small animal oncology

Small Animal Oncology

Joanna MorrisFormerly of Department of Clinical Veterinary Medicine,

University of Cambridge Veterinary School

and

Jane DobsonDepartment of Clinical Veterinary Medicine,University of Cambridge Veterinary School


Joanna MorrisFormerly of Department of Clinical Veterinary Medicine,

University of Cambridge Veterinary School

and

Jane DobsonDepartment of Clinical Veterinary Medicine,University of Cambridge Veterinary School

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A catalogue record for this titleis available from the British Library

ISBN 0-632-05282-1

Library of CongressCataloging-in-Publication DataMorris, Joanna.

Small animal oncology/Joanna Morris and JaneDobson.

p. cm.Includes bibliographical references (p.).ISNB 0-632-05282-1 (pb)1. Dogs – Diseases. 2. Cats – Diseases.3. Veterinary oncology. I. Dobson, Jane M.II. Title.

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Contents

Acknowledgements vi

Disclaimer vi

Introduction 1

1. Pathogenesis and Tumour Biology 4

2. Diagnosis and Staging 15

3. Treatment Options 31

4. Skin 50

5. Soft Tissues 69

6. Skeletal System 78

7. Head and Neck 94

8. Gastro-intestinal Tract 125

9. Respiratory Tract 144

10. Urinary Tract 154

11. Genital Tract 166

12. Mammary Gland 184

13. Nervous System 192

14. Endocrine System 204

15. Haematopoietic System 228

16. The Eye and Orbit 252

17. Miscellaneous Tumours 262

Appendices 279

I General Reading List 279

II Actions, Indications and Toxicity of Cytotoxic Agents used in Veterinary Practice 280

III Bodyweight: Surface Area Conversions 284

IV Protocols for Administration of Doxorubicin and Cisplatin 285

V Glossary of Drugs and Dosages Included in Text 286

Index 292

Please note: the plate section falls between pp. 162 and 163

v

Acknowledgements

DISCLAIMER

vi

The authors have made every effort to ensure thattherapeutic recommendations particularly concern-ing drug selection and dosage set out in the text arein accord with current recommendations and prac-tice. However, in view of ongoing research, changesin government regulations and the constant flow ofinformation relating to drug therapy and drug reac-tions, the reader is urged to check the drug manu-facturer’s instructions for any added warnings andprecautions.

The cytotoxic drugs detailed in this book are notlicensed for veterinary use. All of these agents arepotentially hazardous to the patient and to personshandling or administering them. Veterinary sur-geons who prescribe such drugs to patients in theircare must assume responsibility for their use andsafe handling. Veterinary surgeons who are notfamiliar with the use of cytotoxic agents shouldseek further information and advice from a veteri-nary oncologist.

The authors gratefully acknowledge the help andsupport of friends, families and colleagues in thewriting and production of this book.

In particular we would like to thank DavidBostock, Phil Nicholls, Elizabeth Villiers, KathleenTennant, Andy Jefferies, Mike Herrtage, MalcolmBrearley, Ruth Dennis, Dick White and the Radiol-ogy Department, Queens Veterinary School Hospi-tal, Cambridge, for contributing many of thepictures used to illustrate the text. We should also

acknowledge the artistic skills of John Fuller whowas responsible for the original line drawingsreproduced in this book.

We are also grateful to Dr Davina Anderson forher help in reading the text and advice on surgicalmatters, Malcolm Brearley for his help withChapter 13, Nervous System, Dr David Williams,Chapter 16, on the eye, and Mike Herrtage, Chapter14, Endocrine System.

Introduction

most common sites for cancer in this study. In theUK study, the three most common tumour typeswere benign. Canine cutaneous histiocytoma pre-dominated, followed by lipoma and adenoma. Mastcell tumour and lymphoma were the next mostcommon tumour types (Fig. I.2).

Comparable up-to-date epidemiological figuresare not available for cats in the UK. In othersurveys, lymphoma and other haematopoietictumours are the most common tumour types andare much more frequent than in the dog. Althoughskin and soft tissue tumours are important in thecat, malignant neoplasms such as squamous cell car-cinoma and soft tissue sarcoma are probably morefrequent than benign lesions. Mammary tumoursare less frequent in the cat, but a greater propor-tion are malignant.

The demand for treatment of pets with cancer isincreasing and seems likely to do so for the fore-seeable future as more animals become insured andtheir treatment costs are covered. Conventionalmethods for cancer therapy in animals, as inhumans, are surgery, radiotherapy and chemo-therapy. These techniques, however, need not beused in isolation. Indeed, as our understanding ofthe biology of cancer has increased, it has becomeclear that combining surgical management of aprimary mass with chemotherapy directed at sys-temic disease, is the most logical and potentiallyeffective way of managing malignant tumours.Fears of the side-effects associated with cancertreatment in pet animals are not well founded sincemost are drawn from comparisons with humancancer therapy where the aim of treatment is toprolong life at all costs. The management of animalcancer also seeks to prolong lifespan but aims to

Neoplasia is a common problem in small animalveterinary practice.As facilities in general practicesimprove and more investigations are conductedinto the cause of dog and cat illnesses, it is beingincreasingly diagnosed. Although accurate figureson the incidence of tumours in cats and dogs arelacking, conservative estimates suggest that one inten cats or dogs will develop a tumour during theirnatural life. A few epidemiological studies on smallanimal cancer do exist but most of these refer todogs. In the USA, a post mortem study on 2000dogs revealed that cancer was the most commoncause of death, with 23% of animals dying from thedisease (Bronson 1982). In a more recent studybased on questionnaire responses in the UK, 16%of dogs died from cancer (Michell 1999). Cancerwas the most frequently recognised cause of deathin both male and female dogs, but in neuteredmales heart disease was of equal importance.

Another recently conducted study on the inci-dence of tumours in a population of insured dogsin the UK has provided up-to-date information onthe distribution of tumour types (Samuel et al.1999). The skin and soft tissues were found to bethe most common sites for tumour development,followed by mammary gland, haematopoietictissues (including lymphoid), urogenital system,endocrine organs, alimentary system and orophar-ynx (Fig. I.1). These results are similar to thosereported by Dorn and others (Dorn et al. 1968a, b)in California who used diagnosis of neoplasia inveterinary practices in specified areas of thecountry combined with histological examination ina central laboratory and a probability survey to cal-culate the population at risk. The skin, mammarygland and haematopoietic tissues were the three

1

out by a referral centre. Practical details ofchemotherapy and guidance on safety, however, aregiven, since an increasing number of general prac-tices are using cytotoxic drugs and it is essential thatstringent handling practice is adhered to. Again,more detailed texts exist and specialist help is avail-able at a referral centre.Although, at present, Cam-bridge University has the only radiotherapy unit inthe UK dedicated to small animal use, radiotherapyis covered in some detail since it is helpful forgeneral practitioners to be aware of the aims oftreatment and the tumour types which are suitablefor referral.

The remaining chapters provide specific infor-mation on the epidemiology, aetiology, pathology,presentation, staging, management and prognosisfor tumours occurring in the different body systems.These specific sub-headings are used in each of thesystem chapters to enable the reader to find the rel-evant information more easily. Chapters are mini-mally referenced using large case series or reviewswhere possible.

2 Small Animal Oncology

achieve a good quality of life as well. All treatmentmodalities are adjusted to achieve this aim and ifany patient is deemed to be suffering, treatment canbe stopped or the animal euthanased.

The purpose of this book is to provide a basicclinical approach to the diagnosis and treatment ofthe more common tumours in cats and dogs for the practising veterinary surgeon, undergraduatestudent and veterinary nurse. It is not intended tobe a comprehensive reference textbook, coveringall aspects of veterinary oncology, since severalsuch texts exist (see general reading list in Appen-dix I). Rather it seeks to provide a core of basic,easily accessible and clinically relevant informationon general aspects of veterinary oncology.

The first three chapters present general back-ground information on pathogenesis, tumour biol-ogy, managing the cancer patient and the mostfrequently used methods of treatment. Surgicalapproaches and instructions are not given since thisinformation is best sought from specific surgicaltexts or, if particularly specialised, should be carried

Fig. I.1 Standardised incidence rates for main tumour sites (per 100000 dogs/year).

Introduction 3

References

Bronson, R.T. (1982) Variation in age at death of dogs ofdifferent sexes and breeds. American Journal of Veteri-nary Research, (43), 2057–9.

Dorn, C.R., Taylor, D.O.N., Frye, F.L. & Hibbard, H.H.(1968a) Survey of animal neoplasms in Alameda andContra Costa counties, California. I Methodology anddescription of cases. Journal of the National CancerInstitute, (40), 295–305.

Dorn, C.R., Taylor, D.O.N., Schneider, R., Hibbard, H.H.

& Klauber, M.R. (1968b) Survey of animal neoplasmsin Alameda and Contra Costa counties, California. IICancer morbidity in dogs and cats from AlamedaCounty. Journal of the National Cancer Institute, (40),307–18.

Michell, A.R. (1999) Longevity of British breeds of dogand its relationships with sex, size, cardiovascular vari-ables and disease. Veterinary Record, (145), 625–9.

Samuel, S., Milstein, H., Dobson, J.M. & Wood, J.L.N.(1999) An epidemiological study into the incidence ofneoplasia in a population of insured dogs in the UK.Proceedings of the British Small Animal VeterinaryAssociation Congress.

Fig. I.2 Standardised incidence of main tumour types (per 100000 dogs/year).

1Pathogenesis and Tumour

Biology

• Be activated (known as oncogenes); or• Be inactivated (known as tumour suppressor

genes); or• Have their level of expression altered.

Sometimes oncogenes or tumour suppressor genesmay be altered indirectly by genetic changes occur-ing in DNA repair genes. These fail to carry outtheir normal repair function, causing abnormal sec-tions of DNA to accumulate, some of which may bein important for cell growth.

The transition from a normal growth-controlledcell to a malignant cancer cell requires severalmutations. Research on human colon cancer showsthat the progression of the disease from benignadenoma (polyp) to invasive carcinoma is paral-leled by an increase in the number of genes, pre-dominantly tumour suppressor genes, which aremutated. At least four or five mutated genes areneeded for carcinoma development but fewerchanges are required for adenomas. Similarly,as human gliomas increase in histopathologicalgrade and become more aggressive, the number of mutated genes increases from 2 to 3 (grade II) to 6 to 8 (grade IV). In both examples, it is the total number of accumulated mutated genes

What is cancer?

Neoplasms are abnormal ‘new growths’ of tissuewhich develop faster than adjacent normal tissuesand in an uncoordinated, persistent manner. Theymay be benign or malignant but the term ‘cancer’is generally restricted to the malignant growths.Neoplastic cells differ from normal cells in that theyshow:

• Uncontrolled proliferation which is independentof the requirement for new cells

• Impaired cellular differentiation• Altered cell communication and adhesion.

What causes cancer?

Cancer development is a multistep process whichinvolves an accumulation of changes or ‘errors’ incellular DNA. The steps that lead to neoplastictransformation of a cell are not fully understoodbut the fundamental change involves disruption ofthe genes which control cell growth and differen-tiation. Specific genes may either:

PATHOGENESIS

� Pathogenesis, 4� Tumour biology, 11

4

Pathogenesis and Tumour Biology 5

that is paramount and not the order in which theyoccur.

Genetic changes may occur in germ line cells andtherefore be present in all cells of the body at birth,or much more commonly, they may occur sponta-neously in somatic cells as part of the ageingprocess. The accumulation of spontaneous muta-tions occurs quite slowly but often external riskfactors speed up the rate of accumulation. Cancerdevelopment can therefore be discussed under thefollowing headings:

• Spontaneous genetic events• External stimuli

– biological (viruses, parasites, hormones)– physical (UV light, radiation, trauma)– chemical

• Inherited genetic events (familial cancers).

Spontaneous genetic events

The majority of cancers result from spontaneousgenetic events and these can occur at either thechromosomal or molecular level. Although spon-taneous cancer is usually associated with olderanimals because of the time needed to accumulategenetic changes, there are some exceptions whichaffect young animals, for example canine cutaneoushistiocytoma, some types of feline lymphoma andsome anaplastic sarcomas.

Molecular changes

As cells divide and their DNA replicates, errorswhich alter the DNA may occur. Usually, DNArepair mechanisms act very effectively to correctthe errors, but as an individual ages, more eventsescape the repair mechanisms and permanentDNA changes accumulate. The multistep accumu-lation of these changes leads to cell transformationand the development of a cancer cell. Although thekey changes occur within the DNA sequence, addi-tional changes may also occur in the conversion ofDNA to mRNA (transcription) or the synthesis ofproteins (translation).

Changes which affect gene function include:

• Point mutation – loss or substitution of one basefor another in the DNA helix, thus coding for adifferent amino acid or none at all.

• Small or large deletion – loss of a few or several

hundred base pairs, thus altering the geneproduct or stopping its production.

• Amplification – repetition of sections of DNA,perhaps increasing the number of copies of partor all of a gene, although not necessarily increas-ing its level of expression.

The protein product coded from the DNA may bealtered by one amino acid, truncated, overex-pressed or not expressed at all. Only isolatedreports of mutations in dog and cat genes haveappeared in the literature in the last decade (Table1.1). However, this area of research in pet animalsis expanding rapidly and knowledge of the mo-lecular changes in animal cancers will probablyincrease very quickly in the next five or ten years.There is often conservation of genes betweenspecies allowing some of the probes which havebeen developed for human or other animalreasearch to be used for canine and feline work(Miyoshi et al. 1991a, b; Momoi et al. 1993).Recently, there has been much interest in thetumour suppressor gene p53 which codes for aprotein of molecular mass 53 kilodaltons, and which plays a key role in the carcinogenesis ofmany human tumours. It has been shown to be mut-ated in a number of canine and feline tumours(Table 1.1).

Chromosomal changes

Changes in cellular DNA can also be brought aboutby gross chromosomal changes which may be eithernumerical or structural. Losses or gains of wholechromosomes alter the total DNA content of a celland the number of copies of the genes present onthose chromosomes. This may either reduce oramplify the level of expression of a particular genewithin the cell. Alterations to chromosome struc-ture such as deletions, insertions, inversions,translocations or local amplifications may alsooccur, affecting the function of genes located at thealtered regions of the chromosome. Many suchchanges are well documented in human cancers.Specific reciprocal translocations have been identi-fied in several types of human leukaemia and non-Hodgkin’s lymphoma and more recently in sometypes of human sarcoma (Rabbitts 1994; Look1995).The translocations bring together genes fromdifferent chromosomes, resulting in a new fusiongene(s) and therefore a new fusion protein(s).

which are difficult to interpret using conventionalGiemsa-banding techniques.

Structural and numerical chromosome changeshave been reported in dog and cat tumours but the literature is still relatively sparse (Grindem &Bouen 1986; Hahn et al. 1994; Mayr et al. 1994; Mayret al. 1998a,d; Reimann et al. 1998). A commonobservation in dog tumours is a reduction in the


Alternatively, they may bring genes at the break-points close to different regulatory elements whichresult in altered gene expression. Examples of suchtranslocations are given in Table 1.2. In contrast tothe situation with haematopoietic tumours, fewtranslocations have yet been identified for themajority of human solid tumours since they usuallyhave very complex chromosome rearrangements

Table 1.1 Molecular changes in dog and cat tumours.

Altered gene Species Tumour types Reference

p53 Dog Osteosarcoma Sagartz et al. 1996Squamous cell carcinoma Gamblin et al. 1997Nasal adenocarcinoma Mayr et al. 1998a, 1999Peri-anal gland adenocarcinoma Veldhoen et al. 1999Mammary adenoma/carcinoma Nasir & Argyle 1999Lymphoma

p53 Cat Mammary carcinoma Mayr et al. 1998b, cOsteosarcomaFibrosarcomaSpindle cell sarcomaPleomorphic sarcoma

K-ras Dog Lung carcinoma Kraegel et al. 1992

N-ras Dog Acute non-lymphocytic leukaemia Gumerlock et al. 1989

yes-1 Dog Mammary and other tumours Miyoshi et al. 1991bRungsipipat et al. 1999

myc Dog Plasma cell tumours Frazier et al. 1993Cat Lymphoma Neil et al. 1984

Table 1.2 Chromosome translocations in human tumours.

Tumour/disease Translocation Genes affected

Acute T cell leukaemia t(8;14) TCRa and MYCAcute promyelocytic leukaemia t(15;17) RAR and PMLChronic myeloid leukaemia t(9;22) BCR and ABLBurkitt’s lymphoma t(8;14) IgH and MYC

t(2;8) IgL kappa and MYCt(8;22) IgL lambda and MYC

Follicular lymphoma t(14;18) IgH and BCL1t(11;14) IgH and BCL2

Alveolar rhabdomyosarcoma t(1;13) FKHR and PAX7t(2;13) FKHR and PAX3

Synovial sarcoma t(X;18) SYT and SSXEwing’s sarcoma t(11;22) EWS and FLI-1,

t(21;22) EWS and ERGt(7;22) EWS and ETV-1

Liposarcoma t(12;16) FUS and CHOP


total number of chromosomes due to the formationof large metacentric chromosomes, probably gen-erated by centric or telomeric fusion (Reimann et al. 1994). Although the cat has 36 chromosomeswhich are reasonably easy to identify using con-ventional banding techniques, the dog has 78 chro-mosomes, most of which are very similar inappearance and there is still no agreed Giemsa-banding standard for chromosomes 22–36 withwhich to refer (Switonski et al. 1996). A bandedkaryotype using the fluorescent dye DAPI hasrecently been published, however, and this willfacilitate the identification of canine chromosomesviewed under a fluorescence microscope (Breen etal. 1999). Whole chromosome-specific fluorescencein situ (FISH) probes known as ‘chromosomepaints’ (Fig. 1.1) have also been developed for the

dog (Langford et al. 1996; Yang et al. 1999) andthese will help future cytogenetic studies of caninetumours enormously (Tap et al. 1998).

External stimuli

A variety of external factors may produce geneticchanges within the cell.

Biological factors

VirusesViruses may influence tumour development eitherby affecting the cellular DNA directly or byincreasing the rate of cell division so that sponta-neous changes occur more rapidly within the celland may not be repaired effectively.

Several animal viruses (both DNA and RNA-containing viruses) are responsible for tumour formation (Table 1.3). DNA-containing viruses normally propagate within host cells withoutcausing cancer. More rarely, they integrate all orpart of their genome into the host genome and donot replicate themselves. Stable integration maylead to cell transformation when viral genes whichcontrol the host’s replicative machinery are tran-scribed and act as oncogenes. Occasionally, ex-pression of several viral oncogenes or cellularoncogenes is needed for full transformation. FewDNA-containing viruses cause tumours in dogs andcats, although papilloma viruses may be respon-sible for a recently described type of squamous cellcarcinoma in the cat (Bowen’s disease) and trans-formation of papilloma to squamous cell carcinomahas also been rarely reported in the dog.

Retroviruses, a group of RNA-containing viruses,play a much more important role in cancer for-mation in the cat and probably some types ofcancer in the dog too, although direct evidence forthe latter is not yet available. Feline leukaemiavirus (FeLV) causes lymphoma and leukaemia incats although not all cases of these cancers are viruspositive (Chapter 15). The virus is prevalent inyoung cats, particularly in breeding colonies or cat-teries. Multiple strains of a related virus, felinesarcoma virus (FeSV), cause sarcoma formation,also in young cats (Chapter 5) but affected animalsare also FeLV positive. There is no evidence thatFeSV can be transmitted between cats or to otherspecies.

Fig. 1.1 Hybridisation of dog chromosome 1 paint toa metaphase from a canine sarcoma. Chromosome 1paint is labelled with the fluorescent dye Cy3 (pink)and the other chromosomes are counterstained withDAPI (blue). One normal copy of chromosome 1 (largearrow) is present in the metaphase, but the other copy(small arrow) has split and translocated to a third chro-mosome (arrow head). This shows that there is atranslocation involving chromosome 1 and another asyet unidentified chromosome in this sarcoma. (Chro-mosome paint as from Yang et al. 1999) (Colour plate1, facing p. 162.)

inserts adjacent to the myc oncogene, affecting theregulatory elements which control the transcriptionof this gene and resulting in an increased level ofgene expression (Neil et al. 1984).

ParasitesFew parasites are responsible for cancer formationin animals. The most frequently quoted example isthat of Spirocerca lupi which causes oesophagealtumours in the dog, fox, wolf and jaguar in Africaand south-east USA, where the helminth isendemic (see Chapter 8). Worm eggs develop toform encysted third stage larvae when eaten byintermediate host dung beetles. Beetles may beingested by another intermediate host such aschicken, small mammal or reptile or eaten directlyby the host carnivore. Ingested larvae migrate viathe aorta to the oesophagus, mature into adultworms and produce loose inflammatory nodulesaround themselves. The lesions are highly vascularwith fibroblastic proliferation and central areascontaining worm eggs. As the lesion progresses, theblood vessels decrease and fibroblasts become


The mRNA within a retrovirus is reverse tran-scribed to a double-stranded DNA provirus whichcan insert into the host genome. The DNA poly-merase enzyme ‘reverse transcriptase’ is coded forin the viral genome to allow this process. Someretroviruses also contain ‘oncogenes’ which replaceone of the virus genes and which have been incor-porated from the host genome by a process calledtransduction. These viruses are unable to replicatewithout a related helper virus because the onco-gene replaces part of the necessary replicationmachinery.They are known as acutely transformingretroviruses because when inserted into the hostgenome they act rapidly to transform the cell. Thevarious strains of FeSV belong to this group, eachcontaining an oncogene such as fms, kit, or fgr fromthe feline genome. Helper FeLV virus is needed forreplication. Other retroviruses such as FeLV orbovine leukosis virus (BLV) do not contain onco-genes. The insertion of the viral genome into thehost DNA causes the activation of cellular onco-genes instead. These retroviruses have a longlatency and are replication competent. FeLV often

Table 1.3 Tumour-causing viruses.

Virus Tumour Species

DNA virusesHepadnavirus family Hepatocellular carcinoma Man(hepatitis B virus)

Herpesvirus family Burkitt’s lymphoma in Africa, Man(Epstein-Barr virus) Nasopharyngeal carcinoma in

ChinaHHV-8 Kaposi’s sarcoma ManMareks disease virus Mareks disease/lymphoma ChickenPapovavirus family Papillomas/warts Man and

animals

(papilloma viruses) Carcinomas of cervix Man?Bowen’s disease/squamous cell Cat

carcinoma

Adenovirus family Adenomas Sheep

RNA virusesRetrovirus familyHTLV-1 Adult T cell leukaemia/lymphoma ManFeLV Leukaemia/lymphoma CatBLV Bovine leukosis/lymphoma CowALV Avian leukosis/lymphoma Chicken


more numerous and active. With continued prolif-eration, the fibroblasts transform into neoplasticfoci that eventually combine to form a fibrosar-coma. Secretion of a carcinogen may help the pro-gression to fibrosarcoma or, if bone and osteoid areproduced, osteosarcoma.

HormonesCertain hormones can influence cancer develop-ment by increasing cell replication and the pro-gression of cells which have already accumulatedother initiating events. Oestrogen and to a lesserextent progesterone influence the development ofmammary cancer in humans, dogs and cats (seeChapter 12). Early ovariohysterectomy to removehormonal fluctuations significantly reduces the riskof developing mammary cancer. Anti-oestrogentherapy (tamoxifen) is widely used in post-menopausal women to prevent breast cancer recur-rence and metastasis, but has not been successful inanimals because of the different way in which it ismetabolised. Oestrogen also influences the devel-opment of benign vaginal fibromas in dogs, andovariohysterectomy is usually necessary to preventrecurrence (see Chapter 11).

In male dogs, testosterone is responsible for thedevelopment of perianal adenoma, and castrationis therefore advisable to prevent the risk of furthertumours. Other male dog tumours, such as prosta-tic cancer, however, are unaffected by testosteronesecretion.

Physical factors

A range of physical or environmental factors mayalso influence cancer development.

UV lightIn recent years the climate has subtly changed, andthe harmful effects of UV light which lead to thedevelopment of skin cancer have been increasinglyacknowledged, along with a change in behaviour ofmany individuals with respect to holidays abroadand sunbathing. A depletion of the ozone layer,particularly over Antarctica has produced an 8%increase in UVB at ground level in the southernhemisphere since 1980, leading to an increase innon-melanoma skin cancer in man.Ozone depletionhas occurred to a lesser extent in the northern hemi-sphere but is masked to a degree in industrial coun-

tries by the production of ozone at ground level in aphotochemical reaction with exhaust fumes.

UVB and to a lesser extent UVA induce specificDNA changes in the skin, leading to the productionof cyclobutane dimers and (6–4) photoproducts.Characteristic mutations which are never seen ininternal tumours take place, such as the conversionof cytosine to thymine, and the dimerisation of twoadjacent thymines, which disrupts base-pairing. Inaddition, suppression of the immune response byUV light may play a role in allowing tumours todevelop.

Long-term exposure to UV light allows skintumours such as squamous cell carcinoma todevelop in animals, particularly in areas that lackprotective pigment. Any patches of white skin or non-pigmented mucous membranes can beaffected, for example the nasal planum, lips, peri-ocuar skin or ventral abdomen. Early sun-inducedchanges such as erythema, hair loss or scaling maybe mistaken for inflammatory lesions, but if leftuntreated these will progress to squamous cell car-cinoma (Chapter 4, Figs 4.6–4.8).

Other irradiationAnimals may be exposed to radiation in variousways. An increasing number of dogs and cats maybe exposed to X-rays as part of a routine diagnos-tic investigation and a smaller number to either X-rays or g-rays if they receive radiotherapy for atumour. The doses received from diagnostic X-raysare relatively small and carry a low risk and thosefrom radiotherapy are only given if there is a malig-nant cancer already present, making the develop-ment of a further cancer at the site of treatment lesslikely within the animal’s already shortened lifespan.

Environmental exposure to radon gas or radioac-tive ores may occur more in some parts of the UKthan others, but generally carries a low risk ofcancer development in animals. Similarly, experi-mental exposure of animals to radioactive sub-stances is now rare, although past experimentalwork has shown that exposure to strontium 90causes osteosarcoma and lymphoid tumours, and to radium or plutonium, osteosarcoma and bron-choalveolar carcinoma.

At the cellular level, particulate radiation actsdirectly on the DNA to break chemical bondswhereas electromagnetic radiation causes indirect

agents to treat a malignant cancer may lead to asecondary cancer if the animal survives for longenough, and use of cyclophosphamide in particularhas been associated with the development of blad-der cancer in dogs. Chronic ingestion of brackencan produce cancers of the gastro-intestinal andurinary tract in ruminants but is not a problem forsmall animals.

The extent to which air pollution affects cancerdevelopment in animals is not known although ton-sillar squamous cell carcinoma in dogs and lingualsquamous cell carcinoma were reportedly higher inindustrial cities when smoke pollution was a majorproblem. Inhalation of asbestos dust producesmesothelioma in pet animals and often occurs inthe owner at the same time due to a commonsource of exposure.

Inherited genetic events

A number of familial cancers have been identifiedin man and these usually develop because ofchanges to tumour suppressor genes such as Rbwhich causes the childhood cancer, retinoblastoma,or p53 which is affected in a number of differentcancers. Tumour suppressor genes act in a recessivefashion, requiring both alleles to be inactivated toinhibit the gene’s activity. One copy of an abnormalgene is inherited and therefore present at birth, andthe second copy of the gene becomes abnormal oris lost at some stage in the lifetime of the individ-ual. This usually happens more quickly than if theindividual had to lose both copies of the gene byspontaneous events and thus familial cancersusually arise in children or young adults rather thanat the age at which most spontaneous cancers occurin the general population. Some inherited humancancers and the genes responsible for them arelisted in Table 1.4.

No specific hereditary genes have been identifiedin domestic animals but a number of tumour types, particularly sarcomas, seem to show breedpredispositions and these are listed in Table 1.5. Afamilial incidence of some cancers has been demon-strated within certain breeds, for example malig-nant histiocytosis in the Bernese mountain dog andlymphoma in the bullmastiff (Onions 1984; Padgettet al. 1995).


DNA damage by the production of free radicals.Although the main effect is probably on DNA,damage to other cell components such as RNA andproteins may also be important.

Trauma/chronic inflammationThere is evidence to suggest that squamous cell car-cinoma and sarcomas can develop at the site ofthermal or chemical burns or chronic inflammation,suggesting that these conditions predispose in someway to cancer formation. Repeated microtrauma tothe metaphyses of long bones produced by weightbearing stresses may play a role in the developmentof osteosarcoma in large and giant breeds, as may the insertion of metal implants at the site oflong bone fractures. These may cause subclinicalosteomyelitis at the implant site and stimulate achronic inflammatory response which predisposesto tumour formation, often after a latent period ofseveral years. In cats, intra-ocular sarcoma has beenassociated with the chronic inflammatory reactioncaused by lens trauma.

In the last decade, increasing numbers of felinesoft tissue fibrosarcomas have developed in animalsgiven rabies and FeLV vaccines, with tumoursarising at classical injection sites, especially in theinterscapular space (Hendrick et al. 1992; Esplin et al. 1993; Doddy et al. 1996). Histologically, mosttumours appear pleomorphic and aggressive, with achronic inflammatory cell infiltrate. In many, theperipheral macrophages contain adjuvant, suggest-ing a foreign body type reaction to the vaccine.Despite the strong association of vaccine site,inflammatory reaction and sarcoma formation, theprecise relationship between the act of vaccinationand tumour development is unknown.

Chemical factors

Much of the information about carcinogenic chemi-cals such as food additives, PVC packaging andenvironmental contaminants is derived from thehuman literature, although many chemical carcino-gens have been tested on laboratory animals, andother specific examples for domestic animals doexist. Many chemicals are inactive until convertedto the active form in the body and so species dif-ferences are frequent.

Long-term administration of chemotherapeutic


Neoplasms are classified according to their growthand behavioural characteristics as being benign ormalignant (Table 1.6). Malignant neoplasms arecharacterised by a locally invasive and destructivemanner of growth and the ability to metastasise toother sites in the body.These will cause death unlessradical clinical action is taken. Benign tumours tendto grow by expansion rather than invasion and donot metastasise. They have a more predictable clinical course and are not usually life threatening.Although this division is useful for descriptive pur-poses, neoplasms in fact display a spectrum ofbehaviour. Some canine tumours, for example oralacanthomatous epulis (basal cell carcinoma) andhaemangiopericytoma, have local characteristics ofmalignancy but metastasis is rare. Other tumours,

for example mast cell tumours, can display a widerange of behaviour with some being benign or lowgrade, and others highly malignant. The morpho-logical features of a tumour, for example its cellu-lar and nuclear characteristics and mitotic rate, canbe used to predict its likely behaviour. The histo-logical grade or appearance of the tumour is there-fore important in prognosis (see Chapter 2).

The ability of malignant tumours to spread andgrow in distant organs is their most serious and life-threatening characteristic. Tumours may metasta-sise via the lymphatic route to local and regionallymph nodes or via the haematogenous routeallowing secondary tumours to develop in any bodyorgan.These two systems are widely interconnectedand many tumours use these connections to spread

Table 1.4 Familial cancers occurring in humans.

Disease/tumour Gene Chromosome location

Retinoblastoma RB1 13qWilms tumour WT1 11pvon Hippel Lindau VPL 3pMultiple endocrine neoplasia MEN1 11q

MEN2 10qNeurofibromatosis NF1 17q

NF2 22qLi-Fraumeni syndrome p53 17pFamilial adenomatous polyposis APC/FAP 5qHereditary non-polyposis colon cancer MLH1 3p

MSH2 2pMalignant melanoma MLM 9pBreast cancer BRCA1 17q

BRCA2 13q

Table 1.5 Breed predispositions for cancers occurring in dogs.

Disease/tumour Breed

Systemic/malignant histiocytosis Bernese mountain dogSoft tissue sarcoma Flat-coated retrieverFibrosarcoma Golden retrieverHaemangiosarcoma German shepherd dogOsteosarcoma Irish wolfhound, Great Dane, St BernardMast cell tumour Boxer, golden/Labrador retrieverChemoreceptor tumours Boxer, Boston terrierGastric carcinoma Belgian shepherd dog

TUMOUR BIOLOGY

establish growth. During this process the cell mustevade host defence mechanisms and survive in thecirculation. Current theories suggest that onlycertain clones of cells within a tumour develop allthe abilities required for metastasis but that theseclones probably arise and disseminate in the earlystages of that tumour’s growth, often prior to thedetection of the primary tumour.

References

Breen, M., Bullerdiek, J. & Langford, C. (1999) The DAPIbanded karyotype of the domestic dog (Canis famil-iaris) generated using chromosome-specific paintprobes. Chromosome Research, (7), 401–6.

Doddy, F.D., Glickman, L.T., Glickman, N.W. & Janovitz,F.B. (1996) Feline fibrosarcomas at vaccination sitesand non-vaccination sites. Journal of ComparativePathology, (114), 165–74.

Esplin, D.G., McGill, L.D., Meininger,A.C. & Wilson, S.R.(1993) Postvaccination sarcomas in cats. Journal of the American Veterinary Medical Association, (11),1440–44.

Frazier, K.S., Hines, M.E., Hurvitz, A.I., Robinson, P.G. &Herron, A.J. (1993) Analysis of DNA aneuploidy andc-myc oncoprotein content of canine plasma cell


through the body. In humans, different types ofcancer show different target organ specificity formetastasis. For example:

• Prostatic carcinoma – bone• Breast carcinoma – bone, brain, adrenal, lung,

liver• Cutaneous melanoma – liver, brain, bowel.

In small animals, the lungs are the most commonsite for the development of haematogenous sec-ondary tumours but other sites including liver,spleen, kidneys, skin and bone should not be over-looked. Carcinomas and mast cell tumours usuallymetastasise by the lymphatic route and sarcomasand melanomas by the haematogenous route buttumours do not always follow expected patterns ofbehaviour and some tumours may spread by bothlymphatic and haematogenous routes.

The mechanisms involved in the process ofmetastasis are not fully understood. In order toform a metastasic growth, a cancer cell must detachfrom the primary tumour, move into the vascula-ture to travel to a new location, aggregate withplatelets and fibrin to arrest at the new site,extravasate into surrounding parenchyma and

Table 1.6 Features of benign and malignant tumours.

Benign Malignant

Rate of growth Relatively slow Often rapidGrowth may cease in some cases Rarely ceases growing

Manner of growth Expansive InvasiveUsually well defined boundary Poorly defined borders, tumour

between neoplastic and normal cells extend into and may betissues. May become scattered throughout adjacentencapsulated. normal tissues.

Effects on adjacent Often minimal Often serioustissues May cause pressure necrosis and Tumour growth and invasion

anatomical deformity results in destruction of adjacentnormal tissues, manifest asulceration of superficial tissues,lysis of bone

Metastasis Does not occur Occurs by lymphatic andhaematogenous routes andtranscoelomic spread

Effect on host Often minimal (can be life Often life-threatening by virtuethreatening if tumour of destructive nature of growthdevelops in a vital and metastatic dissemination toorgan, e.g. brain) other, vital organs.


tumours using flow cytometry. Veterinary Pathology,(30), 505–11.

Gamblin, R.M., Sagartz, J.E. & Couto, C.G. (1997) Over-expression of p53 tumour suppressor protein in spon-taneously arising neoplasms of dogs. American Journalof Veterinary Research, (58), 857–63.

Grindem, C.B. & Buoen, L.C. (1986) Cytogenetic analy-sis of leukaemic cells in the dog. A report of ten casesand a review of the literature. Journal of ComparativePathology, (96), 623–35.

Gumerlock, P.H., Meyers, F.J., Foster, B.A., Kawakami,T.G. & deVere White, R.W. (1989) Activated c-N-ras inradiation induced acute nonlymphocytic leukaemia:twelfth codon aspartic acid. Radiation Research, (117),198–206.

Hahn, K.A., Richardson, R.C., Hahn, E.A. & Chrisman,C.L. (1994) Diagnostic and prognostic importance of chromosomal aberrations identified in 61 dogs with lymphosarcoma. Veterinary Pathology, (31), 528–40.

Hendrick, M.J., Goldschmidt, M.H., Shofer, F.S. et al.(1992) Postvaccinal sarcomas in the cat: epidemiologyand electron probe microanalytical identification ofaluminium. Cancer Research, (52), 5391–4.

Kraegal, S.A., Gumerlock, P.H., Dungworth, D.L., Oreffo,V.I., & Madewell, B.R. (1992) K-ras activation in non-small cell lung cancer in the dog. Cancer Research, (52),4724–7.

Langford, C.F., Fischer, P.E., Binns, M.M., Holmes, N.G. &Carter, N.P. (1996) Chromosome-specific paints from ahigh-resolution flow karyotype of the dog. Chromo-some Research, (4), 115–23.

Look, A.T. (1995) Oncogenic role of ‘master’ transcrip-tion factors in human leukemias and sarcomas: a devel-opmental model. Advances in Cancer Research, (67),25–57.

Mayr, B., Reifinger, M., Weissenbock, H. et al. (1994)Cytogenetic analyses of four solid tumours in dogs.Research in Veterinary Science, (57), 88–95.

Mayr, B., Dressler, A., Reifinger, M. & Feil, C. (1998a)Cytogenetic alterations in eight mammary tumours andtumour suppressor gene p53 mutation in one mammarytumour from dogs. American Journal of VeterinaryResearch, (59), 69–78.

Mayr, B., Reifinger, M. & Loupal, G. (1998b) Polymor-phisms in feline tumour suppressor gene p53. Muta-tions in an osteosarcoma and a mammary carcinoma.Veterinary Journal, (155), 103–106.

Mayr, B., Reifinger, M, Alton, K. & Schaffner, G. (1998c)Novel p53 tumour suppressor mutations in cases ofspindle cell sarcoma, pleomorphic sarcoma andfibrosarcoma in cats. Veterinary Research Communica-tions, (22), 249–55.

Mayr, B.,Wegscheider, H., Reifinger, M. & Jugl,T. (1998d)Cytogenetic alterations in four feline soft-tissuetumours. Veterinary Research Communications, (22),21–9.

Mayr, B., Reifinger, M. & Alton, K. (1999) Novel caninetumour suppressor gene mutations in cases of skin andmammary neoplasms. Veterinary Research Communi-cations, (23), 285–91.

Miyoshi, N., Tateyama, S., Ogawa, K.L. et al. (1991a)Proto-oncogenes of genomic DNA in clinically normalanimals of various species. American Journal of Veteri-nary Research, (52), 940–43.

Miyoshi, N., Tateyama, S., Ogawa, K.L. et al. (1991b)Abnormal structure of the canine oncogene, related to the human c-yes-1 oncogene, in canine mammarytumour tissue. American Journal of VeterinaryResearch, (52), 2046–9.

Momoi, Y., Nagase, M., Okamoto, Y. et al. (1993)Rearrangements of immunoglobulin and T-cell recep-tor genes in canine lymphoma/leukaemia cells. Journalof Veterinary Medicine and Science, (55), 775–80.

Nasir, L. & Argyle, D.J. (1999) Mutational analysis of thetumour suppressor gene p53 in lymphosarcoma in twobull mastiffs. Veterinary Record, (145), 23–4.

Neil, J.C., Hughes, D., McFarlane, R. et al. (1984) Trans-duction and rearrangement of the myc gene by felineleukaemia virus in naturally occurring T-cellleukaemias. Nature, (308), 814–20.

Onions, D.E. (1984) A prospective study of familialcanine lymphosarcoma. Journal of the National CancerInstitute, (72), 909–12.

Padgett, G.A., Madewell, B.R., Keller, E.T., Jodar, L. &Packard, M. (1995) Inheritance of histiocytosis inBernese mountain dogs. Journal of Small Animal Prac-tice, (36), 93–8.

Rabbitts, T.H. (1994) Chromosomal translocations inhuman cancer. Nature, (372), 143–9.

Reimann, N., Rogalla, P., Kazmierczak, B. et al. (1994)Evidence that metacentric and submetacentric chromosomes in canine tumours can result from telom-eric fusions. Cytogenetics and Cell Genetics, (67),81–5.

Reimann, N., Bartnitzke, S., Bullerdiek, J. et al. (1998)Trisomy 1 in a canine acute leukemia indicating impor-tance of polysomy 1 in leukemias of the dog. CancerGenetics and Cytogenetics, (101), 49–52.

Rungsipipat, A., Tateyama, S., Yamaguchi, R., Uchida, K.& Miyoshi, N. (1999) Expression of c-yes oncogeneproduct in various animal tissues and spontaneouscanine tumours. Research in Veterinary Science, (66),205–10.

Sagartz, J.E., Bodley, W.L., Gamblin, R.M., Couto, C.G.,Tierney, L.A. & Capen, C.C. (1996) p53 tumour sup-pressor protein overexpression in osteogenic tumoursof dogs. Veterinary Pathology, (33), 213–21.

Switonski, M., Reimann, N., Bosma, A.A. et al. (1996)Report on the progress of standardization of the G-banded canine (Canis familiaris) karyotype. Chromo-some Research, (4), 306–09.

Tap, O.T., Rutteman, G.R., Zijlstra, C., de Haan, N.A. &Bosma, A.A. (1998) Analysis of chromosome aberra-tions in a mammary carcinoma cell line from a dog byusing canine painting probes. Cytogenetics and CellGenetics, (82), 75–9.

Veldhoen, N., Watterson, J., Brash, M. & Milner, J. (1999)Identification of tumour-associated and germ line p53mutations in canine mammary cancer. British Journalof Cancer, (81), 409–15.

Yang, F., O’Brien, P.C.M., Milne, B.S. et al. (1999) A com-

Jarrett, O. (1985) Feline leukaemia virus. In Practice, (7),125–6.

Jarrett, O. (1994) Feline leukaemia virus. In: Feline Medi-cine and Therapeutics, (eds E.A. Chandler, C.J. Gaskell& R.M. Gaskell), 2nd edn, pp. 473–87. Blackwells,Oxford.

Miller,W.H.,Affolter,V., Scott, D.W. & Suter, M.M. (1992)Multicentric squamous cell carcinomas in situ resem-bling Bowen’s disease in five cats. Veterinary Derma-tology, (3), 177–82.

Rosenkrantz,W.S. (1993) Solar dermatitis. In: Current Vet-erinary Dermatology, The Science and Art of Therapy.(eds C.E. Griffin, K.W. Kwochka & J.M. MacDonald),pp. 309–15. Mosby Year Book, St Louis.


plete comparative chromosome map for the dog, redfox and human and its integration with canine geneticmaps. Genomics, (62), 189–202.

Further reading

Alberts, B., Bray, D., Lewis, J., Raff, M., Roberts, K. &Watson, J.D. (1994) The Molecular Biology of the Cell,3rd edn. Garland Publishing Inc, New York.

Hardy, W.D. (1981) The feline leukemia virus. Journal ofthe American Animal Hospital Association, (17),951–80.

Hardy, W.D. (1981) The feline sarcoma viruses. Journal ofthe American Animal Hospital Association, (17),981–97.

2Diagnosis and Staging

of treatment and prognosis or whether the patientis treated at all.

The objectives of the initial evaluation of thecancer patient may thus be summarised:

• Diagnosis of the histological type and grade ofthe disease

• Determination of the extent or stage of the disease• Investigation of tumour-related complications• Investigation of any concurrent disorder.

The treatment and prognosis for an individual withcancer will depend on the nature and the extent oftheir disease. Thus for treatment to succeed, the histological type (and grade) of the tumour and itssize and anatomical extent must be defined prior totreatment. It is also important to detect possiblehaematological or metabolic complications relatedto the disease and to investigate concurrent illness,since all of these factors may influence the method

� Tumour diagnosis, 15� Tumour staging, 17� Tumour-related complications, 22

15

TUMOUR DIAGNOSIS

Neoplastic tissues have certain features which distinguish them from hyperplastic or inflam-matory conditions and further features which distinguish benign from malignant growths, asshown in Table 2.1. Although an experienced clinician can sometimes make an informed guess as to the likely nature of a tumour according to its site, gross appearance and history, a defini-tive diagnosis can only be made by micro-scopic examination of representative tissue or cells from the tumour. This may be achieved byeither:

• Collection of tissue from the tumour – histolo-gical diagnosis; or

• Collection of cells from the tumour – cytologicaldiagnosis.

Histology

Histological examination of representative tissuefrom a tumour is the most accurate method ofcancer diagnosis. A biopsy provides the patholo-gist with the opportunity to examine the cellular components of the tumour, its architecture and itsrelationship to adjacent normal tissues.

A variety of biopsy techniques may be used tocollect tumour samples:

• Needle biopsy – e.g. ‘tru-cut’ for soft tissuetumours, ‘Jamshidi’ for bone

• Skin punch biopsy – for skin and superficial softtissue tumours

• Crocodile action ‘grab’ biopsy forceps – may beused with endoscopic techniques for tumours

On occasions it may be difficult to procure representative tumour tissue, particularly wherethere is surface ulceration or extensive necrosis in a tumour. Factors that should be taken into consideration in order to obtain a representativebiopsy sample with minimum risk to the patient are summarised in Table 2.2. In addition to giving a definitive diagnosis, by providing informationregarding cell type, mitotic rate and tissue architec-ture, histology can also provide an indication of the‘grade’ of a tumour, i.e. its likely clinical behaviourin terms of local invasion and distant metastasis.Increasingly it is appreciated that the histologicalgrade of a tumour is of equal importance to histo-logical type in treatment selection and prognosis(see soft tissue sarcoma and mast cell tumours).Thefollowing features may all be used to help predicttumour behaviour:

• Degree of cellular differentiation• Degree of cellular and nuclear pleomorphism• Mitotic rate (number of mitotic figures per high

power field)• Presence and amount of necrosis• Presence of an inflammatory infiltrate• Stromal reaction• Degree of invasion, i.e. the relationship between

the tumour and adjacent normal tissues.

Other ways to assess tumour prognosis includemeasuring DNA content or ploidy by flow cytome-try, cell proliferation or abnormal expression ofoncogenes (e.g. ErbB2) or tumour suppressor genes


sited in the respiratory, gastro-intestinal and urogenital tracts

• Incisional biopsy• Excisional biopsy.

In most circumstances it is preferable to make the tumour diagnosis prior to treatment, even when the treatment will be surgical, because only when the nature of the disease is known can an appropriate treatment be planned. The margins of surgical resection required to remove a canine cutaneous histiocytoma are considerably less thanthose required to remove a cutaneous mast celltumour. Thus in order to prevent an inadequatesurgery, leading to local tumour recurrence, aneedle, grab or incisional biopsy is preferable to an excisional biopsy (cytology can also be useful in this respect).

The exception to this general rule is when priorknowledge of the histological type of tumour willnot influence the surgical approach; for example,tumours involving internal organs (such as kidneyor spleen) where removal of that entire organ is the most feasible surgical approach, or in the caseof canine mammary tumours, where, irrespective ofwhether the tumour is a benign mixed mammarytumour or a carcinoma, the only surgical approachis to remove the entire mass, often with the affectedgland. Providing all the tumour is removed,the post-surgical prognosis for canine mammarytumours is not dependent on the degree of surgery.

Table 2.1 Cytological and histological features of malignancy.

Cytological featuresCell population Pleomorphism

Presence of mitoses, especially abnormal or bizarre forms

Cellular features Large cell size/giant cells (anisocytosis)Poorly differentiated, anaplastic cellsHigh nuclear to cytoplasmic ratio

Nuclear features Large nuclear size, nuclear pleomorphism (anisokaryosis)Multiple nuclei (often of variable size)Hyperchromatic nuclei with clumping or stippling of chromatinProminent and often multiple nucleoli of variable size and shape

Histological featuresCellular features As outlined for ‘cytology’

Tumour architecture Lack of structural organisation of cells into recognisable form

Relationship with adjacent tissues Invasion of cells into adjacent normal tissues

Evidence of metastatic behaviour Tumour cells invading or present within lymphatics or venules

Diagnosis and Staging 17

(e.g. p53). Cell proliferation may be quantified byusing monoclonal antibodies to nuclear antigenswhich are present in the nuclear matrix of proliferating cells but not in non-proliferating cells. These include Ki-67, DNA polymerase alpha, PCNA.Alternatively, silver staining to detectagrophillic nucleolar organiser regions (AgNORs)can also be helpful in assessing proliferation.For poorly differentiated tumours, haematoxylinand eosin stains may not be sufficient to reach adefinitive diagnosis and special staining techniquescan be applied to help differentiate possible tumourtypes.

Cytology

Cells may be collected from tumours by a varietyof techniques:

• Fine needle aspirate• Exfoliation – tissue imprint, scrape or exudate

smears• Cytospins of body fluids.

Microscopic examination of such samples providesinformation regarding the cell population and themorphology of individual cells. Fine needle aspi-

rates or impression smears from solid tumours andthe cellular content of fluids collected from organsor body cavities can provide a great deal of infor-mation about the lesion and will often differentiatebetween inflammatory and neoplastic processes.The morphology of neoplastic cells will also oftenprovide an indication of the likely nature of atumour and its degree of malignancy. Fine needleaspiration is a quick and simple technique requir-ing a minimum of equipment that can easily be per-formed in practice. The technique is summarised inFigs 2.1–2.4. Many commercial clinical pathologylaboratories will report on cytological samples andwith practice most veterinarians should be able touse cytology to discriminate between reactive andneoplastic lesions and even to diagnose some par-ticularly characteristic tumours, for example mastcell tumours.

Obtaining aspirates for cytology is often quicker,cheaper and easier to perform than obtaining biopsies for histopathology but the latter has theadvantage that tissue architecture can be assessed,along with the degree of invasiveness, haemorrhageand necrosis, and thus not only provide a definitivetumour diagnosis but also information about thegrade of malignancy.

Table 2.2 Factors to consider when planning a tumour biopsy.

Objective Considerations

Procure a representative sample of the tumour Avoid superfical ulceration, areas of inflammation or necrosisEnsure adequate depth of biopsy, particularly for oral tumoursTry to include tumour – normal tissue boundary in the biopsy

sample

Avoid local tumour recurrence or local spread Minimise handling of tumour by adequate surgical exposureEnsure adequate haemostasisMinimise trauma to tumour and normal tissuesAvoid contamination of normal tissue by surgical instruments

Do not compromise subsequent therapy Site any biopsy procedure well within the margins of futureexcision

TUMOUR STAGING

The ‘stage’, that is the extent of a tumour, is of equalimportance to its histological type in determiningprognosis and the feasibility of therapy. Successfultreatment depends on eradication of all tumourstem cells and this can only be achieved if theextent of the disease is fully appreciated. It is there-

fore important to determine the local extent of atumour and investigate the possibility of metastasisas part of the initial evaluation of the cancerpatient, and a logical system for such evaluationshould be followed.

Anatomical classification or clinical staging of

tumours is based on an objective approach to (Fig. 2.5):

• The primary tumour (T)• The local and regional lymph nodes (N)• Distant metastases (M).

Primary tumour (T)

Malignant neoplasms are characterised by an inva-sive, infiltrating pattern of growth. The tendency for local recurrence of such tumours following excisional surgery is a result of a failure to removeor eradicate all tumour (i.e. a failure of the surgery)rather than a preset characteristic of the tumour.

It is essential, therefore, to define the extent ofthe primary tumour as accurately as possible priorto therapy so that appropriate treatment marginscan be applied. A tumour is a three-dimensionalentity and all surrounding structures including skin,fascia, muscles, bone and adjacent viscera must be


Figs 2.1–2.4 Fine needle aspirate technique for subcutaneous mass.Fig. 2.1. The lesion is located and fixed with one hand. Fig. 2.2. The fine needle (usually 23 guage, 1 in.) isinserted into the mass and redirected several times in a stabbing motion. Fig. 2.3. The needle is withdrawn andconnected to an air filled syringe to expel the needle contents onto a clean glass slide. Fig. 2.4. The sample issmeared by laying a second slide perpendicular to the first and carefully drawing the two apart. (Reprinted fromDobson (1999) with permission.)

2.1

2.3

2.2

2.4

Fig. 2.5 Diagrammatic representation of the TNMtumour staging system. (T = primary tumour, N = localand regional lymph nodes, M = metastases.)


Fig. 2.6 Basal cell carcinoma of the premaxilla. The dental displacement and extension of the tumour mass onboth sides of the dental arcade are indicators of bone invasion by the tumour as is shown in Fig. 2.7, an intrao-ral radiograph of the tumour site.

evaluated for evidence of tumour infiltration. Theease of evaluation of the primary tumour willdepend on its location and accessibility. Methods of evaluation include the following.

Physical examination

• Tumour site and relationship to normal anatomicstructures

• Size or volume of the primary mass• Mobility of the tumour with respect to sur-

rounding tissues: fixation usually denotes tumourinfiltration of adjacent structures

• Ulceration denotes infiltration and disruption ofthe epidermis.

For deeper tumours, operative procedures – forinstance celiotomy or thoracotomy – may be necessary to provide access to the tumour for bothhistological and anatomical classification.

2.6

2.7

Radiography

Radiography is especially useful for:

• Tumours involving or adjacent to bone (e.g.tumours of the oral cavity (Figs 2.6 and 2.7)).

• Tumours sited within body cavities. Contraststudies may be required to assist visualisation oftumours sited within hollow organs.

Ultrasonography

Ultrasonography can provide useful informationabout lesions affecting soft tissues and internalorgans such as the liver, spleen and kidneys.

Endoscopy

Endoscopy allows visual examination of the respiratory, gastro-intestinal and urogenital tracts.

all features indicative of neoplastic involvement. Amore subtle lymphadenopathy may indicate a smallmetastatic deposit or may arise as a result of reac-tive hyperplasia.

Aspirate/biopsy

Aspirate/biopsy of lymph node(s) may be re-quired to distinguish between reactive and neo-plastic enlargement.

Imaging techniques

Internal lymph nodes may be evaluated by radiography, ultrasonography, CT or MRI.

Internal lymph nodes may also be evaluated atthe time of surgery.

Distant metastasis (M)

Haematogenous dissemination of malignanttumours gives rise to metastases in distant organs. Soft tissue and osteosarcomas and ma-lignant melanoma characteristically metastasise in this way but some carcinomas and mast celltumours also spread via the blood to distant sites.Although the lungs are the most common site forthe development of metastases in small animals,other potential sites for metastatic spread shouldnot be overlooked:

• Skin• Bones• Brain and spinal cord• Internal organs, spleen, liver, kidneys, heart.

The detection of metastases is problematic:tumours only become large enough to detect at arelatively late stage in their development andmicro-metastases are below the threshold of currently available detection methods (Fig. 2.9).Nevertheless a range of investigative methods for screening the patient with suspected metastaticdisease can be considered:

• History and physical examination• Radiography – especially thorax, right and left

lateral and dorsoventral views; skeletal survey ifbone metastases suspected

• Ultrasonography – liver, spleen, kidneys• Scintigraphy – sensitive method for detection of

bone metastasis


Biopsy

In addition to providing a histological diagnosis,well-orientated biopsies may be used to determinethe extent of tumour invasion.

Specialist imaging techniques

Computed tomography (CT) and magnetic resonance imaging (MRI) are increasing in use.These techniques allow detailed, three dimensionalimaging of soft tissues and bone (see Fig. 2.8).

Lymph nodes (N)

Lymph node metastasis is most common in:

• Carcinomas• Melanomas• Mast cell tumours.

But soft tissue sarcomas may also metastasise bythis route. Methods of evaluation of local andregional lymph nodes include the following.

Physical examination

The size, shape, texture and mobility of local andregional lymph nodes should be assessed. Grossenlargement, irregularity, firmness and fixation are

Fig. 2.8 CT scan of dog’s nose with nasal tumour.(Courtesy of Animal Medical Centre, Referral Services,Manchester.)


the size of 0.5–1.0cm in diameter. Right and leftlateral thoracic radiographs should be included as a routine part of the initial ‘work-up’ of anyanimal with a malignant tumour because thefinding of pulmonary metastases usually leads to apoor prognosis (Figs 2.10 and 2.11). The finding ofa ‘clear’ thoracic film does not however exclude thepossibility of micro-metastases. Metastatic tumourin the liver, spleen or kidneys may be diffuse ornodular in distribution and may not significantlyalter the shape or outline of those organs until thetumour reaches advanced stages. Ultrasonographyis more useful than radiography in screening theseorgans but metastatic disease may also be below the threshold of ultrasonic detection (Figs 2.12 and 2.13).

Clinical tumour staging systems

The TNM anatomical classification of tumours canbe used to provide a precise means of recording theapparent extent of the disease at the time of assess-ment. Coupled with a knowledge of the clinical

Log phase of growth(high GF, short DT)

105

108

1010

Tumour first palpable (mass 1 g)Tumour first detectable by radiography

Plateau phase of growth(low GF, long DT)

Lo

g n

o. c

an

cer

cells

Time

Fig. 2.9 Graph of tumour growth versus clinical detection. A tumour cannot be detected by palpationor radiography until it reaches approximately 1cm indiameter or 0.5–1g in weight, by which time it hasundergone approximately 30 doublings and containsin the order of 108–109 cells.

Figs 2.10 and 2.11 Left and right lateral views of the thorax of a dog. The secondary pulmonary tumours are onlyclearly visible on the left view which indicates that they are in the right lung. Visualisation of pulmonary metas-tases depends on the contrast between the air filled lung and the soft tissue of the tumour. Thus tumours are morelikely to be detected in the upper, inflated lung as opposed to the lower lung which is compressed.

2.10 2.11

• CT or MRI – internal organs including brain• Laboratory investigations – of little value in most

cases• Bone marrow aspirate.

Discrete pulmonary tumours can only be detectedon thoracic radiographs once they have reached

behaviour of individual tumours at specific sites,this information can be used to group tumoursaccording to their prognosis: clinical staging. Whererelevant, clinical staging systems are included underindividual tumour types in later sections of thisbook.

Clinical staging does not necessarily imply aregular and predictable progression of the disease.Some cancers do proceed in a typical course, ad-vancing from primary to nodal to metastatic disease,but many variations exist and it is not unknown formetastasis to be the first sign of the disease.


Fig. 2.12 Extensive nodular metastases from a cuta-neous mast cell tumour in the liver of a dog.

Fig. 2.13 Ultrasonogram of the liver showing multiplehypoechogenic areas correlating with hepatic metas-tases. (Courtesy of Mr M. E. Herrtage, Department ofClinical Veterinary Medicine, Cambridge.)

When relating clinical stage to prognosis, twoimportant points must be taken into consideration:

• There is a difference between the clinical stageand the true pathological stage of a diseasebecause it is not possible to detect microscopictumour extensions or deposits.

• Other factors, apart from clinical stage, are ofprognostic significance including the location ofthe tumour, its histological type and grade.

In practice, cancer therapy must be directed at leasttowards the clinically-defined stage of the tumour.Local treatment may be selected for tumours of lowgrade or tumours with a low metastatic potential(e.g. basal cell carcinoma of the skin). However,local treatment will not be adequate for moreaggressive tumours with a high potential for metastasis (e.g. malignant melanoma, osteosar-coma) and ideally these tumours should be treatedas being potentially stage IV (i.e. as if they had occult disseminated metastasis) even if they present clinically as stage I.

TUMOUR-RELATED COMPLICATIONS

An animal with a tumour may be presented as a result of an obvious mass but often the clinicalpresentation of cancer patients relates to the director indirect effects of the tumour, rather than thetumour mass itself. Tumours may cause clinicalsigns due to:

• Direct effects of tumour growth on adjacentorgans/body systems

• Haematological complications• Metabolic/endocrine complications (‘paraneo-

plastic’ syndromes).


Direct effects of tumour growth

Local growth of neoplasms invariably causesdestruction of adjacent normal tissues which may result in dysfunction of vital organs. Any organ system can be affected in this way either by primary or secondary tumour growth.Some of the more commonly affected or more important organ systems are summarised in Table 2.3.

Haematological complications

Tumours may cause a number of haematologicalcomplications through a variety of mechanisms,the more common of which are summarised inTable 2.4. The haematological problem may be the presenting clinical sign but anaemia and thrombo-cytopenia are quite common findings in cancerpatients and may be detected on routine haemato-logical investigations. In addition to affecting theproduction of blood cells, tumours can also affect

the dynamics of blood flow. The viscosity of the blood may be increased in neoplastic con-ditions such as polycythaemia, and some forms ofleukaemia by high cell numbers, or due to highprotein content from immunoglobulin secretingtumours such as multiple myeloma.

Supportive treatment may be required to sta-bilise and maintain the patient until the underlyingproblem can be identified and treated:

• Whole blood transfusion may be indicated in cases of severe anaemia or for animals in disseminated intravascular coagulation (DIC).

• Heparin therapy (mini-dose: 5 to 10IU/kg sc q 8h) is indicated to halt the intravascular coagulation in DIC but must be given with whole blood or fresh frozen plasma to provideanti-thrombin III.

• Phlebotomy may also be used for managementof polycythaemia. Up to 20ml whole blood/kgbody weight may be removed and replaced withplasma or crystalloid fluids.

• Plasmapheresis may be indicated for treatment

Table 2.3 Direct effects of tumour growth on selected organ systems.

