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Robert Klopfleisch Editor

Veterinary
Oncology
A Short Textbook
Veterinary Oncology
Robert Klopfleisch
Editor

Veterinary
Oncology
A Short Textbook
Editor
Robert Klopfleisch
Institut für Tierpathologie
Freie Universität Berlin
Berlin
Germany

ISBN 978-3-319-41122-4 ISBN 978-3-319-41124-8 (eBook)


DOI 10.1007/978-3-319-41124-8

Library of Congress Control Number: 2016954239

© Springer International Publishing Switzerland 2016


This work is subject to copyright. All rights are reserved by the Publisher, whether the
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v

Contents

1 Basic Principles of Carcinogenesis..................................................................................... 1


Robert Klopfleisch

2 Basic Principles of Cancer Diagnostics ........................................................................... 19


Robert Klopfleisch and Natali Bauer

3 Basic Principles of Cancer Therapy .................................................................................... 37


Mathias Brunnberg, Robert Klopfleisch,
and Melanie Wergin

4 Skin Tumors....................................................................................................................................... 59
Robert Klopfleisch

5 Mammary Tumors ......................................................................................................................... 99


Robert Klopfleisch

6 Hematopoietic Tumors .............................................................................................................. 109


Manfred Henrich

7 Urogenital Tract Tumors ........................................................................................................... 131


Stephanie Plog

8 Hepatobiliary Tumors................................................................................................................. 157


Angele Breithaupt

9 Alimentary Tumors ....................................................................................................................... 167


Angele Breithaupt

10 Tumors of the Exocrine Pancreas ........................................................................................ 199


Stephanie Plog

11 Skeletal Tumors .............................................................................................................................. 203


Robert Klopfleisch

12 Endocrine Tumors ......................................................................................................................... 217


Robert Klopfleisch

13 Nervous System Tumors ........................................................................................................... 245


Robert Klopfleisch

14 Respiratory System Tumors.................................................................................................... 255


Robert Klopfleisch

15 Vascular Tumors ............................................................................................................................. 267


Robert Klopfleisch
vi Contents

16 Ocular and Periocular Tumors .............................................................................................. 273


Robert Klopfleisch

17 Thymomas.......................................................................................................................................... 281
Robert Klopfleisch

18 Mesotheliomas ............................................................................................................................... 287


Robert Klopfleisch

19 Tumors of Mice, Rats, Rabbits, and Guinea Pigs ....................................................... 293


Olivia Kershaw

Index ...................................................................................................................................................................... 312


vii

Contributors

Editor Manfred Henrich, DECVP


Institut für Veterinär-Pathologie
Robert Klopfleisch, DACVP Justus-Liebig-Universität Giessen
Institut für Tierpathologie Giessen, Germany
Freie Universität Berlin
Berlin, Germany Olivia Kershaw, DECVP
Institut für Tierpathologie
Authors Freie Universität Berlin
Berlin, Germany
Natali Bauer
Abteilung klinische Stephanie Plog, DECVP
Laboratoriumsdiagnostik und IDEXX Laboratories Ltd.
klinische Pathophysiologie, Wetherby, United Kingdom
Klinikum Veterinärmedizin
Justus-Liebig-Universität Gießen Melanie Wergin, PhD
Giessen, Germany (Radiation-Oncology)
Abteilung Onkologie/Strahlentherapie
Angele Breithaupt, DiplECVP Medizinische Kleintierklinik,
Institut für Tierpathologie Ludwig-Maximilians-Universität München,
Freie Universität Berlin Munich, Germany
Berlin, Germany

Mathias Brunnberg, Dipl. ECVS,


MSc (Small Animal)
Klinik für kleine Haustiere
Freie Universität Berlin
Berlin, Germany
1 1

Basic Principles
of Carcinogenesis
Robert Klopfleisch

1.1 Hallmarks of Cancer – 2


1.2 Clonal Evolution Theory
Versus Cancer Stem Cells – 8

1.3 Carcinogens – 10

1.4 Clinically Relevant Tumor Effects – 10

Suggested Reading – 16

© Springer International Publishing Switzerland 2016


R. Klopfleisch (ed.), Veterinary Oncology, DOI 10.1007/978-3-319-41124-8_1
2 R. Klopfleisch

1.1 Hallmarks of Cancer repair systems. In addition, gene activity may also
1 be permanently influenced by epigenetic changes
As our knowledge of carcinogenesis advances, it is in the form of DNA methylation and histone
becoming increasingly evident that it is an over- modifications.
whelmingly complex process. Moreover, in many Regardless of whether mutations are caused
ways carcinogenesis does not seem to follow a by obligate carcinogens or impaired DNA repair
predictable pattern; often the process is quite mechanisms, most of the acquired mutations are
unique. But we can identify several universal fea- thought to be either lethal or irrelevant for the fit-
tures of this process, as presented in the hallmark ness of the affected tumor cell. Very few of the
model by Hanahan et al. (2011). According to this acquired mutations seem to be initial “driver
model, tumors are characterized by the following mutations” for tumor progression, invasion, and
main hallmarks of cancer: finally metastasis. The identification of driver
• Genome instability, mutation, and epigenetic genes and mutations is a major goal of cancer
change research. This research has been driven by the
• Sustained proliferation and evasion of growth search for “the one” mutation initiating and driv-
suppression ing carcinogenesis for any given tumor type. Just
• Evasion of apoptosis recently, however, global cancer genome analysis
• Deregulation of energy metabolism has shown that carcinogenesis is a complex
• Induction of angiogenesis process involving several mutations and changes
• Invasion and metastasis in multiple signaling cascades. Cancer genome
analysis has also shown that clinically and
z Genome Instability, Mutation, and morphologically similar tumors may have a
Epigenetic Change high  grade of inter-tumor genetic heterogeneity
The first step of carcinogenesis is the develop- (. Fig. 1.1). For instance, cancer genome sequenc-
ment of genetic aberrations in the potential ing of 510 human breast cancer tumor samples
tumor cells. These aberrations are mainly muta- found 30,626 somatic mutations, of which muta-
tions with actual changes in the nucleotide tions in only three genes, P53, PIK3CA, and
sequence of the cell. Mutations are caused either GATA3, were present in 10–45 % of all tumors. A
by carcinogenic noxa (described in Sect.  1.4) or similar variability in the “genome landscape” has
by other stimulants and mistakes in DNA replica- also been identified in other tumor types, and it is
tion. The latter become more frequent with now assumed that most somatic mutations are
acquired or inherited inefficiency of the DNA only present in <5 % of tumors of a specific type.

. Fig. 1.1 Inter- and intra-tumor genetic heterogeneity. Cancer genome analysis has revealed that tumors, which were
once classified phenotypically by their clinical behavior or pathomorphological appearance, might significantly differ in
their genotypes (inter-tumor genetic variability). Furthermore, genome analysis of tissue samples taken from one tumor
also revealed a high intra-tumor genetic variability
Chapter 1 · Basic Principles of Carcinogenesis
3 1
Cancer genome analysis has also found that develop all other hallmarks of cancer. Of the sev-
most tumors are additionally characterized by a eral genes involved in genome maintenance, so-
high grade of intra-tumor genetic heterogeneity. called caretakers or guardians of the genome, P53
This heterogeneity of tumor cells within one and the BRCA genes have been most intensely
tumor is the result of disruption of the pathways studied. For instance, BRCA1 is a major cause of
responsible for genomic stability like nucleotide the hereditary breast-ovarian cancer syndrome of
excision or double-strand break repair in tumor women, which impressively depicts the relevance
cells. This leads to a constant accumulation of of impaired DNA repair mechanisms on carcino-
random mutations in different tumor cells. Intra- genesis and genome instability. BRCA1 protein is
tumor heterogeneity is a challenge for diagnostics part of a DNA repair complex, which repairs the
in daily practice (. Fig. 1.1). For instance, a com- continuously occurring, multicausal DNA
parison of the genome of numerous biopsies from double-strand breaks and erroneous DNA inser-
different human clear cell renal carcinomas tions and deletions. Disabling BRCA1 mutations
showed that biopsies from different tumors may in women leads to an increased risk of up to 80 %
be more similar than biopsies from one tumor for developing breast cancer and a risk of up to
and that biopsies from one tumor can be very dis- 50 % for developing ovarian cancer. Unfortunately,
tinct from one another. These results raise ques- similar syndromes are suspected but yet not
tions of how to define the genetic status of tumors proven in nonhuman species.
for therapeutic classification. Due to the difficulties of directly observing or
Despite the overwhelming complexity and experimentally inducing the process in vivo, several
variability of the genetic changes associated with questions on the chronological sequence of
carcinogenesis, only few genes seem to be affected genomic alteration during carcinogenesis remain. It
by driver mutations. Deeper pan-tumor analysis is assumed that many tumors evolve from dysplasia
of the cancer genome project data shows that only to benign to malignant tumors by acquiring a set of
approximately 120–140 genes and their different more or less specific mutations. This hypothesis of a
mutations might be relevant for the initiation and gradual malignant transformation has been mainly
progress of carcinogenesis. Of these, approx. 70 developed based on the findings in human colorec-
genes have been identified as tumor suppressors, tal cancer and is summarized in the Vogelstein
which are “brakes of carcinogenesis,” and approx. (multistep carcinogenesis) model (. Fig. 1.2). In
50 genes are proto-oncogenes, which are “accelera- colorectal cancer a first “gatekeeping” mutation in
tors of carcinogenesis.” These driver mutations are the APC gene is considered to be the initial step in
present in variable combinations in different the carcinogenesis process with the develop-
tumors irrespective of histological types. However, ment of a small, slow-growing ( micro ) adenoma.
Vogelstein et  al. (2013) have proposed that all Subsequently, mutations of KRAS, CDC4, and
identified driver mutations have a major impact CIN are required for the development into a large,
on carcinogenesis by influencing a select few (no advanced adenoma. Finally, several mutations
more than 12) signaling pathways, which contrib- including p53, PTEN, BAX, SMAD4, and other
ute to three core cellular functions: cell fate, cell genes are required for transition into a metastatic
survival, and genome maintenance. If this is true, carcinoma. This process can be stretched over several
the complexity of tumor genomes can be reduced years. For colorectal cancer it has been shown to
to a target few and thus potentially treatable take 6 years to develop a small adenoma, another 17
genetic aberrations. years for an early carcinoma, and another 5 years
The theory that genomic instability is a major for the development of metastases.
driver of carcinogenesis is supported by the high The Vogelstein model may however not fully
number of documented driver mutations in genes reflect the carcinogenetic process of other tumor
involved in genome stability and the massive types, especially those which do not have observ-
changes in gene copy number and genome able benign forms, like pancreatic and prostate
sequence in most tumors. Defects in genome carcinomas. In these cases it could be hypothe-
maintenance and repair can therefore be consid- sized that a preceding accumulation of relevant
ered to be an important initial factor in carcino- mutations before the actual gatekeeper mutation
genesis, since they predispose pre- and neoplastic or a generally faster transformation process in a
cells to acquire genotypes that enable them to small number of initial tumor cells takes place.
4 R. Klopfleisch

1 Normal Micro- Small Large Early Advanced Metastasis


epithelium Adenoma Adenoma Adenoma Carcinoma carcinoma

Mutation: APC/ CDC4/CIN KRAS/BRAF PIK3CA/PTEN/ ? ?


b-catenin P53/Bax/Smad4/ (probably few) (probably few)
TGF-βRII
Time to
progression: ~ 6 years ~ 17 years ~ 2 years ~ 3 years

. Fig. 1.2 Vogelstein model of multistep carcinogenesis (Modified from Jones et al. 2008). In this model, originally
describing tumor progression of colorectal cancer, carcinogenesis is driven by a stepwise accumulation of mutations,
which can be stretched over years and decades. In other tumor types, the process can however be shorter without detect-
able benign tumor interstages

Autocrine stimulation

Ligand
receptor/oncogene activation

Receptor
Ligand-independent

Paracrine stimulation
Tumor cell

Cell
division

Inhitbitor

Neighbor cell

Hyperresponsiveness
(Receptor expression↑ or pathway inhibitors↓)

. Fig. 1.3 Mechanisms of increased proliferation stimulation in tumor cells

z Sustained Proliferation and Evasion of expression or loss of receptor pathway inhibi-


Growth Inhibition tors
Increased, sustained, and unregulated cell division • Ligand-independent, constitutive receptor
is another very basic hallmark of cancer, which is activation due to mutations
caused by internal and/or external growth signals
and evasion of growth inhibition. External and For instance, canine mast cell tumors display at
internal growth stimuli may be perceived by at least three of these mechanisms. A de novo expres-
least four mechanisms (. Fig. 1.3): sion of the pro-proliferative interleukin-2 receptor
• Autocrine stimulation by excessive synthesis of and its ligand interleukin-2 on neoplastic but not
growth factors by the tumor cells themselves on normal mast cells has been described, which
• Paracrine stimulation by tumor-induced constitutes an increased autocrine stimulus. In
growth factors secreted by stromal cells in the addition, approx. 30 % of most malignant canine
microenvironment mast cell tumors contain a tandem duplication in
• Hyperresponsiveness to normal levels of exon 11 of the KIT gene, a tyrosine kinase receptor.
growth hormones due to increased receptor This mutation induces a ligand-independent,
Chapter 1 · Basic Principles of Carcinogenesis
5 1
permanent activation of KIT signaling and hence papillomaviruses associate with and may induce
leads to increased proliferation and survival of degradation of RB to induce cell proliferation in
neoplastic canine mast cells. The switch from fibroblasts and squamous cell carcinomas. Genetic
external to autonomous internal growth stimula- or at least functional RB insufficiency is also sus-
tion due to downstream activation of signaling pected for diverse canine and feline tumors,
cascades seems to be a very common step during including hemangiosarcomas, but this is not fully
carcinogenesis. For instance, high-grade, malig- proven yet. In contrast to RB, p53-mediated growth
nant canine mast cell tumors show significantly inhibition is mainly based on intracellular signals
lower membrane-bound KIT receptor expression such as DNA damage or stress-associated meta-
than low-grade mast cell tumors. Similarly, meta- bolic changes. According to the type, intensity,
static canine mammary carcinomas usually have and persistence of these signals, p53 either tempo-
decreased or no estrogen and progesterone recep- rarily halts the cell cycle or triggers apoptosis.
tor expression compared to adenomas. Mutations of p53 have been identified in a small
The sustained proliferation of cancer cells is fraction of canine brain, skin, bone, and mam-
even more impressive, considering how intensely mary tumors. This identification has also been
guarded cell cycle progression is in normal cells. made in similar feline tumors, although it is much
Tumor cells develop mechanisms which allow for more rare. The relevance of both proteins should
evasion of growth inhibition programs that nor- however not be overstated, since several mecha-
mally inhibit unregulated cell proliferation. These nisms functionally redundant to p53 and RB seem
programs are normally dependent on central to be present in cells and may compensate for loss
tumor suppressors that function in diverse ways to of their function.
suppress cell growth and proliferation: Cell-to-cell contact is another important
• Specific and direct negative-feedback mecha- mechanism to preserve tissue homeostasis by
nisms of proliferative signaling cascades growth inhibition. This contact inhibition is lost in
• Central tumor suppressors (“guardians”) of some cancer types. A prototypical example is the
cell cycle progression E-cadherin-/beta-catenin-mediated contact inhibi-
• Contact inhibition by adjacent cells tion. When E-cadherin on an epithelial cell is
bound to its counterpart on the neighboring cell,
For instance, nonneoplastic cells possess sev- its cytoplasmic tail binds beta-catenin. Loss of
eral negative-feedback mechanisms to attenuate pro- E-cadherin expression frees beta-catenin. Beta-
proliferative signaling. A prominent example is the catenin then travels to the nucleus and activates
PTEN phosphatase, which counteracts PI3-kinase expression of several pro-proliferative pathways.
by degrading its product, phosphatidylinositol tri- Aberrant E-cadherin expression is a typical find-
sphosphate (PIP3). Loss of PTEN expression due to ing in malignant canine mammary, prostate, and
mutations promotes proliferation and carcinogen- squamous cell carcinomas. Another mechanism
esis. Accordingly, loss of PTEN has been identified currently in focus is the merlin-cadherin-
as a prognostic factor for canine and feline mam- transmembrane growth factor receptor complex.
mary tumors, which is correlated with an increased This complex strengthens the cadherin-mediated
risk for distant metastases, tumor recurrence, and cell-to-cell attachments, sequesters growth factor
shorter survival. receptors, and thereby restricts their growth sig-
Two prototypical tumor suppressors are usu- nals to the cell limits. Loss of the complex loosens
ally used to explain the principle of central the cell adhesion, increases growth factor signal-
guardians of cell cycle progression. The retinoblas- ing, and induces cell proliferation.
toma-associated protein (RB) plays a central role
in the integration of mostly extracellular growth z Apoptosis Evasion
stimuli. Phosphorylation of RB by diverse cyclin- As mentioned before, DNA damage, overwhelm-
dependent kinases (CDKs) enables RB to release ing proliferation signaling, increased cell stress,
the transcription factor E2F and to progress from and metabolic imbalances can lead either to a
the G1 phase to the S phase of the cell cycle. temporary halt of cell proliferation or induction
Genetic defects of RB and/or functional changes of programmed cell death by apoptosis. In tumor
induced by viral proteins are common features of cells, this mechanism is obviously disturbed,
human tumor cells. Similarly, canine and feline since  genomic instability, metabolic stress, and
6 R. Klopfleisch

excessive proliferation are hallmarks of cancer. z Induction of Angiogenesis


1 Two methods of apoptosis induction exist: the Despite their predominant reliance on anaerobic
extrinsic method, induced by extracellular sig- glycolysis (“Warburg effect”), tumors also require
naling by immune cells, and the intrinsic method, nutrients and oxygen supply and the removal of
induced by several intracellular signals like DNA metabolic end products and carbon dioxide. This is
or mitochondrial damage. Disturbance of the only possible if the tumor cell is in proximity to a
intrinsic apoptosis pathway is considered more functional vessel not further than 100–200  μm
relevant for carcinogenesis. P53 and the anti- away. Tumors therefore have to be able to induce
apoptotic Bcl-2 protein family are the most angiogenesis to survive and grow. In normal tissues,
intensely analyzed apoptosis-associated proteins the microvasculature is largely quiescent, and
with influence on carcinogenesis. Bcl-2 proteins angiogenesis is “switched on” only during wound
inhibit apoptosis by binding and suppressing the healing. In contrast, tumor masses are usually char-
proapoptotic proteins Bax and Bak. Increased acterized by highly active angiogenesis. The induc-
Bcl-2 protein expression has been found in tion of angiogenesis is based on the secretion of
canine mast cell tumors, hemangiosarcomas and proangiogenic growth factors and inhibition of
melanomas, and in feline lymphomas and skin anti-angiogenic pathways. The best analyzed proto-
tumors. In addition, loss of p53 expression or its types of proangiogenic factors are vascular endo-
function is also associated with a failure to tran- thelial growth factor (VEGF) and fibroblast growth
scribe the detection of DNA damage into factor (FGF). VEGF is either secreted by the tumor
apoptotic death. cells or is freed from the extracellular matrix-bound
form by tumor-associated activation of matrix
z Deregulation of Energy Metabolism metalloproteases. In addition, bone marrow-
The sustained and massive proliferation of tumor derived macrophages, neutrophils, mast cells, and
cells also represents a challenge for energy progenitor cells may infiltrate the tumor margins;
metabolism. Normal cells satisfy their energy the associated peritumoral inflammation also sup-
demand under aerobic conditions by mitochon- ports the induction of angiogenesis. VEGF expres-
drial oxidative phosphorylation to produce sion levels within the tumor mass and VEGF serum
ATP. Generating ATP under anaerobic glycolysis levels are also positively correlated with increased
has only 1/18th the efficiency of aerobic glycolysis angiogenesis and occasionally with increased
and produces large amounts of lactate under malignancy in diverse canine tumor types.
hypoxic conditions. Most cancer cells as well as
normal proliferating cells nevertheless use anaer-
obic glycolysis as their major pathway to obtain z Invasion and Metastasis
ATP regardless of the availability of oxygen, a Metastasis is defined as a spread of cancer from
phenomenon termed aerobic glycolysis or “the one organ or organ part to another organ or organ
Warburg effect.” Initially it was thought that can- part. Dissemination of cancer cells throughout
cer cells have a mitochondrial defect and thus fail the body occurs through one or more of three
to use aerobic respiration, an idea that has been routes of metastasis:
omitted in recent years. It is now hypothesized • Lymphogenic spread via lymph vessels mainly
that cancer metabolism focuses on facilitating to lymph nodes
biomass generation rather than efficient ATP pro- • Hematogenic spread via blood vessels to dis-
duction. In addition, efficient ATP production is tant organs
only required when resources are scarce for the • Transcoelomic spread via direct contact to
single cell or the complete organism. Local energy other serosal surfaces in the abdominal cavity
deficiency is usually not a problem for well-vas-
cularized tumors. In any case tumors lose every Lymphogenic dissemination of cancer cells
aspect of their “sense of social responsibility” in includes the invasion of lymph vessels and the
terms of energy saving for the sake of the rest of transport in the lymphatic system to regional
the body. Notably, tumors have been shown to lymph nodes and to distant organs. It is usually
develop subclonal cell populations, which utilize combined with hematogenic spread. For hemato-
the lactate produced by aerobic glycolysis as their genic spread, tumor cells have to invade adjacent
main energy source. blood vessels to gain access to the circulation and
Chapter 1 · Basic Principles of Carcinogenesis
7 1
are then transported with the bloodstream to described above). In contrast, proteins necessary
distant sites. Only a few tumors like canine for invasion and migration through the ECM are
osteosarcomas seem to metastasize exclusively upregulated. These include factors like CD44 and
hematogenously and usually do not develop focal adhesion kinase (FAK) for cell matrix
lymph node metastases. Pancreatic and ovarian interaction as well as various matrix metallopro-
cancer and mesotheliomas often spread by trans- teinases for ECM digestion and loosening.
coelomic metastasis mostly in combination with Neoplastic epithelial cell separation from neigh-
the two other routes of metastasis. Transcoelomic boring cells and ECM invasion are often associ-
metastasis includes breaching of the serosal sur- ated with a change in neoplastic epithelial cell
face and direct implantation of tumor cells on the shape from typical polygonal to more mesenchy-
serosal surface of adjacent organs. mal spindloid, which is called epithelial-mesen-
Distant metastasis, which is based on hemato- chymal transition (EMT). It is now accepted that
genic and often on preceding lymphogenic spread, this permanent or intermittent EMT is associated
can be described as a metastatic cascade, which is with or even a prerequisite for epithelial cells to
composed of five major steps (. Fig. 1.4): separate, invade, resist apoptosis, and metastasize.
• Loosening of contact to adjacent cells Several transcription factors are involved and
• Invasion of the surrounding extracellular used as markers of EMT, including Snail, Slug, and
matrix (ECM) and vessels, often associated Twist. It is currently unclear, if mesenchymal sar-
with epithelial-mesenchymal transition (EMT) coma cells are experiencing a similar transition
• Survival in the bloodstream as circulating but without recognizable changes in their shape
tumor cells (CTC) or if they use different mechanisms. The invasive
• Extravasation and formation of micrometastasis process seems to also be influenced by the sur-
• Development of a macro-metastasis rounding stromal stem cells and macrophages,
which may contribute important factors like
The first step of the metastatic cascade is the matrix metalloproteinases.
separation of a potentially metastatic cell from the After invasion of the vasculature, tumor cells
adjacent cells. This is often associated with a are transported individually or in small clusters by
downregulation of cell adhesion proteins, such as the bloodstream and referred to as circulating
E-cadherin and loss of cell-contact inhibition (as tumor cells (CTC). There is much effort to develop

Serosal surfaces
Primary tumor

Epithelial-mesenchymal
Transcoelomic/-serosal transition (EMT)
metastasis
Separation
ECM invasion

Lymph vessel Blood vessel


Circulating tumor
Lymph node metastasis cell (CTC)
Evtravasation

Lymph node Micro-metastasis

(Dormancy)
Adaption / Proliferation

Macro-Metastasis

. Fig. 1.4 The metastatic cascade and forms of metastatic spread


8 R. Klopfleisch

“liquid biopsy” methods for detection of CTC in invasion by binding to integrins commonly pres-
1 blood samples of patients with potentially meta- ent on cancer cells.
static tumors, which would be less invasive and Establishment of micrometastases is the next
more informative about the actual disease status step after extravasation of CTC. Micrometastases are
than tissue biopsies of the primary tumor. First much more common than the clinically detectable
studies indicate that canine mammary tumor CTC macro-metastases. They are very small groups of
can be detected in the peripheral blood using the often dormant or only slowly growing tumor cells,
markers CLDN7, CRYAB, ATP8B1, and EGFR in which are not detectable by common clinical
the peripheral blood of dogs with canine mammary imaging technologies. In the next step, micrometa-
tumors. Their presence is specifically and sensi- static tumor cells have to adapt to the tissue
tively correlated with the development of meta- microenvironment at the new location to develop
static disease in dogs. Although primary tumors into macro-metastases, a process called colonization.
may shed thousands or millions of tumor cells into Colonization seems to be very difficult for tumor
the circulation, they are usually present in very low cells in many respects beyond physical dissemina-
numbers of <10 CTC per milliliter blood and thus tion. It is assumed that most metastatic tumors dis-
per millions of peripheral blood leukocytes. In seminate millions of tumor cells into the circulation,
addition, not all the circulating tumor cells are of of which only a fraction is able to establish microme-
clinical relevance. It is assumed that <0.1 % of CTC tastases. Most of these micrometastases however stay
are able to establish macro-metastatic disease, and in a state of dormancy. Dormancy is defined as a con-
their total number in the blood is not necessarily dition in which cancer cells do not divide or prolifer-
correlated with the development of metastasis. ate; during dormancy they stay in the G0 or G1 stage
The question of why and where CTC extrava- of the cell cycle and wait for appropriate, mostly
sate and form metastases is still largely unknown. It unknown, signals to proliferate again. Dormant can-
is nevertheless clear that metastatic tumors of dif- cer cells as micrometastases or in the form of mini-
ferent cellular origin have a typical organ-specific mal residual disease (MRD) in the location of the
metastasis pattern. For instance, canine mammary resected primary tumor are the major cause of tumor
tumors and osteosarcomas most commonly relapse. It is known that dormancy can be caused by
metastasize to the lung, while feline pulmonary either inability to activate angiogenesis, nutrient
carcinomas often metastasize to the distal phalan- starvation, systemic factors shed by the primary
ges. On the other hand, certain organs like the tumor, antigrowth signals embedded in the tissue
heart or the skin are only rarely affected by metas- extracellular matrix, or tumor-suppressing actions of
tases. The organ-specific metastasis pattern is the immune system. The elucidation of the mecha-
explained with Paget’s rather general “seed and nisms of micrometastatic and dormant tumor cells
soil” theory of metastasis. It says that a tumor cell to overcome these obstacles is of major importance
(seed) will establish macro-metastases or even for the development of specific therapeutic modali-
micrometastases in a suitable organ (soil) only. ties for long-term treatment of metastatic tumors.
The factors that make an organ or tissue suitable
for organ-specific metastasis are still largely
unknown, despite intense research effort. The 1.2 Clonal Evolution Theory
identification of these factors is however of utmost Versus Cancer Stem Cells
interest, since they would allow for the develop-
ment of targeted therapies to prevent metastatic Initially, carcinogenesis was thought to be an evolu-
disease. So far, research on bone-specific metasta- tionary process that is driven by stepwise, somatic
sis has progressed furthest due to its relevance to cell mutations with sequential, subclonal selection,
human medicine. There are diverse mechanisms similar to Darwinian natural selection within spe-
and factors involved in tumor spread to and colo- cies. This clonal evolution model by Nowell (1976)
nization of the bone microenvironment. Secretion describes carcinogenesis using a cancer clonal evo-
of the chemokines CXCL12, CXCL13, etc., and the lution model that takes place within a tissue ecosys-
receptor activator of nuclear factor-kB ligand tem, which usually tightly suppresses clonal
(RANKL) by osteoblasts and bone marrow stromal expansion of single cells (. Fig. 1.5). This tradi-
cells seem to be involved and attract cancer cells to tional model of clonal evolution suggests that a
the bone marrow. In addition, certain bone sialo- series of clonal expansions and competitions leads
proteins and collagens facilitate bone marrow to a dominance of one or few clones within the neo-
Chapter 1 · Basic Principles of Carcinogenesis
9 1

Cancer stem cell (CSC) Cancer stem cell (CSC)


Clonal evolution model classic, unidirectional model bidirectional plasticity model

Somatic cell Adult stem cell? Induced pluripotent Adult stem cell? Induced pluripotent
cell (ips)? Somatic cell (?) cell (ips) ? Somatic cell (?)

Mutations

Selection
pressure

Mutations Diverse non-CSC subclones Diverse CSC/non-CSC subclones

Clones 1Clone 2 Clone 3 Clone 4 CSC CSC


with self-renewal with self-renewal
and prolonged and prolonged
survival survival

. Fig. 1.5 Three main models of tumor progression

plasm. All of these clones are able to contribute to stem cell (CSC) model (. Fig. 1.5). The classical
progression. Carcinogenesis in this model involves CSC concept assumes that tumor proliferation,
the sequential accumulation of mutations and selec- similar to nonneoplastic tissue proliferation, is
tion of the fittest variants, i.e., tumor clones with the driven by the small subset of stem cells. CSC have
most profitable mutations in the current environ- the ability to divide asymmetrically, allowing self-
ment. These clones evolve by the interaction of renewal and differentiation into non-CSC prog-
advantageous “driver” mutations including the sub- eny. The progeny then lack tumor-initiating
group of “mutator” mutations, i.e., mutations capabilities. There are three main hypotheses on
increasing genomic instability, per se neutral “pas- the origin of CSC, which are still under debate:
senger” mutations, and disadvantageous or “fatal” 1. Malignant transformation of normal adult
mutations, respectively. This process leads to a stem cells into CSC
unique cancer, which is built of impermanent sub- 2. Dedifferentiation of mature cancer cells into
clones of cancer cells. The time frame of a clonal CSC
evolution to the level of metastasis can be anywhere 3. Induction of pluripotent cancer cells (iPS)
from a few months to decades. What this time
frame will be depends on the level of genetic insta- The first hypothesis of a transformation of
bility in tumor cells and epigenetic changes, which adult stem cells into CSC is based on the obser-
contribute to the evolutionary process much faster vation that CSC have a self-renewal capacity
than genetic changes do. There is an ongoing debate similar to normal stem cells. In addition, trans-
over whether malignant clones evolve gradually formation into a malignant tumor cell may take
through a sequence of genetic alterations and clonal several years, a time span that is only survived
expansions or if a few highly relevant punctuated by adult stem cells. The second hypothesis of
genetic alterations by an acute single insult directly CSC development by dedifferentiation of
and indirectly dramatically change the genome. mature tumor cells into CSC is based on the
The original clonal evolution model proposed recent observation of CSC plasticity, which is
that basically all tumor cells contribute to the described in the paragraph below. Finally, the
process of clonal evolution by acquiring muta- third hypothesis on the origin of CSC is related
tions, by cell division, and by propagation of this to the recent identification of induced pluripo-
mutation to its progeny. This idea has been chal- tent stem cells (iPS). iPS are normal somatic
lenged and is now complemented by the cancer cells which are transformed into CSC by
10 R. Klopfleisch

endogenous reprogramming, including the Studies show that there is an extended CSC plastic-
1 activation of at least four transcriptional factors ity within a tumor, which includes a dedifferentia-
known as the “Yamanaka factors”: OCT3/4, tion of non-CSC to CSC and vice versa. According
Sox2, c-Myc, and Klf4. How the Yamanaka fac- to these observations, stemness seems to be an
tors are activated is unclear. acquired and losable, temporary functional state
The classical CSC concept of tumor progression driven by accumulation of mutations and evolu-
is seen as a unidimensional and unidirectional hierar- tionary pressures rather than a feature of a fixed
chy with CSC at the top. It also implies that the bulk and static tumor cell population. The CSC plastic-
of the tumor consists of the differentiated progeny of ity concept of phenotypic reversion therefore
the CSC, which are just passengers but not drivers of fuses the CSC model with the clonal evolution
tumor growth and therefore not the primary target model and implies that an exclusive therapeutic
for treatment. The tumor-initiating abilities of CSC focus on CSC, as is currently often proposed, may
are currently tested by xenotransplantation of tumor fail due to the transition of non-CSC to CSC
cells into immunodeficient mice, which are consid- under selective therapeutic pressure.
ered the gold standard for CSC identification.
According to this model, only CSCs are able to initi-
ate new tumors in the recipient; the bulk of more 1.3 Carcinogens
differentiated tumor cells are not able to do this.
Several CSC markers including CD133, Nanog, A carcinogen is any substance, radiation, or
Oct3/4, ALDH, CD44, and many more have been microbial organism, which is directly involved in
identified in the CSC of animal assays and are now the initiation of cancer. This is usually due to its
used as antibody-based surrogate markers. The ability to directly damage the genome or to indi-
actual frequency of CSC in the blood of cancer patients rectly influence the genome by interruption of
is still under debate. Current xenotransplantation cellular metabolic processes which then induce
studies found CSC to be rare, with a share of only genetic or epigenetic changes. Tables 1.1 and 1.2
<2 % of all tumor cells. This number may however list and summarize some common examples of
underestimate the number of CSC cells due to sub- the 116 group 1 carcinogens with proven carci-
stantial skepticism about the value of xenotransplan- nogenic effect for humans as defined by the
tation studies. It is argued that xenotransplantation International Agency for Research on Cancer
may select only CSC that are able to grow in a mouse (IARC, 7 http://monographs.iarc.fr/). Their car-
and not necessarily all CSC that are able to contrib- cinogenic effect has not been proven for all
ute to tumor progression in other microenviron- domestic animals but is most likely transferable.
ments in the actual tumor host. Table 1.3 summarizes the most important bio-
The recent progress in cancer genome logic carcinogens for domestic animals.
sequencing has revealed high inter-tumor hetero-
geneity, i.e., heterogeneity between tumors of dif-
ferent individuals, and intra-tumor heterogeneity, 1.4 Clinically Relevant Tumor
i.e., heterogeneity between tumor cells of the same Effects
tumor. The tremendous intra-tumor heterogeneity
has especially challenged the unidimensional,
unidirectional, and hierarchical structure of the z Mass Effect of the Primary Tumor and
classical CSC model with one prototypic stem cell Metastasis
at the top. It is now assumed that CSC may be the The term “mass effect” describes the increasing
actual cell accumulating somatic mutations and space occupation of the growing tumor or its
thus underlying a clonal evolution. This implies a metastases. Constant tumor-associated compres-
multidimensional hierarchical structure with sev- sion on neighboring structures leads to atrophy of
eral different tumor subclones with different CSC the adjacent cells and functional disturbances of
at the top (. Fig. 1.5). adjacent nerves. For example, brain tumors inevi-
The unidirectional character of the CSC model tably exert a fatal mass on surrounding tissues due
cascade with an asymmetrical CSC division to the restricted space in the cranial cavity, caus-
resulting in a terminally differentiated non-CSC ing increased intracranial pressure and brain
daughter cell has also been challenged recently. damage.
. Table 1.1 Common group 1 carcinogens for human as defined by the International Agency for Research on Cancer (IARC): chemicals, metals, arsenic, dusts, and fibers

Tissues affected Carcinogenic mechanism

Chemicals

Aromatic amines (incl. 4-aminobiphenyl, benzidine, Urinary bladder Direct genotoxicity


2-naphthylamine, anilines)

Polycyclic aromatic hydrocarbons (PAHs) (incl. benzo[a]pyrene) Lung, skin, urinary bladder Direct genotoxicity

Aflatoxins Liver Direct genotoxicity

Benzene Hemato-lymphatic organs Direct genotoxicity

1,3-Butadiene Hemato-lymphatic organs Direct genotoxicity


Chapter 1 · Basic Principles of Carcinogenesis

Dioxin Soft tissue, lung Direct genotoxicity

Formaldehyde Nasopharynx, hemato-lymphatic Direct genotoxicity

Sulfur mustard Lung Direct genotoxicity

Vinyl chloride Liver, vessels Direct genotoxicity

Arsenic compounds Lung, skin, urinary bladder Oxidative DNA damage, epigenetic effects

Metals

Beryllium and beryllium compounds Lung Chromosome aberrations, aneuploidy, DNA damage

Cadmium and cadmium compounds Lung DNA repair inhibition, genomic instability

Chromium (VI) compounds Lung Direct DNA damage, genomic instability, aneuploidy

Nickel compounds Lung, nasal cavity, and paranasal DNA damage, chromosome aberrations, genomic instability, DNA
sinuses repair inhibition, epigenetic alteration, histone modification

Fibers and dusts


11

Asbestos Lung, pleura, larynx, ovary Macrophage activation, inflammation, generation of reactive oxygen
and nitrogen species, genotoxicity, aneuploidy, epigenetic alteration,
activation of signaling pathways

Erionite Pleural scrosa Genotoxicity

Silica dust, crystalline in the form of quartz or cristobalite Lung Macrophage activation, persistent inflammation
1
1
12
R. Klopfleisch

. Table 1.2 Common group 1 carcinogens as defined by the (IARC): pharmaceuticals

Tissues affected Carcinogenic mechanism

Pharmaceutica

Diethylstilbestrol Breast Estrogen receptor mediated, genotoxicity, epigenetic


change

Estrogen/progestagen contraceptives Breast, cervix, liver, endometrium Estrogen receptor mediated, genotoxicity

Tamoxifen Endometrium Estrogen receptor-mediated events, genotoxicity

Alkylating agents (busulfan, chlorambucil, Hemato-lymphatic organs Genotoxicity


cyclophosphamide, lomustine, treosulfan)

Chlornaphazine Urinary bladder Genotoxicity

Cyclosporine Hemato-lymphatic organs, skin, diverse Immunosuppression

Phenacetin Renal pelvis, ureter Genotoxicity, cell proliferation


Chapter 1 · Basic Principles of Carcinogenesis

. Table 1.3 Microbial agents with proven carcinogenic effect in domestic animals

Tissues affected Carcinogenic mechanism

Papillomaviruses (several species) Diverse, mainly skin and gastrointestinal tract Viral proteins induce proliferation, immune evasion

Retroviruses (feline/bovine leukemia virus (FeLV, Hemato-lymphatic organs, nasal mucosa, type II Insertion-based activation/inactivation of host cell oncogenes/
BLV), jaagsiekte sheep retrovirus (JSRV), enzootic pneumocytes tumor suppressor genes, introduction of new oncogenes
nasal tumor virus 1 (ENTV1))

Spirocerca lupi (nematode) Esophageal soft tissue (dog) Chronic inflammation suspected
1 13
1
14

. Table 1.4 Common tumor-specific paraneoplastic syndromes in veterinary oncology

Paraneoplastic syndrome Tumor type Carcinogenic Mechanism

Acromegaly Somatotrophic pituitary tumors Growth hormone secretion-induced IGF-1


secretion
R. Klopfleisch

Erythrocytosis Renal tumors, lymphoma Secretion of erythropoietin or HIF-1

Gastrointestinal ulceration Mast cell tumor, gastrinoma Hyperhistaminemia, hypergastrinemia

Glomerulonephritis/nephrotic syndrome Leukemia, myeloma Mainly antibody secretion

Hyperadrenocorticism Pituitary corticotropic tumors, adrenocortical tumors Secretion of ACTH, cortisol

Hyperaldosteronism Adrenocortical tumors Aldosterone secretion

Hypercalcemia of malignancy Lymphoma, myeloma, anal sac apocrine gland Hyperparathyroidism, secretion of
adenocarcinoma, parathyroid tumors parathormone-related peptide, bone lysis, diverse
cytokines

Hyperestrogenism Ovarian tumors, Sertoli cell testicular tumors Estrogen secretion

Hypergammaglobulinemia Myeloma, lymphoma Antibody secretion

Hyperglycemia Glucagonoma, cortisol-secreting tumors Glucagon secretion, cortisol-induced peripheral


insulin resistance

Hyperthyroidism Thyroid tumors Thyroid hormone secretion

Hypertrophic osteopathy Primary lung tumors, urinary bladder rhabdomyosarcoma, Unknown


esophageal tumors

Hypoglycemia Insulinoma, hepatic/salivary tumors, lymphoma Insulin secretion, tumor utilization of glucose,
decreased hepatic glycogenolysis or
gluconeogenesis, IGF-1/IGF-2 secretion

Hypothyroidism Thyroid tumors Thyroid gland destruction


Thrombocytopenia Hemangiosarcoma, lymphoma Platelet destruction/consumption, decreased
platelet production

Myasthenia gravis Thymoma, lymphoma, Antibodies against nicotinic acetylcholine


receptors

Necrolytic migratory erythema/superficial necrolytic Glucagonoma Exact mechanisms unclear, glucagon secretion
dermatitis

Nodular dermatofibrosis Renal cystadenoma/cystadenocarcinoma, uterine tumors Unknown

Peripheral neuropathy Lung tumors, leiomyosarcoma, multiple myeloma, lymphoma, Hypoglycemia, unknown
insulinoma

Thymoma-associated exfoliative dermatitis Thymoma Unknown

ACTH adrenocorticotropic hormone, IGF insulin-like growth factor, HIF hypoxia-induced factor
Chapter 1 · Basic Principles of Carcinogenesis
1 15
16 R. Klopfleisch

z Paraneoplastic Syndromes influence the release of renal erythropoietin, or


1 Paraneoplastic syndromes (PNS) are tumor- reduce the life-span of erythrocytes. Mainly
associated clinical signs, which are not the con- hemangiosarcomas, but also gastrointestinal
sequence of the mass effect of the primary tumor tract tumors, may cause severe acute or mild
or its metastases. PNS are usually reversible and chronic hemorrhage and potentially microcytic
successful treatment leads to alleviation of their and hypochromic anemia. Hemangiosarcomas
clinical signs. Knowledge of paraneoplastic signs are also the cause for microangiopathic hemolytic
is often helpful in tumor diagnosis, since they are anemia, which involves shearing of erythrocytes
often the first clinical sign, and for many tumors, at fibrin deposition and/or damaged endothe-
like endocrine tumors, they can be more relevant lium. Another more uncommon cause of tumor-
than the local mass effect of an otherwise non- associated anemia is bone marrow suppression
problematic tumor. PNS are usually mediated by due to hyperestrogenism. Sertoli cell testicular
humoral factors. The more general paraneoplas- tumors and granulosa cell ovarian tumors in
tic syndromes like cancer cachexia, hyperther- dogs are the most common cause of tumor-
mia, and anemia and numerous major derived hyperestrogenism.
tumor-specific paraneoplastic syndromes are
listed in Table 1.4. z Hyperthermia (Fever)
The incidence of fever as a PNS in veterinary
z Cancer Cachexia medicine is unknown but is a moderately com-
Cancer cachexia is a very common paraneoplastic mon paraneoplastic syndrome in human patients.
clinical sign in many cancer patients. It is a multi- Cancer-associated hyperthermia is caused by
factorial and often irreversible syndrome of loss of excess secretion of the cytokines IL-1, IL-6, TNF-
skeletal muscle (sarcopenia) and body fat. α, and prostaglandins. Cancer-associated fever is
Cachexia is assumed to be the cause of death in up nevertheless often caused by cancer-associated
to 20 % of human cancer patients. Comparable infections rather than the cancer itself.
epidemiologic data are lacking for veterinary
oncology. The pathogenesis of tumor cachexia is z Cancer-Type-Specific Paraneoplastic
still not fully elucidated. Several mechanisms are Syndromes
involved in the increased energy wasting in cancer Common tumor-specific paraneoplastic syn-
patients, including changes in the mitochondrial dromes are listed in Table 1.4.
metabolism, lipolysis in adipocytes and an
increased fraction of thermogenically active
brown adipose tissue, chemokine-associated (IL- Suggested Reading
1, IL-6, TNFα) metabolic changes and upregula-
tion of the ubiquitin-proteasome pathway in Argiles JM, Busquets S, Stemmler B, Lopez-Soriano FJ
skeletal muscle metabolism, systemic inflamma- (2014) Cancer cachexia: understanding the molecular
tion, and many more. basis. Nature reviews. Cancer 14:754–762
Bergman PJ (2012) Paraneoplastic hypercalcemia. Top
Companion Anim Med 27:156–158
z Anemia Cancer Genome Atlas Network (2012a) Comprehensive
Anemia is also a very common PNS in veterinary molecular portraits of human breast tumours. Nature
oncology. There is a long list of potential causes 490(7418):61–70
for tumor-associated anemia including anemia of Cancer Genome Atlas Network (2012b) Comprehensive
genomic characterization of squamous cell lung can-
chronic disease, acute and chronic hemorrhage,
cers. Nature 489(7417):519–525
or microangiopathic hemolytic anemia. Anemia Cancer Genome Atlas Network (2012c) Comprehensive
of chronic disease is mainly caused by chronic molecular characterization of human colon and rectal
increase in IL-6-induced hepcidin serum levels, cancer. Nature 487(7407):330–337
which negatively influence iron metabolism. In Cancer Genome Atlas Network, Weinstein JN, Collisson EA,
Mills GB, Shaw KR, Ozenberger BA, Ellrott K, Shmulev-
addition, mainly inflammatory cytokines but
ich I, Sander C, Stuart JM (2013) The Cancer Genome
also many hormones secreted by endocrine Atlas Pan-Cancer analysis project. Nat Genet
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19 2

Basic Principles
of Cancer Diagnostics
Robert Klopfleisch and Natali Bauer

2.1 Diagnostic Cancer Imaging – 20


2.1.1 Ultrasound – 20
2.1.2 Radiography – 20
2.1.3 Computed Tomography – 21
2.1.4 Magnetic Resonance Imaging – 21

2.2 Basic Principles of Cancer Cytology – 21


2.2.1 Cytology Technique: General Considerations – 22
2.2.2 Cytology Technique: Specific Methods – 22
2.2.3 Analysis and Diagnosis of Cytological Specimens – 26

2.3 Basic Principles of Cancer Biopsies – 26


2.3.1 Biopsy Technique: General Considerations – 28
2.3.2 Biopsy Technique: Specific Methods – 28
2.3.3 Biopsy-Associated Risks – 30
2.3.4 Histopathologic Analysis and Diagnosis
of Tissue Biopsies – 30
2.3.5 Immunohistochemistry as an Additional
Diagnostic Tool – 30

© Springer International Publishing Switzerland 2016


R. Klopfleisch (ed.), Veterinary Oncology, DOI 10.1007/978-3-319-41124-8_2
20 R. Klopfleisch and N. Bauer

2.1 Diagnostic Cancer Imaging bone, almost all the acoustic energy is reflected
back toward the transducer. This means the
Diagnostic cancer imaging refers to all noninva- structures behind the border (between, e.g., the
2 sive techniques used to visualize internal tumors bone and muscle) cannot be seen.
and their metastases. It is an essential prerequisite Compared with the other diagnostic imaging
for initial diagnosis, for generating a treatment modalities, ultrasound has the advantages of fast
plan, and for evaluating the success of treatment. real-time imaging, a comparably low cost, and the
The modalities most commonly used in veteri- lack of x-ray exposure. Disadvantages are limited
nary oncology are ultrasound, x-ray radiography, imaging of the bone and air-filled spaces, compa-
computed tomography (CT), and magnetic reso- rably low image resolution, and restricted body
nance imaging (MRI). Each method has its advan- penetration (. Table 2.1). Ultrasound is com-
tages and disadvantages and is of value for specific monly used as a first-line diagnostic tool for the
diagnostic questions (. Table 2.1). evaluation of body cavity effusion and abdominal
tumors.

2.1.1 Ultrasound
2.1.2 Radiography
Diagnostic ultrasound uses ultrasound waves for
visualization of tumors in internal organs. It is Radiography is still the predominant first-line
based on the reflection of sound waves from the imaging modality for many questions in veteri-
border between two tissues with different acoustic nary oncology. It is often used as a comparatively
impedance. The acoustic impedance depends on inexpensive and easily accessible screening test,
the physical density of the tissue and the achiev- which can be supplemented with the higher reso-
able velocity of the sound waves sent from the lution of CT or MRI, if necessary. Radiography
transducer into the tissue. The higher the differ- uses electromagnetic x-rays to visualize internal
ence in acoustic impedance, the more sound is body structures based on variations in their opac-
reflected at the border between two tissues, and ity. Opacity is the ability of a structure to absorb
the more sound is detected by the transducer. If x-rays. A photographic film or a digital detector
the sound wave hits a gas-filled space or a solid captures the nonabsorbed x-rays after passage

. Table 2.1 Advantages and disadvantages of commonly used imaging methods in veterinary oncology

Imaging method Advantage Disadvantage

Ultrasound Low cost Often limited image resolution


Fast Difficult to analyze gas-filled body cavities
High sensitivity Limited use for bone imaging
Real-time results Limited penetration
Fast and inexpensive abdominal Extensive training required
imaging

Radiography Low cost Superimposition of overlying structures


Excellent bone imaging Low soft tissue detail
Easy global screening, especially for Low sensitivity for small tumors
small animals X-ray exposure
Standard method, relatively easy to read

Computed No superimposition of overlying High cost


tomography (CT) structures High x-ray exposure
High sensitivity for small tumors General anesthesia required
Better bone imaging than MRI Extensive training required

Magnetic resonance Excellent (soft) tissue differentiation High cost


imaging (MRI) High resolution General anesthesia required
Excellent brain imaging Extensive training required
Chapter 2 · Basic Principles of Cancer Diagnostics
21 2
through the body. The more a structure absorbs radiation exposure. However, the use of incredibly
an x-ray, the more radiopaque (white) the struc- high-powered magnets is not without its own
ture will appear on a radiograph. Conversely, the dangers, and care must be taken to ensure no
less a structure absorbs an x-ray, the more x-ray is metal objects are brought into the MRI chamber.
able to pass through onto the film, and the less Advantages of MRI include excellent (soft)
radiopaque it will appear (darker). tissue differentiation, a general high resolution of
The major advantages of radiographs are the small tissue structures, and excellent brain
comparatively low cost, the easy global depiction imaging. The disadvantage is that an MRI scan
of large body parts (in small animals), and the takes longer than a CT scan (requiring longer
excellent bone imaging capacity. The disadvan- anesthesia) and that it is more expensive. MRI is
tages are the superimposition of overlying struc- the method of choice for detecting central ner-
tures due to the summation of the opacity of all vous system tumors; it is also increasingly the
structures in the path of the ray, the low detail of imaging modality of choice for analyzing the
soft tissue structures, and the cell-damaging x-ray extent of soft tissue invasion of osteosarcomas.
exposure (. Table 2.1). For these reasons, radio-
graphs are commonly used as a screening tool for
detecting tumor masses anywhere in the body 2.2 Basic Principles of Cancer
except for the cranial cavity. Cytology

Natali Bauer
2.1.3 Computed Tomography
Cancer cytology uses microscopy to examine a
Computed tomography is an enhancement of small amount of tumor cells on a stained slide. It is
classic radiography. It is based on the same mech- an initial diagnostic tool used to type tumors for
anism of x-rays passing through structures of therapeutic and prognostic purposes. Cytology has
varying opacity. However, CT is a composite of several advantages over more invasive biopsy tech-
numerous radiographs taken from different niques: it is rapid, is minimally invasive, generally
angles and integrated by computer processing. does not require anesthesia, carries a lower risk of
This approach produces cross-sectional, i.e., hemorrhage, and is relatively inexpensive and
tomographic, slice images of the body and thus owners are likely to approve the procedure without
avoids superimposition of different tissues. much concern. Thus, it is often the first diagnostic
Other advantages of CT include higher sensi- step when cancer is suspected. More invasive biop-
tivity for detecting small tumors, improved bone sies are taken when cytology does not result in a
imaging compared to MRI, and the possibility of definite diagnosis or when further differentiation
CT-guided biopsies if ultrasound cannot be used. is required (i.e., the subtype of lymphoma or a def-
The main disadvantages are higher cost and inite differentiation between mesothelioma and
higher x-ray exposure compared to radiographs. carcinoma). There are a few contraindications to
Accordingly, CT is commonly used to detect taking a cytology sample. Invasive biopsy tech-
small tumors or metastases, for planning surgical niques are also contraindicated in these cases, and
approaches, or for radiotherapy. removal of the whole tumor or organ is preferred.
It is not recommended as a sampling method of cav-
ernous lesions in organs such as the liver and
2.1.4 Magnetic Resonance Imaging spleen (e.g., when hemangiosarcoma is suspected).
The risks of hemorrhage or metastasis are higher
Magnetic resonance imaging also produces three- than the benefits of diagnostic accuracy. Cytology
dimensional pictures of the body based on a stack and/or biopsy is also not recommended as a tech-
of cross-sectional imaging slices, similar to CT. nique for differentiating between adenoma and
However, whereas CT uses x-rays to produce carcinoma in mammary tumors. These tumors are
images, MRI uses a strong magnetic field and the usually a mixture of benign and malignant neopla-
movement of hydrogen atoms based on their sia, and complete surgical excision with radical
polarity to produce images. The obvious advan- mastectomy and removal of associated lymph
tage to this approach is that it does not require nodes is the treatment of choice.
22 R. Klopfleisch and N. Bauer

2.2.1 Cytology Technique: General masses or organs; larger needles are used for firm
Considerations masses. Slides should always be labeled with a
pencil because the alcohol in the staining solution
2 Additional information can improve the accuracy dissolves ink.
of cytological diagnosis. Information on the sig- Samples for cytological evaluation can be
nalment and history of the patient can narrow obtained by fine needle aspiration, by imprints
down the most likely differentials. Understanding from biopsies or masses, or by aspiration of body
the biological behavior of the tumor (growth rate, cavity fluids. Which method is appropriate
size) can improve interpretation of cytological depends on the type and localization of the tumor.
results. Appropriate aspiration technique, prepa-
ration of high-quality smears, and good staining z Fine Needle Aspiration (FNA)
procedures are required for the cytologist to ade- FNA is commonly used to take samples from
quately assess the sample. organs or solid masses. There are two main meth-
The following general rules for taking of cyto- ods of FNA sampling: the aspiration technique
logical specimens should be followed: and the non-aspiration technique.
1. Signalment of the patient and behavior of the The aspiration technique (. Fig. 2.1) is espe-
tumor should be included with the sample. cially useful for firm masses. The needle with the
2. The more slides and the higher the quality of attached syringe is inserted into the mass. The
the cytological specimen, the better the syringe is aspirated to approximately ¾; negative
diagnosis. pressure will draw up small amounts of tissue. The
3. Samples taken from the margins of the tumor needle can be moved slightly while aspirating (if
provide the most information, especially in the mass is large enough) to obtain cellular mate-
cystic or necrotic masses. rial from several areas. The negative pressure on
4. If possible, samples should be taken from the the needle is gently released before the needle is
projected site of surgical excision to avoid removed from the mass. The needle is carefully
seeding tumor cells into healthy tissue. removed from the syringe. Air is aspirated into
5. Fine needle aspirates are more likely to the syringe without the needle attached. The nee-
represent deeper layers of tissue than fluids or dle is reattached. The aspirated material in the
superficial imprints of a mass. hub of the needle is then expelled onto a glass
6. The more vascularized the mass, the smaller slide by rapidly depressing the plunger of the
the needle and the quicker aspiration syringe.
should be. The non-aspiration technique (. Fig. 2.2) is
7. Aspirated material cannot always be especially useful for highly vascularized tissues as
visualized in the syringe. it helps to avoid contaminating the sample with
8. Use frosted slides labeled with a pencil. blood. Either the needle is inserted into the tissue
9. Cytological specimens should not have without a syringe attached or air is drawn into the
contact with formalin fumes. syringe prior to inserting the needle into the tis-
sue. The needle is moved back and forth rapidly in
several directions approximately ten times to
2.2.2 Cytology Technique: Specific obtain tissue cells which are drawn into the needle
Methods with capillary action alone. The needle is then
removed from the tissue. The material at the hub
is rapidly expelled on a glass slide with the method
2.2.2.1 Sampling Techniques described above.
and Preparation of Cytology Smears are now prepared using a second glass
Specimens slide. The sample material can either be spread
Very little material is required to prepare cyto- evenly across the slide using the same technique
logical specimens; the procedure can be per- used to prepare a blood smear (45° angle), or the
formed in any veterinary practice or clinic. so-called squash preparation technique (or slide-
Materials include glass slides with frosted end, a over-slide technique) is used (. Fig. 2.3). In the
21- or 22-gauge needle, and a 5-cc or 10-cc syringe. squash preparation technique, the smear is cre-
Smaller needles are used for soft, vascularized ated without an angle.
Chapter 2 · Basic Principles of Cancer Diagnostics
23 2
. Fig. 2.1 Principle
of fine needle aspiration,
aspiration technique

1 2

3 4

5 6

. Fig. 2.2 Principle of


fine needle aspiration,
non-aspiration technique

1 2

z Imprint Smears (CSF), or synovial fluid can also be evaluated to


Imprints can be easily obtained from biopsies, diagnose a neoplastic process.
surgically removed tissues, or the surface of ulcer- Direct smears are usually prepared from fluid
ated masses. Excess fluid or blood should be samples to assess cellularity, with the exception of
removed with blotting paper prior to preparing an CSF and BAL fluid, which usually don’t contain
imprint smear to avoid diluting or contaminating enough cells. An evaluation of cells and even a
cellular material. The clean tissue is gently pressed differential cell count can also be performed on
against the glass slide several times, if possible cellular fluids (>20 × 109/L cells) without prior
(. Fig. 2.4a). FNA should be performed in addi- preparation of a sediment smear.
tion to impression smears to assess deeper tissue A sediment smear or cytospin can be performed
layers. on fluids with a lower cell count. Sediment can be
obtained with a sedimentation chamber prepared
z Evaluation of Fluids with a syringe attached to a slide (. Fig. 2.4b).
Fluids such as thoracic or abdominal effusions, urine Cells settle directly on the slide. Low-force cen-
(e.g., for diagnosis of a transitional cell carcinoma), trifugation similar to preparation of urine sedi-
bronchoalveolar lavage (BAL), cerebrospinal fluid ment can also be used, but generally the results
24 R. Klopfleisch and N. Bauer

. Fig. 2.3 Principle of


smear preparation
technique

2 1

are not as good because more cells are destroyed however, these procedures are relatively time-
by mechanical force. Smears are prepared as consuming and expensive and are therefore not
described above. routinely offered.

