture. The distal femur demonstrates “bone within a
bone” configuration suggesting old reactive periostitis

a b

Fig. 67.4 (a) Gaucher disease with avascular necrosis. AP conven-
tional radiograph of the right hip demonstrates a mixture of sclerosis
and lysis of the superior femoral head with joint narrowing and defor-
mity but without secondary osteophytes. This is consistent with stage 2
avascular necrosis with superficial collapse of the articular plate.
(b) Gaucher disease with avascular necrosis. The resected gross speci-
men seen in (a) demonstrating irregular areas of necrosis and viable
bone with separation of the subarticular bone plate and overlying artic-
ular cartilage, giving rise to the so-called crescent sign observed when
this separation can be seen with routine radiographs
67 Gaucher Disease
a b
Fig. 67.5 (a) Gaucher disease, autopsy specimen of distal femur in a
child unsuccessfully treated with enzyme therapy. The metaphyseal
flare is convex rather than concave, accounting for the typical
Erlenmeyer flask deformity, and the cortex is attenuated to almost paper
thinness. The marrow, which is usually yellow at this site at this age, is
red because of replacement of the more proximal marrow with Gaucher
a b
Fig. 67.6 (a) Cortex of specimen seen in Fig. 67.5a demonstrates deli-
cate striate organizing periosteal reaction comprising most of the extant
cortex. The subperiosteal connective tissue, Volkmann canals, and
Haversian canals are filled with storage histiocytes (Gaucher cells)
901
histiocyte storage. Note irregular whitish and yellow areas representing
medullary infarctions. (b) Specimen radiograph of the femur seen in
(a) demonstrates that the cortex is thinned almost to invisibility and the
irregular radiodensities are secondary to dead bone and calcification
of marrow fat in medullary fat necrosis (From Klein et al.; with
permission)
containing glucocerebrosides (hematoxylin-eosin 63×). (b) Higher
power of reaction seen in (a) demonstrates large pink storage
histiocytes (Gaucher cells) filling Haversian systems (hematoxylin-
eosin 157×)
902 M.J. Klein

a b

Fig. 67.7 (a) Gaucher cells admixed with a few normal marrow ele- erythrocytes; the crumpled appearance of the cytoplasm of the storage
ments, emphasizing the “crumpled paper” appearance of the cytoplasm histiocytes is emphasized (polarization contrast microscopy, hematoxy-
(700×, hematoxylin-eosin). (b) Gaucher cells admixed with a few lin-eosin, 787×)
67 Gaucher Disease 903

a b

Fig. 67.8 (a) Aggregations of Gaucher cells within a bone resembling the femur in another patient (Courtesy of George Hermann, MD). (c)
a space-occupying primary bone tumor (so-called Gaucheroma) with Core biopsy of soft tissue mass in (b) Gaucher cells, showing indistinct
organized but incomplete periosteal reaction. (b) T2-weighted axial cell borders, pink, somewhat crinkled cytoplasm enhanced by micro-
MRI demonstrating bright signal in Gaucher pseudotumor adjacent to scopic technique (interference contrast, hematoxylin-eosin, 250×)
904
Recommended Reading
Bonar SF. Inherited and developmental bone diseases. In: Non-
neoplastic diseases of bones and joints (Atlas of non-tumor pathol-
ogy, Fascicle 9). Silver Spring: ARP Press; 2011.
Faden M, Krakow D, Ezgu F, Rimoin D, Lachman RS. The Erlenmeyer
flask bone deformity in the skeletal dysplasias. Am J Med Genet.
2009;149A(6):1334–45.
Grabowski GA, Andria G, Baldellou A, et al. Paediatric non-neuropathic
Gaucher disease: presentation, diagnosis and assessment. Consensus
statements. Eur J Pediatr. 2004;163:58–66.
Hermann G, Shapiro R, Abdelwahab IF, Klein MJ, Pastores G,
Grabowski G. Extraosseous extension of Gaucher cell deposits
mimicking malignancy. Skeletal Radiol. 1994;23:253–6.
Klein MJ, Fiona Bonar F, Freemont T, Vinh TN, Lopez Ben-R, Siegel
HJ, Siegal GP, editors. Non-neoplastic diseases of bones and joints.
Annapolis Junction: American Registry of Pathology, 2012.
M.J. Klein
Oztürk H, Unsal M, Aydingöz U, Koçak N, Gürakan F. Pseudotumor
formation in tibia in Gaucher’s disease. Eur J Radiol. 1998;
2(3):284–6.
Pastores GM, Meere PA. Musculoskeletal complications associated
with lysosomal storage disorders: Gaucher’s disease and Hurler-
Scheie syndrome (mucopolysaccharidosis type I). Curr Opin
Rheumatol. 2005;17:70–8.
Rudzski Z, Okon K, Machaczha M, et al. Enzyme replacement therapy
reduces Gaucher cell burden but may accelerate osteopenia with
patients with type I disease: a histological study. Eur J Haematol.
2003;70:273–81.
Wenstrup RJ, Roca-Espiau M, Weinreb NJ, Bembi B. Skeletal aspects
of Gaucher disease: a review. Br J Radiol. 2002;75(Supp. 1):
A2–12.
Zhao H, et al. Gaucher’s disease: identification of novel mutant alleles
and genotype-phenotype relationships. Clin Genet. 2003;64:57–64.
 Gout
68
Michael J. Klein

Abstract
Gout is a metabolic disorder secondary to hyperuricemia in which crystals of monosodium
urate cause an acute inflammatory response in joints or a foreign body response in the soft
tissues or bones. The most common site is the metacarpophalangeal joint of the great toe
and the knee. Soft tissue deposits of urate crystals, tophi, occur. It may present clinically
with acute onset of severe pain of a joint or as a chronic joint problem. In bones, radio-
graphs may be normal and later present periarticular erosions. With polarized light, the
urate crystals in tophi or synovial fluid appear anisotropic. Prognosis in treated disease is
generally good. Uricosuric drugs and allopurinol are used for treatment.

Definition acute inflammation lowers the pH and this, in turn, makes

• A metabolic disorder secondary to hyperuricemia in
which crystals of monosodium urate cause an acute
inflammatory response in joints or a macrophagic and for-
eign body response in the soft tissues or bones
Synonyms
• Uric acid crystal storage disease
• Podagra
Etiology
• Hyperuricemia results in a saturated solution of uric acid
that precipitates crystals of monosodium urate monohy-
drate. These crystals cause an acute inflammatory reac-
tion in joint fluid and a histiocytic/foreign body
granulomatous response if deposited in the bones or soft
tissues. Within the synovial fluid, the presence of active
the uric acid less soluble.
• Elevated levels of uric acid may be familial or sporadic;
they may also be secondary to other diseases in which
there is rapid turnover of cells with secondary availability
of purines (leukemia, myelodysplastic syndromes, psoria-
sis) and may even be associated with diuretic treatment.
• A minority of patients with hyperuricemia develop clini-
cal evidence of gout, so other predisposing reasons may
also be implicated, including diet, alcohol use, age, and
unknown factors.
• Essential hyperuricemia may occur as a consequence of
X-linked mutations in hypoxanthine-guanine phosphori-
bosyl trans-synovial fluid erase gene.
• The most severe clinical form, associated with mental
retardation and self-mutilation, is Lesch-Nyhan syn-
drome, but partial syndromes are also recognized.
Clinical Features
Epidemiology

M.J. Klein, MD
Department of Pathology and Laboratory Medicine,
Hospital for Special Surgery, New York, NY, USA
e-mail: kleinm@hss.edu
• Primary hyperuricemia accounts for 90 % of the cases.
• Most cases of primary hyperuricemia are secondary to
decreased renal excretion of uric acid.

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 905
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_68, © Springer-Verlag London 2015
906
• A small number of the cases of primary hyperuricemia
are secondary to inherited X-linked mutations.
• Secondary hyperuricemia accounts for 10 % of the cases
and is usually due to increased cell turnover but may be due
to renal failure or to increased dietary purine consumption.
• Unusual genetic diseases (e.g., glycogenoses) may be
associated with gout.
Sites of Involvement
• The most common site affected is the metacarpophalan-
geal joint of the great toe.
• Other joints of the foot are sometimes affected.
• The knee is commonly affected.
• Soft tissue deposits of urate crystals, called tophi, occur
after several years if hyperuricemia is left untreated.
These are most commonly seen in the olecranon bursa,
the Achilles tendon, and on extensor surfaces of the upper
extremities.
Clinical Symptoms and Signs
• May present with acute onset of severe pain with redness
and swelling of a joint.
• May present with soft tissue crystal deposits.
• May present as a chronic joint problem. It is usual for
some joints to be affected, but joints are seldom affected
symmetrically or equally severely at the same time.
• There is a distinct predilection in males.
Image Diagnosis
Radiographic Features
• Imaging findings may not occur early in the disease, so
normal radiographs cannot exclude the diagnosis.
• When gout affects bones, there are often periarticular ero-
sions of the joint margins. These tend to be well circum-
scribed. If crystal deposits are completely within the
bone, they may appear cyst-like.
• There may be soft tissue masses in the soft tissues around
the joint. These may be secondarily calcified.
• The joint space is usually preserved.
• Periarticular osteoporosis secondary to disuse or inflam-
mation is unusual because the joints are not symptomatic
when the disease is quiescent.
• Joint space narrowing is unusual until very late in the
disease.
M.J. Klein
CT Features
• CT has limited usefulness in the diagnosis of gout.
• CT is more sensitive than conventional radiographs, and it
can aid in the detection of small calcifications.
MRI Features
• Not usually used to evaluate gout.
• Tophi are of intermediate to low signal intensity on
T1-weighted images and variable on T2-weighted images.
• Constant low signal areas are thought to represent sec-
ondary fibrosis or hemosiderin.
Image Differential Diagnosis
Infectious Arthritis
• Usually monoarticular.
• Without marginal erosions.
• Joint space narrowing happens early.
Pseudogout (Calcium Pyrophosphate Deposition
Disease Arthritis)
• Usually monoarticular.
• There are visible calcifications in tissue deposits on con-
ventional radiographs; these are usually absent in gout.
• Marginal erosions are usually absent.
Rheumatoid Arthritis
• Usually symmetric
• Usually involves metacarpophalangeal and interphalan-
geal joints of the hands
• Usually accompanied by osteoporosis about the joints
• Female predilection
Pathology
Gross Features
• The synovial fluid is usually turbid, but in many cases, it
is yellowish white and chalky and resembles milky
toothpaste-like fluid or liquid plaster of Paris.
• Tissue tophi are off-white in color, and the contents are
toothpaste-like and chalky.
• Tophi may be seen in soft tissues or bones; they are more
common peripherally, especially in body sites that are
below core body temperature.
68 Gout
Histological Features
• The synovial fluid usually has an elevated white blood
cell count, almost 90 % of which are polymorphonuclear
leukocytes.
• Within the leukocytes and also free within the synovial
fluid are needle-shaped crystals. These are usually easily
seen even in bright field.
• In polarized light, the monosodium urate monohydrate
crystals are highly anisotropic, i.e., they are very bright
when the field is dark. If the microscope stage is rotatable,
there are two planes, corresponding to the optical axes of
the crystal, in which the bright crystals become extinct,
i.e., they are isotropic when in this orientation.
• If a first-order compensator (wave plate) is introduced
between the crossed polarizers, the crystals appear bright
yellow when their long axes are aligned with the extraor-
dinary (slow) wave orientation of the compensator.
Crystals aligned with their long axis parallel to the ordi-
nary (fast) wave orientation of the compensator appear
blue. This defines the fact that they are negatively
birefringent.
• The synovium is hypertrophic and appears villous due to
the presence of acute and chronic inflammatory cells infil-
trating the subsynovium. Aggregates of monosodium
urate crystals are usually dissolved from tissues due to the
fact that they are water soluble. The place that they occu-
pied often appears radially striate and pink, but its border
is marked by fibrous tissue and a foreign body granulo-
matous reaction. The identical histology is seen in soft
tissue tophi.
• Monosodium urate crystals may be preserved in histo-
logic slides by preparing touch preparations and cover-
slipping without the use of water-containing compounds.
Tissue may also be processed by fixation in 100 % alco-
hol prior to processing because this helps to prevent sub-
sequent dissolution of the crystals.
• Crystals preserved by touch prep or in tissues retain their
strong anisotropism and negative birefringence.
Pathologic Differential Diagnosis
Other Crystal Diseases
• Calcium pyrophosphate deposition disease may present
with symptoms similar to gout when the crystals are free
in the joint fluid (“pseudogout”). These crystals often
accompany degenerative joint disease and hyperparathy-
roidism. Because they are calcium containing, they are
visible on radiographs when they form aggregates. They
are often seen in synovium and menisci. Rarely, they can
907
produce tophaceous deposits that may be mistaken for
bone-forming lesions (tophaceous pseudogout). They are
weakly anisotropic and positively birefringent and are
usually tricyclic (rhombic shaped). Because they contain
calcium, they are often basophilic. The crystals may be
seen more brightly in polarized light if sections are stained
with acid eosin only because the hematoxylin coating
often prevents sufficient light from entering the crystals in
hematoxylin-eosin-stained sections.
• Hydroxyapatite deposition disease may present as inci-
dental deposition of hydroxyapatite crystals in the
synovium as an accompanying degenerative joint disease
or it may present as a soft tissue deposit of crystals with a
foreign body reaction. Large soft tissue deposits are
sometimes referred to as tumoral calcinosis; these may be
sporadic or familial/inherited. The sporadic forms often
are sequelae of trauma and usually occur in body parts
that are subject to trauma. The familial forms tend to
occur as massive deposits of hydroxyapatite deposited in
or around large joints; these may also be related to trauma
for their initiation, but most individuals with the inherited
syndrome have biochemical derangements including
abnormally low levels of FGF-23. The crystals range
from very small and amorphous to larger and irregularly
shaped. They stain intensely with hematoxylin because of
their calcium content. They are not anisotropic in polar-
ized light. Rarely, they are associated with cartilaginous
metaplasia in the soft tissues.
• Oxalosis. The tissue deposition of calcium oxalate crys-
tals may be due to a familial inherited defect in enzyme
activity of glutamic-glyoxylic transaminase, causing a
failure of conversion of glyoxylate to glycine. Glyoxylate
is oxidized to oxalate and may deposit in the kidneys,
bones, joints, and soft tissues. Patients with this form usu-
ally have renal failure in childhood. Oxalosis is usually
caused by excessive dietary intake or simply occurring in
the setting of chronic renal failure. The radiographic
appearance depends upon the degree of renal failure, but
is not usually in the differential diagnosis of gout.
Polarized microscopy reveals brightly anisotropic crys-
tals; although they may individually be needle shaped,
they often form starlike clusters. There may be no cellular
response or a tissue reaction ranging from histiocytic to
foreign body type.
Prognosis
• The prognosis in treated disease is generally good. The
acute attacks may be treated with colchicine but also
respond to anti-inflammatory therapy.
908
• Tophaceous deposits and disease progression are deform-
ing, inconvenient, and may be painful. They are innately
harmful if they deposit within renal parenchyma or within
the renal pelvis as urinary calculi, rarely leading to
chronic renal failure.
Treatment
• Uricosuric drugs increase renal excretion of uric
acid; however, they must be given with increased
hydration or there is increased incidence of urate
M.J. Klein
renal stones. Sufficient fluid intake should be encour-
aged even in the absence of uricosuric therapy.
• Allopurinol prevents the conversion of allantoin to uric
acid. The former compound is soluble even at higher con-
centration and is readily excreted.
Images
See Figs. 68.1, 68.2, 68.3, 68.4, 68.5, 68.6, 68.7,68.8, 68.9,
68.10, 68.11, 68.12, 68.13, 68.14, 68.15, 68.16, and 68.17
for illustrations of gout.
68 Gout 909

Fig. 68.1 Joint fluid aspiration, acute gout, 400×. The coverslipped
unstained specimen is viewed in polarized light with a first-order com-
pensator. In this field are many neutrophils with ingested monosodium
urate monohydrate crystals diagnostic of acute gout. The crystals are
needle shaped, and those parallel to the extraordinary (“slow”) compen-
sator axis (vector direction indicated by the black arrow) are bright
yellow, indicating a negative sign of birefringence. Those perpendicular
to this axis are blue, and those that are intermediate either vary in color
or approach extinction

Fig. 68.2 This 43-year-old

patient became hyperuricemic
after having developed chronic
renal failure secondary to
diabetes mellitus. The
radiographs of the foot
demonstrate periarticular
erosions of the foot and hands
with preservation of the joint
spaces and intraosseous
tophaceous urate deposits of the
terminal phalanges (white
arrows). In addition, there is
significant periosteal reaction
about the right first metacarpal
(black arrows) secondary to
subperiosteal urate deposits
extending into the soft tissues
910 M.J. Klein

Fig. 68.3 Tophaceous gout,

right hand of a patient with
chronic untreated gout. The
interphalangeal and
metacarpophalangeal joints are
irregularly eroded and a few
show advanced joint narrowing.
There is obvious soft tissue
swelling in the radiograph. The
gross appearance of the hand
demonstrates the obvious soft
tissue deposits of urate with
overlying erythema, epidermal
atrophy, and skin defects
corresponding to the sites’ gross
drainage of crystalline deposits

Fig. 68.4 Tophaceous deposits of monosodium urate in subarticular region of femoral head with overlying collapse of articular cartilage (left) and
in fragments of the synovium from the same joint (right). Note that the urate deposits appear friable and chalky white
68 Gout
Fig. 68.5 Touch preparation of gouty tophus, unstained and coverslipped
viewed in polarized light with first-order compensator (400×), demon-
strates needle-shaped strongly anisotropic crystals with negative birefrin-
gence (black arrow is the direction of slow compensator axis). When
aqueous fixation and processing is unavoidable, touch preparations are an
important way to permanently document the presence of urate crystals
Fig. 68.6 Resected interphalangeal joint, advanced tophaceous gout.
Crystalline deposits, appearing brownish green are visible at joint mar-
gins and in subarticular regions, and the joint cartilages are focally dis-
rupted (arrows). (Hematoxylin and eosin, 10×)
911
Fig. 68.8 Tophaceous gout deposit, DeGolantha stain for urate. The
needle-shaped monosodium urate crystals appear black, and there is a
prominent foreign body giant-cell reaction surrounding them (200×)
Fig. 68.9 Gout tophus, acid eosin processing, and alcohol fixation
with preservation of monosodium urate monohydrate crystals that usu-
ally dissolve during aqueous fixation and staining (250×, polarized light
with first-order compensator). The arrow designates the direction of the
slow compensator axis
Fig. 68.7 Tophaceous urate deposit, (hematoxylin and eosin, 250×),
after aqueous processing. The crystals are dissolved by the processing,
leaving amphophilic, striate-appearing ghosts still surrounded by a for-
eign body reaction
912 M.J. Klein

Fig. 68.10 Chondrocalcinosis.

Deposition of calcium
pyrophosphate is particularly
common in association with
degenerative joint disease,
metabolic bone disease, and
other disorders. In this AP
radiograph of both knees,
chondrocalcinosis can be seen
as radiodensities in the region of
the menisci (arrows)

Fig. 68.11 Chondrocalcinosis. Calcium pyrophosphate dihydrate

deposits are seen in the synovium, meniscus, intercondylar regions of
the femur, and tibial spine. These deposits are chalky and similar
grossly to those seen in gout
68 Gout 913

Fig. 68.12 Calcium pyrophosphate deposition disease presenting with (black arrow, left). In compensated polarized light on right (400×), a
acute joint pain (pseudogout). Aspirated fluid demonstrates erythro- weakly anisotropic, positively birefringent rhomboid-shaped crystal
cytes with neutrophils in bright field (500×) containing rare, short (yellow) is seen within a neutrophil below center. The direction of the
rhomboid crystals suggestive of calcium pyrophosphate dihydrate slow compensator axis is shown by the white arrow

Fig. 68.13 Calcium pyrophosphate deposition disease (hematoxylin-eosin Fig. 68.14 At higher magnification, most of the pyrophosphate crys-
50×). The crystalline deposits appear purple, granular, and diffuse with a tals are coated with hematoxylin, but a few of the rhomboids are rela-
histiocytic reaction that is seldom as intense as seen with gouty tophi tively translucent and uncoated (hematoxylin-eosin 400×)
914 M.J. Klein

Fig. 68.15 The same field shown in Fig. 68.14 but in compensated
polarized light with slow compensator axis direction indicated by white
arrow (400×). The crystals having their long axis parallel to this are
blue (positively birefringent), and their anisotropism is weaker than that
of urate crystals

Fig. 68.17 Hydroxyapatite deposition disease. Low power (25×) dem-

onstrates dark purple amorphous calcifications in and about the subar-
ticular joint capsule (top). Higher power demonstrates an area of
cartilage metaplasia in synovial histiocytic proliferation (250×)

Fig. 68.16 Hydroxyapatite deposition disease. There are diffusely

radiodense deposits in the carpometacarpal thumb joint and in a periar-
ticular location
68 Gout 915

Recommended Reading
Bakshi NA, Al-Zaharani H. Bone marrow oxalosis. Blood.
2012;120(1):8.
Desmond P, Hennessy O. Skeletal abnormalities in primary oxalosis.
Australas Radiol. 1993;37(1):83–5.
Dieppe P, Swan A. Identification of crystals in synovial fluid. Ann
Rheum Dis. 1999;58:261–3.
Freemont A. Joint diseases. In: Non-neoplastic diseases of bones and
joints (Atlas of non-tumor pathology, Fascicle 9). Silver Spring:
ARP Press; 2011.
Girish G, Melville DM, Kaeley GS, et al. Imaging appearances in gout.
Arthritis. 2013;2012:673401.
Hamburger M, Baraf H, Adamson TC, et al. Recommendations for the
diagnosis and management of gout and hyperuricemia. Postgrad
Med. 2011;123(6 suppl 1):3–36.
Harrold L. New developments in gout. Curr Opin Rheumatol. 2013;
25(3):304–9.
Ishida T, Dorfman HD, Bullough PG. Tophaceous pseudogout. Hum
Pathol. 1995;26(6):587–93.
Lioté F, Ea HK. Recent developments in crystal induced inflammation
pathogenesis and management. Curr Rheumatol Replace.
2007;9:243–50.
Reginato AM, Olsen BR. Genetics and experimental models of crystal-
induced arthritis. Lessons learned from mice and men: is it crystal
clear? Curr Opin Rheumatol. 2007;19:134–5.
Richman KM, Boutin RD, Vaughan LM. Tophaceous pseudogout of the
sternoclavicular joint. Am J Roentgenol. 1999;172(6):1587–9.
Rosenthal AK. Update in calcium deposition diseases. Curr Opin
Rheumatol. 2007;19:158–62.
Schlesinger N, Moore DF, Sun JD, Schumacher Jr HR. A survey of cur-
rent evaluation and treatment of gout. J Rheumatol. 2006;33(10):
2050–2.
Yamakawa K, Iwasaki H, Ohjimi Y, et al. Tumoral calcium pyrophos-
phate dihydrate crystal deposition disease. A clinicopathologic
analysis of five cases. Pathol Res Pract. 2001;197(7):499–506.
 Osteomyelitis
69
Michael J. Klein

Abstract
Osteomyelitis is the inflammation of bone and bone marrow, usually secondary to an infec-
tious agent. It can be hematogenous or following a trauma. Children have a higher inci-
dence of infection in the metaphysis of long bones and adults in axial skeletal. Staphylococcus
aureus is the more frequent culprit. In intravenous drug users, Pseudomonas is common.
Salmonella has a predilection for patients with sickle cell disease. Irregular areas of radio-
lucency are later associated with the formation of a sinus tract and osteosclerosis. Findings
in a small biopsy will vary significantly with the area biopsied and disease time: acute
inflammation, necrosis, or chronic active inflammation. Systemic antibiotic is the treatment
of choice. For all cases, the cure rate is considered above 90 %.