NeurologicCNS Increased intracranial pressure, depression,

altered mental state, seizures, disorientation,neurological deficits, endocrine disorders

Spinal cord Spinal cord compression or invasion – pain,paresis, paralysis

CardiopulmonaryNasopharyngeal Upper airway obstructionAnterior mediastinum Superior vena cava syndrome – facial swelling

Pleural/mediastinal effusion – dyspnoeaHeart Arrhythmias

Pericardial effusion and cardiac tamponade

GastrointestinalStomach Gastrointestinal obstruction or perforation,Small intestine intra-abdominal haemorrhage, peritonitis,Large intestine intra-lumenal haemorrhage,

vomiting, diarrhoea, dyschezia

UrogenitalRenal Haematuria, dysuria, post renal obstruction Bladder with azotemiaUrethraProstate

Metabolic and endocrinecomplications – paraneoplasticsyndromes

Tumours can produce profound systemic or metabolic disturbances through the production of hormones or hormone-like substances that act on organs at sites distant to the primary tumour. The resulting clinical syndromes are


of severe hyperviscosity due to hypergam-maglobulinaemia. This is achieved by collecting20ml blood/kg body weight and replacing thiswith centrifuged blood cells from the patient,which have been resuspended in crystalloid fluid.

Haematological assessment of the cancer patient is also very important to provide a base-line from which to monitor the response and toxicity offuture treatment.

Table 2.4 Haematological complications of tumours.

Tumour directly affects production of blood cellsNeoplastic invasion of the bone marrow Usually manifest as reduction in cell numbers (cytopenia):(myelophthisis) seen with Non-regenerative anaemialymphoproliferative and myeloproliferative Thrombocytopeniaconditions. Leucopenia

May be elevated numbers of abnormal cells in the blood inleukaemia (see below)

Tumour indirectly affects production of blood cellsOestrogen producing tumours (Sertoli Usually manifest as:cell and granulosa cell tumours) lead to Non-regenerative anaemiaoestrogen-induced myelotoxicity Thrombocytopenia

GranulocytopeniaMyelofibrosis may be tumour induced

Hyperviscosity syndromes Lethargy, disorientation, ataxia, tremors, episodicweakness, seizures, thrombo-embolic disease, bleedingdiathesis, retinal detachment

Lymphoproliferative and Excessive numbers of circulating (neoplastic) blood cells causemyeloproliferative diseases, forms of sludging of blood and poor circulationleukaemia and primary polycythaemia

Renal tumours, also reported with Excessive production of erythropoietin leading to secondarytesticular tumours and haemangiosarcoma. polycythaemia

Secretory multiple myeloma Excessive production of gammaglobulins may also lead tohyperviscosity syndrome

Other tumour-mediated abnormalities Regenerative anaemia/thrombocytopenia may be associatedwith auto-immune haemolytic anaemia, or immune-mediatedthrombocytopenia secondary to lymphoid neoplasia

Microangiopathic anaemia, associated with fragmentation of redblood cells in haemangiosarcoma

Thrombocytopenia due to sequestration of platelets in largeabnormal tumour blood vessels, e.g. haemangiosarcoma

Disseminated intravascular coagulopathy (DIC) – triggered bymany disseminated malignant tumours, results inthrombocytopenia and bleeding diathesis

Blood loss Regenerative anaemia/thrombocytopenia may be due to:Haemorrhage from a tumourBleeding from gastroduodenal ulceration due to

hypergastrinaemia or hyperhistaminaemiaSecondary to a bleeding disorder


well recognised syndrome where tumour in-duced metabolic alterations in carbohydrate,protein and lipid metabolism lead to a net loss ofenergy to the patient despite adequate energyintake. In many cases the problem is compoundedby tumour or treatment induced anorexia, impaireddigestion and absorption and protein loss througheffusions or haemorrhage. Cancer cachexia is amajor cause of morbidity and death in humancancer patients and is of significance in veterinarycancer medicine (Vail et al. 1990) (Fig. 2.14).Fever is another syndrome which accompaniesmany types of tumour usually associated with theproduction of cytokines, such as tumour necrosisfactor and interferon.

Paraneoplastic syndromes can arise as a result of autonomous secretion of normal hormones byfunctional tumours of endocrine origin, as listed in Table 2.5 and discussed in Chapter 14. Variousnon-endocrine tumours can also produce andrelease hormones or hormone-like substances.Several commonly recognised syndromes are listedin Table 2.6. Tumours may also cause cutaneous,neurological and skeletal manifestations, some ofwhich are summarised in Table 2.7.

Fig. 2.14 Cachectic patient. Severe cachexia is notcommon in canine cancer patients.

Table 2.5 Endocrine disorders resulting from tumours of endocrine origin.

Syndrome Tumour(s) Clinical signs*

Hyperadrenocorticism Adrenal adenoma Polydipsia/polyuria(Cushing’s syndrome) Adrenal adenocarcinoma Polyphagia

Pituitary adenoma Coat changes: alopecia, calcinosis cutisMuscle weaknessHepatomegalyPendulous abdomen

Hyperthyroidism Thyroid adenoma (cats) Polyphagia, polydipsiaThyroid adenocarcinoma Weight loss, diarrhoea

(dogs and occasionally cats) Tachycardia associated with hypertrophiccardiomyopathy

Hyperexcitability

Primary hyperparathyroidism Parathyroid adenoma Due to hypercalcaemia:Polydipsia/polyuriaAnorexia, vomitingMuscle weaknessBradycardia/arrhythmias

Hypoglycaemia Pancreatic islet (beta) cell Episodic weakness, collapse, disorientationtumour (insulinoma) and seizures

Hypergastrinaemia Pancreatic gastrin producing Gastric and duodenal ulceration(Zollinger-Ellison syndrome) neoplasm Vomiting (haematemesis)

* See Chapter 14 for more detailed information on these conditions.

termed ‘paraneoplastic syndromes’ and it is oftenthis metabolic/endocrine disorder which alerts theowner to a problem. Some paraneoplastic con-ditions are specific to certain tumours or certainmetabolic abnormalities (see later); others aremore general, for example cancer cachexia is a

Hypercalcaemia can also affect the heart, resultingin bradycardia and arrhythmias.

The renal effects of hypercalcaemia are of great-est importance. In the early stages hypercalcaemiaaffects the renal tubules causing an inability to concentrate urine which leads to hyposthenuria and polyuria with secondary polydipsia. The renalnephropathy is initially reversible but if the hyper-calcaemia persists, the renal damage becomes irre-versible and eventually metastatic calcification ofthe renal tubular epithelium and basement mem-branes occurs. The renal effects of hypercalcaemiacause the animal to become dehydrated and hypo-volaemic and further fluid loss may occur fromvomiting. Renal failure caused by the hypercal-caemia is therefore exacerbated by pre-renalfailure due to hypovolaemia, and the animalbecomes azotemic.

DiagnosisIn most cases hypercalcaemia is detected on biochemical analysis. Most laboratories routinelymeasure the total plasma calcium which comprises:

• Ionised, biologically active calcium; and• Calcium that is complexed or bound to protein.

An equilibrium exists between the two states suchthat in normal circumstances the total plasmacalcium is a good indicator of the biologicallyactive, ionised calcium. This equilibrium can be disturbed in cases of hypoalbuminaemia, whereionised calcium will make a proportionately greatercontribution to the total value. It may also be influ-enced by the acid:base balance.


Hypercalcaemia

Neoplasia is the most common cause of hypercalcaemia in the dog and cat, although other, non-neoplastic causes are recognised (e.g.hypoadrenocorticism). Cancer associated hyper-calcaemia results from the production of substancesby haematopoietic and solid neoplasms which stimulate bone resorption. Several hypercalcaemic mediators produced by tumours have been identi-fied, including parathyroid hormone (PTH), aparathyroid hormone-related protein (PTHrP),and a lymphokine osteoclast activating factor(OAF). In many cases, however, the active sub-stance is not known. In the dog, hypercalcaemia is most commonly associated with:

• Lymphoproliferative disorders, e.g. lymphoma• Adenocarcinoma of the apocrine glands of

the anal sac• Other solid tumours with or without bone

metastases• Functional adenoma of the parathyroid gland

(primary hyperparathyroidism).

Clinical signs of hypercalcaemiaThe predominant clinical signs are:

• Polydipsia/polyuria – due to the renal effects ofhypercalcaemia

• Anorexia, vomiting – due to gastro-intestinaleffects

• Lethargy, depression and muscular weakness –due to neuromuscular effects.

Table 2.6 Common paraneoplastic syndromes in small animals.

Syndrome Tumour(s) Clinical signs

Hypercalcaemia Lymphoid tumours, myeloid tumours Polyuria/polydipsiaAnal gland adenocarcinoma Anorexia, vomitingSolid tumours with skeletal metastases DehydrationOther solid tumours Muscular weakness, tremor

Bradycardia

Hypoglycaemia Hepatic tumours, especially hepatocelluar Episodic weakness, collapse,carcinoma disorientation and seizures

Other tumours, especially large intra-abdominaltumours

Hyperhistaminaemia Mast cell tumours Gastroduodenal ulcerationAnorexia, vomitingHaematemesis, melaena,Anaemia


Determining the cause of the hypercalcaemia can be straightforward, if for example the dog ispresented with generalised lymphadenopathy. Insome cases, however, the cause of the hypercal-

caemia is not immediately obvious and a series of investigations (as summarised in Table 2.8) may be carried out based on the known causes ofhypercalcaemia.

Table 2.7 Paraneoplastic syndromes affecting skin, bone and neuromuscular system.

System Syndrome Associated tumours/affected references

Bone Hypertrophic (pulmonary) osteopathy Primary or secondary lung tumours(Marie’s disease) Oesophageal tumours

Painful, proliferative periosteal new Rhabdomyosarcoma of bladder,bone growth on distal limbs associated Nephroblastoma with rapid increase in peripheral blood Carcinoma of the liverflow to the distal extremities. Exact Other non-neoplastic causesaetiology unknown

Skin Hepatocutaneous syndrome/epidermalnecrosis

Ulcerative dermatosis resembling human Glucagon producing pancreaticnecrolytic migratory erythema carcinoma (Gross et al. 1990), also

Hyperkeratosis and fissuring of the foot reported with hepatic disease, often pads with symmetrical erythema, concurrent with diabetes mellitus (Bondulceration and crusting of the face, feet et al. 1995)and external genitalia

Exfoliative dermatitisGeneralised scale and erythema Thymoma in cats

(Scott et al. 1995)AlopeciaProgressive alopecia involving limbs and Cats with pancreatic carcinoma, metastatic

ventrum to liver and other distant sites.(Brooks et al. 1994; Tasker et al. 1999)

Sterile nodular panniculitis Bile duct carcinoma leading topancreatic necrosis(Paterson 1994)

Nodular dermatofibrosisCutaneous nodules usually affecting the Renal cystadenocarcinoma

extremities associated with bilateral (Moe & Lium 1997)renal tumours. Autosomal inheritance in

German shepherd dog. Cutaneous lesionsmay be due to growth factors secretedby the tumour

Neuromuscular Peripheral nerve syndromesA variety of neuropathies, including Bronchogenic carcinoma, insulinoma,

demyelination and axonal degeneration leiomyosarcoma, haemangiosarcoma,in peripheral nerves have been reported undifferentiated sarcoma, synovialin dogs with tumours sarcoma and adrenal adenocarcinoma.

(Braund 1990, 1996)Multiple myeloma (Villiers & Dobson

1998)Myasthenia gravisFailure of neuromuscular transmission, Thymoma and other tumours,

in cancer patients probably immune- cholangiocellular carcinoma, osteogenicmediated due to autoantibodies directed sarcomaagainst nicotinic acetylcholinereceptors

nisolone 1–2mg/kg daily). These agents are cyto-toxic to lymphoid cells and also reduce serumcalcium by limiting bone resorption, reducingintestinal calcium absorption and enhancing renalexcretion of calcium. The value of glucocorticoidsin the treatment of hypercalcaemia associated withnon-lymphoid neoplasms is debatable. Once theanimal’s condition is stabilised, treatment of theprimary cause of the hypercalcaemia is essential forlong-term control.

There are a number of drugs which have beendeveloped for the symptomatic treatment of humancancer patients where hypercalcaemia may be asso-ciated with refractory tumours, including:


Treatment of hypercalcaemia (Table 2.9)Immediate management of hypercalcaemia isaimed at rehydration of the patient. Normal saline(0.9%) is the fluid of choice. Restoration of circu-lating volume will aid the lowering of the serumcalcium by improving the glomerular filtration rateand thereby assisting renal excretion of calcium.Once the animal is rehydrated, calcium excretioncan be further promoted by saline diuresis (0.9%saline at two to three times maintenance rate) andassisted by frusemide.

In hypercalcaemia associated with lymphoprolif-erative neoplasms, lowering of serum calcium canbe assisted by the use of glucocorticoids (pred-

Table 2.8 Investigation of hypercalcaemia.

(1) Look for lymphoma/leukaemia – lymphoproliferative disease is the most common cause of hypercalcaemia in the dog

Check all peripheral lymph nodes and aspirate/biopsy any that are slightly enlarged or firmer than usualRadiograph the thorax – anterior mediastinal and thymic forms of lymphoma are often associated with

hypercalcaemiaCheck haematology – is there any abnormality which might indicate lymphoproliferative or myeloproliferative

disease?Evaluate bone marrow

(2) Check the anal glands – Apocrine gland adenocarcinoma tends to be most common in middle aged bitch.Tumours can be quite small and only appear as a slight thickening of the anal sac

(3) Check for hypoadrenocorticism – sodium and potassium values, ACTH stimulation test

(4) Consider a parathyroid tumourPalpate/examine by ultrasound the neck – looking for enlargement of one parathyroid glandParathyroid hormone (PTH) assay

Note:Hypercalcaemia has been associated with assorted generalised inflammatory/skeletal problemsCalcium is normally elevated in young animalsAlways check for laboratory error

Table 2.9 Treatment of hypercalcaemia.

Objective Action

Restore circulating volume Intravenous fluid therapy: 0.9% sodium chloride over24 + hours

Reduce plasma calcium concentration Saline diuresis: 0.9% NaCl at 2–3 ¥ maintenance rateFrusemide 2 mg/kg bid or tidGlucocorticoids for lymphoid tumours, e.g. prednisolone

2 mg/kg daily

Identify and treat inciting cause Specific chemotherapy, surgery or radiation as appropriate


• Bisphosphonates – currently treatment of choicein human medicine, e.g. alendronate, etidronate,pamidronate, clodronate

• Mithramycin (25mg/kg single dose) – used lesssince development of bisphosphonates

• (Calcitonin)• (iv infusion of phosphate solutions, phosphate

enemas, sodium EDTA and peritoneal dialysis –all largely outdated).

It is unusual for these agents to be required in veterinary medicine as most cases of hyper-calcaemia in animals can be managed effectively by fluid therapy and treatment of the primarycause.

Mast cell tumours and hyper-histaminaemia

Mast cells are characterised by intra-cytoplasmicgranules that contain vaso-active amines and pro-teases including histamine and heparin. Degranula-tion may occur spontaneously in some mast celltumours or may be precipitated by manipulation ofthe tumour or therapeutic intervention.The inflam-matory mediators thus released may have bothlocal and systemic effects.

Local effectsLocal effects include oedematous swelling of thetumour and surrounding area, erythema and some-times pruritis. If significant amounts of heparin arepresent there may be a tendency for local bleeding.

Proteases may also cause delayed wound healing orwound breakdown following surgery.

Systemic effectsMassive and sudden histamine release may pre-cipitate an anaphylactic reaction which requiresemergency treatment with fluids, corticosteroidsand anti-histamines. Although this is extremelyunusual, premedication of animals with anti-histamine (e.g. chlorpheniramine) prior to sur-gical manipulation of such tumours is often recommended.

A more common yet less obvious effect of hyper-histaminaemia occurs in the gastro-intestinal tract,where overstimulation of the gastric H2 receptorsresults in excessive gastric acid production andchanges in the vascular supply and motility of thegastric mucosa leading to gastro-duodenal ulcera-tion. Clinical signs vary according to the severityand duration of the problem and range from mildanorexia to vomiting, haematemesis, melaena andanaemia resulting from intra-luminal bleeding.Ultimately the ulcers may perforate leading to peri-tonitis, collapse and death. Cimetidine 5–10mg/kgtwo to four times daily, or ranitidine 2mg/kg twicedaily, block H2 receptors and reduce the secretionof gastric acid.

Summary

In summary, tumours can behave and manifestthemselves in many different ways. An animal with

Table 2.10 Check-list for diagnostic evaluation of the cancer patient.

Technique Apply to

Aspirate/biopsy Primary tumourEnlarged lymph nodesAny other suspicious lesionsBone marrow, if relevant

Radiography Primary site, if relevantThorax (right and left lateral chest views)

(abdomen)Ultrasound Primary site, if relevant

Internal organs, liver, spleen, kidneysRoutine haematology Haematological complicationsRoutine biochemistry Metabolic/endocrine complicationsFeLV/FIV serology In cats

Texbook of Small Animal Medicine, (ed. J.K. Dunn), pp.985–1028. W. B. Saunders, London.

Gross, T.L., O’Brien, T.D., Davies, A.P. & Long, R.E.(1990) Glucagon producing pancreatic endocrinetumours in two dogs with superficial necrolytic dermatitis. Journal of the American Veterinary MedicalAssociation, (197), 1619–22.

Moe, L. & Lium, B. (1997) Hereditary multifocal renalcystadenocarcinomas and nodular dermatofibrosis in 51 German shepherd dogs. Journal of Small AnimalPractice, (38), 498–505.

Paterson, S. (1994) Panniculitis associated with pancreaticnecrosis in a dog. Journal of Small Animal Practice,(35), 116–18.

Scott, D.W., Yager, J.A. & Johnson, K.M. (1995) Exfoliative dermatitis in association with thymoma in three cats. Feline Practice, (23), 8–13.

Tasker, S., Griffon, D.J., Nuttall, T.J. & Hill, P.B.(1999) Resolution of paraneoplastic alopecia following surgical removal of a pancreatic carcinoma in a cat.Journal of Small Animal Practice, (40), 16–19.

Vail, D.M., Ogilvie, G.K. & Wheeler, S.L. (1990) Meta-bolic alterations in patients with cancer cachexia.Compendium of Continuing Education for the Prac-tising Veterinarian, (12), 381–7.

Villiers, E. & Dobson, J.M. (1998) Multiple myeloma withassociated polyneuropathy in a German shepherd dog.Journal of Small Animal Practice, (39), 249–51.


cancer may present with an obvious mass or as aresult of a tumour-related complication. In everycase it is important to adopt a methodical approachto the patient in order to define the nature andextent of the problem. Only when this is achievedcan an appropriate treatment be devised. A check-list for the ‘work-up’ of a cancer patient is providedin Table 2.10.

References

Bond, R., McNeil, P.E., Evans, H. & Srebernik, N.(1995) Metabolic epidermal necrosis in two dogs with different underlying diseases. Veterinary Record, (136),466–71.

Braund, K.G. (1990) Remote effects of cancer on thenervous system. Seminars in Veterinary Medicine andSurgery (Small Animal), (5), 262–70.

Braund, K.G. (1996) Endogenous causes of neuropathiesin dogs and cats. Veterinary Medicine, (91), 740–54.

Brooks, D.G., Campbell, K.L., Dennis, J.S. et al.(1994) Pancreatic paraneoplastic alopecia in three cats.Journal of the American Animal Hospital Association,(30), 557–63.

Dobson, J.M. (1999) Principles of cancer therapy. In:

3Treatment Options

of treatment currently available cannot achieve thisaim in every case. The decision to treat an animalwith cancer is one which must be made jointly bythe veterinarian and the owner. Owners must becounselled thoroughly in the nature of the disease,the prognosis, the options for treatment and theexpectations of such treatment and should be giventime to consider the options and reach a deci-sion. The methods of cancer therapy which will bedescribed are generally tolerated very well byanimal patients provided that there are no pre-existing complications which make the patientmore susceptible to toxicity.

The three main methods of cancer treatment inanimals, as in humans, are:

• Surgery• Radiotherapy• Anti-cancer/cytotoxic chemotherapy.

Cancer therapy must always be tailored to suit the individual case, taking account of the biology,histology, grade and extent of that tumour (seeChapter 2). Clearly a cure, i.e. total eradication ofall tumour stem cells, is the desirable outcome of treatment, but even the most effective methods

� Surgery, 31� Radiotherapy, 34� Chemotherapy, 39� Novel methods of cancer therapy, 46

31

SURGERY

Surgery is the most effective means of treatment forthe majority of solid neoplasms in animals and usu-ally offers the best chance of cure for such tumours.

Indications

Surgery may play a number of roles in the diagno-sis and treatment of cancer:

• Diagnosis – biopsy, needle, incisional or exci-sional (see Chapter 2)

• Definitive treatment for solid, solitary, low gradetumours (see below)

• Cytoreduction of tumour mass prior to radio-therapy (see later)

• Pain management – for example amputation of alimb in the case of a painful tumour or patho-logical fracture

• Prophylaxis – for example, spaying a bitch beforeher first or second oestrus significantly reducesthe risk of later development of mammarytumours.

• Ask the pathologist to examine the margins ofthe excision. These can be marked with ink orcoloured sutures to identify the orientation andsites of concern.

Surgical approaches

Local excision

Truly benign tumours, e.g. fibroma, lipoma andmammary adenoma, can be cured by local surgicalresection with a minimal margin of normal tissue(Fig. 3.1). Local surgical resection is a simple andstraightforward procedure when lesions are small.A tumour which is left to enlarge will eventuallyrequire a more extensive procedure which is lesslikely to be curative.

Wide local excision

Locally invasive tumours, e.g. basal cell carcinomaand squamous cell carcinoma are characterised bylocal extension of the tumour into surroundingnormal tissues. In such cases local surgical excisionis unlikely to remove all tumour cells and localrecurrence will ensue unless a more aggressive sur-gical approach is adopted. Thus wider margins of


The primary objective of surgical treatment of anytumour, be it benign or malignant, is to physicallyremove all the tumour cells. In most cases it will be necessary to include a margin of normal tissuein the surgical excision in order to achieve this aim.Failure of surgical treatment may result from:

• The tumour being incompletely resected at the first attempt, in which case the tumour willregrow at or adjacent to the primary site

• Contamination of normal tissue with tumourcells at the time of surgery through haemorrhage,from surgical instruments or via surgical drains

• The tumour having metastasised to distantorgans prior to surgical treatment, in which casethe animal will subsequently develop problemsrelating to metastatic tumour elsewhere.

Surgery is rarely an effective or feasible means ofmanaging disseminated disease and chemotherapyis more appropriate in such cases. Local tumourrecurrence is strongly influenced by the surgicalapproach and the main advances in surgical oncol-ogy have been in defining the margins of exci-sion which are necessary to achieve eradication of different tumours and in developing techniqueswhereby such margins can be achieved. It is notwithin the remit of this chapter to cover the surgi-cal and reconstructive techniques used in oncologyin detail but a brief description of surgical tech-niques which have proved efficacious in the man-agement of certain tumours is appropriate.

Surgical principles

• Plan the surgical approach based on the biopsyresult and the anatomy of the affected area.

• Try not to change the surgical plan mid treat-ment. If a tumour seems unexpectedly aggres-sive, collection of further biopsy material toreview the original diagnosis may be the bestimmediate course of action.

• Aim not to touch tumour tissue or invade thetumour capsule with instruments (or hands).

• If tumour tissue does contaminate instruments,then gloves and instruments should be changedbefore dissecting into normal tissue.

• Take advantage of clean fascial planes and tissuecompartments.

• Submit excised tissue to confirm the biopsy diagnosis.

Fig. 3.1 Diagram depicting local surgical excision(excisonal biopsy). The tumour is excised through itsimmediate boundaries with a minimal border of sur-rounding normal tissue. (Reprinted from Dobson(1999) with permission.)

Treatment Options 33

excision, including at least 1–2cm of apparentlynormal tissues lateral and deep to the tumour,are often required to achieve a successful outcome.Some tumours, e.g. mast cell tumours, may requiremore generous margins than this to effect a com-plete excision. Such a procedure is termed a ‘widelocal excision’ (Fig. 3.2).

For tumours sited on the chest or abdominalwalls, achieving excisional margins of this magni-tude is usually possible. Problems may arise,however, in the case of tumours sited on limbs orin the head region, particularly in the oral cavity.For tumours on limbs and the head, excisionalmargins can usually be achieved but, because of thelack of mobile skin and soft tissues, reconstructivetechniques may be necessary to close the resultingdeficit. Tumours in the oral cavity present a par-ticular problem because of their proximity to bone. Locally invasive tumours arising at this sitefrequently extend into the underlying bone suchthat successful surgery requires removal of portionsof bone. Various techniques for mandibulectomy,premaxillectomy and maxillectomy have been welldocumented (White 1991; Salisbury 1993). Theseprocedures are tolerated very well in dogs and theresults for low grade oral tumours are very good(Fig. 3.3) (see Chapter 7).

Compartmental excision

Certain solid tumours such as soft tissue sarcoma(e.g. fibrosarcoma, haemangiopericytoma), infil-trate adjacent tissues so widely that even 1–2cm

margins of excision are not adequate to ensurecomplete removal of all tumour cells. Surgicalremoval of tumours such as these requires resectionof every tissue compartment which the tumourinvolves, termed a ‘compartmental’ or ‘en bloc’resection (Fig. 3.4). To achieve such a resection intumours arising on the trunk invariably requiresfull thickness resection of either the abdominal or chest wall. The resulting deficits must be recon-structed using prostheses and skin flaps (Pavletic1999). In tumours arising in the proximal limb, it issometimes possible to achieve an ‘en bloc’ resectionby removal of a muscle mass and overlying skin,leaving the animal with a functional limb. In othercases amputation may have to be considered.

All the surgical techniques described require

Fig. 3.2 Diagram depicting wide local excision. Thetumour is excised with a predetermined margin of sur-rounding tissue both lateral and deep to the tumourmass. (Reprinted from Dobson (1999) with permission.)

Fig. 3.3 Appearance of dog following a bilateralmandibulectomy. (Courtesy of Dr R.A.S. White,Department of Clinical Veterinary Medicine, Cambridge.)

Fig. 3.4 Compartmental or ‘en bloc’ resection. Thetumour is resected together with the contents of theanatomic compartment in which is it contained.Fascial planes which are undisturbed by tumour inva-sion form the outer margins of the resection. (Reprintedfrom Dobson (1999) with permission.)

increasingly appreciated that the best chance oferadication of locally aggressive tumours is at thefirst surgical attempt. Subsequent surgical proce-dures are fraught with difficulties due to loss ofnormal anatomical relationships through scarringand fibrosis, and local dissemination of the tumourat the previous surgery through haemorrhage or oninstruments.


careful planning, particularly when reconstructivetechniques are involved. The treatment and theexpected cosmetic and functional results should be fully discussed with the owner. It is thereforeessential that the nature of the tumour is iden-tified, preferably by biopsy (or cytology), and thatregional lymph nodes are carefully assessed priorto embarking on the definitive treatment. It is

Fig. 3.5 Linear accelerator in the Cancer Therapy Unit, Department of Clinical Veterinary Medicine,Cambridge.

RADIOTHERAPY

Radiotherapy (RT) is widely used in the treatmentof human cancer patients and is equally applicableto the treatment of the disease in small animals.Radiotherapy requires specialised equipment andfacilities which are expensive to install and main-tain (Fig. 3.5). Consequently, the use of radiationtherapy in animals is restricted to larger referralestablishments. Although most veterinarians inpractice will not have direct access to such facilities,it is useful to review the principles and practice of radiation therapy, in order that suitable casesmight be identified and referred at an appropriatestage.

Principles of radiotherapy

The mode of action of radiation

Radiation is a form of energy which, whenabsorbed by living tissues, causes excitation andionisation of component atoms or molecules in thepath of the beam. Subsequent chemical reactionsresult in breaking of molecular bonds and can resultin apoptotic cell death if molecules critical for cellviability are disrupted. The ‘critical target’ is gener-ally regarded as being nuclear DNA but other molecules in other parts of the cell (e.g. proteinsand lipids) may also be damaged and contribute toradiation-induced cellular injury.

Types of radiation used for therapy

Different types of ionising radiation may be usedfor therapeutic purposes, including:

• X-rays• Gamma rays• Electrons.

There are essentially two techniques for the appli-cation of radiation to tumours:

• Teletherapy – radiation is applied in the form ofan external beam of X-rays, gamma rays or electrons which are directed into the tumour(Fig. 3.6).

• Brachytherapy – radioactive substances whichemit gamma or beta rays, may be applied to thesurface of a tumour, implanted within the tumour(Fig. 3.7) or administered systemically to thepatient, for example iodine131 therapy for thyroidtumours in cats (see Chapter 14, Endocrinesystem).


Each technique has advantages and disadvantages.Whilst external beam therapy is relatively safe forthe operator, the equipment is expensive and mul-tiple doses of radiation are required over a four tosix week course of treatment. Brachytherapy oftenoffers better localisation of the radiation andpermits the delivery of high doses of radiation tothe tumour with minimal normal tissue toxicity.However, the implant and the implanted patientpresent a radiation hazard for the operator and anystaff caring for the patient. Radioactive isotopescan only be used on licensed premises and strictlocal rules for handling the isotope and patientmust be applied. Both techniques require careful

planning in consultation with medical physicists toensure that the required dose of radiation is deliv-ered to the tumour.

Radiation biology

The response of living cells and tissues to radiationdepends on the applied dose of radiation and theradiosensitivity of the cell population. Radiosensi-tivity varies according to a number of factors, oneof the most important being the growth fraction ofthe cell population.

• Dividing cells are generally more sensitive to radiation than non-dividing, differentiatedcells. Thus tissues with a high proportion of dividing cells, e.g. bone marrow, gastrointestinalepithelium, are more radiosensitive than non-proliferating tissues, e.g. fibrous tissue and skele-tal muscle.

• The same applies to tumours: those with a highgrowth fraction tend to be more sensitive to radi-ation than those with low growth fractions.

• Individual cells vary in their radiosensitivity asthey pass through the phases of the cell cycle.Cells in the M (mitotic) phase of the cycle aremost radiosensitive and those in the S (DNA syn-thesis) phase are most resistant. The resting (Go)cells are also radioresistant.

• The oxygenation of cells is also thought to be sig-nificant in determining radiosensitivity. Tumourcells which exist at a low oxygen tension, i.e.hypoxic cells, may be two and a half to threetimes less sensitive to radiation than normallyoxygenated cells.

Whilst radiation is a potent means of causingtumour cell death, it is not selective and can beequally damaging to normal tissues; indeed certainnormal tissues may be more sensitive to radiationthan many tumours. In order to be of therapeuticbenefit, radiation must be employed in such a wayas to minimise normal tissue injury whilst achievingmaximum tumour cell kill. One way in which thismay be approached is by attempting to localise theradiation to the tumour. Radioactive implants andradio-labelled substances which are taken up bytumour cells (e.g. radioactive iodine for thyroidtumours) afford a degree of selectivity. With exter-nal beam radiation, the beam can be collimated tothe area of the tumour and several treatment portsemployed in order to reduce the amount of entry

Fig. 3.6 External beam therapy. The patient andmachine are positioned to direct the radiation beaminto and through the treatment field, in this case atumour of the nasal cavity.

Fig. 3.7 Brachytherapy – irridium wires in afterloadingcatheters implanted following cytoreductive surgeryfor a periocular squamous cell carcinoma in a horse.

Tumours vary considerably in their response toradiation. In general, small, rapidly growingtumours tend to respond more favourably to radi-ation than large, slowly growing tumours whereradiation treatment is unlikely to achieve morethan a partial and temporary remission. The rela-tive radiosensitivity of common animal tumours issummarised in Table 3.1.

Normal tissue toxicity

Radiation has a reputation for causing serious tox-icity to the patient; however, radiation sickness andsevere morbidity only arise when large areas of the body or vital organs are exposed to high doses.In order to avoid such side effects, radiation israrely used in this manner in the treatment ofanimals. Tumours most suitable for radiotherapytend to be superficial or those sited on the extrem-ities of the body. The skin, superficial connectivetissues, oral and nasal mucous membranes and boneare therefore the tissues most commonly includedin the treatment field and some radiation-inducedchanges will occur in these tissues.

Radiation toxicity is usually described in terms of‘acute’ reactions occurring during and shortly afterthe radiation treatment and ‘late’ reactions whichare not observed for weeks or even months follow-ing treatment. This division is not absolute.


and exit beam radiation affecting the surroundingnormal tissues.

A further means of reducing normal tissue injuryfrom external beam therapy is to ‘fractionate’ thetreatment, that is to apply the radiation in multiplesmall doses over a period of time rather than as one large dose. In this way tumour cell kill may be increased whilst normal tissue damage can belimited to some extent by allowing time for repairbetween doses. At the present time most radiationschedules for human patients employ daily or alter-nate day treatments over a period of four to sixweeks. In animals, where general anaesthesia isrequired for restraint of the patient during treat-ment and where radiation facilities are not widelyavailable, larger less frequent fractions tend to beused, although some centres in North America areable to treat animals on a daily basis.

Tumour response and normal tissue toxicity

Whilst the chemical events leading to radiation-induced damage occur almost instantaneously,the biological expression of this injury may takedays, weeks or even years to become apparent.Radiation therefore appears to have delayedactions in terms of both tumour response andnormal tissue toxicity.

Table 3.1 Relative radiosensitivity of common animal tumours.

Relative radiosensitivity Tumour

High Lymphoproliferative disordersMyeloproliferative disordersTransmissible venereal tumour

Sensitive Squamous cell carcinomaBasal cell carcinomaAdenocarcinoma (various)

Moderate Mast cell tumours (variable)Malignant melanoma of the oral cavity

Low FibrosarcomaOsteosarcomaChondrosarcomaHaemangiopericytoma

Factors such as tumour site and tumour extent also influence the suitability ofa particular tumour for radiotherapy.


Acute reactions

• Result from the death of actively dividing cellpopulations, e.g. epithelium of the skin andmucous membranes

• Range from a mild reddening or erythema of theskin/mucosa to desquamation and severe exfo-liative dermatitis/necrosis (the latter is rare) (Fig. 3.8)

• Usually resolve spontaneously as the normal cellpopulation regenerates.

Localised hair loss is a common result of irradiationof the skin in animals (Fig. 3.9). This results fromdamage to the hair follicle epithelium at the timeof treatment but the resulting alopecia does notusually occur until the existing hair is shed and notreplaced. Ultimately some hair usually regrows butthis may be patchy and lacking pigmentation.

Late toxicity

• Is less predictable and more serious• Tends to occur in slowly proliferating tissues, e.g.

connective tissues and bone• Is often progressive and irreversible.

Examples of late radiation toxicity:

• Skin – Radiation induces fibrosis in the dermalconnective tissues resulting in a thickened,

rubbery texture and subsequently contraction ofthe skin and subcutis can occur. As a result of thefibrosis and vascular changes, irradiated skin and soft tissues can be very slow to heal. Woundsin such tissues are difficult to repair as they areavascular and even the most minor surgical pro-cedure can result in a non-healing, necroticwound.

• Bone – Osteonecrosis is a major concern in fieldscontaining bone, particularly in cases where thebone is already compromised by tumour invasion.

• Nervous tissue – Late reactions in nervous tissuescan result in neural degeneration and necrosis.Irradiation of the spine should be avoided if atall possible as it can result in paralysis.

• Eye – Retinal degeneration and cataract forma-tion may be late consequences of radiation of theeye.

Indications for radiation therapy insmall animals

It follows from the above that the main indicationsfor radiotherapy in animals are in the control ofmalignant solid tumours sited on the extremities,which cannot be controlled by surgical means

Fig. 3.8 Acute radiation skin reaction – erythema ofthe skin and moist desquamation of the nasal planumfollowing treatment of a SCC of the nasal planum. (Seealso Colour plate 2, facing p. 162.)

Fig. 3.9 Post radiation alopecia. (See also Colour plate3, facing p. 162.)

of combining these two modalities. Cytoreductivesurgery reduces the tumour burden to microscopiclevels leaving small numbers of well oxygenatedand rapidly proliferating cells which, in theory,should be sensitive to radiation. Radiation will,however, delay the healing of the surgical woundand must be commenced either immediately following surgery or once the wound has healed.The combination of radiation and surgery in thismanner is potentially most beneficial in the man-agement of problematic solid tumours, e.g. softtissue sarcomas and intermediate grade mast celltumours. It is preferable that radiation and surgeryshould be combined as a carefully planned thera-peutic strategy. The use of radiation as an after-thought to salvage inadequate surgery is fraughtwith difficulties in planning the radiation fields andthis practice is strongly discouraged.


alone. The types of tumour most commonly treatedwith radiotherapy in small animals are summarisedin Table 3.2. It is desirable that local and/or distant metastases are not present, although locallymph nodes can be included in the treatmentfields.

Because of the difficulties in localisation and therisk of toxicity, tumours sited deep in the chest,abdomen or pelvis are not usually treated with radi-ation in animals. Benign tumours are often not veryradiosensitive, and, because radiation is potentiallycarcinogenic, other means of treatment shouldalways be sought to manage such tumours.

Radiation may be combined with surgery in themanagement of selected tumours which cannot betreated adequately by surgery alone. Radiation canbe used prior to, following or during surgery. Post-operative radiation is the most common method

Table 3.2 Tumours commonly treated with radiotherapy in smallanimals.

Anatomical site Tumour types

Nasal cavity and paranasal sinuses Adenocarcinoma(Chapter 7) Squamous cell carcinoma

Chondrosarcoma, and other sarcomas(Lymphoma)

Oral cavity (Basal cell carcinoma)**(Chapter 7) Squamous cell carcinoma

Fibrosarcoma and other sarcomas*Malignant melanoma

Skin and soft tissues Mast cell tumours*Head, neck and limbs Soft tissue sarcomas*(Chapters 4, 6, 7 and 14) Thyroid carcinoma in dogs

Brain Glioma(Chapter 13) Meningioma

* Post-operative radiotherapy used as an adjunct to cytoreductive surgery inthese tumours.** Surgery is the preferred treatment for such tumours because of the risk oflater development of a second malignancy at the same site (White et al. 1986).


Table 3.3 Classes of cytotoxic drugs.

Alkylating agents CyclophosphamideMelphalanChlorambucil

Anti-metabolites Cytarabine5-FluorouracilMethotrexate(Azathioprine)

Anti-tumour antibiotics DoxorubicinEpirubicinMitoxantroneBleomycin

Vinca alkaloids VincristineVinblastine

Miscellaneous agents CisplatinCarboplatinL-Asparaginase

CHEMOTHERAPY

Anticancer chemotherapy has become an acceptedmethod of cancer treatment in small animal prac-tice and the indications for cytotoxic drugs are everincreasing.

Principles of chemotherapy

What are cytotoxic drugs and how dothey work?

Many pharmacologically different drugs have beenidentified as having anti-cancer activity. Theseagents can be divided into groups on the basis oftheir mode of action, anti-tumour activity and tox-icity as shown in Table 3.3 and Fig. 3.10.

Alkylating agents, anti-tumour antibiotics andsome of the miscellaneous agents interfere with the replication and transcription of DNA. Anti-metabolites interfere with the synthesis of DNA orRNA by enzyme inhibition or by causing the syn-thesis of non-functional molecules. The vinca alka-loids are anti-mitotic, acting specifically on themitotic spindle and causing a metaphase arrest.

Thus all these agents act on the processes of cell growth and division and therefore cytotoxicdrugs are most effective against growing or divid-ing cells.

Tumour response

Different tumours are not equally sensitive orresponsive to cytotoxic drugs (Table 3.4).The majorfactors that determine the response of a tumour todrugs are:

• Tumour growth rate, as previously discussed• Drug resistance.

Metabolltes

Purinesynthesis

Pyrimidinesynthesis

DNAsynthesis

DNAreplication

Mitosis

Anti-metabolitesMethotrexateMercaptopurineThioguarnine

Anti-metabolitesMethotrexateFluorouracilCytosine arabinoside

Alkylating agents

Anti-tumour antibiotics

Platinum compounds

Vinca alkaloids

Fig. 3.10 Diagrammatic representation of the mode ofaction of cytotoxic drugs. (Reprinted from Dobson &Gorman (1993) with permission.)

Table 3.4 Relative tumour sensitivity to cytotoxicdrugs.

Chemosensitivity Tumour type

High LymphomaMyelomaForms of leukaemia(Transmissible venereal tumour)

Moderate High grade sarcomas(E.g. osteosarcoma,

haemangiosarcoma)Mast cell tumours

Low Slowly growing sarcomasCarcinomasMelanoma

according to the intended result, as depicted in Fig. 3.11. (This does not apply when chemotherapyis used as an adjuvant to surgery in the treatmentof solid tumours.)

Induction therapyThe aim of induction therapy is to reduce thetumour burden to a minimal level below the limitsof detection, i.e. remission. Induction usuallyinvolves an intensive course of treatment adminis-tered over a defined period of time. A clinicalremission is not synonymous with cure and unlesstreatment is continued a rapid expansion of theresidual tumour mass will result in a ‘relapse’ orrecurrence of the disease.

Maintenance therapyWhere clinical remission can be achieved by induc-tion treatment, a less intensive treatment regimemay be adopted to maintain this remission.

Rescue therapyIn some cases the tumour may not respond to theinitial therapy; in others, the initial responseappears to be good but the tumour recurs orrelapses despite continued treatment (usually as aresult of drug resistance).The aim of rescue therapyis to establish a further remission of the tumour andthis usually involves recourse to more aggressivetherapy, preferably with agents to which the tumourhas not been exposed.


The growth fraction (GF) is the single most impor-tant factor governing tumour response to chemo-therapy because most cytotoxic drugs are onlyactive against dividing cells.

Drug resistance describes the ability of a tumourcell to survive the actions of an anti-cancer drugwhen administered at a dose which would normallybe expected to cause cell damage and death.Certain tumours or tumour cells are intrinsicallyresistant and can circumvent the actions of cyto-toxic drugs through various biochemical/metabolicmechanisms. Tumour cells may also acquire drugresistance, as exemplified by the clinical situation in which a previously drug-responsive tumourregrows or relapses and is no longer sensitive tofurther treatment with the same agent.Tumour cellscan acquire resistance to drugs which are unrelatedto the drug groups used to treat the tumour initially,through a process known as multi-drug resistance(MDR). MDR is associated with a transmembraneP-glycoprotein pump which can transport cytotoxicdrugs directly from the cell membrane before suchdrugs enter the cytoplasm, or from the cytoplasm,thus limiting the concentration of the drug reach-ing the target.

Cytotoxic drug administration

Cytotoxic drugs kill tumour cells according to firstorder kinetics, i.e. a given dose of a cytotoxic drugkills a fixed percentage of the total tumour popula-tion as opposed to a set number of tumour cells.Thus:

• Cytotoxic drugs should always be used at thehighest possible dose to effect the highest pos-sible fractional kill

• Even a highly effective drug acting on a highlysensitive tumour cell population is unlikely toeradicate the tumour cell population in a singledose

• Chemotherapy should be instituted when thetumour burden is at its lowest

• Chemotherapy is unlikely to be effective if usedas a last resort for the treatment of extensive andadvanced disease.

Stages of therapy

Chemotherapy usually involves courses of treat-ment in which different phases are described

Remission Limit of clinicaldetection

Time

Induction Maintenance Rescue

Relapse

Tum

ou

r vo

lum

e

Fig. 3.11 Diagrammatic representation of the phasesof chemotherapy. (Reprinted from Dobson & Gorman(1993) with permission.)


Single agent versus combinationtherapy

In general, combinations of cytotoxic agents haveproved to be more effective in cancer therapy thana single agent. By treating a tumour with a combi-nation of agents which employ different mecha-nisms of action and have different spectra ofnormal tissue toxicity, the overall response can beenhanced without an increase in toxicity. A typicalexample of combination chemotherapy in veteri-nary practice is the COP protocol for treatment oflymphoma which employs:

• C cyclophosphamide – alkylating agent• O vincristine – vinca alkaloid• P prednisolone – glucocorticoid.

Dosage and timing of treatments

Cytotoxic drugs are usually administered atrepeated intervals (or in ‘pulses’), allowing time forthe normal tissues to recover between treatments.The interval between treatments has to be carefullytimed to allow for recovery of the normal tissueswithout expansion of the residual tumour popula-tion. For most myelosuppressive cytotoxic agents(e.g. doxorubicin) maximum bone marrow sup-pression occurs at about day 7–10 following treat-ment, with recovery by day 21. Hence three weekcycles of treatment are used in clinical practice.For other agents or combinations of agents, weeklytreatment regimes or semi-continuous protocolsmay also be used (see Chapter 15).

DosageAs a general rule the dosages of cytotoxics used inhuman therapy are not appropriate in the dog andcat because the severe toxicity resulting from suchtreatment cannot be managed on a routine basis in veterinary medicine. Dosages recommended foranimals are invariably a compromise between efficacy and toxicity.

Dose rate calculationDoses of cytotoxic drugs are usually calculated as afunction of body surface area (in square metres: m2)rather than body weight (in kg) because the bloodsupply to the organs responsible for detoxificationand excretion (liver and kidneys) is more closely

related to surface area than body weight. Conver-sion charts are provided in Appendix III at the endof this book.

Indications for chemotherapy

The main indication for chemotherapy as a first linetreatment is in lymphoproliferative and myelopro-liferative disorders, for example:

• Lymphoma• Myeloma• Types of leukaemia.

These diseases are systemic in their nature andusually respond favourably to cytotoxic drugs.Details of treatment protocols for these conditionscan be found in Chapter 15. Chemotherapy is rarelyof value as the sole treatment for solid, i.e. non-lymphoid, tumours, for example carcinomas, sarco-mas and melanomas. Such tumours are best treatedby surgical resection and/or radiotherapy.

Adjunctive chemotherapy

It is increasingly appreciated that cytotoxic drugsmay have a role as an adjunct to surgical (or radio-therapeutic) management of some solid tumours,for example:

• Osteosarcoma – cisplatin or carboplatin• Haemangiosarcoma – doxorubicin (± cyclophos-

phamide and vincristine),

where they may be used to prevent or delay devel-opment of metastases. In such circumstances, wherethere is no measurable tumour from the outset ofchemotherapy, a set number of treatments (usuallyfour to six) are prescribed as the total course.

Complications of chemotherapy

Normal tissue toxicity (side effects)

Complications of chemotherapy can arise at anytime during therapy. Some cytotoxic agents caninduce immediate hypersensitivity reactions; someagents are highly irritant and can cause severe localtissue reactions if perivascular leakage occurs.The actions of cytotoxic drugs are not selective fortumour cells and their effects on normal tissuesresult in toxicity or side effects. Organs containing

infection in animal cancer patients. Identification or detection of sepsis can be difficult in the neutropenic patient because the inflammatoryresponse is altered by the neutropenia. Pyrexia isthe most consistent sign of sepsis.

TreatmentManagement of neutropenic patients depends onthe neutrophil count and clinical presentation, assummarised in Table 3.5. Most animals recoverspontaneously from drug induced myelosuppres-sion within 36–72 hours of ceasing administrationof the offending agent through stem cell recruit-ment. Lithium carbonate may be used to assist thisrecovery and a number of human recombinantgranulocyte (G-CSF) and granulocyte-monocyte(GM-CSF) stimulating factors are available tospeed recovery from myelosuppression in humancancer patients. Human recombinant cytokineshave been shown to be useful for treatment in catsand dogs with chemotherapy-induced neutropeniaand although these species may mount a neutralis-ing antibody response to the human recombinantprotein, this does not seem to be a problem in thesecircumstances (Ogilvie 1993a; Henry et al. 1998).Their use in veterinary medicine may be limited bycost.

Anorexia, vomiting and gastrointestinal toxicity

Many cytotoxic drugs have adverse effects on thegastro-intestinal tract either as a direct result of theaction of the drug on the oral, gastric and intestinalepithelium or as a result of non-specific myelosup-pression. Death and desquamation of alimentaryepithelium usually occurs 5–10 days followingadministration of the drug and leads to stomatitis,vomiting and mucoid or haemorrhagic diarrhoea.In most cases such problems are self-limiting andthe animal recovers spontaneously as the normalalimentary epithelium regenerates. Some drugsinduce nausea and vomiting by direct stimulationof the chemoreceptor trigger zone. These includecisplatin and doxorubicin.

TreatmentTreatment is symptomatic:

• Anorexia in cats may be helped with ciprohep-tadine.


a high proportion of dividing cells are most sus-ceptible to drug-induced toxicity. Hence the mostcommon side effects of chemotherapy are:

• Bone marrow toxicity – myelosuppression,neutropenia and thrombocytopenia

• Gastrointestinal toxicity – anorexia, nausea,vomiting and diarrhoea.

Fortunately, these normal tissues are able torecover from cytotoxic drug damage throughrecruitment of resting stem cells. Hence, althoughpotentially life threatening, these toxic effects areusually quickly reversible on discontinuation oftreatment.

Some cytotoxic agents have other toxic actionsthat are less reversible. These include:

• Cyclophosphamide – haemorrhagic cystitis• Doxorubicin – cardiomyopathy• Cisplatin – nephrotoxicity.

Myelosuppression and infection

Most cytotoxic drugs are myelosuppressive. Themost notable exceptions are:

• Vincristine• L-asparaginase.

Myelosuppression is the main dose-limiting factorin veterinary chemotherapy. The main effects ofmyelosuppression are:

• Anaemia – rarely clinically significant and oftenindistinguishable from anaemia associated withthe neoplasm itself.

• Neutropenia (a neutrophil count of less than 2 ¥109/l) – results in a clinically significant risk ofoverwhelming infection and sepsis.

• Thrombocytopenia (a platelet count of less than70 ¥ 109/l) – rarely severe enough to cause spon-taneous bleeding but may require care with biopsies/surgery.

Haematological monitoring is vital in all casesreceiving potentially myelosuppressive drugs andthese drugs should never be administered untilbaseline haematological values have been estab-lished for that patient.

Neutropenia predisposes the cancer patient toinfection and sepsis. Absorption of enteric bacteriae.g. E. coli and Klebsiella spp., through damagedintestinal mucosa is the most common source of


• Anti-emetics, e.g. metoclopramide or ondanse-tron, are useful in the prevention or control ofdrug-induced vomiting.

• Antacids and ulcer healing drugs may be used toassist in the control of gastric ulceration.

Products containing bismuth subsalicylate(Pepto Bismol) may assist management of entero-colitis caused by doxorubicin in some dogs.

• Intravenous fluid therapy should be given incases where the vomiting/diarrhoea is severe orprolonged.

• Mucosal injury can also predispose to systemicinfection and parenteral antibiotics may be indi-cated, as discussed above.

Hypersensitivity/anaphylaxis

Hypersensitivity reactions to cytotoxic drugs arerare but have been reported in dogs followingadministration of:

• L-asparaginase• Doxorubicin• (Cisplatin)• (Cytarabine).

Some cytotoxic drug hypersensitivities areimmune-mediated reactions (e.g. L-asparaginase);some drugs (e.g. doxorubicin) cause degranulationof mast cells and others may activate the alterna-tive complement pathway.

Prevention

• The route of administration can affect the inci-dence of hypersensitivity reactions. L-asparagi-nase may produce anaphylaxis in up to 30% ofdogs when administered intravenously. For thisreason it is recommended that the drug shouldalways be given by the intramuscular route.

• Pre-treatment with antihistamines e.g. chlor-pheniramine, can reduce the frequency of some drug reactions and this is usually recom-mended prior to administration of doxoru-bicin.

TreatmentIn the event of a hypersensitivity reaction:

• Stop administration of the drug immediately• Treat with intravenous fluids, soluble corticos-

teroids, adrenaline and antihistamines.

Table 3.5 Haematological monitoring for chemotherapy.

Neutrophil count(¥ 109/l) Status of patient Recommended action

>3 Normal Continue chemotherapyRepeat white blood count in 3–4 weeks

2–3 Evidence of myelosuppression Reduce dosage of myelosuppressive drug(s) by 50%Repeat WBC count in 2 weeks

<2 Moderate myelosuppression Stop myelosuppressive chemotherapyMonitor patient and WBC carefully

Patient asymptomatic/afebrile If patient has existing predisposition to infectione.g. ulcerated tumour, administer potentiatedsulphonamide or fluoroquinolone antibiotics

<1 Severe myelosuppression Stop all cytotoxic treamentPatient asymptomatic/afebrile Administer potentiated sulphonamide or

fluoroquinolone antibioticsPatient pyrexic Collect samples in attempt to identify infective agent

Supportive therapy: intravenous fluids, electrolytes,glucose as indicated

Bactericidal antibiotics: cephalosporins plusgentamicin, or fluoroquinolones (can alter laterbased on sensitivity)

area immediately. This may be assisted by subcu-taneous injection of 0.9% sodium chloride todilute any residual drug. Try to draw someblood/fluid back from the catheter.

• Remove catheter.• Soluble corticosteroids (e.g. hydrocortisone)

should be administered systemically, (intra-venously), locally as subcutaneous injections andtopically (as cream) around the site of extrava-sation.

• Cold compresses may also help reduce theinflammatory response.

• Specific recommendations for different agentscan be found in Appendix IV at the end of thebook.

Specific drug associated toxicity

Cyclophosphamide: haemorrhagiccystitis

Metabolites of cyclophosphamide (in particularacrolein) are excreted in the urine and have an irri-tant action on the bladder mucosa, resulting in anacute inflammation, often accompanied by profusebleeding. This sterile haemorrhagic cystitis canoccur at any time during cyclophosphamidetherapy in dogs but is more common followingadministration of high doses or after long term,continuous low dose therapy. In some cases the cys-titis resolves following withdrawal of treatment but,in severe cases, resolution can take considerabletime. Haemorrhagic cystitis does not appear to bea problem in cats.

Treatment/preventionThere is no specific treatment for cyclophos-phamide-induced haemorrhagic cystitis, althoughinstillation of dimethylsulphoxide (DMSO) intothe bladder has been reported to assist in its reso-lution (Liang et al. 1988). Because of the distressingnature of the problem it is preferable to try andminimise the risk of haemorrhagic cystitis inpatients receiving cyclophosphamide by:

• Administration of the drug in the early morning• Ensuring a good fluid intake• Encouraging frequent emptying of the bladder• Concurrent glucocorticoid administration will

assist diuresis• The urine of dogs receiving cyclophosphamide


Phlebitis and tissue necrosis

Many cytotoxic drugs are irritant or vesicant andmay cause severe local tissue necrosis followingperivascular injection or extravasation from theintravenous injection site (Fig. 3.12).

• Vesicants include: cisplatin, doxorubicin, epiru-bicin, vincristine, vinblastine

• Irritants include: carboplatin, mitozantrone.

Prevention

• Adequate restraint of the patient.• An intravenous catheter must be used for admin-

istration of the drug. This should be flushed withsaline prior to and following administration ofthe agent.

TreatmentIn the event of perivascular leakage:

• Stop the infusion but do not remove the catheter.• Aspirate the extravasated drug from the affected

Fig. 3.12 Local tissue damage following perivascularleakage of vincristine. (See also Colour plate 4, facingp. 162.)


should be checked regularly for blood andprotein to help detect the problem in its earlystages.

Doxorubicin (and related drugs):cardiotoxicity

Doxorubicin can cause acute and chronic cardiactoxicity through actions on myocardial calciummetabolism. The rate of infusion can influence thiscardiac toxicity and it is recommended that thedrug is administered as an infusion over at least 15minutes (see Appendix IV).

• In acute cardiac toxicity, tachycardia and arrhyth-mias may occur on administration of the drug.The pulse rate and character should be moni-tored throughout administration and im-mediately afterwards, if tachycardia or otherrhythm disturbances occur the infusion should be stopped or slowed.

• Chronic changes are due to cumulative, dose-related damage to the myocardium that leads insome cases to an irreversible cardiomyopathy.

Treatment/prevention

• All dogs should have thoracic radiographs, anECG and ultrasound assessment of ventricularfractional shortening prior to treatment.

• There is no absolute dose at which cardiomy-opathy occurs in all dogs, and there is tremen-dous variation between patients. The total doseof the drug administered should be limited to 240mg/m2, according to some texts, but cardio-myopathies have been reported at total dosesfrom 180–200mg/m2.

• Cardioprotectant agents, e.g. dexrazoxane, areused in some parts of the world for humanpatients, but such agents have not been evaluatedin companion animals and dexrazoxane is notlicensed for use in the UK.

In cats, doxorubicin can cause nephrotoxicity,especially when used in combined protocols with cyclophosphamide. Renal toxicity has beenreported at total doses as low as 80mg/m2 in thisspecies (Ogilvie 1993b).

Cisplatin (carboplatin) – nephrotoxicity

Platinum co-ordination compounds accumulate inrenal tubular epithelial cells where they block

oxidative phosphorylation leading to acute proxi-mal tubular necrosis.The drug may also affect renalblood flow. In order to minimise these effects cis-platin must be administered with fluid diuresis, andrenal parameters should be monitored carefullythroughout the course of treatment. Several differ-ent regimes have been described for cisplatinadministration (see Appendix IV).

Safety of handling cytotoxic drugs

Many cytotoxic drugs are carcinogenic and muta-genic; some are teratogenic. Some drugs are alsoextremely irritant and produce harmful local effectsafter direct contact with the skin or eyes. Personshandling and administering these agents should beaware of the potential dangers and take steps tominimise any risk to themselves, their staff andtheir clients. Detailed local rules and working practices should be established in practices wherecytotoxic drugs are used. The following are generalconsiderations concerning the use of these drugs inveterinary practice.

Cytotoxic drugs are commonly available in twoforms:

• Tablets or capsules for oral administration• Powder or solutions for injection.

Tablets/capsules

• Tablets should never be broken or crushed andcapsules should not be opened.

• Disposable latex gloves should be worn whenhandling any tablet which does not have an inertbarrier coat.

• Where tablets are provided in individual wrap-pers, they should always be dispensed in thisform.

• In addition to the statutory requirements for the labelling of medicinal products, all contain-ers used for dispensing cytotoxic drugs must be child-proof and carry a clear warning to keep out of the reach of children. Containersshould be clearly labelled with the name of theagent.

• Staff and owners should receive clear instruc-tions on the administration of tablets.

• Disposable latex gloves should be worn whenadministering these tablets because the protec-tive barrier may break down on contact withsaliva.

basis they should be reconstituted in a protective,biological safety cabinet.

• Careful technique should prevent high pressurebeing generated within the vials and should minimise the risk of creating aerosols.

• If it is necessary to expel excess air from a filledsyringe it should be exhausted into an absorbentpad (disposed of in appropriate manner – seebelow) and not straight into the atmosphere.

Administration

• Luer lock fittings should be used in preference topush connections on syringes, tubing and givingsets.

• All animal patients must be adequatelyrestrained by trained staff (who should also wearprotective clothing). Fractious or lively animalsmay need to be sedated.

In the event of spillage the following actions shouldbe taken:

• The spilt material should be mopped up with dis-posable absorbent towels (these should be dampif the spilt material is in powder form). Thetowels should be disposed of as detailed below.

• Contaminated surfaces should be washed withplenty of water.

Waste disposal

• Adequate care and preparation should be takenfor the disposal of items (syringes, needles etc.)used to reconstitute and administer cytotoxicdrugs.

• ‘Sharps’ should be placed in an impenetrablecontainer specified for the purpose, and sent forincineration.

• Solid waste (e.g. contaminated equipment,absorbent paper etc.) should be placed in doublesealed polythene bags and disposed of by hightemperature chemical incineration by a licensedauthority.


• Always wash hands following handling of anydrug.

• Excess or unwanted drugs should be disposed ofby high temperature chemical incineration by alicensed authority.

Injectable solutions

The main risk of exposure arises during the prepa-ration and administration of injectable cytotoxics,many of which are presented as freeze-dried material or powder, requiring reconstitution with a diluent. Potential dangers are:

• The creation of aerosols during preparation/reconstitution of the solution

• Accidental spillage.

Protective clothing should be worn during recon-stitution, administration and disposal of theseagents. The level of protection required variesaccording to the agent. The minimum requirementshould be:

• Latex gloves• Protective arm sleeves or• A gown with long sleeves to protect the skin• A protective visor or goggles to protect the eyes• A surgical mask to provide some protection

against splashes to the face.

(Specialised chemoprotective clothing is availablefrom several manufacturers, such as the Chemo-protectTM range distributed by Codan Ltd, Woking-ham, Berkshire RG11 2PR.)

Reconstitution

• The drug should only be reconstituted by trainedpersonnel.

• Reconstitution of the drug should only be per-formed in a designated area, free from draughts,and well away from thoroughfares and food.

• If drugs such as doxorubicin are used on a regular

NOVEL METHODS OF CANCER THERAPY

There is no doubt that cancer will continue to be amajor problem facing veterinary practice. Currentlyavailable treatment techniques do not provide asolution for many cancers and carry a high poten-tial for serious patient toxicity.Thus cancer researchcontinues to look for new approaches to cancer

therapy. Alongside the conventional methods ofsurgery, radiation and chemotherapy a number ofother techniques, such as hyperthermia and photo-dynamic therapy, have been used in attempts toselectively kill cancer cells. For the future, develop-ments in immunology and molecular biology may


hold the key to a much more targeted approach tocancer therapy.