2.2.2.2 Staining Techniques z May-Grünwald-Giemsa or Wright Stain


Romanowsky-type stains such as May- The May-Grünwald-Giemsa and Wright stains
Grünwald-Giemsa, Wright, or Diff-Quik are the are commonly performed in larger veterinary
standard stains for cytological specimens in laboratories. Their advantage is that they provide
oncology. Cytological specimens should not a standardized staining result and excellent
come in contact with formalin fumes as they visualization of chromatin structure and nucleoli
can markedly impair the staining quality. (. Fig. 2.5a). Their disadvantage is that they take
Immunocytological stains can be performed for longer (i.e., approximately 30 min versus approxi-
classification of atypical cell populations; mately 5 min for Diff-Quik).
Chapter 2 · Basic Principles of Cancer Diagnostics
25 2
. Fig. 2.4 Principles
of smear preparation.
(a) Imprint smear.
(b) Material and assembly
of a self-made
sedimentation chamber.
Approximately 200 μL of
fluid are filled in the
chamber, the cells are
allowed to settle on the
slide for 1 h, and the
supernatant is then
removed thoroughly

a b

. Fig. 2.5 Staining


characteristics and a b
differences in staining quality
of May-Grünwald-Giemsa
stain (a) and Diff-Quik stain
(b), large granular lymphoma,
abdominal lymph node, cat,
1000×. Note the lymphatic
blasts with the clumped
chromatin pattern (red arrow,
a) and the large azurophilic
intracytoplasmic granules
(black arrow, a) seen in the
May-Grünwald-Giemsa-
stained slide compared to
the relatively indistinct
chromatin structure
(red arrow, b) and
the weakly stained
intracytoplasmic azurophilic
granules (black arrow, b)
observed in the
Diff-Quik-stained smear

z Fast Stains structure and nucleoli are less distinct compared to


Fast stains such as Diff-Quik are commonly per- the May-Grünwald-Giemsa or Wright stain, which
formed in veterinary practices or during emergency makes the signs of malignancy more difficult to evalu-
duty. The disadvantage of fast stains is that the results ate (. Fig. 2.5b). In addition, mast cell granules and
are not standardized. Moreover, the chromatin granules of large granular lymphocytes (. Fig. 2.5b)
26 R. Klopfleisch and N. Bauer

do not always take up Diff-Quik stains. A second slide quality and identify regions with potential tissue
with May-Grünwald-Giemsa or Wright may be cells rather than aspirated blood.
required to identify atypical round cells. Under the microscope, the slide is first thor-
2 oughly evaluated at a low magnification (100×)
without oil to assess the stain quality and prepara-
2.2.3 Analysis and Diagnosis tion of the smear; the background and the overall
of Cytological Specimens cellular picture including the predominating
cellular population; the presence of potential focal
The major advantage of cytology over histopa- processes (e.g., clusters of metastasized cells);
thology is the ability to evaluate single-cell mor- signs of malignancy such as high cellularity, mac-
phology. Some details such as intracytoplasmic rocytosis, anisocytosis, anisokaryosis, and pleo-
granules in large granular lymphoma (. Fig. 2.5) morphism; and the presence of mitotic figures.
or intracytoplasmic vacuoles in B-cell lymphoma The area where cells are spread in a monolayer is
with Mott cell differentiation cannot be visualized identified to be assessed later at a higher magnifi-
on histopathology. Cytology provides a fast and cation (. Fig. 2.8a).
minimally invasive accurate diagnosis, especially In the next step, the cellular detail is evalu-
in tumors which are classified by cellular details ated at a high magnification (600× or 1000×)
such as intracytoplasmic granules (. Fig. 2.6). with oil immersion. Here, the color and struc-
The major limitation of cytology is that tissue ture of cytoplasm and nuclear chromatin as well
architecture cannot be evaluated. This means as the morphology of nucleoli are assessed
well-differentiated tumors cannot be discerned (. Fig. 2.8b).
from hyperplastic or dysplastic tissue. Moreover,
small focal processes might be easily missed by
fine needle aspiration (. Fig. 2.7). Punch biopsies 2.3 Basic Principles of Cancer
or incisional biopsies are good alternatives. Core Biopsies
biopsies have no advantage over cytology.
A biopsy is a tissue fraction of a tumor taken for
z Microscopic Evaluation of Cytological diagnosis, grading, and therapy considerations.
Specimen There are several advantages of full-tissue
Before evaluating a slide under the microscope, it biopsies compared to fine needle aspiration and
is helpful to macroscopically assess their overall cytology. Biopsies allow a more comprehensive

. Fig. 2.6 Poorly


differentiated melanoma,
dog, May-Grünwald-Giemsa,
1000×. Note the
spindle-shaped poorly
pigmented melanocytes
with a few dustlike
intracytoplasmic melanin
granules (red arrow), which
can be excellently seen in
cytological specimens. This
is a nice example of the
advantage of cytology as a
diagnostic tool in evaluating
single-cell morphology
Chapter 2 · Basic Principles of Cancer Diagnostics
27 2
histopathologic and eventually immunohisto- in intra- or peritumoral lymph or blood vessels.
chemical analysis of tumor cells in situ: the The disadvantages of tissue biopsies are that
general tumor texture can be evaluated; the they are in general more elaborate, time-
amount of necrosis and fibroplasia can be consuming, and costly than cytology; they may
determined; the position of tumor cells relative also require anesthesia and induce larger
to each other can be assessed; and the loss of cell wounds.
adhesion can be assessed in epithelial tumors. Pretreatment biopsies are highly relevant for
When performed correctly, tissue biopsies also planning and executing of a treatment protocol
allow for the evaluation of tumor margins and once cancer has been diagnosed. They are used
confirm the presence or absence of tumor cells when cytology is not sensitive and specific enough

. Fig. 2.7 Limitations of


cytology, fine needle
aspirate of the spleen, dog,
May-Grünwald-Giemsa,
1000×. Note the small
region with predominance
of lymphatic blasts (red
arrow) surrounded by
normal splenic tissue
represented by small
mature lymphocytes (black
arrow). Histopathology is
required to evaluate the
architecture of the splenic
tissue and differentiate
focal lymphoma from
splenic lymph follicles

. Fig. 2.8 Technique of


microscopy, metastasized a b
carcinoma in the
mandibular lymph node,
cat, May-Grünwald-Giemsa,
100× (a), 1000× (b). (a) First,
the slides are evaluated at a
100× magnification to
detect the overall cell
population (here:
small- and medium-sized
mature lymphocytes, black
arrow) and potential focal
processes (here: clusters of
atypical epithelial cells, red
arrow). (b) Then, interesting
areas are examined at a
1000× magnification to
evaluate cellular details
(here: finely stippled
chromatin structure and
macronucleoli in the
carcinoma cells, red arrow)
28 R. Klopfleisch and N. Bauer

for a definite tumor diagnosis. Specific indications destruction due to unnecessary mechanical forces
for a pretreatment biopsy are: from coarse forceps, or thermal destruction of cell
1. Uncertainty of the neoplastic (vs. inflamma- nuclei due to electrocautery are common avoidable
2 tory) character of a mass artifacts. The following general rules for taking a
2. Uncertainty of the tumor type biopsy should therefore be considered:
3. A major impact of the tumor type/subtype on 1. The larger the biopsy, the better the diagnosis.
the therapy protocol (e.g., required tumor 2. The larger the biopsy, the more fixative is
margins, presurgical chemo-/radiotherapy, required (tissue: fixative ratio of 1:10).
euthanasia due to poor prognosis, etc.) 3. Tumor margins are usually the most
informative area for pathologists (except for
Postsurgical biopsies of resected tumors are bone tumors).
also commonly submitted for histopathologic 4. Surgical instead of coarse anatomical forceps
evaluation for the following indications: avoid unnecessary mechanical trauma.
1. Confirmation of the pretreatment diagnosis 5. Avoid seeding tumor cells in the biopsy
obtained from a small biopsy or cytological channel or body cavities.
specimen 6. Avoid electrocautery and associated thermal
2. Evaluation of the surgical margins for tissue destruction.
evidence of incomplete resection 7. Fix biopsies immediately in 4 % formaldehyde
to prevent autolysis and reduction of
countable mitotic figures.
2.3.1 Biopsy Technique: General
Considerations
2.3.2 Biopsy Technique: Specific
Proper biopsy location within a tumor and Methods
adequate tissue preservation once the biopsy has
been taken are both fundamental for the quality
of the histopathologic diagnosis. (A common z Core Needle Biopsy
saying of pathologists is “Garbage in, garbage Core needle biopsies (CNB) use a cutting-edge
out.” Or a poorly performed biopsy gives poor biopsy needle with a hollow core (. Fig. 2.9). A
histopathology results.) small cylinder-shaped tissue sample, usually 14
The preferable location of a tumor biopsy gauge/1 mm in diameter and 1 cm long, is obtained.
depends on the type, stage, and location of the CNB is used for external skin masses and masses
tumor and is therefore often not perfectly in internal organs. Bone tumor biopsies are
predictable. Biopsies taken from the tumor center
of a malignant, fast-growing neoplasia may only
contain necrotic tissue (due to hypoxia as vascu-
larization moves outward toward the tumor Tumor
periphery where active cell division is taking
place). Biopsies taken from the tumor periphery
are very helpful in the evaluation of tumor
margins and vascular invasion but may only con- Tumor
tain cells from the tumor capsule or inflamed
peripheral nonneoplastic tissue if the biopsy is
not large enough. Under best possible conditions, Tumor
several biopsies from different areas of the tumor
center and tumor margins are taken for maximal
representation. Tumor psy
Bio
An accurate histopathologic diagnosis of a
biopsy is only possible if the tissue handling pre-
serves the original morphology of the cells and
tissue structure. Autolysis due to insufficient or
delayed formalin fixation, tissue and cell . Fig. 2.9 Principle of core needle biopsy
Chapter 2 · Basic Principles of Cancer Diagnostics
29 2
obtained using more stable hollow core drill nee- actual tumor mass. The base of the core is cut off
dles, trocars, or regular core needles in cases of using scissors, and the wound has to be closed
accessible, superficial bone tumors. In contrast to using one or two sutures or staples. Anesthesia is
other tumors, bone tumor biopsies should be taken necessary similar to core needle biopsies.
from the center of the tumor to avoid peripheral
reactive nonneoplastic bone tissue. z Incisional Biopsy
Computed tomography or ultrasound guidance An incisional biopsy is a wedge-shaped segment of
is usually necessary to get a sufficiently accurate tissue excised using a scalpel (. Fig. 2.11). Tumor
biopsy for diagnostic evaluation when taking core samples are larger using this method, which allows
needle biopsies of internal organs and bone for a more accurate diagnosis. Incisional biopsies
tumors. Local anesthesia and a small skin cut are are recommended if:
necessary to avoid unnecessary pain and blunting 1. Both core needle and punch biopsies failed to
of the needle. Several needle cores of different obtain a representative tissue sample.
areas of the tumor may be obtained through one 2. A larger tissue sample is required from a
skin incision to increase the representativeness of necrotic/ulcerated tumor.
the biopsy. CNB is more accurate than cytological 3. An exploratory laparotomy allows the
samples but less accurate than excisional or inci- removal of a larger tumor piece.
sional biopsies, which are usually larger.
Anesthesia and wound closure with sutures or
z Punch Biopsy staples are necessary. Electrocautery should not
A punch biopsy removes a round cutaneous tissue be used prior to complete removal of the tissue
sample using a sharp hollow cutting punch with a biopsies to avoid thermal artifacts.
diameter of 3–7 mm (. Fig. 2.10). It was originally
designed for obtaining skin biopsies and allows the
excision of wider but shorter tissue samples than z Excisional Biopsy
core needle biopsies. For deeper subcutaneous Excisional biopsy includes the complete excision of
tumors, the skin has to be incised first to reach the the tumor without presurgical analysis of the
tumor type (. Fig. 2.12). It is the method of choice
for small, slowly growing cutaneous tumors, splenic
tumors, and pulmonary tumors. These tumors are
treated with standard protocols, regardless of the
specific tumor type. For all other tumor types,
non-excisional biopsies should be considered first
because histopathologic tumor classification may
allow for a customized treatment protocol based
on a pretreatment diagnosis.

l
lpe
Biop
sy Sca
Skin

Tumor
Tumor

. Fig. 2.10 Principle of punch biopsy . Fig. 2.11 Principle of incisional biopsies
30 R. Klopfleisch and N. Bauer

2.3.4 Histopathologic Analysis


Tumor and Diagnosis of Tissue
Biopsies
2 Organ
The major advantage of histopathologic evaluation
l of biopsies over cytology is the possibility to eval-
lpe
Sca uate tumor cells in their structural context. For
Tumor
instance, biopsies of tumor margins can be used
to evaluate invasiveness, to assess whether the
tumor capsule is intact, and to look for anaplastic
Organ epithelial tumor cells.
The basic and most commonly used method
for histopathologic evaluation of tumor samples is
the hematoxylin-eosin (H/E) stain of formalin-
. Fig. 2.12 Principle of excisional biopsies fixed and paraffin-embedded biopsies (. Fig. 2.13).
The major principle of paraffin embedding, micro-
tome sectioning, and H/E staining is illustrated in
Fig. 2.13a–e.
2.3.3 Biopsy-Associated Risks Veterinary oncology bases its tumor classifica-
tion system on the WHO Histological Classification
There is a significant body of literature that warns of Tumors of Domestic Species (publisher Armed
clinicians about the risk of seeding tumor cells Forces Institute of Pathology and World Health
(needle tract metastasis, NTM) or even inducing Organization, . Figs. 2.14 and 2.15). The WHO
distant metastasis by taking biopsies in compan- classification is supplemented by relevant scientific
ion animals. A recently published meta-analysis reports on the clinicopathologic features of animal
found that although NTM is a very rare event, tumors. Histopathologic diagnoses are currently
biopsy-induced seeding of tumor cells into the still based on trained human skills for pattern recog-
biopsy tract may be a potential risk. There is no nition and experience. Attempts to substitute human
evidence that supports the hypothesis of biopsy- histopathologic skills by image analysis software
induced malignancy in the available literature on using pattern recognition programs have so far
human or veterinary oncology. There are only failed to achieve similar sensitivity and specificity.
seven reported cases in the literature of needle Intraoperative consultation by pathologists
tract metastases or tumor seeding in companion using frozen section of tumors while the patient is
animals. Five cases of transcutaneous fine needle still under anesthesia is very common in human
aspirations of canine transitional cell carcinomas of oncologic surgery. It allows the surgeon to adapt
the urogenital tract have been reported in the lit- the surgical approach to the pathologic diagnosis,
erature. One case of canine prostate carcinoma i.e., detection of tumor cells at the margins of the
and one case of pulmonary adenocarcinoma with excised tumor, malignant versus benign appear-
NTM have also been reported. Similarly, studies ance of the tumor, or the presence of metastases in
on the incidence of NTM in human oncology the regional lymph node. In veterinary medicine,
show some risk when biopsying mesotheliomas, these obvious advantages are offset by the high
melanomas, and gall bladder tumors but not for cost and efforts of the procedure, which is why it is
other tumor types. According to the available lit- not routinely implemented.
erature, it’s reasonable to postulate that the risk of
biopsy-induced metastasis and tumor progression
is negligible when compared to the value of the 2.3.5 Immunohistochemistry
information obtained by biopsies for daily clinical as an Additional
practice. Diagnostic Tool
Other biopsy risks include hemorrhage in
highly vascularized tumors like hemangiosarco- Occasionally, histopathology is not sufficient for a
mas or the introduction of pathogens into other- final and conclusive diagnosis of atypical or ana-
wise sterile structures like the globe of the eye. plastic epithelial or stromal tumors. In addition,
Chapter 2 · Basic Principles of Cancer Diagnostics
31 2

a b

c d

. Fig. 2.13 Principle of hematoxylin-eosin staining of formalin-fixed and paraffin-embedded tissue biopsies.
(a) Formalin-fixed biopsies are cut into several mm-thick tissue slices and (b) put into histology cassettes.
(c) Subsequently, tissue samples are embedded in paraffin and cut with a microtome into histologic sections a few μm
thick. (d, e) Finally, sections are deparaffinized, stained with hematoxylin and eosin, and placed on cover-slipped slides
32 R. Klopfleisch and N. Bauer

. Fig. 2.14 Hematoxylin-


eosin (H/E) stain of intravas-
cular metastatic tumor cells
of a canine mammary
2 carcinoma (arrow). Cell
nuclei are blue while the
cytoplasm and most other
structures are purple

. Fig. 2.15 Hematoxylin-


eosin (H/E) stain of an
almost solid canine
hemangiosarcoma. A few
erythrocytes and vessel-like
cavities (white arrows) are
interspersed between
abundant mostly plump
neoplastic endothelial cells
(black arrows)
Chapter 2 · Basic Principles of Cancer Diagnostics
33 2
hematopoietic round cell tumors like B-cell or
T-cell lymphoma are not finely discernable by
Brown dye their histopathologic features in H/E-stained
slides. Immunohistochemistry (IHC) for the detec-
Enzyme tion of tumor-specific proteinaceous markers is a
common method to supplement histopathology.
IHC is based on the high sensitivity of antibodies
Primary antibody- for specific epitopes in and on the cells in
Antigen-specific
specific secondary histopathologic sections (. Fig. 2.16). Enzymatic
antibody
primary antibody reactions with dyes of different colors are stably
incorporated into the tissue around the antibody
binding site, which can then be visualized.
Table 2.2 summarizes the most commonly used
Specific tumor antigen
IHC markers in veterinary oncology.

. Fig. 2.16 Principle of indirect immunohistochemistry:


the tumor is marked with an antigen-specific primary
antibody; the primary antibody is marked with a primary
antibody-specific secondary antibody; the secondary
antibody is conjugated with an enzyme; the bound
enzyme converts a colorless medium into a brown dye

. Table 2.2 Common immunohistochemical tumor markers in veterinary oncology

Tumor marker Detected cell type Typical staining pattern

CD3 T-lymphocyte origin

PAX5 B-lymphocyte origin

(continued)
34 R. Klopfleisch and N. Bauer

. Table 2.2 (continued)

Tumor marker Detected cell type Typical staining pattern


2 CD45R, CD79 B-lymphocyte origin

KIT (CD117) Diverse, mainly mast cell origin,


gastrointestinal stromal tumors
(GIST)

Vimentin Mesodermal (stromal) cell origin

Pan-cytokeratin Epithelial cell origin


Chapter 2 · Basic Principles of Cancer Diagnostics
35 2

. Table 2.2 (continued)

Tumor marker Detected cell type Typical staining pattern

Smooth muscle Smooth muscle cell origin


actin (SMA)

Melan A Neuroectodermal (melanocyte)


cell origin

S100 Neuroectodermal cells

Synaptophysin Neuroendocrine cell origin

(continued)
36 R. Klopfleisch and N. Bauer

. Table 2.2 (continued)

Tumor marker Detected cell type Typical staining pattern


2 Chromogranin Neuroendocrine cell origin

Von Willebrand Endothelial cell origin


factor (vWF)

CD31 Endothelial cell origin


37 3

Basic Principles of Cancer


Therapy
Mathias Brunnberg, Robert Klopfleisch, and Melanie Wergin

3.1 Oncologic Surgery – 38


3.1.1 Patient Preparation – 39
3.1.2 General Aspects of Oncologic Surgery – 39
3.1.3 Oncologic Surgery of Bone Tumors – 40
3.1.4 Oncologic Surgery of Skin Tumors – 41
3.1.5 Oncologic Surgery of Central Nervous
System Tumors – 41
3.1.6 Oncologic Surgery of Tumors of Viscera/Internal
Organs/Body Cavities – 43
3.1.7 Postoperative Patient Care – 43

3.2 Cancer Chemotherapy – 43


3.2.1 General Forms of Chemotherapy Protocols – 44
3.2.2 Chemotherapeutic Agents – 45
3.2.3 Mechanisms of Chemotherapy Resistance – 46

3.3 Radiation Oncology in Veterinary Medicine – 48


3.3.1 Biology of Radiation Therapy – 48
3.3.2 Indications for Radiation Therapy – 49
3.3.3 Adverse Side Effects of Radiation – 52
3.3.4 Radiation Treatment Devices – 53
3.3.5 Therapy Planning – 54
3.3.6 Internal Beam Radiation – 56

Suggested Reading – 56

© Springer International Publishing Switzerland 2016


R. Klopfleisch (ed.), Veterinary Oncology, DOI 10.1007/978-3-319-41124-8_3
38 M. Brunnberg et al.

Therapeutic treatment of cancer often depends and magnetic resonance imaging (MRI) are the
in large part on finances in veterinary oncology. preferred methods for diameter measurement.
While surgery is still the most commonly used Progressive disease (PD) is defined as a 20 %
treatment option, chemotherapy, radiotherapy, increase in the sum of the largest diameters of the
and imaging modalities such as PET scans used in lesions after or during therapy.
human medicine are prohibitively expensive in vet- Stable disease (SD) is defined as being neither
3 erinary medicine. However, new state-of-the-art in remission nor in progression.
treatment centers are being built in most countries, Median survival is the length of time after ini-
which make cutting-edge diagnostics and therapy tial therapy at which 50 % of the patients have
available to veterinary patients. Although still a died and 50 % of the patients are alive.
sobering diagnosis, cancer is no longer the death Disease-free interval (DFI) is defined as the
sentence that it once was, and treatment options in time between complete remission and local recur-
veterinary oncology are evolving rapidly. rence or development of metastases.
The most common therapeutic modalities in vet- Progression-free interval/survival (PFI/PFS) is
erinary oncology are surgery, chemotherapy, and defined as the time period after therapy during
radiotherapy, each applied with variable success. which stable disease (SD) was achieved.
Selection of the treatment option and success of
treatment, both very much depend on the tumor
type, the stage of tumor development, and the loca- 3.1 Oncologic Surgery
tion of the tumor. Defining some of the common
terms and definitions used in veterinary oncology will M. Brunnberg
help us in our discussion in the following chapters
on general and specific aspects of cancer therapy. “Surgery is the oldest treatment for cancer and, as
Curative therapy aims at and anticipates the a single modality, cures more animals and people
complete removal or killing of all tumor cells and with cancer than any other treatment”(VSSO).
thus the complete cure of the patient. Surgery plays a key role in most treatment plans
Palliative therapy, in contrast, aims at pallia- for small animal cancer patients. Oncologic sur-
tion of unpleasant symptoms associated with the gery describes the use of surgery as sole treat-
neoplastic disease. Cure is neither achievable nor ment. In contrast, the term surgical oncology is
expected. usually used to describe surgical procedures per-
The definition of the extent of remission during formed in conjunction with other treatments like
or after therapy is defined by the Response chemotherapy or radiation therapy.
Evaluation Criteria In Solid Tumors (RECIST). Typical surgical procedures in oncology
Remission is difficult to differentiate in its stages include complete resection with a curative inten-
and to define in veterinary medicine. In human tion, palliative procedures to alleviate pain and
medicine, PET scans are often used as the imaging improve quality of life, and diagnostic surgeries
modality of choice to detect the presence of including biopsies and cytoreductive or debulk-
neoplastic cells after therapy and determine ing surgeries. Numerous factors influence which
remission status. This is not commonly available type of surgery is appropriate in a given case,
in veterinary medicine due to cost considerations. including tumor type, the presence of local or dis-
Complete remission (CR) is the complete dis- tant metastasis, patient health status, patient age,
appearance of the tumor during or after therapy. and owner expectations. The surgeon should be
The tumor is no longer detectable by physical well informed on these factors prior to surgery in
examination, imaging, or hematologic or bio- order to choose the most appropriate treatment.
chemical analysis. A multidisciplinary approach to patient assess-
Partial remission (PR) is defined as a 30 % ment, with collaboration between pathologists,
decrease in the sum of the largest diameters of radiologists, oncologists, and internists, is
two neoplastic lesions in one organ or five lesions required to evaluate the need and the invasiveness
in the whole body. Computed tomography (CT) of the surgery, the resectability of the tumor, as well
Chapter 3 · Basic Principles of Cancer Therapy
39 3
as the determination of possible pre-, intra-, and Most general surgical principles are also valid
postoperative complications. for oncologic surgery. This includes the fact that
the first procedure is the most likely to succeed.
With each successive procedure, the chances for a
3.1.1 Patient Preparation curative outcome are reduced. It is also impor-
tant to follow Halsted’s principles, which include
Evaluating the patient’s status prior to surgery gentle tissue handling, control of hemorrhage,
using diagnostic imaging, fine needle aspirates or strictly aseptic technique, preservation of blood
biopsies, and laboratory tests is important for two supply to tissues, elimination of dead space, and
reasons. First, an initial tumor characterization has accurate tension-free wound closure. Halsted’s
to be performed to estimate factors like tumor type, principles are particularly important when treat-
dimensions, stage, vascularization, and lymph ing skin tumors. Surgical tumor removal
node involvement. Those factors have a direct approaches can be characterized as intralesional,
influence on the choice of surgical procedures. marginal, and wide or radical resection. The type
Second, veterinary cancer patients are usually older of resection should be selected based on the
animals and often suffer from several comorbidi- tumor type, location, and further comorbidities
ties, which put them at a higher risk of intra- or (. Table 3.1).
postoperative complications. For instance, oncol- The skin incision is usually performed with a
ogy patients are often cachectic which might com- scalpel blade. Scalpel incisions provide the clear-
plicate wound healing. Since most oncology est margins for histopathological diagnosis.
surgeries are elective procedures, treatment of A combination of sharp and blunt dissection
comorbidities and stabilization of the patient can along tissue planes is usually performed with
and should be initiated prior to surgery. scissors. Direct manipulation of the mass with
Reconstructive techniques for wound closure forceps or other graspers can lead to fragmenta-
need to be carefully considered before surgery tion of the mass and subsequent tumor seeding.
when treating large skin tumors or undertaking In general the surgery should be as atraumatic as
widespread resections. The widest possible surgi- possible.
cal field is clipped, sterilized, and draped, keeping During surgery the following important
in mind that it might be necessary to increase the tumor zones have to be considered: the tumor
operating field during surgery or change the type mass, the pseudocapsule, the reactive zone, and
of resection intraoperatively. Perioperative antibi- the surrounding healthy tissue (. Fig. 3.1). If the
otic treatment is usually indicated. goal of the surgery is complete removal of the
mass, then the intralesional pseudocapsule zones
should be resected. Marginal resection has to be
3.1.2 General Aspects of Oncologic avoided whenever possible due to the risk of leav-
Surgery ing tumor cells behind. Vessels supplying or
draining the tumor should be ligated early during
The basic surgical instrument set includes atrau- surgery to avoid tumor cell migration during
matic forceps and variable numbers of traumatic manipulation.
and atraumatic tissue clamps. Direct manipula- Wound closure with a monofilament suture
tion of the mass should be avoided. Instruments material close to the tumor bed is recommended
and gloves should be changed after direct tumor to minimize the risk of tumor cell trapping.
contact since repeated contact increases the risk of Wound lavage or body cavity lavage in onco-
tumor seeding. Electrosurgery, laser surgery, and logic surgery is controversial. On the one hand,
cryosurgery tend to cause severe tissue degenera- lavage might induce tumor cell migration, but
tion at the line of incision, which can impede on the other hand, removal of blood clots and
proper margin assessment by the pathologist. foreign material and hydration of tissue are
Although these are useful tools, they may not be strongly recommended to avoid complications
the most appropriate choice for oncologic surgery. in wound healing.
40 M. Brunnberg et al.

. Table 3.1 Technique and indication for different resection types in oncologic surgery

Type of resection Technique Indication

Intralesional Intracapsular piecemeal removal of the mass Benign lesions


Most of the tumor not removed Cytoreductive surgery
3 Debulking surgery

Marginal Extra- or pseudocapsular dissection through the reactive Benign tumors (e.g., lipomas)
zone Prior to radiation therapy
Microscopic satellite tumors not removed

Wide Intended to remove all tumor cells Curative intent surgery


With additional tumor type/grade-dependent margin of Most solid tumors
healthy tissue

Radical Removal of the tumor with the entire compartment Bone tumors
including abundant healthy tissue Highly malignant tumors

screening of the entire patient and tumor staging


should be performed. Advanced diagnostic tools
Tumor like scintigraphy might also be indicated. Surgical
*
treatment is usually curative in cats but is consid-
ered palliative in dogs.
The most common types of surgery in bone
tumors are radical resections (amputations) and
wide resections. Prior to limb amputation, the
. Fig. 3.1 Carpal neurofibrosarcoma mass of a 7-year-old
male Staffordshire terrier. The pseudocapsule/reactive animal should be examined for orthopedic or
zone (star) and resection margins (green intralesional, blue neurologic diseases of the contralateral limb,
marginal, orange wide) are indicated which influence postoperative functionality and
quality of life. Furthermore, the owner should be
The use of drains is generally not indicated in thoroughly informed of what to expect after
oncologic surgery. In case of seroma formation amputation. Radical amputations, including scap-
drains can be used after margin assessment of the ulectomy for treating tumors of the forelimb and
mass. If postoperative external beam therapy is femur osteotomy for treating tumors of the hind
planned, it is useful to mark the wound bed and limb, are both controversial procedures. Subtotal
the tumor margins to determine the extent of the amputations offer some degree of lateral protec-
radiation field. For histopathologic margin assess- tion of the thorax or caudal abdomen and are
ment, the margins should be labeled with sutures, often easier to perform. However, subtotal ampu-
ink, or other marking techniques. Most common tations also leave additional dead weight in the
mistakes in oncologic surgery include incomplete form of nonfunctional stumps in the place of the
resection, intraoperative tumor seeding, and the limbs. This additional weight can have an impact
use of inappropriate suture material and instru- on postoperative gait mechanics. Total limb
ments as well as traumatic techniques. amputations have the advantage of removing this
dead weight.
Tumors of the phalanx and digits are usually
3.1.3 Oncologic Surgery of Bone treated by amputation of the digit or phalanx only.
Tumors Limb-sparing surgeries (. Fig.  3.2) or osteosyn-
thesis of pathologic fractures are less commonly
Osteosarcomas is the most common bone tumor performed. Possible tumor locations for limb-
in dogs and cats. It is often metastatic, and hence sparing surgeries are shown in . Table 3.2.
Chapter 3 · Basic Principles of Cancer Therapy
41 3
good success rates with varying degrees of mandib-
ulectomies or maxillectomies, respectively.

3.1.4 Oncologic Surgery of Skin


Tumors

Primary wound closure can be sacrificed for the


purpose of achieving appropriate margins in
oncologic surgery. Understanding open wound
management, tension-relieving techniques, skin
grafting, and reconstruction techniques is there-
fore essential for oncologic surgery. Body wall
reconstructive techniques might be necessary if
the body wall is involved.
Various local or subdermal plexus skin flaps
can be used for small- or moderate-sized skin
defects. Preservation of the local blood supply to
the flap is the key to flap survival. Skin defects on
the lower extremities are treated with tension-
relieving techniques like relaxing incisions or free
skin grafts. Axial pattern flaps are used for large
. Fig. 3.2 Radiograph of the right front limb of a skin defects. They contain a cutaneous artery and
flat-coated retriever with an appendicular osteosarcoma
vein, which allows preparation of larger flaps and
before (left) and after (right) partial ulnar resection
a better flap survival compared to free grafts.
Different skin-closing techniques and common
axial pattern flaps are listed in . Table 3.3.
Although wide and radical resections are
described as the treatment of choice in appendic-
ular bone tumors, there are cases where osteosyn- 3.1.5 Oncologic Surgery of Central
thesis of tumor-associated pathologic fractures Nervous System Tumors
makes sense. Neurologic or orthopedic disease of
the contralateral limb, as well as cosmetic con- Tumors of the nervous system can be differenti-
cerns, might be good reasons not to amputate. ated into intracranial, spinal, and peripheral
Most discussions in the literature mention plate tumors. There are some case reports of successful
osteosynthesis as the method of choice for patho- treatment of intra- and extra-axial tumors,
logic fracture stabilization, but all stabilization although brain surgery in small animal patients is
methods commonly used for traumatic fractures still in its infancy. Surgery should only be under-
can also be used for pathologic fractures as long as taken for primary brain tumors. Due to the high
stable fixation of the implant can be achieved. risk of intra- and postoperative complications, a
Bone tumors of the head or the axial skeleton state-of-the-art anesthesiology including detailed
usually cannot be treated by wide or radical resec- monitoring of the patient and an intensive care
tions. Instead debulking procedures or surgeries unit is mandatory for intracranial oncologic sur-
with marginal resections are performed. Advanced gery. Studies with significant case numbers in vet-
imaging techniques like computer tomography erinary medicine of surgical treatment of
(CT) or MRI should be performed prior to surgery intracranial neoplasia are only available for feline
to evaluate the dimensions of the tumor and possi- meningioma. Tumors of the peripheral nervous
ble intradural or intraaxial involvement. Mandibular system are most commonly peripheral nerve
or maxillary tumors in dogs can be treated with sheath tumors. Tumors that are limited to the
42 M. Brunnberg et al.

. Table 3.2 Limb-sparing surgeries of appendicular bone tumors

Location Options Remarks

Scapula Partial scapulectomy Preservation of the mid-scapula


Dorsal scapular tumors
3 No soft tissue involvement

Subtotal scapulectomy Preservation of the glenohumeral


joint
Mid-distal scapular tumors
No soft tissue involvement

Radius Radial resection and substitution: Involvement of the radius ≤50 %


Cortical allografts Combined with pancarpal
Endoprosthesis arthrodesis
Pasteurized autografts
Vascularized ulnar transposition
Bone transport osteogenesis

Ulna Partial ulnar resection Only ulnar tumors below the elbow

Pelvis Hemipelvectomy Based on the location at the pelvis


Total hemipelvectomy Includes amputation of the hind
Mid-caudal hemipelvectomy limb
Mid-cranial hemipelvectomy

Hemipelvectomy Only limb-sparing hemipelvectomy


Caudal hemipelvectomy The acetabulum is preserved

. Table 3.3 Examples of common skin wound-closing techniques

Approximate defect size/


Technique Type localization Remarks

Direct closure <5 cm diameter

Tension-relieving Undermining >5 cm diameter Risk of seroma formation


techniques
Walking sutures >5 cm

Relaxing incisions >5–10 cm lower Cosmetic appearance


extremities

Local plexus flap Advancement flap >10–15 cm a.k.a. single pedicle flap

Rotation flap >10–15 cm

Transposition flap >10–15 cm

Interpolation flap >10–15 cm Bridging incision


necessary

Skin fold flap >10–30 cm Elbow fold flap


Flank fold flap

Axial pattern flaps Thoracodorsal Thorax, shoulder,


forelimb, axillary defects

Omocervical Facial, ear, cervical,


shoulder, axillary defects

Caudal superficial Caudal abdominal,


epigastric inguinal, flank, perineal,
thigh defects
Chapter 3 · Basic Principles of Cancer Therapy
43 3
periphery are usually treated by amputation with tumor is usually possible, depending on the organ
a curative intent, while central nervous nerve involved. Autotransfusion of blood from abdomi-
sheath tumor surgery is usually only palliative. nal or thoracic effusion is contraindicated in neo-
plastic disease. Lavage of the abdominal or
thoracic cavity is indicated in case of a ruptured
3.1.6 Oncologic Surgery of Tumors neoplasia. Gloves and instruments are changed
of Viscera/Internal Organs/ after mass removal and cavity lavage.
Body Cavities Manipulation of abdominal viscera can lead to
cardiac arrhythmias, which can progress to life-
Surgery of tumors located in the body cavities can threatening dysrhythmias that require treatment.
be challenging. Obvious masses that seem to be Therefore, EGC-monitoring is indicated both
limited to one organ during preoperative staging intraoperatively and postoperatively for 3 days.
might turn out to involve other organs as
well (. Fig.  3.3). Therefore, in-depth knowledge
of surgical techniques for partial or complete 3.1.7 Postoperative Patient Care
resection of visceral organs is mandatory if these
procedures are to be undertaken. An understand- Postoperative patient care is based on the organ
ing of temporary vascular occlusion and vascular system involved, the general health status of the
surgical techniques is also necessary in certain patient, and the tumor type and localization.
circumstances (e.g., liver tumors, adrenal gland Patients with tumors removed from the thoracic
tumors). In addition to basic surgical instruments, or abdominal cavity usually require intensive care
advanced surgical equipment like staplers, vascu- and continuous monitoring for several days. If
lar clips, vessel-sealing devices, harmonic scal- primary wound closure was not possible, daily
pels, and others might be required. Tumors wound treatment might be indicated.
located in the abdominal or thoracic cavity have a
higher risk for seeding tumor cells than tumors
located elsewhere. Therefore, final tumor staging 3.2 Cancer Chemotherapy
and surgical planning is performed intraopera-
tively once access to the body cavity is established R. Klopfleisch
and the entire body cavity has been explored.
Separation of adjacent tissues or organs with One classical feature of tumors is their pro-
laparotomy sponges can reduce the risk of tumor liferative character, i.e., the high fraction of mitoti-
seeding. Partial or complete resection of the cally active cells in a tumor. Classical cancer

a b c

. Fig. 3.3 11 year old male mix breed dog. (a) Lateral radiograph of the abdomen with obvious mass effect. (b)
Intraoperative view of the spleen with mass. (c) Additional at the base of the greater omentum
44 M. Brunnberg et al.

chemotherapy drugs take advantage of this by tar- tumor size at which the tumor may switch into
geting mitotically active cells. Unfortunately, the the plateau phase is a volume of 1 cm3. According
processes targeted by these drugs are also present to Gompertzian kinetics, chemotherapy is thus
in nonneoplastic dividing cells such as the bone most efficient when the tumor is small, which is
marrow, intestinal epithelium, and skin. This is unfortunately often before it is clinically detect-
why myelosuppression, leukopenia, and cutane- able.
3 ous and gastrointestinal tract toxicity are the most
common side effects of cancer chemotherapy.
One major goal of research on new chemo- 3.2.1 General Forms
therapeutic compounds is the identification of of Chemotherapy Protocols
unique signaling cascades, metabolic processes, or
tumor markers expressed only by neoplastic cells. The term primary chemotherapy defines a therapy
Newly developed cancer chemotherapy drugs focus plan, which is based solely on chemotherapy
on these more specific features. One recent exam- without other tumor-directed therapy modalities.
ple is the mutational activation of pro-proliferative It is applied when the tumor is primarily systemic
signaling cascades like KIT tyrosine kinase recep- as is often the case for hematopoietic leukemic
tor signaling in canine mast cells, which can be tumors.
inhibited by tyrosine kinase inhibitors. Monoclonal Curative chemotherapy is applied with the
antibodies with or without attached toxic proteins intention to cure neoplastic disease or at least to
are also used to specifically target surface recep- allow for prolonged survival of more than 2 years.
tors on human tumors like the HER/NEU recep- Unfortunately, very few tumors can be success-
tor on human breast cancer or the interleukin-2 fully cured by this definition with chemotherapy
receptor on human T-cell lymphoma. Therapeutic alone. One example would be low-stage canine
monoclonal antibodies are currently not used for B-cell lymphoma.
routine treatment of tumors in domestic animals, Palliative chemotherapy, in contrast, is given to
mostly due to their high costs. alleviate tumor-associated symptoms and to slow
Classical chemotherapy drugs targeting down tumor growth but not to cure neoplastic
dividing cells are thus still by far the most disease.
important group of drugs used in veterinary Monochemotherapy is a treatment protocol that
chemotherapy. Their efficacy very much depends includes only one drug. The advantage of this
on the fraction of dividing cells, which is much approach is to offer palliative care at an accessible
less constant during tumor growth than one cost for patients that might otherwise be euthanized.
may intuitively assume. The growth curve of Polychemotherapy is a treatment protocol,
most tumors is similar to what has been which includes a combination of more than one
described for the human population by the drug. Polychemotherapy protocols have a higher
Gompertzian growth curve. Growth of both treatment efficacy in most cases. The protocols
tumor cells and human populations is charac- aim for a synergistic therapeutic effect, targeting a
terized by an initial slow growth phase, which broader range of heterogeneous tumor cells and
develops into a fast exponential growth phase decreasing the risk of chemotherapy resistance
when a sufficient nutrient supply is available. development.
Finally, it reaches a plateau phase when space, Neoadjuvant chemotherapy is defined as a che-
nutrients, and oxygen are limited. In the plateau motherapy given prior to surgery or radiotherapy.
phase a large fraction of the tumor’s cells are in Its rationale is to shrink the tumor so that less
the nondividing G0 phase of the cell cycle and extensive surgery or radiotherapy is required.
therefore not possible targets for classical che- Adjuvant chemotherapy is given after surgery
motherapeutical drugs. The tumor size to or radiotherapy to kill any remaining tumor cells
growth phase correlation is most probably in the surgical or radiation fields. In addition,
tumor type specific and very much depends on it  is used to prevent or at least slow down
the ability of the tumor to induce vasculariza- growth  of distant micrometastases outside the
tion. However, an often postulated maximal treatment field.
Chapter 3 · Basic Principles of Cancer Therapy
45 3
Induction chemotherapy describes the first z Platinum-Containing Drugs
more intense phase of chemotherapy protocols Platinum complexes are cytotoxic via several
when higher doses or more complex drug combi- mechanisms. They induce cross-linking of the
nations are given at shorter intervals. The ratio- DNA double strand and thereby prevent cell divi-
nale is to kill as many fully sensitive tumor cells sion, induce point mutations, and inhibit DNA
before resistance can develop. repair mechanisms, all of which finally trigger
Consolidation chemotherapy is less aggressive apoptosis (. Table 3.5).
and applied after initiation therapy if complete
remission is not achieved. z Antitumor Antibiotics
Maintenance chemotherapy is an even less Antitumor antibiotics are produced by fungi of
intense protocol initiated after complete remis- the Streptomyces genus. They have multiple toxic
sion by induction or consolidation therapy. The effects on dividing cells, which include intercala-
rationale here is to prevent growth of potentially tion with the DNA double strands, induction of
residual tumor cells. There is an ongoing discus- DNA double-strand breaks, and inhibition
sion about whether maintenance chemotherapy of topoisomerase II.  They thus prevent cell
should be replaced by more intense short-term division and induce apoptosis in dividing cells
protocols in dogs with complete remission. (. Table 3.6).
Metronomic chemotherapy is most often
defined as a long-term, low-dose chemotherapy z Antimicrotubule Agents
protocol, which is of minimal toxicity. The goal is Antimicrotubule agents are plant-derived alka-
to specifically target the endothelium and thus loids. Of these, vinca alkaloids and taxanes
prevent intra-tumor angiogenesis and subse- are the two most important drug groups. All
quently tumor growth.
First-line or standard chemotherapy is a proto-
col which has been selected by empirical evi- . Table 3.4 Alkylating agents and their most
dence or by prospective studies to have the common indications in veterinary oncology
highest probability of successful treatment of a Alkylating agent Indication
given tumor type.
Second-line/rescue therapy chemotherapy is Cyclophosphamide Lymphoma, carcinoma,
the switch to a second protocol when first-line sarcoma
standard chemotherapy fails to achieve the Chlorambucil Lymphoma, myeloma,
expected results. Again, empirical evidence or mast cell tumor
scientific studies are used to identify these rescue
Ifosfamide Lymphoma
protocols or drugs.
Lomustine Lymphoma, mast cell
tumor

3.2.2 Chemotherapeutic Agents Carmustine Lymphoma, brain tumors

Streptozocin Insulinoma

z Alkylating Agents
Alkylating agents are a large group of cytostatic
. Table 3.5 Platinum-containing drugs and their
drugs that work by attaching an alkyl group to cel-
most common indication in veterinary oncology
lular DNA (. Table  3.4). This alkylation induces
cross-linking of the DNA double helix strands. Platinum
Cross-linking inhibits uncoiling and separation drug Indication
and thus duplication of the DNA strands, which
Cisplatin Carcinoma, sarcoma, mesothelioma,
in turn inhibits cell division. The cytostatic effect
transitional cell carcinoma
of alkylating agents is not restricted to tumor
cells. They are also cytotoxic or even carcinogenic Carboplatin Similar to cisplatin but not
nephrotoxic and more expensive
for nonneoplastic cells.
46 M. Brunnberg et al.

. Table 3.6 Antitumor antibiotics and their . Table 3.8 Antimetabolites and their most
most common indications in veterinary oncology common indications in veterinary oncology

Antibiotic Indication Antimetabolite Indication

Doxorubicin Carcinoma, sarcoma, lymphoma Methotrexate Lymphoma


3 Mitoxantrone Lymphoma, transitional cell Cytosine arabinoside Lymphoma
carcinoma
5-Fluorouracil, 5-FU Carcinoma
Actinomycin Lymphoma

Bleomycin Squamous cell carcinoma z Prednisolone and L-Asparaginase


Prednisone non-specifically inhibits DNA synthe-
sis and cell division. It is inexpensive and com-
. Table 3.7 Antimicrotubule agents and their paratively well tolerated. It is commonly used in
most common indications in veterinary oncology the treatment of lymphomas, plasma cell tumors
and, mast cell tumors. The usefulness of predni-
Antimicrotubule
agent Indication sone in the treatment of canine lymphoma has
been questioned by recent studies.
Vincristine Lymphoma, canine L-Asparaginase is a bacterial enzyme that
transmissible venereal tumor, degrades the amino acid asparagine. It is thought
mast cell tumor
to induce a systemic asparagine deficiency,
Vinblastine Lymphoma, mast cell tumor which mostly affects proliferative cells. However,
Vinorelbine Mast cell tumor, lung tumor
increased asparagine synthesis by increased
asparagine synthetase activity is a commonly
observed resistance mechanism in tumor cells
antimicrotubule drugs cause microtubule dys- treated with L-asparaginase.
function, which is not understood in all aspects.
They are believed to inhibit both the formation
and disassembly of microtubules, which ulti- 3.2.3 Mechanisms of Chemotherapy
mately prevents the completion of mitosis Resistance
(. Table 3.7).
As described above, multiple drug protocols play
z Antimetabolites a key role as neoadjuvant or adjuvant treatment
Antimetabolites are highly similar to endogenous in veterinary oncology. Unfortunately most
nucleotides like purines and pyrimidines required tumors do not respond to the majority of anti-
for DNA synthesis. Antimetabolites block the cancer drug groups and are therefore intrinsically
enzymes involved in DNA synthesis. They work resistant. Other tumors are initially sensitive but
either by competitive binding or by incorporating develop an acquired resistance during treatment.
into newly synthesized but fragile DNA strands. Resistance, whether acquired or intrinsic, is often
Both mechanisms inhibit cell division and are the reason chemotherapy ultimately fails. The
believed to induce apoptosis (. Table 3.8). exact mechanisms behind intrinsic and acquired
chemotherapy resistance in the tumors of veteri-
z Tyrosine Kinase Inhibitors nary patients are unknown. There is nevertheless
The tyrosine kinase inhibitors masitinib and toc- an increasing understanding of the mechanisms
eranib have been tested for the treatment of of resistance in human tumors; the first drugs to
several canine tumor types but seem to have the overcome or prevent chemotherapy resistance
highest efficacy in the treatment of canine mast are now on the market. Tumors in human patients
cell tumors. They inhibit several tyrosine kinase and in veterinary patients in veterinary medicine
receptors including the stem cell factor receptor share some clinical behaviors and responses to
KIT, the platelet-derived growth factor receptor chemotherapeutic drugs so it is not unreasonable
(PDGFR), the vascular endothelial growth factor- to hope that these drugs will also be of use in vet-
2 (VEGFR2), and several others. erinary oncology.
Chapter 3 · Basic Principles of Cancer Therapy
47 3
of reversing acquired doxorubicin resistance in
Box 3.1. Most Important Mechanism of canine lymphomas.
Chemotherapy Resistance in Tumors
1. Increased efflux by ABC transporter z Drug Inactivation in Tumor Cells
proteins Most research on chemotherapeutic resistance is
2. Drug inactivation in tumor cells focused on intracellular drug activation and inac-
3. Changes in drug targets tivation in tumor cells, although all phases of drug
4. Increased DNA damage repair metabolism in the body, i.e., absorption, distribu-
5. Apoptosis evasion tion, hepatic metabolism, and excretion, probably
6. Cancer stem cells and quiescence contribute to resistance. The most important
pathways of drug activation and inactivation
include the cytochrome P450 (CYP) system, the
Six main mechanisms of chemotherapy glutathione S-transferase (GST) superfamily,
resistance have been postulated and are dis- and uridine diphospho-glucuronosyltransferase
cussed briefly in this chapter: ABC transporter (UGT) superfamily.
proteins, drug inactivation, drug target change, The cytochrome P450 (CYP) system is the
DNA repair, apoptosis evasion, and tumor major enzyme involved in drug metabolism and
stem cells. therefore of importance for chemotherapy resis-
tance in cancer. Many genetic polymorphisms in
z Increased Efflux by ABC Transporter the CYP system have been identified in tumors
Proteins compared to nonneoplastic cells. However, the
Drug efflux from the cell is executed mainly by relevance of these polymorphisms for tumor
membrane transporter proteins known as ATP- resistance mechanisms in veterinary patients is
binding cassette (ABC) transporters. There are at unknown.
least 49 ABC transporters, of which the multidrug Glutathione of the GST superfamily and
resistance protein 1 (MDR1, P-glycoprotein (PGP), metallothionein are metabolic pathways that
ABCB1), the MDR-associated protein 1 (MRP1, contribute to resistance to doxorubicin, alkylat-
ABCC1), and the breast cancer resistance protein ing agents, and platinum drugs. Expression of
(BCRP, ABCG2) have been the most intensely both glutathione and metallothionein has been
investigated. All ABC transporters can eliminate identified in several canine and feline tumors.
hydrophobic chemotherapy drugs from cells, Increased GST expression is associated with
including antimetabolites, platinum compounds, increased risk of lymphoma development and
microtubule inhibitors, and tyrosine kinase inhib- resistance to chemotherapy protocols in canine
itors (TKI). MDR1 is overexpressed in tumors lymphomas.
prior to chemotherapy and thus contributes to The uridine diphospho-glucuronosyltransferase
intrinsic resistance. It may also increase in expres- (UGT) superfamily of enzymes catalyzes gluc-
sion during chemotherapy and would therefore uronidation and is thus involved in the inactiva-
contribute to acquired resistance. MDR1, MRP1, tion of hydrophilic glucuronides used by cytotoxic
and BCRP expressions are also detectable in sev- drugs. A downregulation of UGT transcription
eral canine tumors; their expression level may be has been described in human tumors, but its rele-
correlated with the efficacy and outcome of chemo- vance for chemotherapy resistance in animals is
therapy protocols or intrinsic resistance of canine not clear.
lymphomas and mammary tumors. In addition,
MDR1 expression in feline tumors is thought to z Changes in Drug Targets
contribute to resistance in this species. Three gen- Quantitative and qualitative changes of drug tar-
erations of ABC transporter modulators/inhibi- gets represent well-known mechanisms of che-
tors have been developed to address this problem. motherapy resistance in human oncology. For one
Only the first-generation MDR1 inhibitors vera- quantitative change can occur, such as decreased
pamil and cyclosporine A have been successfully or lost expression of the target gene product by the
tested, both in canine mammary tumors and cuta- tumor cells. Tumor cells can also be selected for
neous mast cell tumor cells. In addition, tyrosine bearing a qualitatively different mutated drug tar-
kinase inhibitors including masitinib seem capable get, which causes a change in the drug-binding
48 M. Brunnberg et al.

site. For instance, prolonged treatment of canine vivin and myeloid cell leukemia sequence 1
mast cell tumor cells with tyrosine kinase inhibi- (MCL1) is a negative prognostic factor for early
tors (TKI) leads to overexpression or de novo treatment of canine lymphoma with a CHOP-
expression of alternative proliferative pathways or based protocol.
to the selection of tumor cell subclones with muta-
tions in the KIT gene, which may cause ineffective z Cancer Stem Cells and Quiescence
3 TKI binding to KIT. There is increasing evidence that cancer stem
cells (CSC) are of central relevance for chemoresis-
z Increased DNA Damage Repair tance. It has been repeatedly shown that CSC
Insufficient DNA damage repair systems are have highly active drug efflux pumps, increased
major mechanisms of carcinogenesis in several detoxification enzyme levels, enhanced DNA
tumor types. For instance, dysfunctional p53 repair efficacy, and apoptosis resistance, all of
activity is suspected in some canine and feline which are mechanisms of chemotherapy resis-
tumors. Although intact DNA damage response tance. In addition, CSC are able to switch into a
(DDR) is desirable in health, its desirability is state of quiescence or dormancy and therefore can
questionable in terms of chemotherapy resistance. evade the effects of classical chemotherapeutic
Induction of DNA damage and subsequent cell drugs, which are usually only effective on prolif-
death by apoptosis is the main mechanism of erating cells. Therapy modalities directly targeting
action for platinum-based drugs and alkylating CSC or quiescent CSC are therefore a major
agents. This requires apoptosis induction via DNA focus in tumor research. Activity of a few signal-
damage sensors and p53. If these pathways are ing pathways, namely, WNT, Notch, and
dysfunctional due to mutations, the drugs are Hedgehog (HH), contributes to the CSC pheno-
ineffective. Highly effective DDR is also a cause of type. Application of bone morphogenetic protein
resistance because it allows tumor cells to repair (BMP), a WNT signaling inhibitor; cyclopamine,
and survive chemotherapy-induced DNA dam- a nHHS pathway inhibitor; or antibodies against
age. Application of DDR inhibitors together with Notch pathway proteins has been used to directly
DNA-damaging agents is a promising although target CSC in human breast cancer and glioblas-
somewhat counterintuitive therapy strategy. The toma CSC.
most prominent DDR inhibitors, such as olaparib,
interfere with the single-strand break DNA repair
enzyme poly-ADP-ribose polymerase (PARP1).
Unfortunately, there are no studies available on 3.3 Radiation Oncology in
the efficacy of PARP1 inhibitors in tumors of vet- Veterinary Medicine
erinary patients.
M. Wergin
z Apoptosis Evasion
Evasion of chemotherapy-induced apoptosis is Radiation treatment of human and veterinary
another common mechanism of resistance to patients has seen tremendous progress in the past
chemotherapy. The best understood mechanism few decades. Common research topics included
of apoptosis evasion by tumor cells is based on fractionation schemes, dosing, and improvements
overexpression of apoptosis genes, of which Bcl-2 in technical equipment.
and TNF-related apoptosis-inducing ligand
(TRAIL) are the most intensely studied.
Compounds like navitoclax are able to antago- 3.3.1 Biology of Radiation Therapy
nize Bcl-2 overexpression, while recombinant
TRAIL and TRAIL receptor (TrailR)-activating In ionizing radiation, incoming rays have enough
antibodies have been successfully tested in stim- energy to eject an orbital electron from an atom
ulating apoptosis induction in combination with or molecule. Ionizing radiation used in radiother-
classic chemotherapeutic drugs. Unfortunately apy is divided into x-radiation (x-ray) and gamma
there is little available data on apoptosis evasion radiation (γ-radiation). By consensus, the term x-
in veterinary oncology. However, it is known that ray refers to ionizing radiation with energy of up
overexpression of the anti-apoptotic proteins sur- to 200 KeV, an energy range that is used primarily
Chapter 3 · Basic Principles of Cancer Therapy
49 3
in diagnostic imaging. γ-radiation is an ionizing Tumor cells can divide and repopulate the tumor
radiation with energy between 200  KeV and if the course of radiation is interrupted for too
26 MeV. The energy absorbed by tissues is given long. The time between radiation fractions
in gray (Gy). One gray corresponds to an energy should therefore not be prolonged, especially for
deposit of 1 J/kg. fast dividing tumors like squamous cell carcino-
Energy is absorbed as the rays slow down and mas.
pass through tissue, establishing energy deposits.
These deposits can eventually lead to direct or
indirect damage. The direct damage is caused by 3.3.2 Indications for Radiation
the initiation of DNA double-strand breaks Therapy
(DSB). These DSB lead to chromosomal aberra-
tions, which can simultaneously affect many Radiation therapy is applied for different tumor
genes and cause mutation, malfunction, and cell types (. Table 3.9).
death. Ionizing radiation causes mainly indirect The total dose and the fractionation scheme
damage. Energy absorption by the water mole- depends on the radiosensitivity of the tumor. It is
cules in the tissue causes hydroxyl radicals (·OH) restricted by the radiosensitivity of normal tissue
to form. These free radicals have unpaired elec- within the treatment field. The skin and underly-
trons, which can cause DNA damage. Another ing muscle are more radiation resistant than neu-
indirect effect of ionizing radiation is the pro- ral tissues like the brain or the spinal cord.
duction of reactive oxygen species (ROS). ROS Radiation can be given as a single, primary
can only be built when oxygen is present in the treatment, for example, in brain tumors, squa-
cell. Tumors are often hypoxic due to their mous cell carcinoma of the nasal planum in cats
abnormal and chaotic vasculature. Hypoxia (. Fig.  3.4), or nasal tumors. In addition to pri-
causes radioresistance to ionizing radiation, mary radiation, radiotherapy can be adjunctive
because ROS cannot be built. It has been shown to surgery and/or chemotherapy. Adjuvant radi-
that ionizing radiation must be 2.9 times higher ation means that surgery or chemotherapy is
to kill hypoxic tumor cells than to kill well-oxy- given before radiation treatment. This option is
genated tumor cells. chosen if the tumor can be removed surgically
Many tumors can be treated with a curative (. Fig. 3.5). If the tumor is too big to be removed,
intent with doses between 30 and 55  Gy. When a neoadjuvant radiotherapy can be advantageous.
radiation is applied, the dose must be fraction- Neoadjuvant radiation means that radiation is
ated into multiple small doses. The 4R’s of radia- given before surgery and/or chemotherapy.
tion explain the need for fractionation: repair, Radiation can reduce the tumor burden, making
reoxygenation, radiosensitivity, and repopula- the tumor more amenable to surgery.
tion. Repair of radiation-induced damage is pos- The typical radiation treatment in veterinary
sible in normal cells when radiation is given in medicine is given four to five times a week until
small doses. Normal cells can repair the damage the total dose is reached. Hypofractionation is
within 6 h, but the repair capacity of tumor cells when radiation is given only two to three times a
is significantly reduced. Reoxygenated tumor cells week. This is usually done for palliative care. An
are easier to kill. When radiation is given in mul- exception is the curative treatment of oral malig-
tiple fractions, some tumor cells are killed during nant melanoma. If tumors have a rapid tumor
the course of fractionation. This reduces the vol- doubling time, then an accelerated protocol can be
ume of the tumor. When the volume of the tumor used to reduce the repopulation during treatment.
is reduced, the oxygenation of the remaining This protocol is, for example, used to treat squa-
tumor is increased. Reoxygenated tumor cells mous cell carcinoma of the nasal planum and the
need a smaller dose to be killed, and radiation is eyelid in cats.
more effective. The radiosensitivity of cells Before starting radiation, the goal of the treat-
depends on the cell cycle. Cells are more radio- ment should be determined. Often many factors
sensitive during mitosis and in the G2 phase. The need to be taken into consideration to choose the
redistribution of cells from more resistant cell best treatment for an individual patient. A cura-
cycle phases to sensitive phases can increase the tive treatment is chosen if a cure or a long-term
effect of radiation. The fourth R is repopulation. tumor control can be achieved and if the patient
50 M. Brunnberg et al.

. Table 3.9 Current radiotherapy protocols for common tumors and associated prognosis

Tumor Radiotherapy
localization Tumor type protocol Prognosis References

Skin and subcutis Sarcoma (dog) Curative S: 70 months Forrest et al. (2000),
3 McKnight et al. (2000)

Palliative S: 12 months Plavec et al. (2006)

Injection site Curative S: 36 months Eckstein et al. (2009)


sarcoma (cat)
Palliative S: 10 months Eckstein et al. (2009)

Mast cell tumor Curative Depending on Frimberger et al. (1997),


grade: grade 2 MCT, Poirier et al. (2006a, b)
cure in 90 %

Palliative Thamm et al. (2006)

Oral tumors Malignant Palliative S: 10 months Proulx et al. (2003), Freeman


melanoma et al. (2003)

Squamous cell Curative S: 12–36 months LaDue-Miller et al. (1996),


carcinoma Théon et al. (1993, 1997a, b)

Sarcoma Curative S: 12–24 months Théon et al. (1993),


Poirier et al. (2006a, b)

Palliative S: 10 months Théon et al. (1993)

Acanthomatous Curative Curative in 80–90 % Théon et al. (1997b)


epulis

Nasal tumors Carcinoma Curative S: 12–24 months Théon et al. (1993), Adams


sarcoma et al. (2005)
lymphoma
Palliative S: 10 months Buchholz et al. (2009),
S: cat with nasal Haney et al. (2009)
lymphoma,
24 months

Tumors of the Squamous cell Curative 70 % cure rate Melzer et al. (2006)
nasal planum carcinoma (cat)

Brain tumors Meningioma Curative S: 30 months Rohrer Bley et al. (2003,


2005), Théon et al. (2000a)

Glioma Curative S: 30 months Rohrer Bley et al. (2003, 2005)

Pituitary tumor Curative S: 24–48 months RohBley et al. (2005), Kent


et al. (2007)

Thyroid tumors Carcinoma Curative 12–36 months Théon et al. (2000b)

Palliative 12–24 months Brearley et al. (1999)

Mediastinum Thymoma Curative or Cat: 24 months Smith et al. (2001)


palliative Dog: 8 months
Chapter 3 · Basic Principles of Cancer Therapy
51 3

a b

c d

. Fig. 3.4 Radiation of an SCC of the nasal planum of a cat. Primary radiation of a squamous cell carcinoma (SCC)
of the nasal planum of a cat. Radiation was applied as the sole treatment option. An accelerated protocol with ten
fractions twice daily was used. (a) The SCC before radiation. (b) The SCC at the end of radiation: the tumor already
appears smaller. (c) 3 weeks after completion of therapy. The tumor is healed and the hair has fallen off. (d) The tumor
has been cured and the hair has grown back 3 months after radiation

has no other life-threatening disease. A curative growth or to reduce tumor volume with only mild
radiation protocol is usually given within 14–20 to no acute radiation side effects. The higher the
fractions of 2.5–4  Gy. The radiation is given radiation dose per fraction, the more severe are
4–5 days a week. In general, a curative protocol is the late reactions developing. In a palliative
more strenuous and is accompanied by more approach, the life expectancy of the treated
severe side effects. patients is so short that late reactions will most
Palliative radiation is used to improve quality likely not develop. Radiation to control pain in
of life when the patient cannot be cured due to patients with osteosarcoma contains 2–5 fractions
several reasons, for example, risk of developing with 6–10 Gy per fraction. One study showed that
distant metastasis or presence of distant metasta- treatment with two fractions of 8  Gy was suffi-
sis at the time of diagnosis. Another reason to cient to treat bone pain in these dogs. Pain control
choose palliative treatment might be age of the starts approximately 3 weeks after finishing radia-
patient or overall health. Palliative treatment is tion. The pain can be controlled for 2–4 months
also used to reduce pain in both neoplastic and with radiation. Palliative radiation can also be
benign disease processes. The protocols for pallia- used to treat pain in benign disease such as
tive radiation should be designed to slow tumor arthrosis.
52 M. Brunnberg et al.

a b

c d

. Fig. 3.5 Adjuvant treatment of a dog with a mast cell tumor. An adjuvant curative radiation treatment was chosen
for this dog with a Grade II mast cell tumor. The tumor was removed 2 weeks before radiation. (a) The skin has healed 2
weeks after completion of therapy. (b) The hair has not regrown at the 3-month recheck, (c, d) but at the 6-month
recheck, the hair has grown back in white (leukotrichia)

3.3.3 Adverse Side Effects the healing process. The severity of radiation reac-
of Radiation tion depends on the localization of radiation, the
volume of irradiated skin, and the individual radia-
The side effects of radiation depend on the type of tion sensitivity. In general, the skin of dogs is more
healthy tissue in the field of radiation and on the radiation sensitive than the skin of cats.
applied dose. The skin or mucosa or surgical scars, Leukotrichia, white hair, is typically seen when
in the case of adjuvant radiation, are most fre- haired skin was in the radiation field (. Fig. 3.7).
quently affected. Side effects of radiation are Late reactions may develop months to years
divided into acute and late reactions. after radiation. Late reactions are more common
Acute reactions are typically affecting the skin when hypofractionated, high-dose per fraction
and mucosa but can also affect other tissues within protocols are applied. Keratoconjunctivitis
the radiation field. The irradiated skin develops a sicca, cataracts, and retinopathy are common
moist desquamation comparable to a sunburn. late reactions to radiation. Cataracts develop
Necrosis and hyperemia (also called mucositis) of over years and are usually not clinically relevant.
irradiated mucosa can also be observed (. Fig. 3.6). Irradiation can also be carcinogenic, but this is a
Self-mutilation of affected skin areas is another long-term effect that is of minor relevance in
common problem. An Elizabethan collar should be veterinary medicine due to shorter patient life
used, if necessary. Bandaging is not recommended span. The risk of developing irradiation-induced
because irradiated skin is very delicate. Antibiotics, tumors 5  years after radiation has been calcu-
steroids, or NSAIDs are commonly used to support lated to be 3.5 %.
Chapter 3 · Basic Principles of Cancer Therapy
53 3

a 3.3.4 Radiation Treatment Devices

Ionizing radiation can be applied in different


ways:
• External beam radiation
• Internal radiotherapy
• Particle therapy
• Therapy with nuclides
External beam radiation, also called telether-
apy, is the most common form of radiation ther-
apy in human and veterinary medicine. The
patient is positioned, and an external source is
b pointed at the target tissue. For external beam
radiation, different sources can be used:
• Superficial x-rays: 50–200 keV
• Orthovoltage x-rays: 200–500 keV
• Supervoltage x-rays: 500–1000 keV
• Megavoltage x-rays: 1–25 MeV
Megavoltage x-rays are the most common; in
veterinary medicine the use of 3–9  MeV is
sufficient for the treatment of small animals.
Superficial x-rays and orthovoltage x-rays can only
be used for skin-associated tumors, because the
. Fig. 3.6 (a) Acute side effects of radiation of moist energy is too weak for a deeper penetration. The
desquamation of the skin and mucositis of the oral maximum dose of energy is deposited at the skin
mucosa at the end of curative radiation. (b) Skin reactions
at the end of curative radiation. A rapid healing of
surface, and only 10 % of the energy reaches a 2 cm
affected skin within 3 weeks is usually seen depth. Severe cutaneous side effects are the result.

. Fig. 3.7 Leukotrichia (regrowth of white hair) is a typical observation in irradiated skin. Both dogs received curative
radiation. No further late reactions are present
54 M. Brunnberg et al.

Megavoltage irradiation is mainly given with


linear accelerators (Linac). Linacs utilize x-rays,
also called photons or electron beams. Photons
build up in tissue by depth. This buildup has a
skin-sparing effect. Electrons can be used to treat
skin tumors and subcutaneous tumors. The
3 advantage of electrons is the limited penetration
so that the underlying tissue is protected from
radiation damage. The source-to-skin distance
with electron radiation is 100  cm allowing big
fields to be irradiated.
Linacs provide very clear margins of the treat-
ment field, allowing high-precision radiation.
They are also equipped with a multileaf collimator
(MLC), which allows the radiation field to be
shaped individually (. Fig.  3.8). Usually, photon
irradiation is given with multiple beams to achieve
a homogenous dose distribution within the treat-
ment field. For complex planning a specific plan-
ning software is used (. Fig. 3.9).

. Fig. 3.8 Multileaf collimator. A coronal CT scan of the 3.3.5 Therapy Planning
head of a dog with a nasal adenocarcinoma is shown.
Primary curative radiation was planned. To protect the
eyes (dark blue and light blue color), a multileaf collimator
The first step in therapy planning is to define the
(MLC) was used for treatment planning. The MLC is shown fractionation scheme of radiation. The second
by the blue lines, and the individually shaped field is shown step is to define the treatment volume. Planning
Chapter 3 · Basic Principles of Cancer Therapy
55 3

a b

c d

. Fig. 3.10 Positioning devices. (a) Dog is placed in a Plexiglas box with a vacuum cushion. The cushion helps to keep
the body in the same position for every treatment. The box has a bridge to place the head. (b) A bite block is placed on
the bridge. (c) The same system is used for cats. (d) The box is placed on the treatment table, and the position of the box
and of the patient in the box is checked before every single treatment

software is used to achieve the optimal dose dis- precise than CT in determining the tumor vol-
tribution within the treatment volume. A com- ume. Modern tumor planning software allows
puter tomography (CT) is needed for planning. CT and MRI to be overlaid, to precisely deter-
Before the CT scan, a positioning device is mine the radiation volume. The gross tumor
adapted to the patient. Precise positioning volume (GTV) is the visible tumor seen by CT
assures that the treated volume is as small as and/or MRI. The clinical tumor volume (CTV)
possible, and high-risk organs are protected. A is defined by the visible tumor volume and
bite block of the upper jaw can be used for posi- healthy tissue most likely being invaded by
tioning (. Fig.  3.10). The planning must assure tumor cells. The planning tumor volume (PTV)
that the dose within the tumor is 95–105 % of adds the positioning inaccuracy to the CTV. The
the prescribed dose. The tumor volume must be more precise the positioning device, the smaller
determined by diagnostic imaging. MRI is more the PTV (. Fig. 3.9).

. Fig. 3.9 Radiation therapy planning for teletherapy. A transversal, coronal, and sagittal image of a CT scan is shown.
The dog had a brain tumor and received curative radiation. The dose distribution within the tissue is shown. Red color
indicates a high dose (100 %) and the blue and green colors show a low dose. Note that the tumor volumes are given on
the transversal view: gross tumor volume (GTV), clinical tumor volume (CTV), and the planning tumor volume (PTV). The
tumor was treated with 95–105 % of the prescribed dose, and non-effected parts of the brain were largely protected
from radiation
56 M. Brunnberg et al.