Definition enter the bone. Because the bones are isolated from the
external environment, this means that infectious agents
• Inflammation of bone and bone marrow, usually second- must be directly introduced into the bone (e.g., from
ary to an infectious agent direct open trauma or overlying infections of soft tissues
that extend into the underlying bone) or from an infection
from some other source in the body that gains hematoge-
Synonyms nous access to the bone.

• Pyogenic bone infection

• Brodie’s abscess Clinical Features

Etiology
• While inflammation of any body site can be secondary to
physical or chemical trauma, most cases of osteomyelitis
are secondary to an infectious agent. The most common
infectious agents are bacterial, but mycobacteria, fungi,
and even viruses have been implicated.
• The establishment of an infection in the bone requires not
only an infectious agent but also a route for this agent to
M.J. Klein, MD
Department of Pathology and Laboratory Medicine,
Hospital for Special Surgery, New York, NY, USA
e-mail: kleinm@hss.edu
Epidemiology
Sex
• There is no preferred gender, race, or ethnic group.
Age
• No particular age group is predilected, but the site of
involvement and the type of infectious agent are often age
related.
• Patients with diseases affecting the microcirculation or
immune system are more prone to develop osteomyelitis.
This includes patients with diabetes mellitus, patients
with chronic renal failure, patients with sickle cell dis-
ease, patients on steroid therapy, and elderly patients.

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 917
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_69, © Springer-Verlag London 2015
918
• Intravenous drug users are more prone to develop osteo-
myelitis because of contaminated needle exposure.
Sites of Involvement
• In very young children, the mode of infection is usually
hematogenous, and because of the vascular supply of the
bone, the metaphysis is affected. In addition, the vascular
anatomy prior to the development of secondary ossifica-
tion centers is often associated with spread to the bone
ends with accompanying joint infections.
• In children with secondary ossification centers and ado-
lescents, hematogenous infections usually begin in the
metaphysis, probably because the metaphyseal arteries
end in arteriovenous loops with momentary stagnation of
blood flow near the growth plate.
• In adults with hematogenous osteomyelitis, the infection
may gain ingress at the metaphysis, diaphysis, or epiphy-
sis. Infections near the bone end often spread to involve
adjacent joints.
• Trauma, especially contaminated open fractures, may
happen at any age and allows external bacteria or fungi
direct access to osseous structures.
• Superinfection of skin ulcers associated with peripheral
vascular disease is a common source of osteomyelitis in
the elderly and with diabetic patients.
• Children have a higher incidence of infection in the long
bones, and adults have a higher incidence of axial skeletal
involvement, particularly of the vertebrae.
• Certain patient populations are affected by particular
infectious agents. The most common organism to infect
bones hematogenously is Staphylococcus aureus. In adult
intravenous drug users, Pseudomonas species are particu-
larly common. Salmonella species have a predilection for
patients with sickle cell disease.
Clinical Symptoms and Signs
• Pain, erythema, swelling, warmth, and loss of function in
the area affected
• Fever, chills, malaise, and nausea
• Draining exudate through the skin
Image Diagnosis
Radiographic Features
• There is usually a 1–2-week lag time between the develop-
ment of symptoms and the presence of radiographic find-
ings because the secondary effects of infection in bone
M.J. Klein
develop over a period of time. If there is significant soft tis-
sue edema, there may be a loss of intermuscular fat planes.
• Later in the course of disease, there is usually radiolu-
cency associated with bone resorption. This may take the
form of localized radiolucency, generalized radiolucency,
or sometimes a focal radiolucency associated with the
formation of a sinus tract.
• Especially if an infection becomes chronic, there may be
osteosclerosis. This may be within the bone or it may be
as a result of periosteal new bone formation.
• The joint space is usually preserved.
• Periarticular osteoporosis secondary to disuse or inflam-
mation is unusual because the joints are not symptomatic
when the disease is quiescent.
• Joint space narrowing is unusual until very late in the disease.
Bone Scan
• There is usually increased uptake at the periphery of the
affected area even when nothing is visible on conven-
tional radiography.
• Specificity is low and anatomic localization is suboptimal,
but if negative, infection is almost certainly not present.
CT Features
• Because it is more sensitive than conventional radio-
graphs, subtle early bone resorption, dead bone frag-
ments, and sinus tracts are more demonstrable earlier than
in routine radiography.
• CT detects cortical destruction better than other imaging
modalities.
• CT detects fluid earlier than conventional radiography.
MRI Features
• The procedure of choice after a baseline radiograph
because of early detectional abilities, contrast, and dem-
onstration of anatomy.
• Very fluid sensitive and demonstrates abnormal areas, but if
increased tissue blow flow persists after treatment, it may give
a false impression of treatment failure. If fluid persists, it may
also be insensitive at detecting recurrence of infection.
Image Differential Diagnosis
Fractures
• Undisplaced (greenstick) fractures may have similar
localizing symptoms.
69 Osteomyelitis
• Fracture line is best demonstrated as cortical break with
edema on MRI.
• Fracture line may not be visible in initial radiographs but
become visible on subsequent radiographs.
Tumors
• May have metaphyseal destruction and periosteal reac-
tions, but the periosteal reactions tend to be continuous or
solid in infections.
• The periosteal reaction tends to be discontinuous in
tumors.
• MRI demonstrates a soft tissue mass when tumors are
present.
• Soft tissue masses may contain mineralized matrix if the
tumor is an osteosarcoma.
• Bone abscesses can be distinguished from osteoid oste-
oma because the center of osteoid osteoma, especially if it
is poorly mineralized, gives an increased signal on MRI
in fluid-sensitive sequences, whereas necrotic bone in an
abscess gives a low signal. A CT may also show mineral
within an osteoid osteoma and perilesional sclerosis.
• Rarely, tuberculosis of the bone may masquerade as a
tumorous process. If a patient is skeletally mature and the
process affects the bone end, the radiographic appearance
may mimic a primary giant cell tumor of the bone.
Langerhans Cell Histiocytosis
• Distinction from infection is difficult radiographically.
While many of the findings are similar, there is usually no
sinus tract in Langerhans cell histiocytosis.
• Periosteal reactions tend to be lamellated, but the layers
are usually continuous.
• Radiographs tend to demonstrate that radiolucent lesions,
while well circumscribed, have an edge of gradually
decreasing radiolucency as the periphery is approached
(“beveled edge”).
Pathology
Pathophysiology
An infection in the bone causes pathological changes that
differ markedly from those in viscera or in soft tissues
because of the combination of skeletal rigidity and vascular-
ity. The marrow compartment receives its vascular supply
from nutrient vessels derived either from periarticular arter-
ies supplying the bone ends, metaphyseal nutrient arteries, or
diaphyseal nutrient arteries. The compact bone is supplied
by segmental periosteal perforating vessels that supply the
outer third of the cortex and anastomose with side branches
of penetrating nutrient arteries supplying the middle third of
the cortex and branches derived from the medullary nutrient
919
vessels supplying the medullary cavity. A bone infection
causes increased pressure in an essentially rigid medullary
compartment, and there is limited space to house the puru-
lent exudate, which compresses nonrigid structures includ-
ing the vasculature of the infected segment. If the vasculature
is end arterial, such as that in the medullary cavity, this
results in medullary septic infarction of the bone. The cortex,
having duality of circulation, is spared from necrosis unless
its blood supply is also interrupted, and if the exudate is
under enough pressure, it is forced out of the marrow com-
partment, dissecting away the periosteum and compressing
perforating vessels. This combination of circumstances may
cause devitalization of the compact bone, resulting in the for-
mation of a sequestrum. If regions of a bone have separate
compartments and separate blood supplies, e.g., an actively
growing epiphyseal plate separating epiphysis and metaphy-
sis, it is usual for the infection to remain unicompartmental.
When exudate collects in the subperiosteal space, not
only may the underlying cortex become devitalized, but the
periosteum may then form a reactive shell of new bone on
the outside of the devitalized cortex, or involucrum.
Continuing accumulations of exudate may, in turn, cause
enough pressure to dissect the periosteum from the involu-
crum, causing sequestration of the involucrum and additional
involucrum. The exudate may also dissect entirely through
the periosteum, into the soft tissue, and even out through the
overlying skin. Such a draining sinus is termed a cloaca.
Although the sinus tract comes to be lined by granulation
tissue, the overlying skin may proliferate and epithelialize
the sinus tract, creating a chronic nonhealing draining sinus.
Because there is such an admixture of devitalized tissue frag-
ments containing bacteria, it is very difficult to treat a chronic
and established focus of osteomyelitis even with antibiotics
and surgical intervention.
Gross Features
• The gross features depend upon the stage of the disease.
In general, pathological specimens are seen late in the
course of the process when osseous changes are devel-
oped and are not reversible. In the early stages, there is
pus produced, which may be cultured but usually does not
come to the dissecting bench.
• Osseous specimens coming to the laboratory that are large
enough to have anatomical landmarks demonstrate the
interaction of bone with infectious agents. The affected
marrow, which should be yellow in appendicular areas and
red in axial hematopoietic areas, is often gray from an
admixture of fibrous tissue and inflammatory infiltrates.
Active areas may show encystification and contain pus.
• Dead bone, or sequestrum, is usually dull rather than
shiny when compared to adjacent normal bone. Larger
920
segments of this type of dead bone are often found in the
cortex of bones with long-standing chronic disease.
• New reactive bone, or involucrum, is identified grossly as
bone that is deposited on the outside of the old cortex. It
may be compact, but it often has a more porous character
than the underlying cortex. Involucrum that is deposited
on the surfaces of bone trabeculae is better identified his-
tologically. The reactive bone may be so exuberant as to
effectively form a neocortex and even noticeably increase
the diameter of the bone.
• Sinus tracts, marking the sites of egress of suppurative
inflammation, may be observed tracking through the
cortex and may even extend to the overlying skin
(cloacae).
Histological Features
The histologic changes are consonant with the stage and type
of infection.
• In the early phases, a bacterial infection results in an acute
inflammatory reaction in which the predominant inflam-
matory cells are neutrophils and which causes fluid accu-
mulation that increases osseous pressure.
• If intraosseous pressure is increased sufficiently, the
medullary circulation is compromised, resulting in the
sequestration of some or all of the cancellous bone and
marrow necrosis. Histologically, this corresponds to
bone devoid of osteocytes and empty osteocyte lacunae,
but prior to these histologic changes, the bone marrow
will demonstrate fat necrosis and will be devoid of nor-
mal marrow.
• Osteoclastic resorption, activated by various cytokines,
results in resorption of necrotic trabeculae bordering
those areas where the circulation remains intact. In addi-
tion, if the circulation has been compromised by an
increase in pressure that keeps the vascular structures
intact, release of that pressure will permit ingress of other
cellular elements into the necrotic areas. This can result in
appositional osteoblastic activity on the surfaces of dead
bone trabeculae.
• As the infection becomes more chronic, lymphocytes,
plasma cells, and fibrosis predominate, but there may
still be foci of neutrophilic aggregates (chronic active
osteomyelitis).
• Later in the course of infection, necrotic bone and
fibrous tissue predominate, and the amount and type of
inflammatory cells vary with the type and number of
organisms and whether inflammatory cells can still
reach the site.
• Findings in a small biopsy will vary significantly with the
area biopsied.
M.J. Klein
Pathologic Differential Diagnosis
Osteonecrosis
• Devitalized bone looks the same histologically regardless
of its cause. Avascular necrosis of the type that affects the
convex surfaces of large joints produces bone trabeculae
devoid of osteocytes and acellular marrow. In addition,
the healing process that revascularizes bone at the periph-
ery of a focus of avascular necrosis is associated with
marrow fibrosis and appositional new bone on dead bone
trabeculae (“creeping substitution”). These are all find-
ings that can be seen in osteomyelitis. Fortunately, the
clinical spectrum and gross findings are usually more than
adequate to differentiate the findings from infection.
Infections involving an articular end of the bone present
as acute events and are associated with septic arthritis.
They are not limited to a confined, often triangular seg-
ment of subarticular bone, and the overlying articular car-
tilage, which remains viable and intact in avascular
necrosis, is destroyed very early in joint infections.
Fracture
• By far, the most common reason for osteonecrosis is devi-
talization of bone at a fracture site. In most cases, the
presence of a fracture will be known prior to obtaining
tissue, and tissues are usually obtained only in open frac-
ture or pathologic fracture to rule out a neoplastic process.
As with infection, the histological features of fracture
vary with the time of sampling and the focus sampled. It
is usually during the early phases of fracture that the his-
tological features alone may be mistaken for infection.
This happens particularly during the types of microfrac-
ture that occur in the subarticular areas of hip and knee
joints associated with osteoarthritis. Since inflammation
is one of the earliest tissue responses to injury, there are
often collections of neutrophils associated with acute
microfractures, and these sterile microabscesses may be
mistaken for infection. It is very important not to do so,
because the total joint arthroplasties that yield these spec-
imens are contraindicated in infections.
Treatment
• Acute infections are treated early with systemic antibiotic
therapy.
• Antibiotic therapy is supplemented with surgical therapy
if clinically indicated.
• Ancillary antibiotic therapy including antibiotic-laden
cement or beads is used when clinically warranted.
• More complicated surgical management is more often
used in late stage or chronic infections.
69 Osteomyelitis 921

Prognosis oncologic procedures, at least 30 % of cases of osteo-

myelitis were considered incurable.
• Early stages of the disease remain more curable than late • For all cases, the cure rate is now considered above 90 %.
stages.
• The prognosis of osseous infections depends upon the
type of organism, the site of infection, host factors, and
the chronicity of the process. Images
• Prior to the development of surgical techniques includ-
ing limb lengthening procedures and vascular free flaps See Figs. 69.1, 69.2, 69.3, 69.4, 69.5, 69.6, 69.7, and 69.8 for
largely invented for limb salvage in orthopedic illustrations of osteomyelitis.
922 M.J. Klein

a b

Fig. 69.1 (a) Acute osteomyelitis. In the earliest phase, there is no resorption in the proximal tibia to have produced an osseous defect in
change in the bone (left); the MRI panels demonstrating fluid in the the left tibial metaphysis. (c) Fluid from the defect in the metaphysis
marrow taken at the right demonstrate a circumscribed lesion in the demonstrates that almost all the cells are neutrophils
posteromedial tibia. (b) Ten days later, there is enough osseous
69 Osteomyelitis 923

Fig. 69.2 (a) Subacute

osteomyelitis. The so-called a
Brodie’s abscess here in the
cortex of the tibia is well
circumscribed and lucent and has
stimulated an organized sclerotic
periosteal cortical reaction. The
clinical picture mimics osteoid
osteoma. (b) The content of the
bone abscess may be
inflammatory or even fibrous. In
this case, the main constituent
was neutrophil (200×) which
helps in the pathologic
differentiation

b
924 M.J. Klein

Fig. 69.3 (a) This bone abscess

was thought to be infected a b
radiographically because it was
too large and ovoid to be an
osteoid osteoma and crossed the
closing growth plate to involve
the epiphysis. (b) The CT scan
also helped in differentiating this
lesion from infection because it
plainly demonstrates that the
lesional contents have a sinus
track that extends to the posterior
cortex. (c) The lesion was
explored, and the histology
demonstrates acute inflammatory
infiltrate associated with
sequestered (dead) mature bone

c
69 Osteomyelitis 925

b c

Fig. 69.4 (a) Bone abscess, metaphysis of a 9-year-old male. The AP
and lateral radiographs demonstrate an eccentric radiolucency that was
confused with a tumor radiographically; however, this patient presented
clinically with fever, redness, swelling, and local tenderness. (b)
A decompression osteotomy was performed along with drainage of the
defect, demonstrating dense acute inflammation (lower left) and
primary spongiosa (mixed cartilage and bone spicules) upper right. The
basophilic clumps represent thrombi of the metaphyseal arteriovenous
arcades filled with coagulase-positive Staphylococcus aureus bacteria
(50×). (c) Demonstrates a gram stain from the primary spongiosa at
500× clearly showing clumps of gram-positive cocci. This degree of
bacteria is a very rare histologic finding
926 M.J. Klein

b c

Fig. 69.5 (a) This 28-year-old female complained of arthritis-like
joint pain, local tenderness, and decreased range of motion of her knee
for several months. There was a well-circumscribed destructive lesion
of her upper tibia without a periosteal reaction extending to the knee
joint that was thought likely to represent giant cell tumor of bone.
(b) The biopsy demonstrated necrotizing granulomatous inflammation
in a lymphocytic background (200×). (c) Stain for acid-fast bacilli dem-
onstrated rare beaded acid-fast bacilli (787×), and cultures were posi-
tive for M. tuberculosis. No abnormalities were discerned on chest
radiographs
69 Osteomyelitis
b c
Fig. 69.6 (a) This 12-year-old female had been experiencing lower leg
pain for months with occasional episodes of low-grade fever. Her distal
leg was tender and had soft tissue swelling. The radiographs demon-
strated diffuse distal sclerosis of the tibia containing a few irregular
radiolucencies. There was a modeling deformity of the distal tibia with
a loss of normal taper and increased anteroposterior diameter and orga-
nized periosteal new bone formation. (b) A biopsy including tibial cor-
tex demonstrates waves of thickening and remodeling of the compact
bone marked by long cement lines separating layers of the lamellar
927
bone. The innermost and outermost lamellae are viable, but the inner
layers are necrotic and represent sequestrum (“creeping substitution”).
(c) Portions of the cancellous bone in the biopsy demonstrate thicker
than normal osseous trabeculae which are partially viable and which
show evidence of active osteoclast resorption (upper left) and old inac-
tive resorption (middle left). The intertrabecular spaces are actively
replaced by neovascularized fibrous tissue and contain scattered inflam-
matory cells. The cultures were repeatedly negative
928
Fig. 69.7 Organized chronic osteomyelitis and abscess formation of
the lower tibia thought to be Langerhans cell histiocytosis clinically.
The AP and lateral radiographs (a) demonstrate a radiolucent, very
well-circumscribed lesion of the tibial diametaphysis predominantly in
the medullary cavity but also causing scalloping of the cortex. The mass
has no sclerotic border but its edge was described as “beveled” by the
radiologist. There is a long periosteal new bone reaction (arrows) that
is multilayered but continuous, as would be associated with a benign
process. (b) Interface of lucent lesion (upper left) and adjacent bone
M.J. Klein
(middle and lower right) shows a dense, vascularized polymorphous
inflammatory infiltrate at upper left, compact bone at lower right with
inflammatory fibrous tissues in the expanded Haversian systems, and
osteoclastic resorption of the inner cortex at the interface of bone and
inflammatory infiltrate (100×); (c) shows the interface resorption at
higher power (400×). (d) Other areas of the cortex are devitalized, and
their vascular canals show scalloped resorptive edges and contain resid-
ual purulent exudate (200×)
69 Osteomyelitis 929

b c

Fig. 69.7 (continued)

930 M.J. Klein

Fig. 69.8 (a) Chronic active

osteomyelitis, distal femur of an a
11-year-old female. The
radiographs demonstrate
permeative destruction with
mottling of the bone and no
delimitation of the process. There
is a diffuse periosteal reaction
(arrows) that is at least partially
interrupted, forming a classic
Codman triangle in the lateral
view. This appearance is
characteristic for highly
malignant fast-growing tumors
without matrix, most especially
Ewing’s sarcoma. The
rectangular radiolucency seen in
both views represents the site of
biopsy and is not part of the
process. (b) Endosteal tissue
from the biopsy (250×)
demonstrates osteonecrosis
(microsequestration) of the large
central bone trabecula and an
acute inflammatory infiltrate in
the hematopoietic marrow which
obliterates most of the marrow
fat but does not entirely displace
the marrow (note a few residual
megakaryocytes)

b
69 Osteomyelitis
Recommended Reading
Abdelwahab IF, Present DA, Zwass A, et al. Tumorlike tuberculous
granulomas of bone. Am J Roentgenol. 1987;149(6):1207–8.
Abdelwahab IF, Norman A, Hermann G, et al. Atypical radiographic
appearances of tuberculous granulomas of bone. Can Assoc Radiol
J. 1990;41(2):72–5.
Chandrasekar PH, Narula AP. Bone and joint infections in intravenous
drug abusers. Rev Infect Dis. 1986;8(6):904–11.
Collert S, Isacson J. Chronic sclerosing osteomyelitis (Garré). Clin
Orthop Relat Res. 1982;164:136–40.
931
Gifford DB, Patzakis M, Ivler D, Swezey RL. Septic arthritis due to
Pseudomonas in heroin addicts. J Bone Joint Surg. 1975;57:631–5.
Ogden JA, Lister G. The pathology of neonatal osteomyelitis. Pediatrics.
1975;55:474–8.
Sato R, Matsui Y, Yokoi H, et al. Chronic osteomyelitis of the tibia
resembling benign bone tumors. Pediatr Int. 2007;49(5):663–7.
Trueta J. The three types of acute hematogenous osteomyelitis. J Bone
Joint Surg Am. 1959;41(B):671.
Vinh T. Infections and inflammatory diseases. In: Non-neoplastic dis-
eases of bones and joints (Atlas of non-tumor pathology, Fascicle 9).
Silver Spring: ARP Press; 2011.
 Amyloidosis in Bone
70
Edward McCarthy

Abstract
Amyloidosis is the deposition of protein in the extracellular space of various tissues. It
occurs as a manifestation of plasma cell dyscrasia or long-term dialysis. Amyloidosis com-
plicates 5–15 % of cases of multiple myeloma and may present as radiolytic bone lesions
that may be solitary, amyloidomas. The most common sites are the skull and spine. The
average age of patients is 57 years. Radiologically, amyloidoma of the bone is an expansile
lytic lesion; stippled radiodensity may be present. Waxy eosinophilic Congo red-positive
deposits are present in the marrow space, synovial membrane, and juxta-articular soft tis-
sues. Plasma cells are monoclonal with kappa and lambda light-chain immunostains.
Solitary amyloidoma of the bone almost always progresses to disseminated amyloidosis or
multiple myeloma.