Hyperthermia

Hyperthermia is a technique for treatment ofcancer which is based on the observation thatmalignant cells can be destroyed selectively byexposure to temperatures of 42–45°C. The mecha-nisms of this selective cell kill are complex butinclude direct cellular actions, through inhibition ofcellular aerobic metabolism, inhibition of cellularnucleic acid and protein synthesis, increased intra-cellular lysosomal acitivity and alterations in thepermeability of cell membranes. Hyperthermia also acts at a tumour level with direct actions ontumour vasculature, causing stasis, thrombosis andendothelial degeneration.

Hyperthemia is thus of great interest in cancertherapy and as such has been the subject of inten-sive study over the past 25 years both in laboratorymodels and in clinical trials. It has been used as alocal/regional treatment, often in combination withradiation, and as a whole body treatment, combinedwith chemotherapy (Dobson 1991). Despite thepotential of this technique, it has not become widelyused in either human or veterinary clinical practice,largely due to technical difficulties in the localheating of tumours and the complex care and management required for whole body treatment.

Photodynamic therapy

Photodynamic therapy (PDT) is another techniquein which there has been considerable interest formany years. PDT is based on the preferential accu-mulation of a photosensitising agent in malignantcells following systemic or topical application.Stimulation of the tumour (and thus the agent) with light of an appropriate wavelength activatesthe photosensitiser and causes a photochemicalreaction culminating in the production of cytotoxic free radicals and cell death (Fig. 3.13). Porphyrin-based photosensitisers were the first agents used forPDT and argon-pumped dye lasers were used as the light source.Although the technique was shownto be effective in human and veterinary clinicalstudies, a number of problems were encountered(Peaston et al. 1993). Whilst haematoporphyrin-derivatives do accumulate in malignant cells, they

also enter normal cells and result in photosensiti-sation of the patient. Furthermore, argon-pumpeddye lasers were expensive and unwieldy pieces ofequipment.

In recent years, new more selective or shorteracting photodynamic agents have been developed,some of which can be applied topically (e.g. ALAcream), laser technology has advanced and it hasbeen recognised that much cheaper sources of redlight can be used for treatment of superficialtumours (Stell et al. 1999) (Fig. 3.14). As a resultPDT has become much more feasible in the clini-cal setting and whilst it remains an investigationaltechnique in cancer therapy, a number of clinicaltrials are in progress.

Immunotherapy, gene therapy andnew targets

The potential for harnessing the immune system tocombat cancer has for a long time been one of themajor goals of cancer therapy. A variety of strate-gies have been devised and applied in veterinarypatients with mixed results. Autogenous vaccina-tion of tumour lysates has been used to promoteregression of virally induced papilloma in cattle anddogs, but because these tumours often regress spon-

Fig. 3.13 Diagrammatic representation of the mode ofaction of PDT.

Individual cytokines (e.g. interferon, IL-2) andagents such as muramyl tripeptide (MTP) can stimulate cytotoxic activity of effector cells (T lym-phocytes, natural killer cells and macrophages) but success in the clinical setting has been limitedbecause, as is now recognised, in addition to beingstimulated, these cells need to be directed to theirtarget. Most tumour cells are not easily recognisedas ‘foreign’ by the cells of the immune system asthey do not express aberrant cell surface antigensor, if they do, the immune system may eitherbecome tolerant to those antigens or suppressed bytumour derived agents. Hence the concept of the‘magic bullet’, a monoclonal antibody designed tocarry a toxin directly to the tumour cell, has notbeen realised. However, with improved under-standing of the complex mechanisms and interac-tions of the immune system, strategies are beingdeveloped which hold promise for overcomingsome such problems, for example the use of den-dritic cell vaccination in the treatment of melanomapatients (Nestle et al. 1998). The advent of molecu-lar techniques which allow the introduction of newgenetic material into cells offers other opportu-nities and there is no doubt that cytokine technol-ogy will play a role with gene therapy in futuredevelopments in cancer therapy.

Other developments which hold hope for thefuture stem from a better understanding of thebiology of cancer. Certain growth factor receptorshave been identified as having key influence on thegrowth and development of certain cancers (e.g.epidermal growth factor – breast cancer) and someof these have been targeted. The mechanisms oftumour growth and invasion have been elucidatedand strategies are being developed to attack atumour in a much more specific manner than is currently the case with cytotoxic drugs; forexample, through inhibition of enzymes which facilitate tumour invasion and metastasis (e.g.metalloproteinases) and inhibition of tumourdriven angiogenesis (e.g. angiostatin, endostatinand interferon-alpha). These strategies look verypromising in the laboratory and some are startingto enter human clinical trials.

References

Bell, J.A., Sundberg, J.P., Ghim, S.A. et al. (1994) A for-malin-inactivated vaccine protects against mucosal


taneously, the true benefit of this approach isunclear (Bell et al. 1994). Passive immunotherapyusing antibodies directed against tumour cells hasnot met with much success, but a monoclonal anti-body (MAb-231) is available in the USA for thetreatment of canine lymphoma (Jeglum 1991). Non-specific immunostimulants have been widely usedin veterinary medicine. Bacillus Calmette-Guerin(BCG), an attenuated mycobacterium, was one ofthe first agents to be used for immunotherapy. BCGhas been used to treat dogs with mammary carci-noma but although there was evidence that itdelayed onset of metastasis, toxicity proved to be aproblem (Bostock & Gorman 1978). Muramyltripeptide-phosphatidylethanolamine (MTP-PE), asynthetic molecule resembling part of the mycobac-terial cell wall, has been shown to be efficacious inprolonging post-amputation survival times in dogswith osteosarcoma (MacEwen et al. 1989).

Several other agents have been reported to havenon-specific immunostimulatory activity which maybe beneficial in treatment of some tumours. Ace-mannan, a complex plant carbohydrate, which isreported to have several effects on immune func-tion is approved for adjunctive treatment of softtissue sarcomas in the USA (King et al. 1995) andthe non-steroidal anti-inflammatory agent Piroxi-cam is used for its ‘immunostimulatory’ propertiesin the treatment of transitional cell carcinoma ofthe bladder in dogs (Knapp et al. 1992). The H2

antagonist cimetidine has also been reported tohave immunomodulatory actions, beneficial in thetreatment of melanoma, although this has not beensubstantiated in large scale clinical trials.

Fig. 3.14 Red light source being used to treat superfi-cial SCC on cat’s nose. (See also Colour plate 5, facingp. 162.)


papilloma virus infection. A canine model. Pathobiol-ogy, (62), 194–8.

Bostock, D.E. & Gorman, N.T. (1978) Intravenous BCGtherapy of mammary carcinoma in bitches after surgi-cal excision of the primary tumour. European Journalof Cancer, (14), 879–83.

Dobson, J.M. (1991) Hyperthermia. Manual of SmallAnimal Oncology, (ed. R.A.S. White), pp. 175–83.British Small Animal Veterinary Association, Chel-tenham.

Dobson, J.M. (1999) Principles of Cancer Therapy. In:Textbook of Small Animal Medicine (ed. J.K. Dunn),pp. 985–1028. W.B. Saunders, London.

Dobson, J.M. & Gorman, N.T. (1993) Cancer Chemother-apy in Small Animal Practice. Blackwell Science Ltd,Oxford.

Henry, C.J., Buss, M.S. & Lothrop, C.D. (1998) Veterinaryuses of recombinant human granulocyte colony-stimulating factor. Part I Oncology. Compendium onContinuing Education, Small Animal, (20), 728–35.

Jeglum, K.A. (1991) Monoclonal antibody treatment ofcanine lymphoma. Proceedings of the Eastern StatesVeterinary Conference, (5), 222–3.

King, G.K. et al. (1995) The effect of acemannanimmunostimulant in combination with surgery andradiation therapy on spontaneous canine and felinefibrosarcomas. Journal of the American Animal Hospi-tal Association, (31), 439–47.

Knapp, D.W., Richardson, R.C., Bottoms, G.D., Teclaw, R.& Chan, T.C.K. (1992) Phase I trial of piroxicam in 62dogs bearing naturally occuring tumours. CancerChemotherapy and Pharmacology, (29), 214.

Liang, E.J., Muiller, C.W. & Cochrane, S.M. (1988) Treat-ment of cyclophosphamide-induced haemorrhagic cystitis in five dogs. Journal of the American VeterinaryMedical Association, (193), 233–6.

MacEwen, E.G. et al. (1989) Therapy for osteosarcoma in dogs with liposome-encapsulated muramyl tripep-tide. Journal of the National Cancer Institute, (81),935.

Nestle, F.O., Alijagic, S., Gilliet, M., Sun, Y.S. & Grabbe, S.(1998) Vaccination of melanoma patients with peptideor tumour lysate pulsed dendritic cells. NatureMedicine, (4), 328–32.

Ogilvie, G.K. (1993a) Haematopoietic growth factors:tools for a revolution in veterinary oncology andhaematology. Compendium on Continuing Education,(15), 851–4.

Ogilvie, G.K. (1993b) Recent advances in cancer,chemotherapy and medical management of the geri-atric cat. Veterinary International, (5), 3–12.

Pavletic, M.M. (1999) Atlas of Small Animal Reconstruc-tive Surgery, 2nd edn. W.B. Saunders, Philadelphia.

Peaston, A.E., Leach, M.W. & Higgins, R.J. (1993) Photo-dynamic therapy for nasal and aural squamous cell carcinoma in cats. Journal of the American VeterinaryMedical Association, (202), 1261–5.

Salisbury, S.K. (1993) Maxillectomy and mandibulectomy.In: Textbook of Small Animal Surgery, (ed. D. Slatter,2nd edition, pp. 521–30.

Stell, A.J., Langmack, K. & Dobson, J.M. (1999) Treat-ment of superficial squamous cell carcinoma of thenasal planum in cats using photodynamic therapy. Pro-ceedings of BSAVA Congress, p. 314.

White, R.A.S. (1991) Mandibulectomy and maxillectomyin the dog: long term survival in 100 cases. Journal ofSmall Animal Practice, (32), 69–74.

White, R.A.S., Jefferies, A.R. & Gorman, N.T. (1986)Sarcoma development following irradiation of acan-thomatous epulis in two dogs. Veterinary Record, (118),668.

Further reading

Couto, C.G. (1990) Clinical Management of the CancerPatient. Veterinary Clinics of North America, SmallAnimal Practice, (20), 4.

Dobson, J.M. & Gorman, N.T. (1993) Cancer Chemother-apy in Small Animal Practice. Blackwell Science,Oxford.

Hahn, K.A. & Richardson, R.C. (1995) CancerChemotherapy. A Veterinary Handbook. Williams &Wilkins, Baltimore.

Safety

COSHH Regulations (1988) General Approved Code ofPractice for the Control of Substances Hazardous toHealth and Approved Code of Practice Control of Carcinogenic Substances. Stationery Office, London.ISBN 0118854682.

Guidance Notes MS21 from the Health and Safety Executive (1983) Precautions for the safe handling ofcytotoxic drugs. Stationery Office, London. ISBN0118835718.

Allwood, M. & Wright, P. (eds) (1993) The CytotoxicsHandbook, 2nd edn. Radcliffe Medical Press, Oxford.

4Skin

opment in the cat, although benign tumours tend tobe less frequent than malignant ones in this species.

Aetiology

Several external agents and biological factors arerecognised to be important in the development ofcertain tumours of the skin but for the majority theaetiology is unknown. Long term exposure to ultra-violet light (especially UVB) is implicated in thedevelopment of squamous and basal cell tumoursin unprotected, non-pigmented and lightly hairedskin (see Chapter 1). Cutaneous papillomatosis,induced by host specific DNA papovaviruses, occurinfrequently in the dog; virally induced papillomasusually affect the oral cavity in young dogs (solitarycutaneous papilloma in older dogs is not associatedwith a viral aetiology). In male dogs, testosteronepromotes the development of perianal, hepatoidgland adenoma.

Pathology

The skin is a complex organ (Fig. 4.1), essentiallycomprising two layers:

The skin is the largest and most easily observedorgan in the body and therefore it is perhaps notsurprising that tumours of the skin (and soft tissues)are the most common neoplasms in the dog and cat.By virtue of its complex structure, a large variety oftumours may arise in the skin and it is also a possi-ble site for the development of secondary, metasta-tic tumours.

This chapter will consider those tumours arisingfrom or within the epidermis, dermis and relatedstructures. Soft tissue tumours, which may arisewithin dermal connective tissues, are considered inChapter 5, Soft tissues.

Epidemiology

Cutaneous tumours represent at least one third ofall canine tumours. Approximately two thirds of allcanine cutaneous tumours are solitary, benignlesions originating from the epithelium or fromadnexal structures including sebaceous glands,sweat glands and hair follicles. The age, breed andsex incidence varies from type to type, as discussedin the relevant sections.

The skin is also a common site for tumour devel-

OVERVIEW

� Overview, 50� Epithelial tumours, 53� Melanoma, 58� Mast cell tumours, 59� Multifocal/diffuse cutaneous neoplasia, 63� Histiocytic and granulomatous skin conditions, 66

50

Skin 51

of the more common tumours will be discussedunder separate headings. Paraneoplastic syndromesare only included where relevant.

Investigations

A presumptive diagnosis of a solitary skin tumourmay be made on clinical examination, includingvisual inspection and palpation. Skin tumourswhich present as multifocal lesions may be harderto distinguish from other dermatological condi-tions. In both cases skin tumours must be differen-tiated from:

• Hyperplastic lesions• Granulomatous lesions• Inflammatory lesions• Immune-mediated lesions• Developmental lesions.

A useful clinical approach to a lesion affecting theskin is to determine the location of the lesion, i.e.whether it is epidermal, dermal or subcutaneous, asthis will give some indication of its origin and thusits possible histogenesis. The distinction betweensolitary and multiple lesions is also of clinical value.However, definitive diagnosis can only be made

• The epidermis, a stratified squamous epithelium• The dermis, of vascular dense connective tissue.

In addition, there are associated sebaceous andsweat glands and hair follicles, collectively termedthe adnexae, plus melanocytes, histiocytes anddermal mast cells. Any of these tissues/cells maygive rise to benign or malignant tumours (Table4.1). In the dog benign tumours are twice ascommon as malignant tumours of the skin. Caninecutaneous histiocytoma and sebaceous gland ade-nomas are the most common tumours in thisspecies. Mast cell tumours are the most common‘malignant’ tumours, although in reality manycanine mast cell tumours follow a relatively benigncourse (see later). Benign skin tumours are lesscommon in the cat, with the exception of basal celltumours. Squamous cell carcinoma is the most frequent malignant tumour of the skin in thisspecies.

Tumour behaviour and paraneoplasticsyndromes

Because of the diverse nature of tumours affectingthe skin, the behaviour, presentation and treatment

Fig. 4.1 Diagram of the structure of the skin to show the variety of different tissues and cell types which may giverise to tumours affecting the skin. (Reprinted from Freeman & Bracegirdle (1976) with permission.)


upon histopathological examination of representa-tive tissue.

Bloods

Routine haematological/biochemical analyses arenot generally very helpful in the diagnosis of skintumours although some skin tumours may be asso-ciated with haematological or paraneoplastic com-plications (e.g. mast cell tumours – anaemia due togastric ulceration) and these investigations wouldbe indicated in the general evaluation of suchtumours.

Imaging techniques

Radiography of the primary tumour is not usuallynecessary unless the lesion is invasive and sitedclose to bone (e.g. squamous cell carcinoma of thedigit). Radiography of the thorax is required in theclinical staging of malignant tumours, and ultra-sound evaluation of abdominal organs (liver, spleenand kidneys) is important in the clinical staging ofmast cell tumours. Both techniques may be used toassess the internal iliac/sublumbar lymph nodes forstaging malignant skin tumours sited on the hindlimbs and perianal region.

Table 4.1 Classification of tumours affecting the skin.

Tissue type Specific tumours Sub types

Epithelial tumours PapillomaBasal cell tumour/carcinomaSquamous cell carcinomaAdnexal tumours

Sebaceous gland tumours Sebaceous gland adenomaSebaceous epitheliomaSebaceous gland adenocarcinoma

Tumours of perianal glands Perianal gland adenoma/adenocarcinoma

Sweat gland tumours Adenoma/adenocarcinomaTumours of hair follicles Pilomatricoma

TrichoepitheliomaIntracutaneous cornifying

epithelioma

Mesenchymal tumours Fibrous tissue tumours Fibroma(see Chapter 5) Fibrosarcoma

Canine haemangiopericytomaAdipose tissue tumours Lipoma

LiposarcomaBlood vessel tumours Haemangioma

Haemangiosarcoma

Melanocytic tumours Benign melanomaMalignant melanoma

Mast cell tumours Well differentiated, intermediate and poorly differentiated

Cutaneous lymphoid neoplasia PlasmacytomaPrimary cutaneous T cell lymphomaEpitheliotrophic lymphoma (mycosis fungoides)‘Histiocytic’ lymphomaLymphomatoid granulomatosis

Histiocytic and granulomatous Canine cutaneous histiocytomaskin conditions Cutaneous histiocytosis

Sterile pyogranulomatous/granulomas dermatosesSystemic histiocytosis

Skin 53

important. Areas of ulceration and necrosis shouldbe avoided, as should the temptation to collect toosuperficial a sample of the tumour. Excisionalbiopsy (i.e. local resection of the whole mass) is notgenerally recommended, except as a diagnostic pro-cedure in a case with multiple skin lesions.

Staging

Clinical staging of primary tumours of the skin is byclinical examination and radiography. The primarytumour is assessed on the basis of its size, infiltra-tion of the subcutis and involvement of other struc-tures such as fascia, muscle and bone, as shown inTable 4.2.

Biopsy/FNA

Cutaneous masses are easily accessible for fineneedle aspiration (FNA) and this is a quick, mini-mally invasive and useful technique for assessingany mass within the skin. In some cases (e.g. mastcell tumours, cutaneous lymphoma) cytology mayprovide a diagnosis, although histological examina-tion of the tumour is still required to assess thegrade of the lesion. Fine needle aspiration of locallymph nodes is also useful to assess metastaticspread.

Skin punch, needle or incisional biopsies arerequired for a definitve histological diagnosis.Collection of a representative sample of tissue is

Table 4.2 Clinical stages (TNM) of canine or feline tumours of epidermal or dermal origin (excluding lym-phoma and mast cell tumours) (Owen 1980).

T Primary tumourTis Pre-invasive carcinoma (carcinoma in situ)T0 No evidence of tumourT1 Tumour <2 cm maximum diameter, superficial or exophyticT2 Tumour 2–5 cm maximum diameter, or with minimal invasion irrespective of sizeT3 Tumour >5 cm maximum diameter, or with invasion of the subcutis, irrespective of sizeT4 Tumour invading other structures such as fascia, muscle, bone or cartilage

(Tumours occurring simultaneously should have the actual number recorded. The tumour with the highest T category is selected and the number of tumours indicated in parenthesis. Successive tumours should be classified independently.)

N Regional lymph nodes (RLN)N0 No evidence of RLN involvementN1 Movable ipsilateral nodes

N1a nodes not considered to contain growthN1b nodes considered to contain growth

N2 Movable contralateral or bilateral nodesN2a nodes not considered to contain growthN2b nodes considered to contain growth

N3 Fixed nodes(-) histologically negative, (+) histologically positive

M Distant metastasesM0 No evidence of distant metastasisM1 Distant metastasis detected (specify sites)

No stage grouping is at present recommended.

EPITHELIAL TUMOURS

Papilloma/cutaneous papillomatosis

Cutaneous papillomatosis is a viral disease which is rare in dogs and very rare in cats. Virally-

induced oral papillomatosis is seen more fre-quently in dogs. Lesions usually regress sponta-neously as immunity develops, although can persist for as long as nine months. This is dis-tinct from non-virus induced spontaneous


papillomas of skin which occur occasionally inolder dogs.

Basal cell tumour/carcinoma

This tumour is relatively common in the dog andcat and usually affects middle-aged to olderanimals. It is reported to account for 4% of canineand 14% of feline skin tumours (Bostock 1986) orfor 11% of canine and 34% of feline epithelialtumours (Goldschmidt & Shofer 1992).

Tumours are usually solitary, discrete, firm, wellcircumscribed masses, sited in the dermis and sub-cutis of the head and neck. The overlying skin maybe ulcerated. Most tumours are small, 0.5–2.0cm indiameter, although on occasion may reach up to 10cm. Some basal cell tumours especially in the cat, contain abundant melanin pigment and maytherefore be confused on gross inspection withmelanoma. Various subtypes have been describedbased on the histological appearance, e.g. solid,cystic, adenoid and medusoid.

Behaviour/treatment/prognosis

These are usually slow-growing, non-invasivetumours which follow a benign course and rarelymetastasise. Occasionally, more invasive tumoursmay be seen which are similar to the human ‘rodentulcer’. Local/wide local surgical excision is thetreatment of choice. The prognosis is good in mostcases. Local recurrence can occur following incom-plete surgical excision.

Benign adnexal tumours

These are relatively common in the dog but uncom-mon in the cat.

Tumours of hair folliclesPilomatricoma and trichoepithelioma are usuallysolitary lesions sited in the dermis. Both tend tooccur in older animals, over 5–6 years of age. No sexor breed predisposition is recognised for tricho-epithelioma, whereas the Kerry blue terrier andpossibly the poodle have been reported to be pre-disposed to the development of pilomatricoma(Nielsen & Cole 1960).

Sebaceous gland tumoursThese are the most common skin tumour of theolder dog with a mean age of affected animalsbetween 9 and 10 years (Nielsen & Cole 1960). Thecocker spaniel is predisposed to develop thesetumours, and they are also common in poodles.Lesions may be solitary or multiple and arise anywhere on the body but the head and trunk arethe most common sites, in particular the eyelid.Various types of benign sebaceous gland tumourare described according to their gross and histologi-cal appearance:

• Nodular sebaceous hyperplastic lesions aresmall, discrete, superficial, lobulated, oftenpedunclated lesions (Fig. 4.2).

• Sebaceous gland adenomas tend to be larger andless lobulated.

• Sebaceous epitheliomas present as firm, well cir-cumscribed dermal masses with hairless andsometimes ulcerated overlying skin.

Intracutaneous cornifying epitheliomaThese are quite common tumours in the dog,accounting for approximately 5% of canine epithe-lial tumours (Goldschmidt & Shofer 1992). Theyarise from the outer portion of the hair follicle andpresent as a dermal or subcutaneous mass, oftenwith a superficial, exophytic component. Many ofthese tumours contain a dilated pore through which

Fig. 4.2 Sebaceous gland tumour. Common skinlesions in older dogs, often referred to as ‘a wart’.

Skin 55

Perianal/hepatoid gland tumours

Perianal (circumanal, hepatoid) glands are modi-fied sebaceous glands located in the skin of the peri-anal region.They develop throughout life under theinfluence of sex hormones and it is often difficult to distinguish hyperplasia of these glands from abenign adenoma.

Perianal gland adenomas

These are common in elderly male dogs and occa-sionally occur in spayed bitches. No breed predis-position has been reported, although the cockerspaniel, English bulldog, samoyed and beagle hadthe highest incidence of these tumours in one study(Hayes & Wilson 1977). These tumours do notoccur in cats. Tumours usually present as a solitary,discrete, button-like lesion in the perianal skin (Fig.4.4) but may also occur around the base of the tail,prepuce or midline and can be multiple. As lesionsenlarge they tend to ulcerate and whilst most arepresented at 1–2cm diameter they can attain quitelarge size, up to 10cm in diameter.

Perianal gland adenocarcinomas

These are far less frequent than their benign coun-terparts.They arise in similar locations but are char-acterised by a more rapid and infiltrating growthresulting in large, ulcerated circumanal masses (Fig. 4.5).

grey-brown keratin can be expressed. Sites ofpredilection are on the back and tail and whilstlesions are usually solitary, some dogs may deve-lop multiple tumours (especially the Norwegianelkhound). Their behaviour is benign and manyundergo partial or even complete regression fol-lowing the initial growth phase.


All these tumours are slowly growing, non-invasiveand benign in their behaviour. Treatment is surgi-cal (if required) and the prognosis is good. Seba-ceous epithelioma may recur following incompletesurgical excision. In dogs that are prone to devel-oping multiple tumours surgical management maynot be appropriate and further lesions are likely.Successful treatment of multiple intracutaneouscornifying epitheliomata using isotretinoin hasbeen reported (Henfrey 1991).

Malignant adnexal tumours

Malignant tumours arising from the adnexal struc-tures of the skin are uncommon in the dog but seba-ceous gland and sweat gland adenocarcionomas areoccasionally reported. Such tumours are extremelyrare in the cat.


These tumours can be very aggressive and locallyinvasive, often presenting with satellite nodulesaround the primary mass. They may also result inoedema, ulceration and inflammation of the sur-rounding skin due to infiltration of dermal lym-phatics (Fig. 4.3). The incidence of metastasis isvariable but tends to be to local and regional lymphnodes and then to the lungs and other organs.

Surgical excision is the treatment of choice butwide margins of excision are required due to theinfiltrative nature of the lesion. Limited experiencesuggests that these tumours may be reasonablyradiosensitive and radiotherapy may offer an alternative for local control in cases where surgeryis not possible. The role of chemotherapy in the management of such tumours has not beenestablished.

The prognosis is usually guarded to poor becauseof the locally invasive and malignant behaviour ofthese tumours.

Fig. 4.3 Sweat gland adenocarcinoma, infiltratingwidely throughout the skin. (See also Colour plate 6,facing p. 162.)



Most perianal gland tumours follow a benigncourse. Perianal gland carcinomas metastasise viathe lymphatic route to internal iliac lymph nodesand then, via the blood to lung, liver, kidney andbone.

Surgical excision is the treatment of choice forbenign adenomas and where possible for carcino-mas. Castration will usually prevent the develop-ment of benign tumours, and is recommended to prevent recurrence. Carcinomas appear to beless hormonally dependent than adenomas andthere is little evidence that castration or hormonaltreatment is beneficial in the management of malignant perianal tumours. Perianal gland carci-nomas are reasonably radiosensitive and radio-therapy may offer an alternative for local control incases where surgery is not possible. The role ofchemotherapy in the management of such tumourshas not been established. The prognosis is favo-urable for benign tumours but guarded for car-cinomas.

NotePerianal adenoma/adenocarcinoma is distinct fromcarcinoma of the anus and from adenocarcinoma of the anal sac. These tumours are described inChapter 8, Gastrointestinal tract.

Squamous cell carcinoma (SCC)

Squamous cell carcinoma (SCC) is one of the morecommon malignant cutaneous tumours in the dogand the most common in the cat. It usually affectsolder animals and there is no known breed predis-position in either species. SCC can occur anywherein the skin. The trunk, legs, scrotum, lips and nailbed are the most frequent sites of occurrence in thedog, whereas lesions are more common on the headof the cat affecting the nasal planum (Fig. 4.6),pinnae, eyelids and lips. SCC may be productive,forming a friable, papillary growth, or it may beerosive, forming an ulcerated lesion. It is notunknown for these tumours to be dismissed asinflammatory or infective lesions on initial presentation.

Fig. 4.4 Perianal gland adenoma. (See also Colourplate 7, facing p. 162.)

Fig. 4.5 Perianal gland adenocarcinoma. (See alsoColour plate 8, facing p. 162) (Courtesy of Dr R. A. S.White, Department of Clinical Veterinary Medicine,Cambridge.)

Skin 57

and eventually invasive SCC (Figs 4.7. and 4.8) butnot all cutaneous SCC are UV induced.


SCC is a locally invasive tumour that infiltrates theunderlying dermal and subcutaneous tissue. Metas-tasis tends to be via the lymphatic route but theincidence of metastasis is variable. SCC of the skinis usually well differentiated and slow to metasta-sise; at other sites, for example the nail-bed of thedigit, behaviour can be much more aggressive.

Wide local surgical excision is the treatment ofchoice and, in cases where this can be achieved,the prognosis is favourable. SCC is moderatelyradiosensitive and radiotherapy may be indicatedas an alternative or adjunctive treatment in caseswhere adequate surgical resection is not possible.Photodynamic therapy has been used successfullyfor treatment of early, superficial lesions of thenasal planum in cats. Chemotherapy is not usually

Fig. 4.6 SCC nasal planum – cat. (See also Colourplate 9, facing p. 162.)

Figs 4.7 and 4.8 SCC of the pinnae in a cat. (See also Colour plates 10 and 11, facing p. 162) Fig. 4.7 Early stagelesion with erythema and crusting is seen on the right ear. Fig. 4.8 A more advanced, ulcerated and invasivetumour is affecting the left pinna of the same cat.

Aetiology

Prolonged exposure to UV light (especially UVB)is recognised to be an important factor in the devel-opment of actinic solar dermatitis, carcinoma in situ

4.7

4.8


indicated in the management of localised SCC andthe role of chemotherapy in the management ofmetastatic SCC has not been established.

SCC of the digit

SCC of the nail-bed region of the canine digit is anaggressive tumour and invasion and destruction ofthe distal phalanx is common (Fig. 4.9).Amputationof the affected digit(s) is the treatment of choice butthese tumours may metastasise to the local andregional lymph nodes and the prognosis is guarded.

A phenomenon of SCC affecting several digitshas been reported in large breed, black dogs, e.g.standard poodles, giant schnauzers (Paradis et al.1989). These tumours appear to have a lesser ten-dency for metastasis but over a period of time mayaffect multiple digits on different feet.

Multiple digital carcinomas have also beenreported in cats but here the digital lesions appearto be secondary, metastatic tumours from a pri-mary pulmonary carcinoma (Scott-Moncrieff et al.1989).

Fig. 4.9 Radiograph of digital SCC with bone destruction.

MELANOMA

Melanocytic tumours are relatively uncommontumours of the skin in the dog and cat, represent-ing between 4 and 6% of all canine skin tumoursand 1–2% of all feline skin tumours (Bostock 1986;Goldschmidt & Shofer 1992). In dogs, cutaneousmelanoma principally affects older animals (7–14 years of age) and is most common in the Scot-tish terrier, Boston terrier, Airedale and cocker

spaniels (and in other breeds with heavily pig-mented skin). Older cats are also affected with amean age of 8 years; there is no sex or breed pre-disposition in the cat.

Grossly tumours may appear as flat, plaque-liketo domed masses, up to 2cm in diameter, sitedwithin the dermis. They are usually dark brown toblack and quite well defined. Malignant tumoursmay attain larger size, contain less pigment and fre-quently ulcerate. In the cat cutaneous melanomamust be distinguished from the more common pig-mented basal cell tumour.


Tumour site seems to be an important factor gov-erning the behaviour of cutaneous melanoma. Mostmelanocytic tumours of the canine skin are solit-ary, slowly growing lesions which follow a benigncourse. Tumours arising on the digits and on muco-cutaneous junctions, e.g. eyelids and lips, are moreaggressive and behave in a similar manner to oralmelanoma (see Chapter 7) with a high incidence ofmetastasis to local lymph nodes and via the bloodto the lungs and other organs.

Wide surgical excision is the treatment of choicefor benign dermal melanoma and the prognosis fol-lowing complete surgical excision is good. Tumoursmay recur locally if excision is incomplete. Surgicalexcision is also indicated for local control of malig-nant tumours but the prognosis in such cases isguarded to poor because of the high incidence ofmetastasis. These tumours are not considered to bechemosensitive.

Skin 59

adjacent tissue has been shown to be of prognosticvalue. Three histological grades of mast cell tumourare described:

• Well differentiated tumours are generally of lowgrade/benign nature and carry a favourable prog-nosis.

• Poorly differentiated tumours are invasive with ahigh rate of metastasis and therefore a poorprognosis.

MAST CELL TUMOURS

Fig. 4.10 Low grade mast cell tumour – a well circumscribed, erythematous mass on the upper lipadjacent to the nasal planum.

Fig. 4.11 Aggressive mast cell tumour – the main massis sited in the skin of the axilla; multiple satellitenodules of locally invasive tumour spreading throughthe dermal lymphatics surround this mass.

Mast cell tumours (MCT) are one of the mostcommon tumours in the skin of the dog, represent-ing up to 20% of all canine skin tumours (Bostock1986). They tend to affect older animals (mean age8 years) but may occur at any age, from 4 monthsto 18 years. There is no sex predilection but severalbreeds of dog including the boxer, Boston terrier,bull terrier, Staffordshire bull terrier, fox terrier andpossibly the Labrador and golden retriever appearto be predisposed to development of this tumour.Cutaneous mast cell tumours occur less frequentlyin the cat. The presentation and behaviour of mastcell tumours differ between the cat and dog and willbe considered as separate entities.

Canine mast cell tumours

Canine mast cell tumours show tremendous diver-sity in gross appearance, clinical behaviour, rate ofmetastasis and response to treatment as a result ofwhich they present considerable prognostic andtherapeutic problems.

Presentation/clinical signs

There is no typical presentation for a canine mastcell tumour. The gross appearance can mimic any other cutaneous tumour and MCT should beconsidered in the differential diagnosis of any skin tumour. Low grade, well-differentiated mastcell tumours usually present as a solitary, slowlygrowing, dermal nodule (Fig. 4.10). Some tumoursulcerate through the skin and in some cases, localrelease of histamine from tumour cells may causethe lesion to fluctuate in size and become red and‘angry’ looking at times. More aggressive mast celltumours may present as large, ill-defined soft tissuemasses and some may be surrounded by satellitenodules as the tumour spreads though surroundingcutaneous lymphatic vessels (Fig. 4.11).

Tumour behaviour

Mast cell tumours can vary in behaviour fromslowly growing, low grade tumours which follow abenign course to rapidly growing, invasive, highlymalignant tumours, and many stages in-between.Histological grading based on the degree of cellu-lar differentiation, the mitotic index and invasion of


• Moderately differentiated tumours are inter-mediate both in their histological appearanceand also in behaviour. Unfortunately, many mastcell tumours fall into this intermediate categorywhere the prognosis is difficult to predict.

Malignant mast cell tumours may metastasiseeither by the lymphatic route or via the blood. Inmost cases the first sign of metastasis is enlarge-ment of the local lymph node. Discrete pulmonarymetastases are rare; disseminated mast cell tumoursmore commonly metastasise to the spleen, liver andkidneys. The skin is also a common site for devel-opment of metastastes.

Paraneoplastic syndromes

Solitary and metastatic mast cell tumours can havelocal or systemic effects via the release of histamineand other vasoactive amines from the tumour cells.Locally histamine release may be associated withoedema and erythema of the tumour and adjacenttissues. Histamine release may also be associatedwith gastro-duodenal ulceration leading to ano-rexia, vomiting, melaena, anaemia and, in somecases, perforation (see Chapter 2).

Investigations

BloodsRoutine haematological assessment is indicated incases with mast cell tumours. This may indicateanaemia due to blood loss from a bleeding intesti-nal ulcer. It is rare to see circulating mast cells (mastocytosis), even on buffy coat smears, buteosinophilia may be a feature of widespread,metastatic mast cell tumours.

Biopsy/FNAMast cells can be readily identified by FNA cytol-ogy (Fig. 4.12), and this simple technique should beperformed prior to surgical removal of any cuta-neous lesion. MCT cannot be graded accurately oncytology alone, although some indication of thedegree of differentiation of the tumour cells may bepossible. Thus excisional samples should be sub-mitted for histological grading and assessment ofthe margins of surgical excision.

StagingThe clinical staging system for canine mast celltumours is shown in Table 4.3. Local and regional

lymph nodes should always be evaluated by palpa-tion, radiography and/or cytology as appropriate.Ultrasound evaluation of liver, spleen and kidneysis valuable in the staging of these tumours; radiog-raphy of the chest is less useful. The skin is acommon site for mast cell tumour metastasis andskin nodules should be investigated by FNA orbiopsy.

Treatment

SurgerySurgical resection is undoubtedly the treatment ofchoice for well differentiated mast cell tumours.Even well differentiated tumours can infiltrate intoadjacent tissues; hence the minimal requirement toensure complete resection of the tumour is a wide

Fig. 4.12 Cytological appearance of a mast celltumour. Mast cells may be recognised by the charac-teristic heavily staining cytoplasmic granules. Stainedwith ‘neat-stain’–Haematology and Gram–by GuestMedical (See also Colour plate 12, facing p. 162.)

Table 4.3 The clinical staging of canine mast celltumours. Owen (1980).

Clinical stage Description

I One tumour confined to dermis, no nodal involvement

II One tumour confined to dermis with local or regional lymph node involvement

III Large infiltrating tumours with or without regional lymph node involvement

IV Any tumour with distant metastases

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ChemotherapyThe use of cytotoxic drugs in the treatment of mastcell tumours remains controversial. Empirical clin-ical evidence suggests that some mast cell tumoursdo regress in response to high dose corticosteroidtreatment (prednisolone). Whether or not the addi-tion of more potent cytotoxic drugs, e.g. vincristine,vinblastine, cyclophosphamide, doxorubicin, L-asparaginase, or CCNU, improves the response isunknown at this time. Although there have beenseveral publications suggesting that such agentsmay be beneficial, large scale controlled clinicalstudies of chemotherapy for canine mast celltumours are lacking.

OtherClaims that deionised water injected into thetumour bed post-surgery may be beneficial in reduc-ing tumour recurrence rates have not been substan-tiated in more recent studies (Jaffe et al. 2000) andthis technique remains the subject of controversy.

Prognosis

The post-surgical prognosis for canine mast celltumours has been well documented and is sum-marised in Table 4.4.

A suggested therapeutic approach to canine mastcell tumours based on the histological grade andclinical stage of the tumour is summarised in Table 4.5.

Feline mast cell tumours

Mast cell tumours are less common in the cat thanin the dog and are also less of a diagnostic problem.

local resection. Surgical resection is also indicatedin the management of moderately differentiated or intermediate grade tumours, but in this instanceresection of the tumour with generous (3–5cm)margins around the tumour is required. Deepmargins are also important but as mast cell tumoursdo not usually invade through fascial planes, resec-tion to a clean fascial plane deep to the tumour isusually adequate.

The most common cause of treatment failure formast cell tumours is inadequate resection of theprimary tumour leading to local tumour recurrence.This is often the result of badly planned or executedsurgery rather than a feature of a bad tumour! Thefirst surgical attempt stands most chance of success.Cure rates for subsequent surgical excisions oradjunctive therapies are low. For this reason it isvitally important to identify a mast cell tumourprior to any attempt at treatment so that appropri-ate surgical margins can be planned and achievedat the first attempt. Mast cell tumours are relativelyeasy to diagnose by cytological examination of fineneedle aspirates, as previously described.

RadiotherapyThere is no unequivocal evidence to show thatradiotherapy as a sole treatment is particularly ben-eficial in the management of mast cell tumours ofany grade; indeed in situ destruction of tumour cellsby radiation can precipitate severe local reactions.Radiotherapy may be beneficial as a post-surgicaltreatment in cases of moderately differentiatedtumours where complete surgical resection is notfeasible (Al-Sarraf et al. 1996) and, on occasions,may be used in conjunction with chemotherapy forthe treatment of tumours which cannot be surgi-cally excised due to their site.

Table 4.4 Post-surgical prognosis for canine mast cell tumours.

Histological grade Number of dogs Median survival Dead from(weeks) tumour (%)

Well differentiated 19 40 10Intermediate 16 36 25Poorly differentiated 15 13 73

Figures from Bostock et al. (1989). This study was based on mast cell tumoursexcised by veterinary surgeons in general practice. Margins of excision werenot examined or specified.

Visceral and systemic mast cell tumoursin cats

Lymphoreticular mast cell tumours are occasion-ally seen in cats. In this condition, also called systemic mastocytosis, the tumour primarilyinvolves the spleen. Presenting signs are usuallyvomiting and anorexia with common clinical find-ings of mastocytosis, marked splenomegaly andbone marrow infiltration, the latter often leading to anaemia and other cytopenias. Occasionallymediastinal involvement can lead to a pleural effusion, and lymph nodes elsewhere may also beinvolved. A diffuse cutaneous infiltration has sometimes been reported with this form of thedisease, and this has been the cause of some con-fusion regarding the clinical behaviour of cuta-neous mast cell tumours (most of which arebenign). The diagnosis may be confirmed by fineneedle aspirates from the enlarged spleen, andsplenectomy is the treatment of choice. Long termsurvival has been reported in cats receiving noother therapy (Liska et al. 1979). It has been postu-lated that the response to splenectomy alone mayinvolve the cat’s immune system, hence the use ofpost-operative corticosteroids in these animals is controversial.

Intestinal mast cell tumour in the cat is distinctfrom systemic mastocytosis (which does not involvethe bowel). This form of feline MCT is malignant,with widespread metastases and carries a poorprognosis.


Two forms of mast cell tumour are recognised in thecat: cutaneous and visceral.

Cutaneous mast cell tumours

The majority of feline cutaneous mast cell tumours are solitary cutaneous/dermal nodules.These tumours are usually histologically well dif-ferentiated and have a benign clinical course. Onoccasion a cat may be affected by multiple skinnodules, or a solitary lesion may be invasive.However, the majority of cutaneous mast celltumours in the cat are benign, and histologicalgrading of feline cutaneous mast cell tumours hasnot been shown to be clinically useful.

Treatment and prognosisSurgical resection is the treatment of choice forfeline cutaneous mast cell tumours and the prog-nosis is usually good (Molander-McCrary et al.1998). In cats with multiple tumours corticosteroidsmay be of palliative value. Invasive or incompletelyexcised tumours may be treated with adjunctiveradiotherapy.

NoteA variant of feline mast cell tumour has beenreported predominantly affecting Siamese cats.This tumour, which may be multicentric, is charac-terised histologically by sheets of histiocyte-likemast cells with scattered lymphoid aggregates andeosinophils. These tumours may regress sponta-neously without therapy.

Table 4.5 Suggested strategies for the clinical management of canine mast cell tumours.

Histological grade Clinical stage Therapy

Well differentiated tumour I Wide local surgical excision

Intermediate, moderately I As above differentiated tumour (Post operative radiation may be required if adequate surgical

margins cannot be achieved)II Surgical excision and/or radiation of primary tumour and node.

(± chemotherapy)

Poorly differentiated III Chemotherapy: Prednisolone 40 mg/M2 daily for 14 days, thentumour gradually reducing to 20 mg/M2 for maintenance

Any tumour with IV ± Cyclophosphamide 50 mg/M2q 48 hoursdistant metastases ± Vincristine 0.5 mg/M2 or vinblastine 2 mg/M2 iv weekly

Any animal showing systemic signs should also be treated with either cimetidine or ranitidine (Zantac–GlaxoTM).

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MULTIFOCAL/DIFFUSE CUTANEOUS NEOPLASIA

Treatment and prognosis

In the early stages the cutaneous tumours mayrespond to chemotherapy schedules used in thetreatment of multicentric lymphoma (see Chapter15); however, periods of remission are usually shortand the prognosis is poor with average survivaltimes rarely exceeding 2–3 months.

Fig. 4.13 Primary cutaneous T cell lymphoma, gener-alised erythematous plaques and nodules. (See alsoColour plate 13, facing p. 162.)

Fig. 4.14 Primary cutaneous T cell lymphoma. Closeup of erythematous nodule from a different dog. Noteinfiltration of surrounding skin. (See also Colour plate14, facing p. 162.)

Fig. 4.15 Histological appearance of primary cutane-nous lymphoma. The tumour infiltrate affects thedermis; the epidermis is intact. (See also Colour plate15, facing p. 162.)

As a result of the increasing use of skin biopsies inthe investigation of skin disease, disseminated neo-plastic infiltration of the skin is assuming increasingimportance in the differential diagnosis of ulcera-tive, nodular or crusting skin lesions. AlthoughMCT and metastases from both carcinomas andsarcomas can present as multiple, nodular skinlesions, lymphoid neoplasms are those most com-monly associated with multifocal or diffuse skinlesions. A spectrum of granulomatous to histiocyticskin lesions may also give rise to ulcerative ornodular skin disease in dogs. Some of these may bepreneoplastic or neoplastic in nature but ourcurrent understanding of these conditions is farfrom complete.

There are two forms of cutaneous lymphoma,both of T cell origin, which primarily affect the skin:primary and epitheliotropic.

Primary cutaneous (T cell) lymphoma

This is a very aggressive neoplasm. This tumour ini-tially presents with multiple cutaneous nodules,plaques or erythroderma (Figs 4.13 and 4.14). His-tologically there is a nodular infiltration of thedermis and subcutis with malignant lymphoid cells(Fig. 4.15). The disease usually has a rapid courseand the tumour quickly disseminates to involveother organs such as the liver, spleen and bonemarrow.

Mycosis fungoides (MF) runs a very protractedcourse often spanning many months. In humansmycosis fungoides can be divided into three distinct phases:

• Premycotic• Mycotic or plaque stage• Tumour stage.

In dogs these phases are less well defined and maycoexist. In the early stage canine MF may presentas an erythematous, exfoliative or seborrhoeic skincondition, which is often very pruritic, with lesionsthat heal in one region and then erupt in another.This gradually progresses with the development of plaques and ulceration of the skin. Finally, the‘tumour stage’ is characterised by well definedtumour nodules or plaques. At this stage there isusually a rapid progression of the disease culmi-nating in widespread dissemination to other organs.The mucous membranes of the mouth, eyes andgenitalia may be affected at all stages (Figs 4.17 and4.18).

Treatment

No single treatment has been established as beingeffective in the control of MF. Topical treatmentwith nitrogen mustard was once advocated forhuman patients. This is a very hazardous agent tohandle and its use in animals with MF is not rec-


Epitheliotropic lymphoma (Mycosis fungoides)

The epitheliotropic form of cutaneous lymphoma is distinct from primary cutaneous (T cell) lym-phoma in several important respects. Histologicalsections show a diffuse infiltration of the epi-dermis by lymphocytes and other inflammatorycells (Fig. 4.16). In the advanced stages of thedisease the tumour cells invade into deeper layersof the dermis, heralding systemic dissemination.

Fig. 4.16 Histological appearance of epitheliotropiclymphoma. In contrast to Fig. 4.15, the tumour cellinfiltrate is in the epidermis. (See also Colour plate 16,facing p. 162.)

Fig. 4.17 Epitheliotropic lymphoma – (a) shows generalised nature of skin lesions; (b) close up showing erythe-matous crusting nature of lesions. (See also Colour plates 17 and 18, facing p. 162.)

(a) (b)

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ommended.The response of the disease to systemicchemotherapy is variable but in some cases animprovement in the lesions can be achieved. Thedisease has been reported to respond favourably to L-asparaginase (MacEwen et al. 1987), and toretinoids (White et al. 1993). Radiotherapy can beused for localised lesions. Photodynamic therapy isbeing investigated for localised lesions in humanpatients.

Histiocytic lymphoma

Cutaneous lesions may also occur as part of a systemic or multicentric lymphoma. ‘Large cell’ or ‘histiocytic’ lymphomas are often associated with cutaneous lesions. Although these are relatively infrequent tumours they may respondmore favourably to chemotherapy than the morecommon lymphoblastic or lymphocytic forms oflymphoma.

Lymphomatoid granulomatosis

Lymphomatoid granulomatosis is a rare lympho-histiocytic disorder in humans that has been recog-nised in the dog. Most human patients primarilyhave pulmonary lesions but other organs such askidneys, liver, brain and skin may be affected. It is currently believed that lymphomatoid granulo-matosis is not a preneoplastic granulomatous condition (as the name infers) but a rare variant of angiocentric peripheral T-cell lymphoma. In

most of the canine cases reported the disease hasbeen described primarily as a pulmonary disorder(Fitzgerald et al. 1991) but several canine cases ofprimary cutaneous lymphomatoid granulomatosishave now been recognised (Smith et al. 1996).These dogs have presented with multiple cutaneousnodules, plaques and ulcers, with or without pul-monary involvement. In humans and in some of the canine cases reported the cutaneous and pul-monary lesions can regress in response to immuno-suppressive therapy with cyclophosphamide andcorticosteroids but the prognosis is guarded. Mosthuman patients succumb to the development ofunresponsive CNS lesions.

Plasmacytoma

Plasma cells are derived from B lymphocytes and can give rise to a spectrum of neoplastic con-ditions. Multiple myeloma is a systemic condition,often associated with inappropriate secretion ofimmunoglobulins from neoplastic plasma cells sited in the medullary cavity of bone (Chapter 15).Extramedullary plasma cell tumours may arise in soft tissues and are usually solitary soft tissuetumours although potentially might representmetastasis from a primary multiple myeloma.

Plasmacytomas are common in dogs but rare incats (Lucke 1987; Rakich et al. 1989). They usuallyaffect older dogs but no breed predilection hasbeen established. In dogs they usually present as asolitary skin or mucocutaneous tumour. They canarise at any site but the oral cavity, feet, trunk andears are most common. Plasmacytoma may alsoaffect mucocutaneous junctions and occasionallyarise in the gingiva. Their gross appearance isusually of a raised red or ulcerated, quite welldefined mass. They do not usually attain large size,varying from 2–5cm in diameter. Histological diag-nosis can be difficult if the tumour cells are lackingclear differentiation and special staining techniquesmay be required to differentiate plasmacytomafrom poorly differentiated sarcoma and otherround cell tumours.


Cutaneous and oral forms of plasmacytoma areusually benign and are rarely associated with sys-temic signs. Surgical resection is usually curative.

Fig. 4.18 Epitheliotropic lymphoma affecting oralmucocutaneous junctions and mucosae. (Colour plate19.)

termed ‘cutaneous histiocytosis’ or ‘granulomatousdermatoses’ are also recognised where the cellsinvolved are not morphologically malignant(Panich et al. 1991).

Cutaneous histiocytosis/sterilepyogranulomatous skin conditions

Granulomatous and pyogranulomatous dermatosesappear clinically as skin nodules. These may be solitary or multiple, localised or diffuse, haired,alopecic or ulcerated (Figs 4.19 and 4.20). Clinicallyit can be difficult to differentiate these lesions from certain tumours. These dermatoses may bedivided into infectious and non-infectious cate-gories. Overall, ‘infectious’ agents such as bacteria,fungi, protozoa and algae are probably the mostcommon cause of such lesions and these should be excluded by culture, special staining of skin biopsies and response to antimicrobial therapy.Conditions where no inciting cause can be identi-fied are termed idiopathic sterile granulomas and several variants are described, as shown inTable 4.6.

Some of these conditions (e.g. sterile panniculi-tis) have a characteristic histological appearance,others (e.g. sterile pyogranuloma and cutaneoushistiocytosis) are harder to differentiate by lightmicroscopy; indeed, cutaneous histiocytosis may be an extension of the pyogranuloma/granulomasyndrome. In all cases the infiltrating inflammatorycells are morphologically normal and do not showany characteristics of neoplastic transformation.Most of these conditions are potentially immune-mediated, or at least related to dysregulation of theimmune system, and some (e.g. sterile pyogranu-loma/granuloma syndrome) show a favourableresponse to immunosuppressive therapy. In cuta-neous histiocytosis and systemic histiocytosis the lesions typically wax and wane over a variableperiod of time. The response of cutaneous histiocy-tosis to immunosupressive doses of prednisolone is variable and the response of systemic histiocyto-sis is poor. It is difficult to make specific recom-mendations about the treatment of these twoconditions and the long-term prognosis is guardedto poor.


HISTIOCYTIC AND GRANULOMATOUS SKIN CONDITIONS

Canine cutaneous histiocytoma(CCH)

CCH is a benign cutaneous tumour, unique to theskin of the dog and representing up to 10% of allcanine cutaneous tumours. CCH is more commonin young dogs with 50% of these tumours occurringin animals under two years of age. The tumour typically arises on the head (especially the pinna),the limbs, feet and trunk and presents as a rapidlygrowing, intradermal lesion. The surface maybecome alopecic and ulcerated. The boxer anddachshund are reported to be predisposed to CCHand it also appears to be common in the flat-coatedretriever.

Histological sections show infiltration of the epidermis and dermis by neoplastic histiocytic cells.Numerous mitotic figures and an indistinct bound-ary give this lesion the appearance of a highlymalignant neoplasm. (This may lead to CCH beingmisdiagnosed by non-veterinary pathologists whoare unfamiliar with this canine tumour.)


Despite the histological appearance and the rapidgrowth rate, CCH is a benign tumour which usuallyregresses spontaneously. Regression is associatedwith infiltration of the tumour by cytotoxic T cells. Lymphocytic infiltration is a feature oftendescribed in histological reports. Surgical excisionis usually curative and the prognosis is good.

Other histiocytic/granulomatous skin conditions

A group of ‘histiocytic’ skin lesions are recognised,particularly in dogs, which have yet to be fully characterised. In such cases there is a diffuse ornodular infiltration of the dermis by mononuclearcells that have a histiocytic appearance. In somecases these cells may be a variant of lymphoid neoplasia (i.e. ‘histiocytic’ lymphoma) as demon-strated through the use of canine lymphocyte cellsurface markers (Baines et al. 2000) but conditions

Skin 67

Figs 4.19 and 4.20 Cutaneous histiocytosis/pyogranulomatous skin condition in a retriever. Figure 4.19 The dogpresented with a soft tissue swelling over the bridge of the nose. Figure 4.20 Several other dermal masses werenoted. (See also Colour plates 20 and 21, facing p. 162.)

Table 4.6 Granulomatous and pyogranulomatous dermatoses.

Condition Clinical features

Sterile pyogranuloma/granuloma Uncommon in dogs, rare in catssyndrome (Panich et al. 1991) Reported in collie, boxer, great Dane, Weimaraner, golden retriever

? Male predisposition in dogs Papules, nodules and plaques located on the head (periocular, muzzle

and bridge of nose) and feetAffected animals are systemically healthy

Sterile panniculitis (Scott & Uncommon in dogs and catsAnderson 1988) Associated with both infectious and non-infectious

aetiologies

Lesions often solitary, subcutaneous, fluctuant. Mayulcerate and result in discharging fistulae

Granulomatous sebaceous adenitis Rare condition, usually affects young adult dogs, reported in vizsla,(Scott 1986) akita, samoyed and standard poodle

Pyogranulomatous inflammation destroys sebaceous glands resulting inalopecia and scaling. May be focal or generalised

Cutaneous histiocytosis Rare disorder of dogsNodular skin lesions may be alopecic and ulcerated. Usually affect face,

neck and trunk. Nasal mucosa may be involved resulting inrespiratory stridor. Affected animals are usually systemically healthy

Systemic histiocytosis Rare familial condition affecting young adult Bernese mountain dogs.(Paterson et al. 1995) Skin lesions comprise papules, nodules and plaques and are most

common on the flanks, muzzle, nasal planum, eyelids and scrotum.Ocular lesions, uveitis, chemosis, episcleritis and scleritis are alsocommon. Variable lymphadenopathy.

Affected animals may also show anorexia, weight loss and lethargy.

4.19 4.20

Owen, L.N. (1980) TNM Classification of Tumours inDomestic Animals. World Health Organization,Geneva.

Paradis, M., Scott, D.W. & Breton, L. (1989) Squamouscell carcinoma of the nail-bed in three related giantschnauzers. Veterinary Record, (125), 322–4.

Panich, R., Scott, D.W. & Miller, W.H. (1991) Canine cutaneous sterile pyogranuloma/granuloma syndrome:a retrospective analysis of 29 cases (1976 to 1988).Journal of the American Animal Hospital Association,(27), 519–28.

Paterson, S., Boydell, P. & Pike, R. (1995) Systemic histi-ocytosis in the Bernese mountain dog. Journal of SmallAnimal Practice, (36), 233–6.

Al-Sarraf, R., Maudlin, G.N., Patnaik, A.K. & Meleo(1996) A prospective study of radiation therapy for the treatment of grade 2 mast cell tumours in 32 dogs. Journal of Veterinary Internal Medicine, (10),376–8.

Rakich, P.M., Latimer, K.S., Weiss, R. & Steffens, W.L.(1989) Mucocutaneous plasma cytomas in dogs: 75cases (1980–1987). Journal of the American VeterinaryMedical Association, (194), 803–10.

Scott, D.W. (1986) Granulomatous sebaceous adenitis indogs. Journal of the American Animal Hospital Associ-ation, (22), 631–34.

Scott, D.W. & Anderson, W. (1988) Panniculitis in dogsand cats: a retrospective analysis of 78 cases. Journal ofthe American Animal Hosptial Association, (24),551–59.

Scott-Moncrieff, J.C., Elliott, G.S., Radovsky, A. &Blevins, W.E. (1989) Pulmonary squamous cell carci-noma with multiple digital metastases in a cat. Journalof Small Animal Practice, (30), 696–9.

Smith, K.C., Day, M.J., Shaw, S.C., Littlewood, J.D. &Jeffery, N.D. (1996) Canine lymphomatoid granulo-matosis: and immunophenotypic analysis of three cases. Journal of Comparative Pathology, (115), 129–38.

White, S.D., Rosychuk, R.A., Scott, K.V., Trettien, A.L.,Jonas, L. & Denerolle, P. (1993) Use of isotretinoin andetretinate for the treatment of benign cutaneous neo-plasia and cutaneous lymphoma in dogs. Journal of the American Veterinary Medical Association, (202),387–91.

Further reading

Goldschmidt, M.H. & Shofer, F.S. (1992) Skin Tumours ofthe Dog and Cat. Pergamon Press, Oxford.


References

Baines, S.J., McCormick, D., McInnes, E., Dunn, J.K.,Dobson, J.M. & McConnell, I. (2000). Cutaneous T-celllymphoma mimicking cutaneous histiocytosis: differen-tiation by flow cytometry. Veterinary Record.

Bostock, D.E. (1986) Neoplasms of the skin and sub-cutaneous tissues in dogs and cats. British VeterinaryJournal, (142), 1–18.

Bostock, D.E., Crocker, J., Harris, K. & Smith, P. (1989)Nucleolar organiser regions as indicators of post-surgical prognosis in canine spontaneous mast celltumours. British Journal of Cancer, (59), 915–18.

Fitzgerald, S.D., Wolf, D.C. & Carlton, W.W. (1991) Eightcases of canine lymphomatoid granulomatosis. Veteri-nary Pathology, 28 (3), 241–5.

Freeman, W.H. & Bracegirdle, B. (1976) An AdvancedAtlas of Histology. Heinemann Educational Books Ltd,London.


Hayes, H.M. & Wilson, G.P. (1977) Hormone dependentneoplasms of the canine perianal gland. CancerResearch, (37), 2068–71.

Henfrey, J.I. (1991) Treatment of multiple intracutaneouscornifying epitheliomata using isotretinoin. Journal ofSmall Animal Practice, (32), 363–5.

Jaffe, M.H., Hosgood, G., Kerwin, S.C., Hedlund, C.S. &Taylor, H.W. (2000) Deionised water as an adjunct tosurgery for the treatment of canine cutaneous mast cell tumours. Journal of Small Animal Practice, (41), 7–11.

Liska, W.D., MacEwen, E.G., Zaki, F.A. & Garvey, M.(1979) Feline systemic mastocytosis: a review andresults of splenectomy in seven cases. Journal of theAmerican Animal Hospital Association, (15), 589–97.

Lucke, V.M. (1987) Primary cutaneous plasmacytomas inthe dog and cat. Journal of Small Animal Practice, (28),49–55.

MacEwen, E.G., Rosenthal, R., Matus, R. et al. (1987)An evaluation of asparaginase: polyethylene glycolcongugate against canine lymphosarcoma. Cancer, (59),2011–15.

Molander-McCrary, H., Henry, C.J., Potter, K., Tyler, J.W.& Buss, M.S. (1998) Cutaneous mast cell tumours incats: 32 cases (1991–1994). Journal of the AmericanAnimal Hospital Association, (34), 281–4.

Nielsen, S.W. & Cole, C.R. (1960) Cutaneous epithelialneoplasms of the dog. A report of 153 cases. AmericanJournal of Veterinary Research, (21), 931–48.

5Soft Tissues

Soft tissue tumours are typically solitary and tendto arise in older animals.

Dogs

Benign soft tissue tumours are common and showno particular breed or sex predisposition, althoughlipoma, which is probably the most common benignsoft tissue tumour of the dog, does seem to be morecommon in animals that are overweight. Soft tissuesarcomas are more common in the larger breedsand some breeds may be predisposed to developcertain soft tissue tumours:

• Bernese mountain dogs – malignant histiocytosis(see Chapter 17)

• Flat-coated retrievers – anaplastic sarcomas(Morris et al. 2000)

• Golden retrievers – fibrosarcoma• German shepherd dogs – haemangiosarcoma.

Although the average age of onset of canine softtissue sarcoma is 8–9 years, it is not unknown foryounger animals of these and other large breeds tobe affected. For example, in our clinic we quite fre-quently see golden retrievers 4–6 years of age withfibrosarcoma. On occasion rhabdomyosarcoma and anaplastic sarcomas may occur in juveniles asyoung as four months. For most soft tissue sarco-mas there is no clear sex predisposition although ahigher incidence of synovial sarcoma and malignanthistiocytosis has been reported in males.

Cats

Benign soft tissue tumours are uncommon. There is no breed or sex predisposition to soft tissue

Definition

Soft tissue tumours are those that arise from themesenchymal connective tissues of the body.Benign tumours of this group usually carry thesuffix ‘oma’ and their malignant counterparts aretermed ‘sarcoma’. Tumours of fibrous, adipose,muscular and vascular tissues are included in thisdefinition and by convention it also includestumours of the peripheral nervous system becausetumours arising from nerves present as soft tissuemasses and pose similar problems in differentialdiagnosis and management.