3.3.6 Internal Beam Radiation differentiated mast cell tumors in the dog: 37 cases
(1989–1993). J Am Anim Hosp Assoc 33:320–324
Gillette EL, LaRue SM, Gillette SM (1995) Normal tissue tol-
Internal beam radiation, also called brachyther- erance and management of radiation injury. Semin Vet
apy, is a less commonly used approach. Med Surg (Small Anim) 10:209–213
Brachytherapy is delivered from a short distance. Hall EJ (2000) Time, dose, and fractionation in radiother-
The radiation source is placed directly into or next apy. In: Hall EJ, Giaccia AJ (eds) Radiobiology for the
3 to the tumor using small pellets, seeds, or wire. radiologists, 6th edn. Lippincott William & Wilkins,
Philadelphia, pp 378–397
The insert can be either temporary or permanent. Haney SM, Beaver L, Turrel J et al (2009) Survival analysis of 97
Iridium-192 is the most commonly used radioac- cats with nasal lymphoma: a multi-institutional retro-
tive substance. Iridium can be inserted directly spective study (1986–2006). J Vet Intern Med 23:287–294
into the tumor. However, the delivered dose can- Harris D, King GK, Bergman PJ (1997) Radiation therapy tox-
icities. Vet Clin North Am Small Anim Pract 27:37–46
not be planned as accurate as external beam radi- Hill RP, Bristow RG (2004) The scientific basis of radiother-
ation. The afterloading technique is a newer apy. In: Tannock IF, Hill RP, Bristow RB, Harrington L
treatment approach. With this technique, one or (eds) The basic science of oncology, 4th edn. McGraw
multiple catheters are inserted into the tumor, and Hill Companies, New York, p 305
the radiation source is placed in the catheter. The History of radiation oncology, University of Alabama at
Birmingham Comprehensive Cancer Center. Archived
advantage of this system is that medical staff is from the original
exposed to lower radiation doses. Newer planning Kent MS, Bommarito D, Feldman E et  al (2007) Survival,
systems are available in human medicine to assure neurologic response, and prognostic factors in dogs
an accurate dose delivery, but these systems are with pituitary masses treated with radiation therapy
not yet used in veterinary medicine. and untreated dogs. J Vet Intern Med 21:1027–1033
Klopfleisch R, Kohn B, Gruber AD (2016) Mechanisms of
tumour resistance against chemotherapeutic agents
in veterinary oncology. Vet J 207:63–72
Suggested Reading LaDue T, Klein MK (2001) Toxicity criteria of the veterinary
radiation therapy oncology group. Vet Radiol
Adams WM, Bjorling DE, McAnulty JE et al (2005) Outcome Ultrasound 42:475–476
of accelerated radiotherapy alone or accelerated LaDue-Miller T, Price GS, Page RL et al (1996) Radiotherapy
radiotherapy followed by exenteration of the nasal of canine non-tonsillar squamous cell carcinoma. Vet
cavity in dogs with intranasal neoplasia: 53 cases Radiol Ultrasound 37:74–77
(1990–2002). J Am Vet Med Assoc 227:936–941 Mayer MN, Grier CK (2006) Palliative radiation therapy for
Brahme A (ed) (1988) Accuracy requirements and quality canine osteosarcoma. Can Vet J 47(7):707–709
assurance of external beam therapy with photons and McKnight JA, Mauldin GN, McEntee MC et  al (2000)
electrons. Acta Oncol, 4th edn (Suppl 1) Radiation treatment for incompletely resected soft
Brearley MJ, Hayes A, Murphy S (1999) Hypofractionated tissue sarcomas in dogs. J  Am Vet Med Assoc
radiation therapy for invasive thyroid carcinoma in 217:205–210
dogs. J Small Anim Pract 40:206–210 Melzer K, Guscetti F, Rohrer Bley C et al (2006) Ki67 reactiv-
Bristow RG, Hill RP (2004) Molecular and cellular basis of ity in nasal and periocular squamous cell carcinomas
radiotherapy. In: Tannock IF, Hill RP, Bristow RB, in cats treated with electron beam radiation therapy.
Harrington L (eds) The basic science of oncology, 4th J Vet Intern Med 20:676–681
edn. McGraw Hill Companies, New York, pp 273–279 Northrup NC, Roberts RE, Harrell TW, Allen KL, Howerth
Buchholz J, Hagen R, Leo C et al (2009) 3D conformal radia- EW, Gieger TL (2004) Iridium-192 Interstitial
tion therapy for palliative treatment of canine nasal Brachytherapy as Adjunctive Treatment for Canine
tumors. Vet Radiol Ultrasound 50:679–683 Cutaneous Mast Cell Tumors. J  Am Anim Hosp Assoc
Eckstein C, Guscetti F, Roos M et al (2009) A retrospective 40(4):309–315
analysis of radiation therapy for the treatment of feline Pioneer in X-Ray therapy (1957) Science 125(3236):18–19
vaccine-associated sarcoma. Vet Comp Oncol 7:54–68 Plavec T, Kessler M, Kandel B et  al (2006) Palliative radio-
Forrest LJ, Chun R, Adams WM et  al (2000) Postoperative therapy as treatment for non-resectable soft tissue
radiotherapy for canine soft tissue sarcoma. J  Vet sarcomas in the dog – a report of 15 cases. Vet Comp
Intern Med 14:578–582 Oncol 4:98–103
Freeman KP, Hahn KA, Harris FD et al (2003) Treatment of Poirier VJ, Adams WM, Forrest LJ et  al (2006a) Radiation
dogs with oral melanoma by hypofractionated radia- therapy for incompletely excised grade 2 canine mast
tion therapy and platinum-based chemotherapy cell tumors. J Am Anim Hosp Assoc 42:430–434
(1987–1997). J Vet Intern Med 17:96–101 Poirier VJ, Rohrer Bley C, Roos M et  al (2006b) Efficacy of
Frimberger AE, Moore AS, LaRue SM et  al (1997) radiation therapy for the treatment of macroscopic
Radiotherapy of incompletely resected, moderately canine oral soft tissue sarcoma. In Vivo 20:415–420
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Pommer A (1958) X-ray therapy in veterinary medicine. In: Thamm DH, Turek MM, Vail DM (2006) Outcome and prog-
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spective analysis of 140 dogs with oral melanoma Théon AP, Madewell BR, Harb MF et al (1993) Megavoltage
treated with external beam radiation. Vet Radiol irradiation of neoplasms of the nasal and paranasal
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59 4

Skin Tumors
Robert Klopfleisch

4.1 Skin Tumors of the Dog – 60


4.1.1 Canine Epithelial Tumors – 60
4.1.2 Canine Cutaneous Melanomas – 66
4.1.3 Canine Soft Tissue Sarcomas – 68
4.1.4 Canine Cutaneous Hematopoietic Tumors – 73

4.2 Skin Tumors of the Cat – 79


4.2.1 Feline Epithelial Tumors – 79
4.2.2 Mesenchymal Tumors – 83
4.2.3 Feline Hematopoietic Tumors – 87

4.3 Equine Skin Tumors – 90


4.3.1 Equine Sarcoids – 90
4.3.2 Equine Melanomas – 92

4.4 Bovine Skin Tumors – 93


4.4.1 Bovine Cutaneous Papillomas/Papillomatosis – 93

Suggested Reading – 94

© Springer International Publishing Switzerland 2016


R. Klopfleisch (ed.), Veterinary Oncology, DOI 10.1007/978-3-319-41124-8_4
60 R. Klopfleisch

4.1 Skin Tumors of the Dog Pilomatricomas are benign tumors, which
are thought to arise from cells of the hair bulb.
There is a wide variety of skin tumors in the dog; They are more common in middle-aged dogs
tumors derive from the epithelial cells of the epi- than in older dogs. There is no confirmed breed
dermis and adnexa, the melanocytes, dermal stro- disposition. Malignant pilomatricomas are
mal cells, subcutaneous adipocytes, or infiltrating rarely observed and are characterized by local
hematopoietic cells. Mast cell tumors are the most infiltration, tumor satellites, and metastasis
common canine skin tumor. Soft tissue sarcomas into the lung, bone, and less commonly into
4 including (i.e., lipomas, subcutaneous peripheral other organs.
nerve sheath tumors, fibrosarcomas) histiocyto-
mas, squamous-cell carcinomas, melanomas, hair z Clinical Appearance
follicle tumors, and cutaneous glandular tumors The three main types of canine hair follicle
are other common tumors, which all have a simi- tumors cannot be separated by their clinical
lar but lower incidence. appearance. All present as solid, well-circum-
scribed, <5 cm in diameter large, partly cystic,
slowly growing tumors. They may be ulcerated
4.1.1 Canine Epithelial Tumors and hairless. Pilomatricomas may be firmer due
to calcification and rare ossification. All three
4.1.1.1 Canine Hair Follicle Tumors tumors are mostly benign but the surrounding
skin and the regional lymph nodes should
be checked for tumor satellites or regional
Box 4.1. Canine Hair Follicle Tumors in Three metastasis.
Facts
1. Mostly benign or merely locally invasive. z Cytology and Histopathology
2. Surgery mostly curative. Cytology of hair follicle tumors presents with rela-
3. Subclassification into histologic subtypes tively well-differentiated squamous epithelial cells
is of minor clinical relevance. admixed with mostly large amounts of cellular
debris or keratin (. Figs. 4.1, 4.2, and 4.3).
Histopathology is necessary to identify the specific
z Epidemiology and Pathogenesis tumor type and invasive character and to analyze
Hair follicle tumors are common skin tumors of the surgical margins.
the dog. They are divided into three main tumor
types according to their histopathologic appear-
ance, which are nevertheless very similar in their
clinical appearance and biologic behavior.
Trichoblastomas are benign tumors, which
are currently believed to arise from epidermal
basal cells or follicular stem cells. The tumor
was previously called a basal cell tumor but has
been renamed recently and is now known as
trichoblastoma in the dog. Trichoblastomas are
tumors of middle-aged to older dogs. A breed
disposition for some terrier breeds may be
present.
Trichoepitheliomas are also benign tumors,
which present with histologic growth patterns
resembling hair follicles. They are tumors of . Fig. 4.1 Cytology, trichoblastoma, dog,
middle-aged to older dogs. A breed disposition May-Grünwald-Giemsa, 500×. Note the clusters of small
basaloid epithelial cells showing a typical “ribbonlike”
may be present for retrievers and poodles. An growth pattern (Photo: with permission of Dr. N. Bauer,
invasive and metastatic malignant form of the Faculty of Veterinary Medicine, Justus-Liebig-University,
tumor has been described but is very rare. Giessen, Germany)
Chapter 4 · Skin Tumors
61 4
4.1.1.2 Canine Squamous Cell
Carcinomas

Box 4.2. Canine Cutaneous Squamous Cell


Carcinomas in Five Facts
1. Rather rare tumors.
2. UV light may be involved in
carcinogenesis.
3. Mostly flat, ulcerated plaques.
4. Rarely metastasize but grow invasively.
5. Surgery with wide margins is the
therapy of choice.
. Fig. 4.2 Cytology, trichoblastoma, dog,
May-Grünwald-Giemsa, 1000×. Note the clusters of small,
uniform cuboidal to slightly spindle-shaped basaloid Epidemiology and Pathogenesis
z
epithelial cells with round nuclei and fine chromatin
pattern (Photo: with permission of Dr. N. Bauer, Faculty of Squamous cell carcinomas (SCC) of the skin are
Veterinary Medicine, Justus-Liebig-University, Giessen, rather rare tumors in dogs. There is no breed or age
Germany) predisposition. Actinic damage due to UV light
plays a role in carcinogenesis in light-colored
dogs or body areas. Rare, multicentric, noninva-
sive SCC are potentially induced by Papillomavirus
infection and called Bowen’s disease based upon
the feline disease. Black-coated dogs are predis-
posed to develop subungual SCC at the digits.

z Clinical Appearance
SCC usually presents as ulcerated, invasive
plaque-like lesions; only rarely do they present
as  prominent, cauliflower-like actual masses
(. Fig. 4.4). Metastasis is uncommon but the
regional lymph node should be palpated or biop-
sied, and lung metastases should be excluded
radiographically in animals with large tumors.
. Fig. 4.3 Cytology, cystic mass with keratinized debris Advanced SCC of the nasal planum has a more
indicative of epidermal inclusion cyst or hair follicle tumor guarded prognosis due to the aggressive invasive
that look similar in cytological specimens, dog, character and the difficulties associated with sur-
May-Grünwald-Giemsa, 100×. Note numerous anuclear gery in this location.
keratinocytes (red arrow) between large amounts of
amorphous keratinized debris (black arrow) (Photo: with
permission of Dr. N. Bauer, Faculty of Veterinary Medicine, z Cytology and Histopathology
Justus-Liebig-University, Giessen, Germany) Cytology of SCC usually presents with variably
differentiated epithelial cells, keratin, and signs of
secondary inflammation due to a superficial
z Therapy infection of ulcerated tumors (. Figs. 4.5 and 4.6).
Surgery with appropriate tumor margins is usu- Histopathology of an incisional biopsy or of the
ally curative. excised tumors is necessary for final diagnosis
and evaluation of surgical margins. SCC is char-
z Suggested Reading acterized by variably differentiated epithelial
(Abramo et  al. 1999; Brachelente et  al. 2013; tumor cells, with typical keratinization and kera-
Carroll et al. 2010; Hoshino et al. 2012; Masserdotti tin pearls. Stromal proliferation and secondary
and Ubbiali 2002) inflammation due to ulceration are common.
62 R. Klopfleisch

4
. Fig. 4.4 Subungual squamous cell carcinoma (relapse
after amputation of one digit) with invasion of the bone
and osteolysis, dog. Ulcerated flat mass at the right hind
paw of an 11-year-old Giant Schnauzer (Photo: with
. Fig. 4.6 Cytology, metastatic squamous cell
permission of Prof. M. Kramer, Faculty of Veterinary
carcinoma, lymph node, dog, May-Grünwald-Giemsa,
Medicine, Justus-Liebig-University, Giessen, Germany)
1000×. Note the large cluster of round to cuboidal
epithelial cells (red arrow) with moderate anisocytosis,
anisokaryosis, pleomorphism, and variation of
nuclear-to-cytoplasm ratio. The epithelial cells possess one
to several prominent nucleoli, often macronucleoli (gray
arrow, i.e., nucleoli with a diameter >5 μm and thus
approximately of the size of an erythrocyte). They are
surrounded by few small mature lymphocytes (black arrow)
representing the lymphoid tissue (green arrow) (Photo: with
permission of Dr. N. Bauer, Faculty of Veterinary Medicine,
Justus-Liebig-University, Giessen, Germany)

Chemotherapy using 5-fluorouracil, doxorubi-


cin, cisplatin, mitoxantrone, or Cox-2 inhibitors
has been applied intralesionally or systemically
for tumors where excision was impossible. Short-
term reduction of tumor size was observed in
. Fig. 4.5 Cytology, squamous cell carcinoma, Giant these cases but relapsed tumor growth will occur.
Schnauzer (the same dog as in . Fig. 4.4),
May-Grünwald-Giemsa, 1000×. Marked anisocytosis, z Suggested Reading
anisokaryosis, and pleomorphism of epithelial cells as well (Belluco et al. 2013; Langova et al. 2004; O’Brien
as marked variation in maturation reflected by a high
et  al. 1992; Thomson 2007; Waropastrakul et  al.
variation in nuclear-to-cytoplasm ratio and increased,
highly variable cytoplasm basophilia. Often, multiple 2012; Webb et al. 2009)
perinuclear vacuoles containing colorless keratohyalin
(arrows) are seen also strongly suggestive of 4.1.1.3 Canine Tumors
squamous-cell carcinoma (Photo: with permission of Dr. of the Sebaceous and Apocrine
N. Bauer, Faculty of Veterinary Medicine, Skin Glands
Justus-Liebig-University, Giessen, Germany)

Therapy Box 4.3. Canine Tumors of the Sebaceous


z
and Apocrine Glands in Three Facts
Surgery with wide margins is the treatment of
1. Usually benign tumors.
choice for SCC. Tumor-free margins are strongly
2. Wide surgical excision curative.
correlated with a good prognosis, while metastasis
3. Carcinomas very rarely metastasize.
or nonsurgical treatment is associated with a poor
prognosis.
The efficacy of radiotherapy is not tested for z Epidemiology and Pathogenesis
cutaneous SCC of the dog. However, SCC in other Sebaceous gland adenomas are benign tumors of
locations is usually sensitive to radiation. sebaceous gland origin. They are commonly
Chapter 4 · Skin Tumors
63 4
found on the head, limbs, and trunk; a breed pre-
disposition exists for cocker spaniels, poodles,
miniature schnauzers, and terriers at the age of
10 years. Sebaceous gland carcinomas are very
rare tumors with low-grade malignancy com-
monly found on the head and neck. Adenomas
show a sex predisposition for males; carcinomas
have a breed predisposition for cocker spaniels
and terriers.
Apocrine gland adenomas are fairly common
tumors of the head and neck of longhaired dog
breeds and cocker spaniels. They have an almost
similar incidence to apocrine gland carcinomas,
which are more common in golden retrievers . Fig. 4.7 Cytology, sebaceous gland adenoma, dog,
and are often found on the front legs. Both May-Grünwald-Giemsa, 1000×. Note the round to
benign and malignant tumors are mostly diag- cuboidal uniform epithelial cells with centrally located
nuclei, fine chromatin pattern, and abundant amounts of
nosed in dogs between the ages of 8 and 10 years.
basophilic cytoplasm containing multiple, clearly
Eccrine gland adenomas and carcinomas are circumscribed vacuoles (Photo: with permission of Dr.
rare tumors of the sweat glands of the footpad. N. Bauer, Faculty of Veterinary Medicine,
Justus-Liebig-University, Giessen, Germany)
z Clinical Appearance
Sebaceous gland adenomas usually present as rather
small, slowly growing, multiple papilloma-like
nodules. They may have a sebaceous surface and
are often inflamed due to secondary bacterial
infection. Adenomas are usually well circum-
scribed and do not metastasize. Sebaceous gland
carcinomas are fast and invasively growing tumors,
which are often ulcerated and inflamed.
Apocrine gland adenomas are usually solitary,
well-circumscribed, and sometimes cystic tumors.
Apocrine gland carcinomas are fast-growing often-
ulcerated tumors with invasion of the surround-
ing tissues and sometimes lymph and blood
vessels. Regional or distant metastasis is neverthe- . Fig. 4.8 Cytology, apocrine gland adenoma, dog,
less very uncommon. May-Grünwald-Giemsa, 400×. Note the clusters of
epithelial tumor cells (arrow) surrounded by erythrocytes
(red) and degenerate neutrophilic granulocytes
z Cytology and Histopathology
Cytology is only occasionally able to differentiate
benign from malignant gland tumors. Sebaceous mulation of well- to moderately well-differentiated
gland tumors present cytologically with large, uni- proliferations of sebaceous glands with well-
form single cells and cell groups with a foamy defined tumor borders, sebaceous gland carcinomas
(sebaceous) cytoplasm (. Fig. 4.7). Basal cells are characterized by loss of differentiation and
without foamy cytoplasm are usually concurrent invasive growth into surrounding tissues. Similarly,
findings in cell groups. Apocrine gland tumors are apocrine gland carcinomas are differentiated from
characterized by mostly uniform to pleomorphic adenomas by an increased cellular pleomorphism
epithelial cells (. Fig. 4.8). and infiltrative growth at the tumor borders.
Histopathology of incision or excision biopsies is Apocrine gland mixed tumors present very much
necessary to confirm malignancy of the tumors. like mixed mammary gland tumors, with intratu-
While sebaceous gland adenomas present as an accu- moral cartilage.
64 R. Klopfleisch

z Therapy around the anal sacs, which are located ventrolat-


Surgery with wide tumor margins is usually cura- eral to the anus. Cocker spaniels seem to have a
tive. Reports on the application of chemotherapy breed predisposition. There is no gender predis-
or radiotherapy are not available. position. The medium age of dogs with apocrine
gland adenocarcinoma is 10 years.
4.1.1.4 Canine Perianal Gland Tumors
z Clinical Appearance
Hepatoid gland adenomas are slow and expan-
4 Box 4.4. Canine Perianal Gland Tumors in sively growing benign tumors. They usually
Four Facts appear as pain-free single or multiple nodules of up
1. Mostly benign, testosterone-dependent to 4 cm around the anus but may also be present
hepatoid gland adenomas. on the prepuce, scrotum, or tailhead. Occasionally,
2. Less often malignant hepatoid gland they may ulcerate and become infected; they are
carcinomas or anal sac apocrine gland rarely adherent or fixed to deeper structures.
adenocarcinomas. Hepatoid gland carcinomas are malignant,
3. One-third of dogs with apocrine gland invasive, and fast-growing tumors with a meta-
adenocarcinomas with PTHrP-induced static rate of 15–50 %. The regional sublumbar and
hypercalcemia. pelvic lymph are commonly affected; distant
4. Cytology is usually not able to metastases to the lungs, liver, kidney, and bone are
conclusively confirm malignancy. rather rare. Macroscopically, the tumors look
similar to adenomas but they are usually faster
growing and more often fixed to the underlying
z Epidemiology and Pathogenesis tissues (. Fig. 4.9). Obstruction of the pelvic canal
Two types of glands commonly develop neo- by sublumbar/pelvic lymph node metastasis occa-
plasms in the perianal area of dogs: the nonsecre- sionally leads to clinical signs of rectal obstipa-
tory, sebaceous hepatoid glands and the apocrine tion, dyschezia, or perianal pain. Ultrasound is
glands of the anal sac. commonly used to evaluate the status of the
Hepatoid gland adenomas are the most com- regional lymph nodes. If lymph node metastasis is
mon tumors of the perianal region and represent detected, thoracic radiographs should be taken to
up to 90 % of all perianal tumors. Old intact male evaluate the presence of lung metastases.
dogs, male dogs with testicular interstitial cell Histology of tissue biopsies is required to confirm
tumors, and ovariohysterectomized female dogs the diagnosis.
with a deceased estrogen to testosterone ratios are Apocrine gland adenocarcinomas of the anal
predisposed. The development of these benign sacs are highly malignant usually unilateral
tumors is therefore thought to be testosterone tumors. Metastatic rates of 50–90 % have been
dependent. This assumption is also supported by
the observation that castration of male dogs is
usually therapeutic. Cocker spaniels, Beagles,
Bulldogs, and Samoyeds may have a breed predis-
position. The mean age of affected animals is 10
years old.
Hepatoid gland carcinomas are rare tumors of
the perianal glands with an incidence of <10 % of
all perianal tumors. Affected dogs are on average
11 years old. These tumors occur in intact and
castrated males and females, indicating a
decreased developmental dependency on hor-
monal factors. There is a mild predisposition for
large-breed males.
Apocrine gland adenocarcinomas of the anal
. Fig. 4.9 Ulcerated, multinodular hepatoid gland
sacs are rather rare but highly malignant perianal carcinoma in a dog (Photo: with permission of Dr.
tumors. They develop from the apocrine glands O. Beger, Small Animal Practice, Cossebaude, Germany)
Chapter 4 · Skin Tumors
65 4
described. The regional sublumbar lymph nodes are in general associated with an improved 2-year
and pelvic nodes are affected in most cases at the disease-free interval. The prognosis for dogs with
time of the initial diagnosis. Distant lung, liver, metastatic disease is poor.
spleen, and bone metastases usually develop at Apocrine gland adenocarcinomas are usually
later stages of the diseases. A paraneoplastic treated with aggressive surgery. However, complete
hypercalcemia of malignancy, due to the release resection is often not possible, and more than
of parathyroid hormone-related peptide (PTHrP), 50 % of the animals develop metastatic disease at
is present in one-third of the animals. Clinical the time of initial diagnosis. Removal of affected
signs of dogs with apocrine gland adenocarci- lymph nodes may have a palliative effect. Survival
noma are either related to the mass effect of the times of 6–18 months have been reported for dogs
primary tumors and its metastases, including with apocrine gland adenocarcinomas treated
perianal discomfort, dyschezia, tenesmus, or con- with surgery. Chemotherapy and RT are recom-
stipation, or due to paraneoplastic hypercalcemia. mended as standard adjuvant treatment options
Concurrent clinical signs often include polyuria/ for anal sac adenocarcinoma in the literature.
polydipsia, anorexia, lethargy, bradycardia, and However, clinical data on the success of these
paresis. Abdominal radiographs, ultrasound, and modalities are scarce. Chemotherapy using carbo-
magnetic resonance imaging are commonly used platin, cisplatin, and actinomycin D has been
to identify lymph node or distant metastasis. reported. A few reports on the efficacy of curative
and palliative radiotherapy of the primary tumors
z Cytology and Histopathology and affected lymph nodes weakly indicate a
Cytology is usually not able to differentiate benign potential clinical effect for both approaches.
from malignant hepatoid gland tumors. Apocrine Metastatic disease and, to a lesser extent, hyper-
gland adenocarcinomas are characterized cyto- calcemia have been described as negative prog-
logically by polyhedral cells with a blue-gray, nostic indicators for survival.
granular cytoplasm.
Histopathology of tissue biopsies is needed to z Suggested Further Reading
evaluate the invasiveness of the tumor at the bor- (Anderson et  al. 2015; Bennett et  al. 2002;
ders and to confirm malignancy of the primary Bergman 2012; Bowlt et al. 2013; de Swarte et al.
hepatoid tumor. In addition, malignant tumors 2011; Emms 2005; Hobson et  al. 2006; Polton
also show a less orderly arrangement of the epi- 2007; Polton and Brearley 2007; Ross et al. 1991;
thelial cells and an increased number of mitotic Vail et al. 1990)
figures. Apocrine gland adenocarcinomas are his-
tologically characterized by solid sheets of tumor 4.1.1.5 Canine Cutaneous Papillomas
cells, rosette formation, or a tubular arrangement
of the tumor cells. The tumors cells are usually
highly monomorphic despite their malignant Box 4.5. Canine Cutaneous Papillomas in
behavior. Four Facts
1. Induced by canine papillomaviruses.
z Therapy 2. Mostly young dogs.
Castration is the treatment of choice for hepatoid 3. Immunosuppression/deficiency
gland adenomas. Complete regression and a lack predisposes to infection.
of recurrence are common after castration. In 4. Spontaneous remission within weeks is
cases with lack of or incomplete regression in common.
female dogs, surgical excision is recommended.
Hepatoid gland adenocarcinomas usually do
not respond to castration. Aggressive surgery with z Epidemiology and Pathogenesis
appropriate margins is therefore indicated. Papillomas are rare Papillomavirus-induced benign
Recurrence after extensive surgery is a negative tumors of the skin and the oral cavity (see Chap. 9)
prognostic indicator that is unfortunately rela- of juvenile and young dogs. In older dogs, a virus-
tively common. Postsurgical radiotherapy may associated etiology is not always confirmed.
improve the long-term outcome but there is a lack Canine papillomaviruses infect and stimulate
of reliable data. Tumors with a diameter of < 5 cm proliferation in differentiated keratinocytes. These
66 R. Klopfleisch

proliferation and neoplastic transformation are 4.1.2 Canine Cutaneous Melanomas


mainly induced by the Papillomavirus proteins
E6 and E7, which destabilize p53 and inhibit the
retinoblastoma protein. An association has been
Box 4.6. Canine Cutaneous Melanomas in
suggested between Papillomavirus infection and
Five Facts
the development of squamous-cell carcinomas
(SCCs) due to the detection of Papillomavirus 1. Cutaneous melanomas mostly benign
protein and DNA in SCC. Immunosuppression or and pigmented.
4 deficiency is thought to be an important factor 2. Surgery mostly curative.
for acute and persistent Papillomavirus infection. 3. Amelanotic tumors and malignant
Infected dogs usually develop immunity against tumors develop rarely.
new infections. 4. Digital melanomas often metastatic,
even after early amputation of the digit.
z Clinical Appearance 5. Immunohistochemistry occasionally
Papillomas are single or multiple, prominent or necessary to confirm diagnosis in
pedunculated, superficially frayed tumors. amelanotic melanomas.
Inverted papillomas are a rare benign variant,
which grows into the subcutaneous tissue
rather than externally. Spontaneous regression z Epidemiology and Pathogenesis
within weeks or a few months is commonly Melanomas are tumors of the melanin-produc-
observed. ing melanocytes, which are derived from the
neural crest and thus are not mesenchymal or
z Cytology and Histopathology epithelial tumors. Common locations are the
Cytology may present with a dominance of pro- oral cavity (see chapter GIT), the skin, and the
liferating spindle cells from the tumor base and digits and intra- or periocular (see Chap. 6). In
center and is rather unspecific. Histopathology is contrast to the mostly malignant melanomas of
necessary to confirm the diagnosis and to the oral cavity and the digit, cutaneous melano-
exclude other epithelial skin tumors. The pres- mas of other skin regions are usually benign with
ence of a strong mesenchymal proliferation at a minority of malignant cutaneous melanomas.
the base of the tumor leads to the diagnosis of a There is a predisposition of dark-coated breeds
fibropapilloma. for cutaneous and digital melanomas.
Melanomas may occur at any age but are most
z Therapy commonly found at the age of 9–10 years. The
Surgical excision is curative but due to the usual etiology of melanomas in the dog is unclear; a
spontaneous remission often not necessary. A contribution of UV-light exposure to carcino-
local application of 5-fluorouracil on papillo- genesis as in human melanomas is not con-
mas has been described but is associated with firmed, and specific driver mutations are not
side effects that override the benefits of the identified.
treatment.
z Clinical Appearance
z Current Trends in Research Cutaneous melanomas are usually presenting as
Research is ongoing on the identification of new slow-growing, small, solitary, pigmented, well-
emerging canine papillomaviruses, their poten- circumscribed masses anywhere in the skin
tial association with other tumors like SCC, and (. Fig. 4.10). Amelanotic cutaneous melanomas,
the cellular immune response to papillomaviral common in the oral cavity, are the exception but
infection. are possible. In contrast, digital melanomas are
usually fast-growing, ulcerated, not necessarily
z Suggested Further Reading pigmented tumors. Metastasis of digital melano-
(Beckwith-Cohen et  al. 2014; Lange and Favrot mas to the regional lymph node and the lung is
2011; Luff et al. 2012; Munday et al. 2011; Munday common and often apparent at the time of diag-
et al. 2015) nosis.
Chapter 4 · Skin Tumors
67 4

. Fig. 4.10 Poorly differentiated melanoma (confirmed


with histology), dog. Pigmented dermal mass at the jaw of
. Fig. 4.11 Cytology, poorly differentiated, mostly
a 12-year-old Giant Schnauzer (Photo: with permission of
amelanotic melanoma, dog (the same dog as in . Fig. 4.10),
the Faculty of Veterinary Medicine,
May-Grünwald-Giemsa, 100×. Note the clusters of
Justus-Liebig-University, Giessen, Germany)
cohesive, spindle shaped to polygonal mainly poorly
pigmented melanocytes with few scattered pigmented
melanocytes/melanophages (red arrows) (Photo: with
z Cytology and Histopathology permission of Dr. N. Bauer, Faculty of Veterinary Medicine,
Cytology of pigmented melanomas is usually Justus-Liebig-University, Giessen, Germany)
straightforward due to the cytoplasmic dark
brown to black granules (. Figs. 4.11, 4.12,
4.13, and 4.14). Amelanotic tumors are how-
ever more difficult to diagnose by cytology due
to the highly diverse histologic appearance of
melanomas. This is also true for the histopa-
thology. Detection of melanin cells in pig-
mented tumors allows for diagnosis of a
melanoma. Cellular and nuclear pleomorphism,
a high number of mitotic figures, and invasive
behavior at the tumor borders are associated
with malignant behavior. Amelanotic tumors
are, however, challenging due to their pleomor-
phic appearance. They may show spindle cell,
epitheloid, or even round cell-like growth pat-
terns. Immunohistochemical markers may help . Fig. 4.12 Cytology, poorly differentiated, mostly
amelanotic melanoma, dog (the same dog as in
for a conclusive classification of these tumors,
. Fig. 4.10), May-Grünwald-Giemsa, 1000×. Note the
however challenging due to their pleomorphic spindle shaped to polygonal mainly poorly to
appearance. Immunohistochemical markers nonpigmented melanocytes with few dustlike melanin
may help for a conclusive classification of these granules (black arrow). In contrast, melanophages contain
tumors. numerous round, markedly bigger granules of engulfed
melanin (red arrow) (Photo: with permission of
Dr. N. Bauer, Faculty of Veterinary Medicine,
z Therapy Justus-Liebig-University, Giessen, Germany)
Surgery with wide margins is the treatment of
choice for both cutaneous benign and malignant within 1 or 2 years after digit amputation due to
melanomas. Surgery alone is associated with a distant metastases.
good prognosis and cure of the majority of benign Chemotherapy using doxorubicin, cisplatin,
cutaneous, non-digital melanomas. Surgical exci- and other anticancer drugs has been described
sion of malignant cutaneous and digital melano- preferentially for the treatment of oral mela-
mas is however often associated with recurrence. noma and may be a potential adjunctive treat-
Most dogs with digital melanomas are euthanized ment option.
68 R. Klopfleisch

. Fig. 4.13 Cytology, well-differentiated, melanotic . Fig. 4.14 Cytology, lymph node metastasis,
melanoma, dog, May-Grünwald-Giemsa, 1000×. melanoma, dog (the same dog as in . Fig. 4.10),
Pigmented melanocytes are usually easy to diagnose due May-Grünwald-Giemsa, 1000×. Note the group of highly
to the presence of abundant and typical dark blue pigmented melanocytes with numerous melanin granules
melanin granules. However, melanoma cells are often almost masking the nucleus (Photo: with permission of
fragile in cytological specimens. Cellular borders therefore Dr. N. Bauer, Faculty of Veterinary Medicine,
tend to be indistinct and ruptured and free melanin Justus-Liebig-University, Giessen, Germany)
granules are often present (Photo: with permission of Dr.
N. Bauer, Faculty of Veterinary Medicine,
Justus-Liebig-University, Giessen, Germany) . Table 4.1 Prognostic factors for canine
cutaneous melanoma
Radiotherapy is an important therapy option
Influence on
for oral melanomas but not for a common Factor prognosis
approach for the treatment of the mostly benign
cutaneous melanomas. Distant metastasis Negative

Tumor size Possibly


z Prognostic Factors and Markers negative
Melan-A, S100, PNL2, CSPG4, and tyrosinase are
Histologic classification as Variably
variably specific and sensitive immunohisto- malignant negative
chemical markers for cells of melanocytic origin.
In combination they are however very helpful in Nuclear atypia Negative
the diagnosis of amelanotic and pleomorphic Mitotic index Negative
malignant melanomas. Prognostic factors for
Lack of pigmentation Negative
canine cutaneous melanomas are presented in
. Table 4.1. Ulceration Negative

(Vascular) infiltration Negative


z Current Trends in Research
High Ki67 index Negative
There is ongoing research on the use of vaccina-
tion against melanoma-specific antigens in DNA ploidy Negative
melanoma-bearing dogs. Chondroitin sulfate pro-
teoglycan-4 (CSPG4), tyrosinase, and disialogan-
glioside GD3 have been tested for their value as 4.1.3 Canine Soft Tissue
vaccination targets for canine melanoma with Sarcomas
variable success.
Canine malignant mesenchymal tumors of all body
z Suggested Further Reading areas are commonly designated as soft tissue sarco-
(Abramo et al. 1999; Brockley et al. 2013; Herzog mas (STS) due to their similar clinical behavior
et al. 2013; Lange and Favrot 2011; Ottnod et al. and  response to treatment. Commonalities of this
2013; Smedley et al. 2011; Spangler and Kass 2006; heterogeneous tumor group are highly invasive
Waropastrakul et al. 2012) growth, high rate of recurrence, low-to-moderate
Chapter 4 · Skin Tumors
69 4
frequency of local and distant metastases, and a eosinophilic, sometimes fibrillary, matrix between
similar response to treatment. The term STS the cells. Depending on the histotype, i.e., lipo-,
embraces tumors of different histogenesis such as rhabdomyo-, or fibrosarcomas, etc., several other
fibrosarcomas, rhabdomyosarcomas, leiomyosar- features may also be present. Histologically, all STS
comas, peripheral nerve sheath tumors, perivas- are characterized by the presence of more or less
cular wall tumors, and liposarcomas. Synovial cell spindloid tumors cells. In addition, every STS sub-
sarcomas, hemangiosarcomas, and osteosarco- type may show other features like adipocyte-
mas are sometimes but not consistently also or rhabdomyocyte-like appearance. STS grade is
included into the STS group. This chapter covers of higher clinical relevance than histotype
in its first part the current general ideas on diag- (. Table 4.3). Immunohistochemical markers
nosis, therapy, and prognosis of STS which are (see Dennis et al. 2011) can be used to further
also correct for non-cutaneous STS.  In the differentiate the histologic type/origin of STS
remaining chapter, there is a more detailed if standard histopathology is not sufficiently
description of cutaneous liposarcomas, fibrosar- typical.
comas, and subcutaneous peripheral nerve sheath
tumors (PNST) since they are unequivocally
specific tumor entities, although their specific z Therapy
characteristics are currently clinically irrelevant. Surgical resection with 2–3 cm lateral margins in
Cutaneous vascular tumors including hemangio- the normal tissue and at least one fascial plane
sarcomas, hemangiomas, and perivascular wall into the deep is recommended to decrease the
tumors are described in more detail in Chap. 15. recurrence rate. This may also include amputa-
STS are relatively common tumors of middle- tion. Confirmed or assumed incomplete resec-
aged to old dogs. There is no confirmed sex or tion with smaller margins in difficult anatomic
breed predisposition. locations requires adjuvant radiotherapy and
chemotherapy.
Radiotherapy is an important adjuvant ther-
z Clinical Appearance
apy for STS. It is associated with 3-year survival
Soft tissue sarcomas are mostly solitary, slowly but rates of up to 70 % of patients. Coarse fraction-
infiltratively growing tumors which can arise in ated radiotherapy and hypofractionated radio-
every anatomic location. Due to their infiltrative therapy are most commonly recommended. Of
growth, they are usually not freely moveable on pal- note, one study found that radiation within the
pation. The minority of STS develops metastases. first month after surgery was associated with a
The clinical symptoms associated with the tumors higher risk for recurrence than radiation after
almost completely depend on the location and the
1 month.
mass effect of the tumor on the affected and adja- Adjuvant, metronomic chemotherapy, i.e.,
cent organs. Cytology, histopathology (biopsies), the administration of low doses of, for instance,
and imaging are necessary for the final diagnosis, cyclophosphamide with an increased frequency
complete staging, and therapy planning of STS. and may be for longer periods, is currently seen
Computed tomography (CT) and magnetic res- as a promising approach to prevent intratu-
onance imaging (MRI) with or without the use of moral angiogenesis and tumor growth. In
contrast agents are necessary to perceive the full addition, classical non-adjuvant, doxorubicin-
extension of the usually highly infiltrative based chemotherapy protocols are considered
STS. Palpation and sight are often underestimat- to be promising for the treatment of non-
ing the full extension of STS. A staging system has resectable STS.
been developed for all tumors falling into the cat-
egory of canine STS independent from their his-
togenesis (. Table 4.2). z Prognosis
The prognosis for STS is good, if local tumor control
z Cytology and Histopathology is achieved. Thus, incomplete resection and recur-
Fine-needle aspirates of STS are characterized by rence (recurrent tumors are usually more difficult
the presence of cells with a more or less spindloid to be treated) but also tumor grade are the most
cell shape, indistinct cellular borders, and often an important prognostic factors.
70 R. Klopfleisch

. Table 4.2 Staging system for canine soft tissue sarcomas (Liptak and Forrest 2012)

Stage Tumor size Lymph node metastases Metastasis Histologic grade

1 Tany (any r size) N0 (none) M0 (none) I–II

II T1a (<5 cm, superficial) N0 (none) M0 (none) III


T1a (<5 cm, deep)
T2a (>5 cm, superficial)
4 III T2b (>5 cm, deep) N0 (none) M0 (none) III

IV Tany (any r size) N1 (present) Many I–III


Tany (any r size) Nany M1 (present)

4.1.3.1 Canine Lipomas


. Table 4.3 Grading system for soft tissue
sarcomas (Dennis et al. 2011)
and Liposarcomas

Histologic criteria Points Features


Box 4.7. Canine Cutaneous Lipomas in Four
A. Differentiation 1 Resembles normal Facts
adult 1. Benign, slowly growing tumors.
mesenchymal
tissue
2. Cytologically not differentiated from
normal adipose tissue.
2 Specific histologic 3. Surgery curative.
subtype but poor
4. Malignant tumors often recur even after
differentiation
aggressive surgery.
3 Undifferentiated,
unknown
histotype
z Epidemiology and Pathogenesis
B. Necrosis 1 None Lipomas, benign tumors derived from the subcu-
2 ≤50 % necrosis taneous adipocytes, are very common tumors of
the canine skin. Other adipocytic tumors of the
3 >50 % necrosis
skin include the less common semimalignant
C. Mitoses per 10 1 0–9 mitoses/10 infiltrative lipomas and the rare malignant lipo-
HPF (400×) HPF sarcomas. Lipomas are more common in older
2 10–19 mitoses/10 dogs and females and commonly appear at the
HPF trunk. They belong to the group of soft tissue sar-
3 >19 mitoses/10
comas (STSs).
HPF
z Clinical Appearance
Total score ≤3 Grade I
Lipomas are single, cutaneous, small to very large
(A + B + C)
4–5 Grade II lesions. They are soft to the touch and are not
≥6 Grade III
associated with alopecia or ulceration. Infiltrative
lipoma and liposarcoma are firmer on palpation
and less movable due to their infiltrative growth
z Suggested Reading into the surrounding tissues. The common staging
(Bacon et al. 2007; Baker-Gabb et al. 2003; Burton system for canine soft tissue sarcoma is used for
et  al. 2011; Demetriou et  al. 2012; Dennis et  al. liposarcoma (. Table 4.2).
2011; Dernell et  al. 1998; Elmslie et  al. 2008;
Hohenhaus et  al. 2016; Kung et  al. 2014; Kuntz z Cytology and Histopathology
et al. 1997; Lawrence et al. 2008; Liptak and Forrest Cytology of lipomas and in most cases of infiltra-
2012; Matz 2015; Ogilvie et al. 1989; Prpich et al. tive lipomas presents with well-differentiated adi-
2014; Rassnick 2003) pocytes, which cannot be differentiated from
Chapter 4 · Skin Tumors
71 4
normal adipocytes of the skin (. Figs. 4.15, 4.16, 4.1.3.2 Canine Cutaneous Fibromas
and 4.17). and Fibrosarcomas
Histologically, lipoma tumor cells cannot be
differentiated from normal adipocytes in expan-
sively growing tumors. Similarly, infiltrative lipo- Box 4.8. Canine Fibrosarcomas in Three Facts
mas are also composed of differentiated 1. Benign fibromas are cured by surgical
adipocytes, which nevertheless are growing inva- resection.
sively into adjacent muscles and fascia. The com- 2. Fibrosarcomas are invasively growing
mon grading system for canine soft tissue sarcoma and often recurring after surgery.
is used for liposarcomas (. Table 4.3). 3. Adjuvant radiotherapy is reducing the
recurrence rate.
z Therapy
Surgery is curative for lipoma. Even very aggressive
surgery sometimes does not prevent local recurrence z Epidemiology and Pathogenesis
of infiltrative lipoma or liposarcoma. Cutaneous fibrosarcomas are moderately common
Postsurgical radiotherapy may prolong the malignant tumors derived from subcutaneous
time to recurrence of infiltrative lipoma but there fibrocytes. They belong to the group of soft tissue
is a lack of sufficient data; it has not been described sarcomas (STS) in the dog. They are more com-
for liposarcoma. mon in older dogs, but are particularly aggressive
in young dogs. The etiology is unclear. Fibromas
z Suggested Further Reading are rather rare benign tumors of the subcutaneous
(McEntee et  al. 2000; Bacon et  al. 2007; Baker- fibrocytes. They are more common in older dogs.
Gabb et  al. 2003; Burton et  al. 2011; Demetriou
et al. 2012; Dennis et al. 2011; Dernell et al. 1998; z Clinical Appearance
Elmslie et al. 2008; Hohenhaus et al. 2016; Kung Fibromas are small, solitary, soft to firm, well-
et al. 2014; Kuntz et al. 1997; Lawrence et al. 2008; circumscribed nodules, which can be ulcerated in
Liptak and Forrest 2012; Matz 2015; Ogilvie et al. mechanically stressed areas of the skin. Fibrosarcomas
1989; Prpich et al. 2014; Rassnick 2003) are fast-growing, locally invasive, usually large tumors
and may be soft and firm on palpation due to necrotic
and cystic tumor areas. Metastasis is common in

. Fig. 4.16 Cytology, infiltrative lipoma, dog,


. Fig. 4.15 Cytology, lipoma, dog, May-Grünwald-Giemsa, 100×. Note the differentiated
May-Grünwald-Giemsa, 100×. Note the cluster of adipocytes (black arrow) closely associated with clusters
well-differentiated adipocytes with eccentrically located of striated muscle tissue (blue arrow) indicative of
oval nuclei and abundant amounts of a clear cytoplasm infiltrative lipoma. However, a definite diagnosis cannot
(Photo: with permission of Dr. N. Bauer, Faculty of be made based on cytology alone (Photo: with permission
Veterinary Medicine, Justus-Liebig-University, Giessen, of Dr. N. Bauer, Faculty of Veterinary Medicine,
Germany) Justus-Liebig-University, Giessen, Germany)
72 R. Klopfleisch

which is associated with a poor prognosis. Since


fibrosarcomas belong to the group of STS, adjuvant
radiotherapy, doxorubicin-based chemotherapy pro-
tocols, and metronomic therapy can reduce the risk
of recurrence.

z Suggested Further Reading


(Beckwith-Cohen et  al. 2014) (Bacon et  al. 2007;
4 Baker-Gabb et  al. 2003; Burton et  al. 2011;
Demetriou et al. 2012; Dennis et al. 2011; Dernell
et al. 1998; Elmslie et al. 2008; Hohenhaus et al. 2016;
Kung et al. 2014; Kuntz et al. 1997; Lawrence et al.
2008; Liptak and Forrest 2012; Matz 2015; Ogilvie
. Fig. 4.17 Cytology, liposarcoma, dog, et al. 1989; Prpich et al. 2014; Rassnick 2003)
May-Grünwald-Giemsa, 1000×. Note the clusters of
moderately cohesive spindle shaped to plump cells with 4.1.3.3 Canine Cutaneous Peripheral
oval nuclei, fine to granular chromatin pattern, and Nerve Sheath Tumors (PNST)
moderate amounts of lightly basophilic cytoplasm
occasionally containing clearly circumscribed vacuoles
(fat). The spindle cell population is intermixed with fatty
vacuoles (blue arrow). There are several mitotic figures and
Box 4.9. Canine Cutaneous Peripheral Nerve
occasional well-differentiated mast cells (red arrow) Sheath Tumors in Five Facts
(Photo: with permission of Dr. N. Bauer, Faculty of 1. Derived from perineuronal Schwann
Veterinary Medicine, Justus-Liebig-University, Giessen, cells or their precursors.
Germany) 2. Difficult to be separated from
perivascular wall tumors.
approximately 20 % of cases. The common staging 3. Surgery with wide margins often
system for canine soft tissue sarcoma is used for curative.
fibrosarcomas (. Table 4.2). 4. Recurrence nevertheless common.
5. Adjuvant radiotherapy or chemotherapy
z Cytology and Histopathology may reduce the risk of recurrence.
Cytology may present with well-differentiated
spindle cells in fibromas, which are sometimes
difficult to discriminate from normal subcutane- z Epidemiology and Pathogenesis
ous fibrocytes. Fibrosarcomas, in contrast, may There is an ongoing debate on the incidence of cuta-
present with pleomorphic plump to spindloid neous peripheral nerve sheath tumors (PNST). Some
cells and oval nuclei. authors state that PNST may be the most common
Histopathologically, fibromas are characterized by STS subtype of the skin/subcutis. This lack of clarity
an accumulation of uniform fibroblasts and abun- is mainly based on the inconsistency in the histo-
dant collagen. Fibrosarcomas may be very variable in pathologic criteria to differentiate PNST from peri-
their appearance with rather well-differentiated vascular wall tumors and hemangiopericytoma,
tumors containing plump spindle-shaped tumor which have similar histologic features. Subcutaneous
cells in a herringbone pattern. Poorly differentiated, PNSTs are thought to be derived from perineuronal
aggressive fibrosarcomas are characterized by a high cells like Schwann cells or their precursors. PNST
cellular and nuclear pleomorphism and a high have a moderately to highly invasive growth charac-
mitotic rate. The common staging system for canine ter and a low metastatic potential.
STS is used for fibrosarcomas (. Table 4.3).
z Clinical Appearance
z Therapy PNST are usually solitary, slow but infiltratively
Surgery is curative for fibromas. In contrast, early growing masses. They can occur in the subcutis of
resection of fibrosarcomas, while the best treat- any body part with a predisposition for the limbs.
ment option, still has a guarded prognosis. Up to The common staging system for canine soft tissue
two-thirds of the tumors develop recurrence, sarcoma is used for PNST (. Table 4.2).
Chapter 4 · Skin Tumors
73 4
z Cytology and Histopathology
Cytology may present with well-differentiated 4. Two currently applied histologic grading
spindle cells, presence of more or less spindloid systems.
cell shape, indistinct cellular borders, and often an 5. Surgery is often curative for low-grade
eosinophilic, sometimes fibrillary, matrix between mast cell tumors.
the cells. Histopathologically, PNST are graded 6. Surgery and irradiation are the
according to the common grading system for treatment of choice for tumors in
canine STS (. Table 4.3). They present as well- difficult locations.
circumscribed tumors with moderate cellularity, 7. Tyrosine kinase inhibitors have strong
spindle to ovoid cells with occasional presence of but short-term effects on tumor
Antoni A/B pattern, and palisading nuclei regression.
(Verocay-like bodies). Cells are often arranged in
whorls around the capillaries or collagen island,
which makes them difficult to be separated from
perivascular wall tumors. z Epidemiology and Pathogenesis
Canine mast cell tumors (MCT) are the most com-
z Therapy mon cutaneous tumor of the dog, representing
Surgery can be curative when performed with suf- approximately 20 % of all skin tumors. They may
ficiently large margins into the normal tissue occur at any age but are most common in older
(2–3 cm). Since PNST belong to the group of STS, dogs with a mean age of 9 years; there is no gender
adjuvant radiotherapy, doxorubicin-based chemo- predilection. There seems to be a genetic basis for
therapy protocols, and ametronomic therapy can MCT because a breed predisposition exists for
reduce the risk of recurrence. boxers, retrievers, pug-dogs, Boston terriers and
Stafford terriers, and Rhodesian ridgebacks.
z Suggested Further Reading However, tumors in these breeds are generally of
(Brehm et al. 1995; Chijiwa et al. 2004; Klopfleisch low malignancy and favorable prognosis. In con-
et  al. 2013; Meyer and Klopfleisch 2014; Suzuki trast, Shar-Peis are also predisposed to develop
et al. 2014) MCT but these are often high-grade tumors with
a poor prognosis.
The molecular pathogenesis and etiology of
4.1.4 Canine Cutaneous canine MCT are mostly unknown. Chronic
Hematopoietic Tumors inflammation, a viral etiology or mutations or
abnormal expression of relevant tumor suppres-
Mast cell tumors are the most common hemato- sors like p53, p21, or p27 as potential causes have
poietic tumor of the canine skin. Cutaneous his- been tested but disproven as direct causes. The
tiocytomas and plasmacytomas are less common. only potential factor currently under review in
Cutaneous lymphomas are rarely observed and the carcinogenesis of canine MCT is the stem cell
are described in Chap. 6. factor receptor (KIT or CD117). Binding of its
ligand stem cell factor (SCF) leads to activation of
4.1.4.1 Canine Cutaneous Mast Cell its tyrosine kinase domain and promotes prolif-
Tumors eration, differentiation, and survival of nonneo-
plastic mast cells. KIT is expressed in both
nonneoplastic and neoplastic mast cells.
Box 4.10. Canine Cutaneous Mast Cell Tumor Expression may however change from normal
in Seven Facts membrane-bound expression to cytoplasmic KIT
1. The most common cutaneous tumor of expression in neoplastic mast cells, indicating
the dog. abnormal function. Several somatic, not inher-
2. KIT receptor signaling major ited, KIT mutations in exons 8, 9, 11, and 12 of the
proliferative stimulus for mast cells. gene have been identified, of which a tandem
3. Activating mutations in the KIT gene duplication of a part of exon 11 has been best ana-
are present in 30 % of the tumors. lyzed. This mutation leads to a permanent and
unregulated activation of KIT signaling and
74 R. Klopfleisch

increased risk of local recurrence, metastasis, and inflammation and edema due to the release of
worse prognosis. Activating KIT mutations are vasoactive amines like histamine. Degranulation
present in up to 30 % of the high-grade tumors, of histamine-containing mast cell granules during
which indicates that other mechanisms of carci- examination may induce Darier’s signs, which
nogenesis have to be relevant in the majority of consist of rapid swelling and wheal formation,
tumors. Another potential mechanism of MCT often described by owners as “growing and shrink-
carcinogenesis may be de novo expression of all ing” of the tumors. Release of histamine by the
subunits of the interleukin-2 receptor (IL-2R), a cutaneous tumors frequently leads to a gastroin-
4 major proliferation stimulus for lymphocytes, and testinal paraneoplastic syndrome. Stimulation of
its ligand IL-2. Both are expressed in almost all gastric histamine receptors leads to massive hydro-
low-grade and a fraction of high-grade MCT cells chloric acid secretion with vomiting, gastric ulcer-
and activated nonneoplastic mast cells but never ation, and abdominal pain. Only dogs with
in resting, nonneoplastic mast cells. massive tumor burden and a sudden massive his-
tamine release are at risk of developing a hypoten-
z Clinical Appearance sive anaphylactic reaction.
MCT are solitary lesions in 90 % of cases. They are Several, often extensive, diagnostic workup
mostly found on the trunk or the limbs, less often schemes for accurate diagnosis of canine MCT are
on the head and neck, and even less often on the available. However, MCT diagnosis is usually
mucous membranes. A visceral form, called sys- based on FNA, although it is not sufficient for
temic mastocytosis or gastrointestinal MCT, may proper tumor grading (see the next chapter). In a
occur; this is described in the chapter on hemato- next step, clinical staging is performed according
poietic cancer and GIT cancer, respectively (see to a World Health Organization (WHO) system
Chaps. 6 and 9). MCTs are always considered (. Table 4.4). Due to the overlapping clinical
potentially malignant. Nevertheless, well-differen- behavior and the strong influence of therapy and
tiated tumors have a metastatic rate of less than histologic grading on prognosis, the staging sys-
10 %. High-grade MCTs are locally invasive and tem is of reduced clinical value and repeatedly
develop metastases with a rate ranging from 50 % criticized.
to almost 100 % depending on the studies. The A standard workup scheme for canine cutane-
first step in metastasis is usually metastasis to the ous MCT has been developed by Thamm and
local lymph nodes and then to the spleen, liver, Vail. Any suspicious ultrasound findings in the
and other visceral organs. Lung involvement is liver and spleen should be analyzed by fine-nee-
uncommon. dle aspirates. Screening of buffy coat smears of
Low-grade MCT may be slow growing and centrifuged blood for mast cells, ultrasound of
present for years. In contrast, high-grade MCT the primary tumor, or thoracic radiographs are
may be ulcerated and rapidly growing with not considered to be of significant prognostic
smaller surrounding satellite nodules and massive value. Histopathologic grading and analysis of

. Table 4.4 Staging system for canine mast cells tumors (WHO)

Stage Tumor Lymph node metastases Systemic signs Prognosis

0–1 One tumor, No No Better than III/IV


0–2 incompletely excised No Yes

I–1 One tumor in the No No Better than III, IV


I–2 dermis No Yes

II–1 One tumor in the Yes No Similar to II in most


II–2 dermis Yes Yes treatment protocols

III–1 Multiple or large or Yes/No No Worse than I/II


III–2 infiltrating tumors Yes/No Yes

IV Any tumor Yes Yes Worse than I/II


Chapter 4 · Skin Tumors
75 4
surgical margins and eventually of suspicious fying clinical or therapeutic criteria for malig-
lymph nodes or hepatic and spleen lesions are nancy or benign classification. A new Kiupel
necessary for a final decision on the appropriate 2-tier grading system avoids these problems and
therapy option. separates MCT in only two groups, low- and
high-grade MCT.
z Cytology and Histopathology
Fine-needle aspiration (FNA) of an MCT is a very z Therapy
helpful and easy method to make a presurgical Surgery, radiotherapy, and chemotherapy with
diagnosis of this tumor type (. Figs. 4.18, 4.19, different drug classes can be used for the treat-
4.20, 4.21, and 4.22). Its sensitivity and specificity ment of MCT. Their application and combination
for tumor grading are, however, low compared to very much depend on tumor staging and grading.
histopathology of biopsies. There is a single study Exclusive surgery is the treatment of choice for
that refuses this finding. Identification of lymph localized, low- and intermediate-grade, non-
node metastasis (>3 % mast cells) is also difficult metastatic MCT at promising locations where wide
using FNA due to the presence of similar num- excision is possible. In these cases, surgery alone is
bers of mast cells in lymph nodes of healthy dogs. mostly curative. A 3-cm surgical margin extending
Histopathologic analysis using tissue biopsies at least one fascial plane deep has historically been
is the definitive technique to diagnose and grade recommended. Recently, it has been shown that
canine MCT and to evaluate tumor borders. lateral margins of 2 cm and only one fascial plan
Besides the standard hematoxylin and eosin or even 1 cm lateral and 4 mm deep margins are
(H&E) stain, toluidine stain is also used to sufficient to avoid recurrence or metastasis of
increase sensitivity due to the specifically eosin- low- or intermediate-grade MCT.  High-grade,
or purple-stained metachromatic granules in aggressive MCT nevertheless should still be
well- to moderately differentiated mast cells. resected with at least 3  cm margins due to their
Variable amounts of concurrently present eosin- infiltrative growth. Preoperative ultrasound or
ophilic granulocytes dispersed between the computed tomography is helpful to evaluate the
MCT cells also help in the diagnosis of MCT. Two extent of the tumor. Histopathological identifica-
concurrent grading systems are currently avail- tion of incomplete resection at the surgical mar-
able for canine MCT (. Table 4.5). The classic
3-tier Patnaik grading has been used for decades
but is increasingly criticized for classifying 40 %
of tumors as intermediate grade, without speci-

. Fig. 4.19 Cytology, cutaneous mast cell tumor grade II/


low grade, dog, May-Grünwald-Giemsa, 1000×. Note the
moderately differentiated mast cells (red arrows) with
moderate amounts of fine dustlike intracytoplasmic
granules indicating a moderate grade of differentiation.
. Fig. 4.18 Cytology, cutaneous mast cell tumor grade I/ There is a moderate pleomorphism, anisocytosis, and
low grade, dog, May-Grünwald-Giemsa, 1000×. anisokaryosis and coarse chromatin structure (blue arrow)
Well-differentiated mast cells with large amounts of fine of mast cells. Few scattered eosinophils (black arrow) are
intracytoplasmic granules (Photo: with permission of Dr. seen (Photo: with permission of Dr. N. Bauer, Faculty of
N. Bauer, Faculty of Veterinary Medicine, Veterinary Medicine, Justus-Liebig-University, Giessen,
Justus-Liebig-University, Giessen, Germany) Germany
76 R. Klopfleisch

. Fig. 4.20 Cytology, cutaneous mast cell tumor grade III/ . Fig. 4.22 Cytology, lymph node metastasis of a
high grade, dog, May-Grünwald-Giemsa, 1000×. Note the cutaneous mast cell tumor grade III/high grade, dog,
presence of moderate to undifferentiated mast cells, May-Grünwald-Giemsa, 1000× (the same dog as in
mitotic figures (black arrow) and erythrophagocytosis (red . Fig. 4.21). Note the presence of numerous
arrow) (Photo: with permission of Dr. N. Bauer, Faculty of pleomorphic undifferentiated mast cells, some of which
Veterinary Medicine, Justus-Liebig-University, Giessen, with prominent macronucleoli (black arrow) and
Germany) numerous eosinophils (red arrow). There are several
small mature lymphocytes (blue arrow) as well as few
plasma cells (green arrow) and lymphatic blasts (yellow
arrow) (Photo: with permission of Dr. N. Bauer, Faculty
of Veterinary Medicine, Justus-Liebig-University,
Giessen, Germany)

This approach may lead to a long-term control


of the disease for low- and intermediate-grade
MCT.  There is however an ongoing discussion
on whether low or intermediate MCT in  loca-
tions difficult to resect can be successfully
excised with margins of less than 0.5 cm without
additional radiotherapy or neo-adjunctive che-
motherapy. Prednisolone or tyrosine kinase
. Fig. 4.21 Cytology, cutaneous mast cell tumor grade III/ inhibitors (TKI, toceranib, and masitinib) can
high grade, dog, May-Grünwald-Giemsa, 1000×. Note the
be used to shrink MCT prior to surgery to
presence of bizarre, macrocytic multinucleated
undifferentiated mast cells (nuclei marked with black increase efficiency of surgery at difficult loca-
arrows) (Photo: with permission of Dr. N. Bauer, Faculty of tions. Radiotherapy certainly increases the
Veterinary Medicine, Justus-Liebig-University, Giessen, probability of disease control.
Germany) There are an increasing number of studies show-
ing promising results for surgery and chemotherapy
gins is a poor prognostic factor. However, of incompletely excised low-to-intermediate MCT
detection of few mast cells at the margin of low- when radiotherapy is not possible. Multidrug proto-
grade tumors does not necessarily lead to tumor cols seem to be advantageous over single-drug pro-
recurrence. It has been shown that only 20–30 % tocols. Postoperative administration of prednisone in
of these tumors recur, while 20 % of tumors with combination with vinblastine, a cocktail of predni-
free margins also recur. Nevertheless, incomplete sone, lomustine, and vinblastine, and prednisone
margins should be treated with an en bloc resec- together with vinblastine and cyclophosphamide
tion of the scar with 2 cm margins or additional seem to be efficient even in high-grade tumors or
radiation of the area if possible. tumors with a high risk of recurrence.
A combination of surgery and radiotherapy is High-grade tumors or tumors with regional
the treatment of choice for MCT in difficult loca- or distant metastasis generally have a poor
tions where sufficient margins are not possible. prognosis independent of therapeutic regimen.
Chapter 4 · Skin Tumors
77 4

. Table 4.5 Grading systems for canine mast cell tumors

Grade Histologic features (percentage of tumors) Clinical features

Patnaik system

Survival rate after 48 months

I Monomorphic cells, no mitotic figures, only in the dermis 83 %


(36 %)

II Some pleomorphic cells, 0–2 mitotic figures per 400× field, 44 %


infiltrating the subcutis (43 %)

III Dominantly pleomorphic cells, 3–6 mitotic figures, 6%


infiltrating the subcutis and deeper (20 %)

Kiupel system

Kiupel Median time to recurrence/


median survival time*

Low grade 14 weeks/23 months

High grade Per ten 400× fields: 3 weeks/<4 months


>6 mitotic figures
or
>2 multinucleated cells
or
>3 bizarre nuclei (at least 10 % of cells vary by at least
twofold)

HPF = 0.24 mm2


*Follow-up time at least 28 months

A combination of surgery, radiotherapy of the resistance to TKI associated with tumor relapse
tumor and the regional lymph node, and che- and disease progression is a common finding after
motherapy is recommended. 6–18 months of treatment for both drugs.
Exclusive chemotherapy and exclusive radio- Presurgical treatment with antihistamine such
therapy without concurrent surgery are usually as diphenhydramine is advised to reduce the sys-
not efficient for long-term control of bulky MCT temic effects of mast cell degranulation. In addi-
and are therefore not recommended. tion, administration of proton pump inhibitors
Treatment with tyrosine kinase inhibitors like omeprazole should be considered to prevent
(TKIs) has been established as an alternative treat- gastric lesions.
ment option for MCT in recent years. Toceranib
induces rapid and impressive response rates in z Prognostic Factors and Markers
almost 50 % of recurrent intermediate- and high- The general survival time of dogs with canine MCT
grade MCT, especially in those with activating is strongly dependent on tumor grade (. Table 4.5)
KIT mutations. Time to tumor progression is and to a lesser extent on clinical staging (. Table 4.4)
restricted under this regimen to 18 weeks. A long- according to the WHO staging system. In addition,
term control of recurrent or unresectable MCT several additional factors are also correlated with
has been achieved in some tumors with the appli- prognosis.
cation of the TKI masitinib. Inappetence, weight Molecular markers are currently not commonly
loss, diarrhea, and occasionally vomiting, melena, used in MCT diagnosis mainly due to the signifi-
and myelosuppression are common toxic side cant and reliable prognostic value of the clinical
effects of both drugs. Unfortunately, resistance to staging and histologic grading systems.
TKI associated with tumor relapse and disease pro- Nevertheless, immunohistochemical analysis of
gression is a common finding after 6–18 months the number of proliferating cells using the prolif-
of treatment for both drugs. Unfortunately, eration marker Ki-67, AgNOR, and PCNA and
78 R. Klopfleisch

the pattern and level of KIT expression has been z Clinical Appearance
shown to be of prognostic value. In addition, the Histiocytomas are typically solitary, button-
mutational analysis of the exon 11 tandem dupli- shaped nodules on the cranial aspect of the body.
cation is possible using simple PCR analysis; com- They can be rapidly growing and often regress
plete genetic sequence of KIT requires costly spontaneously within 1–2 months. Multiple
genetic sequencing. tumors may be present.