Definition This form of amyloid is ß2-microglobulin. ß2-

• Amyloidosis is the pathologic deposition of protein in the
extracellular space of various tissues and organs.
• This disorder occurs in a wide variety of clinical settings,
and at least 15 biochemically distinct amyloid proteins
have been identified.
• A common feature of all these proteins is their birefrin-
gence after histologic staining with the Congo red dye.
Etiology
Microglobulin is a low-molecular-weight protein nor-
mally produced by lymphoid cells and other cells with
high turnover. In these cells, ß2-microglobulin stabilizes
the structure of the major histocompatibility complex
(MHC) antigens located on cell surfaces. Approximately
180–250 mg of this protein is generated each day as com-
plexes and shed from cell membranes. Normally, almost
all ß2-microglobulins are filtered by the glomerulus and
catabolized in the renal tubules. However, this protein
does not filter well through dialysis membranes, and, as a
result, accumulates in the tissue.

• The most common form of amyloidosis occurs as a mani-

festation of plasma cell dyscrasia. The amyloid deposited
is AL amyloid – the light chains of the immunoglobulin
molecule.
• A second important form in bone and joint disease is the
amyloid that is deposited as a result of long-term dialysis.
E. McCarthy, MD
Department of Pathology and Orthopaedic Surgery,
Johns Hopkins Hospital, Baltimore, MD, USA
e-mail: mccarthy@jhmi.edu
Clinical Features of Amyloidosis
in Patients with Plasma Cell Dyscrasia
Epidemiology
• Amyloidosis complicates from 5 % to 15 % of established
cases of multiple myeloma, and almost all these patients
have Bence-Jones proteinuria. In this setting, the amyloi-
dosis is usually systemic with deposits occurring in sites
such as soft tissues, lung, skin, tongue, and GI tract.

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 933
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_70, © Springer-Verlag London 2015
934
• The second presentation is the development of amyloidosis
without overt myeloma. However, the presence of a mono-
clonal gammopathy in almost all these patients indicates
they have a plasma cell dyscrasia. Sometimes, the amyloi-
dosis presents as lytic bone lesions and, on rare occasions, a
solitary lesion, known as amyloidoma of bone, is present.
Clinical Features
Sites of Involvement
• Any bone in the body can be involved (Fig. 70.1), but the
most common sites are the skull and spine.
Epidemiology
• The average age of these patients is 57 years.
• Both men and women are affected.
Radiographic Features
• Radiologically, amyloidoma of the bone is an expansile
lytic lesion. However, stippled radiodensity reminiscent
of cartilage calcification may be present (Fig. 70.2).
Image Differential Diagnosis
Metastatic Carcinoma
• Patients usually have a history of a primary neoplasia.
Myeloma
• Since patients have a monoclonal gammopathy, the
lesions may be interpreted as foci of myeloma.
Pathology
Histologic Features
• Waxy eosinophilic deposits, usually with a foreign body
giant cell reaction, are present in the marrow space
(Fig. 70.3).
• The eosinophilic material is identifiable as AL amyloid
by permanganate-resistant Congo red birefringence.
E. McCarthy
• Foci of amorphous calcification may be present within the
amyloid deposits, and metaplastic bone may occur at their
periphery.
• These plasma cells are monoclonal with kappa and
lambda light-chain immunostains, an observation sug-
gesting that amyloidomas of bone represent plasmacyto-
mas with massive amyloid deposition.
Treatment and Prognosis
• Solitary amyloidoma of bone almost always progresses to
disseminated amyloidosis or multiple myeloma.
Additional tumors develop after an interval of 3 months to
9 years. Most patients die within 3 years.
Clinical Features of Amyloidosis in Patients
with Chronic Renal Failure
Epidemiology
• This disorder is common in long-term renal dialysis
patients. After 10 or more years of dialysis, 70–80 % of
patients will be affected.
• The clinical features of amyloid deposition are usually
delayed until after at least 5 years of dialysis therapy.
Sites of Involvement
• Amyloid is deposited in bones and periosteal soft tissues
and is another manifestation of renal bone disease
(Fig. 70.4).
• Although amyloid is deposited throughout the body,
osteoarticular manifestations are the most severe.
• The humeral and femoral heads are most commonly
involved, but the hand and spine are also affected.
• Carpal tunnel syndrome, a common presentation of many
forms of amyloidosis, is the most frequent clinical picture
{1333}. In this presentation, amyloid is deposited in teno-
synovial tissue.
Image Diagnosis
Radiographic Features
• There is often an erosive arthropathy.
70 Amyloidosis in Bone 935

• Subchondral bone cysts are another presentation. In this pre-
sentation, amyloid accumulates in the marrow spaces beneath
the articular cartilage and leads to an erosive arthropathy.
MRI Features
Pathologic Features
• Waxy eosinophilic deposits, similar to other amyloid
deposition diseases, are present in the marrow space,
synovial membrane, and juxta-articular soft tissues.
• Congo red stain is positive.

• Deposition of amyloid around major joints, particularly

the shoulder joint, causes soft tissue masses. These are
best seen on T2-weighted sequences. Treatment and Prognosis

• Joints destroyed by the amyloid can be treated with total

Image Differential Diagnosis joint arthroplasty.
• Further amyloid deposition is arrested by renal
• The changes overlap with renal osteodystrophy. transplantation.
936 E. McCarthy

Fig. 70.3 Photomicrograph of amyloid showing eosinophilic waxy

amorphous material

Fig. 70.1 Plain radiograph of the wrist showing an expansile mass of

amyloid in the distal ulna

Fig. 70.4 Plain radiograph of the pelvis in a person with renal dialysis-
associated amyloidosis. There are erosive lesions in both femoral necks
(arrows)

Fig. 70.2 Plain radiograph of a lytic lesion in amyloidoma of bone of

the humerus showing focal radiodensities within the lytic area
70 Amyloidosis in Bone 937

Recommended Reading Gejyo F, Homma N, Suzuki Y, et al. Serum levels of b-2-microglobulin

as a new form of amyloid protein in patients undergoing long-term
hemodialysis. N Engl J Med. 1986;314:585–6.
Casey TT, Stone WJ, DiRaimondo CR, et al. Tumoral amyloidosis of bone
of beta2-microglobulin origin in association with long-term hemodial-
ysis: a new type of amyloid disease. Hum Pathol. 1986;17:731–8.
 Mastocytosis
71
S. Fiona Bonar and Edward McCarthy

Abstract
Mastocytosis is a generic term referring to a spectrum of rare disorders characterized by the
proliferation of mast cells in tissues. Mastocytosis in the bone is a very rare, systemic dis-
ease usually limited to adults. Osseous changes are the most constant abnormality in sys-
temic mastocytosis. Lesions involve both the axial and appendicular skeleton and may be
diffuse or focal. Rarely, patients with osseous disease lack cutaneous involvement. Patients
may present weight loss, weakness, and hematologic abnormalities due to replacement of
the bone marrow. Bone lesions are usually asymptomatic but may present bone pain. Both
radiolytic and radiodense lesions occur. Radiolytic changes may be focal or diffuse.
Histologically, there is focal or diffuse infiltration by mast cells, admixed with other mar-
row elements, including eosinophils and fibroblasts, or in solid sheets. Immunostain for
mast cell tryptase is positive. Patients with “bone-only” disease follow an indolent course.
Treatment is supportive and is geared to reducing systemic symptoms.

Definition There are two main categories:

• Mastocytosis is a rare disease comprising a heteroge-
neous spectrum of disorders in which marrow-derived
clonally transformed mast cells accumulate in one or mul-
tiple tissues, most commonly the skin and bone marrow.
• Cutaneous mastocytosis (not further elucidated)
• Systemic mastocytosis, largely involving the bone
marrow
Classification (WHO 2008)

General Features In decreasing frequency

• Cutaneous mastocytosis
A broad spectrum of disease occurs. • Systemic mastocytosis (SM)
• From a localized process to a more generalized disorder. – Indolent (Figs. 71.1 and 71.2)
• From a process with indolent behavior to a highly aggressive Smoldering SM (14 %)
disease with multisystem involvement and poor survival. Isolated SM (23 %)
– Systemic mastocytosis with associated hematologic
non-mast cell disease (SM-AHNMD)
S.F. Bonar, MB, BCH, BAO, FRCPI, FRCPath, FRCPA (*) – Aggressive systemic mastocytosis
Department of Anatomical Pathology, Douglass Hanly
– Mast cell leukemia
Moir Pathology, Sydney, NSW, Australia
e-mail: fbonar@optusnet.com.au – Mast cell sarcoma
– Extracutaneous mastocytoma
E. McCarthy, MD
Department of Pathology and Orthopaedic Surgery, (Smoldering implies a high mast cell burden with inter-
Johns Hopkins Hospital, Baltimore, MD, USA mediate clinical features between indolent and aggressive.

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 939
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_71, © Springer-Verlag London 2015
940
Isolated bone marrow mastocytosis occurs without cutane-
ous involvement. Rare cases of individuals with an accumu-
lation of mast cells with normal morphology and lacking
aberrant CD2 and CD25 expression are documented as hav-
ing “well-differentiated mastocytosis.” This is currently not
included in the classification of systemic mastocytosis.)
Synonyms
• Mast cell disease
Etiology
• The cause is not known.
• In most cases, the pathogenesis is linked to activating
mutations in the proto-oncogene c-KIT located on chro-
mosome 4q.12 which encodes transmembrane tyrosine
kinase receptor.
– KIT receptors play an important role in hemopoiesis
and are present in mast cells, hemopoietic stem cells,
gametocytes, interstitial cells of Cajal, and
melanocytes.
– Normal mast cell proliferation, differentiation, and
activation depend on binding the c-KIT ligand, stem
cell factor (SCF), to the KIT receptor.
– Abnormalities in SCF regulation or KIT receptors per-
manently affect the growth, differentiation, apoptosis,
and activation of mast cells.
– Pathological accumulation of mast cells and tissues
ensues.
• A variety of mutations are documented.
– The commonest is KIT D816V.
(Valine substituted for aspartate at codon 816)
– Identified in up to 80 % of cases in adults and
children
• Similar mutations occur in SM-AHNMD in which the
clonal hemopoietic non-mast cell population may exhibit
evidence of other genetic events.
Epidemiology
Mastocytosis has been considered rare estimated to occur in
between 1 in 1,000 and 1 in 8,000 patients visiting dermatol-
ogy clinics.
• More than 80 % have cutaneous mastocytosis.
• The exact frequency of systemic mastocytosis is unknown
as indolent forms may elude detection.
• A recent population study showed that systemic mastocy-
tosis has a prevalence of 13 per 100,000 population at
least in individuals aged over 15 years.
S.F. Bonar and E. McCarthy
• The prevalence increases with age but it is not seen in the
very elderly, possibly reflecting less vigorous diagnostic
work-up in this age group.
– 71 % comprise indolent systemic mastocytosis
– Of which 2 % were of smoldering form.
– 22 % had skin lesions alone and likely had associated
indolent systemic mastocytosis; however, further
investigation was not performed.
– Mastocytosis in the bone is rare, affecting less than
200,000 persons.
Sex
No sex predilection is proven.
Age
Mastocytosis can be seen at any age.
• Cutaneous mastocytosis is most common in children.
– Eighty percent of these present in the first year of life.
– Ninety percent are confined to the skin only.
– Eighty percent of these undergo spontaneous resolution.
• Systemic mastocytosis generally presents in adults after
the second decade.
– Usually adults with a median age of 54.7 are affected,
with a range of 18.6–74.5.
Sites of Involvement
Systemic Mastocytosis
• Skin and bone marrow involvement prevail.
– Fifty percent of patients with systemic mastocytosis
have skin lesions.
• In aggressive mastocytosis, involvement of the spleen,
lymph nodes, liver, and gastrointestinal tract occurs.
• In mast cell leukemia, generalized organ involvement occurs.
• Bone involvement occurs in 90 % of cases.
– Can be diffuse or focal.
– Any bone can be affected.
– Predominates in red marrow; thus the axial skeleton,
pelvis, and proximal aspects of the long bones are
most often affected.
Clinical Signs and Symptoms
These are protean in distribution, severity, and nature.
• Ten percent of patients with mastocytosis have systemic
disease in addition to skin lesions.
71 Mastocytosis
• Mast cells are normally widely distributed throughout the
body. These cells are sensitive sentinels for the immune
system. They detect foreign proteins and initiate a local
inflammatory response. This function is made possible by
numerous chemical mediators contained in their cytoplas-
mic granules, among which are histamine, serotonin, and
heparin. Many of the local or systemic signs of mastocy-
tosis are due to the release of these substances. These
include urticaria, flushing, nausea, and diarrhea.
• Children present in infancy or early childhood with one or
more macular lesions. They also have pruritus and dermato-
graphia. These skin lesions disappear by late childhood.
Systemic mastocytosis, however, is a more extensive disease.
Four main categories of clinical manifestations occur:
• General constitutional symptoms
– Fatigue, weight loss, fever, and diaphoresis
• Cutaneous changes
– Nodular eruptions, urticaria, angioedema, and
dermatographism.
– The most frequent presentation, known as urticaria
pigmentosa, is localized mast cell proliferations in the
skin of children.
• Mediator-related events related to degranulation and
release of histamine, tryptase (a major protease), chy-
mase, heparin, platelet-activating factor, prostaglandin
D2, cytokines, and chemokines
– In the skin
Flushing pruritus, urticaria, and angioedema
– Cardiovascular
Hypotension, syncope, and tachycardia
– Gastrointestinal tract
Abdominal pain and diarrhea
– Respiratory system
Wheezing and throat swelling may occur.
– Naso-ocular region
Pruritus
• Musculoskeletal system effects
– Bone pain
– Osteopenia and/or osteosclerosis
– Fracture
– Arthralgia/myalgia
• Dermatographism is seen in all forms.
• In aggressive forms, symptoms and signs may reflect
organ impairment due to mast cell infiltrates:
– Splenomegaly +/− hepatomegaly +/− lymphadenopathy
• Hematological findings
– Eosinophilia is common.
– Anemia.
– Leukocytosis.
– Neutropenia.
– Thrombocytopenia.
– Circulating mast cells are seen in mast cell leukemia
only.
941
• Objective evidence of mast cell degranulation and media-
tor release includes:
– Increased serum tryptase by at least 20 % + 2 ng/ml
above baseline.
In systemic mastocytosis the serum tryptase is >20 ng/
ml.
– Increased 24 h urinary metabolites of histamine.
– Increased 24 h urinary prostaglandin D2 and PDGF2
alpha.
• Thirty percent of individuals with SM have associated
non-mast cell clonal disorder (SM-AHNMD), and these
may present either before or at the time of diagnosis of
SM or be unmasked after therapy.
– AHMND most often represents myeloid neoplasia
especially chronic myeloid leukemia.
Bone Complications and Skeletal
Manifestations of Systemic Mastocytosis
• Seen in 70–90 % of cases
• Often asymptomatic
• If symptomatic, usually nonspecific
– Pain (28 %) is often poorly localized.
– Diffuse osteopenia and osteoporosis is common.
• Pathological fracture is seen in 16 %.
• Skeletal deformity may occur.
• Arthralgia is not infrequent.
• Bone modeling is increased.
– Bone turnover markers are elevated.
– Increased bone turnover appears to correlate with mast
cell burden.
Mast cell mediators have a complex effect and bone mod-
eling, and both osteopenia and osteosclerosis are seen, vari-
ably distributed and often coexisting.
Rarely, patients with osseous disease lack cutaneous
involvement. Patients may present with weight loss, weak-
ness, and hematologic abnormalities due to replacement of
the bone marrow.
Image Diagnosis
• Changes predominate in the axial skeleton, pelvis, and
proximal aspects of the long bones.
• Are nonspecific in nature.
• Multimodality imaging is most informative.
• Changes may vary over time reflecting disease progres-
sion and/or therapy.
Features
• Focal or diffuse
• Predominantly lytic (radiolucent)
942 S.F. Bonar and E. McCarthy

• Predominantly sclerotic • Lesions enhance with contrast; however, this does not add
• Mixed lytic and sclerotic useful information.

Diffuse Disease
• Mostly affects the axial skeleton. Bone Scan
• Commonly presents as osteopenia or osteoporosis. Radiolytic
change may be diffuse osteopenia, a pattern which mimics • Helpful for highlighting disease extent.
osteoporosis. Focal lytic lesions may also occur (Fig. 71.3). • In some, a superscan can be seen (the ratio of skeletal to
The diffuse pattern of radiolucency may be due, in part, to renal isotope uptake is increased without evidence of
the release of heparin, a potent bone resorbing agent, from renal disease).
the mast cells. Bone from these osteopenic patients shows Imaging is valuable for:
increased remodeling, a finding which suggests that mild • Clarifying the type and extent of lesions
mastocytosis may be responsible for many cases of the so- • Identifying bones at risk of fracture
called “idiopathic” osteoporosis. • Directing biopsies
• Osteosclerosis also develops in many patients. • Staging disease
– Occasionally, patients present with a diffuse increase • Monitoring the effects of therapy
in bone density (6 %) (Figs. 71.4 and 71.5). Presumably,
increased histamine secretion by the mast cells causes
a productive marrow fibrosis with reactive bone Image Differential Diagnosis
formation.
– Most often seen in aggressive systemic mastocytosis The protean manifestations on imaging mimic a variety of
(one third of these cases). congenital, inherited, and metabolic diseases of the bone and
numerous other tumors including metastatic disease in
Focal Lesions particular.
• Lucencies occur Diffuse radiolucency: considerations include:
– Which may be up to 5 cm in diameter. • Osteoporosis (all common associations and causes)
– They may be well defined or poorly defined. • Osteomalacia
– They may have a halo of sclerosis. • Sickle cell disease
• Sclerosis • Hyperparathyroidism
– Involves the medulla and cortex. • Myeloma
– Is usually focal in distribution. • Thalassemia
– May cause trabeculation of bone. Lucency and sclerosis: considerations include:
– Cortical thickening and narrowing of the medullary • Metastasis
cavity may occur. • Erdheim-Chester disease
Radiographs are not very sensitive. • Tuberose sclerosis
• Myelofibrosis
• Fluorosis
CT Features • Paget disease of bone
• Renal osteodystrophy
• Is more sensitive Focal radiolucency: considerations include:
• Identifies marrow involvement and disease extent • Myeloma
• Distinguishes lucent from sclerotic lesions • Metastasis
• Clarifies cortical thickening and medullary narrowing • Broad range of other primary benign and malignant bone
tumors
Focal sclerosis: considerations include:
MRI Features • Metastasis
• Bone islands
• Is the most sensitive technique for identifying disease • Hemangiomas
extent. • Osteopoikilosis
• Distinguishes focal from diffuse disease. • Sarcoidosis
• Lesions are usually T1 hypointense and T2 hyperintense. • In vertebral body lesions
• With marrow fibrosis and in sclerosis, T1- and T2-weighted – Benign notochordal cell lesion
images are hypointense. • Intraosseous hibernoma
71 Mastocytosis
Diffuse sclerosis: considerations include:
• Myelofibrosis
• Fluorosis
• Sclerosing bone dysplasias including osteopetrosis
Pathology
Gross Features
• Surgical excision is not usually performed; thus such
specimens are vanishingly rare and the findings not
documented.
Histological Features
• Normal and reactive mast cells have round to oval nuclei
with clumped chromatin, a low nuclear cell to plasmic
ratio, absent or indistinct nucleoli, and abundant eosino-
philic cytoplasm.
• Cells are dispersed singly in tissue and aggregates are not
expected.
• In marrow aspirate smears, they have centrally placed
round to ovoid nuclei with abundant cytoplasm contain-
ing densely packed metachromatic granules on
Romanowsky stains.
In Systemic Mastocytosis
• There are cohesive clusters or infiltrates of mast cells.
• They may have a focal or diffuse distribution.
• Aggregates occur in paratrabecular, perivascular, and
interstitial locations.
• Associated increase in reticulin fibers is usual with frank
fibrosis in many.
• Cells have a tendency to a spindling morphology.
• They often have other atypical features including:
– Abnormal chromatin pattern
– Nuclear lobation
– Multinucleation (Fig. 71.6)
• Accompanying bone remodeling with increased osteo-
blastic and osteoclastic activity occurs:
– Sclerotic trabeculae or thin slender trabeculae with a
lack of interconnectiveness may be seen reflecting
sclerosis and osteopenia.
• Intermingled lymphocytes and/or eosinophils are
frequent:
– Lymphocytes may surround the mast cell aggregates
or the mast cells may encircle lymphocytic cells.
• Focal lesions, when admixed with other cellular ele-
ments, often contain numerous eosinophils and fibro-
943
blasts. When found in bone marrow biopsy specimens,
these lesions have been called “eosinophilic fibrohistio-
cytic lesions”.
• In aspirates, atypical mast cells have:
– Elongated nuclei
– Irregular immature nuclear chromatin
– Nuclear lobation with or without multinucleation
– Hypogranular cytoplasm and large cytoplasmic
extensions
• Normal and neoplastic mast cells stain positively for chlo-
roacetate esterase.
• A frequent feature, which often obscures the typical mast
cell morphology, is marrow fibrosis. This process occurs
adjacent to the bone trabeculae and is usually associated
with appositional bone formation. This histologic feature
corresponds to the increased bone density seen on plain
radiographs of some lesions.
Ancillary Techniques
Immunohistochemical Findings
• Normal mast cells express:
– CD117
– Mast cell tryptase
• Neoplastic mast cells express:
– CD117
– Mast cell tryptase
– CD2 +/− CD25 (aberrant expression)
• Early myeloid and erythroid precursors can show weak
CD117 expression.
• Aberrant CD30 expression occurs in indolent and aggres-
sive forms of SM:
– However, CD30 positivity may occur in cases not
reaching the current diagnostic criteria for systemic
mastocytosis.
• In all cases, careful morphological assessment of the
other marrow elements should be undertaken to exclude
SM-AHNMD with close examination for abnormal
myelopoiesis in particular.
• Lymphoma and plasma cell myeloma may also occur in
this setting but are much rarer.
• In some, fibrosis may obscure the abnormal mast cell
population which is most readily identified by immuno-
phenotyping with expression of CD117, mast cell trypt-
ase, CD2, and CD25.
• Flow cytometric analysis is an invaluable tool.
– Abnormal mast cells are identified by aberrant CD2
and/or CD25 expression.
Flow cytometry seems more sensitive for aberrant
expression of CD25.
944 S.F. Bonar and E. McCarthy

Co-expression with CD30 is documented in recent • CD2 and CD25 negative.

studies. • c-KIT mutations are not identified.
Flow cytometric analysis also allows characterization
of the non-mast cell population in a setting
SM-AHNMD. Monocytic/Histiocytic Proliferation