Although the term ‘soft tissue sarcoma’ wouldappear to cover a diverse collection of tumours,these may be considered as a group not onlybecause they share overlapping histological fea-tures but also because they share several importantclinical and behavioural features.

Epidemiology

Soft tissue tumours are relatively common tumoursin both the dog and cat. In the dog the majority ofsoft tissue tumours are benign whereas in the catbenign soft tissue tumours are uncommon. Themalignant counterpart, soft tissue sarcomas, areimportant tumours in both the cat and the dog.Collectively they comprise approximately 15% ofall canine and 7% of all feline ‘skin’ and subcuta-neous tumours, but they can arise in other sites,for example oral, nasal and urogenital, hence theactual incidence of soft tissue tumours may behigher than indicated in many studies.

69

macrophages contain adjuvant (Doddy et al. 1996).While no definitive proof has shown that vaccinesor the act of vaccination cause the sarcoma, and infact the incidence of such tumours is low (theannual incidence is estimated to be 0.13% of all cats vaccinated (Lester et al. 1996)), recommenda-tions have been established in North Americaregarding sites for vaccination, avoidance of simul-taneous injections at one site and accurate recordkeeping.

Spirocerca lupi-induced sarcoma

Sarcomas of the oesophagus have been reported inareas where the helminth parasite Spirocerca lupiis indigenous (Africa and south-eastern USA).

Trauma and inflammation

The development of a sarcoma at a site of previoustrauma or inflammation has been documented inanimals and people, although rarely. Examples ofsuch sites include scar tissue following surgical procedures, thermal or chemical burns, fracturesites and sites in the vicinity of plastic or metallicimplants, usually after a latent period of severalyears. Feline ocular sarcomas may be associatedwith trauma to the lens and chronic ocular inflam-mation (Chapter 16).

Radiation

Radiation has been related to the development ofsarcomas and there certainly is a risk that a verysmall proportion of human cancer patients (0.1%)who survive over five years following radiotherapywill develop a sarcoma of either bone or soft tissue.In dogs a 10–20% incidence of sarcoma devel-opment has been reported following irradiation ofacanthomatous epulis/basal cell carcinoma of theoral cavity (White et al. 1986).

Pathology

Soft tissue tumours of cats and dogs may be classified according to their tissue of origin, asshown in Table 5.1. In some soft tissue sarcomas the component cells are so poorly differentiatedthat it is difficult to determine the tissue of originand, in the absence of further cytochemical and


sarcoma reported and most tumours are solitaryand occur in the older animal. There are twonotable exceptions:

• Feline sarcoma virus-induced tumour – This isvery rare and has not been reported in the UK.It occurs in young animals which usually presentwith multiple subcutaneous tumours.

• ‘Vaccine-site’ sarcomas – These have beenreported in younger animals (see later).

Aetiology

With few exceptions, the cause of soft tissue sarco-mas in cats and dogs is not known. Those tumourswhere an aetiology is known or proposed tend tobe very rare but include the following.

Feline sarcoma virus-induced sarcoma

FeSVs are recombinant viruses generated by inter-action of FeLV DNA provirus with endogenousoncogenes in the feline genome (Chapter 1). FeSV-induced fibrosarcomas are rare (probably account-ing for less than 2% of all feline fibrosarcomas) andonly arise in young, FeLV positive cats, most ofwhich are under three years of age. Tumours areusually multicentric and present as multiple sub-cutaneous masses on limbs and trunk. These areaggressive tumours which may metastasise to inter-nal organs. Histologically they are often anaplasticbut may show partial differentiation with areas ofosteosarcoma or chondrosarcoma.

Vaccine-site sarcomas in cats

In the early 1990s an increase in the incidence offeline fibrosarcomas that appeared to coincide with an increase in vaccination with rabies andFeLV vaccines was reported in North America(Kass et al. 1993; Hendrick & Brooks 1994). Pos-sible vaccine-associated sarcomas have since beenreported in North America and in Europe withtumours arising at classical injection sites, especiallyin the interscapular space. The age of onset is variable but it is often younger animals that areaffected. Histologically, most of these tumours arefibrosarcoma although they are reported to have acharacteristic morphology with more cellular pleo-morphism, central necrosis and sclerosis than nonvaccine-site fibrosarcomas. In many the peripheral

Soft Tissues 71

immunohistochemical evaluation, such tumoursmay be described by their morphology, i.e. spindlecell sarcoma, round cell sarcoma, anaplasticsarcoma.

Presentation/signs

Both benign and malignant soft tissue tumours areusually bulky, fleshy tumours, as opposed to inva-sive and ulcerative masses as seen with carcinomas.They may arise from any anatomic site but mostcommonly present as a soft tissue mass of the sub-cutis although they can arise in deeper soft tissuesor within body cavities and internal organs (Figs 5.1and 5.2). The tumour itself is usually painless. Painor discomfort may occur, however, when thetumour involves or abuts sensitive structures. Aclassical example of this is the neurofibrosarcomaof the brachial plexus as seen in the dog that pre-sents with a progressive forelimb lameness andmarked muscle wastage. A painful mass may some-times be palpated deep in the axilla.

Tumours often appear well circumscribed oreven encapsulated; however, in reality these softtissue sarcomas have poorly defined histological

margins and often infiltrate through fascial planes(see below).

Tumour behaviour

Primary tumour

Benign soft tissue tumours are usually slowlygrowing, non-invasive, well circumscribed masses.On occasion growth may cease but some tumours,for example lipomas, may attain massive proportions.

A rare variant of the common lipoma is the infil-trating lipoma. Histologically the tumour is com-prised of mature adipose tissue with no features ofmalignancy and yet the tumour is characterised byan infiltrating pattern of growth around and withinsurrounding muscles and nerves (Fig. 5.3).

Soft tissue sarcomas enlarge in a centrifugalfashion and compress normal tissue so as to give the appearance of encapsulation. This pseudocap-sule is actually composed of an inner compressedrim of normal tissue (compression zone) and anouter rim of oedema and newly formed vessels(reactive zone). Finger-like extensions of tumour

Table 5.1 Classification of soft tissue tumours.

Tissue of origin Benign tumour Malignant tumour

Fibrous tissue Fibroma FibrosarcomaCanine haemangiopericytoma

Fibro-histiocytic – Malignant fibrous histiocytoma/malignant histiocytosis

Adipose Lipoma Liposarcoma(Infiltrative lipoma)

Muscular-skeletal (Rhabdomyoma) Rhabdomyosarcoma-smooth Leiomyoma/ Leiomyosarcoma

fibroleiomyoma

Synovial – Synovial (cell) sarcoma

Vascular Haemangioma Haemangiosarcoma(Lymphangioma) (Lymphangiosarcoma)

Peripheral nerve ‘Peripheral nerve sheath tumours’*Neurofibroma NeurofibrosarcomaSchwannoma Malignant SchwannomaNeurilemmoma

Other Myxoma Myxosarcoma

The terminology for tumours of peripheral nerves is not resolved in veterinarymedicine. The different terms listed essentially describe the same tumours.


can extend into and through this pseudocapsuleand give rise to satellite lesions (Fig. 5.4). Becauseof this pattern of growth, local tumour recurrenceafter surgical excision is common. The pseudocap-sule provides a tempting plane for resection – ‘thetumour shelled out nicely’; however, such a proce-dure leaves microscopic and even gross tumour inthe wound. Excision of any sarcoma within thepseudocapsule is inadequate therapy and will resultin local tumour recurrence.

Metastasis

Overall it is estimated that metastasis occurs in upto 25% of all soft tissue sarcomas. Whilst there is some variation in the incidence of metastasis

Fig. 5.1 Haemangiopericytoma on the distal limb/carpus of a dog.

Fig. 5.2 Rhabdomyosarcoma presenting as a lungmass.

Fig. 5.3 Infiltrating lipoma. Extending from the stifle tothe hock.

Soft Tissues 73

between tumours of different histological types, itis now recognised that the risk of metastasis for aparticular tumour type correlates with the grade oftumour. Histological grading is an assessment of thetumour based on:

• Degree of tumour differentiation (poor differentiation = high grade)

• Cellularity (increases with higher grade)• Cellular pleomorphism (increases with higher

grade)• Amount of stroma (decreases with increasing

grade)• Mitotic activity (increases with increasing grade)• Tumour necrosis (present in high grade tumours).

Using such criteria, sarcomas may be described aslow, intermediate or high grade. A high gradetumour of any histological type will carry a higherrisk of metastasis than its low grade counterpart.Prediction of likely behaviour of an individualsarcoma will therefore depend on consideration ofboth histological type and grade of tumour, asshown in Table 5.2.

Metastasis is usually via the haematological routewith blood borne metastases favouring the lung asthe predominant site for the development of sec-ondary tumours. Other sites for metastasis includeinternal viscera, skin and bone. The incidence andpattern of distant metastasis depend on the site andtype of the primary tumour, for example animalswith splenic haemangiosarcoma show a higher in-cidence of disseminated disease throughout theabdomen. Regional lymph node metastasis is less

common although it is reported for synovial cellsarcoma and, may occur with ‘anaplastic’ tumours.


Paraneoplastic syndromes are not common in softtissue sarcoma although the occasional tumour maybe associated with hypercalcaemia, and masses in the thorax may cause hypertrophic osteopathy.Haemangiosarcoma may be associated withhaematological complications including microan-giopathic anaemia, thrombocytopenia and DIC.

Investigations

Bloods

Routine haematological/biochemical analyses arenot generally very helpful in the diagnosis of mostsoft tissue tumours. Some soft tissue tumours,e.g. haemangiosarcoma, may be associated with haematological or paraneoplastic complications (as above) and blood samples would be indicatedin the evaluation of cases such as these.

Imaging techniques

Radiography of the primary tumour may be indi-cated if the lesion is invasive and sited close to bone(e.g. synovial sarcoma). Radiography of the thoraxto look for pulmonary metastases is required in theclinical staging of all malignant tumours and ultra-

Tumour

Compression zone

Reactive zone

Directextension

TumourSatellite

Fig. 5.4 Pseudoencapsulation of a soft tissue sarcoma – (a) diagrammatic representation of the reactive and com-pression zones comprising the ‘pseudocapsule’ of a soft tissue sarcoma. Tumour cells may exend into and throughboth these layers as shown in (b) histological section at the ‘edge’ of an anaplastic soft tissue sarcoma.

(a) (b)

nique should be planned to minimise tissue traumaand haemorrhage (which may disseminate tumourcells locally) and should be performed at a loca-tion which will be within a future surgical excision.

Staging

Clinical staging of soft tissue tumours is by clinicalexamination, radiography and ultrasonography.CT and MRI are useful if available. The primary


sound evaluation of abdominal organs is importantin the clinical staging of internal tumours and highgrade or anaplastic tumours.

CT and MRI of the primary tumour mass iswidely used in pre-operative evaluation of humansarcoma patients to assess the deep relationships ofsuch tumours and to plan therapy. It is likely thatuse of these techniques will increase in veterinarymedicine.

Biopsy/FNA

The clinical presentation of a soft tissue mass withvariable rate of growth may be suggestive of a softtissue sarcoma; however, histological examinationof biopsy material is essential for diagnosis oftumour type and assessment of histological grade.Although fine-needle aspiration cytology may behelpful in distinguishing differential diagnoses suchas lipoma, mast cell tumour or abscess, cytology isof limited value in the diagnosis of soft tissuesarcoma. Often these tumours do not exfoliate well(Fig. 5.5) and furthermore, their variable tissuecomponents mixed with areas of necrosis andinflammation complicate cytological diagnosis.

Knowledge of tumour type is vital prior to de-finitive treatment and an incisional biopsy is pre-ferable to an excisional technique in all but themost exceptional case. The biopsy site and tech-

Table 5.2 Relationship between histological type and grade for softtissue sarcomas.

Histological type Low grade Intermediate High gradegrade

Haemangiopericytoma +Fibrosarcoma + + (+)Neurofibrosarcoma +Myxosarcoma + +Malignant fibrous histiocytoma + + ?Synovial cell sarcoma + (+)Liposarcoma + (+)Rhabdomyosarcoma + (+)Anaplastic sarcoma + +Haemangiosarcoma (+)* +

Low grade = low risk of metastasis, i.e. less than 10%Intermediate = moderate risk of metastasis, i.e. 25–50%High grade = strong possibility of metastasis i.e. 75–100%* A low grade haemangiosarcoma of the skin is recognised, with low metasta-tic potential.

Fig. 5.5 Cytological preparation of sarcoma. Thespindle shaped cells collected by FNA are suggestiveof a tumour of mesenchymal origin but do not providesufficient information to type or grade the tumour.

Soft Tissues 75

tumour is assessed on the basis of its size,infiltration and involvement of other structuressuch as fascia, muscle and bone, as shown in Table 5.3.

Treatment

Surgery

Surgery is the most effective treatment for softtissue sarcomas. Cures can be achieved in low gradesarcomas with aggressive surgery. The surgicalmargin should be as large as necessary to obtain acomplete excision and in most cases this willrequire a compartmental or ‘en bloc’ resection.This aims to remove the tumour in one piece withall dissection in a separate fascial plane or tissuetype to the tumour. If there is any concern that thesurgical instruments have penetrated the tumourpseudocapsule, the surgeon should change instru-ments and gloves before proceeding with the dissection in a wider tissue plane. For tumours sitedon the limb an amputation may be required forcomplete tumour removal. Careful planning is

necessary to achieve the aim of complete excision,and imaging techniques such as CT can be helpfulin this process.

The best opportunity for a surgical cure is thefirst time the tumour is removed surgically. Not onlydoes inadequate surgical resection result in localtumour recurrence, it also selects for the mostaggressive component of the tumour, i.e. those invasive cells at the periphery of the main mass.Hence locally recurrent tumours tend to be moreaggressive in terms of growth rate and invasionthan the original mass. Second surgeries shouldinclude the whole scar and the sites of any surgicaldrains, and dissection should be extremely radical.

Excisional samples should be sent for his-topathology to confirm the biopsy diagnosis and to assess the margins of the resected tumour for evidence of incomplete excision.

Radiotherapy

Sarcomas are generally considered to be resistantto radiotherapy, although with the use of mega-voltage irradiation allowing more sophisticatedfractionation schemes and treatment planning,results of radiotherapy for soft tissue sarcomashave been more encouraging. Radiotherapy is oflittle value in the management of large, bulkytumours and when used as a sole treatment willonly achieve low control rates for such tumours.Radiotherapy is best combined with cytoreductivesurgery. Post-operative radiotherapy has beenshown to increase the disease-free survival of dogswith haemangiopericytoma and other low gradesarcomas (McChesney et al. 1989). A detailed planof the tumour site pre and post operatively isneeded for treatment planning purposes, especiallyif the area to be irradiated is in a complex anatomicregion. The entire surgical field should be consid-ered contaminated and included in the radiationfield, as well as any entry or exit holes from drainsplaced at closure. Thus the tumour should beassessed pre-operatively by the radiotherapist, andthe treatment plan constructed in consultation withthe surgical team.

Chemotherapy

The role of chemotherapy in treatment of soft tissuesarcomas is poorly defined at this time but theo-retically chemotherapy would be a rational

Table 5.3 TNM classification for soft tissuesarcoma. Owen (1980).

T Primary tumourT1 Tumour <2 cm maximum diameterT2 Tumour 2–5 cm maximum diameterT3 Tumour >5 cm maximum diameterT4 Tumour invading other structures such as

fascia, muscle, bone or cartilage.

N Regional lymph nodes (RLN)N0 No histologically verified metastasisN1 Histologically verified metastasis


Stage grouping T N MIIA T1 N0 M0IB T2 N0 M0

IIIIA T3 N0 M0IIB T4 N0 M0

IIIIIIA Any T N1 M0IIIB Any T any N M1

anti-tumour activity in soft tissue sarcomas and maybe a good alternative to doxorubicin in cats (Ogilvie et al. 1993).

Other

In North America an ‘immunomodulating’ agentcalled ‘Acemannan Immunostimulant’ has beenmarketed for treatment of canine and felinefibrosarcomas in combination with surgery andradiotherapy (King et al. 1995). It is used prior tosurgery, to promote an inflammatory responsewhich causes necrosis of the tumour leading to amore resectable tumour. Controlled studies indi-cating that it is any more effective than radiationand surgery have not been performed.

Prognosis

The prognosis for soft tissue sarcoma is dependenton many factors including size, site and histologicalgrade. The main causes of treatment ‘failure’ are:

• Local recurrence of the tumour – may occur withboth high and low grade tumours as a result ofinadequate surgical resection.

• Metastasis – irrespective of management of theprimary tumour, high grade sarcomas carry a significant risk of metastases.

References

Doddy, F.D., Glickman, L.T., Glickman, N.W. & Janovitz,E.B. (1996) Feline fibrosarcomas at vaccination sitesand non-vaccination sites. Journal of ComparativePathology, (114), 165–74.

Hammer, A.S., Couto, C.G., Filppi, J. et al. (1991) Efficacyand toxicity of VAC chemotherapy (vincristine, dox-orubicin and cyclophosphamide) in dogs with haeman-giosarcoma. Journal of Veterinary Internal Medicine,(5), 160–66.

Hendrick, M.J. & Brooks, J.J. (1994) Post vaccinal sarco-mas in the cat: histology and immunohistochemistry.Veterinary Pathology, (31), 126–9.

Kass, P.H., Barnes, W.G., Spangler, W.L., Chomel, B.B. &Culbertson, M.R. (1993) Epidemiologic evidence for acausual relation between vaccination and fibrosarcomatumorigenesis in cats. Journal of the American Veteri-nary Medical Association, (203), 396–405.

King, G.K., Yates, K.M., Greenlee, P.G., Pierce, K.R.,Fors, C.R., McAnalley, B.H. & Tizard I.R. (1995) The effect of Acemannan Immunostimulant in combination with surgery and radiation therapy


choice for high grade and multifocal tumours. Therehave been reports of response rates of 20% orgreater to doxorubicin as a single agent or in com-bination with vincristine and/or cyclophosphamide(VAC protocol). Mitoxantrone, vincristine, dacar-bazine (DTIC) and carboplatin have also been used with varying degrees of success but the role of chemotherapy in the treatment of measur-able soft tissue tumours is, at best, palliative.

Chemotherapy may be of greater value in thepost-surgical management of high grade sarcoma,such as haemangiosarcoma, where the actions ofdrugs are directed against microscopic disease resid-ual at the tumour site or elsewhere in the body in theform of micrometastases. For example doxorubicinmay be used as a single agent, with cyclophos-phamide (AC) or in the VAC protocol (see Table 5.4) following splenectomy for removal of splenichaemangiosarcoma, to increase post-operative sur-vival time (Hammer et al. 1991). It is possible thatsimilar benefit may be achieved through the use ofthese agents in other high grade sarcomas followingaggressive surgical management of the primarytumour by amputation, chest wall resection etc, butthis has yet to be established in controlled clinicaltrials. Mitoxantrone has also been shown to have

Table 5.4 Chemotherapy protocols used in thetreatment of haemangiosarcoma and other highgrade sarcomas in dogs.

Protocol Agents

Doxorubicin Doxorubicin* 30 mg/m2 IV every three (single agent) weeks (maximum recommended

cumulative dose of doxorubicin= 240 mg/m2)

AC** Doxorubicin* 30 mg/m2 IV day 1Cyclophosphamide 100–150 mg/m2 IV

day 1 or 50 mg/m2 PO days 3,4,5,6Repeat at 21 day cycles

VAC** Doxorubicin* 30 mg/m2 IV day 1Cyclophosphamide 100–150 mg/m2 IV

day 1Vincristine 0.7 IV days 8 and 15Repeat at 21 day cycles

* Recommended dose for doxorubicin in cats is 20mg/m2.** The combination of doxorubicin and cyclophos-phamide is very myelosuppressive and prophylacticantibiotics may be required in these protocols.

Soft Tissues 77

on spontaneous canine and feline fibrosarcomas.Journal of the American Animal Hospital Association,(31), 439–47.

Lester, S., Clemett, T. & Burt, A. (1996) Vaccine site-associated sarcomas in cats: clinical experience and alaboratory review (1982–1993). Journal of the AmericanAnimal Hospital Association, (32), 91–5.

Ogilvie, G.K., Moore, A.J., Obradovich, J.E. et al. (1993)Toxicoses and efficacy associated with the administra-tion of mitoxantrone to cats with malignant tumours.Journal of the American Veterinary Medical Associa-tion, (2023), 1839–44.

Owen, L.N. (1980) TNM Classification of tumours in

domestic Animals. World Health Organisation,Geneva.

McChesney, S., Withrow, S.J., Gillette, E.W., Powers, B.E.& Dewhirst, M.W. (1989) Radiotherapy of soft tissuesarcomas in dogs. Journal of the American VeterinaryMedical Association, (194), 60–63.

Morris, J.S., Bostock, D.E., McInnes, E.F., Hoather, T.M.& Dobson, J.M. (2000) A histopathological survey ofneoplasms in flat-coated retrievers 1990–1998. Veteri-nary Record, (147), 291–95.

White, R.A.S., Jefferies, A.R. & Gorman, N.T. (1986) Sar-coma development following irradiation of acanthoma-tous epulis in two dogs. Veterinary Record, (118), 668.

6Skeletal System

nant tumours which metastasise to bone. Multiplemyeloma and other lymphoid tumours may alsoaffect bone and cause painful, osteolytic lesions (seeChapter 15). Tumours of bone and cartilage mayaffect both the appendicular and axial skeleton;those affecting the skull are given more detailedconsideration in Chapter 7, Head and neck.

For the purposes of this book, the ‘skeletal system’ isdefined as comprising bone, cartilage and joints.Tumours affecting muscle are included in Chapter 5,Soft tissues. A variety of tumours may affect theskeletal system. These may be primary tumoursarising from elements of bone or cartilage, softtissue tumours which invade into bone, or malig-

� Bone and cartilage, 78� Joints and associated structures, 89

78

BONE AND CARTILAGE

Epidemiology

Tumours of bone and cartilage are relatively un-common in the dog and cat population as a whole,representing less than 5% of all tumours. Bonetumours in the dog and cat are usually malignant;benign tumours are rare in both species. In the dog,bone tumours of the appendicular skeleton occurwith increasing frequency with increasing size/bodyweight and predominantly affect large–giant breeds.So great is this size relationship that primary bonetumours are rare in dogs less than 15kg,yet commonin breeds such as the Irish wolfhound, great Dane,rottweiler and St Bernard. Bone tumours tend toaffect middle-aged to old animals, although theymay occur in young dogs of giant breeds. It has beensuggested that males are predisposed.

Primary bone tumours are uncommon in cats.They tend to affect older cats (mean age 10 years)and there is no sex or breed predispositionreported.Tumours of the appendicular skeleton are

more common than those of the axial skeleton andare most frequent in the pelvic limb.

Tumours of cartilage are rare in both species;benign and malignant variants have been described.

Aetiology

The aetiology of most tumours of bone and cartilage is not known. However, the pattern ofdevelopment of primary malignant bone tumours(osteosarcoma) suggests some contributory factorswhich may play a role in their development.Primary bone tumours have a predilection for themetaphyseal regions of long bones especially thedistal radius, proximal humerus, distal femur and proximal tibia and are more frequent in theforelimb than the hind limb. The increased frequency in the forelimb and increased frequencywith size, seems to correlate with weight bearing.Rapid bone growth during early development and bone stress due to weight bearing, possibly

Skeletal System 79

second most common. Bone may also be affectedby lymphoproliferative conditions (notably multi-ple myeloma), may be invaded by soft tissuetumours and may be the site of metastasis for othermalignant tumours. Tumours which may affect thebone are summarised in Table 6.1.

Benign

Benign tumours of bone (osteoma) and cartilage(chondroma) are rare in cats and dogs and are oflittle clinical importance. Several benign conditionswhich affect the skeleton of cats and dogs areworthy of note, although uncommon.

Osteochondroma/multiple cartilagenous exostosesOsteochondroma is a benign ‘tumour’ formed byendochondral ossification from the surface of abone, and is capped with hyaline cartilage. These‘growths’ result from developmental disturbancesin the growing animal, and they cease to enlarge atskeletal maturity. They may form in any bone ofendochondral origin; the scapulae, ribs, vertebraeand pelvis are the most common sites. Thesetumours may be monostotic lesions which are oflittle clinical consequence, except that they may behereditary in the dog. They are usually incidental

resulting in microfractures, are implicated as impor-tant factors. There may also be a genetic predis-postion in the large and giant breed dogs and afamilial incidence has been reported in rottweilersand St Bernards. Tumours may occasionallydevelop at the sites of old fractures (especiallythose with a history of delayed healing) and in bonethat has been included in treatment fields duringradiotherapy.

Pathology

Primary tumours of bone may arise from any tissuewithin the bone ‘organ’ and may develop at any site, i.e. periosteum, endosteum or the medullarycavity. The most common tumours arise in the mes-enchymal precursors of osseus and cartilagenoustissues, giving rise to osteosarcoma and chon-drosarcoma respectively. Osteosarcoma is the mostcommon primary bone tumour in the dog andaccounts for 80–90% of bone tumours in large dogsand 50% of bone tumours in small dogs. Tumoursof fibrous connective tissue (fibrosarcoma) and vascular tissue (haemangiosarcoma) are lesscommon. Osteosarcoma is the most commonprimary bone tumour of cats; fibrosarcoma is the

Table 6.1 Classification of tumours affecting the skeleton of the dog and cat.

Primary tumours of boneBenign MalignantOsteoma Osteosarcoma*Chondroma (rare) Parosteal osteosarcomaEnchondroma ChondrosarcomaMonostotic osteochondroma (dog) Fibrosarcoma

HaemangiosarcomaPolyostotic osteochondroma (multiple Liposarcoma

cartilagenous exostoses) (dog) Anaplastic sarcomaOsteochondromatosis (cats) Giant cell tumour (of bone)

Other primary tumours Multiple myeloma(Lymphoma)

Tumours which invade bone Soft tissue sarcomasSquamous cell carcinoma (digit, jaw)Malignant melanoma digit

Tumours which metastasise to bone Carcinomas, mammary, prostatic(pulmonary carcinoma in cat – digit)

* various histological subtypes, see text.

Malignant

Primary bone tumoursMalignant tumours arising within bone are listed inTable 6.1. In addition to osseus and cartilagenouselements, which give rise to the majority of tumoursoccurring at this site, bone also contains fibrous,vascular and other mesenchymal elements, all ofwhich may undergo neoplastic transformation andgive rise to sarcomas within the bone, e.g. fibro-sarcoma, haemangiosarcoma. Osteosarcoma is themost common primary sarcoma of bone andaccounts for 80–90% of tumours at this site. Chon-drosarcoma is the second most common primarybone tumour in dogs, accounting for approximately5–10% of all canine primary bone tumours; theother sarcomas account for the remaining primarybone tumours.

Osteosarcoma may vary considerably in the his-tological pattern and the amount and type of matrixproduced. Tumours may be classified as poorly dif-ferentiated, osteoblastic, chondroblastic, fibroblas-tic, telangiectatic, giant cell type or combined type,on the basis of the predominant histological features within the lesion. In contrast to humanosteosarcoma, the clinical relevance of histologicalclassification of canine osteosarcoma has not beenestablished. Of more relevance is the site of devel-opment of the tumour. Osteosarcoma of central ormedullary origin (Fig. 6.1) exhibits more aggressiveand malignant behaviour than parosteal (or juxta-cortical) osteosarcoma, which grows outward fromthe periosteal side of the cortex and causes minimalcortical lysis (Fig. 6.2). However, also recognised isa high grade periosteal osteosarcoma which ariseson the outside surface of a bone but has the inva-sive and malignant character of the intraosseusosteosarcoma.

Giant cell tumour of boneThis is a rare tumour affecting bone, whose histio-genesis is uncertain. Tumours appear to arise fromstromal cells of the bone marrow and produceexpansile, osteolytic lesions.

Metastatic and other tumours involving boneBone may be a site for secondary, metastatictumour development, and carcinomas, in particularmammary, prostatic and pancreatic carcinoma,


findings on radiographic examination. Polyostoticlesions (also referred to as osteochondromatosis or multiple cartilagenous exostosis) have, on rareoccasions, been reported to undergo malignanttransformation in the dog.

Osteochondromatosis in cats is a different entityin that the lesions show progressive enlargementwith time, and have a random distribution, includ-ing bones of the skull (formed by intramembranousossification). The condition is usually diagnosed inyoung adult cats (2–4 years). There is no evidenceof breed or sex predilection, nor is there any hered-itary pattern, but viral particles have been foundconsistently in the cartilage caps of the lesions. Thesignificance of the virus in the pathogenesis of thecondition is not known.

EnchondromaEnchondroma is a benign cartilagenous tumourwhich originates within the medullary cavity of abone. Histologically the tumour resembles hyalinecartilage and is thus distinct from chondrosarcoma.The expansile growth of the tumour within thebone eventually erodes the cortex and results in awell-defined, firm palpable mass. The growth of thetumour can be associated with pain and in somecases can precipitate a pathological fracture.Lesions may be monostotic or polyostotic; the lattermay be termed enchondromatosis. The condition isdistinct from osteochondromatosis in that thelesions originate within the bone as opposed to onthe surface.

Multilobular osteoma/chondroma/osteochondrosarcoma, ‘chondroma rodens’This is an uncommon tumour which classicallyarises in the bones of the skull and has a charac-teristic radiographic appearance (see Chapter 7). Ithas been given many names (as above) but is now regarded as a low grade malignancy, becausealthough the rate of growth is often quite slow,metastasis can occur.

Other benign tumours – like lesions includingbone cysts, aneurysmal bone ‘cysts’ and fibrous dysplasia of bone – are occasionally encounteredbut because of their rarity have not been well characterised in veterinary medicine and theirbehaviour is not well documented.

Skeletal System 81

Tumour behaviour

Osteosarcoma is a rapidly growing, invasive anddestructive tumour. Its presence within the bonecauses pain, and the destruction of normal struc-tural bone leads to weakening of the bone, predis-posing to pathological fracture (Fig. 6.6). Thetumour tends to spread along the medullary cavityand may invade through the periosteum and deepfascia to involve adjacent soft tissues, although theyrarely invade or cross joints (Fig. 6.7).

Osteosarcoma (of long bones) in the dog is ahighly malignant tumour which metastasises earlyin the course of the disease. In most cases micro-scopic metastatic disease is present at the time ofpresentation or diagnosis of the primary lesion.Metastasis is haematogenous and the lungs are themost common site for the development of sec-ondary tumours. Other sites of distant metastases

show a tendency to metastasise to bone where theygive rise to painful, osteolytic lesions (Fig. 6.3).Several reports have described a primary lung adenocarcinoma in the cat with a metastaticpredilection for the digits (Scott-Moncrieff et al.1989). Multiple myeloma and, on occasion, lym-phoma may also give rise to osteolytic bone lesions (Fig. 6.4) (see Chapter 15).

Locally invasive soft tissue tumours may invadeinto adjacent bone. Squamous cell carcinoma ofgingiva is often associated with marked destructionof the adjacent maxillary or mandibular bone, espe-cially in the cat (Fig. 6.5) (see Chapter 7) and thatarising in the digit can lead to total destruction of the phalanx (Chapter 4, Fig. 4.9). Soft tissuetumours arising in the periarticular tissues alsoshow a tendency to local bone involvement (seelater in this chapter under tumours of joints).

Fig. 6.1 Typical radiographic appearance of medullaryosetosarcoma (of the distal radius).

Fig. 6.2 Parosteal osteosarcoma. The tumour isgrowing out from the cortex of the bone with very littleinvasion of normal bone.

Chondrosarcoma and fibrosarcoma are generallyslower growing tumours in both species with alower incidence of metastasis. Giant cell tumour ofbone may follow a benign or malignant course.


No specific paraneoplastic syndromes are asso-ciated with osteosarcoma or other primary bonetumours. Hypercalcaemia is rarely associated withprimary bone tumours although it may occur withextensive skeletal metastases from soft tissue


include kidney, liver, spleen and the skeleton itself.Osteosarcoma of the axial skeleton, for example

the skull, is usually less aggressive in terms of localgrowth rate and in terms of the incidence and therate of metastasis.

Osteosarcoma in cats also behaves less aggres-sively with an estimated metastatic rate less than20%.

Fig. 6.3 Skeletal metastasis affecting the proximalradius in a cat with a primary lung carcinoma. The cathad similar lesion in other limbs.

Fig. 6.4 Multiple ‘punched-out’ osteolytic lesions inthe dorsal spinous processes of the lumbar vertebraein a dog with multiple myeloma.

Fig. 6.5 Squamous cell carcinoma of the mandible ina cat; there is a massive bony reaction to the invadingtumour.

Skeletal System 83

tumours and in association with multiple myelomaand lymphoma. Primary tumours of the axial sketeton may give rise to local site-specific com-plications, as detailed below.

Presentation/signs

Long bone osteosarcoma

Affected animals usually present with lameness(gradual or acute onset) with or without painfulswelling of the affected area of the limb. The lame-ness is usually progressive but can become acute ifassociated with a pathological fracture.

The tumour has a predilection for the metaphy-seal regions of long bones especially:

• Proximal humerus• Distal radius• Distal femur• Proximal tibia.

Axial osteosarcoma

The presenting signs of tumours sited in the axialskeleton are site specific. An enlarging mass with or without pain may be the only clinical sign oftumours affecting the skull but in other cases thetumour mass may not be obvious on physical examination and the animal will present with signsrelating to the physical presence of the tumour orcollapse of the affected bone. For example:

• Oral, mandibular, maxillary and orbital tumoursmay present with dysphagia, pain on opening themouth or exophthalmos (Chapter 7)

• Nasal sinus tumours may present with nasal discharge and epistaxis (Chapter 7)

• Tumours affecting the spine may present withneurological signs (Chapter 13).

Investigations

Bloods

Routine haematological/biochemical analyses arenot generally very helpful in the diagnosis ofprimary bone tumours. Total serum alkaline phos-phatase and bone-specific alkaline phosphatase are elevated in dogs with primary osteosarcoma,but whilst this may be of prognostic significance

Fig. 6.6 Extreme destruction of the distal radius by an aggressive osteosarcoma has led to collapse of theradius and pathological fracture of the ulna.

Fig. 6.7 Gross appearance of an osteosarcoma of the proximal tibia. The sectioned limb shows how thetumour has invaded through the cortex and into thesurrounding soft tissues, but has not crossed into the joint. (Picture courtesy of Mr D. Bostock.)

• Osteolysis – destruction of both medullary andcortical bone; this may be focal or disseminated.

• Irregular, haphazard new bone formation, oftenspiculated and at right angles to the originalcortex (‘sun-burst’ appearance), sclerosis ofmedullary areas, and periosteal new bone at theperiphery of the lesion – ‘Codman’s triangle’.

• Soft tissue swelling with or without calcification.


(Ehrhart et al. 1998), it is not really a useful diag-nostic test.

Imaging techniques

Radiography is valuable in the diagnosis of primarybone tumours. Radiography of the affected area(Figs 6.8 and 6.9) will show a variable mixture of:

Figs 6.8 and 6.9 Radiographic appearance of osteosarcoma. Fig. 6.8 A tumour of the distal femur, showing typicalfeatures of Codman’s triangle and ‘sunburst’ periosteal new bone. Fig. 6.9 A tumour of the distal radius is moreosteolytic in nature.

6.86.9

Skeletal System 85

The combination of these changes, along with the presenting history and clinical signs, will lead to a high index of suspicion of a diagnosis of osteosarcoma; however ‘osteosarcoma’ is a his-tological diagnosis. The radiographic diagnosisshould be described as a ‘primary malignant bone tumour’.

Radiography of the thorax is important in clinical staging. Ultrasound, CT and MRI are of little to no value in the diagnosis of primarytumours of the appendicular skeleton, although CTor MRI may be useful for those tumours involvingthe axial sketeton. Scintigraphy may be useful inclinical staging to detect the presence of skeletalmetastases.

Biopsy/FNA

Fine needle aspirate cytology is of limited value inthe diagnosis of primary bone tumours, not leastbecause of the hard, calcified nature of the tissues.FNA of local lymph nodes should be performed ifthey are enlarged but local lymphatic metastasis isunusual.

A biopsy of the lesion is required to reach a histological diagnosis but this can be problematicfor a number of reasons:

• The hard/bony nature of the lesion limits choiceof biopsy techniques and the need for decalci-fication of the tissue prior to sectioning for histological examination introduces a delay inobtaining the results.

• These are aggressive tumours and often containareas of haemorrhage and necrosis; furthermorebone tumours induce a response from normalbone cells.Thus selection of the site for collectionof representative tissue can be a problem.

• It usually requires general anaesthesia of thepatient.

• There is a risk of precipitating a pathologicalfracture.

A Jamshidi core biopsy technique is probably thebest method for biopsy of primary bone tumours(Fig. 6.10), although open biopsy techniques may also be used. Two or three needle samplesshould be taken from different angles or at different sites to ensure collection of representativetissue.

Staging

The extent of the primary tumour can be assessedby radiography. Right and left lateral inflated thoracic radiographs are essential to assess thelungs for the presence of metastases but will notdetect microscopic disease. Scintigraphy (‘bonescan’) may be used to look for skeletal metastases.

Primary malignant bone tumours may be stagedclinically according to the World Health Organi-zation TNM Classification (Table 6.2); tumoursarising at other sites, e.g. oral cavity, could be stagedaccording to the relevant system.

Treatment

The major dilemma following diagnosis of appen-dicular osteosarcoma in a dog is whether to treat or

Fig. 6.10 Jamshidi biopsy needle.

amputation survival times are short, on averagethree to four months.

Limb salvage

In carefully selected cases it may be possible tosalvage the limb by local surgical resection of theaffected segment of bone and replacement by a cortical allograft supported by a plate (LaRue et al. 1989) (Figs 6.11 and 6.12). Limb salvage is not possible in all cases of osteosarcoma. The procedure is restricted to animals with relatively small, early tumours which are contained within the deep periosteal fascia and have not invaded the soft tissues of the limb. The distal radius is the most favourable site to attempt limb salvagebecause it is relatively simple to arthrodese thecarpus compared to other joints. Limb salvage isnot without complications:

• The dog has to be severely restricted for severalmonths after surgery while the leg is maintainedin a cast (this may represent a substantial portionof its remaining life).

• Surgical complications are frequent, rangingfrom loosening of the screws which hold the plateand graft in place to osteomyelitis and failure ofthe graft. Further surgical and or medial inter-vention is inevitable.

• Local tumour recurrence occurs in a significantnumber of cases.

• Limb salvage does not affect the progression ofmetastatic disease which is the ultimate cause ofdeath in these patients.

Radiotherapy

Radiotherapy may be of short term value as a pal-liative for pain relief in a small proportion of casesbut should not be viewed as an effective means oftreatment of the tumour. Pre or post-operativeradiotherapy may be used in conjunction with limbsparing surgery to improve local tumour control incases where only marginal resection of the primarytumour is possible.

Chemotherapy

Systemic chemotherapy usually has little effect onthe growth of the primary tumour, although it has


not. The options for treatment, as set out below,are limited and in the majority of cases do not alter the fatal outcome of the disease. Dogs withosteosarcoma are lame because they are in pain. Ifthis pain cannot be relieved through treatment ofthe primary tumour then euthanasia should becarried out on humane grounds. Non-steroidal anti-inflammatory agents can be used for shortterm relief of pain to allow the owners time to cometo terms with the imminent loss of their pet.

Bone tumours at other sites of the body which are amenable to surgical management may carry a more favourable prognosis as thesetumours are usually less aggressive and slower tometastasise.

Surgery

Surgery is the most effective means of treatment forthe primary tumour but the locally invasive natureof bone tumours means that removal of the tumourrequires a wide margin of excision within andincluding the bone. This may be feasible for sometumours of the skull or axial skeleton, for exampleremoval of a hemi-mandible may achieve a com-partmental resection of a tumour sited within thisbone. For most appendicular tumours a wide surgi-cal margin requires amputation of the affectedlimb. Forequarter or hindlimb amputation is actu-ally quite well tolerated in animals up to 45–50kgand in some cases in dogs much larger than this(Kirpensteijn et al. 1999). Amputation is probablythe treatment of choice for pain relief and for effective removal of the primary tumour, but post-

Table 6.2 World Health Organization TNM classi-fication of canine/feline tumours of the bone (Owen1980).

T Primary tumourT0 No evidence of tumourT1 Tumour confined within the medulla and

cortexT2 Tumour extends beyond the periosteumMultiple tumours should be classified

independently



Skeletal System 87

been used on occasion in a neo-adjuvant setting totemporarily arrest tumour growth prior to surgicalresection/limb salvage. Intralesional or regional(limb perfusion/intra-arterial) adminstration ofcytotoxic drugs has met with little success.

Chemotherapy is indicated as an adjuvant to surgical management of the primary disease in anattempt to prevent or at least delay the onset ofmetastatic disease (Table 6.3). The most commonlyused agent for the treatment of micrometastaticdisease in canine osteosarcoma is cisplatin. (Thisagent should never be used in cats. There is no indi-cation for its use in osteosarcoma in this species and

the drug is highly toxic to cats). Cisplatin is nephro-toxic in the dog and has to be administered withfluids to protect against renal damage. A variety ofprotocols have been described for the administra-tion of cisplatin (Table 6.4). Carboplatin has alsobeen used at a dose rate of 300mg/m2 every 21 daysfor four cycles (Bergman et al. 1996) and althoughcarboplatin is more expensive than cisplatin, it isless nephrotoxic and can be administered withoutdiuresis.

There is no evidence that adjuvant chemo-therapy is of any benefit in preventing metastaseswith chondrosarcoma or other bone sarcomas.

Figs 6.11 and 6.12 Limb salvage. Fig. 6.11 shows a localised osteosarcoma of the distal radius with virtually nosoft tissue involvement. It was possible to surgically remove the affected area of bone, with the tumour containedwithin the deep fascia. Fig. 6.12 shows replacement of the diseased bone with an allograft, held in place by alarge compression plate.

6.11

6.12

Prognosis

The prognosis for appendicular osteosarcoma indogs is universally poor. In 90% of casesmicrometastatic disease is present at the time ofpresentation/diagnosis of the primary tumour andirrespective of method of treatment almost allpatients are eventually euthanased as a result ofmetastatic disease and/or local tumour recurrence.The prognosis for cats with osteosarcoma is more favourable as such tumours in this speciesappear to be less aggressive and carry a far lower risk of metastasis. Osteosarcoma of the


Other

Non-specific immunotherapy with liposome-encapsulated muramyl tripeptide has been used post-amputation for treatment of dogs withosteosarcoma and has been shown to extend survival times compared with dogs receiving amputation only (MacEwen et al. 1989). MTP-PEmay also be used in conjunction with cisplatinchemotherapy to extend post-amputation timesfurther. Unfortunately this is an investigationalproduct and is not available routinely in the UK.

Table 6.3 Post-amputation survival times for dogs with appendicular osteosarcoma with adjuvant chemotherapy.

Protocol Median survival (days) One year survival rate (%) Reference

Cisplatin60 mg/m2 q 21 days ¥ 1–6 300–325 45.5 Berg et al. 1992Carboplatin300 mg/m2 q 21 days ¥ 4 321 35.4 Bergman et al. 1996Doxorubicin30 mg/m2 q 14 days ¥ 5 278 50 Berg et al. 1995

Table 6.4 Protocols for administration of cisplatin (See also Appendix IV).

Cisplatin dose: 50–70 mg/m2 every 3–4 weeks, usually for 4–6 treatments

Six hour infusion with saline diuresisPrehydration – intravenous saline (0.9%) at rate of 25 ml/kg/hour for 3 hoursAntiemetic – metoclopramide 1 mg/kg prior to administration of cisplatinCisplatin 50–70 mg/m2 – given as a slow intravenous infusion over 15 minutesDiuresis – intravenous saline (0.9%) continued at 15 ml/kg/hour for 3 hoursFrusemide – may be administered if urine production is not adequate

Infusion with mannitol diuresisPrehydration – intravenous saline (0.9%) at rate of 10 ml/kg/hr for 4 hours0.5 g/kg mannitol iv in saline over 20–30 minutesAntiemetic – metoclopramide 1 mg/kg prior to administration of cisplatinCisplatin 50–70 mg/m2 – given as slow intraveous infusion over 15 minutesContinue saline infusion (0.9%) at 10 ml/kg/hr for 2 hours.

Handling precautionsCisplatin should be regarded as a very hazardous substance and handled accordingly. Ideally the drug should be

prepared in a flow cabinet. Face masks, protective clothing and gloves should be worn by any person handling theagent or the patient. Following administration, cisplatin is excreted, unchanged, in the urine and this presents apotential hazard. All contaminated equipment and bedding should be incinerated. Cisplatin should not be handledby pregnant staff.

Skeletal System 89

axial skeleton in both the cat and dog is usually lessaggressive than that of the long bones, and althoughlong-term follow-up of such cases has shown thatsome of these tumours do eventually metastasise,if effective treatment of the primary tumour is possible, post-operative survival times can exceed12 months.

Haemangiosarcoma of bone is also highly malig-

nant but the prognosis for other tumours arising inbone is generally more favourable. Chondrosar-coma is slow to metastasise and at some sites,e.g. rib, an en bloc resection may result in cure orat least prolonged survival (Pirkey-Ehrhart et al.1995). Complete surgical resection may also becurative for fibrosarcoma, although metastaseshave been reported in some cases.

JOINTS AND ASSOCIATED STRUCTURES

Epidemiology

Tumours affecting the joints and the adjacenttendon sheaths, bursae and fascia are rare in boththe cat and the dog. Most of the lesions describedin small animals at this site are malignant andtumours of the canine joints are the most commonof this rare group. Large (but not giant) breed dogsappear to be predisposed, and the average age atpresentation is eight years with a range of 1–12years (Madewell & Pool 1978).

Aetiology

The aetiology of tumours of joints and associatedstructures is not determined. Metabolic and inflammatory lesions may occur in the synoviae,which have to be distinguished from synovialtumours.

Pathology

The most commonly reported primary joint tumour in the dog is the synovial sarcoma, a malignant tumour that is thought to arise fromundifferentiated mesenchymal cells in the deepconnective tissue associated with synovial joints,which differentiate into synovioblasts. Histo-logically this tumour is composed of two cellularelements:

• Fibroblastic component• Synovioblastic or epithelioid component.

The proportion of these two, intermingled com-ponents varies considerably both within andbetween tumours. A variety of other soft tissue sarcomas may arise in the periarticular soft

tissues (Table 6.5) and these can be difficult to distinguish clinically or radiologically from truesynovial sarcoma. As with all soft tissue sarcomasthat lack clear differentiation, histological classi-fication can be problematic and is open to individ-ual interpretation. In humans the classification ofsoft tissue tumours affecting joints or tendons iscomplex and detailed but the relevance of suchclassification systems in veterinary medicine is notestablished. In practice all these tumours sharecommon clinical features and prediction of theirlikely behaviour may be better made according tothe grade of the tumour rather than histologicaltype (see also Chapter 5).

Synovial ‘cysts’ have been reported in both catsand dogs and a number of proliferative conditionsof the synovium may also present with nodular orhyperplastic tumour-like lesions. None of theseconditions show bony involvement.

Tumour behaviour

Synovial sarcomas are locally aggressive tumourswhich invade into the subchondral bone at the articular margins, causing osteolysis of the periar-ticular bone and destruction of the joint. They tendnot to affect articular cartilage directly. The rate oflocal progression of the tumour is variable and theclinical course of the disease can vary from acute to protracted over several months, on occasionexceeding one year. The reported metastatic ratefor canine synovial sarcoma varies from 25–40%(Madewell & Pool 1978; Vail et al. 1994), and thepattern of metastasis is to regional lymph nodes,lungs and other organs. However, many animals areeuthanased as a result of the primary tumour andthere are few reports of long-term follow-up intreated animals.

Imaging techniques

Radiography of the affected joint (Fig. 6.14) willgenerally show:

• A quite well-defined periarticular soft tissueswelling

• Permeative or punctate osteolysis of the meta-physes and epiphyses adjacent to the joint

• Multiple bone involvement• Irregular, spiculated periosteal new bone is a

feature in some cases.

These radiological findings of periarticular softtissue swelling and osteodestruction on both sidesof a joint in an older, large breed dog are highlysuggestive of synovial sarcoma but other soft tissue tumours may present in a similar manner (see Table 6.5) and these cannot be distinguishedwithout histopathological examination.

Ultrasonography is not useful in most cases.CT/MR imaging of synovial tumours has become

standard in human clinical practice and is useful indetermining the anatomic extent of the tumour andits relationship with the joint space and other struc-tures such as tendon sheaths or bursae.



No specific paraneoplastic syndromes are associ-ated with synovial sarcoma, or other periarticularsarcomas.

Presentation/signs

Most affected animals present with a progres-sive lameness of the affected limb with a mild to pronounced peri-articular soft tissue swelling (Fig. 6.13). The stifle is the joint most fre-quently affected, followed by the elbow and thehock.

Investigations

Bloods

Routine haematological/biochemical analyses arenot generally very helpful in the diagnosis oftumours of the joints.

Table 6.5 Tumours affecting joints (Whitelock et al. 1997).

Tumour type Number Joint affected Number

Synovial cell sarcoma 8 Stifle 3Hock 2Elbow 2Shoulder 1

Fibrosarcoma 5 Stifle 2Elbow 2Temporo-mandibular joint 1

Osteosarcoma 3 Elbow 3Rhabdomyosarcoma 3 Stifle 1

Elbow 1Shoulder 1

Undifferentiated sarcoma 2 Stifle 1Elbow 1

Liposarcoma 2 Stifle 1Elbow 1

Malignant fibrous histiocytoma 1 Elbow 1Haemangiosarcoma 1 Shoulder 1Haemangiopericytoma 1 Carpus 1Mast cell tumour 1 Stifle 1Squamous cell carcinoma 1 Metacarpophalangeal and

interphalangeal joints 1Amelanotic melanoma 1 Metacarpophalangeal joint 1

Skeletal System 91

Radiography of the thorax would be required for clinical staging, although most cases do not have demonstrable metastases at the time of firstpresentation.

Biopsy/FNA

As with all soft tissue sarcomas, fine needle aspiratecytology is of limited value in the diagnosis of syn-ovial tumours, although an aspirate could help todistinguish between neoplastic and non-neoplasticcauses of periarticular swelling. FNA of local lymphnodes should be performed if they are enlarged butlocal lymphatic metastasis is unusual.

A biopsy of the lesion is required to reach a histological diagnosis, and an incisional biopsy is probably the preferred technique. Needle or

punch biopsies may be appropriate in certaintumours.

Staging

Clinical, surgical and radiographic examination arerequired for clinical staging of tumours of the jointsand associated structures and the TNM system isoutlined in Table 6.6.

Treatment

Surgery

Surgical resection is the treatment of choice for synovial sarcoma and other sarcomas involving thejoints; however, because of the close proximity ofthese tumours to the joint and the invasion of bone,

Fig. 6.13 Peri-articular swelling due to a synovialsarcoma of the hock.

Fig. 6.14 Radiographic appearance of a synovialsarcoma of the stifle, showing osteolytic lesions oneither side of the joint.

Prognosis

Despite the fact that between a quarter to a thirdof these tumours may metastasise, most dogstreated by amputation have disease-free survivaltimes in excess of three years (Vail et al. 1994). Theprognosis with amputation is therefore quite good.

References

Berg, J.,Weinstein, J., Schelling, S.H. & Rand,W.M. (1992)Treatment of dogs with osteosarcoma by adminis-tration of cisplatin after amputation of limb sparing surgery: 22 cases (1987–1990). Journal of theAmerican Veterinary Medical Association, (200),2005–2008.

Berg, J., Weinstein, J., Springfield, D.S. & Rand, W.M.(1995) Results of surgery and doxorubicin chemo-therapy in dogs with osteosarcoma. Journal of the American Veterinary Medical Association, (206),1555–9.

Bergman, P.J., MacEwen, E.G., Kurzman, I.D. et al.(1996) Amputation and carboplatin for treatment of dogs with osteosarcoma: 48 cases (1991–1993). Journal of Veterinary Internal Medicine, 10 (2),76–81.

Ehrhart, N., Dernell, W.S., Hoffmann, W.E., Weigel, R.M.,Powers, B.E. & Withrow, S.J. (1998) Prognostic importance of alkaline phosphatase activity in serumfrom dogs with appendicular osteosarcoma: 75 cases(1990–1996). Journal of the American VeterinaryMedical Association, (213), 1002–1006.

Kirpensteijn, J., Van den Bos, R. & Endenburg, N. (1999)Adaption of dogs to the amputation of a limb and their


surgical resection usually requires an amputation ofthe affected limb.

Radiotherapy

Radiotherapy may be of short term value as a pal-liative for pain relief in a small proportion of casesbut there is no clinical evidence to support the useof radiotherapy as an effective treatment for syn-ovial sarcoma. It is not usually possible to use radio-therapy in an adjuvant, post-operative setting forsuch tumours as the only surgical approach is anamputation.

Chemotherapy

Chemotherapy is unlikely to be of benefit in treatment of the primary tumour, although the use of doxorubicin alone or in combination with cyclophosphamide (see Table 5.4) has beenreported to delay the progression of the disease incases where amputation is not deemed acceptable(Tilmant et al. 1986). Larger scale studies arerequired to validate this observation.

As with other soft tissue sarcomas, theoreticallychemotherapy would be indicated as an adjuvant tosurgical management of high grade, malignanttumours in an attempt to prevent or at least delaythe onset of metastatic disease, but the role ofchemotherapy in this context has not been fullyevaluated in veterinary medicine.

Table 6.6 Clinical stages (TNM) of canine and feline tumours of jointsand associated structures (Owen 1980).

T Primary tumourT0 No evidence of tumourT1 Tumour well-defined, no invasion of surrounding tissuesT2 Tumour invading soft tissuesT3 Tumour invading joints and/or bonesMultiple tumours should be classified independently

N Regional lymph nodes (RLN)N0 No evidence of RLN involvementN1 RLN involved(-) histologically negative, (+) histologically positive



Skeletal System 93

owners’ satisfaction with the procedure. VeterinaryRecord, (144), 115–18.

Pirkey-Ehrhart, N., Withrow, S.J., Straw, R.C. et al. (1995)Primary rib tumours in 54 dogs. Journal of the American Animal Hospital Association, (31), 65–9.

LaRue, S.M., Withrow, S.J., Powers, B.E. et al. (1989) Limbsparing treatment for osteosarcoma in dogs. Journal ofthe American Veterinary Medical Association, (195),1734–44.

Madewell, B.R. & Pool, R.R. (1978) Neoplasms of jointsand related structures. Veterinary Clinics of NorthAmerica, (8), 511–21.

MacEwen, E.G., Kurzman, I., Rosenthal, R.C., Smith,B.W., Manley, P.A., Roush, J.K. & Howard, P.E. (1989)Therapy for osteosarcoma in dogs with intravenousinjection of liposome-encapsulated muramyl tripep-tide. Journal of the National Cancer Institute, (81),935–7.

Owen, L.N. (1980) TNM Classification of Tumours in

Domestic Animals. World Health Organization,Geneva.

Scott-Moncrieff, J.C., Elliott, G.S., Radovsky, A. &Blevins, W.E. (1989) Pulmonary squamous cell carci-noma with multiple digital metastases in a cat. Journalof Small Animal Practice, (30), 696–9.

Tilmant, L.L., Gorman, W.T., Ackerman, N. et al. (1986)Chemotherapy of synovial cell sarcoma in a dog.Journal of American Veterinary Medical Association,(188), 530–32.

Vail, D.M., Powers, B.E., Getzy, D.M. et al. (1994)Evaluation of prognostic factors for dogs with synovialsarcoma, 36 cases (1986–1991). Journal of the AmericanVeterinary Medical Association, 205 (9), 1300–1307.

Whitelock, R.G., Dyce, J., Houlton, J.E.F. & Jefferies,A.R.(1997) A review of 30 tumours affecting joints. Veteri-nary Comparative Orthopaedics and Traumatology,(10), 146–52.

7Head and Neck

tumours may be sited on the head or neck but theseare considered in Chapters 4 and 5 respectively.Likewise tumours of the thyroid gland are consid-ered in Chapter 14 and tumours of the eye inChapter 16.

The head and neck are important sites for devel-opment of tumours in both cats and dogs. Includedin this chapter are tumours affecting the nasalplanum, nasal cavity, oropharynx (including thetonsils and tongue) and tumours of the skull,ears and salivary glands. Skin and soft tissue

� Nasal planum, 94� Nasal cavity and paranasal sinuses, 98� Oral cavity, 104� Site specific tumours of the oropharynx, 115� Osteosarcoma of the skull, 117� Ears, 118� Salivary glands, 121

94

Epidemiology

Tumours of the nasal planum are relatively uncom-mon in the dog but common in the cat, where theyare reported to account for 17% of all skin tumours(Bostock 1986). In the cat they affect older animals,especially those with lightly pigmented skin of thenasal region.

Aetiology

Exposure of non-pigmented, lightly haired skin toUV light (especially UVB) (see Chapters 1 and 4)is an important aetiological factor in the develop-ment of tumours of the nasal planum in cats. Theaetiology of tumours of the nasal planum in dogs isnot known.

Pathology

Squamous cell carcinoma (SCC) is by far the mostcommon tumour arising at this site in cats. Depend-ing on the stage of development, the tumour maybe described as carcinoma in situ, superficial SCCor invasive SCC. Although tumours of the nasalplanum are far less common in dogs, SCC is also the most frequent tumour at this site. Mucosal mastcell tumours, plasmacytoma, basal cell carcinoma,fibrosarcoma and multifocal or diffuse tumours of the skin, e.g. epitheliotrophic lymphoma, mayalso involve the nasal planum in both species.Eosinophilic granuloma should be considered as adifferential diagnosis for an ulcerated lesion of thenasal planum/lip in the cat.

NASAL PLANUM

Head and Neck 95

Mucosal mast cell tumours occasionally affectthe nasal planum, especially in young dogs (Fig.7.5). Such tumours seem to follow a relativelybenign course.


No specific paraneoplastic syndromes are associ-ated with tumours of the nasal planum.

Presentation/signs

Affected cats usually present with an obviouscrusted, ulcerative lesion of the nasal planum asdescribed above and shown in Figs 7.1–7.3. Wherethe tumour is invasive there may be a tendency forthe lesion to bleed and local irritation can give riseto sneezing. Very extensive tumours may result inobstruction of the nares. Occasionally dogs withnasal planum SCC may present with a swollen noseor narrowed nares without an obvious externallesion.

Investigations

Bloods

Routine haematological/biochemical analyses arenot generally very helpful in the diagnosis of SCCof the nasal planum. Such investigations would be indicated in the work up of cases of cutaneouslymphoma or mast cell tumours and also in the pretreatment evaluation of older animals.

Tumour behaviour

In the cat, SCC usually follows a protracted course of development, often progressing over aperiod of many months through stages of actinickeratosis with erythematous crusting lesions tosuperficial erosions and ulcers (carcinoma insitu) (Fig. 7.1) before becoming invasive (Fig. 7.2)and destructive of underlying tissues (Fig. 7.3).Metastasis from this site is unusual in the cat.In contrast, SCC of the nasal planum in the dogtends to be a more rapidly progressing tumourwhich is invasive from the outset and may metastasise to the local and regional lymph nodes(Fig. 7.4).

Fig. 7.1 Early crusting lesion of carcinoma on cat’snose. (See also Colour plate 22, facing p. 162.)

Fig. 7.2 Minimally invasive, early SCC of nasalplanum. (See also Colour plate 23, facing p. 162.)

Fig. 7.3 Invasive SCC of nasal planum in cat. (See alsoColour plate 24, facing p. 162.)


and inflammation. A deep incisional, wedge biopsyis preferred for histological diagnosis and this willalso provide information on the degree of invasionof the tumour.

Fine needle aspirate of lymph nodes is indicatedif these are enlarged.

Staging

Staging tumours of the nasal planum requiresassessment of the degree of invasion and involve-ment of other tissues by the tumour. A modifiedstaging system is shown in Table 7.1.

Treatment

A variety of techniques have been described fortreatment of carcinoma of the nasal planum (SCC)and the choice of treatment really depends on theextent of the lesion. Early, minimally invasivetumours may be managed in a number of wayswhereas surgery is the only effective treatment fordeeply invasive tumours. Clearly it is always prefer-able to institute an effective treatment as early aspossible in the course of the disease.

Surgery

Surgery is the treatment of choice for invasivetumours which have not invaded extensively into

Fig. 7.4 Invasive and destructive SCC of nasal planumin a dog. (See also Colour plate 25, facing p. 162.)

Fig. 7.5 Mucosal mast cell tumour in a young dog.

Imaging techniques

Radiography and ultrasonography are not usuallyindicated in the investigation of nasal planumtumours in cats. Radiography of the nasal chambersmay be indicated in dogs with extensive tumoursthat may extend into the nasal cartilage and bone.

Radiography of the thorax is indicated in the dogbut is of questionable value in the cat.

Biopsy/FNA

Fine needle aspirates or cytological scrapings are oflittle value in the diagnosis of tumours of the nasalplanum; most of these lesions are ulcerated andsuperficial samples may only reveal haemorrhage

Head and Neck 97

Other

Photodynamic therapy appears to be an effectivetreatment for small, superficial (minimally invasive)tumours (Peaston et al. 1993). This technique offersthe advantage of preserving the anatomy of thenose and unlike radiation can be applied repeatedlywithout cumulative damage to normal tissues.Photodynamic therapy is not effective for invasivetumours.