z Current Trends in Research


4 The current research on canine MCT is focusing z Cytology and Histopathology
on the identification of new therapy protocols Cytology presents with typical histiocytic cells
combining TKI, radiotherapy, and classic che- occasionally admixed with well-differentiated
motherapy agents. In addition, several novel lymphocytes (. Figs. 4.23 and 4.24).
compounds targeting selective inhibitor of Histopathology is diagnostic due the typical his-
nuclear export (SINE), oncolytic retroviruses, tiocytic cell shape, the wedge-shaped general
pan-bcl-2 blockers, or aurora kinase inhibitors arrangement of the tumor, and the typical fol-
are currently being tested in in vitro assays and licular aggregates of lymphocytes at the base of
clinical trials. the tumors.

z Suggested Further Reading z Therapy


(Blackwood et al. 2012; Halsey et al. 2014; Kiupel Surgery is curative but not necessary due to the
et al. 2011; London 2013; Meyer et al. 2012, 2013; self-limiting nature (spontaneous regression) of
Patnaik et al. 1984; Stefanello et al. 2015; Thamm the tumors. A successful treatment of multiple
and Vail 2007; Welle et al. 2008) histiocytomas with lomustine chemotherapy has
been described.
4.1.4.2 Canine Cutaneous
Histiocytomas
z Prognostic Factors and Markers
Immunohistochemical markers are usually not
Box 4.11. Canine Cutaneous Histiocytomas necessary to confirm the diagnosis. Histiocytomas
in Three Facts are however typically positive for CD1a, CD11c,
1. There is ongoing debate whether this E-cadherin, and MHC class II.
monoclonal cell population is a tumor or
hyperplasia.
2. Occur in young dogs mainly on the
head.
3. Are benign and regress spontaneously.

z Epidemiology and Pathogenesis


Cutaneous histiocytomas are common benign
tumors most probably derived from epidermal
Langerhans cells. They develop in young dogs
under the age of 2 years. Their clonal character
has been confirmed by genetic analysis. However,
there is ongoing debate whether they are real neo-
plasms or merely reactive hyperplasia, mostly due . Fig. 4.23 Cytology, histiocytoma without regression,
to the observation of spontaneous regression. dog, May-Grünwald-Giemsa, 1000×. Histiocytic cells with
eccentrically located nuclei, fine chromatin pattern, and
Tumor regression is associated with an infiltration abundant amounts of gray-blue cytoplasm (Photo: with
of lymphocytes and thus is most probably immune permission of Dr. N. Bauer, Faculty of Veterinary Medicine,
mediated. Justus-Liebig-University, Giessen, Germany)
Chapter 4 · Skin Tumors
79 4

. Fig. 4.24 Cytology, histiocytoma with advanced . Fig. 4.25 Cytology, cutaneous plasmacytoma, dog,
regression, dog, May-Grünwald-Giemsa, 1000×. Note the May-Grünwald-Giemsa, 1000×. Note the presence of bi- or
moderate infiltration with medium-sized lymphocytes multinucleated plasma cells (black arrow). Few
(gray arrow), plasma cells (black arrow) and few lymphocytes (blue arrow) are also seen (Photo: with
neutrophils (red arrow) (Photo: with permission of Dr. permission of Dr. N. Bauer, Faculty of Veterinary Medicine,
N. Bauer, Faculty of Veterinary Medicine, Justus-Liebig-University, Giessen, Germany)
Justus-Liebig-University, Giessen, Germany)

z Cytology and Histopathology


z Suggested Further Reading Cytologically and histopathologically, plasmacy-
(Delcour et  al. 2013; Maina et  al. 2014; Moore tomas present as an accumulation of well-
2014; Pires et al. 2013) differentiated plasma cells (. Fig. 4.25). Bi- or
multinucleated cells are common.
4.1.4.3 Canine Cutaneous
Plasmacytomas z Therapy
Complete surgical excision is curative. Non-
resectable tumors may be treated with prednisone
Box 4.12. Canine Cutaneous Plasmacytomas or radiotherapy.
in Two Facts
1. Benign tumors.
z Suggested Further Reading
2. Surgical excision is curative.
(Campo 1997; Haga et al. 2013)

z Epidemiology and Pathogenesis 4.2 Skin Tumors of the Cat


Cutaneous plasma cell tumors belong to the group
of extramedullary plasmacytomas. They are com- Squamous cell carcinomas, basal cell tumors,
mon benign skin tumors of the dog and develop at fibrosarcomas, and mast cell tumors are the most
the age of 9–10 years with a predisposition in common skin tumors of the cat, with each repre-
large breeds. senting 10–20 % of all skin tumors. All other
tumors can be considered as rare.

z Clinical Appearance
Plasma cell tumors are solitary, reddish, alopecic, 4.2.1 Feline Epithelial Tumors
raised nodules commonly diagnosed at the head
and limbs. Hypergammaglobulinemia due to Squamous cell carcinomas and basal cell tumors
antibody secretion by tumor cells is not are the most common feline epithelial skin
observed. tumors. Papillomas, hair follicle tumors, and
80 R. Klopfleisch

tumors of the adnexal glands are rare and not z Clinical Appearance
described in detail in this chapter. BISC present as large, mostly multiple, hairless,
pigmented, plaque-like erosions and crusts sev-
4.2.1.1 Feline Cutaneous eral cm in diameter. They can occur on any area of
Squamous Cell Carcinoma the body. Metastasis and invasion are not present
by definition (in situ carcinoma). Left untreated
the tumors may however progress to invasive
Box 4.13. Feline Cutaneous Squamous Cell SCC. Patients with BISC are at risk of developing
4 Carcinomas (SCCs) in Five Facts new BISC in the future.
1. SCC common on UV-exposed, light- Chronic actinic dermatitis is usually the pre-
haired areas (pinnae, nasal planum, eye- stage of SCC. SCC usually present as plaque-like,
lid) erythematous, ulcerated, crust-covered lesions
2. Subtype of potentially and may be confused with chronic ulcerative der-
Papillomavirus-induced Bowenoid in matitis. They are rarely prominent or papillary.
situ carcinoma (BISC) They grow invasively. Metastasis is rare but if
3. SCC with invasive growth but metastasis present is found in the mandibular and retropha-
rare ryngeal lymph nodes and lungs. In general, sur-
4. Surgery with good prognosis at early vival times of cats with SCC at the pinna are
tumor stages slightly longer (~2.5 years) than that of cats with
5. Radiotherapy for difficult location and SCC on the nasal planum. Cats with concurrent
advanced stages with guarded prognosis lesions on both sites have median survival times
of <2 years.
A staging system is available, which is of prog-
nostic relevance for survival and therapy success
z Epidemiology and Pathogenesis (. Table 4.6)
Cutaneous squamous-cell carcinomas (SCC)
are a common malignant skin tumor of the cat. z Cytology and Histopathology
In the cat, they are commonly divided into two Cytologically, the presence of pleomorphic and
tumor types: UV light-induced invasive SCC anisokaryotic cells is helpful in the diagnosis of
and potentially Papillomavirus-induced SCC SCC (. Figs. 4.26 and 4.27).
in situ (syn. Bowenoid in situ carcinoma Histopathologically, BISC appear as sharply
(BISC)). demarcated supra-basal proliferation of atypical
BISCs are defined as locally invasive (in situ) epidermal keratinocytes. Hyperkeratosis and
carcinomas without invasion of the basement hyperpigmentation may be present. SCC consist
membrane of the epidermis. They are thought to of invasive groups and cords of moderately to
be associated with feline Papillomavirus infection. poorly differentiated epithelial cells. Keratinization
Contribution of UV-light exposure in the etiology and keratin pearls are common and help to dif-
of BISC in cats is also discussed in the literature, ferentiate SCC from other epithelial tumors.
but unlike SCC, these tumors often arise in areas
of the body protected from UV light so this is an z Therapy
unlikely cause. BISC occurs in older cats at an Early surgery is the treatment of choice for BISC
age > 10 years, without breed, sex, or hair color and SCC at the pinnae; the procedure is associ-
predisposition. BISC may progress to invasive ated with a good prognosis if tumor-free margins
SCC. of at least 1  cm are achieved. Resection of the
Invasive SCC usually develop in animals over nasal planum and parts of the eyelid is possible
the age of 10 on lightly haired areas of the head and has a good prognosis if tumor-free surgical
that are exposed to UV light. White pinnae are the margins are achieved.
most commonly affected area, while the nasal pla- Radiotherapy is commonly used for treatment
num and the eyelids are less frequently affected. of SCC at the nasal planum. Irradiated in situ SCC
There is no sex or breed predisposition for SCC. in this location have a good prognosis of complete
Papillomavirus infection may also be of etiologic remission, while invasive SCC has a guarded
relevance for invasive SCC. prognosis for remission.
Chapter 4 · Skin Tumors
81 4

. Table 4.6 Staging system for feline cutaneous


squamous-cell carcinoma (WHO, Owen 1980)

Stage Description

Tis Preinvasive carcinoma (carcinoma in situ)


not breaching the basement membrane

T1 Tumor <2 cm diameter, superficial or


exophytic

T2 Tumor 2–5 cm diameter, or with minimal


invasion irrespective of the size

T3 Tumor >5 cm diameter, or with invasion


of the subcutis irrespective of the size
. Fig. 4.26 Cytology, cutaneous squamous-cell
T4 Tumor invading other structures such as
carcinoma, cat, May-Grünwald-Giemsa, 100×. Note the
the fascia, muscle, bone, or cartilage
marked anisocytosis, anisokaryosis, pleomorphism, and
variation in nuclear-to-cytoplasm ratio. There are many
epithelial cells with asynchronous maturation of nucleus
Photodynamic therapy is a treatment option
and cytoplasm (black arrow), i.e., they possess angular
for SCC on the eyelids and the nasal planum. cellular borders and abundant lightly basophilic
Treatment often leads to initial complete remis- cytoplasm typical for mature cells but have retained a
sion, but in 50 % of cases, recurrences are observed large, non-pycnotic nucleus typical for immature
within 1 year. epithelial cells. Some cells show cell cannibalism (red
arrow) (Photo: with permission of Dr. N. Bauer, Faculty of
There are only a few studies on the efficacy of
Veterinary Medicine, Justus-Liebig-University, Giessen,
chemotherapy for feline cutaneous SCC.  These Germany)
studies have not found significant benefits from
doxorubicin, cyclophosphamide, mitoxantrone,
and actinomycin. They have found that local
application of cisplatin and 5-fluorouracil may be
efficient.

z Suggested Further Reading


(Bergvall 2013; Munday et al. 2013; Munday et al.
2011; Murphy 2013; Owen 1980)

4.2.1.2 Feline Basal Cell Tumors

Box 4.14. Feline Basal Cell Tumors in Four . Fig. 4.27 Cytology, cutaneous squamous-cell
Facts carcinoma, cat, May-Grünwald-Giemsa, 500×. Note the
1. Benign tumors of the skin at the head marked anisocytosis, anisokaryosis, pleomorphism, and
variation in nuclear-to-cytoplasm ratio as well as the
2. May be pigmented presence of atypical elongated (“tadpole-like”) turquoise
3. Rare basal cell carcinoma with invasion epithelial cells with multiple perinuclear vacuoles highly
and metastasis suggestive of squamous-cell carcinoma (black arrow)
4. Wide surgical excision as treatment of (Photo: with permission of Dr. N. Bauer, Faculty of
choice Veterinary Medicine, Justus-Liebig-University, Giessen,
Germany)

z Epidemiology and Pathogenesis reserve cells of the epidermis. They are common
Basal cell tumors (BCT) are a common benign tumors in patients aged 8–10 years. Basal cell car-
tumor of the cat, which are derived from basal cinomas (BCC) are a rare malignant version of the
82 R. Klopfleisch

. Fig. 4.29 Viscous, yellow fluid aspirated from a basal


. Fig. 4.28 Basal cell tumor, cat presented with a slowly
cell tumor (the same cat as in . Fig. 4.28). Note that the
growing, soft, pigmented, cystic mass at the head (Photo:
fluids aspirated from cystic areas of tumors rarely reveal
with permission of Dr. N. Bauer, Faculty of Veterinary
the etiology, so that also fine-needle aspirates from the
Medicine, Justus-Liebig-University, Giessen, Germany)
margins of the tumor should be taken (Photo: with
permission of Dr. N. Bauer, Faculty of Veterinary Medicine,
Justus-Liebig-University, Giessen, Germany)
basal cell tumor. BCC grow invasively and can
form regional and distant metastases. There is a z Suggested Further Reading
debate whether basal cell tumors are actually (Byam-Cook et  al. 2006; Stewart et  al. 2006;
trichoblastomas or apocrine gland adenomas. Stockhaus et al. 2001)

4.2.1.3 Feline Melanomas


z Clinical Appearance
Clinically, BCT are well-circumscribed, button-
shaped, hairless nodules commonly located at the Box 4.15. Feline Cutaneous Melanomas in
head or neck (. Fig. 4.28). They are often pigmented Four Facts
and can be confused with melanomas. They are 1. Mostly malignant
usually slow growing. BCC are faster growing and 2. Invasive growth and distant metastasis
may occasionally metastasize regionally and to common
distant organs(. Fig. 4.29). 3. May be amelanotic
4. Surgery with wide margins often
z Cytology and Histopathology associated with recurrence
Cytology of BCT presents with a mixture of squa-
mous cells, sebaceous epithelial cells, melanin-
containing cells, and fibroblasts (. Fig. 4.30).
Differentiation of benign BCT from BCC is usu- z Epidemiology and Pathogenesis
ally not possible. Cutaneous melanomas are rare, mostly malignant
On histopathology, BCT presents as a well- tumors in the cat. They are tumors of the melanin-
circumscribed islands of moderately differenti- producing melanocytes, which are derived from the
ated epithelial cells admixed with a moderately neural crest and thus neither mesenchymal nor epi-
fibrous stroma. BCC are differentiated from BCT thelial tumors. There is no breed or sex predisposition
by their invasive growth at the tumor margins. for feline melanomas. The average age of cats with the
diagnosis of a melanoma is 10–12 years. Melanomas
z Therapy are also found intraocularly or at the eyelids and
Wide surgical excision of BCT and most probably rarely in the oral cavity (7 see Chaps. 9 and 16).
of BCC is usually curative. BCT seems to be sensi-
tive to radiotherapy, which can be used for the
treatment of tumors that are difficult to resect due z Clinical Appearance
to their location. The effect of radiotherapy on Feline cutaneous melanomas are commonly
BCC is unknown. found on the head, the nasal planum, and the
Chapter 4 · Skin Tumors
83 4

. Fig. 4.32 Renal metastases of a cutaneous


. Fig. 4.30 Cytology, basal cell tumor, cat (the same cat melanoma, cat
as in . Fig. 4.28), May-Grünwald-Giemsa, 1000×. Note
the cluster of small basaloid cells with centrally located
nuclei, fine chromatin pattern, and small amounts of
lightly basophilic cytoplasm showing the typical
“ribbonlike” growth (Photo: with permission of Dr.
N. Bauer, Faculty of Veterinary Medicine,
Justus-Liebig-University, Giessen, Germany)

. Fig. 4.33 Cytology, cutaneous mostly amelanotic


melanoma, May-Grünwald-Giemsa, cat

amelanotic melanoma is challenging cytologically


and histopathologically. Immunohistochemical
detection of S-100 and Melan-A helps to differen-
tiate melanomas from non-neuroectodermal
. Fig. 4.31 Lung metastases (white arrows) of a tumors (. Fig. 4.33).
cutaneous melanoma, cat
z Therapy
digits. They are solitary, sometimes hairless and Surgery with wide tumor margins is the treatment
ulcerated nodules; they are mostly pigmented of choice for tumors without detectable metasta-
but can be amelanotic. The majority of the ses. The recurrence rate however is high.
tumors metastasize to the regional lymph node,
the lung, or other organs (. Figs. 4.30 and 4.31).
Histologic differentiation of benign and malig- z Suggested Further Reading
nant often does not correlate with the actual (Martens et al. 2001; Metcalfe et al. 2013; Stadler
clinical behavior in the case of cutaneous mela- et al. 2011)
nomas.

z Cytology and Histopathology 4.2.2 Mesenchymal Tumors


Cytologically, pigmented melanomas present as
pigmented epitheloid, spindloid, or even round Malignant mesenchymal tumors in all body
cell-like tumor cells (. Fig. 4.32). The diagnosis of areas are commonly designated as soft tissue
84 R. Klopfleisch

sarcomas (STSs) due to the similarity of their predisposition. Tumors arise at an average age of
clinical presentation and response to treatment. 8–12 years. FISSs have been observed since the
Commonalities of these tumors are highly inva- introduction of vaccination into feline medicine in
sive growth, high rate of recurrence, and the 1980s. An increased incidence of subcutaneous
low-to-moderate frequency of local and distant fibrosarcomas can be seen months to years after
metastases. The term soft tissue sarcomas vaccination at the site of injection, more commonly
therefore refers to tumors of different histogen- the interscapular region, lateral thorax, and thighs.
esis such as fibrosarcomas, liposarcomas, and This was initially attributed to carcinogenic effects
4 rhabdomyomas. of aluminum-based adjuvants. However, large epi-
In cats the term STS is however less often used demiologic studies have found no correlation
than in dogs. This may be caused by the smaller between any specific adjuvants or vaccine type with
variety of mesenchymal tumors in the cat. The tumor development. Today it is generally accepted
most common cutaneous mesenchymal tumor of that post-vaccination and injection inflammation
the cat is the feline injection-site-associated sar- or most probably any form of chronic inflamma-
coma (FISS), which is described in detail here. tion may induce neoplastic transformation of feline
Rhabdomyomas, leiomyosarcomas, and lipomas subcutaneous myofibroblasts. In particular, the
are very rare in cats. expression of growth factors like TGF and EGF and
The staging and grading systems initially devel- their receptors in the tumors and mutations of the
oped for canine soft tissue sarcomas are occasionally p53 tumor suppressor gene are thought to be of rel-
also used for feline soft tissue sarcomas (. Table 4.7). evance for the molecular carcinogenesis of FISS.
Two risk factors have been identified for the
z Suggested Reading development of FISS: multiple vaccinations and
(Liptak and Forrest 2012) temperature of the vaccine. The number of vacci-
nations or injections given at a site increases the
4.2.2.1 Feline Injection-Site Sarcomas risk of an FISS developing, i.e., three to four vac-
(FISSs) cinations (as opposed to one vaccination) in the
interscapular region double the risk of sarcoma
formation at that site. Furthermore, administra-
Box 4.16. Feline Injection-Site-/Vaccine- tion of cold vaccines versus room-temperature
Associated Sarcomas in Seven Facts vaccines is supposed to increase the risk. Several
1. Induced by injection-/vaccine-associated recommendations for the prevention of FISS have
inflammation. been published (7 Box 4.17).
2. Repeated injection at the same time as
risk factor.
3. Comprehensive vaccination guidelines
Box 4.17. Recommendations for the Prevention
for risk reduction available.
of FISS (Hartmann et al. 2015)
4. Histopathologic evaluation of tumor
1. Vaccination of cats provides essential
margins fails in 20 % of cases.
protection and should not be stopped
5. Best results from radical surgery with
because of the risk of feline injection-site
5-cm margins or amputation.
sarcoma (FISS).
6. Post- or preoperative radiotherapy may
2. Vaccines are not the only injectable
increase disease-free interval.
medical products associated with FISS.
7. Chemotherapy of minor relevance.
3. Cats should be vaccinated no more than
necessary, in accordance with current
guidelines.
z Epidemiology and Pathogenesis 4. The interscapular region should
Fibrosarcomas in cats are classified into the more generally be avoided. Vaccines should be
frequent feline injection-site sarcomas (FISSs) and injected at a site from which a mass can
the non-vaccine-/injection-site-associated sarco- easily be surgically removed, such as dis-
mas (SAs) of unknown etiology. tally on a leg or in the skin of the lateral
FISS is one of the most common skin tumors abdomen.
of  the cat. There is no breed and no sex
Chapter 4 · Skin Tumors
85 4
In addition, macrocytic spindle cells with
5. Vaccines should be brought to room macronuclei and macronucleoli can be seen in
temperature prior to administration, but highly malignant tumor (. Fig. 4.35).
should not be kept unrefrigerated for Histopathology of FISS is characterized by a
hours. poorly circumscribed proliferation of pleomor-
6. Whenever possible, subcutaneous, phic spindle cells around a common necrotic and
rather than intramuscular, injection cystic area within the tumor mass; there is marked
should be performed. inflammatory infiltration at the tumor boarders
7. The preference is for non-adjuvanted which is not seen with FISA. There is no generally
vaccines over those containing adjuvant, accepted grading system for FISS. 2.1.
modified live vaccines or recombinant Histopathology has a moderate to poor speci-
vaccines over inactivated vaccines, and ficity and sensitivity to confirm surgical margins in
vaccines with a long duration of the healthy tissue after surgical resection. Even
immunity. tumors with free margins as diagnosed by a thor-
8. Post-vaccination monitoring should be ough three-dimensional histological approach,
performed. Any lump at the site of which analyzes tumor margins completely in all
injection that is still present 3 months dimensions, have a recurrence rate of 20 %. This
after vaccination, that is larger than observation has led to the hypothesis that
2 cm in diameter, or that is increasing in recurrences may actually be new tumors that
size 1 month after vaccination should be develop from postsurgical inflammation. The
surgically removed. advantage to complete resection is that recurrence
after diagnosis of tumor-free margins occurs later
than recurrence after incompletely resected
tumors.
In contrast, non-injection-associated SAs have
an unknown etiology. They are less common than
FISS and are tumors of older cats. They may arise z Therapy
at any site on the body but mostly found on the Treatment success of FISS very much depends on
head and distal limbs. SAs lack the typical FISS early and aggressive therapy to achieve local
inflammation at all stages of tumor development tumor control.
and size and are thus thought not to be caused by Aggressive surgery with tumor margins of 5 cm
inflammation. laterally and two fascial planes deep will reduce
the recurrence rate to less than 15 %, compared to
z Clinical Appearance recurrence after marginal surgery. Aggressive
Grossly, FISS and SA may appear clinically similar, amputation is usually required to achieve suffi-
except that SA is found on all body sites and is not cient tumor margins for local tumor control;
more common at vaccination sites. Both are firm, amputation usually requires the complete removal
non-ulcerated, subcutaneous masses (. Fig. 4.34). of the limb, dorsal spinous processes, and parts of
FISS may appear partially soft or fluctuating due the scapula and resection of the body wall includ-
to common cystic spaces. Palpation is a poor indi- ing several ribs or hemipelvectomy.
cator of tumor margins; magnetic resonance Radiotherapy is recommended in addition to
imaging (MRI) and contrast-enhanced computed aggressive surgery for appropriate treatment of
tomography (CT) studies have shown tumor vol- FISS, especially in cases where sufficient tumor
ume to be up to double the size appreciated on margins are not achieved. Both pre- and postop-
palpation. Metastasis is observed in up to 25 % of erative radiotherapies are used. The results are
the tumors but usually occurs at later stages of however debatable with only 100–300 days of
tumor development. disease-free intervals and 30 % recurrence after
preoperative irradiation and incomplete resection.
z Cytology and Histopathology Similarly, incomplete resection and postoperative
Cytology of FISS and SA is characterized by irradiation are only associated with a median
cohesive cluster of spindle cells with marked disease-free interval of approximately 1 year and
anisocytosis, anisokaryosis, and pleomorphism. recurrence of up to 30 %. The time span between
4
86
R. Klopfleisch

. Table 4.7 Staging system for soft tissue sarcomas (Liptak and Forrest 2012)

Stage Tumor size Lymph node metastases Metastasis Histologic grade

1 Tany (any r size) N0 (none) M0 (none) I–II

II T1a (<5 cm, superficial) N0 (none) M0 (none) III


T1a (<5 cm, deep)
T2a (>5 cm, superficial)

III T2b (>5 cm, deep) N0 (none) M0 (none) III

IV Tany (any r size) N1 (present) Many I–III


Tany (any r size) Nany M1 (present)
Chapter 4 · Skin Tumors
87 4
long) response in up to 50 % of treated cats after
administration of doxorubicin alone or in combi-
nation with cyclophosphamide.
Immunotherapy with intralesional injection of
interleukin-2 (IL-2) and surgery may lead to a
decrease in the recurrence rate by 50 %.

z Prognostic Factors and Markers


Several factors negatively influence the prognosis
for FISS (7 Box 4.18).

. Fig. 4.34 Feline injection-site sarcoma, cat (Photo: with Box 4.18. Negative Prognostic for FISS
permission of the Faculty of Veterinary Medicine,
Justus-Liebig-University, Giessen, Germany)
1. Tumor size >2 cm
2. Incomplete resection
3. Recurrence after excision
4. High-grade tumor
5. Distant metastasis
6. No pre-/postoperative radiotherapy

z Suggested Further Reading


(Eckstein et al. 2009; Hendrick and Goldschmidt
1991; Hershey et al. 2000; Kass et al. 2003; Ladlow
2013; Liptak and Forrest 2012; Martano et  al.
2011; Richards et al. 2006; Vaccination Guidelines
et al. 2010)

. Fig. 4.35 Cytology, feline injection-site-associated


sarcoma (FISS), cat (the same cat as in . Fig. 4.34), 4.2.3 Feline Hematopoietic Tumors
May-Grünwald-Giemsa, 1000×. Note the cohesive cluster
of spindle cells with marked anisocytosis, anisokaryosis, Mast cell tumors are the most common cutaneous
and pleomorphism. Several macrocytic spindle cells (red
arrow) with macronuclei and macronucleoli are seen (blue
hematopoietic tumor of the cat. Plasma cell
arrow) indicative of a highly malignant tumor (Photo: with tumors are rare, cutaneous lymphomas (Chap. 6)
permission of Dr. N. Bauer, Faculty of Veterinary Medicine, very rare in the cat.
Justus-Liebig-University, Giessen, Germany)
4.2.3.1 Feline Cutaneous Mast Cell
surgery and radiotherapy should be less than 2 Tumors
weeks to minimize recurrence rates. Exclusive
radiotherapy should be restricted to palliative
care. Box 4.19. Feline Cutaneous Mast Cell Tumors
Chemotherapy is of minor relevance in the in Four Facts
treatment of FISS but may have some impact on 1. Often malignant.
survival times of cats treated with surgery and 2. Show an invasive growth and
radiotherapy. An increase in the disease-free occasionally distant metastases.
interval in cats treated with doxorubicin after sur- 3. Surgery with wide margins is usually
gery has been observed. Exclusive chemotherapy curative.
can lead to a short-term (on average 3 months
88 R. Klopfleisch

z Epidemiology and Pathogenesis reliable method for discriminating benign from


Feline mast cell tumors (MCT) are common malignant tumors or for evaluating tumor
tumors in the cat; they make up ~10 % of all feline grade.
neoplasias. MCT are further classified into three Histopathology is required for unequivocal
clinically very diverse forms: cutaneous, intesti- differentiation of feline cutaneous MCT into their
nal, and visceral/systemic MCT (also see Chaps. 6 subclasses. Two distinct subclasses of cutaneous
and 9). Cutaneous MCTs are the second most MCT in the cat have been reported: the masto-
common skin tumor in the cat, making up ~20 % cytic MCT (~90 %) and the histiocytic MCT
4 of all cutaneous tumors. Feline cutaneous MCTs (~10 %). The mastocytic form is further subdi-
are usually diagnosed between the age of 2–4 vided histologically into well-differentiated, com-
years (atypical form) and 10 years (mastocytic pact MCT (up to 90 %) and poorly differentiated,
form). Siamese cat breeds are predisposed to all pleomorphic MCT. Well-differentiated, compact
forms of MCT. MCT are mostly benign with uniform, typical
The etiology and molecular pathogenesis of
feline MCT are mostly unknown. Due to the
breed predisposition in Siamese cats, a genetic
. Table 4.8 Staging system for feline mast cell
basis is assumed. A contribution of mutations in
tumors (Henry 2013)
the stem cell factor receptor KIT is hypothesized.
Up to two-thirds of cutaneous and splenic/vis- Stage Description
ceral MCT have KIT mutations in the exons 8 and
9, which induce ligand-independent activation of 0 One tumor, completely excised
KIT and may thus contribute to proliferation and I One tumor confined to the skin, no
survival of MCT cells. lymph node metastasis

II One tumor confined to the skin with


z Clinical Appearance lymph node metastasis
Feline cutaneous MCT is usually white to pink,
III Many/large infiltrating tumors, with/
solitary, firm, well-circumscribed, or occasionally without lymph node metastasis
pruritic, plaque-like, flat, hairless, dermal masses.
One-quarter of the tumors are superficially ulcer- IV Any tumor with distant spread of the
disease
ated on the head and the neck. Cats may present
with pruritus and erythema; Darier’s sign, which
consists in rapid swelling after manipulation due
to histamine release, has been reported. Multiple
tumors are present in 20 % of cats. Metastasis is
reported in 0 to 22 % of the tumors. Paraneoplastic,
systemic disease is rather uncommon in cats with
cutaneous MCT.
A staging system for feline tumors exists but its
relevance for therapy or prognosis is not con-
firmed (. Table 4.8). Nevertheless, a thorough
physical exam and abdominal ultrasound are
helpful to identify splenic disease in establishing a
general prognosis. A buffy coat analysis for the
detection of circulating mast cells is helpful in
cats, in contrast to dogs, to identify systemic . Fig. 4.36 Cytology, mastocytic, poorly differentiated
spread of the tumor. No paraneoplastic syn- mast cell tumor, cat, May-Grünwald-Giemsa, 1000×. Note
dromes are observed with this tumor type. the pleomorphic mast cells with moderate to marked
anisocytosis, anisokaryosis, and pleomorphism. There are
z Cytology and Histopathology several undifferentiated, large mast cells with rare
intracytoplasmic metachromatic granules indicative of a
Cytology of feline MCT is usually diagnostic low degree of differentiation (red arrow) (Photo: with
except for the uncommon atypical form permission of Dr. N. Bauer, Faculty of Veterinary Medicine,
(. Fig. 4.36). Unfortunately, cytology is not a Justus-Liebig-University, Giessen, Germany)
Chapter 4 · Skin Tumors
89 4
mast cell morphology; they rarely metastasize. the proliferation marker Ki67 is also associated
Poorly differentiated, diffuse MCT have a marked with a more aggressive tumor behavior.
cellular and nuclear pleomorphism, aggressive
infiltrative character, and high mitotic index.
Metastasis to the lymph nodes and the abdomen z Current Trends in Research
may occur but is still the exception even for this There is an ongoing discussion on the relevance of
malignant subtype. Histiocytic MCT possess mor- KIT mutations and TKI in the treatment of feline
phologic features characteristic of histiocytic cutaneous MCT.
cells. Similar to the canine cutaneous histiocy-
toma, they regress spontaneously over a period of
several months. z Suggested Reading
A grading system for feline mast cell tumors is (Blackwood et  al. 2012; Hoshino et  al. 2012;
not available. The Patnaik system for canine MCT Sabattini et al. 2013)
does not have prognostic value for feline MCT.
4.2.3.2 Feline Cutaneous
Plasmacytomas
z Therapy
Surgery is the treatment of choice for feline
MCT.  Simple excision is often curative. Box 4.20. Feline Cutaneous Plasmacytomas
Completeness of surgical excision is not signifi- in Three Facts
cantly correlated with recurrence in well-differen- 1. Mostly benign.
tiated feline MCT. Most studies show that tumor 2. Present as solitary, raised nodules.
recurrence may occur for up to one-third of cuta- 3. Surgery is usually curative.
neous MCT, regardless of the completeness of
surgical excision. Most of these recurring tumors
are poorly differentiated MCT.
Chemotherapy is of questionable value as an z Epidemiology and Pathogenesis
adjunctive therapy for the treatment of feline Cutaneous plasmacytomas are derived from
MCT. Lomustine has been successfully tested and plasma cell tumors. They are rare skin tumors in
may be helpful for cats with poorly differenti- the cat and develop at an age of <10 years.
ated, locally invasive, or metastatic tumors.
Corticosteroids have not been shown to be
effective in the treatment of feline MCT.  The z Clinical Appearance
tyrosine kinase inhibitor (TKI) imatinib has Cutaneous plasma cell tumors are benign, soli-
effects on feline mast cells in cell culture, and tary, alopecic, raised nodules, diagnosed on areas
first reports are available on at least partial of the skin. Metastatic behavior and hypergam-
response in single cases of cats with MCT.  The maglobulinemia are occasionally described.
effect of the TKI masitinib or toceranib has not
been tested in cats with feline mast cells yet.
Radiotherapy is recommended for incom- z Cytology and Histopathology
pletely excised tumors but studies proving its effi- Plasmacytomas present as an accumulation of
cacy are lacking. well-differentiated plasmacytoid cells on cytology
and on histopathology. The presence of multinu-
cleated cells is common (. Fig. 4.37).
z Prognostic Factors and Molecular Marker
As stated previously, the majority of feline MCT z Therapy
carry a mutation in the KIT gene exon 8 or 9. Their Surgical excision is the treatment of choice.
value as prognostic indicator is however question-
able. In contrast, a switch from the normal
membrane-bound KIT protein expression to cyto- z Suggested Further Reading
plasmic expression in feline MCT cells is associ- (Muller et al. 2011; Teixeira et al. 2013; Theon
ated with poor prognosis. Increased expression of et al. 2007)
90 R. Klopfleisch

and antelopes. Sarcoids are the result of a multi-


factorial pathogenesis. However, infection with
the bovine papillomaviruses 1 and 2 (BPV1,
BPV2) is the major factor contributing to their
development. Viral DNAs but not infectious
virions are consistently detected in the tumors.
The amount of viral DNA positively correlates
with the aggressiveness of the sarcoid. Due to the
4 nonproductive infection in equine cells, only
direct contact with infected cattle or indirect con-
tact via fomites or insect vectors is infectious. It is
unlikely that equine sarcoid material or sarcoid-
carrying horses can be infectious to other horses.
. Fig. 4.37 Cytology, plasmacytoma, cat, The viral proteins E5, E6, and E7 primarily
May-Grünwald-Giemsa, 1000×. Note the atypical, often contribute to the neoplastic transformation of
binucleate plasma cells with moderate to marked equine fibroblasts. Both E5 and E6 upregulate the
anisocytosis, anisokaryosis, and pleomorphism. expression of mitogen-activated protein kinase
Occasionally, nuclear fragmentation (red arrow) and
undifferentiated blastoid (blue arrow) cells are seen
(MAPK) and thus fibroblast proliferation; E5 also
(Photo: with permission of Dr. N. Bauer, Faculty of downregulates major histocompatibility complex
Veterinary Medicine, Justus-Liebig-University, Giessen, 1 (MHC-1) and thus contributes to immune eva-
Germany) sion of infected fibroblasts.
There is a breed predisposition in Appaloosas,
4.3 Equine Skin Tumors Arabians, Quarter horses, and Thoroughbreds.
An increased risk has been associated with the
Skin tumors are the most commonly diagnosed MHC alleles A3 and W13. Sarcoids are commonly
neoplasms of the horse. Of these, sarcoids are the first noticed in young horses at an age of 1–7 years
most common tumors followed by melanoma. but may occur at any age. There is no gender or
Squamous-cell carcinomas are also observed but color predisposition.
mostly occur in the periocular area (see Chap. 16)
and the penis (7 see Chap. 7) and are discussed
in their respective chapters. z Clinical Appearance
Macroscopically, sarcoids have a highly variable
appearance, and more than half of the horses may
4.3.1 Equine Sarcoids have multiple tumors. They usually develop at
sites of previous trauma or in areas with thin skin.
Sarcoids are non-metastatic but infiltratively
Box 4.21. Equine Sarcoids in Four Facts growing and thus have a high recurrence rate after
1. Induced by infection with bovine papil- treatment. Spontaneous regression is rare.
lomaviruses 1 and 2 (BPV1, BPV2) Clinically, sarcoids may be classified in to six
2. May grow invasively, often recur, never types according to Knottenbelt: occult, verrucous,
metastasize nodular (types A and B), fibroblastic, malignant,
3. Highly variable macroscopic appearance and mixed. Occult sarcoids are focal areas of alo-
4. Numerous reported therapy options but pecia, scaling, hyperkeratosis, and hyperpigmen-
none very effective tation; they are located at the neck, face, medial
thigh, and shoulder. Verrucous sarcoids have a
raised, alopecic, irregular surface; they are located
at the head, neck, axillae, and groin. Nodular
z Epidemiology and Pathogenesis sarcoids type A are nodular subcutaneous
With a prevalence of up to 10 % of all horses, sar- masses  that can be moved freely under the
coids are the most common tumor of the horse. skin  while nodular sarcoids type B are
Sarcoids have also been reported in other equids connected with the subcutis and thus are not
like zebras, donkeys, mules, and even giraffes movable. Both types are usually haired but may
Chapter 4 · Skin Tumors
91 4
become alopecic and ulcerated. Both are common with surgical treatment. BPV DNA has been
periocularly, at the groin, and the prepuce. detected up to 2  cm outside the macroscopically
Fibroblastic sarcoids are fleshy, ulcerated masses perceived tumor. Surgical margins should there-
which are pedunculated (type 1) or have a broad fore be generous. A “one-cut, one-blade” policy
invasive base (type 2). They are commonly found and a diligent prevention of contact between
at the axillae, groin, legs, and periocularly. tumor material and the surgical site may prevent
Malignant sarcoids are particularly aggressive and implantation of infected cells into the tumor bed.
invasive and may infiltrate lymphatic vessels. Carbon dioxide laser treatment and cryosur-
Although occult, verrucous and nodular sarcoids gery with three cycles of quick freezing and slow
may remain static for years; all sarcoids can prog- thawing of the tumor have been reported as
ress to the more aggressive fibroblastic or malig- potentially effective in some cases.
nant type, most commonly after being irritated Radiotherapy has been reported to be the most
and traumatized. Fibroblastic sarcoids are fleshy, effective treatment with very low recurrence rates.
ulcerated masses which are pedunculated (type 1) However, it is expensive and not easily available.
or have a broad invasive base (type 2). Interstitial brachytherapy with implants of a radia-
They are commonly found at the axillae, groin, tion source (iridium, cobalt, radium) injected into
legs, and periocularly. Malignant sarcoids are par- the sarcoid is also associated with an efficacy of up
ticularly aggressive and invasive and may infil- to 100 % and very low recurrence rates.
trate lymphatic vessels. Although occult, Local chemotherapy with injection or topical
verrucous and nodular sarcoids may remain static application of cisplatin or 5-fluorouracil into the
for years, all sarcoids may progress to the more sarcoid has been reported to either induce remis-
aggressive fibroblastic or malignant type, most sion or reduce recurrence rates in the majority of
commonly after being irritated and traumatized. smaller sarcoids. Debulking surgery is often used
Clinical presentation, histopathology, and PCR in combination with local pre- or postoperative
for the detection of BPV DNA are used for ulti- chemotherapy.
mate diagnosis of equine sarcoids. Antiviral drugs like acyclovir, cidofovir, and
xanthates have been used topically and as injec-
tions with promising results in a few studies.
z Cytology and Histopathology Immunomodulatory therapies including intra-
Cytology of sarcoids usually presents as proliferat- tumoral infection with fragments of
ing fibroblasts and is therefore not specific enough Mycobacterium bovis (BCG vaccine) have been
to differentiate sarcoids from other nonneoplas- used to stimulate an immune reaction against
tic, proliferative lesions like granulation tissue. BPV-infected cells in sarcoids with successful res-
Histopathology of sarcoids usually shows a olution of up to two-thirds of the treated tumors.
dermal proliferation of fibroblasts in a rather Finally, treatment attempts using imiquimod, bay-
mixed-growth pattern usually starting directly at pamun, and extracts from bloodroot (Sanguinaria
the epidermal basement membrane. Fibroblasts canadensis) have been reported.
are usually oriented perpendicular to the base-
ment membrane in a so-called “picket fence” pat-
tern. Epidermal proliferation with rete ridges z Prognostic Factors and Marker
extending deep into the dermis may be present. Treatment of horses under of 4–6 years old with
small tumors at an early stage of development is
z Therapy associated with a good-to-moderate prognosis.
There is no universally effective treatment proto- Trauma of the sarcoid and recurrence after pri-
col for equine sarcoids. A plethora of approaches mary treatment worsen the prognosis signifi-
has been developed, and any one of these may be cantly.
applied depending on the specific tumor, location,
and clinical equipment.
Surgery can be an effective treatment if resec- z Suggested Further Reading
tion with wide margins is possible. Early and radi- (Bergvall 2013; Byam-Cook et al. 2006;
cal removal of small sarcoids has the best prognosis. Knottenbelt 2006; Martens et al. 2001; Stadler
Nevertheless, a high recurrence rate is seen even et al. 2011; Stewart et al. 2006)
92 R. Klopfleisch

4.3.2 Equine Melanomas

Box 4.22. Equine Melanomas in Six Facts


1. Common tumor in gray horses.
2. Also present in non-gray horses.
3. Initially benign tumors may become
4 malignant.
4. No evidence for biopsy-induced
malignant transformation.
5. Early surgery may be curative. . Fig. 4.38 Perianal melanoma, gray horse
6. Radiotherapy, local chemo- and
immunotherapy, and antitumor
vaccination also possible.

z Epidemiology and Pathogenesis


Melanomas are a common skin tumor in horses.
They develop by neoplastic transformation of
cutaneous melanocytes. Melanomas have been
reported in horses of all colors. However, gray
horses are predisposed with a prevalence of up to
80 % at an age of 15 years or older. The tumors
usually have a long initial benign growth phase
but approximately 66 % of them become malignant
with metastasis in distant organs after long peri-
ods of dormancy. Although less common, a large . Fig. 4.39 Perineal melanoma, gray horse
fraction of melanomas in non-gray horses are
malignant.
The high incidence of melanomas in gray
horses has been associated with the graying pro- masses (. Figures 4.38 and 4.39). Amelanotic
cess beginning at 5–8 years of age. This graying tumors are rare but may occur. Melanomas may
process and the increased risk of melanoma devel- be deep dermal masses or located more super-
opment are based on a duplication in intron 6 of ficially in the dermis and epidermis. The latter
the syntaxin 17 (STX17) gene. STX17 activates the may ulcerate at advanced stages. The most
extracellular signal-regulated kinase (ERK) path- common anatomic sites for melanomas in the
way and thereby induces melanocyte proliferation. horse are the perianal region, the ventral tail
In addition, the role of genetic polymorphisms of base, the lip, the skin overlying the parotid sal-
the melanocortin 1 receptor (MC1R) and its antag- ivary gland, and the prepuce. Systemic clinical
onist agouti signaling protein (ASIP) has been ana- symptoms depend on the site of distant, lym-
lyzed for their contribution to the development of phogenic metastasis and include weight loss
equine melanomas but their direct role has not and colic and neurologic symptoms. There
been finally proven. seems to be a slight predisposition of metasta-
sis development for the serosa overlying the
z Clinical Appearance lung, the spleen, and the liver. Final diagnosis is
Cutaneous melanomas of the horse are usually usually based on the signalment of a gray
easy to diagnose due to their pigmentation. horse, the coloration of the tumor, and the his-
They are usually slow growing, pigmented topathology. There is no scientific evidence
Chapter 4 · Skin Tumors
93 4
that taking biopsies triggers malignant trans- experimentally in a small cohort of horses and
formation despite anecdotal rumors. associated with a measurable anti-tyrosinase
Diagnostic imaging can be used to determine response and tumor shrinkage.
the presence of distant metastasis.

z Suggested Further Reading


z Cytology and Histopathology (Jiang et al. 2014; Metcalfe et al. 2013; Muller et al.
Cytology of pigmented tumors confirms the clini- 2011; Phillips and Lembcke 2013; Rowe and
cal diagnosis, but is rarely performed by equine Sullins 2004; Teixeira et  al. 2013; Theon et  al.
practitioners due to the typical clinical picture. 2007)
Amelanotic tumors may be more challenging to
diagnose on cytology due to the high variability of
the histologic appearance of tumor cells from 4.4 Bovine Skin Tumors
spindle cell like to an epitheloid.
Histopathology is usually straightforward in Benign virus-induced papillomas are the most
pigmented tumors. Amelanotic tumors may common skin tumors in bovines. Squamous-cell
resemble sarcoid or epithelial tumors due to the carcinomas have also been described and may
variability of the histologic appearance of pleo- develop in nonpigmented, mainly periocular
morphic tumor cells. Mainly PNL2 and also S100 (“cancer eye”) skin regions in geographic areas
and PGP9.5 have been used as immunohisto- with high UV-light intensity, although occurrence
chemical markers to support histopathologic is rare.
diagnosis of amelanotic tumors.

z Therapy 4.4.1 Bovine Cutaneous Papillomas/


The goal of treatment usually is local disease con- Papillomatosis
trol and the prevention of metastatic spread.
Effective treatment options for internal tumors or
metastases are not available.
Surgery is the standard treatment for equine Box 4.23. Bovine Papillomas in Four Facts
cutaneous melanomas. Due to the observed malig- 1. Are induced by bovine Papillomavirus
nant transformation of equine melanomas over (BPV) infection.
time, it seems reasonable to resect small tumors at 2. Usually develop early in life, but may be
an early, benign stage to prevent metastatic disease. present at any age.
If available and affordable, radiotherapy may be 3. Spontaneous regression after several
an alternative for non-resectable tumors. Both months common.
teletherapy with an external radiation source and 4. Autogenous vaccines produced with the
brachytherapy with an implantation of the radia- local BPV strain may help to prevent
tion source (iridium, cobalt, radium) directly in or papillomas.
on the tumor have been used with some success.
Local chemotherapy with injection of cisplatin
and carboplatin has been successfully used for
treatment of melanomas. Unfortunately, the larger z Epidemiology and Pathogenesis
the tumor, the less successful the treatment. Cattle develop papillomas more often than any
Local immunotherapy using injections of DNA other domestic animal. The nodules are induced
plasmids encoding for interleukin (IL)-12 and IL- by an infection with one of the currently 13 bovine
18 has been tested. Injection of either plasmid led cutaneous Papillomavirus (BPV) types. The devel-
to tumor shrinkage in most horses. opment of virus-induced papillomas is however
Antitumor DNA vaccination using the not restricted to the skin. Gastrointestinal and
human tyrosinase gene, which is almost exclu- urogenital papillomas are also often observed in
sively expressed in melanocytes, has been tested cattle. There is a genotype-phenotype relationship
94 R. Klopfleisch

of the BPV type with the anatomic site of papil- are occasionally used to prevent papillomatosis if
loma development. BPV-1 and BPV-2 cause fibro- it is a relevant herd problem but are not therapeu-
papillomas involving both the epithelium and the tic in cattle that already have lesions. Autogenous
underlying dermis; BPV-3, BPV-4, BPV-6, BPV-9, vaccines, produced from BPV antigen isolated
BPV-10, BPV-11, and BPV-12 are detected in epi- from papillomas of the herd, are usually more
thelial papillomas; BPV-5 and BPV-8 are associ- effective than commercially available vaccines. A
ated with fibropapillomas and epithelial first vaccination has to be performed in week-old
papillomas, and BPV-7 and BPV-13 exclusively calves to prevent infection and papilloma devel-
4 are associated with cutaneous papillomas. opment since repeated boosting is necessary for
Nevertheless, most bovine papillomas may con- protective immunity.
tain multiple BPV types. The virus is transmitted
via direct contact, fomites, and possibly by insect
vectors. Papillomas appear several weeks after z Suggested Further Reading
exposure and may regress after several months. (Campo 1997; Haga et al. 2013; Nasir and Campo
Papillomatosis, concurrent presence of multiple 2008)
papillomas, is common in young cattle. Single
papillomas are more common in older animals,
which do not always contain BPV DNA.
Suggested Reading
z Clinical Appearance Abramo F, Pratesi F, Cantile C, Sozzi S, Poli A (1999) Survey
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Anderson CL, MacKay CS, Roberts GD, Fidel J (2015)
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mal nodules with a papilloma-like surface. resonance imaging for detection of abdominal lymph-
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neck, and shoulders and only occasionally on the adenocarcinoma of the anal sac. Vet Comp Oncol
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Bacon NJ, Dernell WS, Ehrhart N, Powers BE, Withrow SJ
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cause development of new papillomas. 548–554
Baker-Gabb M, Hunt GB, France MP (2003) Soft tissue sar-
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Belluco S, Brisebard E, Watrelot D, Pillet E, Marchal T, Ponce
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by topical aciclovir application. Vet Rec 168:187–187 detection of papillomaviral DNA within canine cuta-
Stefanello D, Buracco P, Sabattini S, Finotello R, Giudice C, neous squamous cell carcinomas, haemangiosarco-
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Vet Med Assoc 246:765–769 19:321–339
99 5

Mammary Tumors
Robert Klopfleisch

5.1 Canine Mammary Tumors (CMT) – 100

5.2 Feline Mammary Tumor (FMT) – 104


5.2.1 Cytology and Histopathology – 106

Suggested Reading – 108

© Springer International Publishing Switzerland 2016


R. Klopfleisch (ed.), Veterinary Oncology, DOI 10.1007/978-3-319-41124-8_5
100 R. Klopfleisch

Mammary tumors are common tumors in dogs recent studies and meta-analyses have challenged
and to a lesser extent in cats, mice, rats, and guinea this simple model and found no effect of age at
pigs. They are rarities with no relevance for daily spaying on tumor risk. Put another way, spaying
veterinary practice in other animal species. later in life may also reduce tumor risk. Estrus sup-
pression using progesterone derivatives also
increases tumor risk and is thus not recom-
5.1 Canine Mammary Tumors mended if spaying is an option. Unlike in humans,
(CMT) where pregnancy and lactation are both thought
to reduce breast cancer risk, in dogs the number
of gestations and pseudopregnancy most probably
5 has no influence on tumor development. The
Box 5.1. Canine Mammary Tumors in Six effect of sex steroids on tumor progression in
Facts CMT is uncertain. All normal mammary gland
1. Most common tumor in the uncastrated epithelial cells and most of the epithelial tumor
female dog. cells in benign mammary tumors express estrogen
2. Sex steroid/spaying influences incidence. and progesterone receptor. In contrast, malignant
3. No known relevant tumor-associated mammary tumors in dogs (and their metastases)
mutations. mostly do not express the receptors. This means
4. Staging and histologic grading is of they are most probably independent of external
prognostic relevance. hormonal stimuli, and spaying at the time of
5. Less than 50 % of the tumors are tumor diagnosis is probably not an effective part
malignant; one quarter or less of treatment.
metastasizes (to the lung). Breed predisposition may have a minor effect
6. Surgery is the treatment option of on the development of mammary tumors in dogs;
choice. the literature reports contradictory results with
several different breeds at potential risk or not,
depending on the sources.
z Epidemiology and Pathogenesis The molecular pathogenesis of CMT is an area
Traditionally, CMT have been considered the of constant and ongoing research. CMT carcino-
most common tumor of the female dog. They are genesis is often hypothesized to have a progressive
still one of the most common tumors of the course to malignancy, developing from dysplasia
female dog in Europe, where early spaying prac- to adenoma to malignant tumors. This assump-
tice is uncommon and many dogs are left intact. tion is mainly based on two observations. The
A potential lifetime risk of greater than 50 % of first is that malignant tumors are on average big-
developing mammary tumors has been reported ger in diameter. The second is that benign and
in Europe. CMT are rare in the United States, malignant tumor cells are simultaneously present
where most dogs are spayed during the first year in malignant tumors. However, proving this on a
of life. Male dogs are rarely affected by mammary molecular level is difficult. It would require
tumors and if so the tumors are histologically and observing tumor growth in situ, which is ethi-
clinically benign. cally untenable. No biologically relevant tumor-
Age is one of the few undisputed factors with inducing mutations or signaling cascades have
influence on development of CMT.  Few tumors been identified so far. One major research focus
are seen before the age of six, and the peak of was the search for spontaneous or hereditary
cases is seen in dogs of 10–14 years. mutations of the BRCA genes, DNA repair genes
The general effect of sex steroids and spaying on associated with hereditary breast cancer in
tumor initiation and early carcinogenesis is univer- women. Despite weak hints, no strong correla-
sally accepted, but the influence of the timing of the tion has been found between the genetic sequence
procedure is continuously under debate. An early of BRCA in dogs and clinical outcome or malig-
study proposed that spaying/ovariohysterectomy nant behavior of CMT. Research on more com-
before the first estrus reduces the tumor risk plex malignancy-associated RNA and protein
200-fold compared to intact dogs, while spaying expression patterns is ongoing and generally
after the second estrus has no effect. Several more promising. Unfortunately, so far this research has
Chapter 5 · Mammary Tumors
101 5
not been translated in ready-to-use diagnostic End-stage CMT are characterized by lympho-
assays with prognostic relevance or predictive genic spread with involvement of the regional
value for therapy selection. lymph node or a probable direct hematogenic
spread with the development of multiple lung
z Clinical Appearance metastases (. Fig. 5.2). Metastasis to other organs
The incidence of CMT is higher in the caudal is observed in less than 10 % of metastatic tumors.
mammary complexes due to higher amounts of Lateral and dorsoventral thoracic radiographs are
mammary gland tissue (. Fig. 5.1). Primary mul- therefore standard procedure prior to surgery to
tiplicity of tumors is common. This means that rule out lung metastasis.
several tumors of the same or different histologi- Complete blood count, clinical chemistry, and
cal types develop concurrently and independently urinalysis are usually normal, but disseminated
within the same complexes. For example, two intravascular coagulation (DIC) may be present
complexes may independently develop adenocar- in dogs with inflammatory carcinomas. No para-
cinoma, or one complex may develop an adeno- neoplastic syndrome is known for this tumor type.
carcinoma and the other an adenoma. Evaluation
of malignancy is usually not appreciable by palpa- z Cytology and Histopathology
tion of the primary tumor except for the highly Cytology is generally not recommended as it has
malignant inflammatory mammary carcinomas. low specificity and sensitivity for CMT diagnosis.
These tumors resemble a severe mastitis, present- It is also inadequate for tumor grading due to
ing with heat, erythema, and edema in the affected marked intratumoral heterogeneity. In some
gland. They are also characterized by a marked cases, however, cytology might be helpful to dif-
firmness in the affected mammary complex, sur- ferentiate mammary tumors from other tumors in
rounding tissues and the hind limbs. This firm- the mammary region such as mast cell tumors or
ness is typical for a neoplastic rather than a solely lymphoma (. Figs. 5.3 and 5.4).
inflammatory process. Fast growth, a size >5 cm Histopathologic analysis using excisional biop-
in diameter, ulceration, and associated swelling of sies is the definitive method for diagnosing and
the regional lymph node are probable but not grading CMT. Classification of CMT is very com-
definite signs of malignancy for noninflammatory plex with more than 40 histologically defined
carcinoma. The regional lymph node for mam- tumor subtypes. Unfortunately, this sophisticated
mary complexes 1–3 is the axial lymph node; the classification is not based on or even correlated
inguinal lymph node is regional for mammary with specific clinical behaviors or recommenda-
complexes 3–5. Clinical staging is currently per- tions for therapy protocols.
formed according to a modified WHO system CMT in the strict sense are tumors of the epi-
(. Table 5.1). thelial cells of the mammary gland, which are
either (malignant) carcinoma or (benign) ade-
noma. Complex adenoma and carcinoma present
with a concurrent proliferation of the perialveolar
myoepithelial cells. Benign mixed tumors, which
are common, contain a neoplastic epithelial com-
ponent accompanied by nonneoplastic cartilage
and bone. Usually less than 50 % of the tumors are
histologically malignant.
Follow-up studies indicate that less than 50 %
of dogs with surgically removed histologically
defined adenocarcinomas developed metastases
or recurring tumors. A 3-tier grading system for
mammary carcinomas has been developed to
improve and standardize the prognostic value of
histopathologic diagnosis (. Table 5.2). Submission
. Fig. 5.1 Ulcerated malignant canine mammary tumor,
of the respective regional lymph node is recom-
dog (From the archive of the Institute of Veterinary Pathol- mended as it improves prognostic accuracy for
ogy, Freie Universität Berlin) metastatic potential.
102 R. Klopfleisch

. Table 5.1 Staging system for CMT (Owen, 1980, WHO classification)

N (lymph node M (distant Survival 1/2 years after


Stage T (tumor diameter) metastases) metastases) mastectomy in %

I T1 (<3 cm) N0 M0 97.9/90–98

II T2 (3–5 cm) N0 M0 Unknown/90–98

III T3 (>5 cm) N0 M0 Unknown/90–98

IV TA (any size) N1 M0 (For NA) 75.8/30–66

5 V TA (any size) NA M1 14/14–30

N0 no lymph node metastases, N1 lymph node metastases, NA lymph node status irrelevant, M0 no distant metasta-
ses, M1 distant metastases detected

tomy, or radical mastectomy is the treatment


of choice.
Nodulectomy is recommended for small
(<1 cm), moveable nodules, which in the majority
of the cases are benign. Nodules should be
removed with a margin of up to 2 cm to ensure
complete resection. If the nodule turns out to be
malignant on histopathology, a more extensive
secondary excision of the complete gland is rec-
ommended.
The idea of regional mastectomy is based on the
finding that the lymphatic system of mammary
glands 1–3 drains to the cranial sternal and axial
lymph nodes, while the lymphatic vessels of the
. Fig. 5.2 Lung metastases (black arrow) of a canine mammary glands 4 and 5 drain to the superficial
mammary tumor, dog (From the archive of the Institute of inguinal and the medial iliac lymph nodes. Due to
Veterinary Pathology, Freie Universität Berlin) this lymphatic communication, glands 1–3 and/or
glands 4 and 5 should be removed en bloc. The
Inflammatory mammary carcinomas are rare, regional lymph node should also be removed and
but they are the most aggressive mammary tumor submitted for histopathologic analysis of the met-
in the dog. They are characterized by macro- astatic potential of the primary tumor.
scopic resemblance to acute mastitis, presenting Unilateral or even bilateral radical mastec-
with edema, firmness, erythema, and pain. tomy involves the removal of all five mammary
Histologically, inflammatory carcinomas lack a glands en bloc. The advantages of radical mas-
discernible tumor mass. They are composed of an tectomy for survival are a matter of debate. The
accumulation of single or small groups of tumor procedure causes a large wound with increased
cells in dermal lymph vessels. Metastasis to dis- risks for postoperative delayed wound healing.
tant organs is usually present at the time of tumor However, due to the primary multiplicity of
diagnosis. Secondary inflammatory carcinomas, canine tumors discussed above, radical mastec-
which develop from primary solid tumors, are tomy may be indicated. Bilateral mastectomy is
possible. only recommended for dogs with pendulous
mammary glands, which allow for tension-free
z Therapy wound closure.
Surgery is still the standard treatment for dogs Chemotherapy is not a treatment option for
with mammary tumors. There is an ongoing CMT. Most of the protocols tested are highly toxic
debate whether nodulectomy, regional mastec- and have had no effect on disease outcome. In
Chapter 5 · Mammary Tumors
103 5

. Fig. 5.3 Cytology, low malignant canine mammary . Fig. 5.4 Cytology, anaplastic mammary carcinoma,
tumor, dog, May-Grünwald-Giemsa, 200×. Note the dog, May-Grünwald-Giemsa, 1000x. Note the highly
moderately pleomorphic epithelial cells with mild pleomorphic epithelial cells with marked anisocytosis,
anisocytosis, anisokaryosis, and mild variation in nuclear anisokaryosis, variation in nuclear to cytoplasm ratio,
to cytoplasm ratio (pink arrow) multiple prominent nucleoli (blue arrow), and cell
cannibalism of neutrophils (red arrow) (Photo: with
permission from Dr. N. Bauer, Faculty of Veterinary
Medicine, Justus-Liebig-University, Giessen, Germany)
contrast, several in  vitro studies on a variety of
anticancer drugs have shown an impact on mam-
mary tumor cell proliferation and cell death but
been the detection of mRNA of circulating
lack in vivo confirmation.
tumor cells (CTC) in the peripheral blood.
The effect of radiotherapy or hormonal therapy
Strong correlations have been found between
with estrogen modulators like tamoxifen on CMT
CTC and the metastatic behavior of primary
is unclear. The few available studies cast doubt
tumors.
their effectiveness. Concurrent ovariohysterec-
tomy and mastectomy as an adjunct therapy have
z Current Trends in Research
been discussed repeatedly, but no effect on sur-
Current research on CMT focuses on the identifi-
vival has been shown.
cation and characterization of cancer stem cells,
the identification of effective anticancer drugs, and
z Prognostic Factors and Markers finding prognostic mRNA and protein expression
Tumor staging and grading are important patterns. Several studies have identified mammary
prognostic factors for CMT (. Tables  5.1 and cancer stem cells using surface markers like OCT4
5.2). Tumor size and lymph node metastases and Nanog and confirmed their remarkable che-
can also be used as independent prognostic moresistance and resistance to radiotherapy.
indicators (. Table 5.3). Lack of estrogen and Several unrelated potential chemotherapeutic
progesterone receptor expression as shown by agents like the hyaluronan synthesis inhibitor
immunohistochemistry in CMT indicates a 4-methylumbelliferone; the COX2 inhibitor cele-
more malignant phenotype and worse progno- coxib; the nonsteroidal anti-inflammatory drugs
sis. Due to the lack of expression hormone tolfenamic acid, piroxicam, and deracoxib; and an
receptors in most CMT, receptor expression is oncolytic vaccinia virus have been successfully
not routinely analyzed in CMT diagnostics in tested in  vivo and are now awaiting clinical
contrast to human breast cancer. Another approval. Finally, complex RNA and protein expres-
receptor commonly analyzed in human breast sion patterns for sensitive and specific discrimina-
cancer samples is the HER2, the human epithe- tion of malignant and benign CMT have been
lial growth factor receptor 2. The relevance of identified using expensive and complex microar-
immunohistochemical detection of HER2 ray and proteomics technology. But these expres-
expression in CMT is unclear. The latest sion patterns have not been translated into less
approach to finding biomarkers for CMT has expensive and easy-to-use diagnostic assays.
104 R. Klopfleisch

. Table 5.2 Grading system for CMT (Pena et al. 2013)

Histologic criteria Points

A. Tubule formation 1 >75 % tubular morphology

2 10–75 % tubular morphology

3 <10 % tubular morphology

B. Nuclear pleomorphism 1 Uniform nuclei, rare nucleoli

2 Moderate variation in nuclear size/


5 shape, presence of nucleoli

3 Marked variation in nuclear size/


shape, often prominent nucleoli

C. Mitoses per 10 HPF 1 0–9 mitoses/10 HPF

2 10–19 mitoses/10 HPF

3 ≥20 mitoses/10 HPF

Rec./Mets.a Cancer deatha

Total score (A + B + C) 3–5 Grade 1 3.4 % 0

Total score (A + B + C) 6–7 Grade 2 15.8 % 15.8 %

Total score (A + B + C) 8–9 Grade 2 58.8 % 58.8 %

HPF = 0.24 mm2


aFollow-up time at least 28 months

5.2 Feline Mammary Tumor (FMT)


. Table 5.3 Prognostic factors for CMT

Disease-free interval
(Beauvais et al. 2012)/ Box 5.2. Feline Mammary Tumors in Six Facts
survival time (Chang
Factor Details et al. 2005)
1. Common in the cat but less common
than in the dog.
Tumor <5 cm 112 weeks (Chang et al. 2. Sex steroid/spaying influences incidence.
diametera 2005) 3. No known relevant tumor-associated
>5 cm 40 weeks (Chang et al. mutations.
2005) 4. Staging and histologic grading is of
prognostic relevance.
Lymph node No <30 % recurrence after
metastasesa 2 years 5. More than 90 % of the tumors are
malignant and metastasize mostly to the
Yes 80 % recurrence after lung.
6 months
6. Surgery is the treatment option of
Or choice.
No 21 % death rate after
2 years
z Epidemiology and Pathogenesis
Yes 86 % death rate after 2 years
The incidence of FMT is half that of CMT. They
aTreated with surgery are nevertheless still a common tumor of the
cat, making up approximately 17 % of all feline
Chapter 5 · Mammary Tumors
105 5
tumors. FMT are usually diagnosed at the age of z Clinical Appearance
10–12 years. A breed predilection has been All four mammary glands of felines, two thoracic
observed for Siamese cats. In rare cases male and two abdominal, can be affected by mammary
cats may also develop mammary tumors, simi- tumors. There may however be a slight predispo-
lar to dogs. sition of the caudal glands, as in dogs. FMT are
Sex steroids and early spaying have an effect usually single subcutaneous, sometimes ulcerated
on tumor initiation and early carcinogenesis. or cystic masses. Macroscopic distinction between
Spaying before the age of 1 year reduces the risk benign and malignant tumors is difficult to
of mammary tumor development by up to 90 %. impossible. Since up to 90 % of the tumors are his-
In contrast, estrus suppression using progester- tologically malignant, all masses in the feline
one derivatives increases tumor risk by three- mammary glands should be treated as such until
fold in females and is thus not recommended if proven otherwise. Multiple mammary masses are
spaying is an option. The effect of sex steroids on possible but less common than in the dog. Signs of
tumor progression and malignant behavior is inflammation, edema, swelling, firmness, ery-
questionable. As mentioned in the discussion of thema, pain, and regional and distant metastases
canine mammary tumors, normal mammary have been seen in the few cases of highly aggres-
gland epithelial cells and benign mammary sive inflammatory carcinomas. They are difficult
tumor cells express estrogen and progesterone to differentiate from acute mastitis or nonneo-
receptors. Very few malignant tumors express plastic fibroadenomatous hyperplasia.
these receptors in felines, and in those that do, The tumor diameter is part of the WHO stag-
only a few tumor cells are affected. Thus, unlike ing system and strongly influences the prognosis
human breast cancer, both canine and FMT are (. Table 5.4). Lymph node metastasis is present
most probably not responsive to external hor- in up to 90 % of cats with mammary tumors at
monal stimuli. the time of surgery. Axillary lymph nodes, ingui-
Other than the influence of sex steroids in nal and to a lesser extent sternal lymph nodes,
early carcinogenesis, the molecular pathogenesis are most commonly affected. Pulmonary metas-
of FMT is unclear. Much effort has been tases are common in cats with mammary
invested in analyzing the malignancy potential tumors, and, similar to the dog, they are the
of overexpression of HER2, but nothing signifi- most common cause of death and euthanasia in
cant has been identified. Cyclooxygenase-2 patients with mammary tumors. Lateral and
(COX2) and vascular endothelial growth factor dorsoventral thoracic radiographs are therefore
receptor 2 (VEGFR2) expression has however standard procedure prior to surgery to rule out
been associated with slightly shorter survival in lung metastasis.
felines. No biologically relevant tumor-inducing Complete blood count, blood chemistry, and
mutations or signaling cascades have been iden- urinalysis are usually normal. No paraneoplastic
tified so far. syndromes are known for this tumor type.