Genetics • CD117 and tryptase negative

• PCR and direct sequencing of exon 17 of c-KIT can be
used to detect the activating point mutations at codon 816.
• Mutation analysis for other substitutions can be performed.
– Aiding the diagnosis of SM-AHNMD.
– Concomitant detection of additional genetic or molec-
ular anomalies by chromosome analysis and/or FISH
test can characterize and confirm the lineage of the
non-mast cell population.
Criteria for Diagnosis of Systemic
Mastocytosis (WHO 2008)
Diagnosis requires one major and one minor criterion or
three minor criteria.
Major criteria:
• Multifocal dense infiltrates of mast cells (greater or equal
to 15 mast cells in aggregates) in an adequate bone mar-
row biopsy specimen and/or other extracutaneous site
Minor criteria:
• Greater than 25 % of mast cells in these sites have a spindled
or atypical morphology or more than 25 % of mast cells in
a bone marrow aspirate smear are immature or atypical.
• Detection of activating point mutations of codon 816 of KIT
in the bone marrow, blood, or other extra cutaneous organ.
• CD2 and/or CD25 expression, in addition to expression of
other mast cell markers (mast cell tryptase, CD117, and
chloroacetate esterase), is identified in mast cells of the
bone marrow, blood, or other extracutaneous site.
• Total serum tryptase persistently exceeds 20 ng/ml.
– This is excluded in the SM-AHNMD group.
• CD68 positive
• Langerhans cell histiocytosis
– Cells have nuclear grooves.
• Express S100 protein, CD1A, and langerin
In all cases, exclusion of coexistent clonal hematologic
non-mast cell lineage disease must be undertaken.
• Morphological assessment of the accompanying bone
marrow and peripheral blood film.
• Flow cytometric studies.
• Genetic studies if necessary.
• Myeloid neoplasia is the most common.
– Weak CD117 expression only.
– Marrow exhibits myeloproliferative features with dys-
plastic features in one or more cell lines.
– With or without an accompanying clonal cytogenetic
abnormality.
In chronic eosinophilic leukemia:
• There may be increased numbers of mast cells.
• Aggregates are not seen.
• Codon 816 mutation is absent.
• Usually FIP1L1-PDGFR a fusion gene rearrangement pertains.
Neoplastic basophils and myeloblasts may be similar to
mast cells.
• These are CD117, CD2, CD25, and chloroacetate esterase
negative.
• Myeloperoxidase is positive.
Myelomastocytic leukemia
• May show CD117 and tryptase positivity.
• Compact clusters of mast cells do not occur.
Prognosis

Pathological Differential Diagnosis • In children, cutaneous mastocytosis is a benign disease

with regression seen in more than 80 % of cases.
Disseminated Lymphoproliferative Disorders • In adults, skin involvement is often associated with sys-
temic mastocytosis usually of indolent type.
• These disorders will stain positive for T and B lymphocytes. • In general, negative prognostic factors in this setting include:
– Advanced age
– Lack of skin lesions
Reactive Mast Cell Hyperplasia – Anemia
– Thrombocytopenia
• Mast cells can be distributed in a diffuse or interstitial – Weight loss
fashion or scattered within the bone marrow. – Hypoalbuminemia
• Mast cells have round nuclei and densely granular cytoplasm. – Elevated lactate dehydrogenase
• CD117 and tryptase positive. – Hypercellularity
71 Mastocytosis 945

– Qualitative peripheral blood smear anomalies • Therapy is aimed at preventing and mitigating the effect
– Elevated alkaline phosphatase of mast cell mediator release.
– Hepatosplenomegaly – Symptom control
• The percentage and morphology of mast cells is also an Trigger avoidance
independent predictor of survival. Prophylaxis
• Individuals with indolent systemic mastocytosis have a Antihistamines.
normal life expectancy. Cromolyn sodium.
• Individuals with aggressive systemic mastocytosis follow Proton pump inhibitors.
a rapid course over several years. Leukotriene antagonists.
• Individuals with mast cell leukemia or mast cell sarcoma Omalizumab (binds free IgE) shows promise.
follow a rapid course over several months Bisphosphonates may be used in osteopenia.
• In aggressive forms, cytoreductive therapy is used.
– Interferon alpha IIB or cladribine.
Treatment – In rare cases, novel tyrosine kinase inhibitors have
shown efficacy.
• Curative treatment is not available, and all therapy is • In SM-AHNMD cases, therapy is directed separately at
palliative. each component.
946 S.F. Bonar and E. McCarthy

a b

c d

Fig. 71.1 (a–e) Indolent systemic mastocytosis: radiographs of the
right and left knee in a middle-aged female show extensive involvement
of the long bones by variable sclerosis (a). The contour of the bones is
that of normal modeling excluding a form of skeletal dysplasia.
Narrowing of the joint spaces medially is present suggestive of accom-
panying osteoarthritis. Section from a femoral condyle retrieved at
arthroplasty shows thick and somewhat sclerotic bony trabeculae in the
subchondral region with a paratrabecular and interstitial cellular infil-
trate. Features of osteoarthritis with fibrillation and fissuring of the car-
tilage and cloning of chondrocytes with reduplication of the tide mark
are present (b). The sclerotic bone trabeculae comprise somewhat thick
coalescent plates of the bone with somewhat prominent cement lines,
giving the bone a somewhat pagetoid architecture (c). Between the tra-
beculae sheets of cells are noted which have a normal nuclear cytoplas-
mic ratio. Most have somewhat epithelioid morphology with a tendency
to spindling. At higher power, a tendency to spindling of most of the
cells is confirmed. There is abundant cytoplasm. Significant cellular
atypia is not present. Intermingled eosinophils are prevalent (d). CD117
highlights the abundance of mast cells present in a paratrabecular loca-
tion (e)
71 Mastocytosis
a b
c d
Fig. 71.2 (a–e) Indolent systemic mastocytosis: coronal MR
T1-weighted image of a humerus in a male aged 35 with nonspecific
arm pain shows subtle abnormality of the marrow with small areas of
altered low T1 marrow signal dispersed in a fatty marrow are noted (a).
The biopsy shows reactive appearing woven bone with intertrabecular
spaces in which enlarged and atypical mast cells are seen including
cells with multilobated nuclei and multinucleate forms. Within the
cytoplasm, subtle metachromatic granules are visible highlighted with
947
the black arrow (b). At higher power, the metachromatic granules are
more easily identifiable in this binucleate cell highlighted with a black
arrow (c). The component cells show strong positivity for CD117 (d)
and express CD25 (e). The latter allows categorization as systemic mas-
tocytosis. Although the patient had dermatographism, the mast cell
infiltration was confined to the bone marrow, and a diagnosis of indo-
lent systemic mastocytosis was made
948 S.F. Bonar and E. McCarthy

Fig. 71.3 Plain radiograph of the pelvis showing a well-circumscribed

lytic lesion in the right proximal femur
Fig. 71.5 Photomicrograph of mastocytosis. The mast cells are uni-
form round cells with pale cytoplasm and centrally located nuclei

Fig. 71.4 Plain radiograph of the pelvis. There is diffuse ill-defined Fig. 71.6 Low-power photomicrograph of mastocytosis. The mast
radiodensity cells are adjacent to trabeculae causing paratrabecular fibrosis (arrows)
71 Mastocytosis
Recommended Reading
Brunning RD, McKenna RW, Rosai J, et al. Systemic mastocytosis.
Extracutaneous manifestations. Am J Surg Pathol. 1983;7:425–38.
Cundy T, Beneton MN, Darby AJ, et al. Osteopenia in systemic masto-
cytosis: natural history and responses to treatment with inhibitors of
bone resorption. Bone. 1987;8:149–55.
Delsignore JL, Dvoretsky PM, Hicks DG, et al. Mastocytosis present-
ing as a skeletal disorder. Iowa Orthop J. 1996;16:126–34.
Fritz J, et al. Advanced imaging of skeletal manifestations of systemic
mastocytosis. Skeletal Radiol. 2012;41:887–97.
Galli SJ. New concepts about the mast cell. N Engl J Med.
1993;328:257–65.
Guillaume N, et al. Bone complications of mastocytosis: a link between
clinical and biological characteristics. Am J Med. 2013;126:75.
E1–7.
Horny HP. Mastocytosis: an unusual clonal disorder of bone marrow derived
haemopoietic progenitor cells. Am J Clin Pathol. 2009;132:438–47.
Horny HP, Parwaresch MR, Lennert K. Bone marrow findings in sys-
temic mastocytosis. Hum Pathol. 1985;16:808–14.
Horny HP, Reimann O, Kaiserling E. Immunoreactivity of normal and neo-
plastic human tissue mast cells. Am J Clin Pathol. 1988;89:335–40.
Horny HP, et al. Mastocytosis. In: Swerdlow SH et al., editors. WHO
classification of tumours of haemopoietic and lymphoid tissue. 4th
ed. 2008. p. 54–63.
949
Ma D, et al. Identification of KIT activating mutations in paediatric
solitary mastocytoma. Histopathology. 2014;64:218–25.
Morgado JM, et al. CD30 expression by bone marrow mast cells from
different diagnostic variants of systemic mastocytosis.
Histopathology. 2013;63:780–6.
Picard M, et al. Expanding the spectrum of mast cell activation disor-
ders: monoclonal and idiopathic mast cell activation syndromes.
Clin Ther. 2013;35:548–62.
Ponto-Lopes P, et al. Indolent systemic mastocytosis limited to the
bone: a case report and review of the literature. Sao Paulo Med J.
2013;131:198–204.
Quintas-Cardama A, et al. Advances and controversies in the diagnosis,
pathogenesis and treatment of systemic mastocytosis. Cancer.
2011;117:5439–49.
Stoecker MM, Wang E. Systemic mastocytosis with associated clonal
haematologic non-mast cell lineage. Arch Pathol Lab Med.
2012;136:832–8.
Te VJ, Vismans FJ, Leenheers-Binnendijk L, et al. The eosinophilic
fibrohistiocytic lesion of the bone marrow. A mastocellular lesion in
bone disease. Virchows Arch A Pathol Anat Histol. 1978;377:
277–85.
Van Doormaal JJ, et al. Prevalence of indolent systemic mastocytosis in
a Dutch region. J Allergy Clin Immunol. 2013;131:1429–31.
Webb TA, Li CY, Yam LT. Systemic mast cell disease: a clinical and
hematopathologic study of 26 cases. Cancer. 1982;49:927–38.
 Erdheim-Chester Disease
72
Edward McCarthy

Abstract
Erdheim-Chester disease, or lipid granulomatosis, is a rare disorder characterized by the pro-
liferation of histiocytes in bone and in extraosseous locations. It is thought perhaps to be a
lipid storage disease, in which foamy lipid-laden histiocytes accumulate in the bone marrow.
Extravasated lipid results in cholesterol granulomas and a fibroinflammatory reaction.

Definition Sites of Involvement

• Erdheim-Chester disease, also known as lipid granulomato- • Bones

sis, is another rare disorder characterized by the proliferation • Parenchymal organs, such as the lung, heart, and kidney,
of histiocytes in bone and in extraosseous locations. may also develop the xanthogranulomatous inflammation.

Synonyms Clinical Symptoms and Signs

• Lipid granulomatosis • Some patients are asymptomatic or some have mild con-
stitutional symptoms from extraosseous involvement, and
most have bone pain and tenderness.
Etiology

• Thought perhaps to be a lipid storage disease, foamy Image Diagnosis

lipid-laden histiocytes accumulate in the bone marrow.
• Extravasated lipid results in cholesterol granulomas and a Radiographic Features
fibroinflammatory reaction.
• Radiographic changes are invariably present in the long
bones, particularly the femur and tibia.
Clinical Features • There is a patchy or diffuse osteosclerosis involving the
medullary canal, a feature most prominent in the diaphy-
Epidemiology sis and metaphysis (Fig. 72.1).
• The cortices are also thickened due to periosteal new bone
• Adults in the fifth through seventh decades are affected by deposition.
Erdheim-Chester disease. • Skeletal involvement is multifocal and is usually sym-
metrical (Fig. 72.2).
• Bone scan shows widespread symmetrical lesions
E. McCarthy, MD
Department of Pathology and Orthopaedic Surgery, (Fig. 72.3).
Johns Hopkins Hospital, Baltimore, MD, USA
e-mail: mccarthy@jhmi.edu

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 951
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_72, © Springer-Verlag London 2015
952 E. McCarthy

Image Differential Diagnosis • This tissue is associated with reactive trabecular thicken-
ing, a feature correlating with the radiodensity.
• Chronic osteomyelitis
– Not multifocal
• Metastatic carcinoma Pathologic Differential Diagnosis
– Usually a history of a primary neoplasm
• Chronic osteomyelitis
• Langerhans’ cell granulomatosis
Pathology – S100 and CD1a positive

• The marrow is extensively replaced by foamy histiocytes

and xanthogranulomatous inflammatory tissue (Fig. 72.4).
72 Erdheim-Chester Disease 953

Fig. 72.1 Erdheim-Chester disease of the distal femur. There is a

poorly defined zone of increased radiodensity with cortical thickening.
This change is identical to chronic osteomyelitis
954 E. McCarthy

Fig. 72.2 Erdheim-Chester

disease showing equal
involvement of both femurs
and both tibias
72 Erdheim-Chester Disease 955

Recommended Reading
Foucar E, Rosai J, Dorfman R. Sinus histiocytosis with massive lymph-
adenopathy (Rosai-Dorfman disease): review of the entity. Semin
Diagn Pathol. 1990;7:19–73.
Lantz B, Lange TA, Heiner J, et al. Erdheim-Chester disease. A report
of three cases. J Bone Joint Surg Am. 1989;71:456–64.
Lin J, Lazarus M, Wilbur A. Sinus histiocytosis with massive lymph-
adenopathy: MRI findings of osseous lesions. Skeletal Radiol.
1996;25:279–82.
Resnick D, Greenway G, Genant H, et al. Erdheim-Chester disease.
Radiology. 1982;142:289–95.
Unni KK. Case report 457. Sinus histiocytosis with massive lymphade-
nopathy (Rosai-Dorfman disease) presenting as lesion in the
sacrum. Skeletal Radiol. 1988;17:129–32.

Fig. 72.3 Bone scan of Erdheim-Chester disease showing diffuse

symmetrical uptake in the lower extremities

Fig. 72.4 A photomicrograph of Erdheim-Chester disease showing

replacement of the marrow by fibroinflammatory tissue. There is thick-
ening of the trabeculae with appositional bone formation (arrows)
 Rosai-Dorfman Disease
73
Edward McCarthy

Abstract
Rosai-Dorfman disease is a rare systemic disease characterized by a histiocyte proliferation
which presents with lymphadenopathy. Some patients present with extranodal disease.

Definition • Any bone can be involved in both the appendicular and

axial skeleton.
• Rosai-Dorfman disease is a rare systemic disease charac- • The radius, ulna, and skull are the most commonly
terized by a histiocyte proliferation which presents with affected.
lymphadenopathy. Some patients present with extranodal
disease.
Clinical Signs and Symptoms

Synonyms • Patients with nodal disease have fever, leukocytosis, an

elevated erythrocyte sedimentation rate, and a polyclonal
• Sinus histiocytosis with massive lymphadenopathy hyperglobulinemia.
• Patients with osseous disease have bone pain.

Clinical Features

Epidemiology Image Diagnosis

• The disease is very rare. Radiographic Features

• Patients are usually teenagers or young adults.
Sites of Involvement
• Nodal disease is most severe in the neck. Axial and medi-
astinal lymph nodes may also be involved.
• Extranodal sites (40 % of patients) include the eye, upper
respiratory tract, skin, CNS, and bone.
• The bone lesions are well-defined lytic areas which are
radiographically similar to the lesions of eosinophilic
granuloma.
• MRI shows focal areas of increased signal on T2-weighted
sequences (Fig. 73.1).
• Osseous involvement is sometimes multifocal.

Image Differential Diagnosis

E. McCarthy, MD
Department of Pathology and Orthopaedic Surgery,
Johns Hopkins Hospital, Baltimore, MD, USA • Metastatic carcinoma
e-mail: mccarthy@jhmi.edu – Any primary bone neoplasm or infection

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 957
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_73, © Springer-Verlag London 2015
958 E. McCarthy

Pathology – Langerhans’ cells stain with CD1a. This is not present

in Rosai-Dorfman disease.
• Histologically, the histiocytes have large vesicular nuclei • Osteomyelitis
and abundant foamy cytoplasm. – Cultures should be positive and emperipolesis is
• These cells are positive with the S-100 stain (Fig. 73.2). absent.
• A characteristic feature of the histiocyte in this disorder is
emperipolesis, the presence of intracytoplasmic intact
lymphocytes (Fig. 73.3). This feature is most prominent Treatment and Prognosis
in the involved lymph nodes and is less commonly seen in
extranodal sites. • Rosai-Dorfman disease is a self-limited disease.
• A lymphoplasmacytic histiocytic reaction is almost • Surgical stabilization may be necessary if there is signifi-
always present. cant bone destruction.
• Fibrosis is also common, particularly in extranodal • In many cases, the disease undergoes rapid and complete
locations. resolution.
• In other cases, especially those with extensive extranodal
disease, the disease follows an indolent course which may
Pathologic Differential Diagnosis last for decades.
• A few patients with severe disease have responded to
• Langerhans’ cell histiocytosis chemotherapy.
73 Rosai-Dorfman Disease 959

Fig. 73.3 High-power photomicrograph of Rosai-Dorfman disease.

There is emperipolesis. Large histiocytic cells have intracytoplasmic
lymphocytes (arrows)

Fig. 73.1 Rosai-Dorfman disease of the vertebrae. The MRI shows a

focal lesion in the vertebral body with extension into the soft tissue

Fig. 73.2 S-100 stain of the cells of Rosai-Dorfman disease. There is

diffuse positivity
960
Recommended Reading
Foucar E, Rosai J, Dorfman R. Sinus histiocytosis with massive lymph-
adenopathy (Rosai-Dorfman disease): review of the entity. Semin
Diagn Pathol. 1990;7:19–73.
Lantz B, Lange TA, Heiner J, et al. Erdheim-Chester disease. A report
of three cases. J Bone Joint Surg Am. 1989;71:456–64.
E. McCarthy
Lin J, Lazarus M, Wilbur A. Sinus histiocytosis with massive lymph-
adenopathy: MRI findings of osseous lesions. Skeletal Radiol.
1996;25:279–82.
Resnick D, Greenway G, Genant H, et al. Erdheim-Chester disease.
Radiology. 1982;142:289–95.
Unni KK. Case report 457. Sinus histiocytosis with massive lymphade-
nopathy (Rosai-Dorfman disease) presenting as lesion in the
sacrum. Skeletal Radiol. 1988;17:129–32.
 Transient Osteoporosis
74
Edward McCarthy

Abstract
Transient osteoporosis is a syndrome of localized osteoporosis. But, unlike disuse atrophy,
this syndrome is not associated with disuse or immobilization. Bone loss is probably initi-
ated by marrow edema and, possibly, transient ischemia. It usually affects the hip or the
knee. Patients are usually men between the ages of 27 and 61 or women in the third trimes-
ter of pregnancy. Symptoms worsen for a few months and then begin to improve. There is
complete clinical resolution in about 6 months or after delivery in pregnant women.
Histologically, it is characterized by bone marrow edema. Treatment consists in pain man-
agement and protection of the osteopenic bone. Some surgeons treat with core
decompression.

Definition Clinical Features

Transient osteoporosis is a syndrome of localized osteoporo- Sites of Involvement

sis. But, unlike disuse atrophy, this syndrome is not associ-
ated with disuse or immobilization. Transient osteoporosis usually affects the hip, although the
knee is another commonly involved site.

Synonyms
Clinical Signs and Symptoms
Regional migratory osteoporosis, localized osteoporosis,
bone marrow edema syndrome • Patients with transient osteoporosis of the hip are usually
men between the ages of 27 and 61 or women in the third
trimester of pregnancy.
Etiology • Some patients have a history of trauma.
• They present with acute hip pain, a limp, and limitation of
The cause is unknown, although bone loss is probably initi- motion.
ated by marrow edema and, possibly, transient ischemia. • Symptoms worsen for a few months and then begin to
improve. There is complete clinical resolution in
4–11 months (mean 6 months).
• Symptoms resolve in pregnant women after delivery.
E. McCarthy, MD
• As many as 41 % of patients have a recurrence in the
Department of Pathology and Orthopaedic Surgery, Johns Hopkins
Hospital, Baltimore, MD, USA same hip or in other sites, a syndrome known as regional
e-mail: mccarthy@jhmi.edu migratory osteoporosis.

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 961
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_74, © Springer-Verlag London 2015
962 E. McCarthy

Image Diagnosis • Dilated, congested small vascular spaces are also

present.
Radiologic Features • Trabecular bone shows many resorption cavities which, in
severe cases, remove entire trabeculae. Seams of new
Plain Radiographs woven bone are also present.
• Plain radiographs in the early phases of this syndrome are
unremarkable.
• Later in the evolution of this disease, the femoral head Pathologic Differential Diagnosis
and intertrochanteric area show diffuse, ill-defined
osteoporosis. Stress Fracture
Cartilage and fractured trabeculae are present.
MRI Features
• The MRI shows changes very early. Osteonecrosis
• The T1-weighted images show low signal intensity, and Osteocytes are absent from necrosis.
the T2-weighted images show high signal intensity indi- There is bone marrow necrosis.
cating bone marrow edema.
• These changes involve the entire femoral head and often
extend into the intertrochanteric region. Prognosis

Lesions resolve spontaneously, although recurrence is pos-

Image Differential Diagnosis sible. Some surgeons treat this disease with a decompression
core biopsy.
Diffuse Permeative Neoplastic Disorder
May present anywhere in the skeleton and not around a joint.
Sometimes only a biopsy can differentiate. Treatment

Osteonecrosis The treatment of transient osteoporosis is pain management

Osteonecrosis has a well-demarcated zone of low signal on and protection of the osteopenic bone. Bisphosphonates are
MR rather than a diffuse high signal. sometimes used to minimize osteopenia. Some surgeons
treat with core decompression.

Pathologic Features
Images
• Transient osteoporosis is characterized by bone marrow
edema. See Figs. 74.1, 74.2, and 74.3 for illustrations of transient
• The edema appears as an amorphous, faintly eosinophilic osteoporosis.
material between marrow fat cells.
74 Transient Osteoporosis 963

Fig. 74.3 Photomicrograph of bone marrow edema. There is pink

Fig. 74.1 Plain radiograph of the pelvis in a woman who recently gave
eosinophilic material in the marrow space
birth to a baby. She has focal osteoporosis of her left proximal femur
and femoral neck

Fig. 74.2 T2-weighted MRI of the same patient showing high fluid
signal in the proximal femur corresponding to the area of radiolucency
964 E. McCarthy

Recommended Reading
Guerra JJ, Steinberg ME. Current concepts review: distinguishing tran-
sient osteoporosis from avascular necrosis of the hip. J Bone Joint
Surg. 1995;77A:616–24.
Lakhanpal S, Ginsburg WW, Luthra HS, et al. Transient regional osteo-
porosis. A study of 56 cases and review of the literature. Ann Intern
Med. 1987;106:444–50.
McCarthy EF. The pathology of transient regional osteoporosis. Iowa
Orthop J. 1998;18:35–42.
 Traumatic Osteolysis
75
Edward McCarthy

Abstract
Traumatic osteolysis is a group of syndromes where bone and articular surfaces adjacent to
a joint are rapidly fragmented and dispelled into the joint cavity as detritic fragments of
bone and cartilage as a result of subchondral insufficiency fracture. Osteomalacia and
osteoporosis are precursors. It is most common in middle-aged and older women. Sites
involved are the femoral head, humeral head, pubis, and the knee. Patients present with joint
pain. Most of the affected area disappears in time. The residual bone shows granulation tis-
sue and impacted portions of detritic bone. Patients with traumatic osteolysis usually require
total joint replacement.