Prophylaxis

In sunny climates where the risk of nasal planumSCC is high in cats with non-pigmented noses,topical application of sun blocks or protection ofthe skin by tattooing may be considered.

Prognosis

The prognosis for SCC of the nasal planumdepends on the degree of invasion of the tumour.The prognosis is good for early, non-invasivetumours in cats, although further lesions maydevelop in adjacent tissues if the underlying causeis not addressed. The prognosis is more guarded forcats with invasive SCC; however a proportion ofthese can be cured with aggressive surgery. A oneyear disease-free survival rate of 75% following‘nosectomy’ for invasive SCC was reported in onestudy (Withrow & Straw 1990). The prognosis fordogs with SCC of the nasal planum is guarded,although with aggressive surgery, disease free sur-vival rates in the order of 12 months may be possible.

the lips or skin. Complete excision of invasivetumours of the nasal planum requires removal ofthe nasal plate, transecting the nasal turbinates, toensure an adequate margin to incorporate invasivetumour within the resection. If there is invasion ofthe lips then these must be included in the resec-tion. Reconstructive techniques may be used toeffect wound closure or, in the cat, a technique hasbeen described that uses a single purse string sutureto pull the skin edges into an open circle around theairways (Withrow 1996). Functional and cosmeticresults are good in the cat. In the dog, where thetumours are often more invasive and extensive atthe time of diagnosis, surgery needs to be aggres-sive with reconstruction, and while the functionalresults are quite good, the appearance of the animalis significantly altered.

Cryosurgery can be an effective method of treatment for superficial SCC but may not be suf-ficiently penetrating for control of more invasivetumours.

Radiotherapy

Superficial (orthovoltage or Strontium) radiation iseffective for management of superficial tumours in cats but has not been very successful in the management of deeply invasive tumours in eitherspecies and the local control rates reported forthese are poor (Carlisle & Gould 1982; Thrall &Adams 1982; Lana et al. 1997). Post-operativeradiotherapy has been used in cases where histo-logical examination of excised samples has showntumour invasion at the surgical margins.

Chemotherapy

Conventional chemotherapy is not indicated in themanagement of local SCC.

Table 7.1 Modified staging system for tumours of the nasal planum.

T group Description

T1 Tumour confined to nasal planum, superficialT2 Tumour with spread on to adjacent areas, e.g. lip, superficialT3 Invasion of subcutisT4 Invasion of other structures, e.g. fascia, muscle, cartilage or bone


Table 7.2 Tumours of the nasal cavity and paranasal sinuses in the cat and dog.

Histological type Comment

Carcinoma Carcinoma is the most common tumour of the nasal cavity in bothAdenocarcinoma cat and dog, representing up to two-thirds of all canine tumours atSquamous cell carcinoma this site and over half of all feline tumours.Undifferentiated carcinoma Adenocarcinoma is the most common diagnosis in both species(including transitional cell carcinoma)

Sarcoma Intranasal sarcomas are less common than carcinomas in the dog andFibrosarcoma rare in the cat.ChondrosarcomaOsteosarcomaUndifferentiated sarcoma

Other Lymphoma is the second most common tumour at this site in the catLymphoma but an unusual diagnosis in the dog. Other tumours are rare.Transmissible venereal tumourMelanomaNeuroblastoma

NASAL CAVITY AND PARANASAL SINUSES

Epidemiology

Tumours of the nasal cavity and paranasal sinusesrepresent approximately 1% of all neoplasms in both the dog and cat (Madewell et al. 1976;MacEwen et al. 1977). They tend to affect olderanimals of both species; an average age of 10 yearsis reported in the dog. Doliocephalic dogs are athigher risk and most affected dogs are of mediumto large breeds such as the collie, Labrador andgolden retriever, German shepherd and spaniels. Aslight male predilection has been reported in thedog. Siamese cats may be at increased risk ofintranasal neoplasia (Cox et al. 1991), but no sexpredilection has been observed in the cat.

Aetiology

The aetiology of tumours of the nasal cavity andparanasal sinuses is not known. There has beenspeculation that the incidence of such tumours inlong-nosed dogs may be associated with pollutants(in urban environments) or with passive smoking,but such associations have not been proved. In cats,nasal lymphoma may be related to the felineleukaemia virus, although most cases are FeLV negative, and nasopharyngeal polyps may be asso-

ciated with otitis media or inflammation of theeustachian tube.

Pathology

The majority of tumours arising in the nasal cavityand paranasal sinuses are malignant, and varioushistological types are reported (Table 7.2).

In the dog approximately two thirds of tumoursat this site are derived from the nasal epithelium,which is for the most part glandular although squamous cell carcinoma is a relatively commondiagnosis. Most of the remainder are sarcomas,arising from cartilage, bone or other connectivetissues within the nose. Adenocarcinoma is themost common tumour of the nasal cavity in the catand lymphoma second. Intranasal sarcomas arerare in the cat.

Tumour behaviour

Malignant tumours of the nasal cavity and par-anasal sinuses are locally invasive tumours whichcause progressive destruction of both the soft andthe bony structures in and surrounding the nasalcavity. These tumours are usually slow to metasta-sise and most patients succumb to uncontrolled orrecurrent local disease rather than metastases.

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sion or aggression. The nature of the problembecomes more obvious when the tumour erodesthrough the bone to form a firm–soft swelling overthe frontal bone (Fig. 7.7).

By virtue of the connections between the nasaland frontal sinuses, tumours of the nasal cavity mayinvade into the ipsilateral frontal sinus or at leastobstruct the flow of mucous from the sinus. Con-versely tumours originating in the frontal sinus maygive rise to nasal signs, hence there is no clear cutdistinction between the two.

Investigations

Bloods

Routine haematological/biochemical analyses arenot generally very helpful in the diagnosis oftumours of the nasal cavity and paranasal sinuses;however haematology and clotting studies areimportant to exclude other causes of epistaxis(thrombocytopenia and coagulopathies) prior tonasal biopsy.

Blood should also be taken for aspergillus serol-ogy as aspergillosis is an important differentialdiagnosis.

Imaging techniques

Radiography is the most useful, widely availablemeans of evaluating the nasal chamber. The bestview for assessment of the nasal cavity andturbinate bones is the ‘dorso-ventral, intra-oral’(DVIO) view. This is taken using non-screen filmplaced within the mouth (Fig. 7.8), with the animal


No specific paraneoplastic syndromes are associ-ated with tumours of the nasal cavity and paranasalsinuses. Most of the problems associated with thesetumours are directly due to local growth and inva-sion by the primary mass as described below.

Presentation/signs

The majority of ‘nasal’ tumours in cats and dogs aresited in the nasal cavity, and in dogs, radiographi-cally most tumours seem to arise in the region of the ethmoturbinate bones. Tumours affecting the paranasal/frontal sinuses are less common.Tumours at both these sites rarely cause any exter-nally observable swelling until the later stages ofthe disease. The most common presenting signs fortumours of the nasal cavity are:

• Nasal discharge (watery/mucoid/purulent/haemorrhagic), often unilateral at first

• Epistaxis• Sneezing• Nasal congestion/upper airway obstruction –

stertor and stridor• Epiphora – due to obstruction of the naso-

lachrymal duct.

Initially these signs are often intermittent but as the condition progresses, usually over a period ofseveral months, the clinical signs become moresevere and persistent and may be accompanied bysigns of the tumour erupting out of the nasal cavityresulting in:

• Facial deformity – tumour associated swelling isoften seen in the naso-frontal regions of the skull,medial to the eyes (Fig. 7.6)

• Exophthalmos – due to tumour invasion of theorbit

• Bowing of the hard palate• Neurological signs (usually seizures) due to

direct invasion of the cranial vault.

Tumours arising in the frontal sinus may cause fewclinical signs in the early stages of growth, althoughsome are associated with occasional epistaxis.The first clinical sign may be associated with painin the region of the frontal bone and this may manifest as the animal becoming ‘head-shy’ orshowing a change in character leading to depres-

Fig. 7.6 Extensive nasal tumour causing exophthalmos.


in sternal recumbency and the X-ray beam directedventrally. The classical radiographic signs ofintranasal neoplasia are:

• Loss of the fine trabecular pattern within thenasal cavity due to destruction of the nasalturbinate bones

• Increased soft tissue/fluid density due to theexpanding tumour mass and/or accompanyinghaemorrhage and discharge (Fig. 7.9).

These changes are often easier to appreciate inearly cases with unilateral lesions, where the asym-metry of the nasal anatomy may be more obviousthan in animals with bilateral involvement.

Lateral skull radiographs are useful for evalua-tion of the frontal sinuses, although a skyline view

Fig. 7.8 Patient positioned for DVIO radiograph.(Courtesy of Mr M.E. Herrtage, Department of ClinicalVeterinary Medicine, University of Cambridge.)

Fig. 7.9 DVIO radiograph of nasal chambers of dogwith history of nasal discharge and epistaxis. The filmshows loss of fine turbinate detail and increased softtissue/fluid opacity on the right side. These changes arehighly suggestive of intranasal neoplasia.

Fig. 7.7 Frontal sinus tumour – (a) the dog presented with a painful swelling above the right eye; (b) radiographsof the skull show ‘sunburst’ reaction to tumour invading through the frontal bone.

(a) (b)

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radiography (Chapter 2, Fig. 2.8) (Thrall et al. 1989;Burk 1992). It is likely that the use of such tech-niques will increase in the future.

Rhinoscopy – the nasal cavity can be visualisedby endoscopic techniques and this may assist local-isation of lesions for biopsy.

Biopsy/FNA

The relative inaccessibility of the nasal cavity cancomplicate collection of representative tissue forhistological diagnosis of tumours at this site.Cytolological techniques, including nasal washings,are not generally very rewarding although a vigor-ous flushing technique can be used to collect solidclumps of tumour tissue for histological examina-tion. Various other means of obtaining biopsysamples have been described; probably the mostconsistently successful are:

• ‘Blind’ grab technique – crocodile action ‘grab’biopsy forceps are inserted via the nostril to thetumour site (determined radiographically); thetumour sample can be collected by graspingtissue and withdrawing the forceps.

• Catheter suction technique – a wide bore urinarycatheter, cut down to a predetermined length(long enough to access the tumour but notdamage the cribriform plate is inserted via thenares with syringe attached. Tumour tissue is col-lected by applying negative pressure when thecatheter is sited within the tumour mass, andwithdrawing. The catheter may be redirected indifferent angles throughout the tumour to obtaina good tissue sample (Withrow 1996).

All these techniques are likely to cause mild tomoderate haemorrhage and it is important that the nasopharynx is packed off to avoid the risk ofblood or tissue fragments being aspirated. In noneof these techniques is it possible to visualise thetumour at the time of biopsy and because manynasal tumours are accompanied by inflammationand sometimes necrosis, a potential problem is thecollection of non-representative tissue and failureto confirm the diagnosis of neoplasia. In this eventit is advisable to repeat the biopsy.

Diagnosis of tumours of the frontal sinusrequires surgical exploration of the mass and anincisional biopsy.

FNA cytology should be performed on anyenlarged lymph nodes.

(using a horizonal beam) provides a better com-parison of right and left (Fig. 7.10). Lateral oroblique skull radiographs may also be used to lookfor destruction of the nasal or frontal bones at sitesof facial swelling (Fig. 7.11).

Right and left radiographs of the thorax areimportant for staging purposes.

MRI and CT offer good alternatives to radi-ographic imaging of the skull for determination ofthe extent of tumours within the nasal cavity andparanasal sinuses. Cross-sectional images of theskull provided by these techniques can provide veryuseful information about the relationships of thetumour, especially in the area of the cribriformplate and orbit, which cannot be ascertained by

Fig. 7.10 Skyline radiograph of frontal sinuses of thecase in Fig. 7.9, showing opacification of right frontalsinus. This may be due to tumour involvement orobstruction of drainage from the sinus.

Fig. 7.11 Lateral skull, showing bone disruption dueto advanced intranasal tumour.


Staging

Clinical staging of tumours within the nasal cavityrequires clinical and radiographic examination.TheTNM system for canine and feline tumours of thenasal chamber and sinuses is shown in Table 7.3a.A modified staging system which may be of greaterclinical relevance has been suggested in Table 7.3b( Theon et al. 1993).

Treatment

Treatment is principally directed at achieving con-trol of local disease but the inaccessibility of thetumour and its proximity to critical organs such asthe brain and eyes restrict treatment options andcomplicate management.

Surgery

Surgical access to the nasal cavity may be gainedvia a dorsal rhinotomy through the nasal bones;however, the majority of nasal tumours in cats anddogs are not managed effectively by surgery alone.Indeed the value of surgery in the treatment of suchtumours is doubtful. On occasion surgery may beindicated for removal of benign lesions such asnasal polyps or for collection of tumour tissue incases where repeated ‘blind’ biopsies have failed toachieve a conclusive diagnosis. It may be possibleto ‘debulk’ a tumour originating in the frontal sinusat the time of surgical exploration but completeremoval of all tumour tissue is unlikely to beachieved at this site.

Radiotherapy

Radiotherapy is the treatment of choice for mostmalignant tumours of the nasal cavity andparanasal sinuses (i.e. carcinomas and sarcomas)and is usually used alone for the treatment of suchtumours in both cats and dogs. In the past, radia-tion was often combined with surgical debulking ofthe tumour but although post-treatment survivaltimes may be marginally greater for the combinedtherapy, the benefit of cytoreductive surgery is notreally sufficient to justify the additional cost andmorbidity of the surgery. With the increasing use ofmegavoltage radiation (which achieves more evendose distribution within the nasal cavity and sinusesthan orthovoltage radiation), the need for surgicaldebulking of nasal tumours has decreased. Avariety of radiotherapy treatment regimes are usedfor nasal tumours at different centres throughoutthe world, with dosage and fractionation regimesvarying quite widely (as shown in Table 7.4). Rarelyis the outcome of treatment curative but mostregimes will achieve a symptom-free survival timeof over 12 months in 50% of treated animals. Amajor factor limiting the efficacy of radiotherapy at

Table 7.3a Clinical stages (TNM) of canine andfeline tumours of the nasal chambers and sinuses(Owen 1980).

T Primary tumourT0 No evidence of tumourT1 Tumour ipsilateral, minimal or no bone

destructionT2 Tumour bilateral and/or moderate bone

destructionT3 Tumour invading neighbouring tissuesThe symbol (m) added to the appropriate T

category indicates multiple tumours




N3 Fixed nodes(-) histologically negative, (+) histologically

positive


Table 7.3b Proposed stage grouping for caninenasal tumours (Theon et al. 1993).

Clinical DescriptionStage

I Unilateral or bilateral neoplasm confined to the nasal passage(s) without extension into frontal sinuses

II Bilateral neoplasm extending into the frontal sinuses with erosion of any bone of the nasal passages

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Prognosis

Without treatment, the prognosis for nasal tumoursis poor and most animals will be euthanased as aresult of progressive local tumour-related problemswithin three to six months of the onset of clinicalsigns. Even with treatment most animals eventuallysuccumb to the local effects of recurrent tumour,i.e. in most cases therapy is palliative. Surgical treat-ment alone does not appear to increase survivaltime. With radiotherapy reported median survivaltimes for canine nasal tumours range from 8 to 14months (see Table 7.4). Direct comparison of dif-ferent studies is difficult because of the variabilityin radiation regimes and defined end points. Somestudies have suggested that histological type oftumour does affect the prognosis (Adams et al.

this site is toxicity to the skin, eyes and oral tissuesadjacent to the nasal cavity (Fig. 7.12) such that thetotal dose of radiation administered is a compro-mise between efficacy and toxicity.

Chemotherapy

Chemotherapy has little role in the treatment ofmost nasal tumours with the exception of nasal lymphoma, where standard chemotherapy treat-ment protocols may be used in both the cat and dog(Chapter 15). Lymphoma is radiosensitive butalthough radiation would be an alternative treat-ment, chemotherapy is usually preferred because ofthe potential for any lymphoma to be or becomesystemic. For example, in the cat renal lymphomahas been observed following radiotherapy of nasallymphoma (Morris et al. 1996a).

Table 7.4 Results of radiotherapy for tumours of the nasal and paranasal cavities in the dog.

Authors Number of Radiation regime Results Toxicityanimals

Adams et al. 67 Various Median survival 8.5 Complications(1987) Orthovoltage/ months reported in 15 dogs

megavoltage +/- 1 and 2 year overall (22%), serious in 3 surgery survival rates (4%)

Total doses 38% and 30%36–48 Gy

Theon et al. 77 Cobalt 60 unit* Median actuarial Chronic ocular(1993) (58 carcinomas) 48 Gy in 12 ¥ 4 Gy survival, 12.6 complications in

(19 sarcomas) fractions on M-W-F months 45% of cases1 and 2 year overall

survival rates60.3% and 25%

Morris et al. 12 Linear accelerator Median survival 63 No severe late(1994) 4MV weeks (14 months) reactions (2 dogs

36 Gy in 4 ¥ 9 Gy 1 and 2 year subsequentlyweekly fractions actuarial survival developed

58% and 13% aspergillosis)

Adams et al. 21 Cobalt Median survival 428 Late effects severe(1998) 42 Gy in 9–10 days (14.2 months) in 6/15 dogs (40%)

fractions over 11– 1 year survival rate with durable tumour13 days 60% control

LaDue et al. 130 Cobalt 60 Median survival 8.9 Late toxicity in 109(1999) Total dose 45–57 months evaluable cases.

Gy in various 39% ocular, 6%regimes neurologic, 5%

osseus and 1%dermal

* 21 dogs in this study had surgery prior to radiotherapy.


1987) but other studies have not supported this.Tumour stage according to the WHO TNM systemdoes not appear to influence prognosis but modi-fied staging systems based on radiographic assess-ment of the severity of the disease have been shownto correlate with survival time, with more extensivetumours carrying a worse prognosis (Theon et al.1993; Morris et al. 1996b; LaDue et al. 1999).Tumours originating in the frontal sinuses seem tofollow a similar clinical pattern to those of the nasal

cavity, in terms of clinical behaviour and radiationresponse, although their closer proximity to thecranial vault and the orbit may complicate therapyand lead to a more guarded prognosis.

The prognosis is similar in the cat,where radiationtreatment for nasal carcinoma and sarcoma resultedin median survival times of 11 months in one study(Theon et al. 1994). Response of feline nasal lym-phoma to radiotherapy or chemotherapy can bevery good and can result in long term remission.

Fig. 7.12 Alopecia and erythema of the skin followingorthovoltage radiotherapy for a nasal tumour.

Epidemiology

The oral cavity is a common site for the develop-ment of tumours in small animals, superceded onlyby the skin and soft tissues, mammary tumours andhaematopoietic tumours. Malignant oral tumours

account for about 6% of all canine cancers and 3%of feline cancers. Oral tumours generally arise inolder animals. Specific age and breed predilectionsare discussed under individual tumour headings.

Aetiology

The aetiology of most tumours affecting the oralcavity is not known. Infectious (viral) papillomasare rare but may occur in the oral cavity of youngdogs. Environmental factors such as pollution mayplay a role in the development of oral carcinomassuch as SCC of the tongue and tonsil in both the catand dog, and this is supported by observations fromthe 1950s to 1970s that such tumours had a higherprevalence in urban areas compared to rural areas(Head 1990).

Pathology

A broad spectrum of tumour types arises in theoropharynx in association with the gingiva, oral soft tissues, dental structures and alveolar bone.Tumours range from the benign ‘epulides’ to themore aggressive squamous cell carcinoma, fibrosar-coma and the highly malignant melanoma (Table7.5). Because of this wide variation, tumours will bediscussed under individual headings.

Presentation/signs

Tumours of the oral cavity and oropharynx maypresent with a variety of signs including:

• Dysphagia• Halitosis• Excessive salivation, purulent/blood stained

saliva

ORAL CAVITY

Head and Neck 105

Imaging techniques

Between 60 and 70% of malignant oral tumoursinvolve bone. Good quality radiographs of thetumour site are essential to evaluate the extent ofsuch tumours. Lateral and dorso-ventral/ventro-dorsal views of the skull may be useful but non-screen, intra-oral films provide better detail. Avariety of bony changes occur in association withoral tumours including:

• Osteolysis (may be punctate or permeative, oroccasionally expansile bony lesions)

• Irregular periosteal new bone• Mineralisation of soft tissue tumours.

These radiographic changes are rarely specific for aparticular tumour type (Fig. 7.13) but the extent ofthe changes is important in planning therapy.

Ultrasound is not generally very helpful forimaging tumours of the oral cavity but it is likely

• Oral haemorrhage• Displacement or loss of teeth• Facial swelling.

Because many owners do not routinely inspecttheir pet’s mouth, such tumours can become quiteextensive before detection.


No specific paraneoplastic syndromes are as-sociated with tumours of the oral cavity andoropharynx.

Investigations

Bloods

Routine haematological/biochemical analyses arenot generally very helpful in the diagnosis oftumours of the oral cavity and oropharynx.

Table 7.5 Tumours of the oropharynx in the dog and cat.

Site Tumour type

Gingiva and dental arcade Benign/non-metastaticPapillomaPeripheral odontogenic fibroma (osseus/

fibrous epulis)(Giant cell epulis)OdontomaAmeloblastomaBasal cell carcinoma (acanthomatous epulis)

MalignantSquamous cell carcinomaMalignant melanomaFibrosarcomaOther sarcomas

(Epitheliotrophic lymphoma)(Plasmacytoma)

Mandible (maxilla) OsteosarcomaFibrosarcoma

Tongue Squamous cell carcinoma(Rhabdomyosarcoma, Granular cell

myoblastoma)Tonsil Squamous cell carcinoma

LymphomaSalivary glands Mixed salivary tumour

AdenocarcinomaCheek and lips Squamous cell carcinoma

Mast cell tumourMelanomaPlasmacytomaEpitheliotrophic lymphoma


that CT and MRI will be used increasingly for evaluation of such tumours.

Biopsy/FNA

Although gross inspection of an oral neoplasm maygive some indication of histiogenisis (see below),

a definitive diagnosis can only be made upon his-tological examination of tumour tissue.

Cytology is of little value in the diagnosis of oraltumours but important for evaluation of enlargedsubmandibular lymph nodes.

Most intra-oral neoplasms are accessible forbiopsy. However, their surface may be infected ornecrotic, and hyperplastic or inflammatory reac-tions in the adjacent tissues are common; thus caremust be taken to ensure a representative sample.Small, superficial biopsies can be misleading. Asmany oral tumours involve the underlying bone a deep wedge or Jamshidi needle-type biopsy is recommended.

Staging

Clinical staging of tumours of the oral cavity andoropharynx is primarily by physical examinationand radiography. More than half the tumoursoccurring at this site are malignant and considera-tion must be given to the possibility of metastasisvia the lymphatic or haematogenous routes. Thelymphatic drainage of the oral cavity is primarily tothe submandibular lymph nodes. Regional drainageis to the retropharyngeal nodes and via the cervicalchain to the prescapular and anterior mediastinalnodes. The tonsils should also be evaluated, espe-cially in the case of malignant melanoma.

The primary tumour is assessed on the basis of its size and invasion of other structures, espe-cially bone, as shown in Tables 7.6. and 7.7. TNMstaging systems are also described for tumours ofthe oropharynx and tumours of the lips (Owen1980).

Treatment

Surgery

Surgical resection is the single most effective meansof treatment for oral tumours. For surgical treat-ment to be successful the entire tumour must beexcised with adequate margins of surroundingnormal tissue. Since a high proportion of oraltumours involve bone it is essential that the surgi-cal margins are achieved in the bone as well as inthe soft oral tissues. The techniques of mandibulec-tomy and maxillectomy have been well docu-mented (Withrow & Holmberg 1983; White et al.

Fig. 7.13 Intraoral radiograph of invasive tumour of the maxilla resulting in dental displacement and bonelysis.

Head and Neck 107

1985). These techniques permit wide local excisionof oral tumours with 1–2cm margins of resectionand have been used successfully in the managementof basal cell carcinoma, squamous cell carcinomaand low grade fibrosarcoma. Such procedures areextremely well tolerated in dogs but may causesome degree of morbidity in cats.

The role of cryotherapy in the management ofthe malignant oral tumours is limited because it is difficult to achieve adequate treatment of thetumour margins, particularly those within the boneresulting in local tumour recurrence. Cryosurgerymay be used in a palliative manner where moreaggressive therapies are not feasible or appropriate.

Radiotherapy

Radiotherapy offers the advantage of treatinglarger areas of tissue surrounding the tumour thanmay be possible by surgery, and high energy mega-voltage radiation has good penetration of bone.

Table 7.6 Clinical stages (TNM) of canine/feline tumours of the oralcavity (Owen 1980).

T Primary tumourTis Pre-invasive carcinoma (carcinoma in situ)T0 No evidence of tumourT1 Tumour <2 cm maximum diameter

T1a without bone invasionT1b with bone invasion

T2 Tumour 2–4 cm maximum diameterT2a without bone invasionT2b with bone invasion

T3 Tumour >4 cm maximum diameterT3a without bone invasionT3b with bone invasion

The symbol (m) added to the appropriate T category indicatesmultiple tumours




N3 Fixed nodes(-) histologically negative, (+) histologically positive.


Table 7.7 Stage grouping for tumours of the oralcavity.

Stage Grouping T N M

I T1 N0 M0N1aN2a

II T2 N0 M0N1aN2a

III T3 N0 M0N1aN2a

Any T N1b

IV Any T Any N2b M0or N3

Any T Any N M1


Local lymph nodes can also be included in thetreatment fields where necessary. The main indica-tion for radiotherapy is in the treatment of oraltumours which, by virtue of their site or extent, arenot amenable to surgical excision. Radiotherapyhas been quite successful as a single agent in themanagement of gingival carcinomas in the dog andfor palliation of oral malignant melanoma. Thecombination of surgery with post-operative radio-therapy is probably the most effective treatment fororal sarcomas in the dog.

Radiotherapy has been less successful in themanagement of malignant oral tumours in the cat.

Chemotherapy

Chemotherapy is not indicated treatment of mostoral tumours in the cat or the dog, with the excep-tion of mucocutaneous forms of lymphoma.

Benign/non-metastatic tumours of theoral cavity – The epulides

The ‘epulides’ are a group of common, non-metastatic oral tumours arising in association withthe gingiva. As a group the epulides represent upto 40% of all oral tumours in the dog; they are relatively uncommon tumours in the cat. There isconsiderable confusion over the classification andnomenclature of these tumours. On the basis ofclinical and radiographic behaviour the epulidescan be considered to comprise two distinct tumourgroups:

• Benign fibromatous/ossifying epulis (also termedperipheral odontogenic fibroma)

• Locally aggressive basal cell carcinoma (BCC)(also termed acanthomatous epulis and in somecases, incorrectly, adamantinoma).

Peripheral odontogenic fibroma(POF)

Epidemiology/aetiology

Fibromatous/ossifying epulis (POF) is the mostcommon oral tumour in the dog, where it typicallyaffects middle aged to older dogs of any breed.Brachycephalic dogs such as boxers may be prone to

developing multiple epuli (Fig. 7.14).These tumoursare rare in the cat.The aetiology is not known.

Presentation

This tumour presents as a firm–hard mass usuallywith a smooth, non-ulcerated surface. It is firmlyattached to the gingiva and periosteum of thedental arcade and grows outward, often from a relatively narrow base.

Pathology

Tumours show varying degrees of mineralisation,leading to the arbitrary distinction between thefibromatous and ossifying forms. The term periph-eral odontogenic fibroma has been proposed toencompass both types on the basis that although

Fig. 7.14 Multiple epulides and gingival hyperplasia ina boxer dog. (Courtesy of Dr R.A.S. White, Depart-ment of Clinical Veterinary Medicine, University of Cambridge.)

Head and Neck 109

tion of all canine oral tumours.Tumours occur prin-cipally in middle-aged dogs (mean age 6.9 ± 2.4years in one series (White & Gorman 1989)),although they are occasionally reported in youngeranimals. Medium to large breeds tend to beaffected; there might be a male predilection. Theaetiology is not known.

Presentation

The gross appearance of this tumour is variable.It may present as an irregular, fungating epithe-lial mass (Fig. 7.15) or may be more invasive withan ulcerated appearance and occasionally con-tains areas of necrosis. Radiographically there isusually lysis of adjacent alveolar bone, and dis-placement or loss of teeth is common (Fig. 7.16).Occasionally the soft tissue of the tumour becomesmineralised.

they contain elements of odontogenic epithelium,they appear to be of mesenchymal origin (Bostock& White 1987).


Clinically these tumours are benign, never invadeinto the adjacent bone and never metastasise. Thetreatment of choice is local surgical excision. Resec-tion of alveolar bone at the base of the mass maybe necessary to effect a complete removal but theprognosis is excellent.

Basal cell carcinoma (BCC)


Whilst less common than the fibromatous/ossifyingepulis the BCC still represents a sizeable propor-

Figs 7.15 and 7.16 Basal cell carcinoma (acanthomatous epulis) of the premaxilla gross (Fig. 7.15) and radiograph(Fig. 7.16). These tumours invariably invade into the underlying bone causing lysis and dental displacement.

7.15

7.16


Pathology

The term basal cell carcinoma has been applied to this tumour on the basis that the lesion is pre-dominantly composed of clumps of basal epithe-lium attached to and apparently originating fromthe stratum germanitivum of the overlying gum.The consistent infiltration into bone is characteris-tic of the behaviour of a carcinoma.

Tumour behaviour/treatment/prognosis

BCC is a locally aggressive tumour and invariablyinvades the adjacent alveolar bone. Although BCCdoes not metastasise, it does present a clinicalproblem by virtue of the invasive pattern of growth.Simple local excision with minimal tumour marginsis rarely sufficient to prevent local recurrence. Thetreatment of choice is wide local excision includinga margin of at least 1cm of alveolar bone beyondthe gross or radiographic limit of the tumour. Thissurgical approach has been shown to be effective in achieving a local cure (White & Gorman 1989).BCC are radio-sensitive and high cure rates canalso be achieved by radiotherapy. However, surgeryis the preferred treatment because there is a risk of the subsequent development of malignanttumours at the site of irradiated BCC (White et al.1986).

Ameloblastoma


Ameloblastoma is a rare dental tumour whicharises from odontogenic epithelium. Typically itoccurs in young animals. In dogs the mandible is the usual site whereas a fibromatous form ofameloblastoma appears to be more frequent in themaxilla of young cats, especially the region of theupper canine.

Presentation

At either site the expansive growth of the tumourresults in gross swelling and distortion of the bone.The tumour is composed of well-defined, largecystic cavities and thus has a characteristic multi-loculate radiographic appearance (Figs 7.17, 7.18and 7.19).


These tumours follow a benign course and can becured by complete surgical resection. There is someevidence that curretage of the bony cavities is suf-ficient to achieve local control.

Squamous cell carcinoma (SCC)

Epidemiology

Squamous cell carcinoma (SCC) is the mostcommon malignant oral tumour in the dog and cat.In the dog it accounts for approximately 20–30% ofmalignant oral tumours and tends to occur in olderanimals (average 8–10 years) of medium to largerbreeds. There is no sex predilection. In the cat, SCCaccounts for 70% of malignant oral tumours; it alsooccurs in older animals (average age 10 years) withno sex predilection.

For descriptive and prognostic purposes oropha-ryngeal SCC may be divided into:

• Gingival• Labial• Tonsillar• Lingual (see tongue later in this chapter).

Gingival SCC – presentation

Gingival SCC may arise at any site in the upper andlower dental arcades. The tumour usually begins atthe gingival margin and its invasive growth leads todestruction of the peridontal tissues and looseningof the teeth. The gross appearance is of an irregu-lar, proliferative or ulcerative epithelial lesion (Fig.7.20).The tumour is often friable and haemorrhagicand secondary bacterial infection is common. Inva-sion and lysis of adjacent bone occurs in over 70%of cases (Fig. 7.21).

Gingival SCC – tumourbehaviour/treatment/prognosis

Gingival SCC has a low rate of metastasis, hencethe major therapeutic priority is control of theprimary tumour. In the dog, surgery is the treat-ment of choice for early stage lesions particularlythose affecting rostral areas of the mouth. Widelocal excision by maxillectomy or mandibulectomy

Head and Neck 111

be more invasive and carry a worse prognosis. SCCis radiosensitive and radiotherapy may provide pal-liation of more advanced tumours or those involv-ing sites where surgery is not feasible.

Gingival SCC is a much more aggressive neo-plasm in the cat and there is often severe, deep inva-sion of bone at the time of presentation (Fig. 7.22,and Chapter 6, Fig. 6.5). The extent of the tumouroften precludes surgery and even those tumoursdeemed operable carry a poor prognosis. Theoutcome following radiotherapy is poor.As a resultof the extensive invasion of bone by the tumour,radiation often results in large necrotic cavitieswithin the bone, which fail to heal. One year sur-vival rates rarely exceed 10%.

On occasion SCC arises in the epithelium of themucosal surface of the lip or cheek. Tumours at thissite are often more ulcerative than proliferative innature and may initially be mistaken for oral ulcer-ation. SCC of the lip is not generally as aggressive

as appropriate is frequently curative, and one yearsurvival rates are in the order of 84% (White 1991).Tumours sited more caudally in the mouth and par-ticularly those involving the caudal maxilla, tend to

Figs 7.17, 7.18 and 7.19 Gross and radiographic appearance of ameloblastoma in the premaxilla of a dog (Figs 7.17 and 7.18) and in the rostral mandible of a young cat (Fig. 7.19).

7.17

7.19 7.18

Fig. 7.20 Gingival SCC, rostral mandible in a dog.


as the lingual form but the lesion is often acutelypainful to the animal. Wide local surgical resectionis the treatment of choice; radiotherapy may also beappropriate in some cases.

Fibrosarcoma

Epidemiology

Fibrosarcoma is the third most common malignanttumour of the canine oral cavity, representing10–20% of malignant tumours at this site. It tendsto occur in younger dogs; the mean age of onset is7.5 years but up to 25% occur in animals under fiveyears of age. There is a 2 :1 male : female ratio andin our experience the retriever breeds appear tosuffer a particularly high incidence. Althoughfibrosarcoma is a common tumour in the cat, itsincidence in the oral cavity is low (less than 20% oftumours at this site), sites of predeliction being thesoft tissues of the head, trunk and limbs.

Presentation

In the dog, oral fibrosarcoma most commonlyinvolves the upper dental arcade often extendingdorsally and laterally into the paranasal region andmedially onto the palate (Figs 7.23 and 7.24).Fibrosarcoma usually presents as a firm, smoothmass with a broad base and in its early stages may be difficult to distinguish on gross inspectionfrom gingival hyperplasia or POF. Radiographicevidence of bone involvement is common in more advanced tumours but in general fibrosar-coma tends to cause less lysis than SCC or BCC and is more often associated with a proliferativeperiosteal reaction.


The histological appearance of fibrosarcoma of theoral cavity does not always correlate well with thebiological behaviour of the tumour. Some tumoursmay appear histologically low grade and yet showa very aggressive and infiltrating behaviour. Localand distant metastasis occurs in around 25% ofcases but the prognosis is always guarded due to theextensive infiltration of adjacent tissues. No singleform of treatment has been found to be entirelyeffective in treatment of oral fibrosarcoma. Widelocal surgical excision by mandibulectomy andmaxillectomy may control early stage, low gradetumours but even such aggressive surgery does notachieve the compartmental type of resection whichis necessary to erradicate most oral fibrosarcomas.

Fig. 7.21 Intraoral radiograph of case in Fig. 7.20.

Fig. 7.22 Oral SCC in a cat, an extensive tumour ofthe maxilla invading into the soft tissue of the cheek.

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One year survival rates with surgery alone areabout 50% (White 1991). Fibrosarcoma is not par-ticularly sensitive to radiation and radiotherapyalone does not appear to offer any significantimprovement in local tumour control over surgery.However, the combination of surgery with radia-tion has been shown to improve the initial tumourresponse and extend patient survival, althoughlocal recurrence can still occur.

Undifferentiated sarcomas

Epidemiology

A number of less well differentiated sarcomasincluding haemangiosarcoma, spindle cell sarcomasand anaplastic sarcomas may also arise in the

oral cavity of the dog. As a group these tumoursrespresent 10–20% of canine malignant oraltumours.

Presentation

In gross appearance they may resemble fibrosar-coma but in many cases they are more aggressivetumours and present as a rapidly growing masswhich may be friable or haemorrhagic and containareas of necrosis.


As with fibrosarcoma these tumours are charac-terised by an infiltrative pattern of growth and are often locally advanced by the time of diagnosis.

Figs 7.23 and 7.24 Canine maxillary fibrosarcomas – the lesion in Fig. 7.23 is invading across the hard palatewhilst that shown in Fig. 7.24 has infiltrated the paranasal tissues.

7.23

7.24

Presentation

Common sites in order of prevalence are the gums(especially in the region of the molar teeth), thelabial mucosa and the hard palate. The tumourusually presents as a rapidly growing friable andhaemorrhagic soft tissue mass. The degree of pig-mentation varies considerably, some tumours beingheavily pigmented whilst others contain little to nopigment (Figs 7.26 and 7.27). Secondary bacterialinfection and necrosis may be present. Invasion ofthe bone is less common in oral melanoma thanwith SCC and fibrosarcoma.

Tumour behaviour/treatment/prognosisCanine oral melanomas are among the most malignant neoplasms encountered in companion


A higher proportion of these tumours metasta-sise, usually via the haematogenous route to thelungs and other internal organs. The principles ofmanagement are essentially as for fibrosarcomaalthough the prognosis is often worse due to therapid growth rate and higher risk of distant metas-tases. Small early stage tumours may be surgicallyresected and, although most soft tissue sarcomasare not very radioresponsive, cytoreductive sur-gery combined with radiation therapy can be ben-eficial in the management of the more advancedtumours.

Rarely, undifferentiated malignant tumours arisein young dogs under two years of age of largebreeds. These highly malignant tumours are usuallysited in the maxilla, involving the palate, uppermolar teeth and often the orbit (Fig. 7.25). Mostanimals present with widespread metastases. Noeffective treatment has been described.

Melanoma

Epidemiology

Malignant melanomas represent about 30–40% ofmalignant tumours of the oral cavity in the dog.Oral melanoma is rare in the cat. In the dog oralmelanomas characteristically develop in olderanimals; the average age is 9–12 years. Thereappears to be a sex predilection with male dogsaffected four times more frequently than bitches.Certain breeds of dog, particularly those with pig-mented oral mucosa, e.g. poodle and pug, may bepredisposed to this tumour.

Fig. 7.25 An extensive anaplastic tumour of themaxilla and nasal cavity in a young bullmastiff.

Figs 7.26 and 7.27 Gross appearance of canine oral melanomas. Figure 7.26 shows a partly pigmented lesion ofthe maxilla. Figure 7.27, a heavily pigmented and well circumscribed lesion in the floor of the mouth.

7.26 7.27

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animals. Local control can be achieved by wide sur-gical resection where the site of the tumour isappropriate or by radiotherapy. The human cuta-neous melanoma is generally regarded as beingradioresistant but our experience in the treatmentof canine oral melanoma suggests these tumours dorespond to hypofractionated radiotherapy, withlocal response rates approaching 70% (Blackwood

& Dobson 1996). Irrespective of local tumourcontrol, the major problem presented by melanomais the high incidence of both regional (nodal) anddistant metastasis. In the absence of an effectivemethod for the prevention or treatment of dissem-inated melanoma the prognosis for these tumoursis poor and survival rates are in the order of threeto six months.

Fig. 7.28 Squamous cell carcinoma of the tongue –dog.

SITE SPECIFIC TUMOURS OF THE OROPHARYNX

Tongue

Tumours of the tongue are not common in eitherthe cat or the dog but squamous cell carcinoma isthe most common histological type of tumour atthis site in both species. Other tumour typesreported to affect the tongue in the dog include:

• Granular cell myoblastoma (see below)• Rhabdomyosarcoma• Mast cell tumour• Fibrosarcoma• Lymphoma• Malignant melanoma.

Presentation

Lingual tumours are often painful and interferewith the function of the tongue. Affected animalsmay present with:

• Difficulties in prehension, mastication and drinking

• Excessive salivation (often purulent or blood-tinged)

• Halitosis• Lack of grooming in cats.

Some tumours may present as an obvious mass onthe surface of the tongue but lingual squamous cellcarcinoma often arises on the ventral surface of thetongue in the area of the frenulum (especially incats) and may not be readily detected on briefvisual inspection of the mouth.


SCC of the tongue is a particularly aggressive neo-plasm which is characterised by rapid extension andinvasion into the tongue such that the tumour often

involves the full thickness of the tongue by the timeof presentation (Fig. 7.28). Lymphatic invasion andmetastasis are common. Surgery is the treatment ofchoice for tumours of the tongue. Dogs will toler-ate partial glossectomy involving up to 50% of thetongue quite well but in the case of lingual SCC theextensive infiltration of the tongue at the time ofpresentation often precludes surgical resection.Although at other sites SCC is usually radiosensi-tive, the tongue is very sensitive to radiation toxic-ity and because normal tissue tolerance at this siteis so poor, radiotherapy has not been a successfultreatment for lingual tumours in cats and dogs.There have been some reports of chemotherapeu-tic treatment of lingual SCC in dogs and cats withdrugs such as cisplatin (not cats), mitoxantrone anddoxorubicin (Carpenter et al. 1993) but chemother-apy has not become established as an effectivetreatment for such tumours. Overall the prognosisfor lingual SCC in both dogs and cats is poor. Indogs where complete surgical resection is possible,one year survival rates may exceed 50% but such

Tonsillar SCC is less common than the gingivalform in the dog and cat but there is considerableregional variation in the reported incidence and itappears that this form of the disease may have beenmore common in the past (particularly in animalsliving in cities). Aetiologic associations with envi-ronmental pollutants have been implied (seeearlier). In the dog the average age of onset of thedisease is 9–10 years and males are affected threetimes more often than bitches. SCC of the tonsil israre in the cat.

Presentation

Tonsillar SCC usually presents as a unilateral lesionalthough bilateral involvement has been reported.In early cases the tonsil is of relatively normal sizebut has a number of small papillomatous growthson its surface. Infiltration and destruction of thetonsil develops rapidly and the tumour progressesto involve the pharyngeal wall and soft palate (Fig.7.30). This lesion is often acutely painful andaffected animals present with signs of:

• Dysphagia• Difficulty swallowing• Gagging• Hypersalivation• Weight loss• Temporal muscle atrophy.

Occasionally the first manifestation of the diseaseis an enlarged retropharyngeal lymph node whichon histological/cytological examination revealsmetastatic squamous cell carcinoma. In such cases


cases are not common and one year survival ratesare usually less than 25%.

Granular cell myoblastoma

Although rare, granular cell myoblastoma isreported to be the second most common tumour ofthe tongue in dogs. The origin of this tumour isunclear, although it has been suggested that it mayarise from Schwann cells in the tongue. Morpho-logically, it is difficult to distinguish from othereosinophilic granular cell tumours such as rhab-domyoma, rhabdomysarcoma and oncocytoma.Ultrastructural and immunocytochemical studiesare required to differentiate these entities (Liggettet al. 1985; Lascelles et al. 1998). Clinically thesetumours present as a soft tissue mass within thetongue (Fig. 7.29). Although the lesions oftenappear large and invasive, their behaviour is usuallybenign. Local surgical removal is usually possibleleading to a favourable prognosis with local controlrates in excess of 80%.

Tonsil

Squamous cell carcinoma is the most commontumour to affect the tonsil in dogs and cats. Othertumours which may arise in the tonsil include:

• Lymphoma (usually as part of multicentric lym-phoma – Chapter 15)

• Metastatic tumours from the oral cavity, espe-cially malignant melanoma.

Fig. 7.29 Rhabdomyoma of tongue – dog. Fig. 7.30 SCC tonsil – dog.

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the primary tonsillar mass may be small and asymptomatic.


SCC of the tonsil is a locally aggressive tumour witha high rate of metastasis to the retropharyngeal andcervical lymph nodes. Haematological dissemina-tion may also occur. By virtue of its rapid local pro-gression and high rate of metastasis, the prognosisfor tonsillar SCC is poor. The results of therapy bysurgical resection or radiotherapy or by combina-tions are usually disappointing and median survivaltimes are in the region of two months; less than10% of affected animals are alive at one year.Thereis no effective chemotherapeutic treatment for thiscondition.

Nasopharyngeal polyps

Nasopharyngeal polyps are not true neoplasms butinflammatory lesions originating from the middle

ear or eustachian tube in young (usually <2 yearold) cats. No breed or sex predilection is known.Polyps may grow into the external ear canal wherethey can be seen as a pink, fleshy mass but mostgrow via a pedicle into the pharynx where they maycause signs of:

• Stridor/stertor/difficulty breathing• Change in voice• Sneezing• Swallowing problems• Rhinitis• Horner’s syndrome (associated with otitis

media).

Nasopharyngeal polyps may be seen as soft tissuemasses on radiographs of the pharynx or visualisedby retraction of the soft palate. Most nasopharyn-geal polys can be removed by traction. If an under-lying cause can be identified (e.g. middle eardisease) then this should be treated appropriatelyto prevent recurrence.

OSTEOSARCOMA OF THE SKULL

Osteosarcoma of the axial skeleton, particularly theskull, is less common than that of the long bones in dogs. There are two distinct variants of osteosar-coma which affect the bones of the canine skull:

• Multilobular osteoma/chondroma/osteochondrosarcoma/chondroma rodens

• Mandibular osteosarcoma.

Multilobular osteochondrosarcoma

Multilobular oesteochondrosarcoma is an uncom-mon tumour which primarily occurs in older,medium to large breed dogs. It is a relatively slowlygrowing tumour which usually affects the bones ofthe calvarium. Animals present with an enlargingmass which is hard and fixed in nature. This is anosteoproductive tumour and gives rise to a charac-teristic radiographic appearance of dense bonymass of nodular or stippled density (Fig. 7.31). Thetumour is locally invasive and may cause lysis ofunderlying bone. Surgical resection is the onlyeffective treatment but complete surgical removalof the tumour may be difficult or impossible. Thesetumours were once considered to be benign as most

animals were animals euthanased because of theprimary mass without any evidence of metastases.However, with the advent of more aggressive sur-gical approaches to the management of thesetumours, leading to prolonged survival, it hasbecome apparent that metastasis will occur in 50%or more cases (Dernell et al. 1998).

Mandibular osteosarcoma

Osteosarcoma may arise in the ramus of themandible; indeed it is one of the five most commontumours of the mandible in the dog. Osteosarcomaat this site is noteworthy as it is often possible toachieve primary tumour control by hemi-mandibulectomy (Fig. 7.32). By virtue of the factthat the tumour is contained within the deepperiosteal fascia, such surgery actually achievescompartmental resection. Rapid metastasis is not a feature of tumours at this site and a one year survival rate of 71% was reported followingmandibulectomy in one study (Straw et al. 1996).

Craniomandibular osteopathy (CMO) is animportant differential diagnosis for a bony swellingof the mandible but in contrast to osteosarcoma:

• CMO usually occurs in juveniles, less than oneyear of age

• CMO usually affects both mandibles, althoughlesions are not necessarily bilaterally symmetrical


Fig. 7.31 Radiograph of skull showing typical radi-ographic appearance of a multilobular osteosarcomaof the caudal zygoma.

Fig. 7.32 Resected mandibular osteosarcoma.

Table 7.8 Tumours which commonly arise on thepinna.

Cats Squamous cell carcinomaBasal cell tumourMast cell tumourCutaneous lymphoma

Dogs HistiocytomaPlasmacytomaMast cell tumourBasal cell tumourCutaneous lymphoma

• CMO is strongly breed associated and occursparticularly in West Highland white and cairn ter-riers, although it can arise in other breeds, e.g.dobermann.

EARS

For anatomical, descriptive purposes, the ear isdivided into three areas:

• The external ear, comprising the pinna and earcanal

• The middle ear, sited in the tympanic bulla of thetemporal bone

• The inner ear, comprising the cochlea and semi-circular canal system.

Primary tumours may arise at any of these sites incats and dogs but the pinna and external ear are

more common than the middle ear or inner ear,both of which are rare. The ear is an unusual sitefor secondary, metastatic tumour development butthe external ear may be involved in widespread ordiffuse cutaneous tumours such as cutaneous lym-phoma. A variety of cutaneous tumours may ariseon the pinna, as listed in Table 7.8; these tumoursare discussed in Chapter 4. Most of the followingdiscussion will concern tumours of the ear canal.

Epidemiology

Tumours of the ear canal are not common in eitherspecies, representing 1–2% of all feline tumours

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and 2–6% of all canine tumours.They tend to occurin older animals, mean age 7–11 years in cats and9–10 years in dogs. (Inflammatory polyps may affectthe ear canal in young cats – see above.) No sexpredilection has been reported in either species, butin the dog the cocker spaniel appears to be atincreased risk of developing tumours of the earcanal.

Aetiology

Chronic, long-standing inflammation may be afactor in the development of both benign andmalignant ceruminous gland tumours (London etal. 1996; Moisan & Watson 1996) and this mightexplain the increased incidence of such tumours inthe cocker spaniel, where otitis externa is acommon problem.

Pathology

The epithelium of the ear canal is rich in sebaceousglands and ceruminous glands (modified apocrineglands). It is these glands that give rise to the mostcommon tumours at this site. Benign ear canaltumours include ceruminous gland adenomas,inflammatory polyps, basal cell tumours and papil-lomas. In the cat, ceruminous gland cysts aretumour-like masses of the ear canal which oftencontain blue–black viscous fluid. Their heavily pig-mented gross appearance may lead to confusionwith melanoma and basal cell tumour.

Excluding inflammatory polyps, approxi-mately 85% of all feline and 60% of all canine ear canal tumours are malignant (London et al.1996). Ceruminous gland adenocarcinoma is themost common malignant tumour of the ear canal in both species; also reported at this site are squa-mous cell carcinoma and carcinoma of unknownorigin.

Any cutaneous tumour may, on occasion, arise inthe ear canal.

Tumour behaviour/paraneoplasticsyndromes

Benign tumours of the ear canal may give rise to anumber of clinical problems as discussed below butthese tumours are not locally invasive and they do

not metastasise. Ceruminous gland carcinomas andother carcinomas of the ear canal are locally inva-sive tumours and not only do they cause surfaceulceration within the ear canal, but will invade intothe deeper cartilagenous and bony structures asso-ciated with the ear. Up to 25% of malignanttumours show radiographic evidence of invasion ofthe tympanic bulla. The incidence of metastasis isnot well documented but these tumours are capableof invasion of local lymphatics and metastasis to theregional (retropharyngeal) lymph nodes and, in asmall percentage of cases, pulmonary metastaseswill be detected at the time of presentation. Thebehaviour of ceruminous gland and other carcino-mas of the ear canal tends to be more aggressive inthe cat than in the dog.

No paraneoplastic syndromes are commonlyassociated with tumours of the ear canal; the pre-senting signs tend to be associated with local, inva-sive growth of the primary mass.

Presentation/signs

Ear canal tumours may arise anywhere in the ver-tical or horizontal portion of the ear canal. On occa-sion there may be an obvious mass visible at theexternal auditory meatus but in most cases the pre-senting signs of an ear tumour will be similar tothose of a chronic ear infection:

• Aural discharge• Aural odour• Aural irritation or discomfort• Aural pain.

Otoscopic examination of the ear canal may be necessary to locate and visualise the tumour.Benign tumours tend to appear as a non-ulcerated,raised, sometimes pedunculated mass. Malignanttumours are more likely to be ulcerated and haemorrhagic.

Where the tumour is invasive and/or located inthe middle or inner ear the animal may present withneurological signs:

• Vestibular signs: circling, head tilt, nystagmus• Horner’s syndrome.

These are reported in 10% of dogs with malignanttumours and in 25% of cats either as a result ofbenign polyps or as a result of invasive malignanttumours.

Whilst conservative surgery may be a temptingoption for carcinomas involving the vertical earcanal, it has been shown that total ear canal abla-tion plus bulla osteotomy provide better surgicalmargins and hence a better prognosis (see below)(London et al. 1996). Possible complications ofmore aggressive surgery include damage to thefacial nerve and the sympathetic trunk.

Radiotherapy

Radiotherapy is a possible alternative or adjunct to surgery although there are few reports docu-menting the efficacy of radiotherapy in either situation. The proximity of the tumour to the brainstem may complicate treatment planning and delivery.

Chemotherapy

Chemotherapy is indicated in the treatment ofcutaneous forms of lymphoma with involvement ofthe pinna or ear canal, but little/no informationexists on the efficacy of chemotherapy in the man-agement of ceruminous gland or other carcinomasof the ear canal.

Prognosis

The prognosis for benign tumours of the ear fol-lowing conservative surgical treatment is good.Occasionally inflammatory polyps may recur, espe-cially if the underlying cause cannot be treatedeffectively.

In the case of malignant tumours of the ear canal,several factors have been shown to be of prognos-tic importance:

In cats:• Histological type – ceruminous gland carcinomas

carry a more favourable prognosis than squa-mous cell carcinoma or carcinoma of undeter-mined origin.

In both cats and dogs, negative prognostic factorsinclude:• Histological evidence of lymphatic or vascular

invasion• Presence of neurological signs• Involvement of the tympanic bulla


Investigations

Bloods

Routine haematological/biochemical analyses arenot generally very helpful in the diagnosis oftumours of the ear.

Imaging techniques

Radiography of the skull is indicated in the inves-tigation of tumours affecting the ear canal as up to25% of malignant tumours at this site show radi-ographic evidence of bulla involvement. Inflamma-tory polyps and evidence of middle ear disease maybe appreciated on skull radiography.

Radiography is also indicated for evaluation of retropharyngeal lymph nodes and thoracicmetastasis.

Biopsy/FNA

In most cases the diagnosis will depend on a grabor incisional biopsy of the aural mass. Fine needleaspirate/cytology is of limited value in the diagnosisof most ear tumours but is useful for evaluation oflocal lymph node enlargement for metastasis.

Staging

A staging system for tumours of the ear canal hasnot been devised.

Treatment

Surgery

Surgery is the treatment of choice for most primarytumours of the ear canal in dogs and cats. The sur-gical approach depends on the nature, the site andthe extent of the tumour. Options include:

• Excisional biopsy – only really indicated forinflammatory polyps

• Lateral ear canal resection – benign tumoursaffecting the vertical ear canal

• Total ear canal ablation and lateral bullaosteotomy – malignant tumours.

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• Conservative treatment – surgical approachstrongly influences the prognosis; those animals

treated conservatively show considerablyreduced survival times (Table 7.9).

Table 7.9 Surgical management of malignant tumours of the ear canal in dogs and cats.

Conservative AggressiveLateral ear canal resection Total ear canal ablation with lateral bulla osteotomy

Cats (ceruminous gland adenocarcinoma*)Median disease free survival = 10 months Median disease free survival = 42 months1 year survival rate = 33% 1 year survival rate = 75%Recurrence rate = 66% Recurrence rate = 25%

Dogs (ceruminous gland adenocarcinoma**)N = 4 N = 11Median follow up = 4 months (range 3–9 months) Median survival = 36 months (range 8–72 months)Recurrence rate = 75% No local recurrence

* Marino et al. 1994.** Marino et al. 1993.

SALIVARY GLANDS

Epidemiology

Tumours of the salivary glands are not common inthe dog and are rare in the cat. In both species theyare reported to occur in older animals; the meanage of affected animals is about 10 years in dogsand 12 years in cats. No breed or sex predilectionshave been reported.

Aetiology

The aetiology of tumours of salivary glands is undetermined.

Pathology

Tumours may arise in any of the major salivaryglands or in the minor glands sited in the oralmucosa, gingiva and palate. Benign tumours of sali-vary glands are rare. Most tumours are malignantarising either from glandular tissue or from ductalepithelium, thus various types of salivary gland carcinoma/adenocarcinoma may be described(Table 7.10).


Salivary carcinomas are usually locally invasivealthough the rate of growth and incidence of metas-tasis can vary considerably. Some tumours maygrow slowly and be slow to metastasise but adeno-carcinomas often display rapid growth and featurecentral tumour necrosis. The pattern of growth isinvasive and such tumours frequently extendthrough the capsule of the gland to infiltrate adja-cent tissues. Infiltration of local lymphatics maylead to local oedema. Metastasis is more commonin the cat than in the dog and is to local and regionallymph nodes. Distant and widespread metastsis canoccur.

No paraneoplastic syndromes are commonlyassociated with tumours of the salivary glands.

Presentation/signs

Most animals present with a firm, painless swellingof the affected salivary gland:

• Parotid – base of the ear• Mandibular – upper neck (Fig. 7.33)

Tumours of minor salivary glands may arise in theoral mucosa of the lip, palate and tongue; thesetumours have a greater tendency to be ulcerated(Fig. 7.34).

Investigations

Bloods

Routine haematological/biochemical analyses arenot generally very helpful in the diagnosis oftumours of salivary glands.

Imaging techniques

Radiography of the skull may be indicated in theinvestigation of tumours which are fixed, invasiveand adjacent to bone, especially those affecting theorbit. Ultrasound of the orbit may also be indicatedin cases with ocular involvement.

Radiography is indicated for evaluation of


• Sublingual – upper neck/floor of the mouth• Zygomatic – lip and maxilla; may also be associ-

ated with ocular signs including exophthalmos.

Excessive salivation and dysphagia may occasion-ally result from obstruction of the oropharynx.

Table 7.10 Tumours of the salivary glands.

Histological type Comment

Mixed tumour (pleomorphic adenoma) Composed of a mixture of epithelium, myoepithelium, chondroidmaterial and bone

Rare tumour in cats and dogs, may be locally invasive and difficultto excise

Monomorphic adenoma Predominantly glandular tumour with little stroma and no myxoidor chondroid areas

Usually well encapsulated. Rare

Mucoepidermoid tumour Composed of mucous filled spaces lined by secretory epithelium andstrands of squamous epithelium

Rare

Acinic cell tumour Tumour of glandular epithelium which may be arranged in acini orsolid sheets. Reported in both major and minor salivary glands inthe dog. May show invasive growth but slow to metastasise

Adenocarcinoma Malignant tumour of glandular tissue forming tubules or solid cordsof epithelial cells

Most common salivary gland tumour in the cat and moderatelycommon in the dog

Undifferentiated carcinoma Spindle shaped to round epithelial cells arranged in irregular masses.Rare tumour but metastasis reported

Non-neoplastic conditions Ductal hyperplasia(differential diagnoses) Sialosis: bilateral enlargement of salivary glands due to hypertrophy

of serous acinar cellsSialocoele (salivary mucocoele)Salivary gland infarction

Fig. 7.33 Salivary carcinoma – firm, immobile mass inthe mandibular salivary gland of a cat.

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retropharyngeal lymph nodes and thoracic metastasis.

Biopsy/FNA

Fine needle aspirates may be helpful in the initialinvestigation to distinguish a salivary gland tumourfrom other salivary lesions (Table 7.9). Lymphomawould also be a differential diagnosis for a mass inthe submandibular/parotid region.

In most cases the definitive diagnosis will dependon a needle or an incisional wedge biopsy of themass.

Staging

A specific staging system for tumours of salivaryglands has not been devised.


Surgical removal is the theoretical treatment ofchoice for tumours of salivary glands but in prac-tice many tumours are too extensive at the time of presentation to permit an aggressive surgicalresection in an area of the body containing manyvital structures. Post-operative radiotherapy mayprolong survival following incomplete tumourremoval, but there is little information available onthe success of radiotherapy alone or on the valueof chemotherapy in the management of suchtumours.

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White, R.A.S. (1991) Mandibulectomy and maxillectomyin the dog: long term survival in 100 cases. Journal ofSmall Animal Practice, (32), 69–74.

Withrow, S.J. (1996) Tumours of the respiratory system.In: Small Animal Clinical Oncology, 2nd edn, (S.J.Withrow & E.G. MacEwen) pp.268–86. JB LippincottCompany, Philadelphia.

Withrow, S.J. & Holmberg, D.L. (1983) Mandibulectomyin the treatment of oral cancer. Journal of the Ameri-can Animal Hospital Association, (19), 273–86.

Withrow, S.J. & Straw, R.C. (1990) Resection of the nasalplanum in nine cats and five dogs. Journal of the Amer-ican Animal Hosptial Association, (26), 219–22.


diagnosis, prognosis and treatment. Journal of theAmerican Veterinary Medical Association, (170), 45–8.

Madewell, B.R., Priester, W.A., Gillette, E.L. & Snyder,S.P. (1976) Neoplasms of the nasal passages andparanasal sinuses in domestic animals as reported by13 veterinary colleges. American Journal of VeterinaryResearch, (37), 851–6.

Marino, D.J., MacDonald, J.M., Matthiesen, D.T. et al.(1993) Results of surgery and long term follow up indogs with ceruminous gland adenocarcinoma. Journalof the American Animal Hospital Association, (29),560–63.

Marino, D.J., MacDonald, J.M., Matthiesen, D.T. &Patnaik, A.K. (1994) Results of surgery in cats withceruminous gland adenocarcinoma. Journal of theAmerican Animal Hospital Association, (30), 54–8.