. Table 5.4 Staging system for FMT (Owen, 1980, WHO classification)

N (lymph node M (distant Average survival


Stage T (tumor diameter) metastases) metastases) time

I T1 (<2 cm) N0 M0 29 months

II T2 (2–3 cm) N0 M0 12.5 months

III T3 (>3 cm) N0 M0 9 months


T1,2 (<3 cm) N1 M0

IV TA (any size) N1 M1 1 months

N0 no lymph node metastases, N1 lymph node metastases, M0 no distant metastases, M1 distant metastases
detected
106 R. Klopfleisch

5.2.1 Cytology and Histopathology dermal lymphatic vessels, with severe secondary
inflammation.
Fine-needle aspiration of FMT is more helpful Benign tumors represent around 10 % of all
than in dogs since most of the tumors are malig- FMT. They are further classified as simple or com-
nant. Cytology is nevertheless not a reliable plex adenomas or fibroadenomas although this
method for discriminating benign from malig- subclassification is irrelevant for prognosis.
nant tumors or for evaluating tumor grade. Complex tumors with concurrent proliferation of
Histopathologic analysis using tissue biopsies myoepithelial cells or mixed tumors with cartilage
is the definitive technique to diagnose and grade and bone are extremely rare in cats, in contrast to
FMT. Up to 90 % of FMT are classified as malig- dogs where they are common.
5 nant carcinomas. These may be further subclassi- Fibroadenomatous hyperplasia is a nonneo-
fied into histologic subtypes according to their plastic, primarily noninflammatory, progesterone-
growth pattern, but the prognostic relevance of induced massive proliferation of the mammary
these subtypes is questionable. A 3-tier grading glands. Usually multiple glands are affected, but
system for mammary carcinomas to improve and on occasion lesions are found in only one gland. It
standardize the prognostic value of the histopath- occurs in young cats <2 years of age after estrus or
ologic diagnosis has been developed and is during pregnancy. Removal of the hormonal
increasingly used (. Table 5.5). In addition to the stimulus by ovariohysterectomy leads to regres-
features involved in the grading system, tumor sion of the swelling in most cases.
size and lymph node involvements are considered
prognostic features strongly correlated with z Therapy
malignancy. Tumors with a maximum diameter Surgery is still the standard treatment for
of >3  cm are associated with a survival of 5 FMT. The lymphatic drainage of the feline mam-
months or less, while cats with tumors <2 cm in mary glands is most probably highly connected. It
diameter may survive for 12 months or more. is assumed that the first and second (thoracic)
Inflammatory mammary carcinomas seem to glands drain mostly to the axillary lymph node,
be rare in cats, and only four cases, all with sur- the third and maybe the second gland to the axil-
vival times of only a few days until euthanasia, lary and the inguinal lymph nodes, and the fourth
have been described so far. Histologically, embo- (inguinal) gland only to the inguinal lymph node.
lism of tumor cells can be seen in superficial In addition, left and right mammary glands also

. Table 5.5 Grading system for FMT (Mills et al. 2013)

Histologic criteria Points

A. Lymphovascular invasion 0 Absent

1 Present

B. Nuclear form 0 <5 % abnormal

1 >5 % abnormal

C. Mitoses per 10 HPF 0 <62

1 >62

Median survival, Survival at 18


months months, %

Total score (A + B + C) 0 Grade 1 31 82

Total score (A + B + C) 1 Grade 2 14 37

Total score (A + B + C) 2–3 Grade 2 8 18

HPF = 0.22 mm2


Chapter 5 · Mammary Tumors
107 5
seem to communicate. Unilateral or even bilateral and chemotherapy resistance and may open the
complete mastectomy is recommended as the way for understandings of FMT biology. Several
treatment of choice due to the aggressive character research groups are also trying to apply the molec-
of these tumors and the close communication ular classification scheme of human breast cancer
between structures. Radical mastectomy signifi- based on estrogen, progesterone, and HER2 protein
cantly reduces the probability of recurrence. expression to FMT, to evaluate the applicability of
A 2-week interval is recommended between proce- felines as a model for human disease.
dures in bilateral mastectomy. The inguinal lymph
node is located adjacent and caudal to the fourth
gland and should always be removed and submit- . Table 5.6 Prognostic factors for FMT
ted for biopsy. Due to the distant location of the
Disease-free
axillary lymph node, it should be removed only if interval (Beauvais
enlarged or positive in fine-needle aspirates; removal et al. 2012)/
does increase survival time. Ovariohysterectomy at survival time
the time of mastectomy has no benefit on survival (Chang et al.
or tumor recurrence. It should be considered if Factor Details 2005)
a fibroadenomatous hyperplasia is confirmed or Tumor <3 cm 21–24 months
suspected. diametera (Beauvais et al.
Chemotherapy with doxorubicin alone or with 2012)
cyclophosphamide may have some beneficial >3 cm 4–12 months
effects on non-resectable tumors. A metronomic (Beauvais et al.
approach with long application of low doses of 2012)
vincristine, cyclophosphamide, and methotrexate Or Or
has been shown to prolong survival and disease-
free interval. The effect of chemotherapy treat- <2 cmb 450 days (Chang
et al. 2005)
ment as an adjunct to surgery is not confirmed
but may increase survival time by up to 600 days. 2–3 cmb 448 days (Chang
Radiotherapy and anti-hormonal therapy have et al. 2005)
no proven effect in the treatment of FMT. >3 cmb 200 days (Chang
et al. 2005)
z Prognostic Factors and Markers
Metastatic No >2100 days
Studies on the correlation between overexpression diseaseb (Chang et al.
of HER2 and overall survival are contradictory. In 2005)
addition, there is only insufficient information on
Yes 331 days (Chang
whether FMT also loose estrogen and progester- et al. 2005)
one expression with increasing malignancy as it is
Location of Lymph >1543 days
common in canine mammary tumors. However,
metastasisb node (Chang et al.
cyclooxygenase-2 (COX2) and vascular endothe- 2005)
lial growth factor receptor 2 (VEGFR2) expression
in FMT has been associated with slightly shorter Lung 331 days (Chang
et al. 2005)
survival times. COX2 and VEGFR2 could thus act
as potential therapeutic targets for mammary Pleura 188 days (Chang
tumors in this species. More prognostic factors for et al. 2005)
FMT are presented in Table 5.6. Type of Regional 428 days
mastectomyb
Unilateral 348 days
z Current Trends in Research
radical
The majority of recent studies on FMT focuses on
the analysis of protein and mRNA and protein Bilateral 917 days
radical
expression patterns of several genes involved in
apoptosis, cell adhesion, or growth factor signaling. aTreated with surgery
In addition, evidence of FMT stem cells has been bTreated with mastectomy and doxorubicin
found and coupled with insights into radiotherapy
108 R. Klopfleisch

z Suggested Reading Novosad CA, Bergman PJ, O’Brien MG, McKnight JA,
(Hughes and Dobson 2012; Mills et  al. 2015; Charney SC, Selting KA, Graham JC, Correa SS,
Rosenberg MP, Gieger TL (2006) Retrospective evalua-
Morris 2013; Novosad et al. 2006; Pang et al. 2013; tion of adjunctive doxorubicin for the treatment of
Perez-Alenza et al. 2004; Viste et al. 2002) feline mammary gland adenocarcinoma: 67 cases.
J Am Anim Hosp Assoc 42:110–120
Pang LY, Cervantes-Arias A, Else RW, Argyle DJ (2011) Canine
mammary cancer stem cells are radio- and chemo-
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news from an old disease. Vet Pathol 48:98–116 C, Van Brantegem L (2011) Canine mammary tumours,
Mills SW, Musil KM, Davies JL, Hendrick S, Duncan C, an overview. Reprod Domest Anim 46:1112–1131
Jackson ML, Kidney B, Philibert H, Wobeser BK, Simko E Viste JR, Myers SL, Singh B, Simko E (2002) Feline mam-
(2015) Prognostic value of histologic grading for feline mary adenocarcinoma: tumor size as a prognostic
mammary carcinoma: a retrospective survival analysis. indicator. Can Vet J 43:33–37
Vet Pathol 52:238–249 Yamagami T, Kobayashi T, Takahashi K, Sugiyama M (1996)
Morris J (2013) Mammary tumours in the cat: size matters, Prognosis for canine malignant mammary tumors
so early intervention saves lives. J Feline Med Surg based on TNM and histologic classification. J Vet Med
15:391–400 Sci 58:1079–1083
109 6

Hematopoietic Tumors
Manfred Henrich

6.1 Lymphatic Tumors – 110


6.1.1 Canine Lymphomas – 110
6.1.2 Canine Lymphocytic Leukemia – 114
6.1.3 Feline Lymphomas – 116
6.1.4 Feline Lymphocytic Leukemia – 119

6.2 Plasma Cell Tumors of Cats and Dogs – 120


6.2.1 Plasma Cell Myelomas (Multiple Myelomas)
of Cats and Dogs – 120
6.2.2 Plasmacytomas in Dogs and Cats – 122

6.3 Histiocytic Tumors – 123


6.3.1 Canine Histiocytic Tumors – 123
6.3.2 Feline Progressive Histiocytosis – 126

Suggested Reading – 128

© Springer International Publishing Switzerland 2016


R. Klopfleisch (ed.), Veterinary Oncology, DOI 10.1007/978-3-319-41124-8_6
110 M. Henrich

6.1 Lymphatic Tumors z Clinical Appearance


Clinical symptoms are variable and depend on
Lymphatic tumors in veterinary patients resemble location and size of the tumor or neoplastic infil-
non-Hodgkin’s lymphomas in humans. They are a tration of other organs. Aggressive multicentric
systemic neoplastic disease of lymphocytes or lymphoma is the most common form followed by
their precursors. They are a highly heterogeneous gastrointestinal (alimentary), mediastinal, cutane-
group of malignant tumors with varied biologic ous, and extra-nodal.
behavior due to their origin from different types Lymphomas can arise anywhere outside the
of lymphocytes, despite the common terminology, lymphatic system (primary extra-nodal forms),
which designates them all as lymphomas. but the skin, central nervous system, eyes, heart,
bladder, and nasal mucosa are the most frequently
affected extra-nodal locations.
6.1.1 Canine Lymphomas The first clinical sign of multicentric lym-
6 phoma is generalized, non-painful swelling of
lymph nodes, often accompanied by enlargement
of the liver and spleen (. Fig. 6.1). Involvement of
Box 6.1. Canine Lymphomas in Four Facts
the bone marrow is common and is associated
1. Common tumors in dogs.
with leukopenia and/or anemia. Nonspecific
2. Many different types with different
symptoms like anorexia, diarrhea, vomiting,
biologic behavior exist.
weight loss, and fever are observed in some
3. Clinical symptoms related to location
patients.
and extend of tumor infiltration.
Animals with gastrointestinal lymphoma may
4. Chemotherapy is the treatment of
present with vomiting, anorexia, diarrhea, weight
choice.
loss, icterus, and tenesmus. On physical examina-
tion, hepatosplenomegaly and mid-abdominal or
cranial abdominal masses may be noted.
z Epidemiology and Pathogenesis Dogs with mediastinal lymphoma have masses
Lymphomas are one of the most common neo- within the cranial mediastinum due to enlarge-
plasms in dogs. Middle-aged to older dogs are at a ment of either mediastinal lymph nodes or the
higher risk; intact females are at a lower risk.
Boxers, bullmastiffs, bulldogs, basset hounds, St.
Bernards, Scottish terriers, Airedale terriers,
Bouvier des Flandres, Labrador retrievers, and
Rottweilers are predisposed. There is also a pre-
disposition for some breeds to develop distinct
types of lymphomas, e.g., T-cell lymphomas in
boxers, spitz, and Asian dog breeds and B-cell
lymphomas in cocker spaniels and basset hounds.
This breed predisposition implies that there are
genetic factors for the development of lympho-
mas. An infectious etiology has not been con-
firmed in dogs so far. Exposure to herbicides,
particularly 2,4-dichlorophenoxyacetic acid (a
common weed killer and one of the ingredients in
. Fig. 6.1 Lateral abdominal radiograph of a dog with
agent orange), is reported to increase the risk of multicentric lymphoma. The spleen (arrowheads) is
lymphomas in dogs. markedly enlarged, and there is a space-occupying mass
Molecular abnormalities found in canine lym- (enlarged mesenteric lymph nodes) between the caudal
phomas include chromosomal aberrations (tri- margin of the stomach (arrows) and replacing the
somy 13 and 31, monosomy 14), aberrations in intestine caudally (Photo: with permission of Dr. Antje
Hartmann, Vetsuisse Faculty University of Bern, Bern,
the expression of certain tumor suppressor genes Switzerland, and the Department of Veterinary Clinical
and oncogenes (p53, Rb, N-ras, and p16), and Sciences, Clinic for Small Animals, Surgery,
telomerase activity. Justus-Liebig-University Giessen, Giessen, Germany)
Chapter 6 · Hematopoietic Tumors
111 6
thymus. Clinical signs are associated with the
. Table 6.1 System for the staging of
mass effect of the tumor compressing adjacent lymphomas in domestic animals according to the
organs, most notably the lung, resulting in dys- WHO, (Owen 1980)
pnea. Tumor-associated pleural effusion may con-
tribute to the compression of the lung. Stage
Compression/invasion of the cranial vena cava
1 Involvement limited to a single node or lymphoid
can cause head and forelimb edema. Stenosis of tissue in a single organ
the esophagus due to the mass effect can result in
regurgitation. 2 Involvement of many lymph nodes in a regional
area (± tonsils)
Cutaneous lymphoma represents 1 % of canine
skin tumors and appears in two forms: epithelio- 3 Generalized lymph node involvement
tropic and non-epitheliotropic lymphoma. 4 Liver and/or spleen involvement (± stage 3)
Epitheliotropic lymphoma (syn. mycosis fungoi-
des) is a multifocal to widespread tumor that can 5 Manifestation in the blood and involvement of the
bone marrow and/or other organ systems (± stage
be highly variable and mimic any inflammatory 1–4)
skin disease. Clinical forms can be principally sub-
divided into exfoliative erythroderma (generalized Each stage is subclassified into:
erythema, scaling, depigmentation, alopecia, and (a) Without systemic signs
variable pruritus), solitary or multiple nodules or
(b) With systemic signs
plaques (scaly, erythematous, and crusted swell-
ings that may coalesce, erode, or ulcerate, but sel-
dom regress), ulcerative oral forms, and lymphomas mediastinal, cutaneous, and extra-nodal). Other
with mucocutaneous localization. Non- classification schemes include histological and
epitheliotropic lymphoma appears as single or mul- immunohistologic features.
tiple nodules in the dermis or subcutis. Any site of The WHO histological classification of hema-
the body can be involved; however, oral forms are topoietic tumors of domestic animals is widely
less common. The nodules may ulcerate. Swelling used by veterinary pathologists and includes ana-
of the regional lymph nodes is common. tomic, histologic, and immunohistologic (B-cell or
Paraneoplastic syndromes (i.e., signs caused by T-cell phenotype) criteria. However, some studies
the neoplasia but unrelated to the mass effect of also use criteria of other classification schemes
the tumor or its metastases) can occur with lym- (e.g., Working Formulation (WF), updated Kiel
phoma. Anemia and hypercalcemia of malig- classification); it is especially common to grade
nancy are two of the most common paraneoplastic lymphomas as high, intermediate, and low grade.
syndromes of lymphoma. The latter is due to the The accuracy of the WHO classification was con-
production of parathyroid hormone-related pep- firmed in one study with 300 cases; another subse-
tide (PTHrP) by the tumor cells. Clinically ani- quent study associated WHO classification with
mals show polyuria and polydipsia, vomiting, and survival, thereby combining the WHO criteria with
dehydration. In severe cases constipation, hyper- a grading scheme (. Table 6.2).
tension, twitching, weakness, shaking, depression,
vomiting, bradycardia, stupor, and possibly coma z Cytology and Histopathology
and death can occur. Cytology of lymphomas (. Figs. 6.2 and 6.3) is an
appropriate and minimally invasive diagnostic
z Staging procedure. It is diagnostically reliable in cases of
The WHO clinical staging system discussed in pre- high numbers of immature cells (>50 % of the cell
vious chapters can be used to stage lymphomas in population). However, accurate diagnosis by
veterinary medicine (. Table 6.1). cytology may be impaired by the presence of low
numbers of recognizable neoplastic cells
z Classification (. Fig. 6.4) and/or a high background of reactive
The classification of lymphomas is very complex lymphocytes (. Fig.  6.5). The same is true for
and different classification schemes exist. well-differentiated (small type) lymphomas, in
Clinically lymphomas are classified by anatomical which neoplastic cells do not differ morphologi-
site (multicentric, gastrointestinal (alimentary), cally from nonneoplastic lymphocytes.
112 M. Henrich

. Table 6.2 Grading of lymphomas classified according to the WHO (Valli et al. 2013)

B-cell lymphomas T-cell lymphomas

Indolent B-cell lymphomas Indolent T-cell lymphomas


Marginal zone lymphomas T-zone lymphomas
Mantle cell lymphomas Low-grade T-cell lymphomas
Follicular lymphomas T-cell anaplastic large cell lymphomas
Low-grade B-cell lymphomas Enteric T-cell lymphomas
Diffuse large B-cell lymphomas LO IB Cutaneous T-cell lymphomas
Diffuse large B-cell lymphomas LO CB High-grade T-cell lymphomas
T-cell-rich large B-cell lymphomas Peripheral T-cell lymphomas
B-cell small lymphocytic lymphomas T-cell lymphoblastic lymphomas
B-cell chronic lymphocytic leukemia T-cell lymphoblastic lymphomas cleft
Diffuse intermediate B-cell lymphomas
6 Intermediate-grade B-cell lymphomas
Diffuse large B-cell lymphomas mid CB
Diffuse large B-cell mid IB
Plasmacytomas
Lymphoid lymphomas
High-grade B-cell lymphomas
Diffuse large B-cell lymphomas HI CB
Diffuse large B-cell lymphomas HI IB
Burkitt-like lymphomas
B-anaplastic large cell lymphomas
B-cell lymphoblastic lymphomas
B-cell lymphoblastic lymphomas cleft
Plasmablastic lymphomas

LO low mitotic rate, mid moderate mitotic rate, HI high mitotic rate, IB immunoblastic, CB centroblastic

Growth patterns and associated architectural


alterations can be assessed with histological exam-
ination of affected tissues. The abovementioned
classification requires histologic examination in
conjunction with immunohistochemistry (for the
assessment of the lineage, i.e., B- or T-cell).
The morphology of neoplastic lymphocytes
differs according to the type of lymphoma. Cells of
undifferentiated lymphomas resemble lympho-
blasts. Cells of well-differentiated (small cell)
lymphomas may be undistinguishable from non-
neoplastic lymphocytes. Lymphomas often show a
diffuse, sheetlike infiltration of the tissue with
effacement of the original architecture. However,
. Fig. 6.2 Cytology, lymphoma, lymph node, dog,
May-Grünwald-Giemsa 1000×. In cytological specimens, exceptions with specific growth patterns exist, e.g.,
the diagnosis of lymphoma is based on the presence of follicular lymphomas.
>50 % lymphatic blasts. In this dog, approximately 80 %
lymphatic blasts and only rare small mature lymphocytes z Assessment of Clonality
(black arrow) are seen. The lymphatic blasts are medium
In some cases, neoplastic lymphocytic prolifera-
sized (approximately 2× the diameter of an erythrocyte)
and possess eccentrically located nuclei, a finely stippled tion cannot be distinguished from reactive prolif-
chromatin with several marginal, prominent nucleoli (red eration by cytology or histology alone. In these
arrow) and moderate amounts of basophilic cytoplasm. cases, assessing the clonality of the lymphocytes by
The cellular morphology is typical for a polymorphic clonality assays can aid in establishing a final diag-
centroblastic B-cell lymphoma (Photo: with permission of
nosis. Neoplastic lymphocytes in lymphomas orig-
Dr. N. Bauer, Faculty of Veterinary Medicine,
Justus-Liebig-University Giessen, Giessen, Germany) inate from a single transformed cell. The neoplastic
Chapter 6 · Hematopoietic Tumors
113 6

. Fig. 6.3 Cytology, B-cell lymphoma with Mott cell . Fig. 6.4 Cytology, reactive hyperplasia, lymph node
differentiation, lymph node, dog, May-Grünwald-Giemsa in a dog with leishmaniasis, May-Grünwald-Giemsa 1000×.
1000×. There are many medium-sized to large lymphatic There is a mixed cellular population consisting of many
blasts (of a diameter ranging between 2 and 3 red blood plasma cells (yellow arrow) as well as several small mature
cells, red arrow) with eccentrically located slightly indented (black arrow) and medium-sized (green arrow)
nuclei, reticular chromatin pattern, and small to moderate lymphocytes. Few lymphatic blasts (red arrow) are also
amounts of basophilic cytoplasm containing rare to many present. In this case, underlying high-grade lymphoma
small clear vacuoles. The presence of several mature characterized by a percentage of lymphatic blasts
plasma cells with multiple intracytoplasmic vacuoles exceeding 50 % is very unlikely, although very early stages
(Mott cells, black arrow) is indicative of a B-cell lymphoma cannot be entirely ruled out. However, such early cases
with Mott cell differentiation as rarely described in dogs would also be difficult to detect with histopathology
and cats. Histopathology confirmed the presence of (Photo: with permission of Dr. N. Bauer, Faculty of
immunoglobulin G (IgG)-positive cells (Photo: with Veterinary Medicine, Justus-Liebig-University Giessen,
permission of Dr. N. Bauer, Faculty of Veterinary Medicine, Giessen, Germany)
Justus-Liebig-University Giessen, Giessen, Germany)

lymphoma. A modified Madison Wisconsin proto-


progeny is therefore genetically monoclonal. In col, a CHOP-based protocol, is widely used by vet-
contrast, reactive lymphocytes are a heterogeneous erinary oncologists. The median overall survival
population of cells recruited to the focus of inflam- times (OST) of dogs with multicentric lympho-
mation and are consequently polyclonal in nature. mas treated with CHOP-based protocols are about
Lymphocytes rearrange their antigen receptor 8–12 months; unfortunately less than 25 % of
genes during their development. Subsequently these dogs survive longer than 2 years.
each cell carries a unique gene sequence coding Surgery may be beneficial in solitary forms of
for an unique antigen receptor. A PCR for antigen lymphomas if multicentric involvement can be
receptor rearrangement (PARR) utilizes this varia- ruled out.
tion in the genome to differentiate a monoclonal Radiation therapy may also be feasible for sol-
population (identical sequence in each neoplastic itary forms of lymphoma or as palliative therapy
cell) from a polyclonal population (mixture of dif- and/or to deplete the bone marrow for bone mar-
ference sequences in nonneoplastic cells). The row or stem cell transplantation.
PARR is not sensitive or specific enough to be
suitable as a stand-alone diagnosis of lymphomas. z Prognostic Factors and Markers
Results must be interpreted in the context of his- Per definition, lymphomas are malignant. However,
tology, immunohistochemistry, and clinical data. due to the variety of lymphoma types, prognosis of
Furthermore, clonality assays cannot replace the disease is highly variable with very aggressive
immunohistochemistry/-cytology for the deter- forms on one side of the spectrum and very slow
mination of the lineage (B- or T-cell). progressive (indolent) forms on the other side.
Overall, T-cell lymphomas are reported to have
z Therapy shorter survival times and remissions. Furthermore,
Chemotherapy using variations of “CHOP” combi- WHO substage b (with clinical signs) is also associ-
nation protocols (cyclophosphamide, doxorubicin ated with poorer outcomes. Grading the WHO
[=hydroxydaunorubicin], vincristine [=Oncovin], stages and associating them with survival time
prednisone) is the preferred therapy for canine allow us to associate histology with prognosis.
114 M. Henrich

6.1.2 Canine Lymphocytic Leukemia

Lymphocytic leukemia is defined as a lymphoid


neoplasm with extensive involvement of the bone
marrow that usually (though it does not have to)
goes along with large numbers of neoplastic cells in
the peripheral blood. Leukemias without detect-
able tumor cells in the peripheral blood are termed
“aleukemic leukemias.” The distinction between
leukemia and stage 5 lymphomas is subjective.

Box 6.2. Canine Lymphocytic Leukemia in


6 . Fig. 6.5 Cytology, follicular hyperplasia, abdominal Six Facts
lymph node, 8-month-old Maine Coon cat, 1. A lymphoid neoplasm with extensive
May-Grünwald-Giemsa 1000×. There are approximately bone marrow involvement.
40 % pleomorphic, medium-sized to large lymphatic
blasts (red arrow) interspersed with several small mature
2. Neoplastic lymphocytes often numerous
(black arrow) and medium-sized (green arrow) in peripheral blood.
lymphocytes. Few nondegenerate neutrophils (yellow 3. Aleukemic leukemias (without neoplastic
arrow) are also present. In this case, reactive hyperplasia cells in peripheral blood) exist.
with a markedly increased amount of lymphatic blasts 4. Acute forms are very aggressive with
cannot be differentiated from high-grade lymphoma in an
early stage as the percentage of lymphatic blasts is close
poor prognosis.
to 50 %, the threshold to diagnose lymphoma. 5. Chronic forms are very slow progressive.
Histopathology is required to differentiate between both 6. Chemotherapy is the treatment of
diagnoses. In this case, it revealed follicular hyperplasia choice.
(Photo: with permission of Dr. N. Bauer, Faculty of
Veterinary Medicine, Justus-Liebig-University Giessen,
Giessen, Germany)
z Epidemiology and Pathogenesis
Lymphocytic leukemia affects many different
High-grade lymphomas are associated with higher
breeds, although a prevalence of large and giant
mortality rates than intermediate- or low-grade
breeds (e.g., German shepherds and retrievers) is
lymphomas. Another factor with influence on prog-
reported. Mean age at diagnosis is usually around
nosis is anatomical site (diffuse lymphomas of the
7–10 years. There is no sex predisposition to the
skin or gastrointestinal tract, hepatosplenic lym-
disease or certain subtypes. The etiology and exact
phomas, and lymphomas of the central nervous
pathogenesis, as with canine lymphomas, remain
system are associated with poorer prognosis).
unclear. Genetic factors likely contribute to the
Furthermore, the frequency of AgNORs (argyro-
development of the disease.
philic nucleolar organizer regions) on immunohis-
tochemistry as well as the potential doubling time
(Tpot) can be used as predictors of outcome in dogs. z Clinical Appearance
Overt clinical signs are dependent on the type of
z Current Trends in Research leukemia.
The aim of many studies is to improve the diagnosis, Animals with chronic lymphocytic leukemia
prognosis, and therapy of canine lymphomas. (CLL) usually present with mild symptoms (leth-
Identification of factors associated with survival and argy, loss of appetite, vomitus, diarrhea, lameness,
response to therapy can result in a more accurate and slightly enlarged lymph nodes and spleen) or
prognosis. New therapeutic approaches and agents no symptoms. White blood count usually reveals
are tested in lymphoma cell lines and in clinical trials. a marked lymphocytosis of mature lymphocytes
that may appear morphologically normal but can
z Suggested Reading be functionally abnormal. Concurrent abnormal-
(Mortier et  al. 2012; Richards and Suter 2015; ities include mild anemia, thrombocytopenia, and
Marconato et al. 2013; Valli et al. 2013; Valli et al. neutropenia. Severity of symptoms and hemato-
2011; Gross et al. 2008) logical abnormalities may increase over the course
Chapter 6 · Hematopoietic Tumors
115 6
of the disease. Monoclonal gammopathy, hemo- lymphocytes). However, the characteristic feature
lytic anemia, pure red cell aplasia, and in some of lymphocytic leukemia is the infiltration of the
cases hypercalcemia are the paraneoplastic syn- bone marrow by neoplastic cells. In ALL lympho-
dromes associated with CLL. blasts are detectable in aspirates in high numbers,
Animals with acute lymphoblastic leukemia whereas in CLL mature cells predominate.
(ALL) usually have more pronounced clinical Histopathology of bone marrow core biopsies
signs with lymphadenopathy, hepato- and spleno- is especially useful if aspiration of the bone mar-
megaly, anorexia, weight loss, and lethargy. row is not diagnostic. Immunohistochemistry is
Massive infiltration and destruction of the bone useful for differentiating ALL from acute myeloid
marrow lead to myelosuppression and eventually leukemia in cases of premature cells on histopa-
myelophthisis, resulting in severe anemia, throm- thology.
bocytopenia, and neutropenia. Infiltration of
extramedullary sites can cause symptoms related z Therapy
to the affected organ or tissue. Chlorambucil is the chemotherapy agent of choice
for the treatment of CLL. Whether or not therapy is
z Cytology and Histopathology indicated depends on the clinical signs and hema-
Cytological examination of the bone marrow tologic changes. Surveillance (clinical examination,
(. Fig.  6.6) and peripheral blood (. Fig.  6.7) can complete blood count) is recommended during
be helpful in diagnosing lymphocytic leukemia. the indolent phase instead of medication. Due to
Bone marrow aspirates may be redundant and thus the aggressive nature of ALL, the disease requires
avoided if cytology of peripheral blood shows aggressive chemotherapy (CHOP-based protocols)
marked lymphocytosis and differential diagnoses and/or bone marrow or stem cell transplantation
of nonneoplastic lymphocytosis (e.g., chronic (currently rarely applied in veterinary medicine).
ehrlichiosis, IL-2 administration, post-vaccine lym-
phocytosis) can be ruled out (e.g., by PARR analy- z Prognostic Factors and Markers
sis, predominance of one phenotype, or atypical The most important prognostic factor is the type
of leukemia. CLL usually progresses slowly, and
on average veterinary patients survive 1–3 years

. Fig. 6.6 Cytology, acute lymphocytic leukemia,


subleukemic stage, bone marrow aspirate, dog,
May-Grünwald-Giemsa 1000×. The dog was presented
with a pancytopenia and rare lymphatic blasts in the . Fig. 6.7 Cytology, chronic lymphocytic leukemia,
peripheral blood. The bone marrow aspirate was highly blood smear, dog, May-Grünwald-Giemsa 1000×. There is
cellular, and normal hematopoietic precursor cells are a severe leukocytosis based on a severe lymphocytosis.
replaced by large lymphoblasts with a diameter of >2.5 The lymphocytes are mainly small and mature (red arrow).
erythrocytes. They possess eccentrically located slightly The presence of several large lymphocytes, however,
indented nuclei, a finely stippled chromatin pattern, and indicates the progression into a more accelerated phase
moderate amounts of a lightly basophilic cytoplasm with of proliferation. Several naked nuclei (black arrow) are also
clear perinuclear halo. Typical for lymphatic cells is the present mainly due to the relatively high fragility of
presence of cytoplasmic fragments (red arrow) (Photo: with lymphatic cells (Photo: with permission of Dr. N. Bauer,
permission of Dr. N. Bauer, Faculty of Veterinary Medicine, Faculty of Veterinary Medicine, Justus-Liebig-University
Justus-Liebig-University Giessen, Giessen, Germany) Giessen, Giessen, Germany)
116 M. Henrich

with a good quality of life. Factors associated with now dominate. There is a breed predisposition for
longer survival times are T-cell phenotype, low Siamese and Oriental cats; a sex predisposition is
lymphocyte numbers in the peripheral blood, not confirmed.
older age, and absence of anemia. Veterinary FeLV infection is a high risk factor for the
patients with ALL have a very poor prognosis development of lymphomas. About 55–70 % of
even with therapy; survival times range from days lymphomas were positive for FeLV before the
to about 8 months. introduction of FeLV vaccines. The integration of
FeLV provirus into the lymphocyte’s DNA can
z Suggested Reading trigger the development of the neoplasia. FeLV-
(Adam et al. 2009; Hodgkins et al. 1980; Leifer and associated lymphomas are more often T-cell origin
Matus 1986; Couto 1985; Matus et al. 1983; Morris neoplasias with mediastinal (thymic) or multi-
et al. 1993) centric lesions and involvement of peripheral
lymph nodes.
6 Feline immunodeficiency virus (FIV) infection
6.1.3 Feline Lymphomas also increases the risk of developing lymphoma.
As the virus was not frequently found within
tumor tissues, an indirect effect (immunosuppres-
sion) is assumed.
Box 6.3. Feline Lymphomas in Six Facts Chronic inflammation is another proposed
1. Common tumors in cats. risk factor for the development of lymphoma in
2. Can be caused by the feline leukemia cats. Some studies have found an association
virus (FeLV). between inflammatory bowel disease and the
3. After the 1980s (FeLV eradication), the development of lymphomas, but this finding is
number of FeLV-positive lymphomas not supported in all studies.
decreased.
4. Many different types with different z Classification
biologic behavior exist. Clinically feline lymphoma can be classified by
5. Clinical symptoms related to location anatomical site. The anatomical classification
and extent of tumor infiltration. within the literature is inconsistent, but many
6. Chemotherapy is the treatment of studies include multicentric, gastrointestinal (ali-
choice. mentary), mediastinal (thymic), and extra-
nodal/unclassified forms (e.g., nasal, renal,
cutaneous, CNS lymphomas).
z Epidemiology and Pathogenesis As with canine lymphomas, feline lymphomas
Hematopoietic tumors represent up to 50 % of can also be classified by histology and immunohis-
cancers diagnosed in cats. Of these 50–90 % are tology. However, a combination of the recent
lymphomas. WHO classification with a grading scheme for
The signalment and characteristics of feline feline lymphoma similar to the one for dogs has
lymphomas have changed with the eradication not yet been published.
and vaccination programs for feline leukemia
virus (FeLV) in the early 1980s. FeLV-associated z Clinical Appearance
lymphomas often appeared in young cats (median The clinical signs are associated with the type of
age 4–6 years). These patients often showed medi- lymphoma and affected anatomic sites.
astinal forms of the disease. The frequency of lym- Cats with multicentric lymphomas may pres-
phomas has increased over the years despite the ent with single enlarged peripheral lymph nodes
fact that the number of FeLV-associated lympho- or nodes of a lymph region. Further clinical signs
mas decreased with the eradication of FeLV infec- are associated with the involved lymph centers
tions. A change in the age of affected patients and and organs.
the anatomical location of lesions are notable. Patients with gastrointestinal forms present
Veterinary patients with non-FeLV-associated lym- with corresponding signs (e.g., weight loss, vom-
phomas are now older (median age 9.5 years), and iting, diarrhea, and anorexia). Abdominal masses
gastrointestinal (primarily intestinal) lymphomas or thickened intestinal walls (. Fig.  6.8) can
Chapter 6 · Hematopoietic Tumors
117 6

. Fig. 6.8 Sonographic picture of a cat with intestinal


lymphoma. Note the enlarged intestinal loop . Fig. 6.9 The kidney of a cat with renal lymphoma. The
(arrowheads) with loss of the typical intestinal wall layers tumor shows a multifocal to coalescing infiltration
(as seen in the adjacent loop (arrow)). The mural striation (arrows) of the renal parenchyma
of the intestinal wall is replaced by a hypoechoic
circumferential wall thickening. The lumen (*) contains
gas, which results in a hyperechoic signal (Photo: with Cats with lymphomas of the CNS show signs
permission of Dr. Antje Hartmann, Vetsuisse Faculty associated with the location within the CNS
University of Bern, Bern, Switzerland, and the Department (intracranial, spinal) including seizures, behav-
of Veterinary Clinical Sciences, Clinic for Small Animals, ioral changes, ataxia, paresis or paralysis, blind-
Surgery, Justus-Liebig-University Giessen, Giessen,
Germany)
ness, and many more, often combined with
systemic signs like anorexia and lethargy.
Paraneoplastic syndromes (i.e., signs caused by
often be palpated. Progression depends on the the neoplasia but unrelated to the mass effect of
type of lymphoma. Lymphocytic forms progress the tumor or its metastases) can occur in cats with
more slowly (months) than lymphoblastic forms lymphomas, but they are less frequent than in
(days or weeks). dogs. Hypercalcemia of malignancy due to the
Mediastinal forms are associated with respira- production of parathyroid hormone-related pep-
tory signs (tachypnea, dyspnea), non-compressible tide (PTHrP) can lead to anorexia, polyuria and
cranial thorax, and often pleural effusion contain- polydipsia, weight loss, lethargy, and weakness.
ing neoplastic cells.
Cats with nasal lymphomas present with z Staging
symptoms related to the upper respiratory tract The WHO clinical staging system can be used for
(e.g., nasal discharge, upper respiratory noise, staging feline lymphoma (. see Table  6.1), but a
ocular discharge, epistaxis). In extreme cases they staging system proposed by (Mooney and Hayes
can present with facial deformation. 1986) is used as well (. see Table 6.3).
Renal lymphoma is associated with signs of
renal failure (polyuria/polydipsia, loss of appetite, z Cytology and Histopathology
weight loss). Irregular, often bilateral, enlargement Cytology is a minimally invasive procedure that
of the kidneys is palpable (. Fig. 6.9). can be diagnostic for lymphoma if an adequate
Cutaneous lymphomas represent ~3 % of number (>50 % of the cell population) of clearly
feline skin tumors and appear in two forms: epi- neoplastic cells can be identified (. Fig.  6.10).
theliotropic and non-epitheliotropic lymphomas. However, accurate diagnosis by cytology may be
Non-epitheliotropic lymphoma is the most com- impaired by the presence of low numbers of rec-
mon form of cutaneous lymphoma in cats. It ognizable neoplastic cells and/or a high back-
appears as single or multiple nodules in the der- ground of reactive lymphocytes. The same is true
mis or subcutis. Any site of the body can be for well-differentiated (small cell) lymphomas, in
involved. The oral mucosa is less commonly which neoplastic cells do not differ morphologi-
affected. The nodules may ulcerate, and swelling cally from nonneoplastic lymphocytes.
of the regional lymph nodes is common. Histopathology may face the same problems, but
Epitheliotropic lymphomas are similar to those it has the advantage of showing growth patterns and
described above for the dog. architectural alterations caused by the growth and
118 M. Henrich

. Table 6.3 System for the staging of feline


lymphomas according to (Mooney and Hayes 1986)

Stage 1

Single tumor (extra-nodal) or single anatomic site


(nodal)

Includes primary intrathoracic tumors

Stage 2

Single tumor (extra-nodal) with regional lymph node


involvement

Two or more nodes on same side of the diaphragm


6 . Fig. 6.10 Cytology, lymphoma, lymph node, cat, Two extra-nodal tumors ± regional lymph node
May-Grünwald-Giemsa 1000×. In cytological specimens, involvement on same side of the diaphragm
the diagnosis of lymphoma is based on the presence of
>50 % lymphatic blasts. In this cat, almost 100 % Resectable primary gastrointestinal
lymphatic blasts are seen. The lymphatic blasts are large tumor ± involvement of associated mesenteric lymph
(approximately >2.5× the diameter of an erythrocyte) and node
possess eccentrically located irregular to indented nuclei, Stage 3
a reticular to clumped chromatin, indistinct nucleoli, and
large amounts of lightly basophilic cytoplasm containing Two extra-nodal tumors on opposite sides of the
several clear vacuoles. Rarely, binuclear cells (bottom left) diaphragm
are seen. The cellular morphology is typical for an
Two or more nodes on opposite sides of the
anaplastic T-cell lymphoma (Photo: with permission of Dr.
diaphragm
N. Bauer, Faculty of Veterinary Medicine,
Justus-Liebig-University Giessen, Giessen, Germany) All extensive primary non-resectable
intra-abdominal disease
All paraspinal and epidural tumors, regardless of
infiltration of the tumor cells. Due to the high vari- other tumor sites
ability of the different types of lymphomas, neoplas- Stage 4
tic lymphocytes differ considerably, and
Stages 1, 2, or 3 with involvement of the spleen and/
morphological identification can be difficult. Cells or liver
of well-differentiated (small cell) lymphomas show
high similarity with nonneoplastic lymphocytes, Stage 5
but less differentiated lymphomas exist as well. Cells Stages 1, 2, 3, or 4 with initial involvement of the
of these tumors resemble lymphoblasts. The histo- CNS or bone marrow or both
logic growth pattern is often a diffuse, sheetlike
infiltration with effacement of the original architec-
ment as well as dogs (response rates of 50–80 %
ture. However, some lymphomas, e.g., follicular
with median remission and survival durations of
lymphomas, show a different growth pattern.
4–6 months), but they often suffer fewer side
effects of the therapy.
z Assessment of Clonality
Radiation therapy is useful for solitary forms. A
7 See Sect. 6.1.1.
high rate of complete remissions can be achieved
with radiation therapy in feline nasal lymphoma.
z Therapy
Chemotherapy is the treatment of choice for feline
lymphoma due to their systemic character. As with z Prognostic Factors and Markers
canine lymphomas, modifications of the CHOP Prognosis depends on the type and anatomical
protocol (cyclophosphamide, doxorubicin [= location of the lymphomas in cats. Gastrointestinal
hydroxydaunorubicin], vincristine [= Oncovin], lymphoma has a significantly shorter survival
prednisone) are used. These protocols are suitable time than mediastinal and nasal lymphoma. As a
to treat all lymphomas except the well- grading scheme correlated with the WHO classifi-
differentiated types. Cats do not respond to treat- cation scheme is lacking, prognosis regarding the
Chapter 6 · Hematopoietic Tumors
119 6
cell type is based on the cellular assessment of the z Epidemiology and Pathogenesis
Kiel classification. High-grade lymphomas have During the FeLV era, acute lymphocytic leuke-
significantly shorter survival times than low- mia (ALL) was the most common type of leuke-
grade lymphomas. Unlike in the dog, a prognostic mia seen in cats. However, after the FeLV
value of the immunophenotype (i.e., B- or T-cell eradication and vaccination programs in the
lymphomas) has not been confirmed. 1980s, this tumor type is seldom encountered,
and the recent literature regarding the disease is
z Current Trends in Research sparse. The majority of cats with ALL are FeLV
Many of the recently published studies aim to positive, and the disease affects young cats (age
improve diagnosis, therapy, and prognosis of less than 4 years).
feline lymphoma. Evaluating different approaches Chronic lymphocytic leukemia (CLL) is only
or therapeutic agents may help to improve thera- rarely diagnosed in cats. The current incidence of
peutic strategies and increase the success of lym- the disease in cats is unknown. Cats with CLL are
phoma treatment. older (median age 12.5  years) and these tumors
are usually FeLV negative. There is no sex predis-
z Suggested Reading position for lymphocytic leukemia.
(Hardy 1981; Vail et  al. 1998; Louwerens et  al.
2005; Carreras et al. 2003; Ragaini et al. 2003; Hart z Clinical Appearance
et al. 1994) Cats with ALL usually present in good condition
with an acute onset of nonspecific signs like leth-
argy, anorexia, vomitus, diarrhea, weight loss, and
6.1.4 Feline Lymphocytic Leukemia polyuria/polydipsia.
CLL is a neoplasia with indolent (slow pro-
Lymphocytic leukemias are neoplastic lymphoid gressive) behavior. If symptomatic at all, cats with
proliferations with extensive involvement of the CLL present with lethargy, reduced appetite, and
bone marrow. Usually, large numbers of neoplas- weight loss. In many cases, an enlarged spleen can
tic cells can be found in the peripheral blood; be palpated.
these are absent in aleukemic leukemia. It can be
difficult in some cases and virtually impossible in
others to differentiate between leukemia and stage z Cytology and Histopathology
5 lymphoma. Cytological examination of the bone marrow
and peripheral blood (. Fig. 6.11) can be helpful
in diagnosing lymphocytic leukemia. Bone mar-
Box 6.4. Feline Lymphocytic Leukemia in row aspirates may be redundant and thus
Seven Facts avoided if cytology of peripheral blood shows
1. A lymphoid neoplasm with extensive marked lymphocytosis and differential diagno-
bone marrow involvement. ses of nonneoplastic lymphocytosis (e.g.,
2. Neoplastic lymphocytes often numerous chronic ehrlichiosis, IL-2 administration, post-
in peripheral blood. vaccine lymphocytosis) can be ruled out (e.g.,
3. Aleukemic leukemias (without neoplastic by PARR analysis, predominance of one pheno-
cells in peripheral blood) exist. type, or atypical lymphocytes). However, the
4. Acute forms are very aggressive with characteristic feature of lymphocytic leukemia
poor prognosis and often associated is the infiltration of the bone marrow by neo-
with feline leukemia virus (FeLV) plastic cells. In ALL lymphoblasts are detectable
infections. in aspirates in high numbers, whereas in CLL
5. With the declining incidence of FeLV mature cells predominate.
infections, the incidence of feline Histopathology of bone marrow core biopsies
leukemia is also declining. is especially useful if aspiration of the bone mar-
6. Chronic forms are very slow progressive. row is not diagnostic. Immunohistochemistry is
7. Chemotherapy is the treatment of useful for differentiating ALL from acute myeloid
choice. leukemia in cases of premature cells on histopa-
thology.
120 M. Henrich

The term myeloma-related disorders (MRD)


can be used to describe all neoplasias of plasma
cells or immunoglobulin-secreting B-lymphocyte
precursors. Besides the tumors described in the
WHO classification, MRD also includes:
• Solitary plasmacytomas of the bone
• Macroglobulinemia
• Immunoglobulin-secreting lymphomas
• Myeloma cell leukemia
The following chapter will concentrate on
plasma cell myelomas and plasmacytomas as they
are the most common forms of plasma cell tumors.
6 . Fig. 6.11 Cytology, acute lymphoblastic leukemia
involving large granular lymphocytes (LGL), blood smear,
cat, May-Grünwald-Giemsa 1000×. There are many large
6.2.1 Plasma Cell Myelomas
lymphocytes with round to indented nuclei, finely (Multiple Myelomas) of Cats
stippled chromatin pattern, mainly indistinct nucleoli, and and Dogs
several perinuclear azurophilic granules (red arrow).
Differential diagnosis is LGL lymphoma, which is in the cat Plasma cell myelomas are characterized by a sys-
mainly arising from the gastrointestinal tract. Involvement
of the spleen leads to a leukemic stage (Photo: with
temic proliferation of neoplastic plasma cells.
permission of Dr. N. Bauer, Faculty of Veterinary Medicine, Multiple bone marrow sites, often within the axial
Justus-Liebig-University Giessen, Giessen, Germany) skeleton, are usually affected (hence the name
“multiple myelomas”).
z Therapy
Response to chemotherapy is poor in cats with
ALL. A combination of vincristine and predni- Box 6.5. Plasma Cell Myelomas in Five Facts
sone has been shown to result in complete remis- 1. Systemic proliferation of neoplastic
sion in 27 % of treated cats. Therapy of CLL with plasma cells often in multiple bone mar-
chlorambucil and prednisone results in a median row sites.
survival of about 14 months with 88 % percent of 2. Infiltration of the bone marrow leads to
the cats achieving complete or partial remission. osteolytic lesions.
3. Primarily found in older dogs, less in
z Prognostic Factors and Markers
other species.
As in dogs, the type of leukemia strongly influ- 4. Clinical signs attributed to bone involve-
ences the prognosis. Patients with ALL have a very ment and circulating (components of)
poor prognosis with short survival times. Patients immunoglobulin.
with CLL have a better prognosis and longer sur- 5. Chemotherapy is the treatment of
vival time due to the indolent nature of CLL. choice.
z Suggested Reading
Campbell et al. (2013), Cotter (1983)
z Epidemiology and Pathogenesis
Plasma cell myeloma is a malignant disease of
6.2 Plasma Cell Tumors of Cats older dogs (age 8–9 years). Cats and other
and Dogs domestic animals are rarely affected; if the dis-
ease appears in other species, they are also usu-
The following plasma cells tumors are listed in the ally older patients. A sex predisposition has not
WHO classification of hematopoietic tumors of been confirmed. The etiology of the disease is
domestic animals: unknown. Chronic immune stimulation (chronic
• Indolent plasmacytomas inflammation), exposure to carcinogens, and
• Anaplastic plasmacytomas breed predispositions (German shepherd dogs
• Plasma cell myelomas (multiple myelomas) are overrepresented in one study) have been
Chapter 6 · Hematopoietic Tumors
121 6
suggested to contribute to the development of z Cytology and Histopathology
the disease. Bone marrow aspiration (. Fig.  6.13) or bone
marrow core biopsies are required for definitive
z Clinical Appearance diagnosis. In plasma cell myelomas the number of
Dogs with plasma cell myelomas often present plasma cells in the marrow exceeds the normal
with lameness. Multifocal osteolytic lesions can be number of plasma cells (<5 %). A cutoff level of
identified radiographically (. Fig. 6.12). 20 % plasma cells in the sample is recommended
In cats, lameness is reported in variable per- (>10 % in the cat, if cells are atypical). Due to the
centages, and this species often shows nonspecific uneven distribution of the neoplastic foci, multi-
signs like weight loss, reduced appetite, vomiting, ple aspirates or biopsies might be necessary. In
and diarrhea. Multiple extramedullary manifes- most cases, neoplastic cells are uniformly shaped
tations (particular in the spleen, liver, and lymph with regular nuclei, occasional binucleated cells,
nodes) have been found in a considerable num- and abundant cytoplasm. Mitotic rate is below the
ber of cases. Sometimes, these cases lack bone mitotic rate of the surrounding bone marrow. In
marrow involvement and are considered as forms that are more aggressive, the cells show
aggressive, multicentric, non-cutaneous, extra- increasing anisocytosis and anisokaryosis with
medullary plasmacytomas. However, the distinc- high mitotic rates.
tion from plasma cell myelomas is blurred, and Benign bone marrow plasmacytosis is the
this tumor is often subsumed under the plasma main differential diagnosis for plasma cell myelo-
cell myelomas. mas; benign plasmacytosis tends to have less cyto-
The malignant plasma cells often produce plasmic volume, but definitive diagnosis should
large quantities of a single type or part of immu- be based on two or more of the typical findings,
noglobulin (M component). Therefore, beside including osteolysis, atypical plasmacytosis,
clinical signs due to infiltration of neoplastic cells monoclonal gammopathy, and/or proteinuria
into the bone and organs, clinical signs are also (Bence Jones proteins).
due to high amounts of circulating M component
and its excretion or storage. Frequent clinical z Therapy
signs include bleeding diathesis (e.g., as epistaxis, The aim of treatment for myeloma is to reduce the
retinal bleeding), hyperviscosity syndrome, renal tumor cell mass and to treat secondary effects of
failure, immunodeficiencies, cardiac failure, and the tumor and its secreted proteins.
CNS signs. Chemotherapy (melphalan in combination
Additional clinical pathology findings include with prednisone) is effective in dogs to reduce the
anemia, hypoalbuminemia, proteinuria (includ- number of tumor cells and the amount of circulat-
ing excretion of immunoglobulin light chain ing M component. Nevertheless, complete elimi-
proteins, so-called Bence Jones proteins), hyper- nation is rare and relapses are common. Mean
calcemia, and azotemia. survival time of dogs is 1.5 years. Cats respond less

. Fig. 6.12 Lateral radiograph of the thoracic spine of a dog with plasma cell myeloma. Within the vertebral bodies,
dorsal spinous processes and the ribs are multiple foci of osteolysis (arrows). The “punched out” appearance of the
lesions are typical for plasma cell myelomas (Photo: with permission of Dr. Antje Hartmann, Vetsuisse Faculty University
of Bern, Bern, Switzerland, and the Department of Veterinary Clinical Sciences, Clinic for Small Animals, Surgery,
Justus-Liebig-University Giessen, Giessen, Germany)
122 M. Henrich

Box 6.6. Plasmacytomas in Five Facts


1. Tumor of mature dogs and rarely cats.
2. Plasmacytomas in the skin and oral
cavity are benign.
3. Solitary osseous plasmacytomas can
evolve to plasma cell myelomas.
4. Surgical excision is curative for skin
tumors.
5. Chemotherapy and radiation therapy
additionally applied in some tumors.

6 . Fig. 6.13 Cytology, plasma cell myeloma, bone z Epidemiology and Pathogenesis
marrow aspirate, dog, May-Grünwald-Giemsa 1000x. Note Plasmacytomas are infrequently seen in dogs and
the dominance of plasma cells with atypical lightly only rarely in cats. Patients are usually older
basophilic vacuolar cytoplasm (black arrow). Some plasma (median age, 9–10 years in dogs) with no sex pre-
cells show eosinophilic material associated with the
cellular border (so-called flame cells or flaming plasma
disposition. Dog breeds with a higher risk of devel-
cell, red arrow) indicative of an IgA-producing multiple oping plasmacytomas are American and English
myeloma (Photo: with permission of Dr. N. Bauer, Faculty cocker spaniels and West Highland white terriers.
of Veterinary Medicine, Justus-Liebig-University Giessen, A higher risk is presumed in Yorkshire terriers,
Giessen, Germany) boxers, German shepherds, and Airedale terriers.

favorable to chemotherapy with common relapses z Clinical Appearance


and survival times of less than 6 months. However, Extramedullary plasmacytomas in dogs are usually
long-term survival (>1 year) has been reported. found in the skin and less often in oral mucous
After chemotherapy has been initiated, tumor membranes or mucosa of the rectum and colon.
sequela may be treated; this includes plasmapher- Other sites of the body (e.g., the stomach, small
esis for the treatment of the hyperviscosity syn- intestine, spleen, liver, genitalia, eyes, uterus, and
drome, treatment of hypercalcemia, fluid therapy lung) are occasionally affected as well. Tumors in
for the renal involvement, and orthopedic treat- the skin are single, soft, slightly raised nodules with
ment of pathologic fractures. no associated clinical signs. Tumors in the gastroin-
testinal tract can be associated with nonspecific gas-
z Prognostic Factors and Markers trointestinal signs. Colorectal involvement can lead
The presence of widespread osteolysis, hypercal- to tenesmus, hemorrhage (rectal bleeding, hemato-
cemia, or excretion of Bence Jones proteins is chezia), or rectal prolapse. The clinical course of dis-
negatively correlated with survival in dogs. ease depends on the type of plasmacytomas.
Indolent plasmacytomas are considered to be
z Suggested Reading benign tumors, whereas anaplastic plasmacyto-
(Osborne et al. 1968; Matus et al. 1986; MacEwen mas are considered to be malignant but with slow
and Hurvitz 1977; Mellor et  al. 2006; Mellor progression and rare metastases.
et al. 2008) Solitary osseous plasmacytomas appear within
the bones as single lesions but often evolve to mul-
tiple myelomas in the course of the disease. Clinical
6.2.2 Plasmacytomas in Dogs presentation depends on the bone involved; lame-
and Cats ness and pain present with long bone involvement
and neurologic signs with vertebral involvement.
Solitary plasmacytomas develop either in the
bone (solitary osseous plasmacytomas) or in the z Cytology and Histopathology
soft tissue (extramedullary plasmacytomas). Cytology of plasmacytomas is often diagnostic. In
These tumors are focal proliferations of atypical some tumors, cells resemble well-differentiated
plasma cells. plasma cells (. Fig.  6.14), but in others, they are
Chapter 6 · Hematopoietic Tumors
123 6
tumors in other locations show a higher risk of
metastasis to local lymph nodes. Plasmacytomas
of the rectal mucosa are less biologic aggressive
and surgical excision is usually curative. Solitary
osseous plasmacytomas have a less favorable diag-
nosis since most progress to multiple myelomas.
However, the time from local disease to systemic
disease may be in the range of months to years.
The microscopic appearance is useful in differenti-
ating benign indolent plasmacytomas from the
(low) malignant anaplastic plasmacytomas.

z Suggested Reading
. Fig. 6.14 Cytology, plasmacytoma lymph node, dog, (Platz et al. 1999; Meis et al. 1987; Baer et al. 1989)
May-Grünwald-Giemsa 1000x. In the lymph node,
infiltration with neoplastic plasma cells cannot be
differentiated from reactive plasma cells, unless the tumor 6.3 Histiocytic Tumors
cells are of atypical morphology. In this case,
plasmacytoma can be easily detected due to the Proliferations of histiocytic cells are common in
dominance of so-called flame cells (or flaming plasma
cells, red arrows) consistent with a clonal proliferation of
dogs and less common in cats. Histiocytes are a
IgA-producing plasma cells characterized by ruffled heterogeneous group of cells derived from the
magenta-staining cellular margins (Photo: with dendritic or macrophage cell line. Several entities
permission of Dr. N. Bauer, Faculty of Veterinary Medicine, of histiocytic proliferative disorders exist.
Justus-Liebig-University Giessen, Giessen, Germany)

less differentiated. Indolent plasmacytomas pres- 6.3.1 Canine Histiocytic Tumors


ent histologically as tumors composed of sheets of
uniform large cells with eccentrically placed 6.3.1.1 Cutaneous Histiocytomas
round to oval nuclei and deeply stained cytoplasm Cutaneous histiocytomas are common benign
(. Fig.  6.15). Binucleation occurs infrequently skin tumors mostly of young dogs (7 see Chap. 4).
and mitoses are rare. Anaplastic plasmacytomas
show marked anisokaryosis, hyperchromicity, 6.3.1.2 Histiocytic Sarcomas
frequent binucleation, and mitoses. Histiocytic sarcomas (HS) derive from interstitial
dendritic cells. These can be found in the perivas-
z Therapy cular region of many organs, with the exception of
Surgical excision is the therapy of choice for extra- the brain (here they are only found in the meninges
medullary plasmacytomas. Adjuvant chemother- and choroid plexus). A related but distinct form of
apy (melphalan and prednisone) or radiation can HS is called hemophagocytic histiocytic sarcomas.
be supportive for recurrent or incompletely This variant originates from macrophages.
removed tumors.
Treatment of solitary osseous plasmacytomas
depends on the bone involved and associated com- Box 6.7. Histiocytic Sarcomas in Six Facts
plications. Surgical excision is recommended in cases 1. Malignant tumor of dendritic cells.
of instable fractures and/or neurologic signs due to 2. Bernese Mountain Dogs are predisposed.
spinal cord compression. Radiation therapy alone is 3. Localized or disseminated (“malignant
suitable for patients with stable fractures or as pallia- histiocytosis”).
tive therapy. Tumors in the axial bones can be treated 4. Disseminated HS has a poor prognosis.
with either surgical excision or radiation therapy. 5. Localized HS has a more favorable
prognosis.
z Prognostic Factors and Markers 6. Therapy of choice: surgical excision
Anatomic location is an important prognostic fac- (localized) or chemotherapy
tor. Extramedullary plasmacytomas in the skin (disseminated).
and oral cavity are considered benign, whereas
124 M. Henrich

a b

6
. Fig. 6.15 Histology of the skin of a dog with solitary cutaneous plasmacytoma. (a) The dermis shows a sheetlike
infiltration with neoplastic cells (hematoxylin and eosin, 100×). (b) Higher magnification of A. Neoplastic cells are
large, relatively uniform with eccentrically placed round to oval nuclei and deeply stained cytoplasm (hematoxylin
and eosin, 400×)

z Epidemiology and Pathogenesis are primary sites as well. Spreading occurs first to
Histiocytic sarcomas are a disease mainly seen in the draining lymph node and subsequently to dis-
dogs and only rarely in other species, including tant sites (often the liver and lung, if not primarily
cats (see below), horses, and cattle. Bernese involved).
Mountain Dogs are predisposed to histiocytic sar- Affected organs of the hemophagocytic HS are
comas, but Rottweilers, golden retrievers, and flat- the spleen, liver, bone marrow, and lung.
coated retrievers have an increased incidence as Clinical signs depend on the organ involved
well. In other breeds, the disease occurs sporadi- but include nonspecific systemic signs (like
cally. The mode of inheritance in Bernese anorexia, weight loss, and lethargy). The mass
Mountain Dogs is reported to be polygenetic. effect of thoracic tumors (especially within the
There is a similarity to histiocytic sarcomas in lung, . Fig.  6.16) leads to coughing and other
humans; similar genetic loci are affected (tumor respiratory signs. Involvement of the CNS can
suppressor genes: CDKN2A, RB1, and PTEN). result in neurologic signs (e.g., seizures, ataxia,
Age of initial diagnosis is between 6 and 8.5 years. and paralysis). Articular HS is associated with
A sex predisposition has not been found. lameness.
The hemophagocytic histiocytic sarcoma also Clinical pathology findings include mild ane-
shows a predisposition for Bernese Mountain mia, which can be profound in cases of hemo-
Dogs, as well as Rottweilers and retrievers. The phagocytic HS, thrombocytopenia, and rare
range of age at diagnosis, 2.5–13 years, is slightly hypercalcemia.
broader than in the non-hemophagocytic variant. Localized and disseminated HS present as soli-
tary or multiple white masses with a smooth cut
z Clinical Appearance surface, whereas the hemophagocytic variant infil-
Histiocytic sarcomas can be focal (localized HS) trates the affected organs diffusely without forma-
within a single organ or site of the body or sys- tion of nodular tumor masses.
temic. If the disease spreads beyond the local
lymph node, it is called disseminated histiocytic z Cytology and Histopathology
sarcoma (previously malignant histiocytosis). It is Cytology shows pleomorphic histiocytic cells
commonly detected in the lung, spleen, and with marked anisocytosis and anisokaryosis
lymph nodes. (. Figs.  6.17 and 6.18). The cells are often bi- or
Localized HS often occurs initially in the sub- multinucleated with a variable number of mito-
cutis of the limbs, but other sites like the spleen, ses. Differentiation of benign histiocytic prolif-
liver, lung, brain, nasal or oral cavity, and joints erations from histiocytic sarcomas can be difficult
Chapter 6 · Hematopoietic Tumors
125 6

. Fig. 6.16 Lateral thoracic radiograph a Bernese . Fig. 6.17 Cytology, histiocytic sarcoma, thoracic mass,
Mountain Dog with histiocytic sarcoma. Note the solitary mixed-breed dog, May-Grünwald-Giemsa 100×. Note the
space-occupying lesion (arrows) within the caudal part of presence of histiocytic giant cells diagnostic for histiocytic
the left cranial lobe of the lung (Photo: with permission of sarcoma (red arrow) (Photo: with permission of Dr.
Dr. Antje Hartmann, Vetsuisse Faculty University of Bern, N. Bauer, Faculty of Veterinary Medicine,
Bern, Switzerland, and the Department of Veterinary Justus-Liebig-University, Giessen, Germany)
Clinical Sciences, Clinic for Small Animals, Surgery,
Justus-Liebig-University Giessen, Giessen, Germany)
ruled out by immunohistology. The hemophago-
cytic subtype shows marked erythrophagocytosis
in cytology and histology.

z Therapy
Wide surgical excision of localized HS can be
curative if the tumor has not spread.
Treatment of disseminated HS with lomus-
tine showed about a 50 % response rate, with
prolonged survival times (median 172 days)
compared to nonresponding dogs (median
60 days).

z Prognostic Factors and Markers


The main prognostic factor is the type of histio-
. Fig. 6.18 Cytology, histiocytic sarcoma, thoracic cytic sarcoma involved. The median survival
mass, mixed breed dog (same dog as in Fig. 6.17), time of dogs with localized HS in a study with 11
May-Grünwald-Giemsa 1000x. Note the presence of dogs was 5.3  years. The aggressive behavior of
smaller (black arrow) histiocytic cells without phagocytic
the disseminated HS causes a very fast progres-
activity as well as larger atypical histiocytes with
macronuklei (red arrow). (Photo: with permission of sive disease, which results in a poor prognosis.
Dr. N. Bauer, Faculty of Veterinary Medicine, Data of survival times is scarce; patients were
Justus-Liebig-University Giessen, Giessen, Germany) euthanized shortly after diagnosis in many
reported cases. Dogs with hemophagocytic HS
with cytology alone. Sheets of large, pleomorphic are reported to have a survival time of 2–32
cells, often multinucleated with numerous bizarre weeks (median about 7 weeks).
mitoses (. Fig.  6.19), are seen on histopathology
of HS. Sometimes a spindle cell component can z Suggested Reading
be observed as well. Due to the pleomorphism, (Moore 2014; Fulmer and Mauldin 2007; Affolter;
anaplastic tumors of different origin need to be Moore 2002 and , Moore 2006)
126 M. Henrich

a b

6
. Fig. 6.19 Histology of the liver of a Bernese Mountain Dog with histiocytic sarcoma. (a) There is extensive infiltration
of the liver sinusoids and the portal areas (P) with neoplastic cells, including multiple tumor giant cells (arrow)
(hematoxylin and eosin, 100×). (b) Higher magnification of A. Note the high level of pleomorphism of the neoplastic
cells including the tumor giant cells (arrow) (hematoxylin and eosin, 400×)

6.3.2 Feline Progressive


Histiocytosis

Feline progressive histiocytosis originates from


interstitial dendritic cells of the skin and repre-
sents a low-grade histiocytic sarcoma.