• Osteomalacia and osteoporosis are precursors of this

Definition
problem. Analgesic use masks the pain of stress fracture
and allows further weight bearing and destruction of
• Traumatic osteolysis is a group of syndromes where bone
bone.
and articular surfaces adjacent to a joint are rapidly frag-
mented and dispelled into the joint cavity as detritic frag-
ments of bone and cartilage. Clinical Features

Epidemiology
Synonyms
• Most common in middle-aged and older women.
• (Depending on location) Rapidly destructive hip arthro- • Most patients have skeletal fragility.
sis, idiopathic pubic osteolysis, osteonecrosis-like syn-
drome of the knee, Milwaukee shoulder
Sites of Involvement
Etiology • Femoral head, humeral head, pubis, pubic ramus, and the
knee joint
• This syndrome is a result of a subchondral insufficiency
fracture in someone who has skeletal fragility (Fig. 75.1).
Clinical Symptoms and Signs

• Patients present with joint pain.

E. McCarthy, MD
Department of Pathology and Orthopaedic Surgery, Johns Hopkins
• Analgesia allows weight bearing or use of the joint. This
Hospital, Baltimore, MD, USA perpetuates a cycle of continued weight bearing and joint
e-mail: mccarthy@jhmi.edu destruction (Fig. 75.2).

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 965
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_75, © Springer-Verlag London 2015
966 E. McCarthy

Image Diagnosis Neoplastic Destruction of Bone

• There is no history of carcinoma and biopsy fails to reveal
Radiographic Features a neoplasm.

• In the early phases, a subchondral insufficiency fracture

can be noted in the femoral head.
• Later portions of the femoral head disappear over weeks
to months.
• In the final stages, most of the femoral head or humeral
head have disappeared.
• In the knee, there is considerable discontinuity of the
articular surface.
• Traumatic osteolysis also occurs in the pubis (Fig. 75.3)
and humerus (Fig. 75.4)
Pathology
Histologic Features
• The joint capsule is filled with fragments and shards of
detritic bone (Fig. 75.5). Many of the bone fragments are
necrotic. Also fragments of articular cartilage are destruc-
tive and in the joint space.
• The residual bone shows granulation tissue and impacted
portions of detritic bone.

MRI Features
• In the knee, there is extensive bone marrow edema and
evidence of subchondral insufficiency fractures.
Pathologic Differential Diagnosis
Primary Osteonecrosis
• In true osteonecrosis, there is evidence of bony repair.

Image Differential Diagnosis Infection

• There is a purulent exudate with acute inflammatory cells.
Osteonecrosis
• In osteonecrosis, a segment of dead bone is apparent
before there is fragmentation and dissolving of the bone. Treatment
• Patients are not in the proper clinical setting for osteone-
crosis syndromes. • Patients with traumatic osteolysis usually require total
joint replacement.
Infection
• Cultures are negative. Patients do not have the signs and
symptoms of infection.
75 Traumatic Osteolysis 967

Fig. 75.1 Plain radiograph of the hip showing a subchondral insuffi- Fig. 75.4 Reconstructive CT image of the rapidly destructive shoulder
ciency fracture (two arrows) arthropathy. Almost the entire humeral head has been fragmented

Fig. 75.5 Photomicrograph of the material removed from a joint after

Fig. 75.2 Plain radiograph of the hip in the same patient 6 months rapidly destructive hip arthrosis. There is abundant detritic bone imbed-
later showing destruction of much of the femoral head ded in the synovial membrane

Fig. 75.3 Plain radiograph of the pubis showing pubic osteolysis with
destruction of the right pubic ramus and ischium
968 E. McCarthy

Recommended Reading Yamamoto T, Bullough PG. Subchondral insufficiency fracture of the

femoral head and medial femoral condyle. Skeletal Radiol.
2000a;29:40–4.
Doherty M, Holt M, MacMillan P, et al. A reappraisal of ‘analgesic
Yamamoto T, Bullough PG. The role of subchondral insufficiency frac-
hip’. Ann Rheum Dis. 1986;45:272–6.
ture in rapid destruction of the hip joint: a preliminary report.
Hall FM, Goldberg RP, Kasdon EJ, et al. Post-traumatic osteolysis of
Arthritis Rheum. 2000b;43:2423–7.
the pubic bone simulating a malignant lesion. J Bone Joint Surg
Yamamoto T, Schneider R, Bullough PG. Subchondral insufficiency
Am. 1984;66:121–6.
fracture of the femoral head: histopathologic correlation with
Nguyen VD. Rapid destructive arthritis of the shoulder. Skeletal Radiol.
MRI. Skeletal Radiol. 2001;30:247–54.
1996;25:107–12.
Watanabe W, Itoi E, Yamada S. Early MRI findings of rapidly destruc-
tive coxarthrosis. Skeletal Radiol. 2001;31:35–8.
 Chest Wall Hamartoma
76
Ricardo K. Kalil

Abstract
Chest wall hamartoma is a congenital malformation of bone composed of mature cartilage
sometimes with foci of enchondral ossification, a loose connective tissue containing reac-
tive bone spicules, and aneurysmal bone cyst-like areas, arising in the rib cage of infants. It
corresponds to less than 0.05 % of primary bone tumors, with a male predominance. All
cases are located in the ribs and may be multifocal. The presence of a mass or an incidental
image finding is its usual clinical presentation. Imaging shows large aneurysmal bone cyst-
like areas in which walls mineral deposits are seen. Spontaneous regression may occur.
Marginal surgical resection is curative.

Definition Epidemiology

• A rare benign lesion of bone composed of mature carti- • A rare lesion, it corresponds to less than 0.05 % of pri-
lage, a loose connective tissue containing reactive bone mary bone tumors.
spicules, and aneurysmal bone cyst-like areas, arising in
the rib cage of infants.
Age

Synonyms • Always seen in infants and may be congenital

• Chondromesenchymal hamartoma
• Mesenchymal hamartoma of the chest wall Sex
• Vascular hamartoma of infancy
• Chondromatous hamartoma of the chest wall • There is a male predominance (2:1).
• Vascular cartilaginous hamartoma of chest wall

Sites of Involvement
Etiology
• All cases are located in the ribs.
• Unknown. • It may be multifocal.
• It is a congenital malformation and not a true neoplasm. • Lesions arising in other sites, like vertebra and nasal
bones, including one reported case with malignant trans-
R.K. Kalil, MD formation, may be variants of chest wall hamartoma and
Laboratory of Orthopaedic Pathology, Buenos Aires, Argentina are not covered in this section.
Department of Pathology,
A.C. Camargo Cancer Center, São Paulo, SP, Brazil
e-mail: rkkalil@gmail.com

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 969
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1_76, © Springer-Verlag London 2015
970 R.K. Kalil

Clinical Symptoms and Signs Histological Features

• The presence of a mass or as an incidental image finding
is its usual clinical presentation.
• Large lesions may lead to respiratory insufficiency.
Image Diagnosis
Radiographic Features
• Radiography usually shows a large expansile rib lesion
with areas of mineralization and soft tissue expansion. It
may suggest an aggressive lesion.
• Composed of a variable proportion of solid and cystic
hemorrhagic areas.
• Solid areas correspond to lobules of mature hypercellular
hyaline cartilage, sometimes with foci of enchondral ossi-
fication, and areas constituted by a loose connective tissue
with variable collagen production and reactive bone
trabeculae.
• Hypercellularity and a few typical mitoses may be seen,
occasionally, in the spindle cell areas.
• Cystic, hemorrhagic areas have histological features
indistinguishable from primary ABC.

Pathology Differential Diagnosis

CT and MRI Features
Aneurysmal Bone Cyst
• Large aneurysmal bone cyst-like areas in which walls • ABC has no cartilage lobules.
mineral deposits are seen.
• The lesion may involve more than one rib.
• The lungs are not involved. Genetics

• No data retrieved for chest wall hamartoma.

Image Differential Diagnosis • Translocation t(12;17)(q24.1;q21) was found in a nasal
chondromatous hamartoma.
Aneurysmal Bone Cyst
• The correct diagnosis may be suggested by the large solid
component with mineral deposits, associated to the clini- Prognosis
cal data.
• There are no reports of recurrence after surgical
Chondrosarcoma excision.
• DD with low-grade chondrosarcoma may be extremely • Spontaneous regression may occur.
difficult. • Large lesions may lead to respiratory insufficiency.

Osteosarcoma
• Is a highly malignant tumor and presents more aggressive Treatment
imaging features.
• Marginal surgical resection is curative.

Pathology
Images
Gross Features
See Figs. 76.1, 76.2, 76.3, 76.4, 76.5, and 76.6 for images of
• The cut surface shows solid lobules of hyaline cartilage chest wall hamartoma.
and hemorrhagic cavities. It has features suggestive of a
chondroma associated to aneurysmal bone cyst.
• It is usually a large, circumscribed lesion.
76 Chest Wall Hamartoma 971

a b

Fig. 76.1 Chest wall hamartoma in a newly born male patient. (a) Radiography shows a large expansile rib lesion with areas of mineralization
and soft tissue expansion. (b) CT scan shows a large heterogeneous lesion with irregular areas of mineral deposition

Fig. 76.4 Medium-power microscopic view. Connective tissue area

with fibroblasts with plump nuclei, vascularization, and some multinu-
cleated giant cells
Fig. 76.2 Medium-power magnification microphotography. Highly
cellular cartilage nodule next to aneurysmal cyst-like cavity (Courtesy
of Prof. Eliane Ingrid Amstalden, Campinas, SP, Brazil)

Fig. 76.5 Higher-power microscopic view of cartilage nodules with

calcified matrix

Fig. 76.3 Medium-power magnification microphotography. Cartilage

nodule undergoing enchondral ossification, a common finding in chest
wall hamartoma (Courtesy of Prof. Eliane Ingrid Amstalden, Campinas,
SP, Brazil)
972
Fig. 76.6 Higher-power view of aneurysmal cyst-like wall
R.K. Kalil
Recommended Reading
Amstalden EM, Carvalho RB, Pacheco EM, Oliveira-Filho A, Stragea-
Neto L, Rosenberg AE. Chondromatous hamartoma of the chest
wall: description of 3 new cases and literature review. Int J Surg
Pathol. 2006;14(2):119–26.
Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F. WHO clas-
sification of tumors of soft tissue and bone. Lyon: IARC; 2013.
p. 302–4.
Li Y, Yang QX, Tian XT, Li B, Li Z. Malignant transformation of nasal
chondromesenchymal hamartoma in adult: a case report and review
of the literature. Histol Histopathol. 2013;28(3):337–44.
McCarthy EF, Dorfman HD. Vascular and cartilaginous hamartoma of
the ribs in infancy with secondary aneurysmal bone cyst formation.
Am J Surg Pathol. 1980;4(3):247–53.
Nielsen GP, Rosenberg AE. Diagnostic pathology – bone. Amirsys;
2013. p. 3.2–3.3.
Unni KK, Inwards C. Dahlin’s bone tumors. 6th ed. Philadelphia:
Lippincott Williams & Wilkins; 2010. p. 179–83.
 Index

A CT features, 634
ABC. See Aneurysmal bone cyst (ABC) definition, 633
Acid beta-glucosidase deficiency, 893 epidemiology, 634
Adamantinoma etiology, 633
anterior tibial diaphyseal cortex, 517 genetics, 636
clinical signs and symptoms, 515 gross and histological features, 635
definition, 515 image differential diagnosis
epidemiology, 515 anteroposterior and roentgenographic lytic image, 644
etiology, 515 anteroposterior radiograph, 650
Ewing’s sarcoma, 367 ballooned destructive lesion, 655
grading and staging, 86 calcification and periosteal bone formation, 650
image differential diagnosis cervical spine, 655
metastatic carcinoma, 516 chondroblastoma, 638
osteofibrous dysplasia, 516 conventional central osteosarcoma, 639
immunohistochemical staining, 75 coronal and axial MRI, 646
intercortical lucencies, 517 CT scan and anteroposterior x-ray, 658
malignant tumor, 4 cystic component arising, 640–642
notochordal tumors, 24–25 cyst lack features, 665
OFD, 368 expanded lesion and lytic, 667
and osteofibrous dysplasia, 12 femoral shaft fracture, 640
pathologic differential diagnosis, 517 fibrovascular stroma, 665
photomicrograph, 518 fibula diaphysis, 647
plain radiograph, 518 giant cell tumor, 634, 643, 662
radiologic features, 515–516 hydatid cyst, 635
tibia, 52 intracortical lucency, 648
treatment and prognosis, 517–518 lytic and rapidly expansible lesion, 637
Adipocytes, 562, 570 lytic eccentrical metaphyseal lesion, 676–677
Aggressive fibromatosis of bone. See Desmoplastic fibroma of bone lytic epiphyseal lesion, 675
Aggressive neoplasm, 423 lytic lesion arising, 674
Alveolar soft part sarcoma, 368 malignant lesion, 669
Amputation meta-diaphysis, tibia, 651
limb sacrificing, 90 metaphyseal lesion, 678
limb sparing, 90 metatarsal bone, 653
Amyloidosis microphotograph, 664, 666
chronic renal failure (see Chronic renal failure) multicameral feature, 647
definition, 931 multicameral hemorrhagic cyst, 652
eosinophilic waxy amorphous material, 934 nonclotted blood, 654
etiology, 931 osteoblastoma, 635, 662
imaging differential diagnosis, 932 patella and clavicle, 660
lytic lesion, 934 periosteal bone formation, 661
MRI, 933 powdery calcification, 664
overt myeloma, 932 radiolucent lesion, 670, 671
pathology, 932 rapid ballooned expansion, 637
radiographic features, 932–933 roentgenogram, 651, 657, 670
renal dialysis, 934 sagittal MRI, 659
treatment and prognosis, 932 SBC and TOS, 634
wrist, 934 simple bone cyst, 662
Anaplastic large cell lymphoma, 386 soft tissue and microphotograph, 668
Ancillary techniques. See Bone pathology solitary bone cyst, 673
Aneurysmal bone cyst (ABC), 349, 350, 968 sphenoid and cavernous sinus, 672
bone scan, 634 spindle cell stroma, 665
clinical symptoms and signs, 634 subperiosteal location, 649

E. Santini-Araujo et al. (eds.), Tumors and Tumor-Like Lesions of Bone: For Surgical Pathologists, 973
Orthopedic Surgeons and Radiologists, DOI 10.1007/978-1-4471-6578-1, © Springer-Verlag London 2015
974 Index

Aneurysmal bone cyst (ABC) (cont.) enchondroma (see Enchondroma)

telangiectatic osteosarcoma, 662 multiple osteochondromatosis, 273–276
vertebral segment, 655, 656 osteochondroma, 265–270
MRI features, 634 periosteal chondroma (see Periosteal chondroma)
pathologic differential diagnosis Benign fibrous histiocytoma (BFH)
giant cell reparative granuloma, 636 atypical cells, 444
giant cell tumor, 635–636 clinical symptoms and signs, 440
hydatid cyst, 635 CT features, 440
simple bone cyst, 635 definition, 439
telangiectatic osteosarcoma, 636 diffuse infiltration, 443
prognosis, 636 epidemiology, 439
radiographic features, 634 etiology, 439
and SBC, 610, 611 fibula, 443
site, 634 gross features, 441
treatment, 636 hemosiderin-laden histiocytes, 444
variants, 633 histological features, 441
Angiosarcoma, 494, 495 image differential diagnosis, 441
clinical symptoms and signs, 505 inflammatory cells and foamy histiocytes, 444
definition, 505 involvement sites, 440
epidemiology, 505 MRI features, 440
epithelioid morphology, 510 multinucleated giant cells, 444
etiology, 505 pathology differential diagnosis, 441
foot, radiography, 509 prognosis, 441
genetics, 507 radiographic features, 440
gross and histopathological features, 507 scapula, 442
imaging differential diagnosis, 506 spindle cell proliferation, 443
immunohistochemistry, 511 spindle cells, foamy histiocytes and inflammatory cells, 444
involvement sites, 505 synonyms, 439
irregular vascular channels, 511 treatment, 441
macrophotography, 510 Benign hyaline cartilage tumor, periosteum.
microphotography, 510 See Periosteal chondroma
pathology differential diagnosis, 507 Benign intraosseous neoplasm, 561, 575
prognosis, 507 Benign notochordal cell tumor
radiography, hand, 508 bone isotope scan, 527
solid proliferation, 510 bone scan, 522
synonyms, 505 bony trabeculae, 528, 529
treatment, 507 clinical symptoms and signs, 522
Articular bone cyst. See Juxta-articular bone cyst CT features, 522
Avulsion injury definition, 521
bone scan, 826 ecchordosis physaliphora spheno-occipitalis, 534
clinical symptoms and signs, 826 epidemiology, 521
cortical avulsion, iliac spine, 827 etiology, 521
definition, 825 faintly eosinophilic cytoplasm, 528
endosteal and periosteal callus, 828 gross and histological features, 523
epidemiology, 825 image differential diagnosis
etiology, 825 chordoma and enchondroma, 522
gross features, 826 enostosis (bone island, osteoma), 522
histological features, 826 intraosseous lipoma, 522
image differential diagnosis, 826 malignant lymphoma, 523
involvement sites, 825–826 metastatic carcinoma, 523
ischial tuberosity, 827 osteoid osteoma, 522–523
low magnification, core needle biopsy, 828 osteomyelitis, 522
pathologic differential diagnosis, 826 osteonecrosis (bone infarct), 522
peripheral muscle fibers and chondroid fracture callus, 828 plasmacytoma, 523
prognosis, 826 involvement sites, 521
radiographic features, 826 MRI features, 522
synonyms, 825 osteosclerotic change, 527
treatment, 826 pathologic differential diagnosis
Avulsive cortical irregularity. See Periosteal desmoid chordoma, 523
intraosseous lipoma, 523
osteonecrosis (bone infarct), 523
B prognosis, 524
Bacteriological culture, 915 radiographic features, 522
Benign bone forming tumor, osteoblasts. See Osteoblastoma sacrum, 525–526
Benign cartilage forming tumor synonyms, 521
chondroblastoma, 271–282 treatment, 524
CMF, 287–293 Benign vascular tumor, 457, 479
Index 975

BFH. See Benign fibrous histiocytoma (BFH) prognosis, 857

Biopsy, 89–90 radiodense lesion, 857, 859
Bizarre parosteal osteochondromatous proliferation (BPOP) radiographic and CT features, 856
clinical symptoms and signs, 831 sarcoma, 857, 866, 868–871
definition, 831 scanning, 856
distal ulna well-circumscribed radiodensity, 836 sclerotic lesion, proximal metaphyseal
endochondral ossification, 837 femur, 857, 859
epidemiology, 831 serpiginous borders and calcification, 857, 861
etiology, 831 synonyms, 855
fibula cortex, 837 treatment, 857
fifth metacarpal bone, 834 x-ray, distal femur, 857, 858
genetics, 833 Bone lymphoma, 368
gross features, 832 Bone myoepithelial carcinoma, 368
histological features, 832 Bone pathology
hypercellularity, 838 blotting, 76–77
image differential diagnosis electron microscopy, 74
myositis ossificans, mature lesions, 832 flow cytometry, 74
osteochondroma, 832 histochemical methods, 73
parosteal osteosarcoma, 832 histomorphometry, 74
involvement sites, 831 immunohistochemistry, 75
lesion, metacarpal bone, 834 karyotyping, 75–76
MRI, 832, 836 PAS Stain, 73–74
osteocartilaginous nodule, 834 Bone scintigraphy
parosteal location, middle phalanx, 835 ES, 25
pathologic differential diagnosis osteoid osteoma detection, 18
chondrosarcoma, 833 polyostotic disease, 16
myositis ossificans, mature lesions, 832 vs. radiography and CT, 14
osteochondroma, sessile type, 832 Tc99m-labeled diphosphonates, 14
parosteal osteosarcoma, 833 Bone surface tumor, periosteum, 259–262
subungual osteogenic melanoma, 833 BPOP. See Bizarre parosteal osteochondromatous
prognosis, 833 proliferation (BPOP)
radiographic features, 832, 834 “Brown tumor” of hyperparathyroidism
reactive fibrous tissue, 837 bone scan, 814
synonyms, 831 clinical symptoms and signs, 814
treatment, 833 CT and MRI, 814
Blotting definition, 813
dot blot, 77 epidemiology, 814
northern blot, 76–77 etiology, 813
southern blot, 76 formation, reactive bone trabeculae, 822
western blot, 77 gross features, 815
Bone biopsy histological features, 815
description, 57–58 image differential diagnosis
needle biopsy, 58–71 giant cell granuloma, 814–815
surgical/open biopsy, 58 giant cell tumor, 814
Bone elastic resistance, 849 metastatic carcinoma, 815
Bone infarct involvement sites, 814
calcification, necrotic fat, 857, 864 mature bone trabecula, 821
clinical symptoms and signs, 856 multiple lytic lesions, pelvis, 820
definition, 855 pathologic differential diagnosis, 815
empty lacunae and necrosis, 857, 865 peripheral areas, 822
etiology, 855 prognosis, 816
femoral neck, 857, 860 proximal tibia with lytic lesion, 818–819
gross features, 856 radiographic features, 814
heterogeneous lesion, 857, 862 radiolucent lesion, diaphysis of tibia, 817
histological features, 856 radius, 820
image differential diagnosis, 856 synonym, 813
involvement sites, 856 treatment, 816
irregular sclerosis medullar, proximal vascular fibrous stroma, 822
humerus, 857, 863 well-demarcated lytic lesion, proximal tibia, 817
lesion simulation, chondroma, 857, 858 Burkitt lymphoma, 386
lytic lesion, 857, 867
MRI, 856
necrotic trabecular bone, 857, 865 C
pathologic differential diagnosis Calcium pyrophosphate deposition disease,
ABC, 857 905, 906, 911
intraosseous lipoma, 857 Carcinoma, metastatic bone. See Metastatic
over-decalcification, 856 bone carcinoma
976 Index