Moisan, P.G. & Watson, G.L. (1996) Ceruminous glandtumours in dogs and cats: a review of 124 cases. Journalof the American Animal Hospital Association, (32),448–52.

Morris, J.S., Blackwood, L., Dobson, J.M. & Villiers, E.J.(1996a) Association between nasal and renal lym-phoma in cats. Clinical Research Abstracts, BritishSmall Animal Veterinary Association Congress,p.241.

Morris, J.S., Dunn, K.J., Dobson, J.M. & White, R.A.S.(1996b) Radiological assessment of severity of caninenasal tumours and relationship with survival. Journal ofSmall Animal Practice, (37), 1–6.

Owen, L.N. (1980) TNM Classification of Tumours inDomestic Animals. World Health Organization,Genera.

Peaston, A.E., Leach, M.W. & Higgins, R.J. (1993) Photo-dynamic therapy for nasal and aural squamous cell car-cinoma in cats. Journal of the American VeterinaryMedicial Association, (202), 1261–5.

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Theon, A.P., Madewell, B.R., Harb, M.F. & Dungworth,

8Gastro-intestinal Tract

phoma predominating. Primary tumours of theliver, spleen and pancreas are also rare, althoughthe liver is a common site for metastatic tumours.

Gastro-intestinal tract tumours of the dog occur most often in the stomach but even at this site they are still uncommon. In the cat, they affect the intestines more frequently, with lym-

� Oesophagus, 125� Stomach, 127� Intestines, 130� Perianal tumours, 135� Liver, 137� Pancreas (exocrine), 140

125

OESOPHAGUS

Epidemiology

Oesophageal cancer is extremely rare in dogs andcats (0.5% of all cancer) except in areas where theparasite Spirocerca lupi is endemic and causes sec-ondary sarcomas (Ridgeway & Suter 1979). Mostanimals are old and no sex or breed predispositionis reported.

Aetiology

In Africa and south-eastern USA oesophagealfibrosarcomas and osteosarcomas are caused by the parasitic worm Spirocerca lupi, probably bysecreting a carcinogen (Chapter 1). No aetiology isknown for carcinomas which usually predominatein other regions, although ingestion of carcinogensmay play a role.

Pathology

Malignant tumours such as squamous cell carci-noma, leiomyosarcoma, fibrosarcoma and osteosar-coma occur most commonly (Table 8.1). Squamouscell carcinoma often occurs in the middle third ofthe oesophagus, anterior to the heart as an annularthickening. Benign tumours are rarely reported butare usually located in the caudal oesophagus andcardia. Primary tumours may arise from tissuesadjacent to the oesophagus and invade it by directextension.

Tumour behaviour

Malignant tumours are usually aggressive andlocally invasive with lymphatic metastasis to draining lymph nodes or haematogenous spread.

or a stricture with or without megaoesophagus.Fluoroscopy may also be useful to assess swallow-ing or regurgitation.

Biopsy/FNA

Endoscopy should allow visualisation and biopsy ofthe lesion.

Staging

The TNM system is applicable to oesophagealtumours but no stage grouping is recommended(Table 8.2). Clinical and surgical examination isrequired for primary tumour, regional lymph nodesand metastatic sites although endoscopy of theprimary tumour may be sufficient. Regional lymphnodes are the cervical and prescapular (cervicaloesophagus) or mediastinal (thoracic oesophagus)nodes. Radiography of the thorax is required toscreen for pulmonary metastases.

Treatment

Surgery

Although surgical resection of oesophagealtumours is the treatment of choice, complete excision of the tumour and anastomosis of the oesophagus are difficult to achieve unless the mass is very small and non-invasive. The majorityof tumours remain untreatable because of their sizeand the difficulties of reconstruction if adequatesurgical margins are to be obtained. The oesopha-


Tumours spread within the oesophagus longitudi-nally and circumferentially and may result in com-plete obstruction.


Hypertrophic osteopathy (Chapter 2, Table 2.7) has been reported with oesophageal tumours,particularly with sarcomas caused by Spirocercalupi.

Presentation/signs

Animals may present with vague signs such asweight loss or anorexia, but usually pain or diffi-culty in swallowing, dysphagia or regurgitation is also noted. Secondary aspiration pneumonia may occur with persistent regurgitation resulting in respiratory signs.

Investigations

A presumptive diagnosis of an oesophageal tumouris usually made on history and clinical signs butsome further investigations may be necessary.

Bloods

No specific haematological or biochemical changesare associated with oesophageal tumours.

Imaging techniques

Plain radiography of the neck and thoracic cavity may reveal a mass, gas retention oroesophageal dilation cranial to a stricture but contrast studies (barium swallow) may be neededto confirm the diagnosis by demonstrating irregu-larities of the oesophageal mucosa, filling defects

Table 8.1 Tumours of the oesophagus.

Benign MalignantLeiomyoma Squamous cell carcinoma

LeiomyosarcomaFibrosarcomaOsteosarcomaPlasmacytoma

Table 8.2 Clinical stages (TNM) of the oesophagus.Owen (1980).

T Primary tumour (add ‘m’ to the appropriate T category for multiple

tumours)T0 No evidence of tumourT1 Tumour confined to the oesophagusT2 Tumour invading neighbouring structures

N Regional lymph nodes (RLN)N0 No evidence of RLN involvementN1 RLN involved

M Distant metastasis M0 No evidence of metastasisM1 Distant metastasis detected

Pathology

Gastric tumours often involve the cardia, lesser curvature or pyloric antrum of the stomach. In the dog, two thirds of gastric tumours are adeno-carcinomas although a variety of tumour types and benign polyps also occur (Table 8.3). In the cat, the predominant tumour type is lymphoma(usually FeLV negative) with adenocarcinomaoccurring less frequently and mast cell tumourmore rarely.

Adenocarcinoma usually occurs in the pyloricantrum extending into the body of the stomach.Grossly it often appears as an ulcerated, plaque-likethickening, a diffuse non-ulcerated thickening orless commonly as a raised sessile polyp (Fig. 8.1).The plaque-like ulcers can be up to 5cm in diame-

Gastro-intestinal Tract 127

gus is prone to wound healing complications due to a segmental blood supply, lack of omentum and absence of serosa. Full thickness resectionshave the added complication of tension on the surgical repair and those greater than 2cm mayrequire sophisticated reconstruction techniques(Fingeroth 1993).

Radiotherapy

Radiotherapy is not used for oesophageal tumoursin small animals because of the potentially harmfulside-effects to surrounding structures and the riskof oesophageal stricture.

Chemotherapy

Chemotherapy has not been shown to be effectivein the treatment of oesophageal tumours. Althoughdrugs such as doxorubicin have a potential role

for the post-operative treatment of sarcomas,trials have not been established to demonstrate aresponse.

Other

For oesophageal tumours causing strictures, pallia-tion of signs such as regurgitation may be achievedby serial bouginage of the oesophagus. Alterna-tively, a gastrostomy tube could be used as a short-term measure to feed an animal which wasotherwise not in pain.

Prognosis

The prognosis for most oesophageal tumours ispoor because they are usually advanced at the timeof diagnosis and the treatment options are there-fore limited.

Table 8.3 Tumours of the stomach.

Benign MalignantPolyps AdenocarcinomaLeiomyoma Squamous cell carcinoma

LymphomaLeiomyosarcomaFibrosarcomaPlasmacytoma

STOMACH

Epidemiology

Tumours of the stomach are more common thanthose of the oesophagus, but are still relativelyuncommon. Male dogs are more frequentlyaffected than females and benign tumours such asleiomyomas tend to occur in much older animals(mean age 15 years) than do carcinomas (mean age 8 years) (Patnaik et al. 1977). Cats affected with gastric carcinoma are generally over 10 yearsold.

Aetiology

Long term ingestion of dietary carcinogens mayplay a role in the aetiology of gastric cancers. Thebacterium Helicobacter pylori is associated withgastric carcinoma and lymphoma in humans butalthough it causes gastritis and ulceration in dogsand cats, its relationship to gastric tumours is uncer-tain (Marks 1997). In the Belgian shepherd dog, agenetic predisposition to gastric carcinoma hasbeen suggested (Scanzianzi et al. 1991). Althoughlymphoma occurs commonly in the stomach of thecat, few cases appear FeLV positive.

toma of the stomach often metastasises to locallymph nodes, unlike cutaneous plasmacytomawhich is benign.


Gastric lymphoma may be accompanied by para-neoplastic syndromes, particularly hypercalcaemia(Chapter 2).

Presentation/signs

Although mild or vague signs may occur early inthe disease, animals with gastric neoplasia oftenpresent with persistent vomiting or haematemesis,with partially digested blood producing a ‘coffeegrounds’ appearance. Anorexia and weight loss are common and overt melaena or occult faecalblood may be present. Some animals show anteriorabdominal pain.

Investigations

Bloods

Regenerative anaemia may be detected on haema-tological analysis due to gastric haemorrhage butdehydration and haemoconcentration due to vomiting may mask the anaemia. Electrolyte imbal-ances may be obvious on biochemical assessmentbecause of vomiting, and renal parameters such as BUN and creatinine may be elevated due todehydration.

Imaging techniques

Plain radiography of the abdomen rarely re-veals gastric neoplasia and so positive contrast with barium or fluoroscopic examination is usuallyrequired (Fig. 8.2). Changes may include:

• Gastric thickening or ulceration• Filling defects• Loss of rugal folds• Delayed gastric emptying• Reduced or abnormal gastric motility in

particular areas.

Ultrasonography can be used to diagnose gastricneoplasia, detect enlarged lymph nodes and assessother abdominal organs for metastasis.A thickened


ter with a depressed base and overhanging margins.Mucosal rugae around the crater are thickened andlost and a very fibrous or scirrhous appearance iscommon.

Leiomyosarcoma arises in the inner smoothmuscle layer producing an extensive, plaque-likebulge into the lumen, usually without surface ulcer-ation. Leiomyoma has a similar appearance and isfrequently multiple.

Lymphoma produces diffuse non-ulceratedthickening similar to adenocarcinoma but not scir-rhous in nature and with less ulceration and craterformation. Multiple plaques may be noted on thegastric lumen, and tumour may be present in the intestines and abdominal organs as well as thestomach.

Tumour behaviour

Gastric adenocarcinoma is usually locally aggres-sive and may lead to perforation of the stomachwall and peritonitis if ulceration is deep. Obstruc-tion to pyloric outflow may occur in some cases.Tumour plugs often develop in surrounding blood vessels causing ischaemic necrosis, and local metastasis to gastroduodenal and splenic lymphnodes may occur. Distant metastasis to abdominalorgans is common, often by the time of diagnosis,although the lungs are rarely involved. In con-trast to gastric carcinoma, leiomyosarcoma rarely metastasises. Lymphoma may be restricted to thestomach, may involve other abdominal organs andlymph nodes, or may be multicentric. Plasmacy-

Fig. 8.1 Gastric carcinoma, gross specimen showingulcerated tumour at pylorus. (Courtesy of Mr A. Jefferies, Department of Clinical Veterinary Medicine,University of Cambridge.)


gastric wall with disruption of the wall layers is characteristic of neoplasia and ulceration may be recognised as a focal outpouching of the lumi-nal surface that contains trapped gas bubbles.Endoscopy will usually allow visualisation of anygastric lesion and enable a grab biopsy to be taken(Fig. 8.3).

Biopsy/FNA

A definitive diagnosis can be achieved by histologi-cal analysis of a representative biopsy. Endoscopicbiopsy is least invasive but can produce false-negative results. Gastrotomy should produce amore representative biopsy of the lesion which mayhave to be combined with surgical treatment.

Staging

TNM staging is applicable to gastric tumours but no stage grouping is recommended at present(Table 8.4). Surgical exploration of the abdominalcavity is required to examine primary tumour,regional (gastrosplenic) nodes and other possiblemetastatic sites, although endoscopy may be suffi-cient for the primary tumour. Radiography of thethorax is necessary to screen for distant metastasis.

Treatment

Surgery

Surgical resection is the treatment of choice for tumours which have not metastasised but wide local excision is often hard to achieve while allowing satisfactory reconstruction of the stomachand adequate post-operative function. Tumours on the lesser curvature are generally consideredunresectable, whereas those on the fundus or

Fig. 8.2 Radiograph of abdomen following oral administration of barium. Gross thickening along the greater curvature of the stomach is evident (seearrows). The histological diagnosis was gastric carci-noma. (Courtesy of Radiology Department, Depart-ment of Clinical Veterinary Medicine, University ofCambridge.)

Fig. 8.3 Endoscopic view of a gastric carcinoma sitednear the pylorus in a rough collie. (See also Colourplate 26, facing p. 162.) (Courtesy of Mr M. Herrtage,Department of Clinical Veterinary Medicine, Univer-sity of Cambridge.)

to the stomach and easily resectable, surgery mayremain the treatment of choice since chemotherapycarries a potential risk of gastric perforation iftumour cells are present across the full thickness ofthe stomach wall and they are lysed by drug treat-ment. For non-resectable or widespread disease,chemotherapy remains an option (see Chapter 15for protocols).

Adenocarcinomas and other tumours do notusually respond well to chemotherapy and so it isnot recommended.

Other

Medical management of clinical signs such as vom-iting may improve quality of life in non-resectabletumours. Anti-emetics, e.g. metoclopramide, and H2

antagonists, e.g. cimetidine and ranitidine, may betried although any response will be of short-termbenefit only.

Prognosis

Highly variable survival times are reported forgastric neoplasms. Even with surgical resection the prognosis for most malignant gastric tumours is poor with survival times of six months or less because of recurrent or metastatic disease.Survival rates for gastric lymphoma are also lowbecause it does not usually respond well tochemotherapy. In contrast, benign gastric tumourshave a good prognosis and are often cured by surgical resection.


body can be resected successfully. Post-operativecomplications are much higher with pyloric resections.

Pylorectomy and gastroduodenostomy or gastro-jejunostomy have been described for wide localexcision of antral tumours but these procedures aretechnically difficult and there is a significant risk of iatrogenic injury to the pancreas, extrahepaticbiliary system and local blood supply.

Radiotherapy

Radiotherapy is not usually used for gastrictumours in animals.

Chemotherapy

Lymphoma is the only gastric tumour that mayrespond to systemic chemotherapy. If restricted

Table 8.4 Clinical stages (TNM) of tumours of thestomach. Owen (1980).


tumours)T0 No evidence of tumourT1 Tumour not invading serosaT2 Tumour invading serosaT3 Tumour invading neighbouring structures

N Regional lymph nodes (RLN)N0 No evidence of RLN involvementN1 RLN involvedN2 Distant LN involved

M Distant metastasisM0 No evidence of distant metastasisM1 Distant metastasis detected

INTESTINES

Epidemiology

The intestines are not a common site for neoplasiain either the cat or the dog. Tumours tend to occurin older animals (cats often older than dogs)although colorectal polyps may occur in middle-aged dogs. More male than female cats may beaffected and the Siamese may have an increasedrisk of adenocarcinoma.

Aetiology

The cause of intestinal tumours is not knownalthough it is possible that diet may play a role. Ahistory of chronic colitis or dietary sensitivity maypredispose to polyps. Cases of lymphoma in the catare usually not FeLV positive.


Pathology

In the dog, most tumours occur in the large intes-tine, particularly the distal third of the colon andthe rectum.Adenocarcinoma/carcinoma is the mostcommon malignant tumour, and leiomyosarcoma isthe most common sarcoma (Figs 8.4 and 8.5). Othertumour types, inflammatory and benign lymphoidlesions, and non-neoplastic adenomatous polypsmay also be found, particularly in the rectum (Table 8.5). In the cat, most tumours arise in thesmall intestine, with the ileocaecocolic junction,jejunum and ileum being most commonly affected.

Fig. 8.4 Post mortem picture of adenocarcinoma of theintestine in a dog. (Courtesy of Dr P. Nicholls.)

Fig. 8.5 Post mortem picture of leiomyoma of theintestine in a dog. (Courtesy of Dr P. Nicholls.)

Table 8.5 Tumours of the intestines.

Benign MalignantPolyps Adenocarcinoma/carcinomaAdenoma LymphomaLeiomyoma Leiomyosarcoma

Mast cell tumourCarcinoid tumourPlasmacytoma

Fig. 8.6 Post mortem picture of intestinal lymphosar-coma in a cat. (Courtesy of Dr P. Nicholls.)

Lymphoma (Fig. 8.6) predominates here followedby mast cell tumour and adenocarcinoma. In thefeline large intestine, adenocarcinoma may be morecommon than lymphoma.

Adenomas are usually plaque-like sessile massesor pedunculated polyps with broad or narrow stalks.Most rectal adenomatous polyps occur within 2cmof the anus and are usually solitary (Fig. 8.7).

Intestinal carcinomas also usually occur as single,discrete lesions and may be either intramural,intraluminal or annular in nature (Fig. 8.4). Thelatter are usually scirrhous and may stenose the lumen, causing partial or total obstruction ofthe gut, or leave it unaffected. Smooth muscleatrophy may occur with non-scirrhous tumours,causing ballooning and perforation of the intestine.Intramural or intraluminal carcinomas may benodular or plaque-like. Nodular tumours mimicpolyps and tend to grow into the lumen, occa-sionally occluding it.


In general, paraneoplastic syndromes are rarelyassociated with gastro-intestinal tumours. Thosethat are reported include:

• Hyperhistaminaemia with mast cell tumours –produces gastric irritation and vomiting (Chapter 2)

• Hypercalcaemia with intestinal lymphoma• Hypoglycaemia with jejunal leiomyoma.

Intestinal carcinoids in man may release serotoninor other amines which produce signs of chronicdiarrhoea and weight loss but this has not been documented in animals.

Presentation/signs

Most animals with small intestinal neoplasiapresent with vague signs such as anorexia, weightloss, vomiting, diarrhoea or melaena. Those withlarge intestinal neoplasia usually present with constipation, tenesmus or haematochezia. Theonset is usually insidious although an acute crisiscaused by gut perforation and peritonitis maysometimes occur. An abdominal mass may be palpable, especially in cats. Alimentary lymphomain the dog may present with a malabsorption typesyndrome.

Investigations

The history and clinical signs are very important formaking a diagnosis of intestinal neoplasia and oftenhelp locate the disease to the small or large intes-tine. Lesions close to the anus may be detected byrectal examination.

Bloods

A regenerative anaemia may be detected onroutine haematological analysis due to intestinalhaemorrhage. Electrolyte disturbances detected on biochemical screening may suggest intestinalobstruction, and low serum proteins may resultfrom infiltrating tumours, especially in the dog.


Carcinoid tumours are derived from the ente-rochromaffin cells of the intestinal mucosa and areonly rarely reported in the ileum, jejunum andrectum of dogs and cats. They are often expansileand infiltrative.

Intestinal lymphoma may be diffuse or local.Local infiltrates may be single or multiple and mayappear plaque-like, fusiform or nodular. Intramuraltumours are most common although intraluminalforms do occur. Lymphocytes invade the intestinalwall and produce muscle atrophy and ballooning ofa segment which may then rupture if it becomesthin enough. Mesenteric lymph nodes, liver andspleen are often involved.

In the cat mast cell tumours can occur as primarytumours in the gut and metastasise widely else-where. This type of visceral mast cell disease is dis-tinct from systemic mastocytosis which primarilyaffects spleen (Chapter 4.)

Tumour behaviour

Most malignant intestinal tumours are locally invasive and have metastasised by the time of diag-nosis to draining lymph nodes and liver. Tumoursmay cause partial or total intestinal obstruction orlead to gut perforation and peritonitis. Abdominaleffusion may result from widespread carcinomato-sis. Benign adenomatous polyps have been demon-strated to progress to carcinoma in situ and theninvasive carcinoma if left alone. Plasmacytomas ofthe intestine often metastasise to local lymphnodes, unlike those of the skin which are benign.

Fig. 8.7 Rectal polyp.


Imaging techniques

Plain abdominal radiography may detect anabdominal mass, dystrophic calcification, or ‘gravelsigns’ suggestive of an obstruction, but it may notreveal any abnormalities.A barium series or enemais usually necessary to see thickening of the intesti-nal wall, luminal narrowing, ulceration or mucosalirregularities, outlining of a polypoid mass, or todetect an abnormal transit time.

Ultrasonography can be helpful in localising anabdominal mass to the intestines and in assessinglocal lymph nodes and abdominal organs for metastasis. The different layers of intestine can beassessed, making it useful in diagnosis too.

Endoscopy may be useful to diagnose intestinalneoplasia, particularly for tumours in the proximalsmall intestine. Proctoscopy is more helpful forvisualising colorectal lesions.

Biopsy/FNA

A suitable biopsy may be obtained by endoscopyor proctoscopy, although in some cases a histologi-cal diagnosis may have to wait for an incisional orexcisional biopsy at celiotomy.

Staging

The TNM system is applicable to intestinal tumoursalthough no group staging is recommended atpresent (Table 8.6). Clinical examination, surgicalexploration of the abdomen and thoracic radiog-raphy are needed for complete assessment of thethree categories. Regional lymph nodes are themesenteric, caecal, colic and rectal nodes.

Treatment

Surgery

Wide local excision is the treatment of choice for intestinal tumours which show no evidence of metastasis. At celiotomy, the liver, spleen andkidneys should be carefully examined first for evidence of metastasis and then the entire gas-trointestinal tract for evidence of diffuse disease or multiple tumours. Finally regional lymph nodesshould be examined and aspirated to check for

metastasis prior to resection of the tumour, orremoved if grossly enlarged. Any mesenteric oromental adhesions should also be removed en bloc.

In the small intestine, enterectomy and anasto-mosis with surgical margins of at least 5cm isusually possible without compromising intestinalfunction. Proximal duodenal tumours, however,may be difficult to resect without damage to thepancreatic blood supply or duodenal papilla.

Large intestinal tumours may be resected with asubtotal colectomy and this is the recommendedprocedure for unidentified colonic masses orcolonic adenocarcinoma in cats. Dogs tend to tol-erate colonic resection less well than cats and itshould be considered a major procedure. Tumoursat the colorectal junction or in the rectum are more difficult to resect owing to reduced mobilityof the rectum and therefore increased tension onthe anastomosis (Fig. 8.8). Rectal resections have ahigh rate of post-operative complications due to thelack of omentum and poor surgical access. Majorresections can be accomplished via an osteotomy ofthe pubis (‘pelvic split’) or a rectal pull-throughprocedure has been described which combinesceliotomy with a per-rectal approach. These arefraught with difficulties at the reconstruction stageand the poor healing and high bacterial load in the large bowel significantly increase the risk ofdehiscence.

Colorectal polyps should be excised with a wide

Table 8.6 Clinical stages (TNM) of tumours of theintestines. Owen (1980).


tumours)T0 No evidence of tumourT1 Tumour not invading serosaT2 Tumour invading serosaT3 Tumour invading neighbouring structures

N Regional lymph nodes (RLN) N0 No evidence of RLN involvementN1 RLN involvedN2 Distant LN involved

M Distant metastasisM0 No evidence of distant metastasisM1 Distant metastasis detected

Radiotherapy

Radiotherapy is not generally used for intestinal or rectal tumours in animals because of the pro-blems associated with accurate delivery of the dose and side-effects on the normal sections of gut which are extremely radiosensitive and easilydamaged.

Chemotherapy

Intestinal lymphoma is the only tumour suitable forchemotherapy but this is not without complicationsas perforation of the intestinal wall may occur, witha dramatic response of tumour cells to the cytotoxicagents. Focal lesions may therefore be more safelytreated by surgical resection, with careful monitor-ing for the development of disease at new sites or a short (six month) course of post-operativechemotherapy. In one study (Slawienski et al. 1997),cats treated with combination chemotherapy afterresection of colonic lymphoma did not survivelonger than those without chemotherapy. However,cats receiving post-operative doxorubicin therapyafter resection of colonic adenocarcinoma didsurvive significantly longer than those which onlyhad surgery.

Other

Medical management with stool softeners (isogel)may provide some palliation for inoperable cases.

Prognosis

Benign tumours of the small intestine carry anexcellent prognosis if surgically resected. Adeno-carcinoma of the small intestine also carries a good prognosis if adequately excised and there are no gross signs of metastatic disease. Cats with resected small intestinal adenocarcinoma havebeen reported to survive for over a year (Kosovskyet al. 1988).

The prognosis for colorectal polyps is also goodalthough recurrence is possible with large or sessilelesions and with carcinoma in situ. Malignanttumours of the large intestine, however, carry a worse prognosis because of the difficulties with surgical access, making local recurrence and


surgical margin because of the potential for malig-nant transformation. They are accessed by a rectalpull-out approach and can be excised using a partialthickness dissection, not perforating the serosa.Wide full thickness resections of rectal tumoursthat are not annular can also be achieved using thisapproach. Post-operatively these patients shouldreceive stool softeners (isogel) for life. For exten-sive or inaccessible benign rectal tumours, transanalendoscopic resection and cautery has also beenproposed (Holt & Durdley 1999).

Post-operatively, all intestinal tumour resectionsshould be closely monitored for 48–72 hours as therisk of dehiscence is high, particularly if diffusetumour tissue is present at the anastomosis site.Hypoproteinaemic patients with a serum albuminof less than 20g/l are also at increased risk of dehiscence.

Fig. 8.8 Carcinoma of the rectum (a) exposed atsurgery (b) resected. (Courtesy of Dr R.A.S. White,Department of Clinical Veterinary Medicine, Univer-sity of Cambridge.)

(a)

(b)


distant metastasis more likely after resection.Subtotal colectomy may be necessary in some casesto achieve prolonged survival times. Colorectal adenocarcinoma which presents as an annular stricture often has a shorter survival time thannodular or pedunculated masses (Church et al.1987).

Diffuse canine lymphoma does not respond well to chemotherapy but solitary or nodulardisease has a better response. Mean survival timesfor cats with alimentary lymphoma treated withcombination chemotherapy are approximately sixmonths.

PERIANAL TUMOURS

Three types of tumour occur commonly around the anus of the dog and since their behaviour is quite different it is important to distinguish them:

• Perianal/circumanal gland (hepatoid) tumour• Apocrine gland tumour of anal sac• Apocrine gland tumour around anus.

Cats may occasionally develop apocrine gland tumours but they have no sebaceous glands analogous to the perianal/hepatoid glands of thedog. The apocrine tumours of the anal sacs andaround the anus are discussed here as part of thegastroinestinal tract, but hepatoid gland tumours ofthe dog are discussed along with other skin tumoursin Chapter 4.

Epidemiology

Apocrine gland tumours of the anal sac tend to occur in old female dogs whereas the other apocrine gland tumours, which are much lesscommon, have no breed or sex predisposition.

Aetiology

There is no obvious cause for the apocrine glandtumours of either type.

Pathology

Apocrine tumours of the anal sac

These tumours are derived from apocrine sweatglands around the anal sac and are therefore modified sweat gland tumours, usually adenocarci-nomas. They can be quite small grossly and easilymissed unless a rectal examination is performed.Bilateral tumours occur infrequently.

Apocrine tumours around the anus

These are derived from apocrine sweat glands inthe skin and are usually solitary adenomas.

Tumour behaviour

Apocrine adenocarcinomas of the anal sac aremalignant despite their small size and may metas-tasise to the regional lymph nodes, abdominalorgans or lungs. Apocrine gland tumours aroundthe anus are usually benign.


Only the apocrine gland adenocarcinomas of theanal sac are associated with a paraneoplastic syn-drome. Hypercalcaemia is frequently present and isoften noted clinically before the tumour is detected(Chapter 2).

Presentation/signs

Apocrine adenomas around the anus present assolitary, discrete, skin masses which may be-come ulcerated or secondarily infected if licked.Apocrine adenocarcinomas of the anal sac usuallypresent with signs of hypercalcaemia such aspolyuria, polydipsia, muscle tremors, weakness and lethargy. A large, subcutaneous, infiltrating or discrete mass may be noted ventro-lateral to theanus (Fig. 8.9) but often only a small mass, invisibleexternally but palpable per rectum, is present.Occasionally, animals may present with consti-pation or caudal abdominal pain if the primarytumour is not obvious, but the sublumbar lymphnodes are sufficiently enlarged to obstruct therectum.

show secondary azotemia. The degree of dehydra-tion can be assessed using PCV and total protein.Haematological assessment is necessary to rule outother causes of hypercalcaemia such as lymphomaand leukaemia.

Imaging techniques

Abdominal and thoracic radiographs are essen-tial for suspected adenocarcinomas to search formetastatic disease in the regional lymph nodes,abdominal organs or lungs. Ultrasonography maybe helpful to look for metastases in sublumbarlymph nodes and abdominal organs and to guidefine needle aspirates or biopsies.

Biopsy/FNA

A fine needle aspirate for cytological examinationmay give an indication of whether the tumour isbenign or malignant and whether metastasis to thesublumbar lymph nodes has occurred. A definitivediagnosis, however, can only be made on histologi-cal examination of a biopsy sample. A punch orgrab biopsy is best for superficial apocrine tumours,whereas a tru-cut technique may be needed for analgland adenocarcinoma.

Staging

Both tumour types are staged using the TNMsystem as for skin tumours (Chapter 4). There is nogroup staging at present.

Treatment

Surgery

Surgical excision is the treatment of choice for bothtypes of tumour. Care should be taken, however,since extensive resection of peri-anal tumours canresult in faecal incontinence if more than 40–50%of the external anal sphincter is removed. Anal sacadenocarcinomas are often difficult to excise com-pletely, unless they present as very small nodules,and local recurrence is a frequent problem. Therapid rate at which they metastasise often meansthat excision of the primary tumour is not appro-priate unless it is causing local problems such asdyschezia.


Investigations

Palpation

Gross inspection and physical palpation of the massincluding a rectal examination should indicatewhether it is discrete, superficial and likely to bebenign or whether it is extensive, infiltrative andlikely to be an adenocarcinoma. Abdominal orrectal palpation may reveal enlarged sublumbarlymph nodes.

Bloods

Blood samples are extremely important for apocrine tumours of the anal sac which present withhypercalcaemia. Routine biochemical analysis willshow the severity of the hypercalcaemia and may

Fig. 8.9 Apocrine adenocarcinoma of the anal sac, inthis case a relatively discrete mass associated with theleft anal sac.


Radiotherapy

Inadequately excised adenocarcinomas, botharound the anus and of the anal sac, may benefitfrom a course of post-operative radiotherapy butcare must be taken to avoid damaging the analsphincter and causing excessive radiation side-effects in the distal rectum. Local recurrence is often delayed but not always prevented by post-operative radiotherapy. Irradiation of the sublumbar nodes is technically difficult and soradiotherapy of cases with nodal spread is notusually attempted.

Chemotherapy

Since most adenocarcinomas respond poorly tocytotoxic drugs, chemotherapy is not usually rec-ommended for their treatment. Some protocolshave been tried but their efficacy is unproven.

Other

Hypercalcaemia associated with anal sac adenocar-cinomas may require special treatment. The sever-

ity of the hypercalcaemia is often less than thatassociated with lymphoma and saline diuresis maynot be necessary prior to surgical excision of thetumour. If excision is complete, the hypercalcaemiashould resolve. However, the hypercalcaemia oftenpersists after treatment of the primary tumourbecause of its inadequate resection or because ofmetastatic disease. Since the response of residualtumour to chemotherapy is often poor, sympto-matic treatment of the hypercalcaemia with drugssuch as bisphonates may be tried although it isoften unrewarding. (Chapter 2).

Prognosis

The prognosis for perianal apocrine adenomas is excellent if surgically excised, although their malignant counterpart carries a worse prognosisbecause of problems with local recurrence and possible metastasis. Apocrine adenocarcinomas of the anal sac have the worst prognosis since complete local excision may be difficult to achieve;they have often metastasised by the time of diagnosis and persistent hypercalcaemia mayremain a long term problem.

Fig. 8.10 Post mortem picture of metastases in catliver, from a small intestinal carcinoma. (Courtesy ofDr P. Nicholls.)

LIVER

Epidemiology

Although primary liver tumours are rare in smallanimals, the liver is a very common site for metastatic tumours because of the rich bloodsupply provided by the hepatic portal vein andhepatic artery (Fig. 8.10). Hepatic carcinoma is seen in older dogs (over 10 years of age) and isreported to be more common in the male than the female. Cholangiocellular carcinoma is morefrequent in the cat and may be more common infemales.

Aetiology

Exposure to carcinogens and toxins such asnitrosamines has been shown to induce hepatictumours experimentally.

Pathology

Metastatic tumours are the most common tumoursoccurring in the liver. These must be distinguished

and is also important in the cat. It usually occurs inthe massive form (Fig. 8.11) and histologically cellsmay vary from well differentiated to anaplastic(Fig. 8.12). Its benign equivalent, the hepatocellularadenoma, is more common than hepatocellular car-cinoma in dogs and can occur as single or multiplemasses which are often spherical but not necessar-ily encapsulated. It may be difficult to distinguish from well-differentiated hepatocellular carcinomain some cases.

Cholangiocellular adenoma/carcinoma

Cholangiocellular (bile duct) adenoma is rare butcholangiocellular carcinoma (Fig. 8.13) is morecommon, particularly in the cat. Intrahepatic formsusually occur in dogs and cats, although extrahep-atic bile ducts may be affected. Carcinomas may bediffuse, nodular or massive and although usuallysolid, cystic forms which secrete mucous may occur(cystadenocarcinomas). Adenomas may be solitaryor multiple and may also be cystic.

Gall bladder adenoma/carcinoma

These are very rare in the dog and cat. Adenomasmay appear as papillary masses protruding into thegall bladder.

Other primary tumours

Neuro-endocrine carcinoid tumours are occa-sionally reported in the dog, and sarcomas such ashaemangiosarcoma, leiomyosarcoma, fibrosarcoma


from benign nodular hyperplasia which is verycommon in dogs.

Primary tumours may be described in three ways:

• Massive – affecting one liver lobe with smallermetastatic nodules throughout

• Nodular – discrete nodules in several lobes• Diffuse – large areas of the liver infiltrated by

non-encapsulated tumour.

The primary tumours affecting the liver are listedin Table 8.7. The most important primary tumoursof the dog are hepatocellular adenoma (hepatoma),hepatocellular carcinoma, cholangiocarcinoma and hepatic carcinoids. In cats, hepatocellular carcinoma and cholangiocarcinoma are mostimportant.

Hepatocellular adenoma/carcinoma

Hepatocellular carcinoma is the most common ofthe malignant primary liver tumours in the dog

Fig. 8.11 Post mortem picture of hepatocellular carci-noma in dog. (Courtesy of Dr P. Nicholls.)

Fig. 8.12 Histological section of a hepatocellular carcinoma from a dog.

Table 8.7 Tumours of the liver.

Benign MalignantHepatocellular adenoma Hepatocellular carcinoma

(hepatoma)Bile duct/cholangiocellular Bile duct/cholangiocellular

adenoma carcinomaGall bladder adenoma Gall bladder carcinoma

Hepatic carcinoidsHaemangiosarcomaOther sarcomasMast cell tumour


or osteosarcoma may occur as primary tumours.Thelatter should be differentiated from metastases.

Tumour behaviour

Both hepatocellular and cholangiocellular carci-nomas are locally invasive and highly metastatictumours, spreading within the liver and to locallymph nodes, lungs, abdominal organs and peri-toneum. The corresponding adenomas grow expan-sively within the liver parenchyma.


Hypoglycaemia is reported with some liver neo-plasms and is attributed to increased use of glucoseor production of hormones with insulin-like activ-ity (Chapter 2, Table 2.5).

Presentation/signs

Liver tumours usually present with vague clinicalsigns such as anorexia, weight loss, vomiting, poly-dipsia, ascites or hepatic encephalopathy (CNSsigns). Icterus is uncommon in dogs (less than 20%of cases) and is usually associated with liver diseaseother than neoplasia. Many hepatic tumours, par-ticularly hepatomas, may be palpable as a mass inthe anterior abdomen.

Investigations

Bloods

The most consistent finding for hepatic tumours on biochemical analysis of blood is increased activity of ALT and SAP, although AST and LDH are also frequently elevated. Serum bilirubinis increased in a minority of dogs but is morecommon in cats with hepatocellular carcinoma.Serum proteins may be low because of interference with their production and since clotting factors may be affected, clotting tests should be performedbefore major surgery. Hypoglycaemia may bedetected.

Imaging techniques

Diffuse or focal hepatomegaly, rounding of livermargins or irregularity of liver outline with dis-placement of adjacent abdominal organs may bevisible on plain radiographs of the abdomen. Occa-sionally localised calcification or loss of abdominaldetail associated with ascites may be seen. Anormal size and shape to the liver does not precludeneoplasia, however, and ultrasonography is morehelpful in defining a mass or assessing a neoplasticinfiltrate in the liver.

Abdominocentesis

If abdominal fluid is present, neoplastic cells may be detected on cytological examination of sediment. Most effusions are modified transu-dates but haemorrhage may occur with tumourrupture.

Fig. 8.13 Gross appearance of a cholangiocellular car-cinoma in a dog. (Courtesy of Dr P. Nicholls.)

Treatment

Surgery

Surgical excision has the best chance of cure for hepatic adenoma, massive hepatocellular carci-noma and hepatobiliary cystadenocarcinoma. Fordiscrete tumours affecting one or more lobe, surgi-cal excision may be possible either by nodulectomyor lobectomy. Large portions of the liver may be removed without its loss of function since itspowers of regeneration are good. Diffuse tumoursand widespread nodular disease are more difficultto deal with, however.

Radiotherapy

Radiotherapy is not usually used to treat livertumours in animals because of the potential side-effects on other abdominal organs.

Chemotherapy

No chemotherapy regimes are recommended for the treatment of primary liver tumours. Somemetastatic sarcomas, e.g. haemangiosarcoma, mayrespond to cytotoxic drugs but treatment for suchtumours is better administered before metastaticdisease is detected clinically (see Chapters 3 and 5).

Prognosis

The prognosis for benign liver tumours is good ifthey can be adequately excised. Malignant tumoursand metastatic tumours have a poor prognosisbecause treatment options are restricted, althoughmean survival times of approximately a year have been reported for massive hepatocellular carcinoma following surgery (Kosovsky et al. 1989).


Biopsy/FNA

Ultrasound guided aspirates often reveal neo-plastic cells and may distinguish between benignand malignant tumours although hepatoma andwell differentiated carcinomas can be difficult. Adefinitive diagnosis is dependent on biopsy. Needlecore biopsies will give more information if sufficenttissue is obtained but if a larger sample is required,a celiotomy will be necessary.

Staging

The TNM staging system can be applied to livertumours (Table 8.8) but no group staging is recom-mended at present. All three categories require surgical examination (celiotomy or laparoscopy)for complete assessment, the regional lymph nodes being the hepatic and diaphragmatic nodes.Radiography of the thorax is also indicated to look for pulmonary metastases.

Table 8.8 Clinical stages (TNM) of tumours of theliver. Owen (1980).


tumours)T0 No evidence of tumourT1 Tumour involving one lobeT2 Tumour involving more than one lobeT3 Tumour invading neighbouring structures

N Regional lymph nodes (RLN) N0 No evidence of RLN involvementN1 RLN involvedN2 Distant LN involved

M Distant metastasisM0 No evidence of metastasisM1 Distant metastasis detected

PANCREAS (EXOCRINE)

Epidemiology

Primary tumours of the pancreas are relatively rarebut the pancreas is also a site for metastatictumours, particularly from the gastro-intestinaltract. Older female dogs (mean age 10 years) and

the Airedale terrier breed may be predisposed topancreatic carcinoma. Affected cats are also old(mean age 12 years).

Aetiology

The cause of pancreatic neoplasms is unknown inboth the dog and cat.


Pathology

It is important to distinguish primary pancreatictumours from metastatic tumours and from nodularhyperplasia which is common in older animals.Primary tumours are derived from the acinar cells or the pancreatic ducts and are therefore adenomas, adenocarcinomas, or carcinomas, thelatter being much more common in both the dogand cat. Most are located in the middle portion ofthe pancreas and may occur as single discretemasses or multiple dispersed masses. Mineralisa-tion and fat necrosis may be noted. Histologically,tubular structures, acini or solid sheets of cells may be seen and these need to be distinguishedfrom carcinomas of the pancreatic islet cells (seeChapter 14).

Tumour behaviour

Pancreatic adenomas are often small, solitarytumours which have functional effects because theycompress the surrounding pancreas but they do notmetastasise. Carcinomas, however, are relativelyaggressive (Fig. 8.14), invading the stomach or duo-denum locally and metastasising most commonly tothe liver, but also to the lymph nodes, other abdom-inal organs, peritoneal surface and lungs. Metas-tases to vertebrae and the femur have also beenreported. Tumours may block the common bile duct and cause an obstruction to biliary flow or, inextreme cases, exocrine pancreatic insufficiency if

pancreatic atrophy occurs. Tumour necrosis mayarise if the vascular supply is inadequate and thismay produce an inflammatory response that canlead to pancreatitis.


Paraneoplastic alopecia affecting the ventrum,limbs, face or diffuse zones has been reported incats with pancreatic adenocarcinoma (Brooks et al.1994; Tasker et al. 1999).

Presentation/signs

Clinical signs are usually non-specific and includeweight loss, anorexia, lethargy, vomiting, diarrhoea,constipation, abdominal pain or distension. Clinicalsigns may be related more to hepatic metastasesthan to pancreatic disease. Animals with biliaryobstruction may present with jaundice or othersigns of liver disease. Pancreatic tumours are not easily palpable in dogs, but in cats they are often larger and more easily felt in the abdomen.

Investigations

Bloods

Haematological and biochemical parameters areoften within normal limits but elevated liverenzymes or bilirubinaemia may indicate cholestasisor biliary obstruction. Hyperglycaemia associatedwith concurrent beta cell destruction, neutrophilia,anaemia and hypokalaemia have been reported.Amylase and lipase serum activities are rarely elevated.

Imaging techniques

An ill-defined mass or a mottled appearance due to local peritonitis may be identifiable on plainabdominal films. The descending duodenum andpylorus may appear displaced but the proximalduodenum often appears fixed in a ‘c-shape’ on theventrodorsal view due to spasticity and dilation.Generalised loss of abdominal detail and increasedradiodensity may be noted with peritoneal metas-tasis and effusion.

Fig. 8.14 Post mortem picture of pancreatic carcinomain dog. (Courtesy of Dr P. Nicholls.)

Treatment

Surgery

Partial pancreatectomy is the treatment of choicefor small pancreatic adenomas identified atceliotomy. Adenocarcinomas, however, are oftenidentified at a late stage when metastasis or con-siderable local invasion has often occurred. Forthose rare cases without metastasis, surgical resec-tion can be attempted but complete excision is noteasy to achieve. A sound understanding of theregional anatomy is essential in order to preventpost-operative morbidity due to obstruction of themain pancreatic duct or damage to the vascularsupply of the proximal duodenum. Tumours in thebody or base of the pancreas are usually consideredinoperable.Total pancreatectomy is associated withhigh morbidity and mortality and should not beattempted.

Radiotherapy

Radiotherapy is of limited value for tumours of thepancreas and is not recommended.

Chemotherapy

Chemotherapy is of limited value for tumours ofthe pancreas and is not recommended.

Prognosis

The prognosis for pancreatic adenocarcinomas ispoor because of their invasive nature and earlymetastasis. Survival times do not exceed a year.

References

Brooks, D.G., Campbell, K.L., Dennis, J.S. & Dunstan,R.W. (1994) Pancreatic paraneoplastic alopecia in threecats. Journal of the American Animal Hospital Associa-tion, (30), 557–63.

Church, E.M., Mahlhaff, C.J. & Patnaik, A.K (1987) Col-orectal adenocarcinoma in dogs: 78 cases (1973–1984).Journal of the American Veterinary Medical Associa-tion, (191), 727–30.

Fingeroth, J.M. (1993) Surgical techniques foroesophageal disease. In: Textbook of Small AnimalSurgery (ed. D. Slatter), 2nd edn, pp. 549–53. W.B.Saunders, Philadelphia.


Ultrasonography can be more helpful, especiallyin cases where radiographic detail in the cranialabdomen is lost. It should give an indication oftumour size and invasiveness.

Biopsy/FNA

Ultrasound guided fine needle aspiration is pos-sible if a suspicious mass is identifiable but often thepancreatic tumour cells do not exfoliate well and a cytological diagnosis is difficult to obtain. Evencytological examination of peritoneal effusionsrarely reveals tumour cells. A histological diagnosisis usually made at exploratory celiotomy, either by excising the whole tumour or if inoperable, bytaking a small sample. Pancreatic biopsy can becarried out by a shave of the abnormal tissue with a scalpel blade or crush ligation of a smallportion with a ligature. Normal pancreatic tissueshould be left undisturbed if possible. In somecases, the diagnosis is not made until post mortemexamination.

Staging

A TNM staging scheme is available for pancreatictumours (Table 8.9) but requires surgical explo-ration (celiotomy or laparoscopy) to evaluate theprimary tumour, regional (splenic and hepatic)nodes and metastatic disease. Radiography of thethorax is also indicated to look for pulmonarymetastases.

Table 8.9 Clinical stages (TNM) of tumours of thepancreas. Owen (1980).

T Primary tumour T0 No evidence of tumourT1 Tumour present

N Regional lymph nodes (RLN)N0 No evidence of RLN involvementN1 RLN involvedN2 Distant LN involved

M Distant metastasisM0 No evidence of metastasisM1 Distant metastasis detected


Holt, P.E. & Durdley, P. (1999) Transanal endoscopictreatment of benign canine rectal tumours: preliminaryresults in six cases (1992–1996). Journal of SmallAnimal Practice, (40), 423–7.

Kosovsky, J.E., Matthiesen, D.T. & Patnaik, A.K. (1988)Small intestinal adenocarcinoma in cats: 32 cases(1978–1985). Journal of the American VeterinaryMedical Association, (192), 233–5.

Kosovsky, J.E., Manfara-Marretta, S., Matthiesen, D.T.et al. (1989) Results of partial hepatectomy in 18 dogswith hepatocellular carcinoma. Journal of the AmericanAnimal Hospital Association, (25), 203–206.

Marks, S.L. (1997) Bacterial gastroenteritis in dogs andcats: more common than you think. Proceedings of theAmerican College of Veterinary Internal Medicine, (15),237–9.

Owen, L.N. (1980) TNM Classification of Tumours inDomestic Animals. World Health Organisation,Geneva.

Patnaik, A.K., Hurvitz, A.I. & Johnson, G.F. (1977) Gastrointestinal neoplasms. Veterinary Pathology, (14),547–55.

Ridgeway, R.L. & Suter, P.F. (1979) Clinical and radi-ographic signs in primary and metastatic oesophagealneoplasms of the dog. Journal of the American Veteri-nary Medical Association, (174), 700–704.

Scanzianzi, E., Giusti, A.M., Gualtieri, M. & Fonda, D.(1991) Gastric carcinoma in the Belgian shepherd dog.Journal of Small Animal Practice, 32, 465–9.

Slawienski, M.J., Mauldin, G.E., Mauldin, G.N. & Patnaik,A.K. (1997) Malignant colonic neoplasia in cats: 46cases (1990–1996). Journal of the American VeterinaryMedical Association, (211), 878–81.

Tasker, S., Griffon, D.J., Nuttall, T.J. & Hill, P.B. (1999)Resolution of paraneoplastic alopecia following surgi-cal removal of a pancreatic carcinoma in a cat. Journalof Small Animal Practice, (40), 16–19.

Further reading

Birchard, S.J., Couto, C.G. & Johnson, S. (1986) Nonlym-phoid intestinal neoplasia in 32 dogs and 14 cats.

Journal of the American Veterinary Medical Associa-tion, (22), 533–7.

Couto, C.G., Rutgers, H.C., Sherding, R.G. & Rojko, J.(1989) Gastrointestinal lymphoma in 20 dogs. Journalof Veterinary Internal Medicine, (3), 73–8.

Fonda, D., Gualtieri, M. & Scanziani, E. (1989) Gastriccarcinoma in the dog: a clinicopathological study of 11cases. Journal of Small Animal Practice, (30), 353–60.

Gibbs, C. & Pearson, H. (1986) Localised tumours of thecanine small intestine: a report of 20 cases. Journal ofSmall Animal Practice, (27), 507–19.

Holt, P.E. & Lucke, V.M. (1985) Rectal neoplasia in thedog: a clinicopathologic review of 31 cases. VeterinaryRecord, (116), 400–405.

Kapatkin, A.S., Mullen, H.S., Matthiesen, D.T. & Patnaik,A.K. (1992) Leiomyosarcoma in dogs: 44 cases(1983–1988). Journal of the American VeterinaryMedical Association, (201), 1077–79.

Lamb, C.R. & Grierson, J. (1999) Ultrasonographicappearance of primary gastric neoplasia in 21 dogs.Journal of Small Animal Practice, (40), 211–15.

Patnaik, A.K. (1992) A morphologic and immunocyto-chemical study of hepatic neoplasms in cats. VeterinaryPathology, (29), 405–15.

Patnaik, A.K., Liu, S.K. & Johnson, G.F. (1976) Fe-line intestinal adenocarcinoma in cats: 32 cases(1978–1985). Veterinary Pathology, (13), 1–10.

Patnaik, A.K., Hurvitz, A.I. & Lieberman, P.H. (1980)Canine hepatic neoplasms: a clinicopathologic study.Veterinary Pathology, (17), 553–64.

Penninck, D.G., Moore, A.S. & Gliatto, J. (1998) Ultra-sonography of canine gastric epithelial neoplasia. Vet-erinary Radiology and Ultrasound, (39), 342–8.

Steiner, J.M. & Williams, D.A. (1997) Feline exocrine pan-creatic disorders: insufficiency, neoplasia and uncom-mon conditions. Compendium of Continuing Educationfor the Practising Veterinarian, (19), 836–48.

Sullivan, M., Lee, R., Fisher, E.W., Nash, A.S. & McCandlish, I.A.P. (1987) A study of 31 cases of gastriccarcinoma in dogs. Veterinary Record, (120), 79–83.

White, R.A.S. & Gorman, N.T. (1987) The clinical diagnosis and management of rectal and pararectaltumours in the dog. Journal of Small Animal Practice,(28), 87–107.

9Respiratory Tract

lung tumours are malignant with adenocarcinomapredominating. Laryngeal and tracheal tumours arerare.

The lung is the commonest site for tumours of therespiratory system (excluding the nasal cavity),although primary lung tumours occur infrequentlycompared to metastatic tumours. Most primary

� Larynx, 144� Trachea, 147� Lung, 148

144

Epidemiology

Cancer of the larynx is rare in the dog and cat.Although most tumour types are likely to occur inmiddle-aged or older animals, the laryngeal specifictumour, the oncocytoma, occurs in young maturedogs.

Aetiology

There are no known aetiological factors for primarylung tumours in animals but smoking and alcoholconsumption predispose to laryngeal cancer inman.

Pathology

A variety of laryngeal tumours have been reportedin the dog (Table 9.1). Of these, squamous cell car-cinoma is the most common, but all are rare. Benigntumours include lipoma, leiomyoma, rhabdomy-

oma and oncocytoma, the latter being unique to the larynx. Occasionally, thyroid carcinomas mayinvade locally to involve the larynx.

In the cat, lymphoma is the most common laryn-geal tumour but squamous cell carcinoma and morerarely, adenocarcinoma, have been reported.

Canine oncocytoma

Grossly, the oncocytoma usually develops as a wellcircumscribed mass (Fig. 9.1) although it canbecome very large and protrude from the laryn-geal ventricle. Histologically, sheets of large, epithe-lioid cells with granular, acidophilic cytoplasm areseen in the submucosa. These are divided intolobules by fibrovascular stroma. Areas of haemor-rhage and necrosis are common, making haeman-giosarcoma an important differential, but theoverlying mucosa is usually intact. The histogenesisof the oncocytes is not known although in man theyare derived from glandular epithelia of the headand neck.

LARYNX

Respiratory Tract 145

Bloods

No haematological or biochemical changes arecommonly associated with laryngeal tumours.

Imaging techniques

Radiography of the larynx is not usually neces-sary but may reveal a soft tissue swelling displacingadjacent structures in the neck and pharyngealregion (Fig. 9.2). Radiography of the thorax isessential for all malignant tumours to screen for pulmonary metastases. Ultrasonography andMRI can also be used to image the larynx and cartilages.

Tumour behaviour

Oncocytomas in the dog are benign and minimallyinvasive but can grow quite large, whereas all malig-nant tumours of the larynx are very locally invasiveand metastatic.


No paraneoplastic syndromes are commonly asso-ciated with laryngeal tumours.

Presentation/signs

Animals with laryngeal tumours usually presentwith insidious signs such as a progressive change invocalisation, stertorous breathing, coughing, exer-cise intolerance, dysphagia or dyspnoea. Advancedcases with respiratory obstruction or animals withacute laryngeal spasm due to inflammation andpain may present with syncope or cyanosis.

Investigations

Direct visualisation

Most laryngeal tumours can be visualised undergeneral anaesthesia although care should be takento ensure a narrow endotracheal tube can be passedto maintain the airway. A tracheostomy should beperformed if a large laryngeal mass is suspected.The larynx often appears very inflamed and oede-matous secondary to air turbulence caused by thetumour.

Table 9.1 Tumours of the larynx.

Benign MalignantRhabdomyoma Squamous cell carcinomaOncocytoma AdenocarcinomaLeiomyoma FibrosarcomaLipoma OsteosarcomaOsteochondroma Chondrosarcoma

RhabdomyosarcomaLymphomaMast cell tumourMalignant melanoma

Fig. 9.1 Oncocytoma of the larynx in a dog. (Courtesyof Dr R.A.S. White, Department of Clinical VeterinaryMedicine, University of Cambridge.)


Biopsy/FNA

Ulcerating neoplasia needs to be differentiatedfrom granulomatous laryngitis which responds tomedical management.A definitive diagnosis of neo-plasia can only be obtained by histological exami-nation of a biopsy taken from the laryngeal mass.This is best obtained via the oropharynx undergeneral anaesthesia. Care should be taken to mini-mise haemorrhage or post-operative inflammationand swelling. After a biopsy procedure, dexam-ethasone may be helpful.

Staging

A combined TNM staging system is available for the larynx, trachea and lungs (see Table 9.4,

lungs). Regional lymph nodes for the larynx are theanterior cervical and pharyngeal nodes.

Treatment

Surgery

The oncocytoma is usually the best candidate forsurgical excision and preservation of laryngealfunction although it may also be possible for otherbenign tumours such as rhabdomyoma. Excision ofmalignant tumours is usually impossible due totheir invasive nature.

Before laryngeal surgery, care should be taken toassess the larynx for other obstructive airwaydisease such as laryngeal paralysis or laryngeal col-lapse which may compromise airflow in the re-covery period. During surgery, the airway should bemaintained with a suitable endotracheal tube ortemporary tracheostomy while the oncocytoma isdissected from its submucosal location. Tumoursare best approached intra-orally to minimise disruption to the larynx. Haemostasis and gentlehandling of the tissues are essential to preventairway obstruction in the recovery period althoughthis risk is also avoided with a temporary tracheostomy.

Although partial, hemi and total laryngectomyare reported for resection of laryngeal tumours,post-operative management is difficult and theyshould only be undertaken with extreme caution.

Radiotherapy

External beam radiotherapy is not usually appliedto laryngeal tumours in small animals because ofpotential radiation side-effects to the normal carti-lage and other radio-sensitive structures in thepharynx and neck. It may, however, be of palliativevalue in selected cases or in laryngeal lymphoma.

Chemotherapy

Chemotherapy may be of use for laryngeal lym-phoma (see Lymphoma in Chapter 15) but mostother tumours are not chemosensitive.

Prognosis

Benign tumours of the larynx carry a good prognosis if they can be surgically resected.

Fig. 9.2 Radiograph of chondrosarcoma associatedwith hyoid apparatus. (Courtesy of Radiology Depart-ment, Department of Clinical Veterinary Medicine,University of Cambridge.)


Oncocytomas are generally slow growing and local recurrence, if they are inadequately excised,may take months or years. Malignant tumours

Presentation/signs

The presenting signs of tracheal tumours are ofteninsidious but usually include coughing, respiratoryobstruction or exercise intolerance.

Investigations

Bloods

No haematological or biochemical changes areexpected with tracheal tumours.

Imaging techniques

A tracheal mass may be visible on plain radi-ographs of the neck or cranial thorax. Narrowing ofthe tracheal lumen is often noted and metastasis to the bronchial lymph nodes may be seen. Thewhole thorax should be radiographed to screen forpulmonary metastases if a malignant tumour is suspected.

Biopsy/FNA

A suitable biopsy can usually be obtained using arigid bronchoscope or an endoscope if the massprotrudes into the lumen of the trachea. Alterna-tively, an excisional biopsy may have to be per-formed when the mass is explored surgically as partof the treatment procedure.

Staging

A combined TNM staging system is available forthe larynx, trachea and lungs (see Table 9.4, lungs).Regional lymph nodes for the anterior trachea arethe anterior cervical and pharyngeal nodes and forthe rest of the trachea, the intrathoracic nodes.

Table 9.2 Tumours of the trachea.

Benign MalignantLeiomyoma Squamous cell carcinomaPolyps AdenocarcinomaOsteochondroma ChondrosarcomaChondroma Rhabdomyosarcoma

OsteosarcomaLymphomaPlasmacytoma

carry a very poor prognosis since wide resection is too difficult and respiratory obstruction isinevitable.

TRACHEA

Epidemiology

Tumours of the trachea occur even more rarely thanlaryngeal tumours in dogs and cats. They are likely to occur in middle-aged or older animals butosteochondromas have been recorded in younggrowing dogs with active osteochondral ossificationsites.

Aetiology

There are no known aetiological factors.

Pathology

Malignant tumours reported in the trachea arelisted in Table 9.2. Benign tumours include leiomy-oma and osteochondroma.The latter grow from thecartilagenous tracheal rings in immature dogs andmay not be truly neoplastic.

Tumour behaviour

Tumours of the trachea may extend into the lumenor invade local tissues. Metastasis to local lymphnodes and lungs is common.


No paraneoplastic syndromes are commonly asso-ciated with tracheal tumours.

Radiotherapy

Radiotherapy is not usually used for trachealtumours because of potential radiation side-effectsto the cartilage of the normal tracheal rings andother structures of the neck and thorax.

Chemotherapy

Few malignant tracheal tumours except lymphomaare amenable to chemotherapy. Even post-opera-tive therapy for highly metastatic tumours is rarelyattempted because so few tumours are amenable tosurgical excision.

Prognosis

Benign tumours carry a reasonable prognosis if sur-gically excised, but malignant tumours are rarelytreated successfully.


Treatment

Surgery

Benign osteochondromas can be surgically excisedrelatively easily and the trachea joined by end-to-end anastomosis. Some malignant tumours may beamenable to surgery if small and minimally inva-sive. Great care must be taken not to damage thecaudal thyroid artery that supplies the trachea.Up to a third of the trachea can be removed inadults provided the remainder can be sufficientlymobilised to allow anastomosis. Puppies and kittenscan only tolerate 25% removal as the tracheal ringsare unable to tolerate the tension in the staysutures. Tension on the anastomosis increases the likelihood of granulation tissue forming and thus stenosis at the surgical site. It may bereduced by using tension sutures, providing lateraland ventral support to the anastomosis or bykeeping the animal’s head in flexion for two weekspost-operatively.

Table 9.3 Primary lung tumours in the dog and cat.

Histological types (Moulton 1990)Adenocarcinoma/carcinoma

bronchial glandbronchogenicbronchiolar-alveolar

Squamous cell (epidermoid) carcinomaAnaplastic carcinoma

small celllarge cell

SarcomasBenign tumoursLymphomatoid granulomatosis (rare)

LUNG

Epidemiology

Primary lung tumours are relatively uncommon in small animals, accounting for approximately 1%of all tumours in the dog and less than 0.5% in thecat. In contrast, the lungs are one of the mostcommon sites for metastatic tumours in smallanimals.

An annual incidence of 4.17 cases per 100 000dogs and 2.2 cases per 100 000 cats has beenreported for primary lung tumours (Dorn et al.1968). Older dogs (mean 9–11 years) and aged cats(mean 11–12 years) tend to be affected. Tumoursmay occur more frequently in the right lung, par-ticularly the caudal lobe in the dog or the left lobesof the cat, although others agree that left and rightlungs are equally affected.

Aetiology

There is experimental evidence of an associationbetween cigarette smoke exposure and develop-ment of lung tumours in beagle dogs mimicking

the effect of similar carcinogen exposure in man.Ionising radiation, atmospheric pollutants and aromatic amines also cause lung tumours in experimental animals.

Pathology

The most common type of primary lung tumour indogs and cats is adenocarcinoma (Table 9.3). Squa-


mous cell carcinoma and anaplastic carcinoma(small and large cell) are less common and sarco-mas and benign tumours are rare.

Carcinoma or adenocarcinoma of the lung maybe classified as differentiated or undifferentiatedand although the site of origin may be difficult todetermine for a large, advanced tumour, it may alsobe classified by its location as:

• Bronchial gland• Bronchogenic• Bronchiolar-alveolar.