Box 6.8. Feline Progressive Histiocytosis in


Four Facts
1. A slowly progressive tumor of interstitial
dendritic cells of the skin.
2. Begins with solitary cutaneous nodules.
3. Often becomes systemic in the course of
. Fig. 6.20 Cytology, feline progressive histiocytosis,
the disease skin tumor, mandibular area, cat, May-Grünwald-Giemsa
4. There is no effective therapy and the 100×. There are numerous pleomorphic large histiocytic
long-term prognosis is poor. giant cells with round to kidney-shaped nuclei
diagnostic for progressive histiocytosis (red arrow). Their
atypically large size can be easily seen in comparison
with a neutrophil (black arrow): a benign histiocytic cell
z Epidemiology and Pathogenesis would possess nuclei that are much smaller than a
Feline progressive histiocytosis is a disease of neutrophil
middle-aged to older cats (7–17 years).

z Clinical Appearance tases to regional lymph nodes and internal organs


The disease presents initially as a solitary cutane- during the course of the disease including the
ous nodule, which usually progresses to multiple lungs, liver, spleen, and kidneys.
non-painful, non-pruritic nodules, papules, or
plaques. Lesions can be alopecic and ulcerated. z Cytology and Histopathology
Affected sites are the head, trunk, and distal Early lesions are composed of well-differentiated
limbs. The lesions may wax and wane; regression histiocytes (. Fig.  6.22). Reactive lesions due to
does not occur. Instead, many cats develop metas- infectious agents have to be ruled out. In the
Chapter 6 · Hematopoietic Tumors
127 6
course of the disease, criteria of malignancy
(atypical cells, bizarre mitoses, and multinucle-
ated cells) are frequently seen (. Figs.  6.20
and 6.21).

z Therapy
No treatment has been reported.

z Prognostic Factors and Markers


The disease shows a slow progression. However,
due to the lack of an efficient therapy, the progno-
sis is poor.

. Fig. 6.21 Cytology, feline progressive histiocytosis, z Suggested Reading


skin tumor, mandibular area, cat (the same cat as in Fig. (Moore 2014; Affolter and Moore 2006)
6.20), May-Grünwald-Giemsa 1000×. There are highly
pleomorphic large histiocytic giant cells (red arrow) with
marked anisocytosis, anisokaryosis, pleomorphism, and
indented nuclei with rough chromatin structure (Photo:
with permission of Dr. N. Bauer, Faculty of Veterinary
Medicine, Justus-Liebig-University Giessen, Giessen,
Germany)

a b

. Fig. 6.22 Histology of the skin of a cat with progressive histiocytosis. (a) There is a sheetlike infiltration of the
dermis with neoplastic cells (hematoxylin and eosin, 100×). (b) Higher magnification of A. Neoplastic cells have large
amounts of cytoplasm and large round to oval, sometimes indented (arrow) nuclei (hematoxylin and eosin, 400×)
128 M. Henrich

Suggested Reading Matus RE, Leifer CE, MacEwen EG, Hurvitz AI (1986)
Prognostic factors for multiple myelomas in the dog.
J Am Vet Med Assoc 188(11):1288–1292
Adam F, Villiers E, Watson S, Coyne K, Blackwood L (2009)
Meis JM, Butler JJ, Osborne BM, Ordonez NG (1987) Solitary
Clinical pathological and epidemiological assessment
plasmacytomas of bone and extramedullary plasma-
of morphologically and immunologically confirmed
cytomas. A clinicopathologic and immunohistochemi-
canine leukaemia. Vet Comp Oncol 7(3):181–195.
cal study. Cancer 59(8):1475–1485
doi:10.1111/j.1476-5829.2009.00189.x
Mellor PJ, Haugland S, Murphy S, Smith KC, Holloway A,
Affolter VK, Moore PF (2002) Localized and disseminated
Archer J, Powell RM, Polton GA, Tasker S, McCormick D,
histiocytic sarcomas of dendritic cell origin in dogs.
Tempest ME, McNeil PE, Scase TJ, Knott CD, Bonfanti U,
Vet Pathol 39(1):74–83
Villiers EJ, Argyle DJ, Herrtage ME, Day MJ (2006)
Affolter VK, Moore PF (2006) Feline progressive histiocyto-
Myelomas-related disorders in cats commonly present
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as extramedullary neoplasms in contrast to myelomas
Baer K, Patnaik A, Gilbertson S, Hurvitz A (1989) Cutaneous
in human patients: 24 cases with clinical follow-up.
plasmacytomas in dogs: a morphologic and immuno-
J Vet Intern Med 20(6):1376–1383
histochemical study. Vet Pathol Online 26(3):216–221
6 Campbell MW, Hess PR, Williams LE (2013) Chronic lympho-
Mellor PJ, Haugland S, Smith KC, Powell RM, Archer J, Scase
TJ, Villiers EJ, McNeil PE, Nixon C, Knott C, Fournier D,
cytic leukaemia in the cat: 18 cases (2000–2010). Vet
Murphy S, Polton GA, Belford C, Philbey AW, Argyle DJ,
Comp Oncol 11(4):256–264. doi:10.1111/j.1476-5829.
Herrtage ME, Day MJ (2008) Histopathologic, immu-
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nohistochemical, and cytologic analysis of feline
Carreras JK, Goldschmidt M, Lamb M, McLear RC, Drobatz
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KJ, Sorenmo KU (2003) Feline epitheliotropic intestinal
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Intern Med 17(3):326–331
Mooney SC, Hayes AA (1986) Lymphomas in the cat: an
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131 7

Urogenital Tract Tumors


Stephanie Plog

7.1 Urinary Tract Tumors – 132


7.1.1 Canine Renal Tumors – 132
7.1.2 Canine Urinary Bladder Tumors – 134
7.1.3 Feline Renal Tumors – 136
7.1.4 Feline Urinary Bladder Tumors – 137
7.1.5 Equine Renal Tumors – 137
7.1.6 Equine Urinary Bladder Tumors – 137
7.1.7 Bovine Renal Tumors – 137
7.1.8 Bovine Urinary Bladder Tumors – 138

7.2 Tumors of the Female Genital Tract – 139


7.2.1 Ovarian Tumors – 139
7.2.2 Uterine and Vaginal Tumors – 141

7.3 Tumors of the Male Genital Tract – 144


7.3.1 Testicular Tumors – 144
7.3.2 Prostatic Tumors – 147
7.3.3 Penile Tumors – 148

7.4 Transmissible Venereal Tumor (TVT) in Male


and Female Dogs – 150

Suggested Reading – 151

© Springer International Publishing Switzerland 2016


R. Klopfleisch (ed.), Veterinary Oncology, DOI 10.1007/978-3-319-41124-8_7
132 S. Plog

7.1 Urinary Tract Tumors Mesenchymal tumors of the kidney include


hemangiosarcomas and fibrosarcomas and various
7.1.1 Canine Renal Tumors metastases from distinct primary focuses that
have to be excluded before the diagnosis of a pri-
In general, renal tumors are rare in dogs, but if they mary renal mesenchymal tumor can be made.
occur, they are mostly malignant. Adenomas consti- Hemangiomas are reported to be the most com-
tute only 15 % of primary neoplasms. Malignant mon benign tumors in the canine kidney.
tumors can occur uni- or bilaterally, and carcino-
mas are the most common canine renal neoplasms. z Clinical Appearance
Clinical findings in dogs affected by renal tumors
7.1.1.1 Epithelial and Mesenchymal are usually unspecific, including weight loss,
Tumors polyuria, lethargy, and hematuria. Some authors
say that hematuria is seen more often in transi-
tional cell tumors. Clinical signs are mainly
Box 7.1. Canine Renal Epithelial and attributed to the destruction of the renal paren-
7 Mesenchymal Neoplasms in Five Facts chyma and can mirror those caused by nonneo-
1. Mostly malignant plastic lesions. Sometimes a painful abdominal
2. Tumors of old dogs, exception: mass can be palpated. Blood chemistry might
cystadenocarcinomas reveal polycythemia, anemia, azotemia, neutro-
3. Clinical signs often unspecific philia, or hypercalcemia. Additional findings like
4. Therapy of choice in cases with bone metastasis and hypertrophic osteopathy
unilateral tumors is nephrectomy due to pulmonary metastases are rarely
5. Commonly metastasize to the lymph described. Since most of the renal neoplasms
nodes, lung, and liver have already metastasized to the lung, lymph
nodes, liver, or heart at the time of diagnosis,
radiography of the thorax and abdominal ultraso-
z Epidemiology and Pathogenesis nography should be included in every case of
Epithelial kidney tumors in the dog are divided suspected renal neoplasia. Metastasis to the skin
mainly into renal cell carcinomas (RCC) and tran- has also been reported.
sitional cell carcinomas. Primary tumors of the
kidneys are mostly malignant. Metastases to the z Cytology and Histopathology
kidneys have been described. Renal clear cells with vacuolated cytoplasm
Renal cell carcinomas (RCC) arise from epi- might be visible in smears of renal carcinomas,
thelium of renal tubules and are the most com- but this finding is not pathognomonic, and his-
mon epithelial tumors in the canine kidney. They topathology is needed for definitive diagnosis
often occur bilaterally and can be highly invasive. and identifying invasion and complete excision.
The mean age is 8 years, with predisposition of Histologically, a variety of different subtypes and
male dogs. cell types can be found in renal cell carcinomas,
Cystadenocarcinomas are a variant of epithe- and the clear cell variant is associated with a
lial tumors in the kidney that occur simultane- significantly decreased survival time. Mitotic
ously with nodular dermatofibrosis mainly in index (<10 mitoses, 10–30 mitoses, >30 mitoses
German Shepherd dogs, similar to uterine tumors. in 10 high power fields) in RCC is assumed to
This disease is caused by a mutation in the follicu- be an important prognostic variable for the sur-
lin gene, and affected dogs usually present with vival time.
skin tumors at the age of 6 years. Concomitantly
occurring renal cystadenocarcinomas are usually z Therapy
bilateral. Occurrence of cystadenomas has been The therapy of choice in unilateral renal tumors is
described as well. nephrectomy, independent of the type of tumor.
Transitional cell carcinomas arise from the lin- Removal of the ureter and adjacent tissue might
ing of the renal pelvis and are rare tumors in the be necessary and is generally recommended.
canine kidney. In comparison to renal cell carci- Particular care should be taken to avoid spread of
nomas, metastasis to the lung is seen less often. neoplastic cells into the abdominal cavity during
Chapter 7 · Urogenital Tract Tumors
133 7
surgery. Chemotherapeutic approaches are not dogs with nephroblastomas develop pulmonary
useful in primary renal tumors in the dog, and metastasis, radiographic examination of the
survival times did not differ between treated and thorax should be included. Palpable abdominal
nontreated animals in a recent study. Successful masses might be detected in some cases.
treatment with surgical excision of the neoplastic
kidney is largely dependent on the functionality z Cytology and Histopathology
of the contralateral kidney. Nephroblastomas are usually composed of blas-
temal, epithelial, and stromal components and
z Prognosis
can have a variable appearance. Thus, cytology is
Although pulmonary metastases are present at the usually not sufficient and histopathology is
time of diagnosis in most cases, survival times of needed for the definitive diagnosis. Histologically,
up to 5 years after nephrectomy have been primitive glomeruli can be seen along with loose
reported. Epithelial tumors are associated with mesenchymal cells and underdeveloped tubules.
longer survival times than mesenchymal tumors. Diagnosis may be confirmed by anti-C-19
Renal hemangiosarcomas have a better prognosis immunohistochemical staining.
than hemangiosarcomas in other organs.
Hemoabdomen due to rupture of the neoplasm,
hematuria, and cachexia are negatively correlated z Therapy and Prognosis
with survival. Nephrectomy is the method of choice, and there is
no reliable information about the usefulness of
7.1.1.2 Canine Nephroblastomas chemotherapeutics. Prognosis is dependent on
the  histological appearance of the tumor, and
well-differentiated tumors composed of clearly
Box 7.2. Canine Nephroblastomas of the identifiable tubules and glomeruli have a better
Kidney in Five Facts prognosis than nephroblastomas with anaplastic
1. Occur in young adult dogs or sarcomatoid growth.
2. Can become huge palpable abdominal
masses
7.1.1.3 Malignant Lymphomas
3. Usually unilateral
4. Nephrectomy as the therapy of choice Details on canine lymphomas are given in Chap. 6
5. Prognosis depends on the degree of (Hematopoietic Tumors). In general, renal
differentiation lymphomas can occur uni- or bilaterally and are
considered rare in dogs. Polycythemia occurs
commonly in association with renal lymphomas.
Pyelectasis is a common finding in ultrasonogra-
z Epidemiology and Pathogenesis
phy, as are the loss of corticomedullary distinc-
Nephroblastomas originate from primitive neph-
tion and renomegaly. Nephrectomy is usually not
rogenic blastema and can also contain cartilage or
the therapy of choice, but chemotherapeutic
muscle, suggesting pluripotent mesenchymal ori-
approaches using COP or CHOP protocols do
gin. In contrast to other tumors of the kidney,
yield good results, with median survival rates of
nephroblastomas commonly occur at a younger
up to 295 and 309 days, respectively. In most
age. Malignancy of the tumor is dependent on its
cases, blastoid cells can be identified as the main
degree of differentiation. Nephroblastomas can
cell population in cytology and point toward the
become huge, causing severe abdominal disten-
presence of a renal lymphoma.
sion, but are usually unilateral. In over 50 % of
cases, metastases to the lung and liver are seen.
Nephroblastomas can also occur as intradural z Suggested Reading
neoplasms of the spinal canal. (Batchelor et  al. 2006; Battaglia et  al. 2005;
Bryan et al. 2006; Chiang et al. 2007; Crow et al.
z Clinical Appearance 1995; Durno et al. 2011; Edmondson et al. 2015;
The clinical appearance in dogs with nephroblas- Hayes and Fraumeni 1977; Locke and Barber
tomas is mainly unspecific, similar to the other 2006; Moe and Lium 1997; Militerno et al. 2003;
renal tumors (7 see Sect.  7.1.1.1). As 75 % of Taylor et al. 2014)
134 S. Plog

7.1.2 Canine Urinary Bladder


Tumors

Tumors of the urinary bladder are the most com-


mon neoplasms of the canine urinary tract. Most
of them are transitional cell carcinomas. Clinical
diagnosis can be difficult because the clinical
signs are unspecific, and the prognosis is
dependent on staging, degree of urinary tract
obstruction, and histological subclassification.

7.1.2.1 Transitional Cell


Carcinomas/TCC

Box 7.3. Transitional Cell Carcinomas of the


7 Urinary Bladder in Six Facts . Fig. 7.1 Invasive transitional cell tumor of the urinary
1. Most common urinary bladder tumor in bladder of the dog (with permission of P. Schlieben,
dogs, especially neutered dogs Landeslabor Frankfurt/Oder and the Archive of the
2. Associated with contact between Institute for Veterinary Pathology and R. Klopfleisch, Freie
Universität Berlin, Germany)
urothelium and carcinogens
3. Often invasive, metastasizing, and
obstructing tract obstruction. These unspecific symptoms are
4. Commonly located at the trigone comparable to those of nonneoplastic diseases,
5. Clinical staging: TNM system and they can even resolve temporarily with anti-
6. Effective therapeutic approaches: biotics. Concurrent urinary tract infections are
combination of surgery and medical common. Sonography is the standard procedure
treatment for detecting a urinary bladder neoplasm, and loss
of the typical layered arrangement of the urinary
bladder wall can hint toward malignant infiltra-
z Epidemiology and Pathogenesis tive growth. TCC can be polypoid, sessile, or papil-
Transitional cell carcinomas of the urinary bladder lary. Differentials include polyps which are often
are the most common urogenital neoplasms in stalked and located in the apex region as well as
the dog and arise from the epithelial lining of the polypoid cystitis. Endoscopic examination allows
urinary bladder. They are often invasive and for a closer investigation of location, morphology,
located in the trigone region (. Fig. 7.1). Primary and dimensions of the neoplasm. Metastasis is
neoplasms of the urethra are rare, but transitional common, but often late, and usually occurs to the
cell carcinomas of the urinary bladder often infil- lymph nodes, liver, and lung, and some say that
trate the urethra. Neutered dogs are more likely to care has to be taken during cystocentesis to avoid
develop TCC than intact dogs, and female sex is seeding of tumor cells. Catheterization might be
considered a risk factor, as is prolonged exposure the method of choice to collect urine. Metastases
of the urinary bladder to various carcinogens like to the skin adjacent to the vulva or prepuce as well
cyclophosphamide or older insecticides, herbi- as metastasis to the bone have also been described.
cides, or pesticides. There seems to be a breed pre- Clinical staging of TCC of the urinary bladder
disposition for Scottish Terriers, West Highland is performed using a World Health Organization
White Terriers, Fox Terriers, Shetland Sheepdogs, (WHO) system (. Table 7.1).
Beagles, and Collies, and obesity is another risk
factor. Affected dogs are usually approximately 10 z Cytology and Histopathology
years old. Urinary tract obstruction is common. Cytology can be useful when dysplastic tumor cells
are visible in the urine, but sensitivity is low.
z Clinical Appearance Histology is the method of choice to reach a
Main symptoms are pollakiuria, hematuria, dysuria, definitive diagnosis. Histologically, the tumor can
and – later in the disease – anuria due to urinary be classified according to invasive growth, pattern
Chapter 7 · Urogenital Tract Tumors
135 7
to partial remission or stable disease. Especially
. Table 7.1 Clinical staging system for
transitional cell carcinomas (Owen 1980)
multiple different treatment protocols used subse-
quently can result in control of the disease.
TNM Piroxicam or deracoxib, COX inhibitors, can result
stage Category in good quality of life and stable disease when
used as single agent, and survival times of up to 2
T Primary tumor
years have been reported. Localized application of
T0 Neoplastic growth not evident mitomycin C and photodynamic agents yielded
T1 Superficial papillary tumor inconsistent results, and severe side effects were
seen. Immunotherapy is not promising in dogs.
T2 Invasion into urinary bladder wall, induration
Radiation therapy in combination with surgery is
T3 Invasion into adjacent tissues (prostate, also possible, but an impairment of life quality
uterus, vagina, intestine) due to extensive fibrosis often accompanies the
N Regional lymph nodes (Lnn. iliacimediales) therapy. However, a recent study reported good
results with 10 once-daily fractions of 2.7  Gy
N0 No involvement
without significant late side radiation effects and
N1 Involvement of regional lymph nodes with a survival time of up to 767 days. All patients
N2 Additional involvement of further lymph
clinically benefited from this therapy. Regular
nodes (Lnn. lumbales aortici, Lnn. urine analysis to check for secondary bacterial
hypogastrici, Lnn. sacrales) infections is crucial.
M Distant metastases
z Prognostic Factors
M0 No distant metastasis Survival is strongly associated with the TNM clin-
M1 Distant metastasis (lung, bone, brain, etc.) ical staging (. Table  7.1). More advanced TNM
stage is associated with younger age, prostate
involvement, and higher T stage, with the longest
(papillary, non-papillary), and tumor grade. median survival being 234 days. Prognosis is also
Multiple layers of neoplastic urothelium covering dependent on the location of the tumor, invasion
a tumor stalk are common, and invasion into the of the urethra and surrounding tissue, obstruc-
stalk and surrounding stroma as well as desmo- tion of the urinary tract, and histological subclas-
plasia are often associated with metastasis. Non- sification. Ultrasonographically, involvement of
papillary and infiltrating variants are most likely the urinary bladder wall, trigone location, and the
to metastasize. There may be areas of glandular or presence of a heterogeneous mass are associated
squamous metaplasia. Immunohistochemical with poorer prognosis.
staining for uroplakin III can be useful in cases of
undifferentiated tumors. Another marker for neo- 7.1.2.2 Other Epithelial Neoplasms
plastic transformation is COX-2 which was of the Urinary Bladder
assumed to be expressed in neoplastic cells only. Squamous cell carcinomas (SCC), undifferentiated
However, a recent study revealed COX-2 to be carcinomas, and adenocarcinomas of the uri-
expressed in proliferative epithelium as well, and nary  bladder are far less common than TCC.
this marker has to be interpreted with caution. Adenocarcinomas and SCC show non-papillary
growth and are often ulcerated. They do not
z Therapy metastasize as often as transitional cell carcino-
Surgery is useful for obtaining specimens for his- mas. SCC can also occur in the urethra of female
topathology, restoration of urine flow, and removal dogs. Since all of them are rare, no information
of the neoplasm. During surgical removal special regarding predispositions can be given. Papillomas
care has to be taken to avoid metastasis seeding. can be multiple and either pedunculated or sessile.
Unfortunately, complete resection is often impos- The transitional epithelium covering papillomas
sible, and recurrence is common. Stents can help is well differentiated, but squamous metaplasia
to reduce obstruction and may thus prolong sur- might be seen. Hematuria due to ulcerations is a
vival time. Chemotherapy, often given as a combi- common clinical finding. Notably, urinary blad-
nation therapy with COX inhibitors, can be a der papillomas in dogs can undergo malignant
promising alternative to surgery and often leads transformation.
136 S. Plog

7.1.2.3 Mesenchymal Tumors z Epidemiology and Pathogenesis


All mesenchymal tumors of the urinary bladder Renal lymphoma is the most common renal neo-
are rare in the dog, and most of these are benign plasm of the cat, often being part of a multicentric
fibromas and leiomyomas. Leiomyosarcomas can lymphoma (7 see Chap. 6). The kidney is either
show local invasion, but metastasis is rare. the primary site of neoplastic growth or involved
A special type of mesenchymal tumours is the in metastatic distribution. Involvement of other
botryoid rhabdomyosarcoma which occurs in the organs besides the kidneys at the time of diagnosis
lower urinary tract in young dogs of large breeds, is nearly always present, and in virtually all cases
especially St. Bernard dogs, and is assumed to arise both kidneys are affected even if only unilateral
from embryonal rests of myoblasts. Female dogs enlargement is encountered. Mean age is 8 years,
are overrepresented. These tumors are often located and the majority of cases are FeLV negative. Renal
at the trigone and are thus difficult to resect, similar lymphomas are mainly B cell lymphomas.
to TCC, and they also show infiltrative growth and
a tendency to metastasize. Histopathology is neces- z Clinical Appearance
sary for definitive diagnosis, and strap cells, multi- Signs of renal lymphomas include anorexia,
7 nucleated cells, and sometimes cross striation are weight loss, polyuria, and polydipsia, but since
the hallmarks of the tumor. renal lymphomas can also metastasize to the CNS,
first signs can also include central nervous symp-
z Suggested Reading toms. Palpable unilaterally or bilaterally enlarged
(Budreckis et al. 2015; Cannon and Allstadt 2015; kidney(s) may be detected, and radiography is
Choy and Fidel 2016; Fulkerson and Knapp 2015; useful to confirm the regular or irregular enlarge-
Gerber and Rees 2009; Glickman et  al. 2004; ment. The most distinctive feature in ultrasonog-
Glickman et al. 1989; Hanazono et al. 2014; Hosoya raphy is a hypoechoic rim surrounding the renal
et al. 2013; Kobayashi et al. 2004; Love and Walshaw cortex which is thought to arise from the com-
1989; McMillan et  al. 2011; Mutsaers et  al. 2003; monly seen invasion of lymphoblasts into the renal
Nolan et al. 2015; Patrick et al. 2006; Ramos-Vara capsule and is highly suspicious for renal lympho-
et al. 2003; Reed et al. 2012; Rocha et al. 2000; Sledge mas. An additional change seen in ultrasonogra-
et al. 2015; Valli et al. 1995; Vignoli et al. 2007) phy is loss of the corticomedullary distinction.
Diagnosis should be confirmed by cytology or
histology of tru-cut biopsies.
7.1.3 Feline Renal Tumors
z Cytology and Histopathology
With the exception of renal lymphomas, neoplasms In most cases of renal lymphomas, cytology after
of the feline kidney are rare. It is nonetheless piv- fine needle aspiration under ultrasonographic
otal to distinguish between renal lymphomas and control is diagnostic, showing uniform lympho-
other tumors since therapeutic approaches differ. blastic cells with a high mitotic rate and only few
mature lymphocytes. Histopathology is useful in
7.1.3.1 Feline Renal Lymphomas cases with a more mixed cell population to distin-
guish between renal lymphomas and chronic
interstitial nephritis. Liquor examination in cases
Box 7.4. Feline Renal Lymphomas in Six Facts of CNS involvement might reveal lymphoblasts,
1. Most common renal neoplasm in cats but the absence of neoplastic cells does not rule
2. Diffuse or nodular out a lymphoma.
3. Usually bilateral, even with unilateral
appearance z Therapy and Prognosis
4. Typical ultrasonographic features: The therapy of choice for renal lymphomas is che-
enlargement, loss of corticomedullary motherapy. Nephrectomy is neither necessary nor
distinction, and characteristic curative since at time of diagnosis the involve-
hypoechoic rim ment of other organs is likely. The most com-
5. Therapy of choice: chemotherapy monly used chemotherapeutic approach is the
6. Definitive diagnosis often obtained via COP combination with cyclophosphamide, vin-
cytology cristine, and prednisolone. If CNS involvement is
suspected, an additional treatment with lomustine
Chapter 7 · Urogenital Tract Tumors
137 7
or cytosine arabinoside is useful. The use of doxo- staging system for cats. Survival times of up to 261
rubicin should be avoided since this drug is neph- days have been reported. Other urinary bladder
rotoxic in cats, and special care should be taken tumors are exceptional.
regarding myelosuppressive effects and worsen-
ing of the general condition. z Suggested Reading
Renal lymphomas can respond well to chemo- (Brearley et al. 1986; Osborne et al. 1968; Patnaik
therapy, and survival times of up to 5 years have et al. 2008; Walker et al. 1993; Wilson et al. 2007;
been reported. Nonetheless, the prognosis for Wimberly and Lewis 1979)
renal lymphomas is worse than for other lympho-
mas in the cat and worsens with involvement of
the CNS. Prednisolone administration before che- 7.1.5 Equine Renal Tumors
motherapy is thought to be a negative prognostic
factor. In contrast, the degree of azotemia and/or In general, renal tumors are uncommon in the
renal enlargement should not be noncritically horse, but the most common primary renal tumor
assessed as prognostic factors and should not be is the renal carcinoma (TCC or adenocarcinoma).
the only reason to decide against chemotherapy, Carcinomas are usually found in older horses and
as long as the cat’s general condition is good. have been reported to metastasize. Interestingly,
renal adenomas are not as rare as in other species,
7.1.3.2 Other Renal Tumors in the Cat but are frequently incidental findings, solitary,
Compared with renal lymphomas, other renal and well differentiated.
tumors in cats are rare. The median age is 10 years
and usually only one kidney is affected, so that – z Suggested Reading
in contrast to renal lymphomas – nephrectomy is (Haschek et al. 1981; Rhind et al. 1999; van Mol
often reasonable, but should be combined with and Fransen 1986; Wise et al. 2009)
chemotherapy. The most commonly encountered
renal tumors in the cat besides renal lymphomas
are renal carcinomas and transitional cell tumors. 7.1.6 Equine Urinary Bladder
The clinical and histopathological features are Tumors
similar to those of the respective tumors in the
dog. Benign tumors in the feline kidney are Primary urinary bladder tumors are uncommon
extremely rare. in the horse. Squamous cell carcinomas (SCC) are
most frequently described, followed by transi-
z Suggested Reading tional cell carcinomas (TCC), polyps, rhabdo-
(Gabor et  al. 1998; Henry et  al. 1999; Mooney myosarcomas, and lymphomas. They are often
et  al. 1987; Taylor et  al. 2009; Vail et  al. 1998; ulcerated and can cause hematuria. SCC are histo-
Valdes-Martinez et al. 2007) logically characterized by the lack of transitional
cell areas, and they are less likely to metastasize
than TCC.  Similarly to dogs, the prognosis is
7.1.4 Feline Urinary Bladder Tumors dependent on invasiveness and occurrence of
metastasis.
There is very low prevalence of urinary bladder
tumors in cats, and they account for less than 1 % z Suggested Reading
of all feline neoplasms. If they occur, affected cats (Fischer et  al. 1985; Hurcombe et  al. 2008;
are usually older (12–15 years), and transitional Patterson-Kane et al. 2000; Turnquist et al. 1993;
cell carcinomas are most common, but lymphomas Zantingh et al. 2012)
are also described. Clinical signs are as unspecific
as they are in the dog, and concurrent urinary
tract infections are frequent. In contrast to dogs, 7.1.7 Bovine Renal Tumors
TCC are most commonly seen in non-trigonal
areas. Histopathological features and treatment Renal tumors are rare neoplasms in cattle, and the
options are similar to those in dogs, although a most frequent neoplasms are renal carcinomas.
combination of surgery and chemotherapy is the Cows are more frequently affected than males
most promising approach. There is no detailed which might be rather attributable to the fact that
138 S. Plog

cows predominate in the population than being a fern, plays a major role in the development of
true gender predisposition. In contrast to dogs urinary bladder tumors in cattle. Bracken fern is
and cats, the metastatic rate is low in cattle, but so far the only plant known to cause neoplastic
renal carcinomas are frequently bilateral. disease in animals, and it contains several carci-
Distinctive features in cows are proteinaceous nogenic substances, ptaquiloside being the most
secretions, deposition of hemosiderin, and occur- important. Acute intoxication leads to severe
rence of corpora amylacea. Renal adenomas are hemorrhages in the urinary bladder, but in most
more common in cattle than in dogs and cats and cases ongoing hematuria is caused by the devel-
are usual incidental findings. opment of ulcerated tumors which are often
located in ventral and lateral areas of the
z Suggested Reading urinary bladder, the main sites of contact
(Kelley et al. 1996; Nielsen et al. 1976b) with urine.
A variety of tumors occur in the urinary blad-
der under the influence of bracken fern, and the
7.1.8 Bovine Urinary Bladder most common are papillomas, fibromas, heman-
7 Tumors giomas, hemangiosarcomas, and carcinomas.
More than one type of neoplasm or mixed tumors
There is a wide variety of neoplastic disease in the can occur together. Local invasion is often seen in
urinary bladder of cattle, accounting for eco- malignant tumors, and metastasis can be observed
nomic losses in some areas of the world. Although in up to 10 %. Bracken fern also drives the pro-
they can be classified according to the WHO clas- gression from benign urinary bladder tumors like
sification scheme of urinary bladder tumors in papillomas to invasive squamous cell carcinomas.
humans, from an economic point of view, their Furthermore, chronic bracken fern intoxication
pathogenesis and outcome are more important causes immunosuppression and promotes chronic
than their subclassification. The most frequently papillomatosis, which is an important cofactor in
observed symptom is hematuria, and the complex neoplastic transformation. There are several dif-
of various urinary bladder neoplasms in cattle is ferent bovine papillomavirus (BPV) types known
well known as enzootic hematuria. worldwide, but their importance as cocarcinogens
varies, dependent on the tissue. Concerning neo-
7.1.8.1 Enzootic Hematuria plasms in the urinary bladder, BPV-1, BPV-2, and
BPV-13 are known to play an important role, and
BPV-2 has also been found in the urothelium of
Box 7.5. Enzootic Hematuria in Six Facts healthy cattle. Many urinary bladder tumors
1. Commonly seen in areas in which express DNA encoding the BPV-2 E5 oncoprotein
bracken fern is common which causes neoplastic transformation by several
2. Economically important disease in cattle molecular ways.
in certain areas of the world The occurrence of neoplastic disease due to
3. Development of a variety of urinary bracken fern ingestion in cattle has also been
bladder tumors linked to a high incidence of gastrointestinal
4. Ptaquiloside of bracken fern as tumors in humans, occurring mainly in areas in
carcinogenic substance; BPV infection which bracken fern is common. Worldwide
is cocarcinogenic research is currently focusing on possible routes
5. Hematuria often the only clinical sign of intoxication (including consumption of con-
6. Ptaquiloside ingestion as possible threat taminated milk) and possible consequences for
for people people.

z Clinical Appearance
z Epidemiology and Pathogenesis Hematuria is the most common – but very unspe-
Although this syndrome is seen worldwide, the cific – clinical sign of chronic bracken fern toxic-
incidence is varying and there are areas of the ity. This can also be caused by acute bracken fern
world in which up to 90 % of cattle can be intoxication or urocystitis which is seen commonly
affected. The ingestion of ferns, especially bracken in concurrence with neoplastic growth.
Chapter 7 · Urogenital Tract Tumors
139 7
z Histopathology and Special Stains z Epidemiology and Pathogenesis
On the basis of their growth pattern, tumors can Epithelial ovarian tumors arise from the outer sur-
be grouped into four distinct categories: flat, exo- face of the ovary, and the majority is malignant.
phytic or papillary, endophytic, and invasive. It is They can be divided into several histological sub-
important to note that hyperplastic and metaplas- types. Metastases, especially seeding metastasis
tic changes often develop into malignant tumors. into the abdominal cavity and metastasis to the
Immunohistochemical uroplakin intensity has lymph nodes, liver, or omentum, are frequent.
been reported to decrease with growing malig- Epithelial ovarian tumors are more commonly
nancy of the urinary bladder tumors. bilateral than other ovarian tumors. Benign vari-
ants include rete adenomas, papillary adenomas,
z Therapy and cystadenomas. Epithelial ovarian tumors
Since enzootic hematuria is incurable, strong efforts mainly develop in older dogs (mean age 10 years).
are made to prevent the occurrence of enzootic Pointers seem to be predisposed.
hematuria rather than to treat already existing neo-
plasms in cattle. One approach is the development z Clinical Appearance
of inactivated and saponized BPV-2 vaccines. The main clinical signs result from the large pal-
pable abdominal mass that causes displacement of
z Suggested Reading the abdominal organs. Hormonal dysfunction is
(Ambrosio et  al. 2001; Castillo et  al. 1998; Cota not to be expected with epithelial tumors, but
et  al. 2014; Hopkins 1986; Pires et  al. 2010; hypercalcemia due to the production of PTH-rp
Pathania et al. 2011; Pathania et al. 2012; Roperto (parathyroid hormone-related peptide) has
et al. 2010; Sharma et al. 2013; Xu 1992) been observed with ovarian adenocarcinomas.
Ultrasonography is of use for the definitive diag-
nosis as well as for detection of metastases and
7.2 Tumors of the Female Genital uterine abnormalities. Malignant tumors appear
Tract mainly solid whereas benign tumors are often cys-
tic. Thoracic radiographs may also be useful for
7.2.1 Ovarian Tumors excluding metastatic spread.

z Cytology and Histopathology


7.2.1.1 Canine Ovarian Tumors
Because of the high risk of tumor seeding, transab-
of the Dog
dominal aspiration is not indicated. Abdominal
Ovarian tumors are rare in dogs with a prevalence fluid may contain malignant epithelial tumor cells
of 0.5–1.2 % worldwide, most likely due to the and can be useful for diagnosis. Histopathologically,
practice of ovariohysterectomy in most areas of the tumors can be classified into subtypes, but
the world. The most common ovarian tumors in these are without any prognostic consequences.
the dog are epithelial tumors. The prognosis is not Differentiation between adenomas and adenocar-
dependent on histological type but on complete cinomas is based on extension and invasion,
excision and metastatic growth. mitotic index, and size. Immunohistochemically,
epithelial ovarian tumors express cytokeratin,
Canine Epithelial Ovarian Tumors
vimentin, HBME-1, and desmin, but not inhibin-α
which is a specific marker for granulosa-theca cell
Box 7.6. Epithelial Tumors of the Canine tumors and can be used to distinguish these
Ovary in Four Facts two tumors.
1. Most common ovarian tumor in the bitch
2. Benign and malignant tumors, the latter z Therapy and Prognosis
being prone to intra-abdominal The therapy of choice for epithelial ovarian
metastasis tumors – as for any other ovarian tumor – is com-
3. Clinical signs often unspecific plete ovariohysterectomy. Bloodwork, especially
4. Ovariohysterectomy is the therapy of the control of thrombocytopenia, is necessary
choice prior to surgery because of possible myelosuppres-
sive effects due to estrogen production. Exclusion
140 S. Plog

of abdominal seeding metastases should follow mesenchymal tumors like hemangiosarcomas.


ovariohysterectomy. The prognosis is generally Although rarely seen, the ovaries can also be the
good in the absence of metastases. site of metastasis.

Canine Granulosa-Theca Cell Tumors z Suggested Reading


The second most common tumor of the canine (Akihara et  al. 2007; Banco et  al. 2011; Buijtels
ovary is the granulosa-theca cell tumor (or granu- et al. 2010; Diez-Bru et al. 1998; Hori et al. 2006;
losa cell tumor), belonging to the group of sex McCandlish et  al. 1979; Nielsen et  al. 1976a;
cord-stromal tumors. They arise from the gonadal Patnaik and Greenlee 1987; Riccardi et  al. 2007;
stroma and can produce a variety of hormones Rota et al. 2013)
which are often responsible for clinical signs like
vulvar enlargement, discharge, persistent estrus or 7.2.1.2 Feline Ovarian Tumors
pancytopenia (due to estrogen production), or The most common tumors in the feline ovary are
cystic endometrial hyperplasia and pyometra (due sex cord-stromal tumors, and the most frequently
to progesterone production). About 20 % of granu- observed is the granulosa-theca cell tumor.
7 losa-theca cell tumors in the dog are malignant.
When metastases occur, they are frequently to the 7.2.1.3 Feline Granulosa-Theca Cell
lymph nodes, pancreas, or lungs. Abdominal seed- Tumor
ing is not as common as with epithelial tumors, but
does occur. English Bulldogs, Boston Terriers, and
German Shepherds are described to be predis-
Box 7.7. Feline Granulosa-Theca Cell Tumors
posed. An enhanced risk is reported when residual
in Five Facts
ovarian tissue is present after insufficient ovario-
1. Most common ovarian tumor in cats,
hysterectomy. Immunohistochemistry with
50 % malignant
inhibin-α can be used to confirm the diagnosis.
2. Clinical signs often associated with
Besides specific hormonal effects, clinical signs are
hormone production
unspecific, and ovariohysterectomy is the therapy
3. Some metastasize widely
of choice.
4. Transabdominal aspiration or biopsy
Canine Teratomas and Dysgerminomas not indicated, but abdominal effusion
can be useful for diagnosis
Teratomas and dysgerminomas arise from pri-
5. Therapy of choice: ovariohysterectomy
mordial germ cells of the ovary and are often
accompanied by uterine changes like pyometra or
endometrial hyperplasia as well as cystic changes in
the contralateral ovary. Dysgerminomas are usually z Epidemiology and Pathogenesis
unilateral, and metastatic rate is low (approxi- The granulosa-theca cell tumor is the most fre-
mately 30 %). They are comprised of a uniform cell quent ovarian tumor in the cat. 50  % of them
population with germ cell appearance, and they exhibit malignant behavior. Similar to dogs, they
usually do not form cysts. Teratomas are composed are able to produce a variety of hormones which
of cell populations of at least two germ cell layers, are often responsible for clinical signs. They are
often including a variety of tissues like muscle, often unilateral. Metastases can be widespread
hair, adipose tissue, nervous tissue, etc. Malignant including the peritoneum and omentum, lumbar
variants are not uncommon, and metastasis, lymph nodes, diaphragm, liver, kidney, spleen,
mainly within the abdominal cavity, is reported in and lung.
up to 50 % of cases. Teratomas may also be seen in
younger bitches. Ovariohysterectomy is the thera- z Clinical Appearance
peutic method of choice. Similar to the dog, clinical signs are rather unspecific
but can be dominated by the hormones produced
Other Tumors of the Canine Ovary by the tumor (7 see section “Canine Granulosa-
Other less common tumors of the ovary in the Theca Cell Tumors”). The space-occupying mass in
bitch include thecomas and luteomas which are the abdomen can also lead to lethargy, vomiting,
benign sex cord-stromal tumors as well as rare and ascites.
Chapter 7 · Urogenital Tract Tumors
141 7
z Cytology and Histopathology after removal of the neoplastic ovary. Cyst forma-
Because of the high risk of tumor seeding, tion and hemorrhage are common. Surgery of the
transabdominal aspiration is not indicated. ovary is the therapy of choice. Other tumors,
Abdominal fluid can contain malignant epithe- including epithelial tumors, tumors of germ cells,
lial tumor cells and can be used for diagnostic and mesenchymal tumors, are rarely found in the
purposes. Histologically, cells in these tumors equine ovary.
may resemble normal follicles, but the histo-
logic arrangement is usually varied, and they z Suggested Reading
often include gland-like or rosette patterns. In (Bailey et  al. 2002; McCue 1992; McCue et  al.
some well-differentiated tumors, Call-Exner 2006; Norris et al. 1968; Stabenfeldt et al. 1979)
bodies composed of protein globules sur-
rounded by tumor cells can be detected histo- 7.2.1.4 Bovine Ovarian Tumors
logically, but in most cases the arrangement of The most important ovarian tumor of cows is the
cells is more diffuse. granulosa-theca cell tumor. These tumors in cat-
tle are mostly benign and unilateral, but metasta-
z Therapy and Prognosis ses can occur. A predisposition is known for
The therapy of choice is complete ovariohysterec- daughters of affected cows. After the unilateral
tomy, and careful exploration of the abdominal tumor has been removed, a similar tumor devel-
cavity for metastasis is crucial. Prognosis is depen- ops in the contralateral ovary is seen in some
dent on complete removal and presence or absence cases. In early stages, a well-differentiated form
of metastases. with the presence of Call-Exner bodies com-
posed of protein globules surrounded by tumor
Other Feline Ovarian Tumors cells may be present. Due to the hormonal activ-
The second most common ovarian tumor in cats ity of the tumor, some affected cows show nym-
is the dysgerminoma, accounting for approxi- phomania. Tumors of the germ cells occur in
mately 15 % of ovarian tumors. They are charac- cattle but are rare. Surgery is the treatment of
terized by their often large size, bilateral growth, choice. Only a few cases of epithelial ovarian
and metastatic spread in up to 33 % of cases. tumors in cattle have been reported. Vascular
They usually do not show cyst formation. hamartomas might be present in the ovaries of
Teratomas and epithelial ovarian tumors are rare, cattle and should not be confused with true neo-
and mesenchymal tumors are obviously not of plasms. A distinctive feature of this species is the
importance in the feline ovary. The ovary can be occurrence of neoplastic cells of malignant lym-
the site of metastasis of malignant lymphomas phomas in the corpora lutea.
(7 see Chap. 6) in cats that are affected by mul-
ticentric lymphomas. z Suggested Reading
(Dobson et  al. 2013; El-Sheikh Ali et  al. 2013;
z Suggested Reading Garcia Iglesias et  al. 1991; MacLachlan 1987;
(Cellio and Degner 2000; Gelberg and McEntee Meganck et al. 2011)
1985)

Equine Ovarian Tumors 7.2.2 Uterine and Vaginal Tumors


Granulosa-theca cell tumors are the most common
ovarian tumors in the mare. Similar to other spe-
cies, they can produce estrogen and progesterone, 7.2.2.1 Canine Uterine and Vaginal
accounting for some of the clinical signs. In addi- Tumors
tion, the granulosa-theca cell tumors in horses In the dog, the most common tumors in the uterus
frequently produce testosterone, and male behav- and vagina are leiomyomas. Uterine tumors in dogs
ior can be observed in mares with high blood tes- are not as common as vaginal tumors. Middle-aged
tosterone levels. The tumor is often unilateral, and to older dogs are often affected. Tumors can also be
atrophy of the contralateral ovary is usually seen, found at uterus stumps after incomplete ovariohys-
which might be due to inhibin-α production. terectomy. Pregnancies do not protect from the
Function of the contralateral ovary can be restored development of uterine tumors.
142 S. Plog

Leiomyomas/Leiomyosarcomas ing within the vaginal wall, causing coprostasis


and swelling of the perineal region. Vaginal and
rectal palpation, vaginoscopic examination, and
Box 7.8. Canine Leiomyomas/Leiomyosarcomas cytology might be useful. Since the presence of
in Four Facts the malignant variant cannot be ruled out grossly,
1. Arise from smooth muscle of the uterus ultrasonographic examination and thoracic radi-
or vagina ography are useful to exclude metastatic spread.
2. Vaginal tumors more common than Ultrasonography of the uterine neoplasm is often
uterine variable. In vaginal leiomyoma, degenerative
3. Most often benign changes can lead to liquefaction and cyst forma-
4. Ovariohysterectomy is usually curative, tion. In contrast to vaginal prolapse, which is an
but leiomyosarcomas can metastasize important differential, tumors may be poorly cir-
widely cumscribed, are often located in the cranial por-
tion of the vagina, and might be ulcerated and
cause bloody discharge.
z Epidemiology and Pathogenesis
7 Leiomyomas arise from smooth muscle cells of z Cytology and Histopathology
the uterus or vagina, and although the malignant Although smooth muscle cells with elongated
variant (leiomyosarcoma) occurs, the benign cytoplasm and blunt-ended (cigar-shaped) nuclei
form is far more common. They occur focally or might be detectable in cytology, histopathology is
at multiple sites. They usually occur in middle- inevitable for assessing complete excision and
aged to older dogs without breed predisposition. dignity. Leiomyomas are composed of spindle-
Leiomyomas are nonrecurring after surgery, non- shaped cells arranged in streams, bundles, or
metastatic, noninvasive, and slowly growing. whorls with blunt-ended nuclei, indistinct cell
They cannot be distinguished macroscopically borders, and eosinophilic fibrillary cytoplasm,
from their malignant counterpart. For vaginal with abundant stroma. The distinction between
leiomyosarcomas, wide metastasis has been leiomyomas and leiomyosarcomas is basically
reported. Vaginal leiomyomas are often hormone made on infiltrative growth and polymorphism of
dependent, and they commonly occur together the cells  – even in the malignant variant, the
with ovarian cysts or granulosa-theca cell tumors, mitotic rate may be low. Immunohistochemistry
endometrial or mammary hyperplasia, or mam- for smooth muscle actin (SMA) can be useful for
mary neoplasm. the definitive diagnosis.
Multifocal leiomyomas can occasionally occur
together with renal cystadenomas and nodular z Therapy and Prognosis
dermatofibrosis in German Shepherd dogs. Complete excision of the neoplastic mass is rec-
ommended for vaginal and uterine leiomyomas,
z Clinical Appearance
and ovariohysterectomy is the therapy of choice
Uterine leiomyomas are often incidental findings for the latter. Subtotal vaginectomy might be a
because they grow slowly and do not invade or possibility in some cases. Surgery is curative for
metastasize. However, they can reach consider- benign tumors and usually – if complete – also for
able size and cause symptoms due to abdominal leiomyosarcomas. The presence of metastasis
distension. Unspecific clinical signs like polydip- worsens the prognosis, and the patient has to be
sia/polyuria, vomiting, and weight loss may checked for local recurrence on a regular base.
occur, as well as abnormal estrus cycles and vagi-
nal discharge. Leiomyosarcomas can appear as Other Uterine and Vaginal Tumors
glandular cystic hyperplasia in ultrasonography. Fibrosarcomas, hemangiosarcomas, and lympho-
They have a glassy, white, or fleshy appearance. mas have been reported in the uterus of dogs,
Vaginal leiomyomas often protrude from the although they are rare, similar to benign mesen-
vulva, and vaginal bleeding, discharge, or chymal tumors. Epithelial tumors are equally rare,
dysuria/hematuria can accompany this finding. but if they occur they are mostly malignant. A
Distinction is made between intra- and extralu- variety of mesenchymal tumors can be seen in the
minal vaginal leiomyomas, the latter often grow- vagina and vulva of dogs, including lipoma in
Chapter 7 · Urogenital Tract Tumors
143 7
young dogs. Besides leiomyoma and leiomyosar- z Cytology and Histopathology
comas, the most common tumors in the vagina Although cytology can be helpful in confirming
and vulva of dogs are fibromas, fibroleiomyomas, the suspected diagnosis, histopathological exami-
and polyps. Epithelial tumors occur rarely. nation of the excised neoplasm is needed for
Complete excision and histopathology are needed definitive diagnosis and assessing invasiveness
for the definitive diagnosis, and metastasis should and surgical margins. Immunohistochemically,
be ruled out in case of suspected malignancy. these tumors routinely express cytokeratin, COX-
Complete surgical excision/ovariohysterectomy is 2, E-cadherin, and β-catenin.
the therapy of choice. In case of extraluminal
masses, a dorsal episiotomy can be useful. z Therapy and Prognosis
Ovariohysterectomy is recommended for the ther-
z Suggested Reading apy of uterine carcinomas. The prognosis largely
(Cave et  al. 2002; Manothaiudom and Johnston depends on the presence of metastasis. Most uter-
1991; Murphy et  al. 1994; Nelissen and White ine adenocarcinomas have already metastasized
2012; Patsikas et  al. 2014; Thacher and Bradley at the time of diagnosis. Chemotherapeutic
1983; Tsioli et al. 2011; Weissman et al. 2013) approaches are not well established yet.

7.2.2.2Feline Uterine and Vaginal Mesenchymal and Metastatic Tumors


Tumors In the feline uterus, mesenchymal tumors, includ-
Feline Uterine Adenocarcinomas ing leiomyosarcomas, rhabdomyosarcomas, fibro-
sarcomas, and muellerian tumors, have been
reported, as well as their benign counterparts
Box 7.9. Feline Uterine Adenocarcinomas in (leiomyoma, fibroma). Lipomas and hemangio-
Four Facts mas also occur. The uterus of cats can be involved
1. Most common tumor in the feline uterus in multicentric tumor spread of malignant lym-
2. Can metastasize widely, including the phoma (7 see Chap. 6). All of these primary
CNS, abdominal organs, and lung tumors are rare compared to uterine adenocarci-
3. Immunohistochemical markers include nomas, and the treatment of choice is always
COX-2 and cytokeratin complete ovariohysterectomy.
4. Ovariohysterectomy is the therapy of In contrast, the most common vaginal tumor in
choice; prognosis depends on metastatic cats is the leiomyoma, similar to the situation in
spread dogs, although vaginal tumors in the cat are gen-
erally rare. They occur most commonly in older
queens. Diagnostic approaches, therapy, and
z Epidemiology and Pathogenesis prognosis are similar to vaginal leiomyomas in
The most common tumor in the feline uterus is dogs (7 see Sect. 7.2.2.1).
the adenocarcinoma arising from the uterine
gland epithelium, which can also arise in the uter- z Suggested Reading
ine stump. Widespread metastases into nearly (Anderson and Pratschke 2011; Cooper et  al.
every organ have been reported. 2006; Gil da Costa et al. 2009; Miller et al. 2003;
Sato et al. 2007)
z Clinical Appearance
Similar to uterine tumors in dogs, clinical signs 7.2.2.3 Equine Uterine and Vaginal
are often nonspecific, including inappetence, poly- Tumors
dipsia, polyuria, or vomiting. Abdominal disten- Uterine tumors are very rare in horses. Of these,
sion and other signs associated with space leiomyomas appear to be the most common. Case
occupation can be observed as well. Complete reports also describe a variety of other mesenchy-
staging including radiography of the thorax and mal tumors. Uterine leiomyomas in the mare are
abdominal ultrasonography is recommended either pedunculated or intramural. Clinical signs
because of a high metastatic risk. Since metastatic and diagnostic features are comparable to those of
spread can also involve the brain, central nervous the bitch and the queen. Leiomyomas usually
signs may accompany other clinical symptoms. have a good prognosis after complete removal, but
144 S. Plog

the prognosis for leiomyosarcomas is guarded.


Epithelial tumors are exceptional. Box 7.10. Canine Testicular Tumors in Five
Facts
z Suggested Reading 1. Most common testicular tumors in the
(Broome et  al. 1992; Govaere et  al. 2011; dog are seminomas, Sertoli cell tumors,
Hurcombe et al. 2008) and interstitial cell tumors
2. Adult to old dogs most commonly
7.2.2.4 Bovine Uterine and Vaginal affected, cryptorchidism as an important
Tumors predisposition
Carcinomas are the most frequent tumors of the 3. Sertoli cell tumors and interstitial cell
bovine uterus, and conversely, cows seem to be tumors cause feminization and
affected by uterine carcinomas more frequently myelosuppression
than other species. The tumors can be single or 4. Metastatic spread reported for up to
multiple and often show a strong desmoplastic 15 % of Sertoli cell tumors, also seen in
reaction which results in a firm and contracted seminomas
7 appearance. Metastasis is not uncommon, and the 5. Castration is always the therapy of
regional lymph nodes and the lung are usually choice, regardless of the type of tumor
involved. Leiomyomas also occur and resemble
their counterparts in the bitch and queen with
regard to appearance and prognosis. The uterus z Epidemiology and Pathogenesis
can be a site of metastatic spread of malignant Testicular tumors are common in the dog, with up
lymphomas as well. to 17 % of a population affected. The main impor-
Vaginal tumors are not common in cows, but tant types are seminomas, Sertoli cell tumors, and
fibropapillomas in the vulva have been described interstitial cell tumors (syn. Leydig cell tumors),
and are thought to be caused by bovine papilloma- but mixed germ cell sex cord-stromal tumors
virus (BPV)-1 infection. Large nuclei, prominent (neoplastic Sertoli and germ cells) also occur.
bizarre nucleoli, and high mitotic rate are common Most testicular tumors in the dog are benign,
and should not be interpreted as signs of malig- although malignant Sertoli cell tumors and semi-
nancy. Desmoplasia and surface ulceration can nomas have been reported. The only way to con-
occur. Vulvar fibropapillomas usually spontane- firm malignancy is detection of metastasis. Mature
ously regress within 6 months. and old animals are usually affected, and the right
testicle is more often affected than the left.
z Suggested Reading Seminomas are derived from cells of the sper-
(Elsinghorst et al. 1984; Elzein et al. 1991; Garcia- matogenic population, thus resembling dysgermi-
Iglesias et al. 1995) nomas in the ovary. Sertoli cell tumors are of
gonadostromal origin and are comparable with
granulosa-theca cell tumors in bitches. Interstitial
7.3 Tumors of the Male Genital cell tumors are derived from the endocrine
Tract gonadostromal cell population. Mixed tumors
also occur. Teratomas are very rare in the dog.
7.3.1 Testicular Tumors Cryptorchidism is a risk factor especially for the
development of Sertoli cell tumors and semino-
7.3.1.1 Canine Testicular Tumors mas. Interstitial tumors are often bilateral and/or
Testicular tumors are common in dogs, and the multiple. Adenomas/adenocarcinomas arising
cryptorchid testis is especially predisposed for from the rete testis are rare.
developing neoplasms. More than one type of
tumor can occur together in one testis. z Clinical Appearance
Metastatic risk depends on the type of tumor. The main clinical finding in non-cryptorchid
Dogs often present clinically with symptoms dogs is unilateral enlargement of the testis, often
ascribed to hormonal activity of the tumor, espe- accompanied by atrophy of the contralateral tes-
cially in the case of interstitial cell tumors and tis. Clinical signs suspicious for testicular tumors
Sertoli cell tumors. include symptoms that are caused by hormonal
Chapter 7 · Urogenital Tract Tumors
145 7
imbalances in both cryptorchid and non- Hypertrophic osteopathy has also been described
cryptorchid dogs. Feminization including vulvar in cases with testicular tumors.
swelling, gynecomastia and galactorrhea, bilat- Metastasis is mainly reported for Sertoli cell
eral alopecia (. Fig.  7.2), and testicular atrophy tumors, with up to 15 % of neoplasms metastasiz-
are often seen, and high estradiol concentration ing to regional lymph nodes, whereas seminomas
in the blood can lead to bone marrow depletion, metastasize more rarely but often widespread,
which is a serious consequence. Feminization, including the lymph nodes, lung, kidney, and
particularly common in Sertoli cell tumors of unusual sites like the brain, eye, or skin. Sertoli cell
cryptorchid testes, tends to be reversible after tumors can reach considerable size, whereas inter-
removal of the testis, but the bone marrow deple- stitial tumors are mainly small and tend to be
tion may be permanent. Squamous metaplasia of multiple. Ectopic or residual testicular tissue might
the prostate can lead to symptoms of prostatic also become the origin of neoplastic growth  –
lesions, thus thorough examination of the testis thus, testicular tumors cannot be excluded in cas-
is necessary in all cases with prostatic symptoms. trated dogs. Sertoli cell tumors may invade local
Inhibin production with inhibiting effects on LH veins and lymphatics, causing enlargement of the
and FSH production has also been described in scrotal area.
Sertoli cell tumors, leading to reduced testoster- Ultrasonography is recommended for all cases
one production. Interstitial cell tumors are with suspected neoplastic growth in cryptorchid
capable of producing testosterone, and hyperan- testes and is also useful for the exclusion of metas-
drogenism with dominant behavior in affected tases. The presumptive diagnosis should be con-
dogs has been described, but elevated estrogen firmed by fine needle aspiration and cytology or
levels are observed more often. Perianal gland histopathology. Advanced cytopenia due to bone
and tail gland hyperplasia as well as prostatic marrow suppression can lead to severe clinical
enlargement can accompany interstitial cell symptoms, and bone marrow cytology is recom-
tumors. There is only one description of hor- mended before castration.
monal imbalance in a patient with seminoma. Gross morphology is rather distinctive in many
They usually do not produce hormones. cases of testicular tumors. Interstitial cell tumors