Cartilage tumors radiographic features

chondroblastoma, 22, 44 calcific foci, 279
chondromyxoid fibroma, 23 knee, 279, 281
chondrosarcoma, 23–24, 44–46 osteolytic bone lesion, 279, 281
dedifferentiated chondrosarcoma, 24, 46 synonyms, 277
osteochondroma, 21–22, 43 treatment, 280
periosteal chondroma, 22, 43 Chondroid neoplasm, 495, 856
CCCHS. See Clear cell chondrosarcoma (CCCHS) Chondroma, 682
CCO. See Conventional central osteosarcoma (CCO) Chondromyxoid fibroma (CMF), 280, 441, 683
Central giant cell granuloma clinical symptoms and signs, 288
clinical symptoms and signs, 799 CT features, 289
definition, 799 definition, 287
epidemiology, 799 epidemiology, 287
etiology, 799 genetics, 290
hemorrhagic fibrous stroma, 801 gross features, 289, 292
histological features, 800 histological features
involvement sites, 799 calcification, lobule, 289, 293
mandible, 801 elongated/stellate cells, 282, 289
prognosis, 800 fibrous bands, 289, 293
radiographic findings, 799 hyaline cartilage, 289
reparative granuloma, periapical radiograph, 801 large bizarre hyperchromatic nuclei, 289
synonyms, 799 lobular configuration, 289, 292
treatment, 800 oval to spindle nuclei and pink cytoplasm,
CGH. See Comparative genomic hybridization (CGH) 289, 292
Chest wall hamartoma image differential diagnosis
ABC, 968 chondrosarcoma, 289
aneurysmal cyst-like wall, 968, 970 fibrous dysplasia (FD), 289
cartilage nodule immunohistochemistry, 290
calcified matrix, 968, 969 involvement sites, 288
enchondral ossification, 968, 969 MRI features, 289
cellular cartilage nodule, 968, 969 pathologic differential diagnosis
chondrosarcoma, 968 chondroblastoma, 290
clinical symptoms and signs, 968 chondrosarcoma, 289
CT and MRI, 968 enchondroma, 289
definition, 967 extragnathic myxoma, 290
epidemiology, 967 prognosis, 290
etiology, 967 radiographic features, 288–289, 291
fibroblast, 968, 969 synonyms, 287
genetics, 968 treatment, 290
gross features, 968 Chondrosarcoma (CHS), 289, 534, 683, 968
histological features, 968 classification, 296
nuclear hyperchromasia, chondrocytes, 968 clear cell, 339, 344
osteosarcoma, 968 craniofacial region, 304, 321
prognosis, 968 dedifferentiated (see Dedifferentiated chondrosarcoma)
radiography, 968 description, 296
sites, 967 hands and feet, 303–304, 320
synonyms, 967 mesenchymal, 333–338
treatment, 968 periosteal (see Periosteal (juxtacortical) chondrosarcoma)
Chondroblastoma primary (see Conventional intramedullary chondrosarcoma)
clinical features, 277 secondary (see Secondary chondrosarcoma)
clinical symptoms and signs, 278 soft tissue, 377
definition, 277 subtype characteristics, 297
genetics, 280 Chordoma, 495
gross features, 279 anteroposterior radiograph, 536–537
histological features bone scan, 533
“chicken wire calcification”, 279, 282 cervical spine, 550
chondroblasts, 279, 282 chondroid, 545
eosinophilic to amorphous pink fibrochondroid clinical symptoms and signs, 532
matrix, 279, 282 computed tomographic scan, 540
focally spindle cell change, 279 CT features, 532
hyaline cartilage, 279 definition, 531
secondary aneurysmal bone cystic change, eosinophilic/cytoplasm, 548
279, 283 eosinophilic epithelioid sheet, 549
image differential diagnosis, 279, 682 epidemiology, 531
involvement sites, 278 epithelial-like cell, strands, 549
MRI features, 279 etiology, 531
pathologic differential diagnosis, 280 genetics, 535
prognosis, 280 gross appearance, 548
Index 977

gross features, 533 chondroblastic differentiation, 191

histological features, 533–534 chondroblastoma-like osteosarcoma, 196
image differential diagnosis clinical features, 176
ABC, 533 clinical symptoms and signs, 177–178
chondrosarcoma, 533 CT and MRI features, 178
giant cell tumor, 533 cystic changes, 194
meningioma, 533 cyst wall, 195
metastatic carcinoma, 533 definition, 175–176
involvement sites, 531–532 destructive neoplasm, fibula, 191
lobular arrangement, 548 distal metaphysis, femur, 200
MRI features, 533 etiology, 176
neoplastic cells, 549 Ewings’s sarcoma, 198
nuclear atypia, 550 expansile lesion, cortical involvement, 200
paranasal sinuses, 544 fibroblastic osteosarcoma, 192
pathologic differential diagnosis genetics, 183
ABC, 535 giant cell-rich osteosarcoma, 197
benign notochordal tumor, 534 gross appearance, 190
chondrosarcoma, 534 gross features, 178–179
ecchordosis physaliphora spheno-occipitalis, 534 high-grade central osteosarcoma, 203
extraskeletal myxoid chondrosarcoma (“chordoid histological features
tumor”), 535 chondroblastoma-like osteosarcoma, 180
giant cell tumor, 534–535 chondromyxoid fibroma-like osteosarcoma, 180
meningioma, 534 epithelioid osteosarcoma, 180
metastatic carcinoma, 535 giant cell-rich osteosarcoma, 179–180
myoepithelioma/myoepithelial carcinoma, 535 multicentric osteosarcoma, 181
myxopapillary ependymoma, 534 osteoblastoma-like osteosarcoma, 180
osteosarcoma, 535 osteosarcoma mimicking plasma cell myeloma, 180–181
parachordoma, 535 primary CCO, 179
pediatric patients, 546–547 secondary CCO, 181
prognosis, 535–536 small-cell osteosarcoma, 180
radiographic features, 532 telangiectatic osteosarcoma, 180
ribbons/chords, tumor cells, 548 image differential diagnosis, 178
sagittal computed tomographic scan, 541–543 involvement sites, 177
treatment, 536 large osteoclast-like giant cells, 197
Chromogenic in situ hybridization (CISH), 79–80 LGCOGS (see Low-grade central osteosarcoma (LGCOGS))
Chromothripsis, 81 lytic tumor, 197
Chronic renal failure malignant cells, 188
epidemiology, 932 medullary cavity, 188
imaging differential diagnosis, 933 mineralized lace-like matrix, 203
MRI, 933 neoplastic spindle cells, 201
pathologic features, 933 osteoblastoma-like osteosarcoma, 198
sites, 932 Paget osteosarcoma, 202
treatment and prognosis, 933 pathologic differential diagnosis
CHS. See Chondrosarcoma (CHS) ancillary techniques, 183
CISH. See Chromogenic in situ hybridization (CISH) ABC, 182
Clear cell chondrosarcoma (CCCHS), 279, 280, 339–344 benign, 181
Closed biopsies, 90, 91 bizarre parosteal osteochondromatous proliferation, 182
CMF. See Chondromyxoid fibroma (CMF) chondrosarcoma, 182
CNB. See Core needle biopsy (CNB) dedifferentiated chondrosarcoma, 182
Coaxial technique ES, 182
advantages, 61, 68 exuberant/hypertrophic callus, 181
disadvantages, 61, 69–71 fibrosarcoma (malignant fibrous histiocytoma), 182
fibrous dysplasia, 61, 69 florid reactive periostitis, 182
giant cell tumor, 61, 71 giant-cell tumor, 182
needles, 58, 60 malignant, 181
osteoid osteoma, 61, 70 myoepithelial carcinoma, 182
Comparative genomic hybridization (CGH), 80–81 myositis ossificans, 182
Computed tomography (CT). See also Positron emission osteoblastoma, 182
tomography-computed tomography (PET-CT) phosphaturic mesenchymal tumor, 183
multiplanar reformatting, 13 stress fracture, 181–182
soft tissue extension and pathologic fractures, 13 synovial sarcoma, 183
Conventional central osteosarcoma (CCO) pelvis, 190
abundant neoplastic bone, 189 pre-necrotic changes, 204
atypical cytologic features and necrosis, 191 preoperative chemotherapy (neoadjuvant), 184
bone-forming tumor, distal metaphysis of femur, 199 prognosis, 183
bone scan, 178 proximal humerus metaphysis, 189
bony trabeculae, “mosaic pattern”, 202 proximal tibia, 198
cell proliferation, 198 radiographic features, 178
978 Index

Conventional central osteosarcoma (CCO) (cont.) MRI features, 327

sclerotic and lytic aggressive tumor, 195 pathologic differential diagnosis, 327, 329–330
soft tissue mass, 192 prognosis, 328
synonyms, 176 radiographic features, 327, 329
telangiectatic osteosarcoma, 193 site, 327
tibial proximal metaphysis, 187 treatment, 328
treatment, 183–184 Degenerative subchondral pseudocyst, 681
tumoral cells, 196 Desmoid tumor of bone. See Desmoplastic
tumor and surrounding bone, 203 fibroma of bone
well-formed trabeculae, 199 Desmoplastic fibroma of bone
Conventional intramedullary chondrosarcoma ancillary techniques, 427
biopsy, 299 cellularity, 429
bone scan, 299 clinical symptoms and signs, 424
borderline/low-grade chondrosarcomas, 300, 316, 317 collagen fibers, 429
clinical symptoms and signs, 298 CT features, 424
CT features, 99 definition, 423
definition, 297 epidemiology, 423
epidemiology, 297 etiology, 423
etiology, 297 femur, 427
genetics, 301–302 genetics, 427
grading, 300–301, 316–318 gross features, 426
gross features histological features, 426
central CHS, femur, 312 humerus, 428
high-grade CHS, 300, 313 image differential diagnosis, 425
low-grade central, humerus and proximal tibia, 298, 311 involvement sites, 424
myxoid changes, 300, 313 MRI features, 425
high-grade cartilaginous tumors, 300, 317, 318 pathology differential diagnosis, 427, 433
histology, 300 peripheral area, lesion, 429
image differential diagnosis, 299 prognosis, 427
immunohistochemistry, 301 radiographic features, 424
MRI features, 299, 314 radius, macrophotography, 425
prognosis, 302 spindle cell proliferation, 429
radiographic findings synonyms, 423
endosteal scalloping, 298 tarsus, 426
ischium, 298, 312 treatment, 428
low-grade central, humerus and proximal tibia, 298, 311 Diagnosis, bone tumors
myxoid changes, 299, 313 classification, 4
permeation, 299, 313 clinical features, 3
site, 297 fine and core needle biopsies, 4–5, 9
synonyms, 297 grading and staging, 5
treatment options, 303 roentgenographic finding, 3–4
Core needle biopsy (CNB) Diffuse large B-cell lymphoma (DLBCL)
humerus, 60, 65 cytoplasmic clearing, 404
solitary myeloma, 60, 64 lymphoid cells, 403
Cortical avulsion, 825 necrosis, 404
Cyst nuclear chromatin smearing, 402
ABC, 793, 857, 968 T cells, 405
angiomatosis, 804 Diffuse permeative neoplastic disorder, 960
bone infarct, 863 Digits
epidermoid bone (see Epidermoid bone cyst) fibro-osseous pseudotumor
juxta-articular bone (see Juxta-articular bone cyst) (see Fibro-osseous pseudotumor of digits)
myositis ossificans, 783 and metacarpal bones, 255
secondary aneurysmal bone, 792 multiple enchondromas, 255
solid ABC, 815
subchondral bone, 933
Cystic angiomatosis, 478, 494 E
Ehrenfried disease, 273
Electron microscopy
D Birbeck granule, 27, 810
Dedifferentiated chondrosarcoma cytoplasmic and extracytoplasmic, 74
clinical symptoms and signs, 327 Enchondroma
CT scan features, 327 age groups, 16
definition, 326 benign lesions, 16–17
epidemiology, 326 CHS, 309, 310
etiology, 326 clinical symptoms and signs, 244
genetics, 328 CT features, 245
gross features, 327 definition, 243
histologic features, 327, 329–331 epidemiology, 243
Index 979

epiphysis, 17 epidemiology, 493

etiology, 243 genetics, 495
first metacarpal, 16, 32 gross features, 494
genetics, 246–247 imaging differential diagnosis, 494
giant cell reparative granuloma, 792 immunohistochemistry, 495
gross features, 245 intracytoplasmic vacuoles, 501
histological features involvement sites, 493
calcification, 245, 248 lumbar and sacral vertebrae, 498
cartilaginous lobules, 245, 248 lytic lesion, 496, 497
cytologic features, chondrocytes, 246, 248 microscopic features, 494–495
low cellularity, 245, 248 MRI features, 494
mature hyaline cartilage, 245 occasional intracytoplasmic vacuoles, 501
myxoid change/necrosis, 246 pathological differential diagnosis, 495
image differential diagnosis, 245 peripheral areas, 499
imaging differential diagnosis, 486 pleura and lungs, 500
involvement sites, 244 positive immunohistochemistry marking, 502
MRI features, 245 prognosis, 495
Ollier’s disease, 17, 34 radiographic and CT features, 494
pathologic differential diagnosis signs and symptoms, 493
fibrous dysplasia, 246 spindle-celled and myxoid stroma, 502
low-grade chondrosarcoma, 246 thin cortical shell, 496
prognosis and treatment, 247 treatment, 495
proximal humeral, 16, 33 ultrastructure, 495
radiographic features vascular arrangement, 502
calcifications, 244, 247 Epithelioid hemangioma, 495
distal femur, 244, 247 aggressive behavior, 477
long tubular bones, 244 CT features, 478
scallopings, endosteum, 244 definition, 477
synonyms, 243 endothelium, 482
third metatarsal, 16, 32 eosinophilic cytoplasm, 482
Endochondral ossification, 848 epidemiology, 477
Enostoma, 109–113, 115, 116 epithelioid endothelial cells, 482
Eosinophilic cytoplasm, 479, 482 gross features, 478
Epidermoid bone cyst imaging differential diagnosis
clinical symptoms and signs, 700 angiosarcoma and hemangioendothelioma, 478
CT and MRI, 700 cystic angiomatosis, 478
definition, 699 immunohistochemistry, 482
epidemiology, 699 involvement sites, 477
etiology, 699 macrophotography and specimen radiograph, 480
growing lesions, 702 microscopic features, 478
image differential diagnosis MRI features, 478
chondroma, 700 multifocal EH, 481
enchondroma, 700 pathology differential diagnosis
eosinophilic granuloma, 700 angiosarcoma, 478
giant cell granuloma, 700 epithelioid hemangioendothelioma, 478
gross features, 700 prognosis, 479
histological features, 700 radiographic features, 478
intraosseous glomus tumor, 700 signs and symptoms, 477
osteomyelitis, 700 treatment, 479
inner lining, 705 ultrastructure, 479
intraosseous phalangea, 702 Erdheim–Chester disease, 895
involvement sites, 699 clinical symptoms and signs, 949
osteolytic lesion, 702 cortices, 951
peripheral cortical bone rim, 705 definition, 949
prognosis, 700 differential diagnosis, 950
radiographic features, 700 distal femur, 951
round osteolytic lesion, 704 epidemiology, 949
squamous epithelial lining and keratinization, 705 etiology, 949
synonyms, 699 lipid granulomatosis, 949
terminal phalanx of hallux, 703 pathology
treatment, 701 differential diagnosis, 950
well-demarcated lytic lesion, sclerotic rim, 705 marrow replacement, fibroinflammatory
Epidermoid inclusion cyst, 486 tissue, 950, 953
Epiphyseal giant cell reparative granuloma, 792 reactive trabecular thinckening, 950
Epithelioid angiosarcoma, 495 sites, 949
Epithelioid hemangioendothelioma skeletal involvement, femurs and tibias, 952
definition, 493 symmetrical lesions, 951, 953
distal metaphysis, 499 Ewing-like sarcomas, 368
980 Index

Ewing’s sarcoma (ES), 3–5, 25, 48, 86, 101, 180–182, 333, 334, 365, epidemiology, 431
386, 804, 850, 928 etiology, 431
atypical, 374, 387 genetics, 433
bone scan, 367, 372 grade 3 fibrosarcoma, 435
clinical features, 366 gross features, 433
clinical symptoms and signs, 366 histological features, 433
costal, 371 image differential diagnosis, 432–433
CT features, 367 immunohistochemistry positivity, 435
definition, 365 involvement sites, 432
etiology, 365–366 maxilla, 435
extension to soft tissue, 371 pathology differential diagnosis, 433
FISH analysis, 375 in posterior vertebral element, 435
gross features, 367 prognosis, 433–434
hemolymphoid tumors, 367 radiographic features, 432
histological features, 367–368 tibia, proximal end, 434
Homer–Wright pseudorosettes formation, 373 treatment, 434
iliac mass, 374 Fibrous dysplasia (FD), 246, 433, 610, 611, 768
immunohistochemistry studies, 369 bone scan, 737
metastasis, 367 calcaneus, 752
molecular biology, 369 cartilaginous component, 764
MRI features, 367 clinical features, 735–736
with osteolytic lesion, 370 clinical symptoms and signs, 736–737
osteomyelitis, 367 core needle biopsy, 761
osteosarcoma, 367 CT features, 737
pathologic differential diagnosis, 368 cystic changes, secondary, 764
pelvis, 372 definition, 735
prognosis, 369 description, 15–16
radiographic features dysplasia lesion, 762
indefinite osteolytic lesion, 367, 370 endocrinopathies, 16
laminated/multilayered periosteal reaction, 367 etiology, 735
saucerization, 367 femur, 16, 30, 741, 742
site, 366 fibroblastic stroma, 762
small-cell osteosarcoma, 376 fibula, 751
soft tissue chondrosarcoma, 377 genetics, 740
synonyms, 365 gross features, 738–739
treatment options, 369 hip, 741, 742
ultrastructure, 369 histological features, 739
Extragnathic myxoma, 290 humerus, 743, 744
Extraskeletal myxoid chondrosarcoma (“chordoid tumor”), 535 ilium, 31
image differential diagnosis, 738
involvement sites, 736
F jaw, 69
Fatigue fracture, 849 Leontiasis ossea, 16
Fibroblastic osteosarcoma, 432 lumbar vertebral body, 752
Fibromatosis of bone. See Desmoplastic fibroma of bone maxilla, 748
Fibro-osseous pseudotumor of digits, 778 Mazabraud’s syndrome, 16, 753–754
bone scan, 840 metatarsal bone, 750
clinical features, 839 monostotic lesions, 16
clinical symptoms and signs, 839 MRI features, 737
definition, 839 myxomatous changes, stroma, 763
histological features, 840 neck and shaft, 743
hypothenar eminence swelling, 842 osteoid, 763
image differential diagnosis, 840 pathologic differential diagnosis, 739–740
multinucleated giant cells, 841 pelvis, 751
pathologic differential diagnosis, 840 PET scan, 737
phalanx, 841 polyostotic, 16, 755–757
prognosis, 840 prognosis, 740–741
radiographic features, 840 proximal femur, 759
synonyms, 839 radiographic features, 737
treatment, 840 radius, 749, 750
woven osteoid bone trabeculae, 841 rib, 16, 31, 748
Fibrosarcoma of bone ringlike sclerosis, 742
clinical symptoms and signs, 439 sarcoma, 760
definition, 431 secondary aneurysmal bone cyst, 758
Index 981

sinus and nasal cavity, 747 image differential diagnosis

skull, 746, 747 ABC, 792
spindle cell stroma, 761 enchondroma, 792
supraorbital region, 745 GCT, 792
tibia, 743, 759 involvement sites, 792
treatment, 741 pathologic differential diagnosis
Fibrous histiocytoma. See Malignant fibrous histiocytoma ABC, 793
Fibroxanthoma. See Benign fibrous histiocytoma (BFH) brown tumor, hyperparathyroidism, 792–793
Fine needle aspiration biopsy (FNA), 59, 60, 63 fracture callus, 793
Florid reactive periostitis, 839 giant cell reparative granuloma, 793
Flow cytometry, 384, 385, 387, 941–942 giant cell tumor, 793
Fluorescent in situ hybridization (FISH), 76, 79–81, 374, 375, 386, metaphyseal fibrous defect, 793
636, 942 MFH, 793
FNA. See Fine needle aspiration biopsy (FNA) phalanx, 794–796
prognosis, 793
radiographic features, 792
G small multinucleated giant cells with reactive
Gaucher disease bone, 797
avascular necrosis, 898 spindle cell stroma and hemorrhagic area, 797
clinical symptoms and signs, 894 synonyms, 791
“crumpled paper” appearance, cytoplasm, 900 treatment, 793
definition, 893 Giant cell tumor
distal femur, child, 899 clinical symptoms and signs, 349
epidemiology, 893–894 CT features, 349
etiology, 893 definition, 347
gaucheroma, 901 distal end, radius, 355
gross features, 895 distal femur, 352, 357
histological features, 895 distal radius, 359
humerus, 897 etiology/pathogenesis, 347–348
image differential diagnosis femur, 356
Hurler syndrome, 895 fibula, 356
Legg–Calvé–Perthes disease, 894–895 foamy histiocytes and inflammatory cells, 360
Morquio syndrome, 895 genetics, 350–351
myeloma, 895 gross features, 349–350
Niemann–Pick disease, 894 histological features, 350
thalassemia, 894 humerus, 358
involvement sites, 894 image differential diagnosis, 279, 441
leg, 898 ABC, 349
modeling deformity and cortical thinning, femur, 897 chondroblastoma, 349
MRI, 894 chordoma, 349
pathologic differential diagnosis clear cell chondrosarcoma, 349
ancillary techniques, 895 giant cell-rich osteosarcoma and telangiectatic
Niemann–Pick disease, 895 osteosarcoma, 349
periosteal reaction, 899 immunohistochemistry, 350
prognosis, 895 involvement sites, 348
radiographic features, 894 knee, 351
synonyms, 893 lung metastasis, 361
treatment options, 896 lytic and permeative lesion, humerus, 353
Genetics mitotic activity, 360
cytogenetic karyotype, 220 MRI features, 349
osteosarcomas, 183 multinucleated giant cells, 359, 360
Giant cell granuloma, 814–815 neoplastic tissue, 361
Giant cell reparative granuloma pathologic differential diagnosis, 280, 350, 815
ancillary techniques, 793 phalanx, 354
clinical features, 791–792 prognosis, 351
clinical symptoms and signs, 792 proximal tibia, epiphyso-metaphyseal multiloculated
CT and MRI, 792 lytic lesion, 355
definition, 791 radiographic features, 349
distal phalanx base, 794 sacrum, 357
epidemiology, 791–792 soft tissue invasion, 361
etiology, 791 spindle cell proliferation, 360
expansile lesion, first phalanx, 796 synonyms, 347
gross features, 792 treatment, 351
histological features, 792 Giant osteoid osteoma. See Osteoblastoma
982 Index