Bronchiolar-alveolar carcinoma accounts for over70% of lung tumours in the dog and cat and isusually peripheral and multifocal in nature. Differ-entiated tumours are characterised by well-formedglands of bronchiolar/alveolar derivation whichmay have a papillary appearance. Metaplasia of thestroma to bone or cartilage may be noted and sometumours may produce mucinous material. Undif-ferentiated tumours are more common in the catand are characterised by irregular, poorly formedglands resembling immature bronchioles or alveoli,and squamous metaplasia.

Bronchial carcinomas, in contrast, are derivedfrom the serous or mucous bronchial glands in thewall of the major airways around the hilus and aretherefore located in this region. Squamous meta-plasia may be noted, or hyperplastic thickening ofthe bronchial epithelium overlying the neoplastictissue.

Bronchogenic carcinoma which is common inman, is very rare in animals. It arises from the pseu-dostratified columnar surface epithelium of a bron-chus and shows papillary or glandular morphology.

Squamous cell carcinoma represents about 15%of lung tumours in the dog and cat, which is muchless than in man. It develops where the bronchialmucosa has undergone squamous metaplasia,usually in the major bronchi. Solid branching cordsof epithelial cells without a glandular pattern andvarying degrees of keratinisation are characteristic.Tumours are very invasive and there is always muchfibrosis of the stroma.

Anaplastic small cell and large cell carcinomasare also much less common than in man and arederived from alveolar epithelium, either type I ortype II pneumocytes. The virtue of dividing theminto small and large cell types is debatable in dogsand cats.

Tumour behaviour

The behaviour of primary lung tumours depends tosome extent on their degree of differentiation,undifferentiated bronchiolar-alveolar carcinoma,which is common in cats, being highly invasive andmetastatic. Squamous cell carcinoma and anaplas-tic carcinoma generally have a higher metastaticrate than adenocarcinoma. Primary lung tumoursmay spread in a limited way via the alveoli andairways or by pleural invasion and adhesions, butmore commonly via the lymphatics or blood.Metastatic spread may be detected within the lungs,the bronchial lymph nodes, distant sites within thepleural cavity or, if haematogenous spread occurs,extrathoracic sites such as skeletal muscle, skin,abdominal organs, bone or brain. Metastasis to thedigits has also been reported as a syndrome associ-ated with primary lung cancer (usually squamouscell carcinoma) in cats (May & Newsholme 1989;Scott Moncrieff et al. 1989).


Hypertrophic osteopathy (Maries’ disease) is thecommonest paraneoplastic syndrome associatedwith a lung mass, occurring in up to 15% of caninecases but more rarely in the cat (Figs 9.3–9.5) (seeChapter 2, Table 2.7 for details). Hypercalcaemiahas also been reported in some dogs with lungtumours, as has adrenocorticotrophic hormone(ACTH) secretion and generalised neuropathy.Both adenocarcinoma and small cell lung carci-noma can secrete neuropeptides in man but this hasnot been reported in animals.

Presentation/signs

Most dogs have clinical signs associated with aprimary tumour although 30% may be asympto-matic (McNiel et al. 1997).Asymptomatic presenta-tion is less common in the cat, although the clinicalsigns detected in a third of cases may not be associ-ated with respiratory disease (Hahn & McEntee1997). The most common presenting signs includenon-productive or productive cough, lethargy,haemoptysis and dyspnoea. Pleural effusion orregurgitation may occur (particularly in the cat) andnon-specific signs such as anorexia, pyrexia, weight


loss (common in the cat), lameness (either as a paraneoplastic syndrome or due to skeletal andbone metastases) and exercise intolerance may bereported.

Investigations

Bloods

No haematological or biochemical changes arecommonly expected with lung tumours.

Imaging techniques

Thoracic radiography is the most important diagnostic tool and will reveal a primary lung neo-plasm in most cases (Fig. 9.6). This may present as:

• A solitary mass• Multiple nodules• A diffuse reticulonodular pattern of all lobes• Consolidation of one or more lobes.

Both lateral views and dorso-ventral views may beneeded to ensure small masses are detected and to

Fig. 9.4 Radiographs of the lower limbs showedperiosteal new bone characteristic of hypertrophicosteopathy.

Fig. 9.5 Radiograph of the thorax showed several largepulmonary masses, the cause of the hypertrophicosteopathy. On histopathology these were anaplasticsoft tissue sarcomas, possibly rhabdomyosarcoma.

Fig. 9.3 Four year old boxer bitch presented withpainful swelling of the distal limbs.


locate the lung lobe affected. Pleural fluid, hilar ormediastinal lymphadenopathy or calcification ofthe lesion may also be present. Radiography of the abdomen and skeleton should be performed to look for distant metastases and hypertrophicosteopathy.

To detect metastatic lung tumours, both left andright lateral thoracic views are essential to view eachlung fully aerated but dorso-ventral views are notalways necessary. Metastases are usually noted as:

• Well defined ‘cannon-balls’• Multiple, small miliary nodules• A diffuse interstitial – more common for lym-

phoma or mast cell tumours.

Ultrasonography may be useful to image a lungtumour in cases where the mass is large and thereis no overlying air-filled lung, i.e. if it contacts thethoracic wall or diaphragm or if pleural fluid ispresent.

Bronchoscopy/tracheo-bronchial washes

Bronchoscopy may be useful in viewing a hilar massand accessing it for grab biopsy, but for moreperipheral cases, endoscopy may not be appropri-ate. Similarly, cytological examination of tracheo-bronchial washes may or may not detect neoplasticcells.

Thoracocentesis

For cases with pleural effusion, a modified tran-sudate is usually obtained at thoracocentesis.Neoplastic cells may be visible on cytological examination.

Biopsy/FNA

In some cases, a diagnosis may be made on cyto-logical examination of tracheobronchial washes orpercutaneous ultrasound-guided fine needle aspi-rates (Fig. 9.7). In some samples, however, inflam-mation, haemorrhage and necrotic debris mayobscure any neoplastic cells. Alternatively, a bron-choscopic grab biopsy or a percutaneous needlebiopsy may be used to obtain a sample forhistopathology. More reliable results may beobtained with cats than dogs, but if non-diagnosticsamples are consistently obtained, a thoracotomymay be needed for a definitive biopsy. Some arguethat the risks of tumour seeding, pneumothorax andhaemorrhage, along with the poor diagnostic assis-tance often obtained from aspirate or biopsy pro-cedures, suggest that surgical exploration should bethe first approach to a solitary lung mass detectedradiographically.

Fig. 9.6 Lateral (a) and dorsoventral (b) radiographs of the thorax of a dog with a solitary soft tissue mass in theright dorsal lung. This was a primary bronchial carcinoma.

(a) (b)

congestion and haemorrhage during dissection.There is little chance of seeding of neoplastic cellsthrough the venous outflow as the lung lobe col-lapses after arterial ligation. With multiple massesor affected lymph nodes it may not be possible toexcise all tumour. Pneumonectomy can be per-formed if lesions have extended to all the lung lobesunilaterally and the contralateral lung is unaf-fected. However, a right sided pneumonectomyremoves more than 50% of lung tissue and is thusfatal. Although nodes should be inspected forstaging of the disease, and metastatic enlargementcarries a worse prognosis, it is not necessarily recommended to remove affected nodes.

The post-operative care involves placement of athoracostomy tube to allow drainage of air andearly detection of haemorrhage if ligatures wereinsufficient or there is bronchial leakage. Post-operative monitoring of ventilation and oxygena-tion are important as the animal’s dependent lungswill be collapsed on recovery and oxygen supple-mentation via a mask or nasogastric tube is stronglyrecommended until the animal has completelyrecovered from general anaesthesia.

Metastatic tumours are usually multiple and not amenable to surgery, although excision of solitary, slow-growing metastases has beenattempted, particularly if in the caudo-dorsal lungfields and easily accessible via a caudal intercostalapproach.


Staging

A combined TNM staging system is available forlaryngeal, tracheal and lung tumours (Table 9.4).All three categories should be assessed clinicallyand surgically in addition to endoscopy, bron-choscopy and radiography of the primary tumour.Radiography of the thorax is necessary to screenfor distant metastases, if not already performed forthe primary tumour. No stage grouping is recom-mended at present.

Treatment

Surgery

Surgical resection of the mass or lung lobe is thetreatment of choice for a primary lung tumour.Thisnecessitates a thoracotomy using a lateral inter-costal approach or sternal split.A sternal split gainsbetter access to both sides of the thoracic cavity butmakes dissection and ligation of the hilar vesselsand bronchus very difficult. An intercostal incisionshould be made further caudally if there is anydoubt as to which lung lobe is affected since ribsare more easily retracted cranially.

Partial lobectomy may be used for peripherallung masses but, without surgical stapling equip-ment, may prove lengthier and technically more difficult than lobectomy. Lobectomy is easier toperform via an intercostal approach, and involvesligation of the pulmonary artery and vein beforetransection and oversew of the bronchus.The arteryshould be ligated first in order to minimise lobe

Table 9.4 Clinical stages (TNM) of tumours of thelarynx, trachea and lungs. Owen (1980).

T Primary tumour (multiple tumours should be classified independently)T0 No evidence of tumourTX Tumour proven by presence of malignant cells in

bronchopulmonary secretions but not seen byradiography or bronchoscopy

T1 Solitary tumour surrounded by lung or visceral pleura

T2 Multiple tumours of any sizeT3 Tumour invading neighbouring tissues

N Regional lymph nodes (RLN)N0 No evidence of RLN involvementN1 Bronchial LN involvedN2 Distant LN involved


Fig. 9.7 Fine needle aspirate of pulmonary carcinoma.


Radiotherapy

The lungs are particularly radiosensitive tissues andsusceptible to radiation side-effects. It is not usuallyrecommended to treat dog and cat primary ormetastatic lung tumours with radiation.

Chemotherapy

Since most primary lung tumours in the dog and catare carcinomas they are not particularly sensitive tochemotherapy. However, treatment with combina-tions of cisplatin, doxorubicin or mitoxantrone,cyclophosphamide and 5-fluorouracil have been rep-orted anecdotally with limited success.Intra-cavitorycisplatin or sclerosing agents such as tetracyclinehave been tried for malignant pleural effusion.

Treatment of metastatic tumours is most suc-cessful in the micrometastatic stage, i.e. before radi-ographic detection. To prolong survival times withtumours known to have a high risk of lung metas-tasis, such as osteosarcoma and haemangiosarcoma,chemotherapy should be employed routinely aftersurgery (see Chapters 3, 5, and 6).

Prognosis

Survival times for many small primary lungtumours with no evidence of metastasis can extendto over 12 months. Factors associated with a poorerprognosis (shorter survival and disease free inter-val) in dogs are:

• Large tumour size (>5 cm diameter)• Detection of clinical signs• Metastasis to regional lymph nodes (TNM

staging).

Adenocarcinoma of the lung tends to have aslightly better prognosis (mean survival time of 19 months) than squamous cell carcinoma (meansurvival time 8 months) and anaplastic carci-noma (Mehlaff et al. 1983). Histological grading oftumours is important in that dogs and cats with welldifferentiated tumours have a better survival timeand disease free interval than those with moder-ately or poorly differentiated tumours.

References

Dorn, C.R., Taylor, P.O., Frye, F.L. et al. (1968) Survey of

animal neoplasms in Alameda and Contra Costa Counties, California. I. Methodology and description ofcases. Journal of the National Cancer Institute, (40),295–305.

Hahn, K.A. & McEntee, M.F. (1997) Primary lungtumours in cats: 86 cases (1979–1994). Journal of theAmerican Veterinary Medical Association, (211),1257–60.

May, C. & Newsholme, S.J. (1989) Metastasis of feline pulmonary carcinoma presenting as multiple digitalswelling. Journal of Small Animal Practice, (30), 302–10.

McNeil, E.A., Ogilvie, G.K., Powers, B.E., Hutchison, J.M.,Salman, M.D. & Withrow, S.J. (1997) Evaluation ofprognostic factors for dogs with primary lung tumours:67 cases (1985–1992). Journal of the American Veteri-nary Medical Association, (211), 1422–7.

Mehlaff, C.J., Leifer, C.E., Patnaik, A.K. & Schwarz, P.D.(1983) Surgical treatment of primary pulmonary neoplasia in 15 dogs. Journal of the American AnimalHospital Association, (20), 799–803.

Moulton, J.E. (1990) Tumours of the respiratory system.In: Tumours in Domestic Animals, 3rd edn., pp.309–346. University of California Press, Los Angeles.


Scott-Moncrieff, J.C., Elliot, G.S., Radovsky, A. & Blevins,W.E. (1989) Pulmonary squamous cell carcinoma withmultiple digital metastases in a cat. Journal of SmallAnimal Practice, (30), 696–9.

Further reading

Barr, F.J., Gibbs, C. & Brown, P.J. (1986) The radiologicalfeatures of primary lung tumours in the dog: a reviewof 36 cases. Journal of Small Animal Practice, (27),493–505.

Barr, F.J., Gruffydd-Jones, T.J., Brown, P.J. & Gibbs, C.(1986) Primary lung tumours in the cat. Journal ofSmall Animal Practice, (28), 1115–25.

Hahn, K.A. & McEntee, M.F. (1998) Prognostic factorsfor survival in cats after removal of a primary lungtumour: 21 cases (1979–1994). Veterinary Surgery, (27),307–11.

O’Brien, M.G., Straw, R.C., Withrow, S.J. et al. (1993)Resection of pulmonary metastases in canine osteosar-coma: 36 cases (1983–1992). Veterinary Surgery, (22),105–109.

Ogilvie, G.K., Haschek, W.M, Withrow, S.J. et al. (1989)Classification of primary lung tumours in dogs: 210cases (1975–1985). Journal of the American VeterinaryMedical Association, (195), 106–108.

Ogilvie, G.K., Weigel, R.M., Haschek, W.M. et al. (1989)Prognostic factors for tumour remission and survival in dogs after surgery for primary lung tumour: 76 cases (1975–1985). Journal of the American VeterinaryMedical Association, (195), 109–12.


10Urinary Tract

bladder and renal tumours are malignant and carrya poor prognosis.

The bladder is the commonest site for urinary tracttumours in the dog; in the cat, it is the kidney. Most

� Kidney, 154� Ureter, 158� Bladder, 158� Urethra, 162

154

KIDNEY

Epidemiology

Primary renal neoplasia is uncommon, accountingfor less than 1.7% and 2.5% of all canine and felinetumours respectively (Crow 1985). Affected dogsare usually old (mean age nine years) except forthose with embryonal tumours which are often lessthan a year old (mean age four years). Males areaffected more than females. The mean age of catswith renal lymphoma is six or seven years but nosex predisposition has been reported. In contrast toprimary renal neoplasia in small animals, secondary(metastatic) cancer is common because of the highblood flow and rich capillary network within thekidney.

Aetiology

For most primary renal tumours, there is no known aetiology. Bilateral renal cystadenocar-cinoma, however, is seen almost exclusively in theGerman shepherd dog as part of a syndromeinvolving nodular dermal fibrosis and uterinepolyps and may be familial (Atlee et al. 1991; Moe& Lium 1997). FeLV may be responsible for renal

lymphoma in the cat but only 50% of cases areFeLV positive.

Pathology

Primary renal tumours are usually solitary and unilateral in contrast to metastatic tumours whichare often multiple and bilateral. Ninety per cent of primary renal neoplasms in the dog and cat are malignant and more than half of these areepithelial. The various histological types are listedin Table 10.1.

Renal adenocarcinoma/carcinoma is derivedfrom tubular epithelium and can be described his-tologically as tubular, solid, acinar or papillary. Itusually grows from one pole and can become quitelarge, with areas of haemorrhage and necrosis (Fig. 10.1). Some may appear well demarcated and resemble renal adenoma while others are moreinvasive.

Transitional cell tumours are derived from renalpelvis epithelium and are rarer than renal carci-noma. Small cauliflower-like lesions without inva-sion are usually papillomas but larger, moreinvasive lesions are usually carcinomas.

Urinary Tract 155

Benign tumours are rare but include fibroma,haemangioma, adenoma, transitional cell papil-loma, leiomyoma and interstitial cell tumour.

Tumour behaviour

Renal carcinoma may be very small and confinedto the cortex or it may extend into the peri-renaltissues and form adhesions. Invasion of the renalarteries and veins, vena cava and aorta may occuras well as metastasis to regional lymph nodes, lung,liver, bone or skin (the latter may often be mis-taken for apocrine sweat gland adenocarcinoma).Tumours are usually fast growing and prone tometastasis by the time of diagnosis.Transitional cellcarcinomas may obstruct urine flow and cause

Twenty per cent of primary renal tumours aremesenchymal and these include haemangiosar-coma, and fibrosarcoma in dogs. Lymphoma is themost common feline renal tumour. It is usuallybilateral and often progresses to generalised formor spreads to the CNS. There may be an associationbetween nasal and renal lymphoma since manycases presenting with nasal lymphoma subse-quently develop the renal form.

Ten per cent of renal tumours are derived fromprimitive tissues. Nephroblastoma which is alsocalled embryonal nephroma or Wilm’s tumour isless common in dogs than other species. Grossly,one pole of the kidney may be affected by a soli-tary mass originating from the renal cortex, butmultiple or bilateral tumours can occur (Fig. 10.2).Primitive epithelial and mesenchymal tissues suchas vestigial tubules, muscle, cartilage and bone areseen histologically.

Table 10.1 Tumours of the kidney.

Benign MalignantAdenoma Adenocarcinoma/carcinomaTransitional cell Transitional cell carcinoma

papillomaLeiomyoma LeiomyosarcomaHaemangioma HaemangiosarcomaFibroma FibrosarcomaInterstitial Lymphoma

cell tumour Nephroblastoma

Fig. 10.1 Gross appearance of renal carcinoma, postmortem. (Courtesy of Dr P. Nicholls.)

Fig. 10.2 Gross appearance of a nephroblastoma (post mortem). (Courtesy of Mr A. Jefferies, Departmentof Clinical Veterinary Medicine, University of Cambridge.)


hydronephrosis but are less metastatic than renaladenocarcinoma.

Nephroblastoma may also extend beyond therenal cortex, and invade the medulla and pelvis.Approximately half of canine nephroblas-tomas metastasise, but nephrectomy is sometimes curative.


Polycythaemia may result if a renal carcinomaautonomously produces erythropoietin (seeChapter 2, Table 2.4). Other paraneoplastic syndromes occasionally reported are hyper-trophic osteopathy, hypercalcaemia and nodulardermatofibrosis.

Presentation/signs

Many renal tumours present with vague signs ofillness such as anorexia, depression, weight loss,lethargy, or sub-lumbar pain. More specific signsmay include:

• An abdominal mass may be palpated and bilateral renomegaly is often palpable in the catwith renal lymphoma.

• Abdominal distension may occur with nephrob-lastoma or bilateral cystadenoma bullet haema-turia may be associated with tumours of the renalpelvis or haemangiosarcoma.

• Hind limb oedema can occasionally be seen iflymphatic drainage is obstructed.

Signs of renal failure such as polyuria, polydipsia,vomiting or diarrhoea are not noted unless there is bilateral involvement. Some tumours, however,may be asymptomatic and discovered as an inci-dental finding on radiography, at celiotomy or atpost mortem examination.

Investigations

Bloods

Regenerative anaemia may be noted if haematuriais present, or polycythaemia if erythropoietin production is increased. Serum biochemistry isoften normal unless renal function is compromised.

Imaging techniques

Renomegaly, a change in renal shape, or undefineddorsal abdominal mass(es) and displacement ofother abdominal organs may be detected on plain abdominal films (Fig. 10.3) but contrast (intravenous urography or renal angiography) will be necessary to demonstrate a change in renal architecture and to help visualise the renalpelvis, cortex and ureters. Dystrophic calcificationmay be noted in some cases. Thoracic radiographyshould also be performed to screen for pulmonarymetastasis.

Ultrasonography is often useful to confirm anabdominal mass as renal and to assess renal architecture. It may also be used to guide an aspirate or biopsy needle. MRI is becoming increasingly used to assess abdominal organs inanimals. Although scintigraphy is used in humansto assess renal blood flow and function, as yet it isnot much used in the veterinary field for thispurpose.

Urinalysis

Proteinuria is a common finding but haematuria is only seen with haemangiosarcoma or transi-tional cell carcinoma of the renal pelvis. Tumour

Fig. 10.3 Lateral abdominal radiograph showing alarge circumscribed renal mass in the caudal–dorsalabdomen. (Courtesy of Radiology Department,Department of Clinical Veterinary Medicine, Univer-sity of Cambridge.)

Urinary Tract 157

Treatment

Surgery

Ureteronephrectomy is the treatment of choice for unilateral renal tumours without evidence of metastatic disease. Ideally, the function of the opposite kidney should be checked by excretionurography or scintigraphy before surgery. Atceliotomy, the tumour should be handled as little aspossible to reduce the risk of peritoneal seedingand the renal vessels ligated as soon as possible toprevent embolic spread. The renal capsule shouldbe left intact if the tumour is contained within it.

Radiotherapy

Radiotherapy is not generally used for the treat-ment of renal tumours in small animals.

Chemotherapy

Combination chemotherapy is more appropriatethan surgery for treating renal lymphoma becauseit is often bilateral or generalised. Standard protocols may be used (Chapter 15). Adjuvanttherapy with 5 fluorouracil, actinomycin-D, dox-orubicin and cyclophosphamide has been used following surgical removal of renal carcinoma butobjective evidence for a response is lacking.Although cisplatin is effective in treating humanurogenital tumours, this is not the case in dogs(Klein et al. 1988).

Prognosis

The prognosis for most renal tumours is poorbecause of their invasive nature and tendency tometastasise. Even after surgical removal, survivaltimes are generally short (6–12 months) althoughoccasional animals survive for a few years.Nephroblastoma carries a better prognosis withmany more cases cured by surgery. Cases of renallymphoma respond less well to chemotherapy thanother forms of the disease and long-term remissionand survival are difficult to achieve.

cells may occasionally be detected on cytol-ogical examination of urinary sediment but this is not a reliable finding on which to make a diagnosis.

Biopsy/FNA

Ultrasound-guided biopsy or fine needle aspirate isfairly non-invasive and easily performed by experi-enced operators. An incisional biopsy can be takenat exploratory celiotomy if surgical excision is notpossible.

Staging

A TNM staging system is available for renaltumours (Table 10.2) and requires clinical and surgical (celiotomy or laparoscopy) examination to view primary tumour, regional (lumbar) nodes and distant metastatic sites as well as radiography of the chest. No group staging is recommended.

Table 10.2 Clinical stages (TNM) of canine tumoursof the kidney. Owen (1980).

T Primary tumour T0 No evidence of tumourT1 Small tumour without deformation of the kidneyT2 Solitary tumour with deformation and/or

enlargement of the kidneyT3 Tumour invading perinephric structures

(peritoneum) and/or pelvis, ureter and/or renal blood vessels

T4 Tumour invading neighbouring structures

N Regional lymph nodes (RLN)N0 No evidence of RLN involvementN1 Ipsilateral RLN involvedN2 Bilateral RLN involvedN3 Other LN involved (abdominal and pelvic LN)

M Distant metastasis M0 No evidence of metastasisM1 Distant metastasis detectedM1a Single metastasis in one organM1b Multiple metastases in one organM1c Multiple metastases in various organs


Pathology

Neoplasia of the ureters is extremely rare but tran-sitional cell carcinoma, leiomyoma, or leiomyosar-coma can develop. Direct extension of renal pelvistumours or of bladder tumours into the distal uretercan also occur.

Tumour behaviour

Most tumours will protrude into the ureterallumen, eventually causing urinary obstruction,hydroureter and hydronephrosis. Local invasion ofsurrounding tissues may occur as well as distantmetastasis to other abdominal organs.

Presentation/signs

Clinical signs for ureteral tumours are generallynon-specific and may include lower back pain orstiffness. Most will be detected in the late stages when hydorureter or hydronephrosis haveoccurred.

Investigations

Bloods

No specific haematological or biochemical changesare expected with ureteral tumours.

Imaging techniques

Normal ureters are rarely visible on radiographs,but plain abdominal radiography may show a softtissue sublumbar mass or a change in renal size orshape due to hydronephrosis. Contrast radiography(IVU) is essential for a more precise diagnosis andwill reveal a filling defect, irregularity or stricture in

the ureter. With complete obstruction, proximaldilation of the ureter may be present or ifhydronephrosis has been present for some time andall nephrons destroyed, no excretion of contrastmay be visible on the affected side. Thoracic radiographs should be performed to screen for pulmonary metastases.

Ultrasonography can be helpful in locating anabdominal mass to the ureter and in assessing associated changes in renal architecture.

Biopsy/FNA

Ultrasound-guided needle biopsy or fine needleaspirate may be possible with a large mass, but oftena histological diagnosis may only be achieved by alaparoscopic biopsy or at exploratory celiotomy.

Staging

A TNM system is not available for ureteral tumours.

Treatment

Surgery

Ureteral tumours which have not invaded locally ormetastasised can often be treated successfully byureteronephrectomy. The function of the oppositekidney and ureter should be assessed prior tosurgery.

Prognosis

Since most malignant ureteral tumours invadelocally and metastasise, surgical resection is notalways an option, making the prognosis generallypoor. Benign tumours carry a much better prognosis.

URETER

BLADDER

Epidemiology

The bladder is the most common site in the canineurinary tract for neoplasia but fewer than 1% of all

tumours in the dog occur here. Aged femaleanimals (mean 10 years) are usually affectedalthough embryonal rhabdomyosarcoma occurs inyoung dogs, particularly those of large breeds.Bladder cancer is much rarer in the cat than the

Urinary Tract 159

dog, accounting for less than 0.5% of all tumours.Aged male cats (mean 9–10 years) are most at risk.

Aetiology

Prolonged contact time between carcinogenicchemicals in stored urine and uropeithelial cells is thought to cause bladder cancer. In man,cigarette smoking, certain industrial chemicals(nitrosamines), tryptophan metabolites, cyclophos-phamide and environmental pollutants are consid-ered bladder carcinogens. Some of these chemicalsmay also predispose to tumour formation in dogsbut it has been proposed that cats metabolise themdifferently and excrete lower quantities of the carcinogenic compounds.

Pathology

Malignant bladder tumours are more common thanbenign ones (Table 10.3). The majority of tumoursin both the dog (97% of cases) and cat (80% ofcases) are epithelial, the most common being tran-sitional cell carcinoma. Squamous cell carcinomaand adenocarcinoma may arise due to metaplasiaof the bladder epithelium but are much lesscommon and appear to behave similarly to transi-tional cell carcinoma. Undifferentiated carcinomais also reported.

All epithelial tumours may be solitary or multi-ple and appear as papillary or non-papillary, infil-trating or non-infiltrating growths. Transitional cellcarcinoma is usually papillary, protruding into thelumen from a broad base, although an infiltrating,thickened plaque or ulcerated nodule may occur

(Fig. 10.4). Tumours most often arise at the trigoneregion of the bladder.

Mesenchymal bladder tumours are mainlyderived from fibrous tissue or smooth muscle andthese include leiomyoma, haemangioma andfibroma along with their malignant counterparts.Rhabdomyosarcoma (botryoid or embryonalsarcoma) is a rare embryonal myoblast tumourwhich sometimes occurs in the bladder wall. Itarises in the trigonal region, is often multi-lobulatedand may occlude the ureteric orifices. Lymphomahas also been occasionally reported.

Tumour behaviour

Transitional cell carcinoma is usually locally inva-sive. After infiltrating through the bladder wall, itextends into adjacent tissues and regional organssuch as the pelvic fat, prostate or uterus, vagina orrectum. Peritoneal seeding may also occur as wellas metastases to internal iliac and sublumbar lymphnodes, lungs, liver, spleen and pelvic bones.

Whereas most mesenchymal bladder tumoursare locally invasive and less likely to metastasisethan transitional cell carcinoma, embryonal rhab-domyosarcoma has a tendency for both local recurrence after surgery and distant metastasis.


Hypertrophic osteopathy may be associated withembryonal rhabdomyosarcoma of the bladder (seeChapter 2).

Table 10.3 Tumours of the bladder.

Benign MalignantLeiomyoma Transitional cell carcinomaHaemangioma AdenocarcinomaFibroma Squamous cell carcinoma

Undifferentiated carcinomaEmbryonal rhabdomyosarcomaLeiomyosarcomaHaemangiosarcomaFibrosarcomaLymphoma

Fig. 10.4 Post mortem picture of bladder carcinoma.(Courtesy of Dr P. Nicholls.)

in the mucosal surface. Epithelial tumours oftenappear ulcerated whereas mesenchymal ones havea smoother mucosal appearance. Hydronephrosisor hydroureter may also be noted (IVU may beneeded) or metastases to sublumbar lymph nodes,lungs, spine or pelvis. Radiography of the skeletallong bones may reveal hypertrophic osteopathy.Thoracic radiographs should be taken to screen forpulmonary metastases.

Ultrasonography of the bladder is often moreuseful to visualise a mass or localised, irregular,bladder thickening, but it requires the bladder to bemoderately distended with urine and should there-fore be carried out before contrast radiography.Saline can be used to distend the bladder if neces-sary. Ultrasonography also gives information on thedepth of invasion of the bladder wall and thusassists clinical staging (Fig. 10.6).

Urinalysis

Full urinalysis and cytological examination is nec-essary to distinguish between cystitis and neoplasia.Haematuria and proteinuria are common findingsfor both but the presence of pleomorphic tumourcells (Fig. 10.7) on cytological examination shoulddifferentiate the two conditions. These are notalways noted, however, since some tumours, par-ticularly sarcomas, do not exfoliate well. Con-versely, atypical epithelial cells may sometimes benoted with cystitis since inflammation can inducechanges which mimic malignancy. Bacterial culture


Presentation/signs

Bladder tumours often present with signs similar tothose of chronic cystitis including haematuria,dysuria and pollakiuria. Any elderly bitch present-ing with recurrent cystitis should be considered forinvestigating the presence of an underlying bladdertumour.

Investigations

Bloods

No specific haematological or biochemical changesare expected with bladder tumours.

Imaging techniques

Plain abdominal radiographs are often unremark-able although a change in bladder shape or pos-sibly just a distinct bladder may be visible. Negative(air) contrast is necessary to visualise most tumours(Fig. 10.5) but double contrast cystography ispreferable. This allows coating of the bladdermucosa with a small amount of positive contrastprior to inflation with air. Multiple, discrete massesor a solitary mass often located at the bladder neckare easily visible, as well as diffuse tumours whichcause thickening of the bladder wall or changes

Fig. 10.5 Pneumocystogram – the air contrast assistsvisualisation of the mass in the caudal bladder.

Fig. 10.6 Ultrasound picture of transitional cell carci-noma of the bladder.

Urinary Tract 161

may also be helpful although infection secondary toneoplasia is common.

Cystoscopy

Using a small diameter flexible endoscope, thebladder lumen can be examined for multiple,pedunculated masses or localised thickenings, theextent of any tumour determined and a biopsyobtained. The technique is easier for bitches thanfor dogs because of the length of the urethra.

Biopsy/FNA

Since some bladder lesions visible on radiographyor ultrasonography may be inflammatory polyps or nodular hyperplasia, cytological or histologicalexamination is required to differentiate these fromneoplasia. Ultrasound-guided fine needle aspira-tion is easily performed for a large, discrete, bladdermass but other tumours may require biopsy. Biopsymay be performed using cystoscopy, or by applyingnegative pressure with a syringe to a catheterinserted into the bladder to suck in some tissuewhich can then be flushed into fixative. This doesnot require expensive endoscopic equipment but is relatively non-specific since it is performed blind and can produce false negatives. In manycases, an incisional biopsy may have to be taken atexploratory cystotomy, when surgical excision ofany tumour may also be attempted.

Staging

A TNM system is available for bladder tumours(Table 10.4) but no group staging is recommendedat present. For complete staging of primary tumour,regional (internal and external iliac) nodes anddistant metastatic sites, clinical examination, cys-tography, radiography of the thorax and celiotomyor laparoscopy are required.

Treatment

Surgery

Early lesions or localised tumours may be resectedby a partial cystectomy. However, this is often notpossible because of the multiple or diffuse natureof many epithelial tumours which makes visualisa-tion of the margins difficult and local recurrence iscommon.The ureters and trigone are often affectedin dogs making resection of the tumour and recon-struction of a functional lower urinary tract difficultor impossible. Mesenchymal tumours may be com-pletely excised more easily since the general rec-ommendation is that two thirds of the bladder maybe resected without interfering significantly with itsfunction. In cats, tumours are often located at thebladder apex making surgical excision more likelyto be effective.

Fig. 10.7 Cytology of urine sediment showing neo-plastic cells, leading to diagnosis of a transitional cellcarcinoma. (See also Colour plate 27, facing p. 162.)(Courtesy of Ms K. Tennant, Department of ClinicalVeterinary Medicine, University of Cambridge.)

Table 10.4 Clinical stages (TNM) of canine tumoursof the urinary bladder. Owen (1980).

T Primary tumour (add ‘m’ to appropriate T category for multiple tumours)Tis Carcinoma in situT0 No evidence of primary tumourT1 Superficial papillary tumourT2 Tumour invading the bladder wall with

indurationT3 Tumour invading neighbouring organs

(prostate, uterus, vagina, anal canal)

N Regional lymph nodes (RLN)N0 No evidence of RLN involvementN1 RLN involvedN2 RLN and juxta RLN (lumbar) involved


toxic, requires special protective measures to theadministrators and is therefore not recommendedfor use in general practice.

Systemic administration of 5-fluorouracil, dox-orubicin, cyclophosphamide or cisplatin may havesome effect, but often the tumour mass is too greatto be significantly reduced in size. Cisplatin hasproved variably effective depending on the doseused but carries a significant risk of renal toxicity.Carboplatin, which is less nephrotoxic, has minimaleffect on survival time (Chun et al. 1997). Para-doxically, cyclophosphamide, a drug which maycause bladder cancer, has also been used in its treatment. A combination of doxorubicin and cyclophosphamide extended survival time in dogs with transitional cell carcinoma in one study(Helfand et al. 1994).

Other

The non-steroidal anti-inflammatory drug piroxi-cam (0.3mg/kg po SID) has been used with partialsuccess to treat transitional cell carcinoma of thebladder or at least obtain several months of pallia-tion (Knapp et al. 1994). It may also be used post-operatively after surgical debulking of a tumour.

In some cases, palliative treatment in the form ofrepeated courses of antibiotics to control secondaryinfection may relieve the clinical signs and improvequality of life without addressing the primaryproblem. Particularly for old animals, some ownersmay prefer this approach.

Prognosis

The prognosis for most bladder carcinomas is poor because of their diffuse or multiple nature and the failure to control them satisfactorily bysurgery or other means. Survival time following surgical excision is usually less than six months.Mesenchymal tumours may have a slightly betterprognosis if diagnosed early and amenable to surgical excision.


Total cystectomy with diversion of the ureters to the distal ileum or proximal colon has beendescribed but gives poor survival times and a veryunsatisfactory quality of life due to reabsorption oftoxic renal metabolites in the colon and the risk ofascending pyelonephritis.

Radiotherapy

External beam radiotherapy is not usuallyattempted for bladder tumours in dogs and catsbecause of the problems of radiation side-effects onother abdominal organs. Intra-operative radio-therapy delivered as one large fraction after surgi-cal debulking of a bladder mass has producedvariable survival times. It avoids side-effects toother abdominal organs since abdominal organscan be shielded and the radiation beam can bedelivered to a more precise area, but there are oftenlong term complications such as bladder fibrosiswhich may cause urinary dyssynergia or inconti-nence. Some of these cases respond to oxybutyninwhich encourages bladder filling. Orthovoltageradiation is generally recommended in the litera-ture but we have used megavoltage radiation withsuitable build-up to deliver the required dose to thebladder wall, while protecting the rest of theabdomen with lead shielding.

Chemotherapy

Various cytotoxic agents have been tried for thetreatment of bladder tumours, intravesically or sys-temically, as a sole treatment or combined withsurgery, but the results have proved inconsistentand the efficacy of such protocols has not beendemonstrated. Direct application within thebladder of drugs such as 5-fluorouracil, cisplatin orthiotepa is only of use with very superficial tumourssince penetration of the bladder wall is limited.Most canine tumours are deep and invasive, makingthis method of therapy rarely effective. Triethyl-enethiophosphoramide (thiotepa) is extremely

URETHRA

Epidemiology

Tumours of the urethra are less common than thoseof the bladder in dogs and extremely rare in cats.

Aetiology

The same aetiological factors that induce bladdertumours probably affect the urethra too.

Urinary Tract 163

Pathology

Transitional cell carcinoma is the most commontumour in the proximal third of the urethra whereassquamous cell carcinoma often predominates in thedistal two thirds. Often, however, carcinomas affectthe whole length of the urethra and it may also beaffected by direct extension of tumours from thebladder neck region.

Tumour behaviour

Urethral tumours may invade locally through thewall of the urethra or protrude into the lumen and cause urinary obstruction as they progress.Metastasis to local lymph nodes, other pelvic andabdominal organs or pelvic bones is frequentlyfound.


No paraneoplastic tumours are commonly associated with urethral tumours.

Presentation/signs

The clinical signs associated with urethral tumoursare those of cystitis and urethritis and are often difficult to distinguish from those of bladder carcinoma. Haematuria, dysuria and pollakiuria are common although incontinence or urinaryobstruction may develop later. Cases presentingwith obstruction may require urinary diversion(cystostomy) while awaiting imaging and biopsyresults.

Investigations

Some urethral tumours will be palpable per rectumor per vagina as a discrete, solitary mass or morediffuse swelling along the length of the urethra.

Bloods

No haematological or biochemical changes areexpected with urethral tumours.

Urinalysis

Urinalysis will usually reveal haematuria and proteinuria as for bladder carcinoma and cytol-ogical examination of sediment may occasionallyreveal neoplastic cells. These abnormalities will notdetermine whether the tumour is in the bladder orurethra, however.

Imaging techniques

Plain radiographs of the caudal abdomen mayreveal some changes such as an elevated rectum,distended bladder due to urinary retention or a soft tissue mass in the region of the urethra.Retrograde urethrography or retrograde vaginou-rethrography, however, are necessary for a moreprecise diagnosis and to distinguish urethraltumours from bladder tumours. Irregularity of theurethral lumen or stricture are suggestive of neoplasia. Enlarged sublumbar lymph nodes andspinal or pelvic metastases may be noted. Chestradiographs should be performed to screen for pulmonary metastases.

Biopsy/FNA

It is important to distinguish urethral neoplasiafrom granulomatous urethritis which responds well to steroid therapy. Urethral tumours can often be sampled by passing a urinary catheter to the approximate location (measured on radiographs) and applying negative pressure via asyringe. Cytological examination of the aspirateshould be possible or if a large piece of tissue isobtained, it can be fixed for histological examina-tion. Alternatively, for more precise sampling,a narrow diameter endoscope can be used to visualise the tumour and biopsy it. In the bitch orqueen, a Volkmann spoon can be passed into theurethral papilla and used to scrape tissue off themucosal surface of the tumour.

Staging

There is no TNM system specifically for urethraltumours.

References

Atlee, B.A., DeBoer, D.J., Ihrke, P.J., Stannard, A.A. &Willemse,T. (1991) Nodular dermatofibrosis in Germanshepherd dogs as a marker for renal cystadeno-carcinoma. Journal of the American Animal HospitalAssociation, (27), 481–7.

Chun, R., Knapp, D.W., Widmer, W.R., DeNicola, D.B.et al. (1997) Phase II clinical trial of carboplatin incanine transitional cell carcinoma of the urinarybladder. Journal of Veterinary Internal Medicine, (11),279–83.

Crow, S.E. (1985) Urinary tract neoplasms in dogs andcats. Compendium of Continuing Education for thePractising Veterinarian, (7), 607–18.

Helfand, S.C., Hamilton, T.A., Hungerford, L.L., Jeglum,K.A. & Goldschmidt, M.A. (1994) Comparison of threetreatments for transitional cell carcinoma of thebladder in the dog. Journal of the American AnimalHospital Association, (30), 270–5.

Klein, M.K., Cockerell, G.L., Harris, C.K., Withrow, S.J.et al. (1988) Canine primary renal neoplasms: a retro-spective review of 54 cases. Journal of the AmericanAnimal Hospital Association, (24), 443–52.

Knapp, D.W., Richardson, R.C., Chan, T.C.K. et al. (1994)Piroxicam therapy in 34 dogs with transitional cell car-cinoma of the urinary bladder. Journal of VeterinaryInternal Medicine, (8), 273–8.

Moe, L. & Lium, B. (1997) Hereditary multifocal cyst-adenocarcinomas and nodular dermatofibrosis in 51German shepherd dogs. Journal of Small Animal Prac-tice, (38), 498–505.


White, R.N., Davies, J.V. & Gregory, S. (1996) Vagi-nourethroplasty for treatment of urethral obstructionin the bitch. Veterinary Surgery, (25), 503–10.

Further reading

Burnie,A.G. & Weaver,A.D. (1983) Urinary bladder neo-plasia in the dog: a review of 70 cases. Journal of SmallAnimal Practice, (24), 129–43.

Cuypers, M.D., Grooters, A.M., Williams, J. & Partington,B.P. (1997) Renomegaly in dogs and cats. Part I.Differential diagnoses. Compendium of ContinuingEducation for the Practising Veterinarian, (19), 1019–32.

Lucke, V.M. & Kelly, D.F. (1976) Renal carcinoma in thedog. Veterinary Pathology, (13), 264–76.

Macy, D.W., Withrow, S.J. & Hoopes, J. (1983) Transitionalcell carcinoma of the bladder associated withcyclophosphamide administration. Journal of the Amer-ican Animal Hospital Association, (19), 965–9.

Magne, M.L., Hoopes, P.J., Kainer, R.A. et al. (1985)Urinary tract carcinomas involving the canine vaginaand vestibule. Journal of the American Animal Hospi-tal Association, (21), 767–72.


Treatment

Surgery

It may be possible to resect small, localised urethraltumours and anastomose the urethra but mosttumours are too extensive for suitable surgicalmargins to be obtained.Access to the pelvic urethrais a problem and requires pubic symphysectomy.Tumours confined to the distal urethra may bemanaged by resection and pre-pubic urethrostomyif there is sufficient urethral length. In the male dog,distal urethral tumours may be managed by wideresection and scrotal urethrostomy. Radical re-section of up to 50% of the urethra and urethraltubercle has been described, using the overlyingproximal vagina to construct the urinary outflowtract. However, this only works well for benigntumours (White et al. 1996).

Radiotherapy

Radiotherapy of urethral tumours is not generallyattempted in cats and dogs because of poor tumourresponse, radiation side-effects to local tissues andpelvic organs and the risk of urethral stricture.

Chemotherapy

Urethral tumours are not considered verychemosensitive and cytotoxic therapy has not beenshown to be effective.

Other

Some animals may be managed on palliative anti-biotic therapy to control secondary infection untilurinary obstruction occurs. The anti-inflammatorydrug piroxicam which has been recommended fortreatment of transitional cell carcinoma of thebladder may also be of benefit for urethral tumours.

Prognosis

The prognosis for urethral tumours is poor becauseof their progressive nature and the difficulties asso-ciated with surgical treatment. Most animals areeuthanased because of progressive symptoms andobstruction of the urethra.

Urinary Tract 165

Mooney, S.C., Hayes,A.A., Matus, R.E. & MacEwen, E.G.(1987) Renal lymphoma in cats: 28 cases (1977–1984).Journal of the American Veterinary Medical Associa-tion, (191), 1473–77.

Norris, A.M., Laing, E.J., Valli, V.E.O., Withrow, S.J. et al.(1992) Canine bladder and urethral tumours: a retro-spective study of 115 cases (1980–1985). Journal of Veterinary Internal Medicine, (6), 145–53.

Patnaik, A.K., Schwarz, P.D. & Greene, R.W. (1986) Ahistopathologic study of 20 urinary bladder neoplasms

in the cat. Journal of Small Animal Practice, (27),433–45.

Stone, E.A. (1985) Urogenital tumors. Veterinary Clinicsof North America, (15), 597–608.

Tarvin, G., Patnaik, A. & Greene, R. (1978) Primary ure-thral tumors in dogs. Journal of the American VeterinaryMedical Association, (172), 931–3.

Weller, R.E. & Stann, S.E. (1983) Renal lymphosarcomain the cat. Journal of the American Animal HospitalAssociation, (19), 363–7.

11Genital Tract

In the male dog, testicular tumours are relativelycommon in contrast to those of the penis, prepuceand prostate which occur more rarely. Only aminority of testicular tumours metastasise and theprognosis is therefore good. In the cat, tumours atall sites of the male genital tract are rare.

In the female dog, genital tract tumours occur mostfrequently in the vagina and vulva and rarely in theuterus or ovary. Vaginal and vulval tumours areusually benign and carry a good prognosis. In thecat, tumours at all sites of the female genital tracthave a low incidence.

� Ovary, 166� Uterus and cervix, 169� Vagina and vulva, 171� Testicle, 174� Penis and prepuce, 177� Prostate, 180

166

OVARY

Epidemiology

Ovarian neoplasia is uncommon in small animalsdue to ovariohysterectomy at an early age. Itaccounts for less than 1.2% and 3.6% of all neoplasms in the dog and cat respectively. Mostanimals are usually middle aged to old whenaffected but teratoma may occur in slightly youngerdogs.

Aetiology

No aetiological factors are reported.

Pathology

Tumours of the ovary may arise from the surfaceepithelium, gonadostromal tissue (sex cord) orgerm cells (Table 11.1).

Surface epithelium

Cystadenoma/adenocarcinoma, papillaryadenoma/adenocarcinomaTumours arising from the surface cuboidal epithe-lium of the ovary account for 40–50% of canineovarian tumours but are very rare in the cat. Theymay be unilateral or bilateral and can vary consid-erably in size. Both adenomas and adenocarcino-mas can occur as papillary or cystic forms andtransitional and undifferentiated carcinomas arealso reported. Papillary adenocarcinoma gives theovary a shaggy surface and histologically appears asmultiple, branched papillae that arise multicentri-cally. Cystadenoma has a cystic appearance, with avariably-sized lumen containing a clear, watery,fluid.

Genital Tract 167

Other gonadostromal tumoursThecomas are derived from the fibrous collagentheca around the tertiary follicle and luteomas arederived from granulosa cells which have becomeluteal cells. Both are extremely rare, benigntumours which grow by expansion and do notmetastasise.

Germ cell tumours

DysgerminomaThis tumour arises from undifferentiated germ cellsand is uncommon in the dog and cat. It is analagousto the seminoma and resembles it histologically ascords or sheets of undifferentiated cells, scatteredwith giant cells and histiocytes. Tumours are oftenlarge, soft masses with a smooth, lobulated surface.

TeratomaThis is rare in the dog and cat. It is often well dif-ferentiated and benign although malignant ter-atomas have been described in both species.

Tumour behaviour

Cystadenocarcinoma/papillaryadenocarcinoma

Surface epithelial carcinomas often metastasise torenal or para-aortic lymph nodes, omentum, liver orlungs and can seed throughout the peritonealcavity. They may cause peritoneal effusion due tolymphatic obstruction in the diaphragm or by fluidproduction from the tumour tissue. Pleural effusionmay also occur.

Granulosa cell tumour

Although most granulosa cell tumours are consid-ered benign, approximately 20% in the dog and upto 50% in the cat are malignant. Metastases aredetected in the sublumbar lymph nodes, abdominalorgans and lungs although peritoneal seeding isalso possible.

Dysgerminoma

Growth of dysgerminomas is by expansion but up to 30% of cases metastasise to regional

Gonadostromal tissue

Granulosa cell tumourThis gonadostromal tumour is derived from theouter layer of cells (granulosa cells) around the ter-tiary follicle. It accounts for approximately 50% ofcanine ovarian tumours and is the most commonovarian tumour in the cat. It is usually unilateral,spherical, firm and smooth surfaced, and can havesolid and polycystic areas (Fig. 11.1). Some mayreach considerable diameter. Histologically, thetumour appearance can be variable but the mostcommon appearance in the dog and cat is of a welldifferentiated, uniform population of small cellsaround a pink or clear fluid.

Table 11.1 Tumours of the ovary.

Benign Malignant

Surface epitheliumCystadenoma CystadenocarcinomaPapillary adenoma Papillary adenocarcinoma

Gonadostromal tissueThecoma Granulosa cell tumourLuteoma

Germ cell tumoursDysgerminoma

Teratoma Teratoma

Fig. 11.1 Granulosa cell tumour of the ovary, postmortem. (Courtesy of Mr A. Jefferies Department of Clinical Veterinary Medicine, University of Cambridge.)


lymph nodes and abdominal organs in the dog andcat.


Granulosa cell tumours in the dog and cat oftenproduce oestrogen which may cause prolongedoestrus, mammary hyperplasia, swollen vulva,bilateral alopecia, cystic endometrial hyperplasia(CEH) or pyometra. Persistently elevated oestro-gen levels may potentially cause myelosuppressionalthough this is not widely reported.

Presentation/signs

Many ovarian tumours are asymptomatic and dis-covered as an incidental finding at celiotomy forovariohysterectomy, or for another reason. In othercases, animals may present with:

• Ascites (peritoneal carcinomatosis)• Lumbar pain• A palpable abdominal mass.

An ovarian mass is often more mobile and may berelatively low in the abdomen compared to a renalmass.Advanced tumour cases may have cachexia orgeneral weakness and lethargy. Abnormal oestruscycles, vaginal discharge or clinical signs associatedwith pyometra/cystic endometrial hyperplasia mayalso be noted.

Investigations

Bloods

No haematological or biochemical abnormalitiesare commonly reported with ovarian tumoursalthough myelosuppression (anaemia, thrombocy-topenia, neutropenia) is a potential problem if agranulosa cell tumour produces persistently ele-vated oestrogen levels.

Imaging techniques

A soft tissue mass adjacent to the kidney may beobvious on plain radiography although it may beobscured by peritoneal effusion. Calcification of the mass may be noted with teratomas. Thoracicradiographs of the chest should be taken to

screen for pulmonary metastases and to stage thetumour.

Ultrasonography may be useful to differentiatean ovarian from a renal mass and to assess its archi-tecture (Fig. 11.2).

Abdominocentesis

If ascites is present, paracentesis usually reveals amodified transudate. Tumour cells may be detectedon cytological examination of an ultra-spin sediment.

Biopsy/FNA

Ultrasound-guided fine needle aspirate or biopsy isoften possible with large ovarian tumours butcarries a theoretical risk of seeding malignant cellsthrough the peritoneum. A definitive diagnosis isusually obtained by excisional biopsy (ovariec-tomy) at celiotomy when the rest of the abdomencan also be assessed.

Staging

A TNM staging system exists for ovarian tumours(Table 11.2) and requires clinical and surgicalexamination (celiotomy/laparoscopy) of the pri-mary tumour, regional (lumbar) lymph nodes anddistant sites of possible metastasis as well as radio-graphy of the thorax.

Fig. 11.2 Ultrasonogram of granulosa cell tumour ofthe ovary in a bitch.

Genital Tract 169

pressed patient since there is often poor haemosta-sis, slow wound healing and decreased resistance toinfection.

Radiotherapy

Radiotherapy is not usually used for ovariantumours since those confined to the ovary are besttreated surgically.

Chemotherapy

The role of systemic chemotherapy in the treatmentof malignant ovarian tumours has not been estab-lished in animals since, in most cases, surgery aloneis adequate. Peritoneal lavage or systemic therapywith chemotherapeutic agents such as cisplatin istheoretically possible where seeding has occurred,but is not widely reported.

Prognosis

The prognosis for benign ovarian tumours isextremely good after ovariohysterectomy. Sincemost tumours in the dog are benign, the prognosisfor canine ovarian tumours is better than that forfeline ones. Malignant tumours carry a moreguarded prognosis especially if peritoneal seedingor other distant metastasis has occurred.

Treatment

Surgery

Ovariectomy is the treatment of choice for ovariantumours. In most cases, a complete ovariohysterec-tomy should be performed, particularly if there isany evidence of cytstic endometrial hyperplasia orpyometra. Care should be taken in a myelosup-

Table 11.2 Clinical stages (TNM) of canine tumoursof the ovary. Owen (1980).

T Primary tumour T0 No evidence of tumourT1 Tumour limited to one ovaryT2 Tumours limited to both ovariesT3 Tumour invading the ovarian bursaT4 Tumour invading neighbouring structures


M Distant metastasis M0 No evidence of distant metastasisM1 Evidence of implantation(s) or other metastases:M1a In the peritoneal cavityM1b Beyond the peritoneal cavityM1c Both peritoneal cavity and beyond

UTERUS AND CERVIX

Epidemiology

Uterine tumours are rare in the dog and cat. Theyoccur mostly in older animals.

Aetiology

There is no known aetiology for tumours of thecervix and uterus.

Pathology

Benign mesenchymal tumours such as leiomyoma,fibroma or fibroleiomyoma are most common in

the dog and may affect uterus, cervix or vagina.They often develop as multiple nodules in theuterine wall and may be associated with cysticendometrial hyperplasia, follicular cysts ormammary neoplasia. In the German shepherd dog,a syndrome associating these tumours with bilateralrenal cystadenocarcinomas and nodular dermatofi-brosis has been reported (Atlee et al. 1991; Moe &Liam 1997). Malignant mesenchymal tumours ofthe uterus are very rare (Table 11.3) butleiomyosarcoma, fibrosarcoma and lymphoma incats have been reported occasionally.

Endometrial carcinoma/adenocarcinoma is morecommon in the cat than the dog. Tumours arisefrom the endometrial glands, often filling theuterine lumen and expanding outwards through theuterine wall (Fig. 11.3). Histologically, cells may bemultinucleated and invade the myometrium singly,


in cords or in glandular formation. Squamous meta-plasia may occur.

Tumour behaviour

Leiomyoma and other benign mesenchymaltumours are non-invasive, non-metastatic and slowgrowing. Uterine adenocarcinoma is locally inva-sive and metastasis is frequent, often by the time of diagnosis. Metastatic deposits may occur inlymph nodes, other abdominal organs, lung, eye orbrain.


No paraneoplastic syndromes are commonly asso-ciated with uterine tumours.

Presentation/signs

Clinical signs associated with uterine tumours areoften vague and non-specific but an abdominalmass is sometimes palpable and vaginal dischargeor pyometra may occasionally be noted. Increasedurinary frequency may be present if the uterinebody is very large and applies pressure to thebladder.Advanced cases may present with cachexiaor malaise but other cases may be detected inci-dentally at celiotomy or post mortem examination.

Investigations

Bloods

No specific haematological or biochemical changesare commonly found with uterine tumours.

Imaging techniques

A soft tissue mass in the mid or caudal abdomenmay be detected on plain abdominal radiography,or if there is an accompanying pyometra, enlargedcoils of uterus may be distinguishable (Fig. 11.4).

Ultrasonography may be useful to distinguishwhether an abdominal mass is derived from uterusor cervix.

Table 11.3 Tumours of the uterus and cervix.

Benign MalignantLeiomyoma LeiomyosarcomaFibroma FibrosarcomaFibroleiomyoma Lymphoma

Adenocarcinoma

Fig. 11.3 Uterine adenocarcinoma, post mortem.(Courtesy of Mr A. Jefferies Department of Clinical Vet-erinary Medicine, University of Cambridge.)

Fig. 11.4 Lateral abdominal radiograph of cat,showing grossly distended, fluid-filled loops of uterus.The animal had pyometra secondary to a uterine adenocarcinoma.

Genital Tract 171

examination (celiotomy/laparoscopy) of theprimary tumour, regional lymph nodes and distantsites of possible metastasis as well as radiographyof the thorax. The regional lymph nodes are thepelvic nodes distal to the bifurcation of the com-mon iliac arteries and the para-aortic nodes proxi-mal to the bifurcation of the common iliac arteries.

Treatment

Surgery

Most uterine and cervical tumours are treated suc-cessfully by ovariohysterectomy.

Radiotherapy

Radiotherapy has not been reported for use withuterine tumours.

Chemotherapy

The role of chemotherapy in treating uterinetumours has not been established.

Prognosis

The prognosis for uterine tumours in the dog isgood because most are benign. The prognosis for uterine adenocarcinoma in the cat is worsebecause of its aggressive nature and the tendencyfor metastases to have occurred by the time of diagnosis.

Biopsy/FNA

Ultrasound-guided fine needle aspirate may be pos-sible although many benign mesenchymal tumoursdo not exfoliate well and cytological examinationmay be unrewarding. Ultrasound guided biopsy isanother option but usually a definitive histologicaldiagnosis is made after ovariohysterectomy and his-tological examination of the tissues.

Staging

A TNM staging system is available for the uterus(Table 11.4) and requires clinical and surgical

Table 11.4 Clinical stages (TNM) of tumours of theuterus. Owen (1980).

T Primary tumour T0 No evidence of tumourT1 Small non-invasive tumourT2 Large or invasive tumourT3 Tumour invading neighbouring structures

N Regional lymph nodes (RLN)N0 No evidence of RLN involvementN1 Pelvic RLN involvedN2 Para-aortic RLN involved

M Distant metastasis M0 No evidence of metastasisM1 Evidence of metastasis:M1a In the peritoneal cavityM1b Beyond the peritoneal cavityM1c Both peritoneal cavity and beyond

VAGINA AND VULVA

Epidemiology

The vagina and vulva are the most common sitesfor reproductive tract tumours in the dog (exclud-ing the mammary gland). Entire, aged dogs (meanage 10–11 years), particularly nulliparous animals,are at risk of benign mesenchymal tumours,whereas lipoma affects a slightly younger age group(mean age six years). Transmissible venerealtumour also affects younger, sexually active orbreeding females. In the cat, vaginal and vulvaltumours are rare but older, intact animals havebeen affected.

Aetiology

There is an association between benign smoothmuscle tumours and oestrogen production in thedog. Such tumours rarely occur in spayed animalsunless they have received oestrogen therapy forsome reason.

Pathology

Benign smooth muscle tumours account for80–90% of vaginal and vulval tumours in the dog


and have also been reported in the cat (Table 11.5).Most are situated in the vestibule and may presentin one of two ways:

• Extraluminal forms are well encapsulated andpoorly vascularised.

• Intraluminal forms are often firm and ovoid,attached to the vestibular or vaginal wall by athin pedicle. These may be multiple and mayulcerate.

Concurrent mammary gland tumours, ovarian cysts and cystic endometrial hyperplasia may occurwith either form. Lipomas arise from the peri-vascular and perivaginal fat and lie within thepelvis. They are usually slow growing and well circumscribed.

Leiomyosarcoma is the most common malignanttumour of the vagina and vulva although other sar-comas, carcinomas and transmissible venerealtumour have also been reported (Table 11.5). Anytype of cutaneous tumours, particularly squamouscell carcinoma and mast cell tumour, may alsooccur at the vulval labia (Fig. 11.5).

Tumour behaviour

Most mesenchymal tumours of the vagina andvulva are benign, well circumscribed and slowgrowing. Distant metastases have been reportedwith leiomyosarcoma.


No paraneoplastic syndromes are commonly asso-ciated with these tumours.

Presentation/signs

Extraluminal tumours present as slow growing per-ineal masses (Fig. 11.6) whereas intraluminal formsmay present as polyps protruding through thevulval lips especially when the animal strains or isin oestrus. These masses may become traumatisedand secondarily infected. Other signs may includevulval bleeding or discharge, tenesmus, vulvallicking, haematuria, dysuria or even urinaryobstruction. In some cases a vulval mass may benoted. In the cat, constipation secondary to com-pression of the colon has been reported.

Table 11.5 Tumours of the vagina and vulva.

Benign MalignantLeiomyoma LeiomyosarcomaFibroma Transmissible venereal tumourFibroleiomyoma AdenocarcinomaLipoma Squamous cell carcinoma

HaemangiosarcomaOsteosarcomaMast cell tumour

Fig. 11.5 An aggressive SCC of the vulva with metas-tasis to the inguinal lymph node. (Courtesy of Dr R.A.S.White, Department of Clinical Veterinary Medicine,University of Cambridge.)

Genital Tract 173

Investigations

Clinical presentation combined with the age of theanimal may be sufficient for a preliminary diagno-sis. Masses are often palpable per vagina or perrectum.

Bloods

No specific haematological or biochemical changesare commonly associated with these tumours.

Imaging techniques

These are rarely needed but retrograde vaginogra-phy or urethrocystography may help to delineate avaginal mass. Plain caudal abdominal radiographymay be useful if the mass extends cranially or toexamine sublumbar lymph nodes if malignancy issuspected. Elevation or compression of the rectum,cranioventral displacement of the bladder, andfaecal or urinary retention may also be seen onplain films. Thoracic films should be taken formalignant tumours, although these are rare.

Biopsy/FNA

Definitive diagnosis can only be made on histolog-ical examination of excised tissue either at biopsyor on complete excision of the tumour.

Chromosome analysis

(See penis/prepuce tumours)

Staging

A TNM staging system is available for vaginal andvulval tumours (Table 11.6) and requires clinicaland surgical examination of each category as wellas radiography of the thorax. The regional lymphnodes are the superficial inguinal, sacral and inter-nal iliac nodes.

Treatment

Surgery

Surgical resection is the treatment of choice forvaginal and vulval tumours but care should be

Fig. 11.6 (a) Perineal swelling in a bitch due to a largevaginal fibroma; (b) seen delivered at surgery via anepisiotomy. (Courtesy of Dr R. A. S. White, Departmentof Clinical Veterinary Medicine, University of Cambridge.)