. Fig. 7.2 Left: Sertoli cell tumor in a 14-year-old dog. Note the bilateral alopecia, hyperplasia of the mammary gland,
and enlargement and hyperkeratosis of the teats, common effects caused by hormone production. Right: Sertoli cell
tumor of a cryptorchid testis with typical fibrous appearance (With permission of (left) Archive of the Institute for
Veterinary Pathology and (right) R. Klopfleisch, Freie Universität Berlin, Germany)
146 S. Plog

are often yellow and show multiple areas of hem- medicine. The prognosis in general is good, but
orrhage and/or cysts. They often cause atrophy of can be affected by metastatic spread or myelosup-
the surrounding tissue. Seminomas tend to be pression.
white and soft, whereas Sertoli cell tumors are whit-
ish and produce collagen, giving them a tough des- z Suggested Reading
moplastic appearance (. Fig. 7.2). (Banco et al. 2015; Grieco et al. 2008; Hayes et al.
1985; Hogenesch et al. 1987; Johnston et al. 1991;
z Cytology and Histopathology Liao et  al. 2009; Lucas et  al. 2012; Masserdotti
Fine needle aspiration and cytology can confirm et al. 2005; Mischke et al. 2002; Quartuccio et al.
the presumptive diagnosis of testicular tumors, 2012; Sanpera et  al. 2002; Spugnini et  al. 2000;
but since castration is the therapy of choice, cytol- Weaver 1983; Yu et al. 2009)
ogy is often not necessary. There are no cytological
or histological markers of malignancy. Cytological 7.3.1.2 Feline Testicular Tumors
appearance is comparable to the histologic find- Testicular tumors have only sporadically been
ings. Cells of interstitial cell tumors are round to described in the cat, which might be associated
7 polyhedral, with abundant, granular, or finely vac- with the fact that most male cats are castrated at
uolated cytoplasm which can contain yellow pig- an early age. Sertoli cell tumors, seminomas,
ment. They may have a more mesenchymal interstitial cell tumors, and mixed tumors have
appearance, but stroma is always scant and mitotic been diagnosed. Clinical appearance, histology,
rate is low. A specific feature of interstitial cell and prognosis are comparable to their canine
tumors is the presence of intranuclear, PAS- counterparts. Interstitial cell tumors may be seen
positive cytoplasmic invaginations. Seminomas are in young cats. Castration is usually curative.
divided into intratubular or diffuse forms and are
composed of sheets of polyhedral cells with large z Suggested Reading
nuclei and scant, often deeply basophilic, some- (Miller et  al. 2007; Rosen and Carpenter 1993;
times acidophilic cytoplasm. Special features of Tucker and Smith 2008)
seminomas include accumulations of CD8 lym-
phocytes and the presence of multinucleated cells, 7.3.1.3 Equine Testicular Tumors
and they stain positive for vimentin and negative The most common testicular tumors of the adult to
for NSE. Mitoses and individual cell necrosis can aged horse are seminomas which can become very
be found in seminomas. Sertoli cell tumors can large and metastasize widely. Notably, the most
also be divided into intratubular and diffuse types, common tumors in the young horse are testicular
and the specific feature is a high amount of stroma. teratomas, which rarely occur in other species. In
Neoplastic cells can resemble normal palisading horses, teratomas are usually benign and they occur
Sertoli cells arranged in tubules in highly differen- in both scrotal and cryptorchid testes. They usually
tiated neoplasms, in which large lipid droplets may do not exceed 10 cm in diameter and can be com-
be present in the cytoplasm as well. Poorly differ- posed of a variety of tissues including hair, adipose
entiated Sertoli cell tumors often lose their ability or sebaceous tissue, or bone. Interstitial cell tumors
to palisade and show small intracytoplasmic lipid virtually occur in the cryptorchid testis only, and
droplets. Sertoli cell tumors are the only testicular they are either well differentiated or contain spin-
neoplasms positive for NSE. dle-shaped neoplastic cells. There are only single
reports of Sertoli cell tumors in the stallion.
z Therapy and Prognosis Hormonally induced changes have not been
The therapy of choice is castration. In case of infil- described in stallions in detail  – thus, the most
trative growth, resection of the scrotum might be prominent clinical signs are enlargement of the tes-
necessary. Abdominal tumors might be highly tis or symptoms ascribed to a mass effect in the
vascularized and caution is advised when remov- abdominal cavity. Surgery is the therapy of choice.
ing these tumors. The regional lymph nodes have
to be checked for metastases and need to be z Suggested Reading
resected if necessary. Surgery is usually curative. (Brinsko 1998; Duncan 1998; Gelberg and
Chemotherapy can be of use in metastatic tumors, McEntee 1987; Govaere et  al. 2010; Hunt et  al.
although there are not many reports in veterinary 1990; De Lange et al. 2015; Pollock et al. 2002)
Chapter 7 · Urogenital Tract Tumors
147 7
7.3.1.4 Bovine Testicular Tumors of the high incidence of BPH compared with rare
Testicular tumors are rare in cattle. Interstitial cell cases of prostatic adenocarcinomas, it is question-
tumors have been reported most often, and there able whether the development of a prostatic neo-
is a comparable higher prevalence in old plasm is a multistage process. Prostatic carcinomas
Guernseys. Sertoli cell tumors also occur, and they usually occur independently of testicular tumors.
can be found in young or even newborn bulls,
pointing toward a role of genetic factors. z Clinical Appearance
Although clinical signs are often those of prostatic
z Suggested Reading enlargement which can also been seen in prostatic
(Jensen et al. 2008; López et al. 1994) hyperplasia, lameness and pain in the pelvis
should raise suspicion for a neoplastic disease,
since metastasis to the bones (vertebra, bones of
7.3.2 Prostatic Tumors the pelvis, long bones) is common. Emaciation,
hematuria, stranguria, polydipsia, and polyuria
7.3.2.1 Canine Prostatic Tumors have also been described. Compared to benign
prostate hyperplasia, prostatic carcinomas tend to
be more irregular in shape and firmer at palpation
Box 7.11. Canine Prostatic Tumors in Four
and sometimes contain ossifying or mineralized
Facts
areas. Firm adhesion of the prostate to the pelvis
1. Rare tumors in dogs; benign prostate may be seen, and metastases also occur in the
hyperplasia is far more common ribs, scapula, and digits. Cytology or histopathol-
2. More than 80 % of prostate carcinomas ogy is  necessary to confirm the diagnosis. Since
with metastases at the time of diagnosis, detection of neoplastic cells in the ejaculate is not
bone involvement common evidentiary, fine needle aspiration under ultraso-
3. Clinical symptoms unspecific, cytology nography or biopsies are more useful, but care has
or histopathology needed to be taken to avoid tumor seeding. Aspiration
4. Surgery often the only possible biopsy via catheter is common and has a specific-
therapeutic approach but seldom ity of 98 %. Radiography is helpful for the detec-
curative; combination with tion of lung or bone metastasis. Enlargement of
chemotherapy is possible, but with the sublumbar lymph nodes and mineralized foci in
severe side effects the prostate is nearly pathognomonic for prostatic
carcinomas in castrated dogs, but not in uncas-
trated dogs. Sonography is not useful to distin-
guish between prostatic tumors and nonneoplastic
z Epidemiology and Pathogenesis disease but mineralization, asymmetry, and infil-
Tumors of the prostate do not often occur in dogs, trative growth point toward neoplasm. Prostate-
and benign prostatic hyperplasia (BPH) is much specific tumor markers are not useful for tumor
more common in cases of enlarged prostate. diagnostics in the dog.
Prostate carcinomas most often occur in older
animals although dogs as young as 4 years can be z Cytology and Histopathology
affected. Large breeds tend to be overrepresented. Up to 75 % of cytological diagnoses are concor-
Adenocarcinomas are most common, whereas dant with histopathology, and in cases where
transitional cell carcinomas, squamous cell carci- cytology confirms the presence of a carcinoma,
nomas, adenomas, and mesenchymal tumors additional histopathological analysis is neither
occur much less frequently. Some authors describe necessary nor recommended. Prostatic carcinoma
an increased risk for castrated dogs. Bouvier des cells are usually heterogenic, and this is the most
Flandres dogs are significantly overrepresented in suspicious feature, with neoplasms showing evi-
some studies. Prostatic adenocarcinomas in dogs dence of high anisocytosis. Inflammatory cells in
derive from basal cells of the ductular epithelium. cytology do not rule out neoplastic growth. Some
Mixed variants have also been reported, and as tumor cells exhibit a signet-ring pattern. If they
distinction is sometimes difficult, the use of the form well-differentiated acini, mucus can often be
term prostate carcinoma is recommended. Because detected in their lumen. Up to 50 % of prostatic
148 S. Plog

tumors show a mixed morphology with a variety of lameness, and stiff gait. Resection of the tumor
differentiation stages, including urothelial, squa- seems to result in longer survival time with fewer
moid, sarcomatoid, or glandular cells. complications compared to dogs, but too few
cases have been described to allow for a general
z Therapy and Prognosis statement. Chemotherapeutic approaches with
Prostatectomy is a possible therapy in prostate doxorubicin and cyclophosphamide have also
carcinomas but can be difficult due to high inva- been described in the cat, with survival times of
siveness, metastatic spread, and postoperative com- up to 10 months.
plications and is seldom curative. Furthermore,
incontinence is a common sequel of prostatec- z Suggested Reading
tomy. Incomplete resection of the prostate com- (Caney et  al. 1998; Hubbard et  al. 1990; LeRoy
bined with chemotherapy prevents from and Lech 2004; Zambelli et al. 2010)
incontinence in some cases, but may result in
serious life-threatening side effects. Prognosis is 7.3.2.3 Prostatic Tumors in Other
thus always guarded or poor. In up to 80 % of Species
7 cases, metastatic spread is present at the time of Prostatic tumors are not of relevance in other spe-
diagnosis. Survival time without surgery or che- cies.
motherapy can be as short as 30 days after diag-
nosis. Chemotherapeutic approaches have not
been regularly used, and outcome is not predict- 7.3.3 Penile Tumors
able. A combination of gemcitabine and carbopl-
atin as well as treatment with mitoxantrone alone 7.3.3.1 Equine Penile Squamous Cell
has been described, resulting in longer survival Carcinomas
times. Dogs treated with piroxicam and carpro-
fen had longer survival times than untreated dogs
in one study. NSAIDs alone can result in signifi-
Box 7.12. Equine Penile Squamous Cell
cant improvement. Radiotherapy bears the risk of
Tumors in Four Facts
a variety of severe side effects, but in cases with-
out side effects, survival time can be increased up 1. Most common penile or preputial tumor
to 12 months. In cases of urethral obstruction, a in the horse
palliative approach is catheterization or stent 2. Characteristics: cauliflower-like,
implantation. ulcerated appearance, and being much
larger than papillomas
z Suggested Reading 3. Tend to metastasize to regional lymph
(Bryan et  al. 2007; Cooley and Waters 1998; nodes
Cornell et al. 2000; Dominguez et al. 2009; Freitag 4. Surgery as the therapy of choice
et al. 2007; LeRoy and Northrup 2009; Powe et al.
2004; Smith 2008; Weisse et al. 2006)
z Epidemiology and Pathogenesis
7.3.2.2 Feline Prostatic Tumors Horses affected by preputial or penile squamous
Prostatic tumors in the cat do occur, but are cell carcinomas (SCC) are usually older than 12
rare. As in dogs, most tumors of the feline pros- years with a mean age of 19.5 years, and a history
tate are malignant, and biphasic carcinomas of squamous papilloma at the same site is often
with more than one cell type have been reported noted; thus, this lesion might be predisposing for
as well. The few cases reported were older, cas- the development of an SCC. Most tumors arise in
trated cats. Clinical behavior is comparable to the glans penis, and equally to SCC in other loca-
that in the dog, with high metastatic risk includ- tions, they often ulcerate. They can also be located
ing to the lung and abdominal organs. In con- at the body of the penis or the inner lamina of the
trast to prostate carcinomas in dogs, those of the preputial fold or at the external fold of the prepuce.
cat have not been described to metastasize into Equine papillomavirus type 2 (EcPV2) has been
bone. Clinical symptoms are comparable to identified in genital SCC as well as in normal gen-
those in dogs, with the exemption of bone pain, ital mucosa, and the E6/E7 oncogenes of EcPV2
Chapter 7 · Urogenital Tract Tumors
149 7
are present in the majority of neoplastic cells and z Therapy and Prognosis
in metastases. Surgery with various dimensions is the therapy of
choice for penile SCC, and depending on the loca-
z Clinical Appearance tion and the invasiveness of the tumor, phallec-
The appearance of a penile or preputial SCC is a tomy, segmental posthectomy, phallectomy plus
large, cauliflower-like, ulcerated mass, and they segmental posthectomy, or en bloc resection of
tend to be very firm due to an intense desmoplastic the penis, prepuce, and superficial inguinal lymph
response. In contrast, squamous papillomas are nodes might be necessary. Apart from local side
usually small and exhibit a papilliform growth effects shortly after the resection, prognosis can be
with less desmoplasia. Horses may show signs of good to fair, but up to 19 % of horses are reported
purulent or sanguineous discharge. Of note, up to to show recurrence after resection.
25 % of penile or preputial SCC in the horse have
already metastasized to regional lymph nodes at z Suggested Reading
the time of diagnosis. Metastasis to the lung and (Doles et al. 2001; Mair et al. 2000; van den Top
liver has also been reported, but is less common. et al. 2008; Vanderstraeten et al. 2011; Zhu et al.
2015)
z Cytology and Histopathology
Since SCC in general tend to be heavily ulcer- 7.3.3.2 Other Penile Tumors
ated and/or necrotic, cytology can yield false- Fibropapillomas in bulls are caused by bovine pap-
negative results of suppurative and necrotizing illomavirus-2. They are usually multiple and can
inflammation due to the high amount of neutro- reach considerable size. They are often seen in
phils admixed with the tumor cells (. Figs.  7.3, younger bulls, in which they are highly cellular
7.4, 7.5, and 7.6). The presence of neutrophils and contain many mitoses. They show benign
and the report of an ulcerative mass at the penis behavior without metastasis, but large fibropapil-
or prepuce of a horse should raise suspicion for lomas can impair retraction of the glans, thus pre-
SCC, and histopathology is recommended to disposing for infections or necrosis. Urethal
confirm the diagnosis. The tumor is usually obstruction and urethral disruption have been
heavily keratinized, multifocally necrotic, and/or observed.
mineralized, and infiltration by neutrophils and Squamous cell carcinomas (SCC) of the penis
eosinophils is common. SCC with poor differen- or prepuce do occur in dogs but are much less fre-
tiation tend to metastasize more often than their quent than in horses. They are associated with
well-differentiated counterparts. papilloma virus infection, as are papillomas. Cases

. Fig. 7.4 Cytology, imprint of a normal penis, healthy


. Fig. 7.3 Cytology, imprint of a normal penis, healthy horse, May-Grünwald-Giemsa, 500×. Note the anucleate
horse, May-Grünwald-Giemsa, 100x. Note the numerous well-differentiated squamous epithelial cells surrounded
anucleate well-differentiated squamous epithelial cells and covered by numerous bacterial organisms (black
(Photo: with permission of Dr. N. Bauer, Faculty of arrow) (Photo: with permission of Dr. N. Bauer, Faculty of
Veterinary Medicine, Justus-Liebig-University, Giessen, Veterinary Medicine, Justus-Liebig-University, Giessen,
Germany) Germany)
150 S. Plog

There are single case reports of melanomas,


malignant lymphomas, mast cell tumors, plasma-
cytomas, hemangiosarcomas, and osteosarcomas
in the canine penis. Osteosarcomas have a high
potential for recurrence, and prognosis is usually
guarded in these tumors. Amputation of the penis
or the glans penis might be curative.

z Suggested Reading
(Bocaneti et al. 2015; Cornegliani et al. 2007; Nasir
and Campo 2008; Peppler et al. 2009; Wakui et al.
1992; Yaghoobi Yeganeh Manesh et al. 2014)

. Fig. 7.5 Cytology, imprint of penis with squamous


cell carcinomas, horse, May-Grünwald-Giemsa, 100×. Note 7.4 Transmissible Venereal
7 the numerous nucleate squamous epithelial cells with
moderate anisocytosis, anisokaryosis, and pleomorphism
Tumor (TVT) in Male
and Female Dogs
(black arrow). There are frequent, often degenerate
neutrophils (red arrow) and few anucleate squamous
epithelial cells (green arrow) (Photo: with permission of Dr.
N. Bauer, Faculty of Veterinary Medicine,
Justus-Liebig-University, Giessen, Germany) Box 7.13 Transmissible Venereal Tumor in
Five Facts
1. Tumor cells transmitted directly via
coitus or sniffing
2. Arise at the outer genital of female and
male dogs, but can also be located in the
eye, nasal cavity, oral cavity, and skin
3. Often spontaneously regress
4. Treatment with chemotherapeutics is
usually successful and results in
regression
5. Surgery is not recommended

z Epidemiology and Pathogenesis


. Fig. 7.6 Cytology, imprint of penis with squamous Transmissible venereal tumors (TVT, syn. Sticker
cell carcinomas, horse, May-Grünwald-Giemsa, 500×. Note sarcoma) are transmitted directly via cell implan-
the numerous nucleate squamous epithelial cells with tation and grow in a graft-like manner. Genetically,
moderate anisocytosis, anisokaryosis, and pleomorphism
as well as highly variable nuclear-to-cytoplasm ratio
tumor cells of TVT are distinct from cells of the
indicating a highly variable degree of differentiation. dogs they arise in, and all neoplasms have one
There are some binucleate squamous epithelial cells (red clonal origin. TVT occur worldwide with espe-
arrow) as well as squamous epithelial cells with multiple cially high incidences in areas of warm and humid
fine, clearly circumscribed vacuoles (black arrow). climate and are transmitted mainly via coitus or
Numerous bacterial cocci (blue arrow) and rods (green
arrow) are also present (Photo: with permission of Dr.
sniffing. Latency before tumor development can
N. Bauer, Faculty of Veterinary Medicine, be 2–6 months. TVT are most often found at the
Justus-Liebig-University, Giessen, Germany) vagina or vestibulum where they arise in the sub-
mucosa, but can also be found in the oral or nasal
cavity and in the skin. In male dogs, the most com-
of idiopathic penile squamous papillomas are mon site is the root of the penis. Metastasis occurs
described. They are usually not heavily keratin- mainly to the regional lymph nodes and is gener-
ized. The mean age in dogs is 10 years. Schnauzers ally rare, but metastatic risk is high in
are predisposed. immunocompromised individuals. Metastases to
Chapter 7 · Urogenital Tract Tumors
151 7
the brain and eye have been reported as well. Mukaratirwa and Gruys 2003; Murchison et  al.
Spontaneous regression accompanied by lympho- 2014; Murgia et al. 2006; Nak et al. 2005; Park et al.
cytic infiltration can occur and leads to lifelong 2006; Strakova and Murchison 2015)
immunity, but is not expected after 6 months of
tumor growth. Tumor cells can evade the immune
system by producing a tumor-associated antigen. Suggested Reading
z Clinical Appearance Akihara Y, Shimoyama Y, Kawasako K, Komine M, Hirayama
K, Kagawa Y, Omachi T, Matsuda K, Okamoto M,
The most frequent clinical symptom is bloody or
Kadosawa T, Taniyama H (2007) Immunohistochemical
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highly vascularized. In male dogs, they appear as Single-drug chemotherapy of canine transmissible
venereal tumor with cyclophosphamide, methotrex-
single or multiple nodules which are sessile or
ate, or vincristine. J Vet Intern Med 4(3):144–147
pedunculated and can reach a diameter of up to Ambrosio V, Borzacchiello G, Bruno F, Galati P, Roperto F
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nodes, eyes, central nervous system, skeletal mus- Bailey MT, Troedsson MH, Wheato JE (2002) Inhibin con-
cle, or abdominal organs must be excluded. centrations in mares with granulosa cell tumors.
Erythrocytosis has been described as a paraneo- Theriogenology 57(7):1885–1895
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often allows for a definitive diagnosis. The round, V (2015) Immunohistochemical study of mixed germ
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157 8

Hepatobiliary Tumors
Angele Breithaupt

8.1 Canine Hepatobiliary Tumors – 160

8.2 Feline Hepatobiliary Tumors – 162


8.3 Hepatobiliary Tumors in Horses,
Ruminants, and Pigs – 163

Suggested Reading – 164

© Springer International Publishing Switzerland 2016


R. Klopfleisch (ed.), Veterinary Oncology, DOI 10.1007/978-3-319-41124-8_8
158 A. Breithaupt

Primary hepatic neoplasms are uncommon in most arranged in cords and trabeculae, but masses lack
animals. A viral etiology has been demonstrated in regular lobular architecture.
woodchucks but not in cats or dogs. Trematodes, Hepatocellular adenocarcinomas appear singu-
Ancylostoma caninum and Trichuris vulpis, may be lar, as massive, nodular, or diffuse neoplasms.
involved in bile duct carcinoma development, but Besides capsular penetration and implant metas-
they are unlikely to be a major carcinogen. Toxins, tasis, distant metastasis is rare and most likely
including aflatoxin, induce hepatocellular carcino- affects hepatic lymph nodes. Not uncommonly,
mas, but reports are restricted to experimental data. animals suffer from internal bleeding and less fre-
In contrast to humans, an association between quent from hepatic effacement or metastasis.
hepatic tumors and cirrhosis or cholelithiasis is not Tumors present with less-differentiated hepato-
confirmed in animals. cytes, probably showing invasion into hepatic
Nodular hyperplasia is common in older dogs veins, vena cava, and penetration of the liver cap-
and most likely does not represent a preneoplastic sule, leading to implant metastasis. Consecutive
lesion. These nodules are found in cats and swine capsular ruptures may lead to fatal internal bleed-
more rarely but not in other species and comprise ings. Differentiation from benign variants in cyto-
nodules with regular, lobular architecture. In con- logical specimens can be difficult due to a
trast, regenerative hepatocellular hyperplasia physiological pleomorphia, but immunohisto-
occurs in association with liver damage and thus chemistry for cell proliferation markers, such as
8 usually with some fibrotic background. Ki67, may improve diagnostic performance.
The general macroscopic appearance is impor- Cholangiocellular adenomas are usually mas-
tant for therapeutic approaches and prognosis sive, pale to gray-white, well circumscribed, and
and can be either massive (large and solitary), more or less spherical and may be cystic, filled
nodular (multifocal in several lobes), and diffuse with watery to viscous fluid. Well-differentiated
(multifocal in all lobes or complete effacement). bile duct epithelium and moderate amount of
Primary hepatic tumors include hepatocellular fibrovascular stroma that may compress the sur-
or cholangiocellular (bile duct) adenomas and ade- rounding tissue characterize this tumor type.
nocarcinomas, mesenchymal tumors (mostly sar- Cholangiocellular carcinomas can be intrahepatic
comas), and carcinoids. (. see Fig. 8.2), extrahepatic, or within the gall
Hepatocellular adenomas are typically massive bladder and usually present as nodular to diffuse,
(. see Fig. 8.1) but can be multiple, might reach pale-beige, and umbilicated mass. Metastasis to
12 cm in diameter, and are usually not associated regional lymph nodes and the lung is common
with clinical signs. Tumors are well demarcated and and implant metastasis occurs in the peritoneal
not encapsulated and are yellow to dark brown. cavity (. see Fig. 8.3). Neoplastic cells grow highly
Tumors comprise well-differentiated hepatocytes invasive in ductular, acinar, or papillary pattern,
often with numerous mitosis and abundant
fibrous stroma (scirrhous response).
Carcinoids are rare in cats and dogs and tend to
occur at a younger age than other primary tumors.

. Fig. 8.2 Liver, goat: intrahepatic cholangiocellular


. Fig. 8.1 Liver, Pekingese dog: hepatocellular adenocarcinoma (scirrhous), with metastasis to the
adenoma, left-lateral lobe, 4 years, histopathological hepatic lymph node (arrow) (Courtesy of Kristina Dietert,
examination of regional lymph nodes did not show PhD, Freie Universität Berlin, Germany)
metastatic spread
Chapter 8 · Hepatobiliary Tumors
159 8

. Fig. 8.3 Diaphragm, horse: multiple implant


metastases of a scirrhous cholangiocellular
adenocarcinoma (Courtesy of Dr. Lydia König, Freie . Fig. 8.4 Cytology, carcinoma, liver, dog,
Universität Berlin, Germany) May-Grünwald-Giemsa 100×. The normal liver tissue is
replaced by clusters of small- to medium-sized cuboidal
epithelial cells with round nuclei, a high nuclear to
They arise from neuroectodermal cells and are
cytoplasm ratio and fine chromatin pattern (red arrow).
mostly diffuse with distant metastasis to the There is an acinar growth pattern. Based on the cellular
regional lymph nodes, peritoneum, and lung. morphology (relatively small cuboidal cells), a bile duct
These tumors are usually not amenable to surgical carcinoma can be suspected; however, the exact origin
resection, and the efficacy of radiotherapy and che- cannot be determined based on cytology (Photo: with
permission of Dr. N. Bauer, Faculty of Veterinary Medicine,
motherapy is not well documented, finally leading
Justus-Liebig-University, Giessen, Germany)
to a poor prognosis. Carcinoids are differentiated
from carcinomas by the use of silver stains (reveal A coagulation profile is mandatory prior to
argyrophilic granules) or by immunohistochemis- hepatic biopsy and surgery, because abnormalities
try for neurosecretory products such as serotonin. of the coagulation parameters are common in
Regarding primary hepatic sarcomas, heman- liver diseases in general, particularly FXIII defi-
giosarcomas are most frequent in cats and ciency in cats with neoplastic disease, and hemor-
leiomyosarcomas most common in dogs. Heman- rhage is the most frequent complication.
giosarcomas are usually metastatic in dogs. In For cats and dogs, a correct diagnosis can be
general, hepatic sarcomas behave aggressively, obtained from hepatic aspirates but is much more
with metastasis to the spleen and lungs. Based on reliable with needle core biopsies. Other authors
their variable origin, they may appear as ill- attest that sensitivity and specificity of cytology is
defined, gray-white masses (fibrosarcomas) or restricted, and histopathology of tissue samples is
cavernous and blood-filled (hemangiosarcomas) recommended. Cytological diagnosis of primary
masses. Particularly hemangiosarcomas may rup- epithelial hepatic tumors is challenging: in cases
ture and are associated with fatal internal bleed- of adequate samples, the identification of epithe-
ing. Hepatic sarcomas present in the typical lial cells with criteria of malignancy is often pos-
histological pattern for either hemangiosarcomas sible but difficult to distinguish from metastatic
or fibrosarcomas as in other organs and will not epithelial disease or even from reactive hepatic or
be discussed in detail. Prognosis is poor because biliary cells (. see Figs. 8.4 and 8.5). A differentia-
metastatic disease is often present at the time of tion between a benign mesenchymal proliferation
diagnosis/surgery. and a malignant mesenchymal proliferation is
Lymphomas are rarely restricted to the liver, often not possible without additional clinical data
particularly in cats, and most likely a systemic dis- (. see Fig. 8.6).
ease. Diagnosis can be challenging, particularly in
diffuse infiltrating variants. For detailed informa- z Suggested Readings
tion, 7 see Chap. 6. (Barr 1995; Cohen et  al. 2003; Cullen and Popp
Benign tumors, including fibromas, myelolipo- 2002; Hammer and Sikkema 1995; Hayes et  al.
mas, and hepatoblastomas, are very rare and will not 1983; Leveille et  al. 1993; Newell et  al. 1998;
be discussed, except for hepatoblastomas in horses. Patnaik 1992; Patnaik et  al. 1980, 1981a; Roth
2001; Stockhaus et al. 2004)
160 A. Breithaupt

. Fig. 8.5 Cytology, carcinoma, liver, dog, . Fig. 8.6 Cytology, sarcoma, fine needle aspirate
May-Grünwald-Giemsa 1000× (the same case as in the hypoechogenic liver mass of 5 × 5 × 5 mm in size, dog,
previous figure). There are small- to medium-sized May-Grünwald-Giemsa 1000×. A small cluster of
cuboidal epithelial cells with round nuclei, a high nuclear moderately cohesive spindle cells with indistinct cellular
to cytoplasm ratio and fine chromatin pattern. The cells borders, oval nuclei, fine chromatin, and moderate
8 show nuclear crowding and nuclear overlap reflecting amounts of lightly basophilic cytoplasm (red arrow) are
malignancy (Photo: with permission of Dr. N. Bauer, associated with the clusters of hepatocytes (black arrow).
Faculty of Veterinary Medicine, Justus-Liebig-University, Based on cytological samples, a differentiation between a
Giessen, Germany) benign mesenchymal proliferation (i.e., fibrous tissue in
case of liver cirrhosis) and a malignant mesenchymal
proliferation (i.e., sarcoma) is generally not possible;
8.1 Canine Hepatobiliary Tumors however, in this case, the presence of a liver mass points
toward a sarcoma (Photo: with permission of Dr. N. Bauer,
Faculty of Veterinary Medicine, Justus-Liebig-University,
Giessen, Germany)
Box 8.1. Canine Hepatobiliary Tumors in Five
Facts
common tumors are bile duct carcinomas, and
1. Metastatic tumors: more common than
Labrador retrievers as well as females appear pre-
primary tumors
disposed. Affected dogs average 8 years. Bile duct
2. Hepatocellular tumors: common
adenomas are very rare and will not be discussed
primary tumors
in detail. Hepatocellular adenomas are often
3. Diagnosis: sonographic examination
found incidentally and mostly do not cause clini-
recommended
cal disease. Common metastatic tumors in dogs
4. Treatment of choice: surgery
include lymphomas, hemangiosarcomas, and
(lobectomy)
pancreas carcinomas but also mammary tumors,
5. Massive hepatocellular
intestinal tumors, thyroid carcinomas, melano-
adenocarcinomas can have a good
mas, and malignant histiocytosis, and mast cell
prognosis
tumors often localize in the liver.

z Epidemiology and Pathogenesis z Clinical Appearance


In dogs, most tumors in the liver are secondary Hepatobiliary – primary and metastatic – tumors
and metastases of tumors from non-hepatic are associated with clinical signs in approxi-
organs or part of systemic diseases such as lym- mately 75 % of dogs, which show inappetence,
phomas, malignant histiocytosis, or mast cell weight loss, lethargy, vomiting, polydipsia–poly-
tumors. uria, and ascites. Ataxia and seizures may be
Hepatocellular carcinomas are the most com- caused by hepatic encephalopathy, paraneoplas-
mon primary liver tumor in dogs. Patients aver- tic hypoglycemia, or central nervous system
age 10–11 years and there is no breed metastasis. A cranial abdominal mass is palpable
predisposition, but some authors indicate that frequently, although nodular and diffuse forms
males are overrepresented. The second most can be missed.
Chapter 8 · Hepatobiliary Tumors
161 8
Morphologically, more than half of the hepa- z Cytology and Histopathology
tocellular carcinomas (HCC) are massive; nodular Unspecific clinical symptoms and at least partly
and diffuse types are less frequent. The left liver limited diagnostic value of imaging methods
lobes are affected in more than two thirds of dogs highlight the relevance of cytology and/or histo-
with HCC.  Metastasis to the regional lymph pathology for diagnosis and treatment strategy.
nodes, peritoneum, and lungs is more common in After coagulation tests ultrasound-guided fine
dogs with nodular and diffuse HCC. needle aspiration for cytology or needle core biopsy
Solid and cystic bile duct carcinomas have sampling for histopathology is useful for diagnos-
been reported, but this distinction does not influ- tic purposes. Surgical sampling of wedge-shaped
ence either treatment or prognosis. Cysts may tissue under visual control is regarded by some
contain yellow, gelatinous material, and these authors as the best diagnostic approach and
tumors in general often have a high amount of enables both diagnosis and initial treatment for
fibrous tissue (scirrhous reaction). Bile duct carci- massive, solitary tumors in a single procedure.
nomas have an aggressive biologic behavior with
common metastasis to the regional lymph nodes z Therapy and Prognosis
and lungs. The prognosis for dogs with liver tumors is deter-
The differentiation of hepatocellular adenomas mined by macroscopic morphology and histol-
from nodular hyperplasia is difficult, even histo- ogy: the prognosis is good for massive hepatocellular
logically. Generally, nodular hyperplasia appears carcinoma (HCC) and benign tumors. Complete
multifocally with definite smaller sizes and a his- surgical resection is possible, and local tumor
tologically regular lobular pattern that is charac- recurrence is reported in 0–13 % of dogs with
teristically lacking in adenomas. massive HCC following liver lobectomy.
Typically, with laboratory tests, several param- Metastasis to other regions of the liver and lungs
eters might be increased including ALP (alkaline has been documented in 0–37 % of dogs, but most
phosphatase), ALT (alanine aminotransferase), deaths are unrelated to HCC.
AST (aspartate aminotransferase), GGT (gamma- Prognostic factors in dogs with massive HCC
glutamyl transpeptidase), total bilirubin, serum include:
bile acid, and α-fetoprotein, but they are nonspe- • Surgical treatment: the median survival time is
cific. Further, leukocytosis, anemia, and hypoal- increased four times after surgery in one study.
buminemia are frequently present. Hypoglycemia • Side of liver involvement: due to intraoperative
is a paraneoplastic syndrome reported secondary death associated with right-sided tumors
to hepatic tumors. • ALT and AST activity: may reflect hepatocellu-
In contrast to human cases, α-fetoprotein has lar injury (large tumor size or aggressiveness).
limited value in the diagnosis and treatment mon- • Ratios of ALP to AST and ALT to AST
itoring of canine HCC.
Sonographic examination is recommended In contrast, the prognosis is poor for dogs
and can provide information about the macro- with malignant tumors other than massive HCC.
scopic phenotype (massive, nodular, diffuse), the Even after lobectomy, dogs may suffer from local
size, the location, and relationship with adjacent recurrence and metastatic disease, and other
anatomical structures. Tumor vascularization can treatments are often not successful.
be determined using Doppler imaging tech- Liver surgical lobectomy is highly recom-
niques, and contrast-enhanced ultrasonography mended with any hepatic tumor that has a mas-
can be useful in differentiating malignant tumors sive morphologic appearance, and radical surgical
from benign lesions. Limitations of sonographic treatments are tolerated based on the remarkable
diagnosis are indicated for the differentiation of reserve capacity of this organ. Surgical techniques
nodular hyperplasia and metastatic disease and as for liver lobectomy include finger fracture, mass
well as visualization of infiltrating tumors, such as ligation, mattress sutures, bipolar vessel sealant
lymphomas. devices, and surgical stapling. Complications
Radiographic findings are mainly nonspe- include hemorrhage, vascular compromise to
cific but might be useful for evidence of lung adjacent liver lobes, transient hypoglycemia, and
metastasis. reduced hepatic function.
162 A. Breithaupt

The role of radiation therapy (RT) and chemo- signs include anorexia, depression, and weight
therapy (CT) for HCC is neglectable. The canine loss, more rarely vomiting, diarrhea, polyuria
liver does not tolerate high radio-therapeutic and polydipsia, icterus, ascites, and abdominal
doses, and liver tumors appear to be chemoresis- pain. Paraneoplastic alopecia is recorded in a
tant, most likely due to the hepatocellular detoxi- minority of cases and presents with bilateral
fication property or expression of P-glycoprotein symmetrical alopecia at the ventral thorax,
(efflux pump associated with multidrug resis- abdomen, and inner thighs.
tance). However, some reports (e.g., for gem- A cranial abdominal mass is palpable in up to
citabine) indicate encouraging results. Other three quarters of cats, but as in dogs, hepatic
treatment options include immunotherapy, hor- enlargement can be absent in nodular and diffuse
monal therapy, and antiangiogenic agents. forms.
Bile duct carcinomas behave aggressively, not
z Further Readings uncommonly with implant metastasis and perito-
(Clifford et al. 2004; Cole et al. 2002; Elpiner et al. neal carcinomatosis.
2011; Kemp et  al. 2013; Kosovsky et  al. 1989; Benign tumors, such as bile duct adenomas,
Kutara et al. 2006; Leveille et al. 1993; Nakamura usually do not cause clinical signs until they reach
et al. 2010; Patnaik et al. 1980, 1981b; Stockhaus critical size and compress adjacent organs.
et al. 2004; Vörös et al. 1991; Yamada et al. 1999) As indicated for dogs, radiographic findings
8 are mostly nonspecific – hepatomegaly with cau-
dal displacement of the stomach  – and sono-
8.2 Feline Hepatobiliary Tumors graphic examination is recommended. Again,
relevant information for staging, including tumor
phenotype (massive, nodular, diffuse), size, loca-
tion, and association with important anatomical
Box 8.2. Feline Hepatobiliary Tumors in Four structures, can be specified. Also for cats, Doppler
Facts imaging techniques (for visualization of tumor
1. Lymphomas are the most common vascularization) as well as contrast-enhanced
tumors in the liver of cats sonography, for differentiating malignant tumors
2. Bile duct carcinomas are common non- from benign lesions, may be used. A systematic
hematopoietic hepatic tumors sonography has been reported with a very high
3. Metastases are usually present at time of sensitivity and specificity for differentiation of
diagnosis benign versus malignant tumors and diagnosis of
4. Surgery is the treatment of choice lymphoma in cats.
In laboratory tests, several parameters might
be increased: the most frequent is neutrophilic
z Epidemiology and Pathogenesis leukocytosis. Some authors state ALP (alkaline
Lymphomas are by far the most common neopla- phosphatase) levels are not diagnostic, and
sia in the liver of cats and usually part of a multi- increased ALT and AST are rare in cats. Thus, reli-
centric disease (. see Fig. 8.7). Lymphomas are ability is questionable, possibly except for
discussed in detail in Chap. 6. increased AST levels in visceral hemangiosarco-
Bile duct carcinomas are the most common mas. But in general, malignant tumors tend to be
non-hematopoietic hepatic tumors in cats fol- associated with higher liver enzyme levels com-
lowed by hepatocellular carcinomas. Benign pared to benign tumors. Bilirubin is elevated in
tumors such as cystic bile duct adenomas or solid some cats with hepatobiliary tumors, most mark-
hepatocellular adenomas are also frequently edly with bile duct carcinoma and bile duct
described in cats. Rarely, cats present with mast obstructive carcinoids.
cell tumors, sarcomas (most of them hemangio-
sarcomas), myelolipomas, and carcinoids. z Cytology and Histopathology
Cytology and/or histopathology is necessary for
z Clinical Appearance diagnosis and development of a treatment strat-
Hepatobiliary tumors are accompanied by clini- egy. Ultrasound-guided fine needle aspiration for
cal signs in approximately 50 % of cats. Clinical cytology or needle core biopsy sampling for histo-
Chapter 8 · Hepatobiliary Tumors
163 8

a b

1,0 cm

. Fig. 8.7 Liver, diffuse lymphoma, cat (Courtesy of Kristina Dietert, PhD, Freie Universität Berlin, Germany)

pathology is useful for diagnostic purposes. mattress sutures, bipolar vessel sealant devices,
And again, surgical sampling of wedge-shaped tis- and surgical stapling with the same perioperative
sue under visual control is probably the best diag- complications (hemorrhage, vascular compro-
nostic approach and useful for initial treatment mise to adjacent liver lobes, transient hypoglyce-
for massive, solitary tumors in a single procedure. mia, reduced hepatic function).
Fine needle aspiration (FNA) is valuable for Significant data on radiation therapy and che-
diagnosis of most hematopoietic tumors. The dif- motherapy for cats with hepatic tumors is lacking,
ferentiation of well-differentiated, low-grade lym- but some chemotherapeutics require adequate
phomas from chronic cholangiohepatitis is liver function and can only be used with caution
however challenging. such as L-asparaginase and cyclophosphamide.

z Therapy and Prognosis z Further Readings


The prognosis for cats is determined by macro- (Balkman 2009; Cole et  al. 2002; Leveille et  al.
scopic and histological findings: as in dogs, the 1993; Marconato et  al. 2007; Newell et  al. 1998;
prognosis is good for massive hepatocellular carci- Patnaik 1992; Patnaik et al. 1975, 2005; Roth 2001;
nomas (HCC) and benign tumors because com- van der Luer et al. 2008)
plete surgical resection is usually possible.
In contrast, the prognosis is poor for cats with
nodular and diffuse, malignant tumors because 8.3 Hepatobiliary Tumors
metastasis is more likely at time of diagnosis, and in Horses, Ruminants, and Pigs
unfortunately, in the vast majority of cases in cats,
tumors affect more than one liver lobe. Thus,
metastases are mostly present at time of diagno-
sis, particularly in the lung, abdominal serosa, Box 8.3 Hepatobiliary Tumors in Horses in
and liver lymph nodes. Two Facts
Surgery is the treatment of choice, particularly 1. Hepatoblastomas are the most common
with any massive hepatic tumor, for single bile hepatobiliary tumor in horses.
duct adenomas or multifocal lesions confined to 2. Hepatoblastomas mainly develop in
one or two lobes. Generally, the liver allows radi- young horses.
cal surgery due to its remarkable reserve capacity.
However, one study indicated a poor outcome
even for massive bile duct tumors because most
patients died within 6 months due to local recur- z Epidemiology and Pathogenesis
rence and metastatic disease. Hemangiosarcomas Primary equine liver tumors are rare, and hepato-
and carcinoids have a poor prognosis and most of blastomas are the most common variant reported.
the patients have to be euthanized perioperatively. This tumor, most likely derives from primitive
Also for cats, surgical techniques for liver hepatic precursor cells and is reported in young
lobectomy include finger fracture, mass ligation, and adult animals (fetuses and up to 4 years of
164 A. Breithaupt

age). Metastases to distant organs have been Cullen JM, Popp JA (2002) Tumors in domestic animals, 4th
described in some cases. Hepatoblastomas are edn. Iowa State Press, Ames
de Vries C, Vanhaesebrouck E, Govaere J, Hoogewijs M,
typically single, firm, lobulated masses and may Bosseler L, Chiers K, Ducatelle R (2013) Congenital
show some hemorrhages and necrosis. ascites due to hepatoblastoma with extensive perito-
Histologically they can contain embryonal or fetal neal implantation metastases in a premature equine
epithelial and mesenchymal parts and are typi- fetus. J Comp Pathol 148:214–219
cally alpha-fetoprotein positive in immunohisto- Elpiner AK, Brodsky EM, Hazzah TN, Post GS (2011) Single-
agent gemcitabine chemotherapy in dogs with hepa-
chemical tests. tocellular carcinomas. Vet Comp Oncol 9:260–268
Domestic pot-bellied pigs have an average life- Haddad JL, Habecker PL (2012) Hepatocellular carcinomas
span of 20–25 years. Most tumors in pigs are there- in Vietnamese pot-bellied pigs (Sus scrofa). J Vet Diagn
fore reported in pot-bellied pigs. One study suggests Invest 24:1047–1051
that aged pot-bellied pigs can be predisposed to Hammer AS, Sikkema DA (1995) Hepatic neoplasia in the
dog and cat. Vet Clin North Am Small Anim Pract
hepatocellular carcinomas, with a possible male 25:419–435
predilection. The rate of extrahepatic metastasis of Hayes HM Jr, Morin MM, Rubenstein DA (1983) Canine bili-
hepatocellular carcinoma was over 10 %. ary carcinoma: epidemiological comparisons with
Reports about primary neoplasia in ruminants man. J Comp Pathol 93:99–107
are scarce and conflicting with respect to the Kemp SD, Panciera DL, Larson MM, Saunders GK, Werre SR
(2013) A comparison of hepatic sonographic features
prevalence of hepatocellular and cholangiocellu-
8 lar tumors. In general, many cases are incidental
and histopathologic diagnosis in canine liver disease:
138 cases. J Vet Intern Med 27:806–813
findings and studies in abattoirs. Likely due to Kosovsky JE, Manframarretta S, Matthiesen DT, Patnaik AK
economic reasons or postmortem diagnosis, (1989) Results of partial-hepatectomy in 18 dogs with
treatments generally have not been undertaken. hepatocellular-carcinoma. J Am Anim Hosp Assoc
25:203–206
Kutara K, Asano K, Kito A, Teshima K, Kato Y, Sasaki Y,
z Further Readings Edamura K, Shibuya H, Sato T, Hasegawa A, Tanaka S
(Anderson and Sandison 1968; Beeler-Marfisi (2006) Contrast harmonic imaging of canine hepatic
et  al. 2010; Bettini and Marcato 1992; de Vries tumors. J Vet Med Sci 68:433–438
et al. 2013; Haddad and Habecker 2012) Leveille R, Partington BP, Biller DS, Miyabayashi T (1993)
Complications after ultrasound-guided biopsy of
abdominal structures in dogs and cats – 246 cases
(1984–1991). J Am Vet Med Assoc 203:413–415
Suggested Reading Marconato L, Albanese F, Viacava P, Marchetti V, Abramo F
(2007) Paraneoplastic alopecia associated with hepa-
Anderson LJ, Sandison AT (1968) Tumors of the liver in tocellular carcinoma in a cat. Vet Dermatol 18:
cattle, sheep and pigs. Cancer 21:289–301 267–271
Balkman C (2009) Hepatobiliary neoplasia in dogs and Nakamura K, Takagi S, Sasaki N, Kumara WRB, Murakami M,
cats. Vet Clin North Am Small Anim Pract 39:617–625 Ohta H, Yamasaki M, Takiguchi M (2010) Contrast-
Barr F (1995) Percutaneous biopsy of abdominal organs enhanced ultrasonography for characterization of
under ultrasound guidance. J Small Anim Pract canine focal liver lesions. Vet Radiol Ultrasound
36:105–113 51:79–85
Beeler-Marfisi J, Arroyo L, Caswell JL, Delay J, Bienzle D Newell SM, Selcer BA, Girard E, Roberts GD, Thompson JP,
(2010) Equine primary liver tumors: a case series and Harrison JM (1998) Correlations between ultrasono-
review of the literature. J Vet Diagn Invest 22:174–183 graphic findings and specific hepatic diseases in
Bettini G, Marcato PS (1992) Primary hepatic tumours in cats: 72 cases (1985–1997). J Am Vet Med Assoc
cattle. A classification of 66 cases. J Comp Pathol 213:94–98
107:19–34 Patnaik AK (1992) A morphologic and immunocytochemi-
Clifford CA, Pretorius ES, Weisse C, Sorenmo KU, Drobatz cal study of hepatic neoplasms in cats. Vet Pathol
KJ, Siegelman ES, Solomon JA (2004) Magnetic reso- 29:405–415
nance imaging of focal splenic and hepatic lesions in Patnaik AK, Hurvitz AI, Lieberman PH (1980) Canine
the dog. J Vet Intern Med 18:330–338 hepatic neoplasms: a clinicopathologic study. Vet
Cohen M, Bohling MW, Wright JC, Welles EA, Spano JS Pathol 17:553–564
(2003) Evaluation of sensitivity and specificity of Patnaik AK, Hurvitz AI, Lieberman PH, Johnson GF (1981a)
cytologic examination: 269 cases (1999–2000). J Am Canine bile duct carcinoma. Vet Pathol 18:439–444
Vet Med Assoc 222:964–967 Patnaik AK, Lieberman PH, Erlandson RA, Antonescu C
Cole TL, Center SA, Flood SN, Rowland PH, Valentine BA, (2005) Hepatobiliary neuroendocrine carcinoma in
Warner KL, Erb HN (2002) Diagnostic comparison of cats: a clinicopathologic, immunohistochemical, and
needle and wedge biopsy specimens of the liver in ultrastructural study of 17 cases. Vet Pathol 42:
dogs and cats. J Am Vet Med Assoc 220:1483–1490 331–337
Chapter 8 · Hepatobiliary Tumors
165 8
Patnaik AK, Lieberman PH, Hurvitz AI, Johnson GF (1981b) van der Luer R, van den Ingh T, van Hoe M (2008) Feline
Canine hepatic carcinoids. Vet Pathol 18:445–453 paraneoplastic alopecia. Tijdschr Diergeneeskd
Patnaik AK, Liu SK, Hurvitz AI, Mcclelland AJ (1975) 133:182–183
Nonhematopoietic neoplasms in cats. J Natl Cancer Vörös K, Vrabely T, Papp L, Horvath L, Karsai F (1991)
Inst 54:855–860 Correlation of ultrasonographic and pathomorpho-
Roth L (2001) Comparison of liver cytology and biopsy diag- logical findings in canine hepatic diseases. J Small
noses in dogs and cats: 56 cases. Vet Clin Pathol 30:35–38 Anim Pract 32:627–634
Stockhaus C, Van den Ingh T, Rothuizen J, Teske E (2004) A Yamada T, Fujita M, Kitao S, Ashida Y, Nishizono K, Tsuchiya
multistep approach in the cytologic evaluation of liver R, Shida T, Kobayashi K (1999) Serum alpha-fetoprotein
biopsy samples of dogs with hepatic diseases. Vet values in dogs with various hepatic diseases. J Vet Med
Pathol 41:461–470 Sci 61:657–659
167 9

Alimentary Tumors
Angele Breithaupt

9.1 Oropharyngeal Tumors – 168


9.1.1 Canine Oropharyngeal Tumors – 169
9.1.2 Feline Oropharyngeal Tumors – 176
9.1.3 Equine Oropharyngeal Tumors – 177
9.1.4 Bovine Oropharyngeal Tumors – 178

9.2 Tumors of Salivary Glands – 179


9.2.1 Canine and Feline Salivary Gland Tumors – 179

9.3 Esophageal Tumors – 180


9.3.1 Canine and Feline Esophageal Tumors – 180
9.3.2 Esophageal and Forestomach
Tumors in Ruminants – 181

9.4 Gastrointestinal Tumors – 181


9.4.1 Canine Gastrointestinal Tumors – 181
9.4.2 Feline Gastrointestinal Tumors – 186
9.4.3 Equine Gastrointestinal Tumors – 191
9.4.4 Bovine Abomasal and Intestinal Tumors – 192

Suggested Reading – 193

© Springer International Publishing Switzerland 2016


R. Klopfleisch (ed.), Veterinary Oncology, DOI 10.1007/978-3-319-41124-8_9
168 A. Breithaupt

9.1 Oropharyngeal Tumors Depending on the localization, sampling for


cytological or histological investigation of the
Oropharyngeal tumors share some similarities in tumor should be performed on narcotized and
terms of clinical signs, diagnostic modalities, intubated patients to prevent possible blood aspi-
therapy, and prognostic factors. ration. Cytologic samples have a rather low sensi-
Typical clinical signs of oropharyngeal tumors tivity and specificity for the diagnosis of the
are facial swellings, excessive salivation, halitosis, tumors. If tumors are well demarcated and fairly
dysphagia, bleeding, snoring respiration, cough, resectable, intended complete resection products
anorexia, weight loss, lymphadenopathy, and can be evaluated histologically and serve as basis
changed voice. Especially tooth loss is frequently for further specific treatment. Ideally, biopsies
associated with neoplasia in cats and can be should extend into the bone.
mistaken for a primary dental disease (see Except for malignant melanomas, canine
. Fig. 9.1). oral squamous cell carcinomas, and sarcomas,
Diagnostic investigation includes inspection of malignant oral cavity tumors rarely metastasize.
the oral cavity and cranium to roughly estimate It seems that more caudally located tumors
the tumor extension and to detect enlargement or result in a poorer prognosis compared to
lysis of bone, gomphiasis and tooth loss, ulcer- rostrally located tumors, possibly due to a
ation, unilateral epiphora, sneezing and rhinor- delayed detection and/or inconvenient surgical
rhea, and not least mobility of the ocular bulb. accessibility.
Regional lymph nodes are checked for adenopa- Surgery and radiotherapy are the most com-
9 thy. However, lymph node size is not an accurate mon treatments for the local control of oral
predictor of metastasis. Fine-needle aspiration of tumors. Oral tumors frequently invade under-
the regional lymph nodes should be performed lying bone; thus, surgical resection ideally
regardless of the size or degree of fixation of the includes bone margins. Margins of at least
lymph nodes. 2 cm are recommended for all malignant can-
Diagnostic imaging of tumors of the jaw cers, partially leading to mandibulectomy,
includes computed tomography (CT) and/or maxillectomy, and orbitectomy. Radiotherapy
magnetic resonance imaging (MRI). Radiography can be used with curative intent or palliatively
of the lung is useful if metastasis is suspected. and in combination with surgery if resection of
Remarkably, even normal-appearing radiographs the tumor is likely to be incomplete. Several
do not exclude bone invasion. Scintigraphic tech- tumors are generally radiation responsive,
niques or contrast-enhanced ultrasonography is including melanomas and squamous cell carci-
helpful to detect the sentinel lymph nodes and nomas, whereas others are considered radia-
guide lymph node aspirates. tion resistant.

. Fig. 9.1 Oral carcinoma


(not further specified), cat,
with tooth loss (Courtesy of
Anja Meyer, PhD, Freie
Universität Berlin, Germany)
Chapter 9 · Alimentary Tumors
169 9
The median survival time may be improved by Clinical staging system for oral tumors in dogs and cats
combined approaches using radiotherapy, sur-
gery, and chemotherapy, particularly for tumors Distant metastasis (M)
suggested to be radiation resistant, including M0 No distant metastasis
canine oral fibrosarcomas or feline oral squamous
M1 Distant metastasis [specify site(s)]
cell carcinomas. Overall, several reports indicate
that histologically complete resection, smaller Stage Tumor Nodes (N) Metastasis
diameter, and a rostral location are favorable prog- grouping (T) (M)
nostic factors for oral tumors. Most likely, tumors I T1 N0, N1a, M0
with rostral location are detected earlier and with N2a
smaller size and chances are that resection is with II T2 N0, N1a, M0
complete surgical margins. Thus, recurrence is N2a
more likely in caudal locations and has negative
III T3 N0, N1a, M0
effect on the survival time. N2a
Based on these diagnostic steps, oral tumors
can be clinically staged according to the WHO IV Any T N1b M0
staging scheme (Owen 1980): Any T N2b, N3 M0

Any T Any N M1
Clinical staging system for oral tumors in dogs and cats

Primary tumor (T)


z Suggested Reading
Tis Tumor in situ
(Herring et al. 2002; Lurie et al. 2006; Owen 1980)
T1 Tumor <2 cm in diameter at greatest
dimension

T1a Without evidence of bone invasion 9.1.1 Canine Oropharyngeal Tumors


T1b With evidence of bone invasion
Tumors of the oral cavity in dogs are almost
T2 Tumor 2–4 cm in diameter at greatest evenly matched benign and malignant. Benign
dimension
tumors in dogs include epulides, oral papillomas,
T2a Without evidence of bone invasion and plasmacytomas. In descending order, the
T2b With evidence of bone invasion
most common malignant canine oral tumors are
malignant melanomas, squamous cell carcinomas
T3 Tumor >4 cm in diameter at greatest (SCCs), and fibrosarcomas, although in few stud-
dimension
ies, SCCs are more common than malignant mel-
T3a Without evidence of bone invasion anomas.
T3b With evidence of bone invasion
Other very rare tumors that will not be dis-
cussed in detail here are lingual granular cell
Regional lymph nodes (N) myoblastomas, mast cell tumors, adenocarcino-
N0 No regional lymph node metastasis mas, neurofibrosarcomas, leiomyosarcomas,
hemangiosarcomas and hemangiomas, rhabdo-
N1 Movable ipsilateral lymph nodes
myomas and rhabdomyosarcomas, myxomas,
N1a No evidence of lymph node and lipomas.
metastasis The tonsils are ten times more often affected in
N1b Evidence of lymph node metastasis animals living in urban compared to rural areas,
implying an association with environmental pol-
N2 Movable contralateral lymph nodes
lutants. Primary tumors are often SCCs (mostly
N2a No evidence of lymph node unilateral) and lymphomas (often bilateral).
metastasis
Metastatic tumors have to be considered, particu-
N2b Evidence of lymph node metastasis larly melanoma. In most cases, tonsillopathy is
N3 Fixed lymph nodes
considered as systemic disease, so tonsillectomy is
generally not curative but diagnostically helpful.
170 A. Breithaupt

z Suggested Reading
. Table 9.1 World Health Organization,
(Brodey 1960; Dennis et  al. 2006; Todoroff and TNM-based staging scheme for dogs with oral
Brodey 1979) melanomas

9.1.1.1 Canine Oral Melanocytic Tumors T: primary tumor

T1: tumor ≤2 cm in diameter


Box 9.1. Canine Oral Melanocytic Tumors in
T2: tumor 2–4 cm in diameter
Six Facts
1. Oral malignant melanomas: one of the T3: tumor >4 cm in diameter
most common tumors in the oral cavity N: regional lymph nodes
2. Distant metastasis is common
N0: no evidence of regional node involvement
3. Up to one third are amelanotic
4. Imunohistochemistry for detecting N1: histologic/cytologic evidence of regional node
amelanotic melanomas: melan-A, PNL2, involvement
TRP-1, TRP-2 N2: fixed nodes
5. Oral melanomas have a poor prognosis
M: distant metastasis
6. Prognostic factors include nuclear
atypia, mitotic, and Ki67 index M0: no evidence of distant metastasis

M1: evidence of distant metastasis


9 Stage I = T1 N0 M0

z Epidemiology and Pathogenesis Stage II = T2 N0 M0


In accordance with the current World Health Stage III = T2 N1 M0 or T3 N0 M0
Organization (WHO) nomenclature, the term
“melanocytoma” refers to the benign neoplasm of Stage IV = any T, any N and M1
melanocytic origin, whereas the term “malignant
melanoma (MM)” refers to the malignant variant. nonpigmented tumors may exhibit microscopi-
Oral MM are the most common tumors of the cally visible melanin pigment. For malignant
oral cavity and predominantly occur in aged dogs tumors, cytology in combination with immuno-
(mean age 11  years). Breed predispositions are histochemistry, using anti-cytokeratin, anti-
indicated for Scottish terriers, golden retrievers, melan-A, and anti-vimentin antibodies, agrees
poodles, and dachshunds. Melanocytomas are very well with histopathological diagnosis.
extremely rare in the oral cavity. Histopathology is necessary to confirm malig-
nancy. If pigment is not detectable, the diagnosis
z Clinical Appearance is aggravated and might merely lead to a diagno-
MM appear mostly as black-brown, frequently sis of (malignant) blastoma. Based on histology,
ulcerated tumors of the gingival, labial, buccal, recommendations for prognostication of canine
and palatal mucosa as well as on the tongue. One melanocytic neoplasms have been worked out in
third of the tumors are amelanotic. Almost every detail (see below). Immunohistochemistry label-
patient develops metastasis in regional lymph ing with a combination of melan-A, PNL2, TRP-1,
nodes and/or the lung or less commonly in other and TRP-2 provides the highest sensitivity for
organs including the liver, kidney, and brain. detecting amelanotic melanomas while main-
Metastasis in regional lymph nodes is not obliga- taining 100 % specificity.
torily associated with their enlargement.
For staging, there is either a four-stage scheme z Prognosis and Therapy
of the Word Heath Organization (WHO, see In general, oral melanocytic neoplasms have a
. Table 9.1) or a more recent three-stage scheme worse prognosis than cutaneous neoplasms, and
available (see . Table 9.2). distant metastasis indicates a poor prognosis. The
value of staging for the prognosis of survival time
z Cytology and Histopathology and remission is debatable. In contrast, histologi-
Cytology and histology generally are straightfor- cal classification as benign or malignant is gener-
ward for pigmented tumors, and even grossly ally associated with the clinical outcome and
Chapter 9 · Alimentary Tumors
171 9
ulceration, and lack of pigmentation are not reli-
. Table 9.2 Alternative staging system
according to Hahn et al. (1994)
ably prognostic.
Due to the common invasion of oral melano-
T Primary tumor mas into the periost and bone, surgical preserva-
tion of underlying bone by conservative excision
T1 Tumor in situ or ≤2 cm
is not recommended. To the contrary, en bloc
maximum diameter
(volume ≤8 cm3) resection is suggested. Partial mandibulectomia,
maxillectomia, and also resection of the tongue
T2 Tumor 2–4 cm maximum
are generally well tolerated in dogs.
diameter (volume
8–64 cm3) Hypofractionized radiotherapy may lead to
partial or complete remission, but some studies
T3 Tumor >4 cm maximum experienced a lack of positive effects of different
diameter (volume >64 cm3)
radiotherapeutic protocols and radiosensitizing
Mitotic index platin-based agents.
a ≤3 per high-power field Chemotherapy is suboptimal due to an explicit
low sensitivity of these tumors for chemothera-
b >3 per high-power field
peutic drugs to date, except for rare case reports
Oral cavity or oropharyngeal location with successful treatments.
1 Rostral mandible/caudal
maxilla z Current Research
Oral melanomas induce an immune response.
2 Others
This antitumor reaction might influence the
N Regional lymph nodes course of disease and survival time.
N0 No evidence of regional
Immunomodulatory approaches for treatment of
node involvement melanocytic tumors are under investigation.
N1 Histological evidence of
z Suggested Reading
regional node involvement
(Blackwood and Dobson 1996; Boria et al. 2004;
N2 Fixed nodes Burk 1996; Hahn et  al. 1994; Przeździecki et  al.
M Distant metastasis 2015; Ramos-Vara et al. 2000; Rassnick et al. 2001;
Regan et al. 2015; Smedley et al. 2011a, b; Smith
M0 No evidence of distant
metastasis
et al. 2002)

M1 Distant metastasis
(including distant nodes) 9.1.1.2 Canine Oral Squamous Cell
Carcinomas (SCCs)
Stage
grouping
T N M
Box 9.2. Canine Oral Squamous Cell
I T1 a1 N0 M0 Carcinomas in Five Facts
II T1 a2, any N0 M0 1. SCCs: one of the most common tumors
T1 b, T2 a1 in the oral cavity
2. Localization: gingiva, tongue, and tonsil
Any T N1 M0
3. Up to one third show distant metastasis
III Any T2 a2, N0 M0 at time of diagnosis
any T2 b 4. Caudally located tumors have a worse
or T3
prognosis
Any T N2 M0 5. Radical surgery is recommended
Any T Any N M1

survival. Recommended parameters with prognos- Epidemiology and Pathogenesis


tic value include nuclear atypia, mitotic index, and SCCs are common tumors of the oral cavity in
Ki67 (proliferation) index. Tumor size or volume, dogs. A papillomaviral etiology has been discussed
172 A. Breithaupt

but seems unlikely. The mean age is 9  years and compared to mandibulectomy. Median survival
medium- to large-sized dogs but also West rates range between few months and more than
Highland white terriers may be predisposed. A 1.5 years. Underlining the impact of histological
breed predisposition for tonsillar SCC is published grading, differences are most obvious regarding
for German shepherds. Half of the lingual tumors lingual SCCs: median survival times after surgical
are SCC with a potential predisposition for poo- resection can range between 16 (grade I) and
dles, golden retriever, samoyeds, and female dogs 3–4 months (grade II, III).
with a mean age of 9.5 years. SCCs are sensitive for radiotherapy, but recur-
rence of tumors is nevertheless often observed.
z Clinical Appearance Median survival times are markedly increased if
SCCs mostly arise in the gingiva, particularly ros- radiotherapy is combined with surgery.
tral to premolar tooth, on the tongue, and tonsils. Chemotherapy can be used for dogs with met-
They appear as light-red masses, often ulcerated astatic disease and unresectable tumors and as
and bleeding, mimicking gingivitis. Invasion, adjuvant treatment. The effect of chemotherapy
osteolysis, and gomphiasis are frequent. Metastasis on the metastatic rate is unknown. Few studies
occurs in advanced stages, preferentially to using piroxicam, cisplatin, or carboplatin are
regional (mandibular) lymph nodes. Lingual available. However, toxicity limits the clinical use-
tumors occur anywhere on the tongue. Staging fulness.
requires investigation of the oral cavity, pharynx,
tonsils, biopsy of enlarged lymph nodes, and z Current Research
9 radiography of the lung. One third of these tumors Novel therapies are under investigation, including
exhibit metastasis at diagnosis. electrochemogenetherapy as well as characteriza-
tion of possible papillomavirus etiologies.
z Cytology and Histopathology
Cytology and histology are similar to cutaneous z Suggested Reading
SCC with variably differentiated epithelial cells, (Carpenter et  al. 1993; Dennis et  al. 2006;
keratin, keratin pearls, and frequently inflamma- Kosovsky et al. 1991; Mestrinho et al. 2014, 2015;
tion due to secondary infection of ulcerated Munday et  al. 2015b, 2016; Reed et  al. 2010;
tumors. Invasion of underlying bone tissue is Wallace et al. 1992; Withrow and Holmberg 1983)
common.
9.1.1.3 Canine Oral Sarcomas
z Prognosis and Therapy
SCCs occur in three distinct localizations that
may correlate with prognosis: (1) gingiva includ- Box 9.3. Canine Oral Sarcomas in Four Facts
ing gum, labial, and buccal mucosa, (2) lingual, 1. Oral fibrosarcomas are the third most
and (3) tonsillar. Caudally located gingival and common tumor.
lingual carcinomas are associated with a signifi- 2. Up to one third develop distant
cantly poorer prognosis compared with more ros- metastasis.
tral tumors. Reasons may include an occult
growth of the former, richer lymphatic and vascu- 3. A histologically low-grade, biologically
lar channels of the caudal oral tissue and that ros- high-grade fibrosarcoma occurs.
tral tumors can be resected with wider margins. 4. The prognosis is guarded to poor.
Atypical p63 labeling and cytoplasmic
E-cadherin staining appear to be related with a
higher tumor grade. Histological grade and PCNA Epidemiology and Pathogenesis
expression may be important prognosis factors in Mesenchymal tumors comprise 12 % of all oral
canine SCC. tumors and 20 % of all malignant tumors in the
Surgery is the common approach for non- oral cavity of dogs. Fibrosarcomas are the third
tonsillar SCC. The common invasion of SCC into most common tumor in the oral cavity of dogs.
the periost, bone, and tongue often requires surgi- Male and medium- to large-sized dogs are over-
cal en bloc resection or glossectomia. The recur- represented. The tumors are found in dogs of all
rence rate is significantly higher after maxillectomy ages. Particularly, the histologically low-grade,
Chapter 9 · Alimentary Tumors
173 9
biologically high-grade fibrosarcomas commonly tumor mass, but resection of the histologically
occur in large breed dogs (e.g., retriever dogs) at low-grade, biologically high-grade fibrosarcomas
younger ages and should not be misdiagnosed as is mostly incomplete. Therefore, a combination of
fibromas or fibromatous epulides. Osteosarcomas surgery and radiotherapy may improve the sur-
and fibromas rarely occur and will not be dis- vival rates. Nevertheless, oral fibrosarcomas are
cussed in detail. considered radiation resistant. Data regarding
systemic chemotherapeutical treatment of oral
z Clinical Appearance fibrosarcomas are sparse.
Oral fibrosarcomas arise equally within the man-
dibula and maxilla. The gingival and palatinal z Suggested Reading
mucosa are most commonly affected. Tumors (Ciekot et  al. 1994; Kosovsky et  al. 1991; Thrall
have a firm consistency and are sometimes ulcer- 1981; Wallace et al. 1992)
ated. The tumors grow highly invasive with osteo-
lytic activity. Up to one third of the patients
develop metastases in regional lymph nodes, the 9.1.1.4 Canine Oral Plasmacytomas
lungs, and other organs, often long after assumed
complete resection of the primary tumor.
Fibrosarcomas developing around the carnas- Box 9.4. Canine Oral Plasmacytomas in Four
sial or premolar teeth and the hard palate are Facts
usually histologically low-grade, biologically 1. Oral plasmacytomas are locally invasive
aggressive tumors. Although well-differentiated but rarely metastasize
histologically, they show a marked infiltrative 2. Histological criteria of malignancy may
growth and metastasis in the regional lymph be present – but biological behavior is
nodes and lungs. generally benign
3. Prognosis is good
z Cytology and Histopathology 4. Surgery is mostly curative
Cytology may present with less differentiated and
more pleomorphic plump to spindloid cells and
oval nuclei compared with well-differentiated Epidemiology and Pathogenesis
spindle cells in fibromas. Histology is needed to Oral (extramedullary) plasmacytomas account
confirm malignancy, for differentiation of other for up to 6 % of all oral neoplasia. Middle-aged
mesenchymal tumors and the evaluation of surgi- dogs (7–9 years) and golden retriever dogs as well
cal margins. Fibrosarcomas may appear remark- as Yorkshire terriers are overrepresented. As pri-
ably well-differentiated histologically, although mary tumors, they arise from plasma cells in the
they may behave very aggressively. Differentiation soft tissue or as metastasis from primary osseous
to (peripheral odontogenic) fibromas can be thus myeloma.
challenging even with large biopsy samples, if
bone invasion and osteolytic activity are not rep- z Clinical Appearance
resented in the sample. The tumor appears as a raised, red, lobulated mass
mostly located on the gingiva or lips. They show
z Prognosis and Therapy an invasive growth pattern but rarely metastasize.
The prognosis for dogs with oral fibrosarcomas is
guarded, particularly due to a high recurrence z Cytology and Histopathology
rate and metastasis to the regional lymph nodes Cytology or histopathology is needed to differen-
and to the lungs (reported in up to 27 % of tiate the tumor from other round cell tumors and
patients). nonpigmented melanomas. Cytologically and his-
Patients with histologically low-grade, biologi- topathologically, this tumor is comprised of well-
cally high-grade fibrosarcomas present with poorer differentiated plasma cells. The biological behavior
survival rates as compared to dogs with soft tissue of these tumors is generally benign despite of
sarcomas of other body sites. With respect to their partially pleomorphic or anaplastic appear-
recurrence, the surgical treatment should include ance and the presence of mitotic figures and bi-
at least 3 cm margins from the visible or palpable and multinucleated cells.
174 A. Breithaupt

z Prognosis and Therapy papillae. A viral etiology can be suspected due to


The prognosis for oral plasmacytomas is good. occurrence of viral cytopathic effects including
Surgical resection is the most common therapy detection of “koilocytes” or basophilic intranu-
and may be curative. The median survival time clear inclusion bodies.
increases significantly if the tumor is completely
resected. A combination of radiotherapy and che- z Prognosis and Therapy
motherapy is recommended for unresectable The prognosis is usually excellent: Papillomatosis
tumors. in dogs is considered to be a self-limiting disease
with spontaneous regression within 4–8  weeks.
z Suggested Reading Regression seems to correlate with a strong anti-
(Rakich et al. 1989; Wright et al. 2008) body response. Thus, treatment is generally not
necessary. Occasionally, papillomas persist, most
likely based on immunodeficiency, and malignant
9.1.1.5 Canine Oral Viral Papillomas progression is reported for few cases. Resection
using cryo-, laser-, and electrosurgery is recom-
mended in refractory cases, to prevent further
Box 9.5. Canine Oral Viral Papillomas in
transmission or if chewing is markedly interfered.
Three Facts
1. Papilloma virus infections induce tumor z Current Research
development.
Recent studies focus mainly on detection of new
9 2. Tumors may interfere chewing and
viruses and potential malignant progression as
require resection.
well as antitumoral immune response.
3. Prognosis is usually excellent due to
regression. z Suggested Reading
(DeBey et al. 2001; Munday et al. 2015c; Sancak
et al. 2015; Watrach et al. 1970)
z Epidemiology and Pathogenesis
Viral papillomas, induced after horizontal trans-
9.1.1.6 Canine Epulides (Fibromatous
mission of papillomavirus (Papillomaviridae fam-
Epulides of the Periodontal
ily), mostly affect dogs of juvenile age. They
Ligament)
develop on the oral mucosa and lips, among oth-
ers, mostly with multiple manifestation. Canine
papillomavirus type 1 (CPV1) is considered to be Box 9.6. Canine Epulides in Four Facts
responsible for most oral cases; CPV13 is rarely 1. The term “epulides” is used for fibroma-
described. Furthermore, canine papillomavirus tous epulides of the periodontal liga-
has been proposed to be associated with oral car- ment only.
cinoma. 2. Epulides have a predilection to the
maxilla, rostral to the third premolar
z Clinical Appearance teeth.
Viral papillomatosis presents with mostly multi- 3. Treatment and prognosis is similar to
ple, up to several cm in size, flat or pedunculated fibrous gingival hyperplasia.
tumors with a smooth to fringy, wartlike surface. 4. Surgical resection is generally curative.
Affected dogs usually do not suffer, but tumors
may interfere chewing and require resection due
to recurrent bleeding. Epidemiology and Pathogenesis
The general term “epulis” means exophytic gingi-
z Cytology and Histopathology val mass but is used only for fibromatous tumors of
Visual examination is usually diagnostic, but a the periodontal ligament (syn.:fibromatous epulis).
biopsy can be performed if necessary. Cytology is The tumor arises from the gingival periodontal
rather unspecific presenting with proliferating ligament. Brachycephalic breeds appear to be pre-
spindle cells. Histologically, a keratinizing squa- disposed and tumors occur at all ages. The term
mous epithelium covers vascularized propria peripheral odontogenic fibroma, derived from
Chapter 9 · Alimentary Tumors
175 9
human tumor nomenclature, should be avoided. z Suggested Reading
The canine tumor is comparable but not similar to (Desoutter et al. 2012; Fiani et al. 2011; Gardner
the human entity. Further proliferative or hyper- 1996; Yoshida et al. 1999)
plastic gingival lesions occur in dogs:
• Fibrous hyperplasia (not longer part of fibro-
matous epulides): mature, low cellular, fibrous
9.1.1.7 Canine Odontogenic
tissue, may contain epithelial nests and inflam-
Tumors
mation, and is familial in Boxer dogs
• Pyogenic granuloma: well-vascularized granu- Box 9.7. Canine Odontogenic Tumors in
lation tissue covered by often ulcerated gingi- Four Facts
val epithelium (pyogenic granuloma is actually 1. Ameloblastomas mostly arise rostral,
a misnomer) grow invasive, and do not metastasize.
• Peripheral giant cell granuloma (not longer 2. Acanthomatous ameloblastomas are
giant cell epulis): well-vascularized granulation unique to the dog.
tissue containing characteristic multinucleated 3. Odontomas mostly grow in the caudal
giant cells of presumed osteoclastic origin parts and comprise of variably
(granuloma would therefore be a misnomer) organized dental tissue.
4. Prognosis is favorable after complete
The fibrous hyperplasia is clinically indistin- resection.
guishable from fibromatous epulis of the peri-
odontal ligament. Treatment and prognosis are
similar for both lesions, so differentiation is
regarded as academic by some authors. Epidemiology and Pathogenesis
Odontogenic tumors include two categories: (1)
z Clinical Appearance “noninductive” types without odontogenic mes-
Epulides commonly develop at the rostral to the enchyma and (2) “inductive” types with the pres-
third maxillary premolar teeth and grow rather ence of odontogenic mesenchyma.
slowly, singular or multiple, and firm and rarely The first category comprisis ameloblastomas
reach 2  cm in diameter. They are gray-pink and and rarely occurring amyloid-producing odonto-
covered by mostly intact epithelium but may genic tumors (APOT). For ameloblastomas,
enclose or displace adjacent teeth. They are medium- to large-sized breeds are overrepre-
attached to the periosteum but do not invade bone. sented. The mean age is 7–10  years, and these
benign tumors do not metastasize.
z Cytology and Histopathology The second category comprises complex or
Epulides are difficult to be unequivocally diag- compound odontomas and the rarely occurring
nosed cytologically because they can be composed ameloblastic fibroma, as well as ameloblastic
of dental epithelial nests enrobed in stromal fibro-odontoma.
fibrous tissue that may be difficult to interpret Malignant variants are extremely rare and
without tissue architecture. Histopathology is nec- include ameloblastic carcinomas and fibrosarco-
essary to confirm initial diagnosis and evaluation mas. All malignant tumors exhibit infiltrative
of surgical margins. The tumors comprise of regu- growth and high mitotic activity.
lar, stellate mesenchymal cells, small fibrillary col-
lagen fibers, and often dilated blood vessels that z Clinical Appearance
rarely contain red blood cells. Osteoid or bone, Odontogenic tumors appear as slowly growing
cementum or dentin may be present, as well as expansile or infiltrative masses that might cause dis-
cords of odontogenic epithelium. location of teeth, teeth loss, and bone destruction.
Ameloblastomas typically arise in the rostral maxilla
z Prognosis and Therapy and mandibula, especially around the mandibular
The prognosis is excellent after surgical treatment, incisive. Tumors can be ulcerated. Despite their
but incomplete removal leads to recurrent growth. invasive growth, osteolysis, and teeth loss, metasta-
The risk for recurrence can be reduced by cryo- sis does not occur. Odontomas appear mostly in the
therapy. caudal parts of the mandible and maxilla.
176 A. Breithaupt

z Cytology and Histopathology mostly kittens as osteolytic masses of the rostral


Cytology presents with clustered interdigitating maxilla.
neoplastic epithelial cells with some degree of Reactive or hyperplastic lesions in the oral
anisocytosis and anisokaryosis. cavity of cats are peripheral giant cell granulomas
Ameloblastomas appear in different histotypes, which is the second most common oral mass after
including spindle cell, basaloid, desmoplastic and fibromatous epulis of periodontal ligament. Both
keratinizing types, and most frequently acantho- entities appear to behave biologically similar as in
matous ameloblastoma. This unique tumor of the dogs (see 7 Sect. 9.1.1.6).
dog can invade the underlying bone and is associ- Mast cell tumors, as in dogs, should be regarded
ated with cyst formation. It is composed of sheets as potentially malignant with potential metastasis
and cords of nonkeratinizing odontogenic epithe- to regional lymph nodes.
lium with prominent intercellular bridges and Oral papillomas and fibropapillomas are very
peripheral palisading of epithelial cells that have rare in cats and mostly associated with papillo-
antibasilar nuclei. mavirus antigen detection. Recently, a novel
Odontomas are benign tumors arising from papillomavirus was detected in the oral cavity of
the dental follicle and contain variable amounts of domestic cats.
well-differentiated epithelial and mesenchymal Odontogenic tumors, oral melanomas, and oral
dental tissues: whereas complex odontomas con- sarcomas are very rare. For prognosis and possible
tain disorganized tissues, compound odontomas treatment following canine tumors, see respective
display completely developed teeth. 7 Sects. 9.1.1.1, 9.1.1.3, and 9.1.1.7).
9
z Prognosis and Therapy z Suggested Reading
A favorable prognosis after treatment is known (Dunowska et al. 2014; Gardner and Dubielzig
for these benign odontogenic tumors. 1995; Munday et  al. 2015a; Sundberg et  al.
Surgery is the most common therapeutic 2000)
approach. Incomplete resection yields in recur-
rence. Especially for acanthomatous ameloblasto-
mas, mandibulectomy or maxillectomy is 9.1.2.1 Feline Oral Squamous Cell
required because of frequent bone invasion by Carcinomas (SCCs)
this benign tumor. Radiation therapy is less com-
mon although ameloblastomas are highly sensi- Box 9.8. Feline Oral Squamous Cell Carcinomas
tive. Many tumors however recur within the in Four Facts
radiation field or exhibit malignant transforma- 1. SCCs are the most frequent oral tumors
tion. Studies on chemotherapeutical treatments in cats
such as intralesional bleomycin application are 2. Common localization: gingiva,
rather scarce. sublingual (frenulum), and tonsil
3. Cats may develop tooth loss,
z Suggested Reading exophthalmos, and lymphadenopathy
(Fiani et  al. 2011; Kelly et  al. 2010; Poulet et  al. 4. Oral SCCs have a poor prognosis
1992; Theon et  al. 1997; Thrall 1984; White and
Gorman 1989)