Glomangioma, 485, 487, 489 blood vessel proliferation, 474

Glomus tumor bone sclerosis, 474
clinical symptoms and signs, 486 clavicle and CT, 472
CT features, 486 clinical symptoms and signs, 458
definition, 485 cortical and medullary hemangiomas, 470
distal phalanx, 491 cortical hemangioma, 466
epidemiology, 485 CT features, 458
etiology, 485 cystic angiomatosis, 471
genetics, 486–487 definition, 457
glomangioma, 489 dense medullar fibrosis, 474
glomangiomyoma, 489 differential diagnosis, 473
gross and histological features, 486 epidemiology, 457–458
imaging differential diagnosis, 486 epithelioid (see Epithelioid hemangioma)
immunohistochemistry, 486, 490 etiology, 457
involvement sites, 486 genetics, 458
macrophotography, 488 gross features, 458
MRI features, 486 histological features, 458
panoramic microscopic view, 488 humerus demonstrating lesion, 474
prognosis, 487 involvement sites, 458
proximal end, phalanx, 491 Maffucci syndrome, 458
radiographic features, 486 metaphysis, 465
soft tissue and bones, ankle, 490 microphotographs, bone, 471, 475
synonyms, 485 MRI features, 458
treatment, 487 pathologic differential diagnosis
Glucocerebroside storage disorder, 893 epithelioid hemangioendothelioma, 458
Glucosylceramidase deficiency, 893 epithelioid hemangioma, 458
Gout prognosis, 459
calcium pyrophosphate deposition disease, 904, 911 radiographic features, 458
chondrocalcinosis, 910 roentgenogram and CT, 464, 467
chronic renal failure, diabetes mellitus, 906, 907 sagittal CT image, 463
clinical symptoms and signs, 904 sclerosing hemangioma, 472
CT and MRI, 904 small vertebral hemangioma, 462
definition, 903 treatment, 459
epidemiology, 903–904 variants, 457
etiology, 903 vertebral hemangioma, 460, 461
gross features, 904 Hemangiosarcoma. See Angiosarcoma
histological features, 905 Hematopoietic diseases, 893
hydroxyapatite deposition disease, 912 Hemolymphoid tumors, 367
image differential diagnosis Hemorrhagic fibrous stroma, 800, 801
infectious arthritis, 904 Hemosiderin-laden cells, 441, 444
pseudogout, 904 Heterotopic ossification, 219, 775, 778
rheumatoid arthritis, 904 High-grade CHSs, 300, 317, 318
involvement site, 904 High-grade surface osteosarcoma
joint fluid aspiration, acute, 907 bone scan, 236
pathologic differential diagnosis clinical features, 235
calcium pyrophosphate deposition disease, 905 clinical signs and symptoms, 236
hydroxyapatite deposition disease, 905 CT features, 236
oxalosis, 905 definition, 235
prognosis, 905–906 etiology, 235
pyrophosphate crystals, 911–912 femur, 239
radiographic features, 904 genetics, 237
resected interphalangeal joint, 909 gross features, 236
tophaceous deposition, 908, 909 histological features, 236
tophus, acid eosin processing and alcohol fixation, 909 histologic differential diagnosis, 236
touch preparation, 909 imaging differential diagnosis, 236
treatment options, 906 involvement sites, 235
uric acid crystal storage disease, 903 left humerus, 238
Grading system MRI features, 236
angiosarcoma, 86 osteoblastic osteosarcoma, 239
chondrosarcomas, 85 prognosis and treatment, 237
Ewing’s sarcoma, 86 radiographic features, 236
nuclear hyperchromatism and pleomorphism, 85 synonyms, 235
RNA/DNA ratio, 85 Histiocytes
Erdheim–Chester disease, 949, 950
hemosiderin-laden, 350, 444, 709
H LCH, 27
Hemangioendothelioma, 478 lipid-bearing, 707, 739, 793
Hemangioma Histiocytosis
angiomatosis, 468–469 LCH (see Langerhans cell histiocytosis (LCH))
axial CT image, 463 sinus, 955
Index 983

Histochemistry, 73 femoral epiphysis, 691

Hodgkin lymphoma, 386 femoral head, 685
Hurler syndrome, 895 femoral neck, 684
Hyaline cartilage tumor, 248, 259–262 gross features, 682–683
Hydatid cyst, 635 histological features, 683
Hydroxyapatite deposition disease, 905, 906, 912 humerus epiphyseal location, 687
Hyperparathyroidism. See “Brown tumor” image differential diagnosis, 682
of hyperparathyroidism intraosseous mucoid cyst, 690, 693
involvement sites, 682
lower epiphysis, tibia, 693, 694
I lunate bone, 689
Image-guided biopsy, 14–15 MRI features, 682
Imaging multiloculated cyst, 696
ABC, 26–27, 50 myxoid areas, 697
adamantinoma, 27–28, 52 pathologic differential diagnosis, 683
bizarre parosteal osteochondromatous prognosis, 683
proliferation, 28, 53 radiographic features, 682
bone scintigraphy, 14 scaphoid, 690
cartilage tumors (see Cartilage tumors) scapula, 688
characteristically benign lesions, 15 synonyms, 681
computed tomography, 13 tibial epiphysis, 692
enchondroma, 16–17 treatment, 683
Ewing sarcoma, 25 upper epiphysis, tibia, 692
fibrous dysplasia, 15–16 Juxta-cortical osteoma, 119, 120
giant cell reparative granuloma, 26, 49
giant cell-rich tumors, 25–26, 48, 49
image-guided biopsy, 14–15 K
LCH, 27, 50 Karyotyping, 75–76, 79, 81
malignant fibrohistiocytic tumor, 25 Keratin, 186, 516, 518, 529, 549, 550, 601, 699,
MRI (see Magnetic resonance imaging (MRI)) 700, 705, 739, 768, 878
NOF, 15
notochordal tumors (see Notochordal tumors)
osteofibrous dysplasia, 28, 52 L
osteogenic lesions (see Osteogenic lesions) Langerhans cell histiocytosis (LCH), 412, 494
Paget’s disease, 17–18 Birbeck granules, 810
PET-CT, 14 CD1a positivity, 810
radiographs, 13 definition, 803
staging, 14 eosinophils, 809
unicameral bone cyst, 26, 49, 50 epidemiology, 803
Immunohistochemistry, 386 etiology, 803
cytokeratins, 110 femoral diaphysis, child, 806
diagnostic pathology, 75 gross features, 804
factors, 75 imaging differential diagnosis
false-negative, 75 bone primary malignancy, 804
false-positive, 75 cystic angiomatosis, 804
staining, 75 metastatic carcinoma, 804
Immunophenotyping, 384, 385 multiple myeloma, 804
Inherited disorder. See Gaucher disease osteomyelitis, 804
Insufficiency fracture, 849 primary lymphoma, bone, 804
Intracortical hemangioma, 129 immunohistochemistry, 805, 810
Intraoperatory biopsy, 58 involvement sites, 803
Intraosseous abscess (Brodie abscess), 129 lumbar spine, 807
Intraosseous lipoma, 522, 856 microscopic features, 804–805
MRI, 804
needle biopsy procedure, 809
J nuclei, 810
Jaws osteomyelitis, 917
giant cell granuloma (see Central giant cell granuloma) pathology differential diagnosis
osteosarcoma (see Osteosarcoma) giant cell tumor, 805
Juxta-articular bone cyst lymphoma, 805
acetabulum, 686 osteomyelitis, 805
astragalus, 695 prognosis, 805
bone scan, 682 radiographic and CT features, 804
clavicle, 696 signs and symptoms, 804
clinical features, 682 skull lytic geographic lesion, 808
clinical symptoms and signs, 682 synonyms, 803
connective tissue membrane, 696 treatment, 805
CT features, 682 ultrastructure, 805
definition, 681 LCH. See Langerhans cell histiocytosis (LCH)
etiology, 681 Legg–Calvé–Perthes disease, 894–895
984 Index

Leiomyosarcoma, 433 definition, 184

clinical symptoms and signs, 555 etiology, 184
CT and MRI features, 556 genetics, 186
definition, 555 gross features, 186
epidemiology, 555 histological features, 186
etiology, 555 image diagnosis, 185
genetics, 556 image differential diagnosis, 185–186, 432
gross and histological features, 556 involvement sites, 185
imaging differential diagnosis, 556 pathology differential diagnosis, 186
immunohistochemistry, 557 prognosis, 186
involvement sites, 555 treatment, 186
long and interwoven bundles, 557 Low grade chondrosarcoma, 245–247
pathology differential diagnosis, 556 Low-grade malignant neoplasms, 493, 517
prognosis, 556 Lymphoblastic lymphoma, 386
radiographic features, 555 Lymphoma of bone
specimen photography and radiography, 557 anaplastic large cell lymphoma, 386
spindle cells, 557 Burkitt lymphoma, 386
treatment, 556 clinical signs and symptoms, 382–383
Leontiasis ossea, 16 cytological findings, 385–386
Limb sacrificing, 89, 90 definition, 381
Limb sparing, 89, 90 diffuse large B-cell lymphoma
Lipid granulomatosis. See Erdheim–Chester disease (see Diffuse large B-cell lymphoma (DLBCL))
Lipoma epidemiology, 382
bilateral calcaneal, 565 etiology, 381
calcaneal location and tibia, 564 genetic findings, 386–387
clinical symptoms and signs, 561 gross findings, 384
coronal view, 563–564 handling of tissue, 384
CT and MRI, 562 histopathology, 384–385
definition, 561 imaging
epidemiology, 561 differential diagnosis, 384
etiology, 561 MRI scan, 383
gross and histological features, 562 multiple bone involvement, 383
imaging differential diagnosis multiple modality, 383
bone infarct, 562 non-Hodgkin lymphoma (see Non-Hodgkin lymphoma)
chondromyxoid fibroma, 562 plain radiographs, 383
enchondroma, 562 radiographic features, 383
osteochondroma, 562 imaging differential diagnosis, 486
osteoporosis, 562 immunohistochemical findings, 386
simple bone cyst, 562 lymphoblastic, 386, 405
involvement sites, 561 mature B-cell neoplasms, 386
macrophotography, 565 Osseous Hodgkin disease, 397–399, 406
microphotography, 565 pathological differential diagnosis, 387–388
pathology differential diagnosis pathologic differential diagnosis, 413
genetics, 562 prognosis, 388
normal fat marrow, 562 sites, 382
prognosis, 562 synonyms, 381
radiographic features, 561–562 treatment, 388
treatment, 562
Liposarcoma
adipocyte and pleomorphic, 570 M
clinical symptoms and signs, 567 Maffucci syndrome, 17, 24, 246, 253–255, 309, 310, 458
definition, 567 Magnetic resonance imaging (MRI)
endosteal scalloping, 569 chemical shift artifact, 13
epidemiology, 567 description, 13
etiology, 567 lesion detection, 14
genetics, 568 Malignant bone forming tumor, 207
gross and histological features, 568 high-grade intraosseous (see Conventional central
host bone external shape, 569 osteosarcoma (CCO))
image differential diagnosis, 567, 568 parosteal osteosarcoma, 217–225
involvement sites, 567 periosteal osteosarcoma, 236
multivacuolated adipocytes and lipoblasts, 570 Malignant cartilage forming tumor
pathology differential diagnosis, 568 CHS (see Chondrosarcoma (CHS))
prognosis, 568 periosteal osteosarcoma (see Periosteal osteosarcoma)
spindle cells, 569 Malignant fibrohistiocytic tumor, 25
treatment, 568 Malignant fibrous histiocytoma
Low-grade central osteosarcoma (LGCOS) clinical symptoms and signs, 448
clinical features, 184 definition, 447
clinical symptoms and signs, 185 epidemiology, 447
Index 985

etiology, 447 Mature B-cell neoplasms, 386

extensive degenerative and cystic changes, 452 Mazabraud syndrome, 16, 736, 753
genetics, 450 McCune–Albright syndrome, 16, 736, 737, 740, 756
gross and histological features, 449 Medullary osteoma
humeral metaphysis, 451 bone scan, 110, 113
image differential diagnosis, 449 clinical features, 109
inflammatory cells, 452 clinical symptoms and signs, 110
involvement sites, 448 CT features, 110
macrophotography, MFH, 450 definition, 109
mitoses, 452 enostoma, 111
MRI features, 449 etiology, 109
panoramic microscopic view, 453 femoral epiphysis, 112
pathology differential diagnosis, 441 gross features, 110
fibrosarcoma, high grade, 449 histological features, 110
giant cell tumor, 449 image differential diagnosis, 110
leiomyosarcoma, high grade, 449 involvement sites, 110
liposarcoma, pleomorphic type, 449 mature bone trabeculae, 116
malignant lymphoma, 449 MRI features, 110, 111
metastatic sarcomatoid carcinoma, 449 osteoblastic sclerotic metastases, 110
osteosarcoma, 449 prognosis, 110
pleomorphic and hyperchromatic cells, 453 radiographic features, 110
prognosis, 450 sclerotic round intramedullary lesion, 111
radiographic and CT features, 448–449 synonyms, 109
specimen radiography, 450 treatment, 110
synonyms, 447 Melorheostosis, 121
treatment, 450 Mesenchymal chondrosarcoma, 75, 86, 180,
Malignant lymphoma, 449, 523 333–338, 589
Malignant spindle cell tumor. See Fibrosarcoma of bone Metaphyseal fibrous defect (MFD)
Malignant tumor, notochordal differentiation, 531 bone scan, 708
Mastocytosis clinical features, 707–708
aggressive disease, 937 clinical symptoms and signs, 708
axial skeleton, pelvis and long bones, 939 CT and MRI features, 708
bone complications and skeletal manifestations, 939 definition, 707
bone scans, 940 epidemiology, 707
categories, 937 etiology, 707
classification (WHO 2008), 937–938 femur, 711–713
clinical signs and symptoms, 938–939 fibrous defect, 713
CT, 940 fibula, 721, 722
definition, 937 gross features, 709
diagnosis, 942 histological features, 709
differential diagnosis, 940–941 humerus, 723
diffuse disease, 940 image differential diagnosis, 708–709
epidemiology, 938 involvement sites, 708
etiology, 938 lipids and hemosiderin, 727
features, 939–940 lytic eccentric lesion, 719
focal lesions, 940 multiple, 725
indolent systemic pathologic differential diagnosis
coronal MRT1-weighted image, 945 benign fibrous histiocytoma, 710
right and left knee, 944 fibrous dysplasia, 709–710
mast cell disease, 938 giant cell tumor, 710
MRI, 940 malignant fibrous histiocytoma, 710
pathological differential diagnosis osteofibrous dysplasia, 710
disseminated lymphoproliferative disorders, 942 osteosarcoma, 710
monocytic/histiocytic proliferation, 942 periosteal desmoid, 709
reactive mast cell hyperplasia, 942 solid aneurysmal bone cyst, 710
pathology with pathologic fracture, 714
ancillary studies, 941–942 prognosis, 710
genetics, 942 radiographic features, 708
gross findings, 941 radius, 723, 724
immunohistochemical findings, 941 sclerosis of lesion, 714, 720
microscopy, 941 storiform pattern, 725, 726
systemic, 941 synonyms, 707
pelvis, 946 tibia, 715–717, 720
prognosis, 942–943 treatment, 710
systemic, 938 typical features, 718
trabeculae causing paratrabecular fibrosis, 946 Metaphysis, 12
treatment, 943 fibrous defect (see Metaphyseal fibrous
uniform round cells, 946 defect (MFD))
986 Index

Metastasis. See also Metastatic bone carcinoma synonyms, 253

adamantinoma, 28 treatment, 255
chordoma, 24 Multiple lytic lesions, pelvis, 820
ES, 368 Multiple myeloma, 494
glomus tumor, 486 definition, 409
malignant fibrous histiocytoma, 25 diffuse osteoporosis, 414
Paget’s disease, 17 humeri and femurs, 417
Metastatic bone carcinoma with sclerosis, 419
and abundant reactive bone, 604 serum immunofixation, 418
adenocarcinoma, 605, 606 survival, 413
blastic osseous metastatic adenocarcinoma, 605 treatment, 413
cancellous and cortical bone, 603 Multiple osteochondromatosis
cortical lucency, 605 clinical symptoms and signs, 273
definition, 599 definition, 273
desmoplastic stroma, 604 epidemiology, 273
distal metaphysis, 603 etiology, 273
epidemiology, 599 genetics, 274
estrogen receptor positive, 605 gross and histologic features, 274–276
etiology, 599 image diagnosis, 274, 275
fine-needle biopsy, 604 involvement sites, 273
follicular adenocarcinoma, 603 synonyms, 273
genetics, 601 Musculoskeletal neoplasms, 86–87
gross features, 600 Myeloma
histologic features, 600–601 amyloid extracellular matrix, 419
immunohistochemistry, 604 clinical features, 410
involvement sites, 600 clinical symptoms and signs, 411
lytic metastases, 600 CT features, 412
osteoblastic metastasis, 604 definition, 409–410
pathological differential diagnosis, 601 etiology, 410
posterior pelvis, 604 femurs, 417
prognosis, 601 gelatinous tumor mass, 418
proximal humerus, 602 gross features, 412
radioisotopic bone scan, 600 histologic features, 412–413
residual cancellous bone, 604 humerus, 415, 417
sclerotic metastases, 600 image differential diagnosis, 486, 895
surgical specimen, 602 LCH, 412
symptoms, 600 lymphoma, 412
treatment, 601 metastatic carcinoma, 412
Metastatic carcinoma, 368, 387, 412, 494, 495, 523, 533 MRI features, 412
Metastatic neuroblastoma, 73, 387 multiple myeloma (see Multiple myeloma)
Metastatic sarcomatoid carcinoma, 449 pathologic differential diagnosis
Microarrays, 80–82 infections, 413
Morquio syndrome, 895 lymphoma and leukemia, 413
MRI. See Magnetic resonance imaging (MRI) plasmacytoid features, 414
Multiple enchondromatosis (Ollier’s disease) prognosis, 413
cartilage masses, 255 proximal humerus, 416
clinical symptoms and signs, 254 radiographic features, 412
definition, 253 secondary fracture, femoral neck, 417
enlarged nuclei and binucleation, chondrocytes, 256 serum immunofixation, 418
epidemiology, 253 synonyms, 410
etiology, 253 treatment, 413
genetics, 255 Myoepithelial carcinoma, 535
gross features, 254 Myoepithelial neoplasms, 495
histological features, 254, 256 Myoepithelioma, 535
image diagnosis, 254, 255 Myositis ossificans, 120, 121, 182, 267
image differential diagnosis, 254 active and immature vascular fibroblastic proliferation, 785
involvement sites, 253–254 active osteoblasts, 787
irregularly distributed lytic lesions, 257 cartilage masses, 787
lobulated cartilage masses, 256 clinical symptoms and signs, 776
medullar enchondromas, 256 cortex, 780
metacarpal bones, 255 deeper lesions, periosteal reaction, 781
mineral deposition, 257 definition, 775
pathologic differential diagnosis, 254 early stage, 778, 785
prognosis, 255 epidemiology, 776
Index 987

etiology, 775–776 Neurinoma, 575

extraskeletal osteosarcoma Neuroblastoma, 368
higher magnification, 789 Neuroectodermal bone tumors, 365, 367
malignant lacelike osteoid, 788 Neurofibroma (NF)
multinucleated giant cells, 789 clinical symptoms and signs, 581
soft tissue mass, 788 collagenic matrix, 583
fibro-osseous pseudotumor of digits, 778 CT scan, 583
floccular radiopacities, “dotted veil” pattern, 780 definition, 581
genetics, 778 epidemiology, 581
gross features, 777 etiology, 581
hemorrhages, fibrinous material and necrotic genetics, 582
muscle fibers, 785 gross and histological features, 582
histological features imaging differential diagnosis, 581
central portion/early stage, 777–778 involvement sites, 581
intermediate portion, 778 pathology differential diagnosis, 582
peripheral portion, 778 prognosis, 582
image differential diagnosis treatment, 582
osteochondroma, 777 Neurofibromatosis, 581, 582
parosteal osteosarcoma, 777 NF. See Neurofibroma (NF)
immature osteoid trabeculae, 785 Niemann–Pick disease, 894, 895
intermediate stage, 786 NOF. See Non-ossifying fibroma (NOF)
involvement sites, 776 Non-Hodgkin lymphoma
limits, zonation phenomenon, 786 acetabular homogeneous T2 hyperintense
low magnification, 786 lesion, 394, 395
mature lesion evolution, 784 amputation specimen, 399
mature peripherally located bone areas, 787 diffuse growth pattern, 400
mature trabeculae, 786 diffuse osteosclerosis, 393
mature well-circumscribed lesion, 782 diffuse sclerosis, 392
necrotic muscle fibers, 786 distal femur, 392
nodular fasciitis, 778 fibrosis, 401
parosteal osteosarcoma, 778 knee, 396
peripheral zone, 787 large soft tissue mass, 390–391
prognosis, 778 left femoral shaft, 394
radiographic features periosteal reaction, 390, 394
bone scan, 777 proximal femur, 389
CT and MRI, 777 swelling, 399
early stage, 777 Nonlipid reticuloendotheliosis, 803
fifth to sixth week, 777 Non-ossifying fibroma (NOF), 441
mature lesions, 777 description, 15
third to fourth month, 777 distal femur, 15, 29
soft part aneurysmal bone cyst, 783 distal tibia, 15, 29
soft tissue density, ill-defined mass, 779 fibrous nature, 15
synonym, 775 multiple, 15
treatment, 778 Nora’s lesion, 831
Myxofibrosarcoma, 433 Notochordal cells. See Benign notochordal
cell tumor
Notochordal tumors
N benign notochordal cell tumor, 24, 47
Necrosis chordoma, 24, 47
alveolar features, 867
area, 856
aseptic, 855 O
avascular, 855 OFD. See Osteofibrous dysplasia (OFD)
bone trabeculae, 856 Ollier’s disease, 17, 34. See also Multiple
and calcification, 856, 860 enchondromatosis (Ollier’s disease)
early stage, 856 Oncogenic osteomalacia (OO), 587–589
and empty lacunae, 856, 865 OO. See Oncogenic osteomalacia (OO)
Needle biopsy Open biopsies
CNB, 58, 59 advantages and disadvantages, 90, 91
coaxial technique, 58, 60–71 placement incision, 90, 95
FNA, 58, 59 principles, 90, 91
types, 58 Osseous Hodgkin disease, 397–399, 406
Neoplastic destruction of bone, 964 Osteoarthritis, 12, 17, 298, 681–683, 918, 944
Neurilemmoma, 575 Osteoarthritis subchondral pseudocyst, 683
988 Index