Epidemiology and Pathogenesis


9.1.2 Feline Oropharyngeal Tumors SCC is the most frequent oral tumor in cats. One
report states that the risk to develop SCC is
Oral tumors in cats are mostly malignant with increased with the use of flea collars and intake of
squamous cell carcinomas (SCCs) being the canned food. The mean age is between 10 and 12
most common malignancy, which will be dis- years and neither sex nor breed predispositions
cussed in detail. Other, more rarely occurring are proven. Recent studies do not support that
neoplasms include fibrosarcomas. Feline induc- papillomavirus plays a significant role in tumor
tive odontogenic tumors are rare and affect development.
Chapter 9 · Alimentary Tumors
177 9
in cats than in dogs, and recurrence is common.
Especially grooming might be compromised after
aggressive resection and results in poor hair-coat
hygiene. Radiotherapy does not seem to improve
the survival time significantly but potentially in
combination with sensitizers or with chemother-
apy. Reliable data after chemotherapeutical treat-
ments are scarce and mostly survival time is not
essentially improved. Nonsteroidal anti-inflam-
matory drugs (NSAIDs) have not been described
consistently effective in literature.

z Current Research
There is ongoing research concerning new che-
motherapeutical treatments and the role of papil-
lomavirus in SCC.
. Fig. 9.2 Oral squamous cell carcinoma, cat: note
marked invasive growth (Courtesy of Stefanie Binder, Freie z Suggested Reading
Universität Berlin, Germany) (Bertone et al. 2003; Bilgic et al. 2015; DiBernardi
et al. 2007; Hayes et al. 2007; Munday and French
2015; Northrup et  al. 2006; Snyder et  al. 2004;
z Clinical Appearance Stebbins et al. 1989)
SCCs occur in decreasing frequency on the (1)
mandibular and maxillar gingiva, (2) (sub)lingual
adjacent to the lingual frenulum, and (3) on the 9.1.3 Equine Oropharyngeal Tumors
tonsils. They are mostly ulcerated and inflamed,
mimicking stomatitis. An early invasion of the
bone with marked osteolysis leads to loose teeth, z Epidemiology and Pathogenesis
tooth loss, and reactive bone proliferation (see Tumors of the oral cavity are uncommon in horses
. Fig. 9.2). Affection of the maxilla is frequently and in other large animals. Fibro-osseous neo-
associated with exophthalmos. Enlargement of plasms including osteomas and ossifying fibromas
regional lymph nodes is frequent, based mostly are reported as well as squamous cell carcinomas.
on associated inflammation and more rarely on Others, such as melanomas, fibrosarcomas, and
metastasis. Scarce reports exist about paraneo- lymphomas are very rare. Odontogenic tumors,
plastic malignant hypercalcemia. including ameloblastoma, ameloblastic odon-
toma, cementomas, and complex odontomas, are
z Cytology and Histopathology also known in horses (see . Fig. 9.3).
Cytology typically exhibits variably differentiated
epithelial cells and possibly keratin. Secondary, z Clinical Appearance
inflammation is frequent due to ulceration. The Oral tumors typically present with ptyalism, hali-
differentiation of SCC from epithelial hyperplasia tosis, quidding, tongue protrusion, nasal dis-
can be difficult. Histopathology is necessary for charge, dysphagia, inappetence, and weight loss.
final diagnosis and especially for evaluation of Invasion of underlying bone is frequent in
surgical margins. advanced stages.
Radiography can be used to determine tumor
z Prognosis and Therapy localization and bone lysis and endoscopy may
SCCs in the oral cavity have a poor prognosis. A visualize posterior masses.
multimodal treatment approach likely offers the
best chance of success; however, surgery, radiation z Cytology and Histopathology
therapy, chemotherapy, and combinations of them Depending on the tumor type, histology is
are rarely satisfactory. Surgical partial mandibu- required for definite diagnosis and evaluation of
lectomia and maxillectomia is less well tolerated tumor margins.
178 A. Breithaupt

infection, occurs in endemic areas such as Brazil,


England, and Scotland. Squamous cell carcinomas
at the same anatomical sites were also detected in
some of these regions, and bracken fern intoxica-
tion was identified as the environmental cofactor
and will not be discussed in further detail here.
Ameloblastic fibromas are the most common
odontogenic tumors of cattle. They occur at any
age but may particularly arise in young cattle.
Other tumors, such as oral squamous cell carcino-
mas, are very rare and will not be discussed in
detail.

z Clinical Appearance
. Fig. 9.3 Odontoma, zebra: note expansive growth
with compression of maxillary sinuses and nasal cavity As for all oral tumors, clinical signs include lumps,
(Courtesy of Stefanie Binder, Freie Universität Berlin, facial swellings, excessive salivation, halitosis,
Germany) pain, dysphagia, bleeding, snoring respiration,
cough, anorexia, weight loss, lymphadenopathy,
and changed voice.
z Prognosis and Therapy Oral papillomas are clinically and morpho-
9 The treatment of choice is surgical excision, prob- logically similar to the canine disease (see
ably including mandibulectomy due to recurrence 7 Sect.  9.1.1.5): mostly multiple, up to few cen-
after excision that is restricted to the mucosal timeters in size, flat or pedunculated tumors
level. with a smooth to fringy, wartlike surface. Lesions
may extent remarkably into the esophagus and
z Suggested Reading rumen.
(Gardner 1994; Kreutzer et al. 2007; Morse et al. Ameloblastic fibromas arise mostly in the
1988) vicinity of the mandibular incisors, are intraosse-
ous, and therefore may destroy adjacent bone see
(. Fig. 9.4a, b).
9.1.4 Bovine Oropharyngeal Tumors
z Cytology and Histopathology
Cytology is mostly not diagnostic for papillomas.
Histopathology is necessary for final diagnosis and
Box 9.9. Bovine Oral Tumors in Four Facts evaluation of tumor margins, particularly for
1. Oral tumors are rare in cattle. ameloblastic fibroma. Histopathology for papillo-
2. Bovine oral papillomatosis is associated mas is similar to lesions described in dogs (see
with BPV-4 infection. 7 Sect. 9.1.1.5).
3. Bovine oral papillomatosis is usually
self-limiting within 12 months. z Prognosis and Therapy
4. Ameloblastomas have a favorable For bovine oral papillomas, the prognosis is usu-
prognosis after resection. ally excellent due to its self-limiting character. The
cell-mediated immune response usually rejects
the tumors within 12  months. In immunosup-
pressed cattle, disease may persist or spread
z Epidemiology and Pathogenesis remarkably.
Large animals have a low prevalence of malignant Ameloblastic fibromas typically behave similar
tumors in the oral cavity. Oral papillomatosis, to ameloblastomas with a favorable prognosis after
associated with bovine papillomavirus 4 (BPV-4) surgical treatment.
Chapter 9 · Alimentary Tumors
179 9

a
Box 9.10. Canine and Feline Salivary Gland
Tumors in Three Facts
1. Tumors of the salivary glands are very
rare.
2. Tumors are almost always malignant.
3. Distant metastasis is frequent at time of
diagnosis.

z Epidemiology and Pathogenesis


Ninety-five percent of all salivary gland tumors are
malignant including various adenocarcinomas, squa-
mous cell carcinomas, basal cell carcinomas, and ana-
b plastic carcinomas. Also mixed tumors of epithelial
and myoepithelial origin are described. Cocker span-
iel dogs and Siamese cats are potentially overrepre-
sented. In cats, males are more frequently affected.

z Clinical Appearance
Mainly, the parotid and mandibular glands are
involved, inducing submandibular or periauricular
unilateral lumps. Local pain, anorexia, dysphagia,
bleeding, and halitosis are reported. Metastasis to
regional lymph nodes is common, particularly in
cats and distant metastasis, especially to the lung that
. Fig. 9.4 (a) (frontal) and (b) (sagittal) Ameloblastic also occur in cats and in dogs. Biopsy of enlarged
fibroma, mandible, calf, 3 weeks: note incorporation and lymph nodes is highly recommended. Radiography
dislocation of the incisor and massive granulation tissue can reveal periost proliferations, osteolytic changes,
proliferation (Courtesy of Moritz Radbruch, Freie
calcification of the mass, and distant metastases.
Universität Berlin, Germany)

z Cytology and Histopathology


Cytological investigation of fine-needle aspirates can
z Suggested Reading suspect salivary gland neoplasia, but histological
(Bocaneti et al. 2016; Campo et al. 1980; Masuda confirmation is often required. It was shown that the
et  al. 2011; Munday 2014; Tsirimonaki et  al. histological grade was not prognostic for the outcome,
2003) but advanced stage was a negative prognostic factor.

z Prognosis and Therapy


9.2 Tumors of Salivary Glands The prognosis for salivary gland cancer is unclear
due to limited data. The phenotype seems not to
9.2.1 Canine and Feline Salivary be relevant for prognosis. Cats tend to have a
Gland Tumors more aggressive disease with more frequent
metastasis to regional lymph nodes. Surgical ther-
Salivary glands are mostly affected by sialadenitis apy is aggravated due to adjacent structures that
and cysts, rarely by neoplasia. In both species, impede radical resection, but macroscopic incom-
these tumors occur in aged animals (>10  years) plete resection yields in recurrence and a poor
without breed or sex predilection, and the etiol- prognosis. Adjuvant radiotherapy significantly
ogy is undetermined. improves the survival time in dogs but not in cats.
180 A. Breithaupt

z Suggested Reading Esophageal tumor in cats are mostly SCC and


(Brown 1989; Hammer et al. 2001; Spangler and affect older animals.
Culbertson 1991)

z Clinical Appearance
9.3 Esophageal Tumors Animals typically show regurgitation, dysphagia,
salivation, vomiting, sometimes dyspnea, and
9.3.1 Canine and Feline Esophageal weight loss. Palpation of the mass can be challeng-
Tumors ing due to the common localization at the termi-
nal esophagus and cardia.
Esophageal SCCs frequently arise at the level
around the second rib and appear as white, nodu-
Box 9.11. Canine and Feline Esophageal
lar, and ulcerated masses. Leiomyomas are often
Tumors in Five Facts
found at the margin to the stomach and are mostly
1. Esophageal tumors are generally rare.
covered by intact, freely moveable mucosa mak-
2. Spirocerca lupi infection may induce
ing endoscopic biopsy unrewarding.
mesenchymal tumors in dogs.
Hypertrophic osteopathy, spondylitis of the cau-
3. Hypertrophic osteopathy may develop
dal thoracal, or more rarely lumbal vertebrae can
in dogs.
develop as paraneoplastic syndromes associated
4. Cats mostly present with SCC.
with esophageal tumors. This reaction is most likely
9 5. Tumors are often not amenable for
due to osteoproliferative growth factors secreted by
surgical resection.
esophageal tumors or their space-occupying effect.
Endoscopy is recommended and enables
biopsy sampling. Radiography (with radiocontrast
z Epidemiology and Pathogenesis media) may be helpful to verify megaesophagus,
Esophageal tumors are rather rare in cats and lung metastases, and secondary aspiration pneu-
dogs. Besides primary tumors, secondary, monia. Further, computer-assisted tomography
metastatic, or invasive growth of tumors, and magnet resonance imaging can also be sup-
including thymomas, chemodectomas, lympho- portive to determine the extent of the tumor.
mas, and ectopic thyroid glandular tissue, should
be considered as differentials. z Cytology and Histopathology
Primary tumors in dogs comprise of squamous Cytology is challenging, particularly for tumors
cell carcinomas (SCCs) and different types of with mesenchymal origin, and histology is required
adenocarcinomas, leiomyomas, leiomyosarcomas, to confirm malignancy, particularly with Spirocerca
fibrosarcomas, osteosarcomas, and plasmacytomas. lupi-associated masses. Leiomyosarcomas are
Affecting mostly aged dogs, there is no breed or mostly of low grade.
sex predisposition. These tumors frequently grow
locally invasive, and affection of the regional z Prognosis and Therapy
lymph nodes is common, either due to invasion or Prognosis for malignant tumors – except for low-
metastasis. Papillomas of the esophagus are grade leiomyosarcoma – is very poor.
uncommon and might be associated with oral Most of the tumors are surgically not amenable
viral papillomas (see 7 Sect.  9.1.1.5). In associa- due to their advanced stage and invasion of sur-
tion with nematode infections, esophageal osteo- rounding tissue. Radiotherapy is often problematic
sarcomas and fibrosarcomas are described. due to associated esophagitis and poor tolerance
Spirocerca lupi-associated tumors occur in indige- of adjacent tissue (lung, heart). Chemotherapeutical
nous areas including Africa, Israel, and the south- treatment is regarded not successful to date.
eastern United States. Adult nematodes are initially Spirocerca lupi-associated tumors can be treated by
found within granulomas with peripheral fibro- surgery and chemotherapy (e.g., doramectin).
blast proliferation. Malignant progression out of
these fibroblast leads to tumor development. z Suggested Reading
Invasive growth and metastasis into the lung, (Dvir et al. 2008; Farese et al. 2008; Kirberger et al.
bronchial lymph nodes, myocardium (rarely), 2013; Lindsay et al. 2010; Mazaki-Tovi et al. 2002;
kidneys, spleen, and adrenals is described. Ranen et al. 2004; van der Merwe et al. 2008)
Chapter 9 · Alimentary Tumors
181 9
9.3.2 Esophageal and Forestomach the middle ages are primarily affected; a predispo-
Tumors in Ruminants sition for male dogs is inconsistently found in the
literature. The relevance of chronic lymphoplasma-
Esophageal and ruminal papillomas caused by cytic enteritis or inflammatory bowel disease (IBD)
bovine papillomavirus-4 (BPV-4) are common in as a predisposing factor is under discussion.
some areas, including Brazil, Bolivia, England, In dogs, approximately 40 % of all intestinal
and Scotland. They may also affect the oral cavity. tumors arise in the large intestine. Mean age of
For details, see 7 Sect. 9.1.4. As in the oral cavity, patients is 8.5 years. Breed predispositions are sus-
some cattle may develop squamous cell carci- pected for West Highland white terriers, German
noma associated with BPV-4 or yet undetermined shepherd dog, and poodle, and male dogs are more
cancerogens. Fibropapillomas are usually associ- frequently affected. The three most common
ated with cutaneous (fibro-) papillomas and are tumors are benign adenomatous polyps
potentially caused by BPV-2, although in the ali- (see 7 Sect. 9.4.1.1), adenocarcinomas (mostly rec-
mentary tumors, BPV-2 expression could not be tal, see 7 Sect.  9.4.1.1), and lymphomas
detected and will not be discussed in detail. (see 7 Sect.  9.4.1.2). Besides this, gastrointestinal
stromal tumors (GIST), leiomyomas, leiomyosarco-
mas (see 7 Sect. 9.4.1.3), plasma cell tumors, carci-
9.4 Gastrointestinal Tumors noids, and signet-ring cell carcinomas are reported.

9.4.1 Canine Gastrointestinal z Clinical Appearance


Tumors Gastric tumors mostly present with blood-tinged
vomiting, anorexia, and progressive weight loss,
more rarely with abdominal pain. Most of the
z Epidemiology and Pathogenesis tumors arise in the distal, pylorus parts.
In dogs, approximately one quarter of all gastro- Ultrasound diagnosis is recommended including
intestinal tumors arise within the stomach. The imaging of lymph nodes and abdominal metasta-
most frequent tumors are adenocarcinomas (see sis in combination with endoscopy.
7 Sect.  9.4.1.1) and lymphomas (see For small intestinal tumors, patients do not
7 Sect.  9.4.1.2), followed by leiomyomas and show any clinical signs in 50 % of the cases, but
leiomyosarcomas (see 7 Sect.  9.4.1.3). Among vomiting, chronic weight loss (due to anorexia
others, adenomas and adenomatous polyps are and malabsorption), abdominal pain, diarrhea,
described and will not be discussed in detail. melena, and ileus are described. Abdominal pal-
Dogs are typically 7–15 years of age, adenocarci- pation of the mass may be possible. At diagnosis,
nomas can also affect younger dogs, and leiomyo- most tumors are in advanced stages. Metastatic
mas often occur in very old dogs. Male dogs are spread to the mesenteric lymph nodes, omentum,
overrepresented, but data are inconsistent spleen, liver, and lung is common.
regarding breed predisposition. The gastric Clinical signs of colorectal tumors are unspe-
mucosa of dogs is often colonized by non- cific and match those of other large intestinal dis-
Helicobacter pylori helicobacters (NHPH). The ease: tenesmus, hematochezia (bloody stool),
pathogenic significance of gastric NHPH in dogs mucous feces, diarrhea, or obstipation. In two
is poorly understood and remains controversial. thirds of cases, the mass can be palpated rectally.
Most authors suggest that Helicobacter species Ultrasound findings typically present with
are not associated with tumor development. bowel wall thickening and loss of normal wall lay-
Small intestinal tumors occur more rarely com- ers. This method has been proven to differentiate
pared to large intestinal tumors and up to 90 % are neoplastic from nonneoplastic disease in many
malignant lymphomas (see 7 Sect. 9.4.1.2), which cases and is more sensitive than radiography for
are the most common intestinal tumors in several identifying a mass. It is also useful for the detec-
reports, followed by adenocarcinomas (see tion of metastasis and guidance of fine-needle
7 Sect.  9.4.1.1) and leiomyosarcomas or gastroin- aspiration/biopsy sampling.
testinal stromal tumors (see 7 Sect.  9.4.1.3). Native radiography is almost always not diag-
Further, carcinoids and mast cell tumors are nostic, but usage of contrast agent can be helpful.
reported but will not be discussed in detail. Dogs in Laparotomy may be indicated in contrast to
182 A. Breithaupt

endoscopic biopsy. The macroscopic evaluation recommended after resection of solid lymphoma.
and the tissue samples obtained from laparotomy Radiotherapy is rarely used for (adjuvant) treat-
are commonly diagnostic. ment of intestinal tumors.
Hypoproteinemia due to malabsorption is In the large intestine, except for lymphoma,
common. Dogs with non-lymphomatous neopla- surgical resection is generally mandatory.
sia may show elevated liver enzymes, specifically Depending on the localization and stage, endo-
alkaline phosphatase or hypoglycemia, particu- scopic, laparoscopic approaches, pelvic osteoto-
larly with smooth muscle tumors, due to insulin- mies, or a “pull-through” technique (eversion of
like growth factor secretion. distal parts through the anus) can be performed.
Postsurgical complications include rectal hem-
z Cytology and Histopathology orrhage, wound dehiscence, tenesmus, or fecal
Cytology and histopathology will be discussed for incontinence. Non-resectable tumors can be
the respective tumor types (see 7 Sects.  9.4.1.2, treated by radiotherapy, and chemotherapy can
9.4.1.3, 9.4.2, 9.4.2.1, 9.4.2.2, 9.4.2.3, 9.4.3, and improve the clinical appearance of patients.
9.4.4).

z Prognosis and Therapy z Suggested Reading


For gastric benign tumors, complete surgery is (Cohen et al. 2003; Danova et al. 2006; Eisele et al.
usually curative. The prognosis for malignant 2010; Frank et  al. 2007; Gaschen 2011; Gieger
gastric cancer is generally poor. Even after sur- 2011; Paoloni et al. 2002; Patnaik et al. 1977, 1978,
9 gical resection of the tumors, most of the 1980; Penninck et  al. 2003; Rassnick et  al. 2009;
patients succumb within 6 months due to recur- Simon et al. 2005; von Babo et al. 2012; Willard
rence or metastasis. Surgery is the most com- 2012)
mon treatment for gastric tumors, particularly
for adenomas, carcinomas, leiomyomas, and
leiomyosarcomas. The procedure should include 9.4.1.1 Canine Gastrointestinal
evaluation of the liver and all abdominal lymph Adenocarcinomas
nodes for metastasis, not least for adequate stag-
ing based on the TNM system. Radiotherapy
Box 9.12. Canine Gastrointestinal Adeno-
with low doses may be helpful to reduce the
carcinomas in Five Facts
tumor size. Generally, systemic diseases (lym-
1. Occur mainly in the pyloric region and
phomas) require chemotherapeutical approaches,
great curvature of the stomach and
but dogs with gastrointestinal lymphomas gen-
rectum
erally have a worse response than do dogs with
2. Infiltrating, nonulcerating are the most
other primary locations of lymphomas.
common types
Nevertheless, resection of large-volume or
3. Tumor cells often induce scirrhous
ulcerative tumors may be palliative for the
reaction (“leather bottle” or “linitis
patient.
plastica”)
Generally, intestinal tumors have a guarded to
4. Most tumors are metastasized at
favorable prognosis if resection is complete. The
diagnosis
prognosis after resection of adenomas and leio-
5. Adenomatous polyps are mostly rectal,
myomas is good. The survival time for sarcomas
and benign but malignant progression is
tends to be longer when compared to carcinoma.
possible
Surgical resection is a common treatment for
intestinal tumors except for lymphomas.
Resection should include tissue margins of 5 cm
cranial and caudal to the tumor, which can be z Epidemiology and Pathogenesis
problematic in the proximal duodenum without Adenocarcinomas in the gastrointestinal tract
resection of the bile and pancreatic duct or require mostly affect dogs at the age of 11–12  years for
anastomosis of ileum to colon. It is unclear gastric and 9–10 years for intestinal tumors. Male
whether chemotherapy is beneficial for (adjuvant) dogs may be overrepresented and German shep-
treatment of epithelial tumors; nevertheless, it is herds appear predisposed.
Chapter 9 · Alimentary Tumors
183 9
z Clinical Appearance well-differentiated neoplastic epithelial cells.
Gastric carcinomas typically develop in the Cytology however often misses the malignant
pyloric region and more rarely at the greater cur- cells, which are usually located deep in the
vature. They are mostly pink to red and can be intestinal wall. Histological analysis of several,
infiltrative or exophytic with or without ulcer- adequately large biopsy samples of affected (and
ation. The infiltrating, nonulcerating variant is unaffected) regions is often necessary for final
the most common type. Infiltrative variants are diagnosis. Histological diagnosis is aggravated
frequently scirrhous (with abundant fibrous tis- by superficial samples of unaffected mucosa or
sue, “leather bottle” appearance, “linitis plas- due to necrosis, ulceration, and inflammation
tica”) leading to an induration of the gastric wall. leading to false-negative biopsies.
Metastasis to regional lymph nodes and more
distant to the lung, liver, and spleen is commonly z Prognosis and Therapy
observed. Gastrointestinal carcinomas have a poor prog-
Intestinal adenocarcinomas grow either hori- nosis. Surgery is the treatment of choice for
zontal/cobblestone-like or circular/annular gastric tumors. However, tumors can rarely be
within the intestinal wall, or they vertically pro- resected with complete margins. In addition,
trude into the lumen as pedunculated masses. The metastasis is often present at the time of diag-
different growth patterns may relate to behavior nosis.
and prognosis. They metastasize rarely but can The treatment of intestinal carcinomas consists
manifest in unusual locations, including the skin of surgical resection. Colon tumors are more
or meninges. The rectum is the most common site prone to dehiscence and are often associated with
and tumors are usually palpable; further, the colon fecal incontinence. If the patient does not experi-
and duodenum are common sites. ence complications, tumor resection may be pal-
Adenomatous polyps are found in the rectum liative for months. Radiation is not commonly
of dogs as solitary masses. They are usually benign performed. Adjuvant chemotherapy can be pallia-
and do not metastasize. Malignant progression to tive.
adenocarcinomas is possible and might be related For adenocarcinoma, the p53 overexpres-
to p53 tumor-suppressor gene mutations, but sion, lower expression of p21, lack of p16, but
immunohistochemically detectable overexpres- increased p16 index immunoreactivity were
sion of p53 is not prognostic. related to histopathological characteristics of
The most sensitive test to find rectal lesions is malignancy.
digital rectal examination. Plain radiographs are C2-O-sLe(x) is a suggested tumor-associated
rarely diagnostic, but the use of contrast media may antigen that may play a role in the invasiveness
document infiltrative gastric adenocarcinomas. and metastatic potential of certain canine gastric
Sonography and endoscopy are useful for the diag- carcinoma types.
nosis of gastric neoplasia. Endoscopy seems to be The expression of gastrin in gastric carcino-
more accurate in identifying gastric neoplasia, par- mas is less common (in contrast to human
ticularly for lymphoma. Percutaneous fine-needle tumors) and therefore not useful as prognostic
aspiration (FNA) of enlarged lymph nodes or thick- marker, and the serum gastrin concentration
ened gastric wall is frequently diagnostic. Endoscopy alone is not a useful biomarker for gastric carci-
is regarded as the most sensitive and specific way to nomas in dogs.
diagnose gastric carcinomas. Proctoscopy (with Colorectal adenocarcinomas often express
biopsy) are recommended for more aboral lesions COX-2, suggestive for promising NSAID-based
with rigid biopsy forceps. They enable deep-mural chemotherapy.
samples that are critical for distinguishing benign
polyps from adenocarcinomas. Further aboral z Suggested Reading
tumors may require ultrasonography. (Carrasco et al. 2011; Church et al. 1987; Hampson
et al. 1990; Janke et al. 2010; Krauser 1985; Marolf
z Cytology and Histopathology et  al. 2015; McEntee et  al. 2002; Patnaik et  al.
Cytology can be difficult to interpret. 1977, 1980; Seim-Wikse et  al. 2014; Tomlinson
Adenocarcinomas are composed of variably et al. 1982; Valerius et al. 1997; Willard 2012)
184 A. Breithaupt

9.4.1.2 Canine Gastrointestinal face the same problems, and several, adequately
Lymphomas large biopsy samples should be taken.
Alimentary lymphomas in dogs are most com-
monly T-cell derived and can be classified as small-
Box 9.13. Canine Gastrointestinal Lympho-
to medium-sized (often epitheliotropic) and large
mas in Five Facts
lymphoblastic cell types. Immunohistochemistry
1. Gastrointestinal lymphomas are mostly
or special staining (e.g., CD79a as B-cell marker,
primary tumors and often T-cell derived
CD3 as T-cell marker, Toluidine blue for detection
2. T-cell types: associated with a poor
of metachromatic granules) is recommended to
response to chemotherapy
distinguish tumor subtypes (B-cell origin, T-cell
3. T-cell types: shorter survival times and
origin, mast cells). A grading system for lympho-
remissions
mas in domestic animals is given in . Table 6.2.
4. High-grade lymphomas are associated
Recently, a stepwise and complex diagnostic
with higher mortality rates
approach using histology followed by immuno-
5. Chemotherapy is recommended
phenotyping and determining the Ki67 index
and finally PCR for clonality has been estab-
lished to improve the accuracy of distinguishing
z Epidemiology and Pathogenesis intestinal lymphomas from IBD in dogs (see
Lymphomas are common in the stomach and the Carrasco et al. 2015).
most frequent canine intestinal tumor in most
9 reports. It is still under debate if chronic z Prognosis and Therapy
lymphoplasmacytic gastroenteritis/inflammatory Gastrointestinal lymphomas are associated with a
bowel disease (IBD) can progress to lymphoma. poorer prognosis compared to multicentric lym-
phomas. Patients with metastases commonly have
z Clinical Appearance a markedly shorter median survival time.
The majority of gastrointestinal lymphomas are a As stated in Chap. 6, in general, high-grade
primary manifestation and not part of a multicen- lymphomas are associated with higher mortality
tric tumor in dogs. The stage of the disease can be rates than intermediate- or low-grade lympho-
assessed by applying the clinical staging system of mas. T-cell lymphomas, the most common variant
the WHO (World Health Organization), given in in dogs, are reported to have shorter survival
. Table 6.1. For further details on different clas- times and remissions. Further, the T-cell pheno-
sification systems, particularly the grading sys- type of high-grade lymphoma is generally associ-
tem, please see . Table 6.2. Multicentric forms ated with a poor response to chemotherapy. Not
present with abdominal lymphadenopathy and/or least, the assessment of the frequency of AgNORs
affection of the liver, spleen, and bone marrow. (argyrophilic nucleolar organizer regions) and the
Endoscopically, lymphomas often appear in a investigation of the potential doubling time (Tpot)
smooth or a cobblestone pattern of a pale-white to can be used as predictors of outcome in dogs (see
pink mucosa, and they arise within the submu- 7 Chap. 6).
cosa and the mucosa-associated lymphatic tissue Chemotherapy using variations of “CHOP”
(MALT). Biopsy samples from the liver spleen, combination protocols (cyclophosphamide, doxo-
and mesenteric lymph nodes should be taken to rubicin [=hydroxydaunorubicin], vincristine
detect possible metastasis. [= Oncovin], prednisone) or a modified Madison
Wisconsin protocol is the preferred therapy (see
z Cytology and Histopathology 7 Chap. 6). Dogs treated with combination che-
Cytology can be difficult to interpret. As men- motherapy (i.e., cyclophosphamide, doxorubicin,
tioned in other chapters, the accuracy of diagnosis vincristine, L-asparaginase, prednisolone, lomus-
for lymphomas is strongly correlated to the quality tine, procarbazine, mustargen) have a more or less
of the slides, i.e., the high proportion of neoplastic 50 % response rate, with a median survival time of
cells. Reactive infiltration of immune cells aggra- approximately 110 days in responders. Particularly
vates the diagnosis, and the differentiation of for solid forms, surgery may be beneficial.
inflammation from well-differentiated small cell Radiation therapy may also be feasible for solitary
lymphomas is challenging. Histopathology may forms or as palliative therapy.
Chapter 9 · Alimentary Tumors
185 9
z Current Research
There is ongoing research focusing on new diag-
nostic and prognostic markers (such as antigen
receptor gene rearrangements, Ki67 index) as well
as chemotherapeutical protocols. Recent studies
suggest that a change in the number of Foxp3-
positive regulatory T cells contributes to the
pathogenesis of intestinal lymphoma.

z Suggested Reading
(Carrasco et al. 2015; Couto et al. 1989; Coyle and
Steinberg 2004; Frank et  al. 2007; Gieger 2011;
Maeda et al. 2016; Ohmura et al. 2015; Rassnick
et al. 2009; Simon et al. 2006, 2008)

. Fig. 9.5 Gastric leiomyoma in the cardiac region, dog,


9.4.1.3 Canine Gastrointestinal adult (Courtesy of Dr. Marie von Deetzen, Freie Universität
Spindle Cells Tumors Berlin, Germany)
(Leiomyomas, Myosarcomas,
and Gastrointestinal Stromal Leiomyosarcomas arise typically in the intes-
Tumors (GIST)) tine and grow slowly and infiltrative. Dogs often
present with anorexia, lethargy, vomiting, weight
Box 9.14. Canine Gastrointestinal Leiomyomas,
loss, abdominal distention, and diarrhea.
Myosarcomas and GIST in Three Facts
Perforation of the intestinal wall may be present.
1. The clinical relevance of differentiating Paraneoplastic hypoglycemia is frequently
GISTs from leiomyosarcomas is unclear. reported with both leiomyomas and myosarco-
2. GIST arise predominantly in the mas. GIST are found in the stomach and intestine
stomach and large intestine. with some preference to the large bowel. They
3. GIST are positive for CD117 (c-Kit) and grow slowly and only late stages exhibit metastasis
CD34 and negative for SMA and to mesenteric lymph nodes, seldomly to the liver
desmin. and spleen.
Plain abdominal radiographs may indicate an
abdominal mass, but ultrasonography is more reli-
able. Endoscopically, these tumors mostly appear
Epidemiology and Pathogenesis as hard masses covered with normal mucosa.
Leiomyomas and leiomyosarcomas are primarily
tumors in aged dogs (>10  years). These tumors z Cytology and Histopathology
grow slowly and metastasize late if at all. Cytology of fine-needle aspirates is generally not
Gastrointestinal stromal tumors (GIST) arise from helpful for tumor diagnosis. Histology is necessary
the cells of Cajal, the so-called intestinal pace for final diagnosis and examination of tumor
makers, and can be differentiated from other mes- margins. Immunohistochemistry is necessary to
enchymal tumors, particularly leiomyosarcomas. differentiate GIST, leiomyomas, or sarcomas.
The clinical importance of this differentiation is GIST are positive for c-Kit (CD117) and CD34,
uncertain at this time. while leiomyomas and leiomyosarcomas are nega-
tive for these antigens but positive for smooth
z Clinical Appearance muscle actin and/or desmin.
Leiomyomas are more common in the stomach,
arise extraluminal, often solitary within the z Prognosis and Therapy
muscular wall and may project into the lumen. Leiomyomas have a good prognosis and surgery is
They are covered by intact mucosa and can reach usually curative.
large size until the dog shows clinical disease Surgical excision is the common treatment
(see . Fig. 9.5). for intestinal leiomyosarcoma. The prognosis is
186 A. Breithaupt

relatively good. The median survival time varies lymphomas are usually not associated with FeLV,
greatly between 1 and 2 years. Even with detect- but some cats have been positive for FIV.
able metastasis at the time of surgery, long mean
survival times are documented. Anyhow, meta- z Clinical Appearance
static rates are low to moderate. Long-term sur- Cats with gastric tumors most commonly present
vival is reported possibly with early, complete with vomiting, hematemesis, anorexia, and less
surgical excision. frequently weight loss. A gastric mass is difficult
GIST appear to have longer median survival to palpate, but endoscopy, ultrasonography, and
times compared to leiomyosarcomas, but data are radiography may help to visualize a distinct mass
inconsistent. GIST can have a mutation in the or thickened gastric wall with loss of physiologic
c-KIT oncogene. Inhibitors of tyrosine kinase layering.
show promising effects, but until now, reliable For intestinal tumors, weight loss due to
data are missing. Proliferation markers (Ki67, anorexia and/or malabsorption and vomiting are
AgNor) seem to have prognostic relevance for reported. For detailed diagnostic approaches, see
GIST. in the following chapters on specific tumors.

z Suggested Reading z Cytology and Histopathology


(Cohen et al. 2003; Frost et al. 2003; Gillespie et al. Cytology and histopathology will be discussed for
2011; Gregory-Bryson et  al. 2010; Hayes et  al. specific tumor types in the following chapters.
2013; LaRock and Ginn 1997; Maas et  al. 2007;
9 Russell et al. 2007; Willard 2012) z Suggested Reading
(Bridgeford et  al. 2008; Canejo-Teixeira et  al.
2014; Gabor et  al. 1998; Patnaik et  al. 1976;
Rissetto et al. 2011; Slawienski et al. 1997)
9.4.2 Feline Gastrointestinal Tumors

9.4.2.1 Feline Gastrointestinal


z Epidemiology and Pathogenesis Lymphomas
Gastric tumors are rare in cats. The most common
tumors are lymphomas (see 7 Sect.  9.4.2.1), fol-
lowed by adenocarcinomas (see 7 Sect.  9.4.2.2) Box 9.15. Feline Gastrointestinal Lymphomas
and leiomyomas; the latter will not be discussed in Five Facts
in detail. 1. Most frequent intestinal tumors
The role of Helicobacter sp. in the development 2. Cats <4 years usually have
of gastric tumors is still under discussion. FeLV-associated lymphomas, which are
Small intestinal tumors in cats include in rare
decreasing order of frequency lymphomas, adeno- 3. Cats >8 years usually have
carcinomas, and mast cell tumors (MCTs). Mean non-FeLV-associated lymphomas,
ages of cats range between 10 and 12  years, but which are more common
(most likely FeLV positive) patients can be 4. Well-differentiated/low-grade/
younger. A gender predisposition is discordantly lymphocytic types have a better
reported. Siamese cats are overrepresented for prognosis
intestinal adenocarcinomas and lymphomas. 5. Poorly differentiated/high-grade/
There is no association between retroviral infec- lymphoblastic types have poorer
tion and nonlymphomatous intestinal neoplasia progression
in cats. Other neoplasias are rare and will not be
discussed in detail.
In cats, 10–15 % of all gastrointestinal tumors Epidemiology and Pathogenesis
arise in the large intestine. Mean age of these cats For detailed information about feline lymphomas
is 12.5 years; no sex and breed predispositions are in general and particularly the association with
proven so far. The most frequent types are adeno- feline leukemia virus (FeLV) and feline immuno-
carcinomas, lymphomas, and MCTs. Colorectal deficiency virus (FIV), see also Chap. 6. Lymphomas
Chapter 9 · Alimentary Tumors
187 9
in cats are associated with a bimodal age distribu-
tion. The first peak, at <4  years of age, is mostly
FeLV associated and less common. The second
peak, at >8 years of age, is usually not FeLV associ-
ated and more common. Siamese cats and males
have been associated with a higher risk to develop
lymphomas.
Gastric lymphomas area relatively uncommon
manifestation with a predominance of large B-cell
lymphoblastic lymphomas.
Lymphomas are the most frequent intestinal
tumors in cats with an increasing incidence, and
most of them are FeLV- and FIV-negative. The
differentiation from chronic inflammatory bowel
. Fig. 9.7 Alimentary lymphoma, cat: note the
disease can be challenging. Some authors suggest ulceration (arrow) (Courtesy of Anja Ostrowski, PhD,
that inflammatory bowel disease is a prelym- Freie Universität Berlin, Germany)
phoma entity.

z Clinical Appearance or radiography, particularly using contrast media.


In general, solid forms are differentiated from dif- Endoscopy is a useful technique to visualize the
fuse forms with mural infiltrations. Solid tumors tumor and enable sampling.
may lead to obstruction and are often ulcerated Intestinal lymphomas cause weight loss, some-
(see . Figs. 9.6 and 9.7). With systemic affection, times associated with diarrhea and vomiting.
enlarged abdominal lymph nodes, liver, spleen, Large intestinal involvement causes more fre-
and kidneys are found. quently diarrhea and can also cause weight loss.
Vomiting is a common clinical sign of gastric Ultrasound is suitable for imaging and guidance
lymphomas. The tumors can present as either a of fine-needle aspiration. Tumors characteristi-
diffuse infiltration or a discrete, solid mass; the cally present with intestinal wall thickening and
latter is more common. Palpation of gastric loss of normal wall layers. Endoscopic evaluation
masses is challenging, but a mass or thickened of tumors is restricted to duodenal masses. Plain
gastric wall might be visible with ultrasonography abdominal radiographs may reveal an abdominal
mass, but the use of contrast media may be more
useful. Thoracic radiographs complete evaluation
of the patient for metastatic disease.
The progression of disease depends on the
type of lymphoma with well-differentiated, lym-
phocytic forms progressing slower (months)
than poorly differentiated, lymphoblastic forms
(days or weeks). Two different staging systems
are commonly used and given in Chap. 6,
including the WHO staging of lymphomas in
domestic animals (Owen 1980, see . Table 6.1)
and the system for staging of feline lymphomas
established by Mooney and Hayes (1986, see
. Table 6.3).

z Cytology and Histopathology


Cytology and histology of feline lymphomas are
. Fig. 9.6 Alimentary lymphoma, cat: manifestation in
given in detail in Chap. 6 including figures (cytol-
the stomach and intestine (Courtesy of Kristina Dietert, ogy) and apply also for lymphomas in the stom-
PhD, Freie Universität Berlin, Germany) ach and the lower gastrointestinal tract.
188 A. Breithaupt

In general, cytology is likely diagnostic with intestinal tract in general, particularly in the jeju-
samples from the actual tumor with adequate num and a B-cell-type predominance in the
numbers of neoplastic cells and less reliable with stomach. The authors suggested that cases of T-cell
samples of the tumor boarder or necrotic tumor lymphoma can be misinterpreted as inflammatory
parts with low numbers of neoplastic cells, abun- bowel disease. Finally, a diagnostic algorithm to
dant reactive lymphocytic background, and if neo- differentiate lymphomas from inflammation in
plastic cells are well-differentiated (see . Fig. 9.8) feline small intestinal biopsy samples has been
Histopathology is also restricted by these fac- established (see Kiupel et al. 2011).
tors, but the evaluation and effacement of the tis-
sue architecture can be helpful. Due to the fact z Prognosis and Therapy
that well-differentiated neoplastic lymphocytes Detailed information on prognosis specific for
can mimic nonneoplastic lymphocytes, and less gastric lymphomas is not available, but reports
differentiated neoplastic lymphocytes resemble indicate that gastric lymphomas can experience
lymphoblasts, the interpretation of the growth survival times comparable to other types of feline
pattern is important. In challenging cases, it is lymphomas with chemotherapy.
highly recommended to include immunohisto- Median survival times for gastrointestinal lym-
chemistry for CD3/CD79a (T-cell/B-cell marker) phomas vary from 2 to 24 months; a specific loca-
and the assessment of clonality (reactive, poly- tion has not been shown to be prognostic, and the
clonal lymphocytes vs. neoplastic, monoclonal most consistent prognostic factor appears to be
lymphocytes) to support the diagnosis. Three his- the response to treatment. Further, low-grade lym-
9 tological grades are recognized: low-, intermedi- phomas seem to have a better prognosis (median
ate-, and high-grade lymphomas. Recent reports survival of, e.g., 17 months) than high-grade lym-
have shown a predominance of high-grade lym- phomas (2.7  months). Other prognostic factors,
phomas arising in the stomach. such as substage, immunophenotype, and pre-
B- and T-cell tumors are almost equally fre- treatment with steroids, inconsistently predict the
quent. Recent investigations indicate a predomi- outcome. A prognostic value of the immunophe-
nance of mucosal T-cell lymphoma types in the notyping (i.e., B- or T-cell lymphomas) could not
be confirmed in general. Recent studies on gastro-
intestinal lymphomas however suggest that low-
grade T-cell lymphomas (small cell type) are
associated with prolonged survival (median
18.9 months); cats with transmural T-cell lympho-
mas (particularly large granular lymphocyte type)
had a much shorter median survival time
(1.5 months). Further, the presence of secondary
leukemia may have an adverse effect on progno-
sis.
Feline lymphomas are mostly a systemic dis-
ease, requiring chemotherapy. So again, modifica-
tions of the CHOP protocol (cyclophosphamide,
doxorubicin [=hydroxydaunorubicin], vincris-
tine [=Oncovin], prednisone) are useful, except
for the therapy of well-differentiated types. Based
on the occurrence of solitary form, particularly in
. Fig. 9.8 Cytology, high-grade B-cell lymphoma
(Burkitt-like lymphoma), intestinal wall, cat, the stomach (and lower intestinal tract), radiation
May-Grünwald-Giemsa 1000×. There are numerous, therapy can be useful.
medium-sized to large lymphatic blasts with round Whereas well-differentiated/lymphocytic/small
eccentrically located nucleus, fine chromatin pattern, cell lymphomas may show a high responsiveness
mainly indistinct nucleoli and moderate amounts of a
and remission rate with prednisone and chloram-
basophilic cytoplasm containing many small vacuoles
(red arrow) (Photo: with permission of Dr. N. Bauer, bucil treatment and a median survival times of
Faculty of Veterinary Medicine, Justus-Liebig-University, nearly 2 years, poorly differentiated/lymphoblastic
Giessen, Germany) lymphomas appear less responsive with lower
Chapter 9 · Alimentary Tumors
189 9
remission rate and median survival times of less
than 3  months. Adjuvant surgery seems not to
improve survival compared to chemotherapy
alone.

z Current Trends in Research


Hematopoietic tumors represent the bulk of neo-
plastic diseases in cats; thus, ongoing research
focuses on the improvement of therapy and diag-
nosis as well as factors and markers that might be
prognostic.

z Suggested Reading . Fig. 9.9 Intestinal adenocarcinoma, cat: note the


typical “bottle neck appearance” (Courtesy of Dr. Stefanie
(Grover 2005; Gustafson et al. 2014; Kiupel et al. Eggert, Freie Universität Berlin, Germany)
2011; Lingard et  al. 2009; Moore et  al. 2012;
Patterson-Kane et  al. 2004; Pohlman et  al. 2009;
Rissetto et  al. 2011; Roccabianca et  al. 2006; leads to a circular stricture with an orally located
Willard 2012) dilation, called “bottle neck appearance” see
(. Fig. 9.9).

9.4.2.2 Feline Gastrointestinal z Cytology and Histopathology


Adenocarcinomas As mentioned for canine adenocarcinomas, cytol-
ogy can be difficult to interpret. Adenocarcinomas
usually have the general characteristics of neo-
Box 9.16. Feline Gastrointestinal Adeno- plastic epithelial cells, but cytological samples
carcinomas in Three Facts often do not include tumor cells because of their
1. Mostly arise in the small intestine. deep location.
2. Distant metastasis is usually present at For histopathology, several adequately large
diagnosis. biopsy samples should be taken. Histological
3. Typical “bottle neck” appearance due to diagnosis is aggravated due to the often unaf-
circular stricture. fected mucosa in only superficial samples or due
to necrosis, ulceration, and inflammation leading
to false-negative biopsies. Samples of mesenteric
Epidemiology and Pathogenesis or ileocecal lymph nodes are recommended for
Adenocarcinomas primarily affect older cats, of detection of metastasis.
which 50 % are older than 11  years. There is no Several histologic subtypes of adenocarcino-
gender predisposition, but Siamese cats are over- mas are described including solid (low grade),
represented. In decreasing order of occurrence, papillary, or tubular and finally mucinous.
adenocarcinomas arise in the jejunum, ileum, Fibrous, cartilaginous, or osseous metaplasia is
ileocecal region, and duodenum. At diagnosis, frequent. Histology is needed for final diagnosis
metastasis is present in mesenteric lymph nodes, on evaluation of surgical margins.
peritoneum (carcinomatosis), liver, and lung in
most patients. z Prognosis and Therapy
The prognosis of gastric adenocarcinomas is
z Clinical Appearance unclear due to the small number of reported cases
Cats with intestinal carcinomas may present with but most likely is guarded to poor. Prognosis for
anorexia, vomiting, obstruction, diarrhea, weight adenocarcinomas might depend on the location
loss, bleeding, and/or intussusception. In approxi- or the histological phenotype. Median survival
mately 50 % of cases, cats have a palpable mass in times vary (weeks to years) depending on the
the abdomen that is also visible on radiographics. progress of the disease.
Mostly, usage of contrast agent visualizes a partial Surgery is the common treatment and in many
or complete obstruction. Typically, the tumor cases possible with complete surgical margins.
190 A. Breithaupt

For adenocarcinomas, solid masses should be


treated surgically with at least 5 cm of unaffected
margins.
To date adjuvant chemotherapy is not proven
to be beneficial. Long-term survival is rare but
possible as long as metastasis is not evident.

z Suggested Reading
(Birchard et al. 1986; Cribb 1988; Kosovsky et al.
1988; Patnaik et al. 1976; Willard 2012)

. Fig. 9.10 Intestinal mast cell tumor, cat: note diffuse


9.4.2.3 Feline Gastrointestinal Mast infiltration (arrow) of the intestinal wall (Courtesy of
Dr. Marie von Deetzen, Freie Universität Berlin, Germany)
Cell Tumors (MCTs)

Box 9.17. Feline Gastrointestinal Mast Cell cumferential, eccentric wall thickening, often with
Tumors in Four Facts loss of physiological wall layering (see . Fig. 9.10).
1. MCTs have to be differentiated from
feline gastrointestinal eosinophilic scle- z Cytology and Histopathology
9 rosing fibroplasia. Cytology may not be diagnostic, and histology of
2. MCT should be considered malignant biopsy sample is the most effective diagnostic
since metastasis is common at time of approach. Mucosal ulceration is rare in feline pri-
diagnosis. mary intestinal mast cell tumors. Neoplastic cells
3. Prognosis is poor. are usually less well differentiated than the cuta-
4. Surgery is the treatment of choice. neous counterpart and may require special stain-
ing (even metachromatic staining is often difficult
to identify) or immunohistochemistry. Sheets of
Epidemiology and Pathogenesis round cells often infiltrate the muscularis and
Intestinal MCTs are the third most common propria with associated fibrosis. Eosinophilic
tumors in the intestinal tract of cats and prefer- infiltrates are uncommon.
entially affect aged animals. Tumors have to be
differentiated from feline gastrointestinal eosino- z Prognosis and Therapy
philic sclerosing fibroplasia. The latter is an In general, these tumors should be considered
ulcerated, intramural mass occurring usually in malignant. Survival time is <4 months. Metastasis
the stomach (pyloric region) or ileocecal junc- is common at time of diagnosis. Surgery is the
tion and may also affect adjacent lymph nodes. treatment of choice for MCT. The overall postsur-
gical prognosis is however poor. Medical manage-
z Clinical Appearance ment with histamine block (H1 and H2 blockers)
Cats with intestinal MCT present with intermit- should be considered. To date, receptor tyrosine
tent vomiting, diarrhea, weight loss, anorexia, and kinase inhibitors have not been tested in large
depression. The most common location for MCT prospective trials.
is the small bowel. Usually there are no eosino-
philia or circulating mast cells present in the z Suggested Reading
blood. Metastasis to the lymph nodes, liver, or (Bortnowski and Rosenthal 1992; Craig et  al.
spleen is common at time of diagnosis. Diagnostic 2009; Henry and Herrera 2013; Laurenson
ultrasound typically depicts a noncircumferential et al. 2011; Linton et al. 2015; Sato and Solano
eccentric wall thickening or very asymmetric, cir- 2004)
Chapter 9 · Alimentary Tumors
191 9
9.4.3 Equine Gastrointestinal
Tumors

Box 9.18. Equine Gastrointestinal Tumors in


Four Facts
1. Squamous cell carcinoma (SCC) is the
most common gastric tumor.
2. SCCs arise usually in the nonglandular
part of the stomach.
3. SCCs usually have a marked stromal
component (scirrhous growth).
4. Most common intestinal tumors are
lymphomas of the small intestine.

. Fig. 9.11 Gastric squamous cell carcinoma, horse:


note the large primary tumor (between arrows) and
z Epidemiology and Pathogenesis numerous serosal metastatic tumors with scirrhous
The most common gastric tumors are squamous reaction (Courtesy of Philipp Olias, PhD, Freie Universität
cell carcinomas (SCCs). Adenocarcinomas, leio- Berlin, Germany)
myosarcomas, gastrointestinal stromal tumors,
papillomas, and benign polyps are rarely visualization and determination of the tumor
reported and will not be discussed in detail. size, but normal findings do not rule out gastric
SCCs are frequently located in the nonglandular neoplasia. Tumors are often in an advanced stage
mucosa. A breed or sex predilection has not at the time of diagnosis. The tumors are usually
been identified. Adult to aged horses are most well-demarcated cauliflower-like and can be
commonly affected, and the mean age ranges very large. The muscular wall is often thickened,
between 7 and 18 years. with a firm (scirrhous) texture. The scirrhous
The alimentary form of lymphomas is the most reaction may extent on the gastric serosa (see
common equine intestinal neoplasm. Typically, . Fig. 9.11). Hematogenous metastasis to the
affected horses are 8 years and older. Other pos- liver and more rarely the lung, kidney, and other
sible but rare equine intestinal neoplasms are ade- organs is rarely observed. The primary tumor
nocarcinomas, leiomyomas, leiomyosarcomas, can be ulcerated and may extend into the esoph-
myxosarcomas, ganglioneuromas, nerve sheath agus, leading to obstruction.
tumors, and carcinoids and will not be discussed The most common location for gastrointesti-
in detail. nal lymphomas is the small intestine. Ultrasound
can be a sensitive diagnostic tool. Annular small
z Clinical Appearance intestinal thickening seems to be characteristic
For gastric SCC, acute onset of disease or several for lymphomas. Mesenteric lymphadenopathy is
years of mild signs are reported, mostly nonspe- frequent. Rectal biopsy may be a sensitive and spe-
cific, and include inappetence, weight loss, cific indicator of infiltrative disease in advanced
abdominal pain, hypoalbuminemia/hyperglobu- clinical cases, but results in some studies indicate
linemia, and anemia due to internal bleeding. poor sensitivity. Furthermore, exploratory abdom-
The peritoneal fluid can be analyzed and is often inal surgery may be valuable for establishing a
abnormal but unspecifically resemble non-septic definitive diagnosis and may enable therapeutic
exudates. Rectal palpation may reveal abdomi- excision if a localized lesion can be identified.
nal masses. Endoscopy and transabdominal Metastasis is commonly observed at the time of
ultrasound examination can be very helpful for diagnosis.
192 A. Breithaupt

z Cytology and Histopathology z Epidemiology and Pathogenesis


For SCC, neoplastic cells are often found in the Neoplasia of the abomasum is generally rare in
peritoneal fluid and enable minimal invasive eval- cattle. The most common tumors in the aboma-
uation. Cytologically, the neoplasms are typical sum are lymphomas. Rarely carcinomas, sarcomas
squamous cell carcinomas with variably differen- and adenomas occur but will not be discussed in
tiated epithelial cells and keratin. Histologically, detail. Lymphomas may also affect the intestine,
SCCs show invasion of the gastric wall and grow but this is very rare. Bovine leukemia virus (BLV)
in cords or nests of cells, often with marked des- causes B-cell lymphomas (enzootic bovine leuko-
moplasia (scirrhous) and prominent intercellular sis) particularly in adult cattle (>2  years of age).
bridges. Immunohistochemistry for cytokeratin This virus is transmitted horizontally by blood-
may be useful for poorly differentiated cells. suckling arthropods and by lymphocyte contami-
As mentioned for lymphomas in general, it is a nated needles. Approximately 98 % of serologically
diagnostic challenge to differentiate lymphomas BLV-positive cattle do not develop tumors.
from inflammatory bowel disease and may require Intestinal neoplasias include polyps and ade-
immunohistochemistry (CD79a, CD3) for B-cell nocarcinomas that may be associated with papil-
and T-cell identification. lomavirus infection or intoxication with bracken
fern and will not be discussed in detail.
z Prognosis and Therapy
Treatment is aggravated in horses because of the z Clinical Appearance
poor accessibility and the usually advanced stage Cattle may present with anorexia, weight loss,
9 of disease. The survival time after diagnosis of gas- decreased milk production, and rarely fever. The
tric neoplasia in horses is usually short. Radiation most sensitive antemortem diagnostic tests include
therapy and chemotherapy can be of benefit, such examinations of peripheral lymph node wedge
as piroxicam and COX inhibitors for SCC. biopsies and percutaneous aspirate or biopsy of a
However, the prognosis for long-term survival in mass. The positive predictive value of BLV serology
horses with intestinal neoplasia is grave. is very low. Further, transabdominal ultrasonog-
raphy may reveal abnormal thickening and loss of
z Suggested Reading the typical layered appearance. Ulceration of the
(Olsen 1992; Recknagel et  al. 2012; Reef et  al. mucosa can lead to hemorrhage, melena, and ane-
1984; Taylor et  al. 2009; Vandenhoven and mia; occasionally abomasal reflux and hypochlo-
Franken 1983) remic alkalosis can be found.
Besides the abomasum, typical manifestations
of BLV-associated tumors include lymph nodes
9.4.4 Bovine Abomasal (e.g., retrobulbar, pharyngeal), the heart, the
and Intestinal Tumors uterus, the epidural space, and the liver and
spleen. The sporadic, non-BLV associated variant
may affect the lymph nodes, the thymus, or the
skin.
Box 9.19. Bovine Abomasal and Intestinal
Tumors in Five Facts z Cytology and Histopathology
1. Lymphoma is the most common aboma- As stated above cytological and histological exam-
sal tumor. inations of peripheral lymph node wedge biop-
2. BLV can cause abomasal B-cell sies, and percutaneous aspirate or biopsy of a mass
lymphomas in adult cattle. are the most sensitive antemortem tests. Cytologic
3. Prognosis is poor; treatment is not examination of fine-needle aspirates (FNA)
economically beneficial. appear less sensitive but highly specific, and due
4. Prevention of infection and elimination to the fact that FNA is quick, uncomplicated, and
of infected cattle is the main prevention relatively cheap to perform, this test might also
strategy. be useful. As mentioned in other chapters, the
accuracy of diagnosis is strongly associated with
Chapter 9 · Alimentary Tumors
193 9
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Assoc 28:271–275
Aspiration of reactive infiltration of immune Bridgeford EC, Marini RP, Feng Y, Parry NMA, Rickman B,
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prognosis. Treatment of enzootic bovine leukosis is 294
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Ultrasonographic appearance of lymphomatous infil-
with high genetic value. Therefore, the strategy is tration of the abomasum in cows with lymphoma.
to identify and eliminate BLV-infected cattle to J Am Vet Med Assoc 238:1044–1047
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