Osteoblastoma, 280, 635 involvement sites, 266

aggressive appearance, 168 medullary cavity, 266, 270
anastomosing bony trabeculae, 163 parosteal osteosarcoma, 267
bone scan, 153 pedunculated/sessile protuberance, 266, 268
chondroid matrix, 165 prognosis, 267
clinical features, 151 roentgenograms, 266, 268
clinical symptoms and signs, 152 secondary chondrosarcoma, 267
cortical and periosteal, 156 sessile osteochondroma, 266, 269
CT features, 153 synonyms, 265
cytologically bland microscopic areas, 169 treatment, 267
definition, 151 Osteoclastoma, 792
degenerative nuclei, 169 Osteofibrous dysplasia (OFD)
distal tibia, 167 bone scan, 768
edge, 163 bowing deformity, tibia, 769
epithelioid osteoblasts, 169 clinical symptoms and signs, 767
etiology, 151 definition, 767
fibrovascular connective tissue, 172 epidemiology, 767
gross features, 153 expansile lucent lesion, tibia, 772
histological features, 153–154 fusiform cortical expansion, 769
host bone trabeculae entrapment, 173 gross features, 768
image differential diagnosis histological features, 768
ABC, when in spine, 153 image differential diagnosis
osteoid osteoma, 153 adamantinoma, 768
osteosarcoma, 153 fibrous dysplasia, 768
involvement sites, 152 involvement sites, 767
misinterpreted histological features, 166 irregular bone trabeculae, prominent osteoblasts, 773
MRI features, 153 large and elongated lesion, multiple cortical lucencies, 771
osteoblastoma-like osteosarcoma, 170–171 MRI, 768
osteoblasts, 172, 174 multilocular defect, anteromedial cortex, 770
osteoid matrix, 169 pathologic differential diagnosis
pathologic differential diagnosis adamantinoma, 768
ABC, in vertebral location, 154 ancillary techniques, 768
fibrous dysplasia, 155 fibrous dysplasia, 768
genetics, 155 prognosis, 768
osteofibrous dysplasia, 155 treatment, 768
osteoid osteoma, 154 radiographic features, 768
osteosarcoma, 154–155 synonyms, 767
posterior/dorsal elements, vertebrae, 162, 163 trabeculae of woven bone
prognosis, 155 with osteocytes, 773
radiographic features, 152–153, 156 spindle cell proliferation, 772
roentgenograms, 168 Osteogenic lesions
scoliosis, 159 osteoblastoma, 19, 37
secondary aneurysmal bone cyst, 163–164 osteoid osteoma, 18–19
single layer, osteoblasts, 172 osteosarcoma (see Osteosarcoma)
spine, 158 Osteogenic tumor, 200, 495
synonyms, 151 Osteoid osteoma, 486, 522–523
total body scan, Tc-99ms, 157 bone scan, 129
treatment, 155 cervical vertebrae, 141–143
vertebral body, 162 clinical symptoms and signs, 129
vertebral column, 157 CT features, 129
x-ray appearance, 167 CT-guided radiofrequency ablation, 19, 36
Osteochondroma definition, 127
bizarre parosteal osteochondromatous proliferation, 267 description, 18
cartilage cap, 266, 269 detection, 18
clinical and signs, 266 differential diagnosis
definition, 265 intraosseous abscess (Brodie abscess), 129
distal femur, 266, 269 stress fracture, 129
epidemiology, 265 epidemiology, 127
etiology, 265 etiology, 127
genetics, 267 femoral neck, 135
gross features, 267 femoral shaft, 18, 36
histological features genetics, 130
chondrocytes, 267, 270 gross features, 129–130
fatty/hematopoietic bone marrow, 267, 270 histological features, 130
hyaline cartilage cap, 267, 270 humeral shaft, 143
peripheral periosteum, 267, 270 immature trabeculae, 147
image differential diagnosis, 266–267 intracortical, 137
Index
intramedullary, 128
involvement sites, 128
lamina, 18, 36
lucent nidus, 133
lumbar vertebra, 140
lytic, 146
metatarsal bone, 146
MRI features, 129
nidus, 145
oval lucency, 137
ovoid, 134
Paget’s disease, 148
pathologic differential diagnosis
intraosseous hemangioma, 130
osteoblastoma, 130
perilesional sclerotic bone, 132
phalanx, 146
prognosis,
proximal femur, 131
proximal fibula, 139
radiographic features, 129
resected, 147
spine, 139
stress fracture, 129
synonyms, 127
tibial shaft, 138
treatment, 130
tumoral trabeculae, 148
ulnar shaft, 144
Osteomyelitis, 367, 494, 522
acute, 919, 920
arthritis-like joint pain, 919, 924
bone abscess, 919, 922
Brodie’s abscess, 919, 921
chronic
and abscess formation,
lower tibia, 919, 926–927
distal femur, 919, 928
clinical symptoms and signs, 916
CT features, 916
definition, 915
diffuse distal sclerosis, 919, 925
epidemiology, 915–916
etiology, 915
gross features, 917–918
histological features, 918
image differential diagnosis
fractures, 916–917
LCH, 917
tumors, 917
involvement sites, 916
LCH, 804
metaphysis, 919, 923
MR features, 916
pathologic differential diagnosis
fracture, 918
osteonecrosis, 918
pathophysiology, 917
prognosis, 919
radiographic features, 916
radionuclide scanning, 916
synonyms, 915
treatment options, 918
Osteonecrosis
bone marrow necrosis, 960
image differential diagnosis, 522
primary, 964
989
Osteopoikilosis, 109
Osteosarcoma, 274, 366, 535
alveolar cortical plate, 208, 209
bone scan, 20
chest wall hamartoma, 968
clinical features, 207
definition, 207
distal femur, 19, 37, 38
etiology, 207
gross features, 208
high-grade surface, 21
histopathological features, 208
image diagnosis, 208
image differential diagnosis, 153
involvement sites, 207–208
lingual plate and tumor invasion, 212
low-grade central, 20, 40
malignant bone forming tumors, 207
maxilla and maxillary sinus, 210, 211
microscopic images, 213–216
neoplasm, 19
parosteal, 20, 40, 41, 217–225
pathologic differential diagnosis, 154
periosteal, 21, 42
permeation, cortex, 172
prognosis, 208
ramus, 210
secondary, 21
stress fracture, 850
synonyms, 207
teeth displacement, 209
telangiectatic, 20, 39
treatment, 208
variants, 179, 181
P
Paget’s disease, 130, 148
acetabular involvement, 17
bone expansion, left pelvis, 880
bone scan, 876
bowing, tibia, 884
clinical symptoms and signs, 874–875
CT and MRI, 876
definition, 874
deformity, tibia, 882
description, 17
diaphysometaphyseal femur, 881
distal femur, 881
distal radius, 885
epidemiology, 874
etiology, 874
gross features, 876
hemipelvis, 17, 35
histological features
late stage, 877
osteoblastic stage, 876–877
osteolytic stage, 876
image differential diagnosis
lymphoma, bone, 876
osteofibrous dysplasia, 876
involvement sites, 874
large lytic defect, ilium, 891
left calcaneus, 885
left patella, 17, 35
mandible, 879, 889
mosaic structure, trabeculae, 888
990 Index

Paget’s disease (cont.) Parosteal osteosarcoma, 229, 267

osteitis fibrosa deformans, 874 bone-forming tumor, 217
osteosarcoma development, 890 bone scan, 219
patella, 882 bone trabeculae, 219, 223, 224
pathologic differential diagnosis cartilage cap, 225
ancillary techniques, 878 clinical features, 217–218
chronic osteomyelitis, 878 cortical bone, Haversian systems, 126
fibrous dysplasia, 877 CT features, 219
hyperparathyroidism, 878 dedifferentiated, 237
metastatic carcinoma, 878 definition, 217
osteofibrous dysplasia, 878 dense homogeneous lesion, 122
phalanx, 878, 886 distal femoral metadiaphysis, 221
phases, 17 distal femur, 222
polyostotic, 878, 887 enlarged nuclei, 224
prognosis, 878 etiology, 217
proximal fibula, 884 genetics, 220
radiodensity and bone expansion, 886 gross features, 219
radiographic features histological features, 219
early stage, 875 histologic diagnosis
late, “burnt-out” stage, 875 heterotopic ossification, 219
lesions, 875 osteochondroma, 219
middle stage, 875 osteoma, 219
monostotic/polyostotic forms, 875 histologic differential diagnosis, 236
sarcoma, 876 homogeneous sclerotic mass, 123
radiolucent defect, tibia, 878, 883 hyaline cartilage, 222, 225
sarcomatous transformation, 18 image differential diagnosis, 120
skull, 878, 879, 889 imaging differential diagnosis, 236
tibia, 17, 34 immunohistochemistry, 219
treatment, 878 low grade, 219
vertebra, 878, 880 malignant, 217, 219
Paget’s sarcoma MRI features, 218–219
gross features, 877 myositis ossificans, 219
histological features, 877 ossifying parosteal mass, 125
Parachordoma, 535 osteochondroma, 219
Parosteal chondrosarcoma, 229 oval sclerotic lesion, 122
Parosteal fasciitis, 839 parosteal osteoma arising, 124
Parosteal osteoma pathologic differential diagnosis, 121
bone scan, 113, 120 posterior cortex, 125
clinical features, 119 prognosis, 220
clinical symptoms and signs, 120 radiographic features, 218
CT features, 114, 120 sclerotic intramedullary lesion, 222
definition, 119 synonyms, 217
etiology, 119 treatment, 220
gross features, 121 tumor cells, 223
histological features, 121 PAS Stain. See Periodic acid-Schiff stain (PAS Stain)
iliac bone, 113 PCR. See Polymerase chain reaction (PCR)
image differential diagnosis Peptide nucleic acid (PNA), 79
melorheostosis, 121 Periodic acid-Schiff stain (PAS Stain)
myositis ossificans, mature lesions, 120 Congo red staining, 73–74
osteochondroma, 120 mucin, 73
parosteal osteosarcoma, 120 Periosteal chondroma
involvement sites, 119–120 clinical symptoms and signs, 260
MRI features, 120 CT features, 260
pathologic differential diagnosis definition, 259
melorheostosis, 121 epidemiology, 259
myositis ossificans, mature lesions, 121 etiology, 259
osteochondroma, sessile type, 121 genetics, 261
parosteal osteosarcoma, 121 gross features, 260
prognosis, 121 histological features, 260, 262
radiodense lesion, 114 image differential diagnosis
radiographic features, 120 periosteal chondrosarcoma, 260
roentgenograms, 115 periosteal osteosarcoma, 260
synonyms, 119 involvement sites, 259
treatment, 121 MRI features, 260
Index 991

pathologic differential diagnosis parosteal chondrosarcoma, 229

periosteal chondrosarcoma, 260 parosteal osteosarcoma, 229
periosteal osteosarcoma, 260–261 peripheral condensation, tumor cells, 232
prognosis and treatment, 261 prognosis and treatment, 229
radiographic features, 260, 262 radiographic features, 228
synonyms, 259 surface-based mass, 231
Periosteal (juxtacortical) chondrosarcoma synonyms, 227
clinical symptoms and signs, 305 Peripheral nerve, 93, 581
definition, 305 Peripheral neuroectodermal tumor (PNET). See Ewing’s sarcoma (ES)
epidemiology, 305 PFFD. See Proximal femoral focal deficiency (PFFD)
etiology, 305 Phosphate depletion, 587
genetics, 306 Phosphaturic mesenchymal tumor (PMT)
gross features, 306, 322 bone scan, 588
histologic features, 306, 323 calcifications, 592
image diagnosis cellular histomorphology, 594
CT features, 305 cellular proliferation, 594
differential diagnosis, 306 chondroid-like area and matrix calcification, 594
MRI features, 306, 321 chondroid matrix, 592
radiographic features, 305, 321 clinical symptoms and signs, 588
pathologic differential diagnosis, 306 definition, 587
prognosis, 306 epidemiology, 587
site, 305 etiology, 587
synonyms, 305 femurs, 591
treatment options, 306 FGF23 marker, 593
Periosteal desmoid genetics, 589
clinical features, 729 gross features, 588
clinical symptoms and signs, 729 hemangiopericytoma-like pattern, 592
collagen production, 732 hemorrhagic and tan soft areas, 591
cortical fibrous defect, 730 histological features, 588–589
cortical irregularity, tibia, 731 image differential diagnosis
definition, 729 osteomalacia/rickets-related DD, 588
etiology, 729 tumor-related DD, 588
gross features, 730 involvement sites, 588
histological features, 730 juxtacortical heterogeneous mass, 590
hypocellular spindle cells, 732 lytic epiphyso-metaphyseal lesion, 593
involvement sites, 729 metastatic nodules, 593
irregularity, cortical bone, 732 MRI, 588, 590
pathologic differential diagnosis, 730 numerous capillaries, 592
prognosis, 730 and numerous multinucleated giant cells, 594
radiographic features, 729 ovoid lesion, 590
synonyms, 729 pathology differential diagnosis, 589
tibial metaphyseal area, 732 peripheral ossification, 591
treatment, 730 prognosis, 589
Periosteal osteosarcoma radiographic features, 588
bizarre parosteal osteochondromatous proliferation, 229 richly vascularized tumor tissue, 592
bone scan, 228 “smudgy” matrix, 592
clinical features, 227 specimen contained cysts, 591
clinical signs and symptoms, 228 treatment, 589
cortical thickening, 230–231 Pigmented villonodular synovitis, 682
CT features, 228 Plasma cell dyscrasia
definition, 227 epidemiology, 932–933
etiology, 227 sites, 932
genetics, 229 Plasma cell lineage, malignant tumor. See Myeloma
gross features, 228 Plasmacytoma, 523
high-grade surface osteosarcoma, 229 Pleomorphic sarcoma, 447
histological features, 228–229, 231 PNA. See Peptide nucleic acid (PNA)
histologic differential diagnosis, 236 Podagra. See Gout
imaging differential diagnosis, 228, 236 Polymerase chain reaction (PCR)
intermediate-grade chondroblastic osteosarcoma, 232 agarose gel electrophoresis, 78
involvement sites, 227 annealing, 77
malignant hyaline cartilage, 232 denaturation, 77
malignant osteoid, 232 extension, 77
MRI features, 228 real-time PCR, 78
osteochondroma, 229 thermal cycling, 77
992 Index

Positron emission tomography-computed tomography Sarcomatous change, 856

(PET-CT), 14, 25 SBC. See Simple bone cyst (SBC)
Primary chondrosarcoma. See Conventional intramedullary Schwannoma
chondrosarcoma clinical symptoms and signs, 576
Primary lymphoma of bone, 381–383, 385–387, 494 definition, 575
Primary osteonecrosis, 964 dense proliferation, 578
Prognosis epidemiology, 575
bone tumors, 85 etiology, 575
factors, 86 genetics, 576
osteosarcomas, 85 gross features, 576
Proximal femoral focal deficiency (PFFD), 93 histological features, 576
Pseudomalignant osseous tumor, soft tissue, 839 image differential diagnosis, 576
Pseudotumor involvement sites, 575
avulsion injury, 825 palisading, 578
fibro-osseous pseudotumor (see Fibro-osseous panoramic radiograph, 577
pseudotumor of digits) pathology differential diagnosis
Pseudotumoral lesion of bone, subungual exostosis, 845–848 malignancy, 576
neurofibromatosis, 576
periosteal, femur, 577
R prognosis, 576
Radiography spindle cell and looser central area, 578
chondroid matrix, 13 synonyms, 575
matrix mineralization, 13 treatment, 576
and scintigraphy, 14 vacuolization and occasional hyperchromasia, 578
Real-time PCR, 77, 601 Secondary aneurysmal bone cyst. See Aneurysmal bone cyst
Reticuloendothelial system, inherited disorder, 893 Secondary chondrosarcoma
Rhabdomyosarcoma, 368 central
Rheumatoid arthritis, 904 clinical symptoms and signs, 309
Roentgenographic finding definition, 309
CT, 4, 8 epidemiology, 309
eosinophilic granuloma, 3, 6 etiology, 309
fibrous dysplasia, 3, 6 genetics, 309–310
giant cell tumor, 3, 7 image diagnosis, 309
moth-eaten pattern, humerus, 3–4, 7 pathology, 309
MRI, 4 prognosis, 310
peripheral sclerosis, 3, 6 site, 309
permeative lesions, 4, 7 synonyms, 309
Rosai–Dorfman disease low-grade, 254
bone lesions, 955 peripheral
clinical signs and symptoms, 955 clinical symptoms and signs, 307
definition, 955 CT scan and MRI features, 307
epidemiology, 955 definition, 307
image differential diagnosis, 955 epidemiology, 307
massive lymphadenopathy, 955 etiology, 307
osseous, 955 genetics, 308, 324, 325
pathology gross features, 308
differential diagnosis, 956 histologic features, 308
emperipolesis, 956, 957 pathologic differential diagnosis, 308
fibrosis, 956 prognosis and treatment, 308–309
lymphoplasmacytic histiocytic reaction, 956 radiographic features, 307, 323
S-100 stain cells, 956, 957 site, 307
sites, 955 synonyms, 307
treatment and prognosis, 956 Secondary hyperparathyroidism, 813, 815
vertebrae, MRI, 957 Secondary tumor, 600
Rotationplasty, 93 Self-limited growth potential, MFD, 707
Round cell malignancies/Ewing’s sarcoma, 850 Silver in situ hybridization (SISH), 80
Simple bone cyst (SBC)
anteroposterior and lateral x-ray, 617
S bone scan, 610
Sarcoma calcaneus, 619, 620
associated to multiple osteochondromatosis, 274 caption and ilium, 618
in multiple enchondromatosis clinical symptoms and signs, 610
chondrosarcoma, 255 CT and MR features, 610
dedifferentiated chondrosarcoma, 255 definition, 609
high-grade osteosarcoma, 255 diaphyseal location, 622
synovial sarcoma, monophasic, 433 epidemiology, 609–610
Index 993

epiphyseal involvement, 626, 627 fracture line and small periosteal reaction, 851
etiology, 609 gross features, 850
femoral neck, 614 histological features, 850
fibrinous deposits, 629 image differential diagnosis
fibula, 621 metastatic carcinoma, 850
genetics, 611 osteosarcoma, 850
gross and histological features, 611 round cell malignancies
hot signal and fracture, 625 (Ewing’s sarcoma), 850
humerus, 613 involvement sites, 849
image differential diagnosis middle shaft, fibula, 852
ABC, 610 pathologic differential diagnosis, 850
fibrous dysplasia, 610 periosteal reaction and medullary sclerosis, 852
immature trabeculae, microphotograph, 628 prognosis, 850
“latent and inactive”, 612 proximal tibia, 851
metaphysiodiaphyseal lucency, 612 radiographic features, 850
methylprednisolone, 630 reactive woven bone and small necrotic preexisting
multilocular appearance, 613 bone, 853
pathologic differential diagnosis synonyms, 849
ABC, 611 treatment, 850
fibrous dysplasia, 611 Subungual exostosis
pathologic fracture and humerus, 623, 624 cartilage cap, 846, 848
periosteal reaction, 615 clinical symptoms and signs, 845
peripheral areas, 629 definition, 845
prognosis, 611 distal phalanx
rack sign, 625 fifth toe, 846, 847
radiographic features, 610 great toe, 846, 847
radius, 625 second finger, 846, 848
rich vascularization, 628 epidemiology, 845
roentgenogram and CT, 619 etiology, 845
solitary bone cyst, 616 gross features, 846
synonyms, 609 histological features, 846
trabeculation, 613, 614 image differential diagnosis
treatment, 611 myositis ossificans, 846
ulna, metaphysis, 622 osteochondroma, 846
Sinus histiocytosis with massive lymphadenopathy, 955 involvement sites, 845
SISH. See Silver in situ hybridization (SISH) pathologic differential diagnosis
Skull chondrosarcoma, 846
curettage/excision, 701 myositis ossificans, 846
distal phalanges, 699 osteochondroma, 846
eosinophilic granuloma, 700 subungual osteogenic melanoma, 846
lesion, 699 prognosis, 846
lytic lesion, 704, 705 radiographic features, 846
round osteolytic lesion, 704 residual cartilage, endochondral ossification, 846, 848
squamous, 700, 705 treatment, 846
SKY. See Spectral karyotyping (SKY) Surface lesion. See also Periosteal desmoid
Small-cell osteosarcoma, 368 florid reactive periostitis, 182
Smooth muscle, 555, 556 hypothenar eminence swelling, skin, 840, 842
Spectral karyotyping (SKY), 79 Surface osteosarcoma, 826
Staging, 14. See also Grading system Surface tumor. See also High-grade surface
musculoskeletal neoplasms, 86–87 osteosarcoma
Sternberg variants, 385, 386, 406 high-grade surface osteosarcoma, 228, 229
Storage disease, 949 of long bone (see Osteochondroma)
Storage disorder Surgery treatment
Erdheim–Chester disease and xanthomatosis, 895 intralesional excision
glucocerebroside, 893 chemical adjuvants, 91–92
hematopoietic diseases, 893 mechanical adjuvants, 91
Niemann–Pick disease, 895 thermal adjuvants, 92, 96, 97
Stress fracture marginal excision, 92, 98
bone scan, 850 radical excision
clinical symptoms and signs, 849 pelvic lesions, 93, 102, 103
CT and MRI, 850 shoulder girdle, 94, 104
definition, 849 spine, 94
diaphysis, second metatarsal bone, 853 wide excision, 92, 99, 100
epidemiology, 849 Surgical biopsy
etiology, 849 intraoperatory, 58
fracture callus, 853 paraffin-embedded sections, 58
994 Index

Surgical margins, 90, 91 MRI features, 960

Surgical staging system pathologic differential diagnosis, 960
malignant lesions, 86, 87 pathologic features, 960
MRI, 14 plain radiographs, 960
Synovial sarcoma, monophasic, 433 prognosis, 960
regional migratory and localized
osteoporosis, 959
T sites, 959
Telangiectatic osteosarcoma (TOS) treatment, 960
ABC, 27 Traumatic osteolysis
giant cell-rich osteosarcoma, 349, 350 clinical symptoms and signs, 963
sarcoma, 20 definition, 963
Thalassemia, 894 epidemiology, 963
Tibia, 515, 517, 518 etiology, 963
adamantinoma, 52, 517, 518 histologic features, 964
bowing, 28 image differential diagnosis, 964
chondroblastoma, 44 material removal, joint, 964, 965
diffuse osteosclerosis, 393 MRI, 964
enostoma, 111 pathologic differential diagnosis, 964
ES, 48 pubicosteolysis with destruction, 963, 965
FD, 759 pubis, 964, 965
fibrosarcoma, 434 radiographic features, 964
giant cell tumor, 7 sites, 963
hemangioma, 465 subchondral insufficiency fracture, hip, 963, 965
intracortical nidus, 138 synonyms, 963
JBC, 692–694 treatment, 964
low-grade central CHS, 311
MFD, 715, 717, 720
NOF, 29 U
OFD (see Osteofibrous dysplasia (OFD)) Undifferentiated high-grade pleomorphic sarcoma, 447
osteoid osteoma, 70 Undifferentiated pleomorphic sarcoma, 433
Paget’s disease, 34 Undifferentiated synovial sarcoma, 368
peripheral sclerosis, 6 Uric acid crystal storage disease, 903
telangiectatic osteosarcoma, 193
TOS. See Telangiectatic osteosarcoma (TOS)
Transient osteoporosis V
bone marrow edema, 959–961 Vascular monocytes, 347
clinical signs and symptoms, 959 Vascular space, 337, 486, 507, 510, 516, 960
definition, 959
etiology, 959
focal, 961 X
high fluid signal, proximal femur, 961 Xanthogranuloma. See Benign fibrous histiocytoma (BFH)
image differential diagnosis, 960 Xanthomatosis, 895