(a)

(b)


taken to identify and preserve the urethral papilla.Most benign mesenchymal tumours are well encap-sulated and easily excised but because of the strongassociation of most tumours with oestrogen pro-duction, resection should be combined with ovari-ohysterectomy to prevent tumour recurrence. Adorsal episiotomy may be needed to access extra-luminal tumours. Vaginal carcinomas may beharder to excise surgically because they are rarely

as well circumscribed as benign mesenchymaltumours.

Radiotherapy

Post-operative radiotherapy may be appropriatefor some vulval carcinomas or mast cell tumourswhere complete surgical resection has not beenpossible. Transmissible venereal tumour is alsoradiosensitive and can be treated successfully withrelatively low doses of radiation (15Gy) if onlysuperficial lesions are present.

Chemotherapy

Chemotherapy is not usually used for the commonbenign tumours nor for the rarer carcinomas.Trans-missible venereal tumour, however, is amenable toweekly therapy with vincristine sulphate (0.5mg/m2 q 7 days) with complete responses obtainable infour to six weeks.

Prognosis

Since most vaginal and vulval tumours are benign,surgical resection combined with ovariohysterec-tomy carries a good prognosis. Malignant tumourssuch as adenocarcinoma and squamous cell carci-noma carry a poor prognosis because of local recur-rence and metastasis.

Table 11.6 Clinical stages (TNM) of canine tumoursof the vagina and vulva. Owen (1980).


tumours)T0 No evidence of tumourT1 Tumour <1 cm maximum diameter, superficialT2 Tumour 1–3 cm maximum diameter, with minimal

invasionT3 Tumour >3 cm or every tumour with deep invasionT4 Tumour invading neighbouring structures (skin,

perineum, urethra, paravaginal wall, anal canal)

N Regional lymph nodes (RLN)N0 No evidence of RLN involvementN1 Movable ipsilateral nodesN2 Movable bilateral nodesN3 Fixed nodes


TESTICLE

Epidemiology

Testicular tumours are the second most commontumours of the male dog and account for 75% ofall tumours in the male reproductive tract (Hayes& Pendergrass 1976). Older, intact males (mean11.5 years) commonly develop interstitial celltumours in the descended testicle. Cryptorchidshave a much greater risk of developing Sertoli celltumours and seminomas than normal dogs and theaverage age of affected animals is younger (9 yearsfor Sertoli cell tumours, 10 years seminomas). Theright testicle is more often affected than the left(Lipowitz et al. 1973).Testicular tumours are rare inthe cat and cryptorchidism does not appear to be arisk factor (Mills et al. 1992).

Aetiology

Abdominal or inguinal positioning of the testis isimportant in the development of half of Sertoli celltumours and two thirds of seminomas in the dog.The higher temperature of the abdomen destroysspermatogenic cells and this may allow Sertoli cellsto develop.

Pathology

Testicular tumours can be categorised as gona-dostromal (Sertoli and Leydig), or germ cell (semi-noma, teratoma).The histological types are listed inTable 11.7.

Genital Tract 175

TeratomaTeratomas are rare in the dog and cat and arealmost always benign compared to those in man.They comprise multiple tissues derived from dif-ferent germ layers and may contain epithelium,bone, cartilage or brain.

Tumour behaviour

Interstitial cell (Leydig) tumours are the mostbenign testicular neoplasms and do not usuallymetastasise.Although most Sertoli cell tumours areslow growing and benign, up to 15% of tumoursmay be malignant and metastasise. Metastasis isusually via the lymphatics to regional lymph nodes,although distant spread to abdominal organs is alsoreported. A smaller proportion of seminomas aremalignant with between 5 and 10% reported tometastasise.

Gonadostromal tissue

Interstitial cell tumour/Leydig cell tumourThese arise from the endocrine Leydig cells of the testis. Histologically, tumour cells have foamycytoplasm, and are sometimes associated withhaemorrhage, necrosis or cysts. Grossly, tumoursare often encapsulated, remain within the testicleand may be pink to tan in colour. They are usuallythe smallest, softest tumours to palpate and can besolitary or multiple within the same or the oppositetestis. The affected testicle may be enlarged ornormal in size.

Sertoli cell tumourThese arise from the Sertoli cells of the testis whichsupply the nutrients for spermatogenesis. Pallisad-ing rows of elongated Sertoli cells accompanied by fibrous connective tissue are seen histologically.Tumours with the cells arranged in well formedtubules tend to be less malignant than those with more infiltrative cells, arranged in a morediffuse pattern. Grossly they are usually unilat-eral, often firm and white, with cysts (filled withbrown fluid) and fibrous septa enlarging the testis(Fig. 11.7).

Germ cell tumours

SeminomaSeminomas arise from the primitive gonadal cellsof the testis and may appear histologically verysimilar to dysgerminomas of the ovary. Initially thetumour cells, which are often large and multinucle-ated, develop within atrophic seminiferous tubules,but later they invade the interstitial stroma andappear more diffuse. Grossly, tumours are usuallyfirm, unencapsulated, lobulated and white to pink-grey in colour.

Table 11.7 Tumours of the testis.

Benign Malignant

Gonadostromal tissueInterstitial cell (Leydig) tumour Sertoli cell tumour

Germ cell tumoursTeratoma Seminoma

Fig. 11.7 Post mortem picture of a Sertoli cell tumour;the other testicle is atrophied. (Courtesy of Dr P.Nicholls.)



Sertoli cell tumours may produce oestrogen whichcauses a feminisation syndrome (Fig. 11.8). Signsmay include:

• Bilaterally symmetrical alopecia• Gynaecomastia• Pendulous prepuce• Attractiveness to other male dogs• Atrophy of the other testis• Myelosuppression (anaemia, neutropenia and

thrombocytopenia).

Any metastases which are present can be secretoryand therefore castration to remove the primarytumour may not remove the feminisation signs.Seminomas have also been associated with a femi-nisation syndrome but much less frequently.

Interstitial (Leydig) cells secrete male hormonesin the normal male, but the tumours derived fromthese cells do not show autonomous secretion.Theyare often associated with peri-anal adenoma andperineal hernia but these conditions are common innormal male dogs. Hypercalcaemia, however, hasbeen reported as a paraneoplastic syndrome asso-ciated with interstitial cell tumours.

Presentation/signs

Affected animals may present with testicles ofuneven size or an obvious testicular mass, althoughmany testicular tumours are an incidental finding

on clinical examination or at post mortem exami-nation. In cryptorchid dogs, particularly if thedescended testicle has been removed, diagnosismay be difficult unless a feminisation syndromeoccurs. In this case:

• Bilaterally symmetrical alopecia and possiblypruritus

• Attractiveness to other male dogs• Lethargy or decreased libido.

may alert the clinician to the possibility of anabdominal testicular tumour. Oestrogen myelotox-icosis may present as a non-regenerative anaemia,thrombocytopenia or neutropenia. Very occasion-ally, signs of hypercalcaemia such as muscle trem-ors, weakness, polyuria and polydipsia may benoted with testicular tumours, particularly intersti-tial cell tumours.

Investigations

Palpation of the testes is usually sufficient to makea presumptive diagnosis of neoplasia, although adefinitive diagnosis will require histological analy-sis of tissue.

Bloods

Unless there are clinical signs of feminisation,blood samples are of limited use. If feminisation ispresent, plasma concentrations of oestradiol andoccasionally progesterone are generally elevatedwhereas testosterone is low. If increased oestrogensecretion is suspected, haematological assessment is vital to reveal the extent of myelosuppressionpresent. Platelet and neutrophil numbers can fallparticularly low, carrying a risk of spontaneoushaemorrhage or sepsis.

Imaging techniques

Ultrasonography may help to define the number orextent of testicular lesions but is rarely necessaryfor a diagnosis. Abdominal radiographs may iden-tify a retained testicle.

Biopsy/FNA

Cytological analysis of a fine needle aspirate maydistinguish between the different tumour types but

Fig. 11.8 Dog with alopecia and coat changes due tohyperoestrogenism from a Sertoli cell tumour causingfeminisation syndrome. (Courtesy of Mr D. Bostock.)

Genital Tract 177

which may have metastasised. For scrotal tumours,castration is routine, although cryptorchids willrequire inguinal or abdominal exploration to locatethe retained testicle and tumour. The clinical signsassociated with oestrogen production will usuallyresolve within six weeks after removal of theprimary tumour unless metastatic tissue is alsopresent.

Radiotherapy

Radiotherapy is not necessary for testiculartumours since surgical treatment is so effective.

Chemotherapy

Chemotherapy is of limited use for testiculartumours in animals. Although theoretically appli-cable for tumours which have metastasised, noreports have demonstrated its effectiveness.

Other

For cases with severe myelosuppression due tooestrogen secretion, supportive measures such asbroad spectrum antibiotic therapy, platelet infusionor whole blood transfusion may be necessary priorto castration.

Prognosis

The prognosis for most testicular tumours is goodsince surgical treatment is relatively easy and onlya minority of tumours metastasise. If, however, thefeminisation signs are not quickly linked to oestro-gen secretion from a testicular tumour and myelo-suppression is allowed to become severe, fatalitiesmay arise.

this is not usually necessary and a definitive diag-nosis is made after castration and histologicalexamination of the tumour tissue. Cytologicalexamination of bone marrow aspirates may be indi-cated for cases of suspected myelosuppression.

Staging

A TNM staging system is available for testiculartumours (Table 11.8) and requires clinical and surgical examination of primary tumour, regional(sublumbar, inguinal) lymph nodes and sites ofdistant metastasis, in addition to radiography of thethorax.

Treatment

Surgery

Removal of the primary tumour by castration isusually curative except for the minority of cases

Table 11.8 Clinical stages (TNM) of canine tumoursof the testis. Owen (1980).


tumours)T0 No evidence of tumourT1 Tumour restricted to the testisT2 Tumour invading the tunica albugineaT3 Tumour invading the rete testis and/or the

epididymisT4 Tumour invading the spermatic cord and/or the

scrotum

N Regional lymph nodes (RLN)N0 No evidence of RLN involvementN1 Ipsilateral RLN involvedN2 Contralateral or bilateral RLN involved


PENIS AND PREPUCE

Epidemiology

Penile and preputial tumours are rare except in parts of the world affected by transmissible

venereal tumour, namely the Mediterranean countries, south-east USA and the Caribbean.While most tumours are more common in olderdogs, transmissible venereal tumour occurs inyounger, sexually active dogs, stud dogs or the stray


population. Males are often less affected thanfemales.

Aetiology

No aetiology is known for most tumours of thepenis and prepuce but transmissible venerealtumour is transmitted by transplantation of cells at coitus. Although a viral aetiology has been pro-posed, viral particles have only been inconsistentlyreported on electron microscopy, and the theoryhas not been unequivocally substantiated.

Pathology

The histological types of tumour occuring on thepenis or prepuce are listed in Table 11.9. Squamouscell carcinoma is the most common tumour of thepenis of dogs in the UK but papillomas may alsooccur. Transmissible venereal tumour (TVT) is thepredominant tumour type in areas of the world in which it is enzootic. Squamous cell carcinomaoccurs as an ulcerated, sessile region of the glanspenis or inner lining of the prepuce although it canalso more rarely produce a cauliflower-like growth.TVT also produces pedunculated, vegetative, pap-illary or nodular lesions of the glans or more caudalpenis. Histologically ovoid or round cells appear incompact sheets, cords or rows and are scatteredwith inflammatory cells such as lymphocytes,plasma cells and macrophages.

The prepuce and scrotum may be affected by anyskin tumours, but tumours commonly located in thisregion are mast cell tumours, melanomas and peri-anal gland hepatomas (see Chapter 4).

Tumour behaviour

Squamous cell carcinoma of the penis is locallyinvasive and may spread to the inguinal lymphnodes as well as distant sites if left untreated.

Transmissible venereal tumour does not com-monly metastasise but may be transplanted to otherareas of the skin, face or nose by trauma andlicking. Metastasis to inguinal lymph nodes andabdominal organs does occur infrequently. Since animmune response to the tumour does occur in time,growth usually slows down as this develops andtumour regression may be seen eventually.

Mast cell tumours of the prepuce and scrotumoften occur multiply and behave very aggressively,spreading to the inguinal lymph nodes or more dis-tantly even if histologically they do not appearundifferentiated. Local oedema and erythema arecommon due to mast cell degranulation and mayextend down the hind limbs with enlargement ofthe inguinal lymph nodes due to metastasis.


Mast cell tumours may be associated with hyper-histaminaemia (see Chapter 2).

Presentation/signs

Tumours of the penis may bleed or become secon-darily affected. Clinical signs may include:

• Preputial discharge• Licking of the region• Dysuria• Frank blood in the urine• Phimosis or paraphimosis (occasionally).

An obvious lesion is not usually apparent unless the penis is fully extruded (Fig. 11.9). Skin tumoursof the external prepuce or scrotum are oftenobvious as discrete masses although mast celltumours may present with diffuse, inguinal swelling,oedema and erythema and no distinct tumour mass.

Table 11.9 Tumours of the penis and prepuce.

Benign Malignant

PenisPapilloma Squamous cell carcinoma

Transmissible venereal tumour

Prepuce and scrotumPeri-anal gland

hepatoma Mast cell tumour

Genital Tract 179

Investigations

Bloods

No specific haematological or biochemical changesare associated with tumours of the prepuce andpenis.

Imaging techniques

Imaging techniques are not usually required forthese tumours.

Biopsy/FNA

Direct impression smears may be made from ulcer-ated penile lesions for cytological examination.Alternatively, a small incisional or grab biopsy maybe possible. Fine needle aspirates of enlargedinguinal lymph nodes may be helpful in revealingthe tumour type if metastasis has occurred and areessential for staging the disease.

Chromosome analysis

Transmissible venereal tumour is characterised bya modal chromosome number of 59 ± 5 instead ofthe usual 78 seen in normal canine cells (Murray et al. 1969). Karyotypic analysis of tumour cells cantherefore be used to confirm the diagnosis.

Staging

Tumours of the penis and prepuce can be stagedusing a TNM staging system (Table 11.10) whichinvolves clinical and surgical examination of allthree categories, as well as radiography of thethorax.The regional lymph nodes are the superficialinguinal nodes. A separate staging system is appli-cable to mast cell tumours of the prepuce oringuinal region (Chapter 4).

Treatment

Surgery

Penile tumours are rarely treated by local surgicalexcision and penile amputation is usually the rec-ommended option even for early lesions. If theamputation is performed cranial to the bulb, thesheath is left intact but more radical amputationcranial to the scrotum will require a scrotal ure-throstomy, castration, scrotal and preputial abla-tion. Radical surgery is not usually necessary,however, for transmissible venereal tumour.

Treatment of preputial mast cell tumours andmelanomas may be attempted but complete sur-gical excision is rarely possible and metastasisremains a common problem.

Fig. 11.9 Squamous cell carcinoma of the penis.(Courtesy of Dr R.A.S. White, Department of ClinicalVeterinary Medicine, University of Cambridge.)

Table 11.10 Clinical stages (TNM) of caninetumours of the penis (prepuce and glans). Owen(1980).


tumours)T0 No evidence of tumourT1 Tumour <1 cm maximum diameter, strictly

superficialT2 Tumour 1–3 cm maximum diameter, with minimal

invasionT3 Tumour >3 cm or every tumour with deep invasionT4 Tumour invading neighbouring structures

N Regional lymph nodes (RLN)N0 No evidence of RLN involvementN1 Movable ipsilateral nodesN2 Movable bilateral nodesN3 Fixed nodes


Poorly differentiated mast cell tumours of theprepuce may be palliated by chemotherapy withprednisolone and/or other cytotoxic drugs (Chapter 4).

Prognosis

The prognosis for squamous cell carcinoma of thepenis is favourable if amputation can be performed,although local and distant metastasis may stilldevelop. TVT carries an extremely good prognosissince the response to chemotherapy is usually dra-matic. Mast cell tumours of the preputial skin havea very poor prognosis because of their aggressiveand malignant nature.


Radiotherapy

Radiotherapy is not usually used for squamous cellcarcinoma of the penis or preputial tumours. TVT,however, is radiosensitive and will regress inresponse to relatively low doses (15Gy).

Chemotherapy

Chemotherapy is not appropriate for squamous cell carcinoma of the penis but TVT will respondwell to vincristine therapy. Complete regression will occur with weekly doses of vincristine sulphateat 0.5mg/m2 q 7 days for a course of four to sixweeks.

PROSTATE

Epidemiology

Prostatic neoplasia is much less common thanhyperplasia in dogs and is extremely rare in cats.Affected dogs are usually old (mean age 10 years)and of medium or large breeds.

Aetiology

Prostatic carcinoma develops independently ofhormonal status and occurs in both castrated andentire dogs. This is in contrast to human prostaticcarcinoma which is androgen dependent.

Pathology

The most common prostatic tumour is the adeno-carcinoma or undifferentiated carcinoma althoughtransitional cell carcinoma and squamous cell car-cinoma have also been reported (Table 11.11).Leiomyosarcoma and benign mesenchymaltumours such as leiomyoma and fibroma are rare.Tumours of other pelvic organs may sometimesextend locally to invade the prostate.

Prostatic adenocarcinoma develops from thebranching tubuloalveolar glands of the prostate.The prostate is usually enlarged, hard, irregularlynodular and asymmetrical although it may becystic, haemorrhagic or abscessated and may

adhere to other pelvic structures. Histologically,papillary projections of glandular epithelium areseen within large, irregular alveoli or variably sizedacini surrounded by dense, fibrous stroma.

Undifferentiated carcinoma occurs less com-monly and consists of scattered carcinoma cells,or cells arranged in solid clusters, strands or syncytia.

Tumour behaviour

Prostatic adenocarcinoma is very invasive locallyand may extend to other pelvic organs such asbladder, colon and urethra. It is very malignant andmetastasises quickly to sublumbar lymph nodes,abdominal organs and lungs, as well as to thelumbar vertebrae, pelvis and other bones. Approxi-mately 70% of cases will have metastasised by thetime of diagnosis.

Table 11.11 Tumours of the prostate.

Benign MalignantLeiomyoma AdenocarcinomaFibroma Undifferentiated carcinoma

Squamous cell carcinomaTransitional cell carcinomaLeiomyosarcoma

Genital Tract 181


No paraneoplastic syndromes are commonly asso-ciated with these tumours.

Presentation/signs

Prostatic neoplasia often presents with lowerurinary signs such as:

• Haematuria• Dysuria• Purulent, penile discharge• Faecal tenesmus, ribbon-like faeces or constipa-

tion (due to constriction of the rectum).

Metastatic lesions to the pelvic bones or spine maybe painful and cause hindlimb weakness, lamenessor neurological deficits. Although prostatic hyper-plasia may also put pressure on the rectum andproduce similar faecal signs, it rarely causes urinarysigns or pain. An enlarged, painful prostate may be palpable in the caudal abdomen, along withenlarged sublumbar lymph nodes, or alternativelyan irregular or enlarged prostate may be palpatedper rectum.

Investigations

Rectal examination

A uniform, non-painful enlargement of the prostateis more likely to indicate hyperplasia than neopla-sia. Prostatic carcinoma usually produces irregular,asymmetrical, painful enlargement due to sec-ondary abscessation. However, primary prostaticabscesses and paraprostatic cysts may also produceasymmetrical enlargement. Underlying neoplasiamay be associated with both these conditions andso the prostate should always be biopsied for adefinitive diagnosis. Enlarged sublumbar lymphnodes, common with prostatic neoplasia, may alsobe palpable per rectum.

Bloods

Haematological and biochemical changes are occasionally associated with prostatic tumours.Renal failure secondary to urinary obstruction may be detected, along with regenerative and non-

regenerative anaemia, elevated alkaline phos-phatase and ALT, hypoalbuminaemia and hypocalcaemia.

Imaging techniques

The prostate may vary in size on plain abdominalfilms from normal to grossly enlarged. Althoughprostatic neoplasia may produce asymmetricalenlargement around the bladder neck, pro-statomegaly is not necessarily present. Enlargedsublumbar lymph nodes, lytic or sclerotic bonelesions in the vertebrae or pelvis or pulmonarymetastases on thoracic films will help to distinguishprostatic neoplasia from other prostatic conditions(Figs. 11.10 and 11.11). A pneumocystogram or ret-rograde urethrogram may help to demonstratecranial displacement of the bladder due to prosta-tic enlargement, stenosis or irregularity of theurethra in the prostatic region or extravasation ofcontrast into irregular prostatic crypts.

Ultrasonography will demonstrate changes in theprostatic parenchyma but these are not always dis-tinguishable from other types of prostatic pathol-ogy such as prostatitis, abscessation or cystichyperplasia.

Fig. 11.10 Lateral abdominal radiograph of a dog witha prostatic carcinoma – although the prostate is notgrossly enlarged, the tumour has spread locallycausing bony changes in the lumbar vertebrae.

Treatment

Surgery

Most prostatic carcinomas are not amenable to suc-cessful surgical resection because of their invasivenature and frequent metastasis by the time of diag-nosis. Complete resection of the prostate with anas-tomosis of the urethra has been described but is notcompatible with good quality life or urinary conti-nence and is therefore not recommended.


Biopsy/FNA

Cytological examination (Fig. 11.2) can be per-formed on urethral washings obtained by insertinga catheter into the prostatic urethra, inserting asmall volume of saline and massaging the prostateper rectum to aid release of cells or by applyingnegative pressure with a syringe to the catheter tosuck in a small tissue sample. Fine needle aspiratesor needle biopsies may also be performed throughthe abdominal wall in the inguinal region if theprostate is palpable and can be fixed, or ultrasoundguidance can be used. If the prostate is palpable inthe pelvic canal, the needle may have to be insertedthrough the perineum, although a per rectal tech-nique has also been used. Alternatively, an endo-scopic biopsy may be possible with a narrowdiameter, flexible endoscope. If none of thesemethods are successful, an incisional biopsy can beperformed at celiotomy (Fig. 11.12).

Staging

There is a TNM staging system specific to theprostate (Table 11.12) which requires clinical andsurgical examination, urography, endoscopy andbiopsy as well as radiography of the thorax, pelvisand skeleton. The regional lymph nodes are theexternal and internal iliac nodes.

Fig. 11.11 Paraprostatic cysts are a differential diag-nosis for caudal abdominal masses in male dogs.

Fig. 11.12 Fine needle aspirate cytology of prostaticadenocarcinoma. (Courtesy of Mrs E. Villiers, Depart-ment of Clinical Veterinary Medicine, University ofCambridge.)

Table 11.12 Clinical stages (TNM) of caninetumours of the prostate. Owen (1980).

T Primary tumour T0 No evidence of tumourT1 Intracapsular tumour, surrounded by normal

glandT2 Diffuse intracapsular tumourT3 Tumour extending beyond the capsuleT3 Tumour fixed or invading neighbouring structures

N Regional lymph nodes (RLN)N0 No evidence of RLN involvementN1 RLN involvedN2 RLN and juxta RLN (lumbar) involved

M Distant metastasis M0 No evidence of distant metastasisM1 Distant metastasis detected

Genital Tract 183

Radiotherapy

Palliative external beam radiotherapy has beenused intra-operatively for localised prostatictumours but with limited sucess (Turrel 1987).

Chemotherapy

Cytotoxic drugs are not usually recommended forthe treatment of prostatic neoplasia.

Other

Most prostatic tumours develop independently ofhormonal stimulation and appear not to respond to castration or hormonal therapy with anti-androgens.

Prognosis

The prognosis for prostatic tumours is gravebecause of the lack of surgical options, their highlymalignant characteristics and the tendency for earlymetastasis by the time of diagnosis.

References

Atlee, B.A., DeBoer, D.J., Ihrke, P.J., Stannard, A.A. &Willemse,T. (1991) Nodular dermatofibrosis in Germanshepherd dogs as a marker for renal cystadenocarci-noma. Journal of the American Animal Hospital Asso-ciation, (27), 481–7.

Hayes, H.M. & Pendergrass, T.W. (1976) Canine testicu-lar tumors: epidemiologic features of 410 dogs. Inter-national Journal of Cancer, (18), 482–7.

Lipowitz, A.J., Schwartz, A. et al. (1973) Testicular neo-plasms and concomitant clinical changes in the dog.Journal of the American Veterinary Medical Associa-tion, 163, 1364–8.

Mills, D.L., Hauptman, J.G. & Johnson, C.A. (1992) Cryptorchidism and monorchism in cats: 25 cases(1980–1989). Journal of the American VeterinaryMedical Association, (200), 1128–30.

Moe, L. & Lium, B. (1997) Hereditary multifocal cys-tadenocarcinomas and nodular dermatofibrosis in 51German shepherd dogs. Journal of Small Animal Prac-tice, (38), 498–505.

Murray, M., James, H. & Martin, W.J. (1969) A study ofthe cytology and karyotype of the canine transmissible

venereal tumor. Research in Veterinary Science, (10),565–8.


Turrel, J.M. (1987) Intraoperative radiotherapy of carci-noma of the prostate gland in ten dogs. Journal of theAmerican Veterinary Medical Association, (190), 48–52.

Further reading

Baldwin, C.J., Roszel, J.F. & Clark, T.P. (1992) Uterineadenocarcinoma in dogs. Compendium of ContinuingEducation for the Practising Veterinarian, (14), 731–7.

Bell, F.W., Klausner, J.S., Hayden, D.W. et al. (1991) Clin-ical and pathologic features of prostatic adenocarci-noma in sexually intact and castrated dogs: 31 cases(1970–1987). Journal of the American VeterinaryMedical Association, (199), 1623–30.

Brodey, R.S. & Roszel, J.F. (1967) Neoplasms of thecanine uterus, vagina, vulva. A clinicopathologic surveyof 90 cases. Journal of the American Veterinary MedicalAssociation, (151), 1294–1307.

Caney, S.M.A., Holt, P.E., Day, M.J., Rudorf, H.& Gruffdd-Jones, T.J. (1998) Prostatic neoplasia in two cats. Journal of Small Animal Practice, (39), 140–43.

Gelberg, H.B. & McEntee, K. (1985) Feline ovarian neo-plasms. Veterinary Pathology, (22), 572–6.

Hargis,A.M. & Miller, L.M. (1983) Prostatic carcinoma indogs. Compendium of Continuing Education for thePractising Veterinarian, (5), 647–53.

Herron, M.A. (1983) Tumors of the canine genital system.Journal of the American Animal Hospital Association,(19), 981–94.

Kydd, D.M. & Burnie, A.G. (1986) Vaginal neoplasia inthe bitch: a review of 40 clinical cases. Journal of SmallAnimal Practice, (27), 255–63.

Patnaik, A.K. & Greenlee, P.G. (1987) Canine ovarianneoplasms: a clinicopathologic study of 71 cases, includ-ing histology of 12 granulosa cell tumours. VeterinaryPathology, (24), 509–14.

Richardson, R.C. (1981) Canine transmissible venerealtumors. Compendium of Continuing Education for thePractising Veterinarian, (31), 951–6.

Stein, B.S. (1981) Tumors of the female genital tract.Journal of the American Animal Hospital Association,(17), 1022–5.

Thatcher, C. & Bradley, R.L. (1983) Vulvar and vaginaltumors in the dog. Journal of the American VeterinaryMedical Association, (183), 690–92.

Weaver, A.D. (1981) Fifteen cases of prostatic adenocar-cinoma in the dog. Veterinary Record, (109), 71–5.

12Mammary Gland

although at lower concentrations than in humanbreast tumours (Hamilton et al. 1977; MacEwen et al. 1982; Cappelletti et al. 1988; Sartin et al. 1992).More malignant, undifferentiated tumours tend to be receptor negative. Low concentrations ofprogesterone receptors are reported in feline mam-mary tumours and approximately 10% of tumourscontain oestrogen receptors (Hamilton et al. 1976;Rutteman et al. 1991).

The administration of some progestagens in-cluding medroxyprogesterone acetate, megoestrolacetate and chlormadinone acetate may increasethe risk of benign but not malignant mammarytumour development in dogs. Use of progesterone-like drugs in cats may increase development ofbenign or malignant mammary masses.

Although A-type and C-type retroviruses havebeen identified in feline mammary carcinomas,their causative role has not been established.

Pathology

The mammary gland consists of epithelial ducts and alveoli situated among stromal connectivetissue. Around each alveoli are myoepithelial cells.Tumours arising from epithelial tissues are de-scribed as either simple – epithelial elements only –or complex (mixed) – epithelial and myoepithelialelements. Other benign (e.g. lipoma) and malignantmesenchymal tumours (e.g. mast cell tumours) canoccur in the mammary gland although they are notstrictly mammary tumours.

In dogs, most histopathological studies haveshown that approximately 50% of tumoursrecorded are benign, but this figure may be artifi-cially low because there is a bias towards submit-

Mammary tumours are very common in both thedog and cat. A wide variety of histological typesoccur in the dog, although at least half are benign.In the cat, most tumours are malignant and veryaggressive.

Epidemiology

Mammary tumours are the second most commontumours in all dogs and the commonest tumours in the bitch. They occur in older animals (mean 10years), usually those that are entire or have beenspayed after numerous seasons. All breeds may beaffected.

In the cat, mammary tumours occur less fre-quently but are still the third most common type ofall tumours. Old (mean 10–12 years), entire animalsare usually affected and Siamese cats may be moreat risk than other breeds.

Aetiology

The production of the female hormones, oestrogenand progesterone, is linked to the development of mammary tumours in both dogs and cats. The relative risk of developing a mammary tumour isrelated to the number of oestrus cycles a dog hasexperienced. The risks for spaying prior to firstoestrus, after first oestrus or after second oestrusare 0.05%, 8% and 26% respectively (Schneider et al. 1969). In entire cats, there is a seven-foldincreased risk of mammary tumours compared tothose spayed at puberty (Dorn et al. 1968). Bothoestrogen and/or progesterone receptors arepresent in 40–70% of canine mammary tumours

184

Mammary Gland 185

Malignant tumours

Approximately 90% of malignant tumours are carcinomas although some malignant mixedtumours (sometimes called carcinosarcomas) andsome sarcomas do occur.

Carcinomas may be described as:

• Solid (sheets of dense cells)• Tubular or lobular (derived from alveoli)• Papillary (derived from ductal epithelium and

appearing as branching papillae or cystic)• Anaplastic (very pleomorphic and lacking any

definite pattern).

Occasionally squamous cell carcinoma maydevelop from squamous metaplasia of ductalepithelium. Grossly, carcinomas may vary from

ting malignant samples for histological analysis.Therelative frequency of the various canine tumourtypes is shown in Table 12.1. Several differenttumour types may occur in the same gland or affect different glands in the same animal.

In cats, over 80% of mammary tumours are carcinomas, the rest being mainly fibroadenomas.Lobular hyperplasia (palpable masses in one ormore glands) and fibroepithelial hyperplasia (felinemammary hypertrophy) of the mammary glandalso occur and are thought to be associated withhormonal stimulation of the glandular tissue.

Benign tumours

Benign tumours are classed as simple adenomas,complex adenomas (benign mixed tumours) orbenign mesenchymal tumours. The term fibroade-noma is also used for benign mixed tumours andthese are the most common type of benign tumourin dogs and cats. Grossly they may appear firm and nodular and histologically they may containbone or cartilage (derived from myoepithelial elements) in addition to epithelial elements (Figs 12.1 and 12.2).

Simple adenomas may be classed as lobular ifderived from alveolar epithelium or papillary if derived from ductal epithelium. If the ductsappear dilated or cystic they may be classed as cystadenomas.

Table 12.1 Frequency of histological types ofmammary tumours in dogs (Bostock 1986).

Relative frequency/Tumour type incidence (%)

Benign 51.0Benign mixed tumours/ 45.5

fibroadenomas/complexadenomas

Simple adenomas 5.0Benign mesenchymal tumours 0.5

Malignant 49.0Solid carcinomas 16.9Tubular adenocarcinomas 15.4Papillary adenocarcinomas 8.6Anaplastic carcinomas 4.0(Total carcinomas) (44.9)Sarcomas 3.1Carcinosarcoma/malignant mixed 1.0

tumours

Fig. 12.1 H&E section of a benign mixed mammarytumour. (Courtesy of Mr D. Bostock.)

Fig. 12.2 Gross appearance of benign mixed tumourin a bitch. (Courtesy of Mr D. Bostock.)

Malignant tumours may behave relativelybenignly or very aggressively. Histologically, themost important feature of carcinomas which willpredict their behaviour and likely outcome iswhether they appear well differentiated anddefined or whether they are infiltrative and invasive(Table 12.2). Those showing local invasion tend tometastasise rapidly to local lymph nodes (superfi-cial inguinal for caudal glands, axillary or cranialsternal for cranial glands) and lungs, althoughabdominal organs and bone may also be affected(Figs 12.6 and 12.7). Feline mammary carcinomasare especially aggressive and have often metasta-sised by the time of presentation.


well circumscribed, small nodules to ulcerated,diffuse and inflamed, infiltrative masses extendinginto the inguinal region and down the hind legs(inflammatory anaplastic carcinoma) (Figs 12.3,12.4 and 12.5).

Tumour behaviour

Benign tumours do not invade locally or metasta-sise but there is a tendency for bitches to developmultiple tumours and for new benign tumours todevelop in the same or other glands after excisionof an existing nodule.

Fig. 12.3 H&E section of a well defined, non-invasive,solid mammary carcinoma; there is a distinct bound-ary between the tumour and normal tissue. (Courtesyof Mr D. Bostock.)

Fig. 12.4 H&E section of a poorly differentiated, inva-sive mammary carcinoma. Tumour cells are scatteredthrough the adjacent connective tissues with vascularinvasion. (Courtesy of Mr D. Bostock.)

Fig. 12.5 Gross appearance of a mammary carcinoma.(Courtesy of Mr D. Bostock.)

Fig. 12.6 Lateral chest radiograph with multiple‘cannon-ball’ type secondary tumours, metastatic froma primary mammary carcinoma.

Mammary Gland 187


Some dogs with stage IV mammary tumours mayhave haemorrhagic diatheses or disseminatedintravascular coagulation but this is an uncommonclinical problem. A greater proportion of dogs may show subclinical haemostatic abnormalities(Stockhaus et al. 1999).

Presentation/signs

The caudal two pairs of mammary glands are mostoften affected in the dog but the anterior glands aremost affected in the cat. Mammary tumours may besingle or multiple and are usually easily palpable asdiscrete nodules or masses within the mammaryglands. They may be attached to underlying skin or muscle or may be ulcerated. Small benign massesmay be found as incidental findings on clinicalexamination or at post mortem examination. Occa-sionally an extremely small primary tumour may beeasily missed but an enlarged inguinal lymph nodemay be palpable. Some aggressive inflammatorycarcinomas may present with diffuse mammaryswelling, oedema and ulceration. Respiratory dis-tress is rarely noted in dogs with pulmonary metastasis but is common in cats because of pleural carcinomatosis and extensive pulmonaryinvolvement.

Investigations

A presumptive diagnosis of mammary tumour can be made on clinical examination and pal-pation in most cases. Care should be taken to differentiate mammary hypertrophy and mastitis,however.

Table 12.2 Tumour behaviour in dogs according to histological type(Bostock 1975).

Histological type Post surgical death rate (%) Median survival

1 year 2 year(weeks)

Complex adenoma 0 0 125Benign mixed 6 6 114

mammaryWell differentiated, 21 25 110

non-invasivecarcinoma

Invasive papillary 35 47 40and tubularcarcinomas

Invasive solid and 73 75 20anaplasticcarcinomas

Fig. 12.7 Lateral chest radiograph showing miliarymetastases which are sometimes seen with metastaticmammary carcinoma.

Group staging can also be performed, as shownin Table 12.5.

Treatment

Surgery

Treatment for most mammary tumours is surgicalexcision. Options include:

• Nodulectomy/lumpectomy• Removal of the affected gland (mammectomy)• Removal of the affected gland along with any

glands which drain lymph or blood from it (localmastectomy)

• Mammary strip (total/radical mastectomy).

In dogs, the first three glands drain cranially andglands four and five caudally although there may belymphatic communication between adjacent glands.


Bloods

These are not generally very helpful in the diagno-sis of mammary tumours although a recent studyhas revealed significant haemostatic abnormal-ities in cases of untreated mammary carcinoma (Stockhaus et al. 1999).

Imaging techniques

Radiography of the primary tumour is not neces-sary, but thoracic films are essential for all malig-nant tumours to look for pulmonary metastases.These may be discrete nodules or miliary in nature(Figs 12.6 & 12.7). Pulmonary effusion may bepresent in cats.Abdominal films may show enlargedsublumbar lymph nodes and skeletal surveys mayreveal bone metastases. Scintigraphy may also beused to screen for bone metastases.

Biopsy/FNA

Although easy to perform, fine needle aspirates ofmammary lesions are not always easy to interpretby cytological examination. They should, however,give an indication of whether the lesion is neoplas-tic or non-neoplastic. Fine needle aspiration is morehelpful to assess regional lymph nodes for metasta-tic spread. Mammary wedge biopsies may be usefulfor large lesions but small nodules are often exci-sionally biopsied as part of the treatment proce-dure. Biopsy is not usually necessary for mammarytumours since the type of surgical treatment formost cases will not depend on their histologicaltype (see below). It is helpful, however, to distin-guish tumours from other non-neoplastic condi-tions which may not require surgery.

Staging

TNM staging systems are used for mammary carcinomas in both the dog and cat (Tables 12.3 and 12.4). Multiple tumours should be evaluated independently. The primary tumour should beassessed with regard to its size and whether it isfixed to underlying tissues, by clinical and surgicalexamination. Inguinal and axillary nodes should beexamined clinically and surgically to see if they areenlarged or fixed, and thoracic radiographs shouldbe taken to look for pulmonary metastases.

Table 12.3 Clinical stages (TNM) of caninemammary tumours. Owen (1980).

T Primary tumour (evaluate multiple tumours independently)T0 No evidence of tumourT1 Tumour <3 cm maximum diameter

T1a Not fixedT1b Fixed to skinT1c Fixed to muscle

T2 Tumour 3–5 cm maximum diameterT2a Not fixedT2b Fixed to skinT2c Fixed to muscle

T3 Tumour >5 cm maximum diameterT3a Not fixedT3b Fixed to skinT3c Fixed to muscle

T4 Tumour any size, inflammatory carcinoma

N Regional lymph nodes (RLN)(axillary or inguinal; clinical or histological evaluation)N0 No evidence of involvementN1 Ipsilateral involvement

N1a Not fixedN1b Fixed

N2 Bilateral involvementN2a Not fixedN2b Fixed

M Distant metastasis (clinical, radiographic or histological evaluation)M0 No evidence of metastasisM1 Distant metastasis including distant lymph

nodes

Mammary Gland 189

centrally positioned within the gland, but mostlarger and multiple tumours will require local orradical mastectomy depending on their position inthe mammary chain. Inguinal lymph nodes areexcised as part of gland five but axillary lymphnodes need only be removed if enlarged or shownto contain neoplastic cells cytologically or histo-logically. It is often easier and quicker to perform aradical mastectomy rather than multiple mammec-tomies although the influence on survival time maybe minimal. Mammary strip has a greater rate ofdehiscence and bilateral mammary strip is not recommended. For all radical mammary surgery,an active (preferably) or passive drain should beplaced for a few days post-operatively and antibi-otic cover used.

There has been much debate on the effect ofovariohysterectomy at the time of excision of amammary tumour, but it is now generally agreedthat it has no effect on development of new benigntumours, the progression of malignant tumours,time to metastasis or overall survival (Fowler et al.1974; Brodey et al. 1983; Kitchell 1994; Yamagamiet al. 1996; Morris et al. 1998). In cats, there may bemore reason to perform ovariohysterectomy sinceovarian and uterine disease occasionally coexistwith mammary tumours.

Radiotherapy

Radiotherapy has not been shown to be effective in the treatment of canine or feline mammarytumours.

Table 12.4 Clinical stages (TNM) of felinemammary tumours. Owen (1980).

T Primary tumour (evaluate multiple tumours independently)T0 No evidence of tumourT1 Tumour <1 cm maximum diameter

T1a Not fixedT1b Fixed to skinT1c Fixed to muscle

T2 Tumour 1–3 cm maximum diameterT2a Not fixedT2b Fixed to skinT2c Fixed to muscle

T3 Tumour >3 cm maximum diameterT3a Not fixedT3b Fixed to skinT3c Fixed to muscle

T4 Tumour any size, inflammatory carcinoma

N Regional lymph nodes (RLN)(axillary or inguinal; clinical or histological evaluation)N0 No evidence of involvementN1 Ipsilateral involvement


N2 Bilateral involvementN2a Not fixedN2b Fixed

M Distant metastasis (clinical, radiographic or histological evaluation)M0 No evidence of metastasisM1 Distant metastasis including distant nodes

Table 12.5 Stage grouping of canine or felinemammary tumours. Owen (1980).

Stage grouping T N M

I T1a, b or c N0(-) M0N1a(-)N2a(-)

II T0 N1(+) M0T1a, b or c N1(+)T2a, b or c N0(+) or N1a(+)

III Any T3 Any N M0Any T Any Nb

IV Any T Any N M1

(-) histologically negative (+) histologically positive.

Theoretically this necessitates the removal of theadjacent glands for most tumours and a full strip for tumours in gland three. In the dog, no study has shown that the type of surgery performed will influence the outcome dramatically and manysurgeons favour simple mastectomy over radicalmastectomy, ignoring the drainage patterns. Inpractice, wherever the tumour is positioned, glandsone, two and three are often easily excised as ananatomical unit, and the same for glands four andfive. In the cat, communication between glands is less obvious but since size of the primary mass is an important prognostic factor and tumours are usually very aggressive, radical treatment is recommended.

In general, lumpectomy should be regarded as a biopsy procedure or reserved for very small,unfixed lesions less than 0.5cm diameter. Mam-mectomy is sufficient for fixed or unfixed tumours

although new tumours may develop and some ofthese may be malignant.

The prognosis for well differentiated carcinomasis reasonable with survival times over two years for some histological types (Bostock 1975). Forinvasive carcinomas, however, the prognosis isgrave since most will metastasise rapidly despitesurgical removal and survival times are short (36 weeks and 11 weeks for solid and anaplastic carcinomas respectively). Sarcomas also have ashort survival time (approximately six months).

As well as the histological type and degree of differentiation, other prognostic indicators forcanine mammary tumours include:

• Tumour size and volume• Tumour stage, i.e. nodal metastasis, attachment to

underlying structures, ulceration• Oestrogen receptor positivity (more malignant

tumours tend to be oestrogen receptor negative)• DNA ploidy (aneuploid tumours carry a worse

prognosis)• AgNOR count (high AgNOR count carries a

worse prognosis.

In cats, the prognosis for mammary tumours ismuch more guarded since the majority are highlymalignant and local recurrence and metastasis arecommon. Tumour size, histological grading and theextent of surgery performed are the most importantprognostic indicators.

References

Bostock, D.E. (1975) The prognosis following the surgicalexcision of canine mammary neoplasms. EuropeanJournal of Cancer, (11), 389–96.

Bostock, D.E. (1986) Canine and feline mammary neoplasms. British Veterinary Journal, (142), 506–15.

Brodey, R.S., Goldschmidt, M.H. & Roszel, J.R. (1983)Canine mammary gland neoplasms. Journal of theAmerican Animal Hospital Association, (19), 61–90.

Cappelletti, V., Granata, G., Miodini, P., Coradini, D. et al.(1988) Modulation of receptor levels in canine breasttumours by administration of tamoxifen and etretinateeither alone or in combination. Anticancer Research,(8), 1927–1302.

Dorn, C.R., Taylor, D.O.N., Schneider, R. et al. (1968)Survey of animal neoplasms in Alameda and ContraCosta Counties, California. II. Cancer morbidity indogs and cats from Alameda County. Journal of theNational Cancer Institute, (40), 307–18.

Fowler, E.H., Wilson, G.P., Koestner, A.A. et al. (1974)Biologic behaviour of canine mammary neoplasms


Chemotherapy

Carcinomas are not particularly chemosensitivetumours and although many chemotherapeuticregimes have been attempted in the treatment ofmammary carcinomas, none has shown to be veryeffective in improving disease free interval or survival beyond that obtained by surgery alone.Doxorubicin appears to have some antitumoureffect on mammary tumour cells in vitro but itseffect in the clinical situation is variable and needsfurther evaluation. A combination of cyclophos-phamide and 5-fluorouracil with or without dox-orubicin may be beneficial but the efficacy stillneeds to be established in clinical trials. In mostcases of invasive carcinoma, the disease is tooextensive at the time of diagnosis for chemotherapyto be successful.

In cats, some success has also been claimed withdoxorubicin therapy post-surgery (with or withoutcyclophosphamide) but the drug is nephrotoxic incats as well as causing anorexia and myelosuppres-sion, and should be administered with caution. Theadvanced nature of most feline mammary tumoursmeans that in general chemotherapy has a poorresponse.

Other

Anti-oestrogenic compounds such as tamoxifen areextremely useful for human mammary tumours in delaying recurrence and metastasis. Unfortu-nately, tamoxifen is metabolised to oestrogeniccompounds in the dog, causing pyometra in entireanimals and other oestrogenic effects such as vulvalswelling, vulval discharge and attractiveness tomale dogs in spayed animals (Morris et al. 1993).For these reasons, its tumouristatic properties indogs have not been fully evaluated.

Biologic response modifiers such as Bacillus Cal-mette-Guerin (BCG), Corynebacterium parvum,neuraminidase or levamisole have been used experimentally to treat mammary tumours, but noclear therapeutic benefit has been demonstrated.

Prognosis

The prognosis for most benign canine mammarytumours which are surgically excised is good,

Mammary Gland 191

based on a histogenic classification. Veterinary Pathol-ogy, (11), 212–29.

Hamilton, M., Else, R.W. & Forshaw, P. (1976) Oestrogenreceptors in feline mammary carcinoma. VeterinaryRecord, (99), 477–9.

Hamilton, M., Else, R.W. & Forshaw, P. (1977) Oestrogenreceptors in canine mammary tumors. VeterinaryRecord, (101), 258–60.

Kitchell, B.E. (1994) Mammary carcinoma in dogs: updateon biology and therapy. Proceedings of 12th AmericanCollege of Veterinary Internal Medicine Forum, 884–6.

MacEwen, E.G., Patnaik, A.K., Harvey, H.J. et al. (1982)Estrogen receptors in canine mammary tumours.Cancer Research, (42), 2255–9.

Morris, J.S., Dobson, J.M. & Bostock D.E. (1993) Use of tamoxifen in the control of canine mammary neo-plasia. Veterinary Record, (133), 539–42.

Morris, J.S., Dobson, J.M., Bostock, D.E. & O’Farrell,E. (1998) Effect of ovariohysterectomy in bitches with mammary neoplasia. Veterinary Record, (142),656–8.


Rutteman, G.R., Blankenstein, M.A., Minke, J. &Misdorp, W. (1991) Steroid receptors in mammarytumours of the cat (Suppl 1). Acta Endocrinologica,(125), 32–7.

Sartin, E.A., Barnes, S., Kwapien, R.P. et al. (1992) Estro-gen and progesterone receptor status of mammary carcinomas and correlation with clinical outcome.American Journal of Veterinary Research, (53),2196–200.

Schneider, R., Dorn, C.R. & Taylor, D.O.N. (1969) Factorsinfluencing canine mammary development and post-surgical survival. Journal of the National Cancer Insti-tute, (43), 1249–61.

Stockhaus, C., Kohn, B., Rudolph, R., Brunnberg, L. &Giger, U. (1999) Correlation of haemostatic abnormal-ities with tumour stage and characteristics in dogs withmammary carcinoma. Journal of Small Animal Practice,(40), 326–31.

Yamagami, T., Kobayashi, T., Takahashi, K. & Sugiyama,

M. (1996) Influence of ovariectomy at the time of mastectomy on the prognosis for canine malignantmammary tumours. Journal of Small Animal Practice,(37), 462–4.

Further reading

Bostock, D.E., Moriarty, J. & Crocker, J. (1992) Correla-tion between histologic diagnosis, mean nucleolarorganiser region count and prognosis in caninemammary tumours. Veterinary Pathology, (29), 381–5.

Ferguson, R.H. (1985) Canine mammary gland tumors.Veterinary Clinics of North America Small AnimalPractice, (15), 501–11.

Giles, R.C., Kwapien, R.P., Geil, R.G. & Casey, H.W.(1978) Mammary nodules in beagle dogs administeredinvestigational oral contraceptive steroids. Journal ofthe National Cancer Institute, (60), 1351–64.

Hahn, K.A., Richardson, R.C. & Knapp, D.W. (1992)Canine malignant mammary neoplasia: biologic behav-iour, diagnosis and treatment alternatives. Journal ofthe American Animal Hospital Association, (28), 251–6.

Hahn, K.A. & Adams, W.H. (1997) Feline mammary neo-plasia: biological behaviour, diagnosis and treatmentalternatives. Feline Practice, (25), 5–11.

Hayes, A. & Mooney, S. (1985) Feline mammary tumours.Veterinary Clinics of North America, (15), 513–20.

Jeglum, K.A., de Guzman, E. & Young, K.M. (1985)Chemotherapy for advanced mammary adenocarci-noma in 14 cats. Journal of the American VeterinaryMedical Association, (187), 157–60.

Kurtzman, I.D. & Gilbertson, S.R. (1986) Prognosticfactors in canine mammary tumours. Seminars in Veterinary Medicine and Surgery, (1), 25–32.

MacEwen, E.G., Hayes, A.A. & Harvey, H.J. (1984) Prog-nostic factors for feline mammary tumours. Journalof the American Veterinary Medical Association, (185),201–4.

Susaneck, S.J., Allen, T.A., Hoopes, J. et al. (1976)Inflammatory mammary carcinoma in the dog. Journalof the American Animal Hospital Association, (19),971–6.

13Nervous System

tumours of peripheral nerves are included withtumours of the soft tissues, as discussed in Chapter5. Tumours of the eye will be discussed in Chapter16. This chapter is devoted to tumours affecting thecentral nervous system, i.e. the brain and the spinalcord.

The nervous system may be divided into the centralnervous system (CNS) comprising the brain(including the optic nerve) and the spinal cord, andthe peripheral nervous system (PNS) comprisingperipheral nerves and nerve roots, including partsof the autonomic nervous system. By convention

� Brain (intracranial) tumours, 192� Spinal cord, 199

192

BRAIN (INTRACRANIAL) TUMOURS

Epidemiology

Primary tumours of the brain are not common inmost epidemiological tumour studies; however withthe advent of advanced imaging techniques (CTand MRI), tumours of the brain are assuming moreimportance in canine and feline medicine. Thereported incidence of primary brain tumours is14.4/100000 dogs and 3.5/100000 cats (Moore et al.1996).

Most primary brain tumours are solitary lesions.They may occur in all breeds of dog but the boxer,golden retriever, dobermann, Scottish terrier andold English sheepdog have been reported to be at increased risk. Primary brain tumours may occurat any age but the incidence increases over fiveyears of age with a median age of nine yearsreported in dogs (Heidner et al. 1991). There doesnot appear to be any breed predilection for menin-gioma in the dog but glial cell tumours have apredilection for brachycephalic breeds, particularlythe boxer.

Aetiology

The aetiology of brain tumours in cats and dogs isunknown.

Pathology

Intracranial tumours of dogs and cats may be eitherprimary or secondary and are classified on the basisof cytological and histological criteria. Primarytumours arise from tissues of the nervous system:nerve cells, neuroepithelial tissues, neural connec-tive tissues (the glia) and the meninges (as listed in Table 13.1). The most common primary braintumours in the dog are meningioma, glioma (e.g. astrocytoma) and undifferentiated sarcomas.Tumours of the choroid plexus are also reported.Meningioma is the most common brain tumour incats and multiple meningiomas may occur in thisspecies.

The brain may be a site for haematogenous

Nervous System 193


The distinction between ‘benign’ and ‘malignant’ isless relevant for tumours of the brain than fortumours at most other sites. Many intracranialtumours are relatively slow growing but may

metastasis of malignant tumours sited elsewhere inthe body or may be affected by local extension oftumours of the nasal cavity and paranasal sinuses,from the skull and from the middle ear. Pituitarygland tumours and tumours of the cranial nervesare considered to be secondary tumours as theyaffect the brain by means of local extension(LeCouteur, 1999).

Table 13.1 Classification of intracranial tumours.

Tissue/origin Tumour Site/comment

Nerve cells Ganglioblastoma/gangliocytoma/ Cerebellum & brain stem, mature dogsganglioneuroma slow growing, rare

Neuroblastoma Cerebellum/olfactory epithelium, rareMedulloblastoma ? Origin, young dogs, highly malignant

Neuroepithelial Ependymoma (neuroepithelioma) Associated with ependyma ofventricular system in maturebrachycephalic dogs. Infiltrating andaggressive

Chondroid plexus tumours (papilloma) Usually associated with ventricularsystem, well defined, slowly growing

Glial Oligodendroglioma Rare. Frontal and pyriform lobes ofcerebrum, most common site inbrachycephalic dogs. Infiltratinggrowth

Glioblastoma Rare but reported in brachycephalic dogsAstrocytoma Common in brachycephalic dogs

usually located in cerebellum. Grow byexpansion and infiltration

Meningeal Meningioma Common in cats and dogs. Sitesinclude base of brain, and convexity ofcerebral hemispheres. Growth usuallyby expansion

Meningeal sarcoma Rare, malignant

Nerve sheath Peripheral nerve sheath tumours Included because these tumours are(Schwannoma, neurofibroma, associated with nerve tissue but are

neurilemoma, neurofibrosarcoma, not usually intracranial in sitemalignant schwannoma) Acoustic neuroma is a notable exception

Neurohypophysis Pituitary adenomaPosterior pituitary astrocytoma

Other LymphomaHaemangiosarcomaTeratoma/germ cell tumour

Metastatic tumours Mammary, prostatic, pulmonarycarcinoma

HaemangiosarcomaMalignant melanoma

Tumours which Pituitary adenoma/adenocarcinomadirectly invade into Skullthe brain from: Nasal/paranasal sinuses

Middle ear


present with acute or rapidly progressing clinicalsigns when compensatory mechanisms are over-whelmed.An intracranial tumour may possess cyto-logical features to suggest a benign behaviour, andindeed may not possess the capacity for distantmetastasis, but may still be life threatening in bio-logical terms. Some tumours, for example caninemeningioma, may be classified as benign but maybe locally invasive of normal brain tissue. Felinemeningioma are usually well defined with cleardemarcation between normal and affected braintissue. It is rare for primary brain tumours to metas-tasise outside the cranial cavity.

Primary brain tumours are not usually associatedwith paraneoplastic syndromes as such althoughtumours adjacent to or involving the pituitary glandmay cause a variety of endocrinopathies as detailedin Chapter 14.

Presentation/signs

Intracranial tumours may manifest in a variety ofways. Behavioural and temperament changes suchas:

• Abnormal mental status• Disorientation• Loss of trained habits.

are common, but these may be insidious in onsetand may be dismissed as ageing in older animals.

More specific neurological signs depend primar-ily on the site of the tumour within the brain (Table13.2), its size and rate of growth. Initially such signsmay be transient but as the tumour enlarges theymay become more severe and permanent. Seizuresare common and are often one of the first signs ofa tumour of the cerebral cortex. Multiple cranialnerve deficits may be associated with tumours ofthe ventral brain stem, while dysmetria, intentiontremors and ataxia may be seen with tumours of thecerebellum. Visual impairment or blindness may beassociated with tumours of the hypothalamus orwith meningioma of the optic nerve.

Intracranial tumours may also result in increasedintracranial pressure, either due to a mass effect ordue to cerebral oedema, ultimately this may lead toherniation of the brain through the foramen magna.Clinical signs of these secondary effects include

Table 13.2 Possible signs of intracranial tumours according to location.

Location of tumour Associated neurological signs

Cerebral cortex Abnormal movement, circling (usuallytowards the side of the tumour)

Continual pacingHead pressingSeizures

Hypothalamus Altered mental statusVisual impairment, due to defects in optic

(II) nerve at optic chiasm(Diabetes insipidus)

Midbrain Defects in oculomotor (III): strabismusand abnormal pupil dilation

Contralateral spastic hemiparesis

Cerebellum Dysmetria, ataxiaWide base stanceIntention tremor

Vestibular Head tiltCirclingNystagmusVestibular strabismus

Ventral brain stem Cranial nerve deficits (V,VI,VII,IX,X)Hemiparesis to tetraparesisIrregular respiration

Nervous System 195

may be useful for assessment of tumours of thenasal cavity and paranasal sinuses or tumours of the skull (including the tympanic bullae) that mayextend into the cranial vault.

Survey radiographs of the thorax and abdomenand ultrasound evaluation of liver, spleen and otherinternal organs should be performed as part of theevaluation of the patient to rule out extracranialcauses of the neurological problems and the possi-bility that an intracranial lesion may be a metasta-tic tumour from elsewhere. Most intracranialtumours do not metastasise so the finding of multi-ple tumours elsewhere in the body would supporta diagnosis of a secondary brain tumour.

Advanced imaging techniques such as CT andMRI have revolutionised the detection of intracra-nial lesions. Although these techniques are complimentary, MRI is generally superior to CT inproviding high quality images of intracranial softtissues which allow detection of subtle changes suchas oedema, changes in vascularity, haemorrhageand necrosis as well as the detection of the primarymass. MRI also permits better definition of theanatomical relationships of a tumour and sur-rounding normal tissues.

In the absence of a histological diagnosis (seebelow) the CT or MRI features of a brain lesion areoften used to suggest the type of tumour (Table13.3, Figs 13.1–13.3). However as some non-neoplastic, space-occupying lesions and metastatic

altered states of consciousness, lethargy or irri-tability, compulsive walking, circling, head pressingand locomotor disturbances. Brain herniation willresult in respiratory failure and death.

Investigations

A full neurological examination is required in apatient presenting with any of the signs outlinedabove or in Table 13.2, in order to confirm that theproblem is of neurological origin and to attempt todefine the location of the lesion.

Bloods

Routine haematological and biochemical analysesare indicated in the investigation of an animal pre-senting with neurological signs in order to rule outextracranial causes but, with the exception oftumours affecting the pituitary gland, there are nospecific changes associated with most intracranialtumours.

Imaging techniques

Plain radiography of the skull is of little value in thedetection of most intracranial tumours, although onoccasion osteolysis or hyperostosis of the skull maybe seen with feline meningioma. Skull radiography

Table 13.3 Presumptive diagnosis of brain tumours based on MRI fea-tures (Brearley et al. 1999).

MRI features Likely tumour type

Extra-axial MeningiomaHomogeneously enhancing mass located (also Schwannoma andoutside the brain parenchyma choroid plexus tumour)(Fig. 13.1)

Intra-axial Glial tumourHeterogeneously enhancing mass locatedwithin the brain parenchyma(Fig. 13.2)

Pituitary based Pituitary macroadenomaHomogeneously enhancing mass involvingthe pituitary gland and extending upwardsinto the thalamus(Fig. 13.3)


Fig. 13.1 MRI scan showing extra-axial tumour. Alarge meningioma in a 14 year old domestic short haircat with seizures. The contrast enhanced transverse T1-weighted scan shows the mass to be extra-axial withdense contrast enhancement. The adjacent cerebrumis compressed and displaced and there is marked over-lying hyperostosis. (Courtesy of Ruth Dennis, Centrefor Small Animal Studies, Animal Health Trust, Newmarket.)

Fig. 13.2 (Left.) MRI scan showing intra-axial tumour.MRI scan of an 11 year old collie-cross bitch withseizures. The contrast-enhanced transverse T1-weighted scan shows a large, intra-axial cerebral mass,showing ring enhancement, typical of a glioma. (Cour-tesy of Ruth Dennis, Centre for Small Animal Studies,Animal Health Trust, Newmarket, previously publishedby In Practice (1998), (20), 117–124, with permission)

tumours may mimic the CT or MRI appearance of a primary brain tumour, this situation is notideal.

Biopsy/FNA

Cytological/histological diagnosis of an intracranialtumour requires collection of cells or tissue fromthe lesion. The brain is not easily accessible for col-lection of either fine needle aspirates or biopsyspecimens. Exploratory surgery carries quite highrisks and is generally not undertaken unless thereis a reasonable chance of an excisional biopsy of thelesion (see treatment). For this reason many brain

Fig. 13.3 MRI scan showing a pituitary tumour – and MRI scan of a 5 year old Labrador with pituitarydependent hyperadrenocorticism. The image shows ahomogeneously enhancing mass involving the pitui-tary gland and extending upwards into the thalamus.(Courtesy of Animal Health Trust, Newmarket.)

Nervous System 197

Treatment

Surgery

Some primary brain tumours are amenable to sur-gical resection and this can be an effective treat-ment for meningiomas, especially those sited overthe frontal lobes of the cerebrum in cats. Evenpartial removal of a brain mass may relieve someof the associated clinical signs, provide tissue forhistological diagnosis and allow a better responseto subsequent treatment such as radiotherapy.

Neurosurgery is a highly specialised area. Surgi-cal approaches to the brain, anaesthetic considera-tions and post-operative care are beyond the scopeof this book but the following may be useful cri-teria to aid selection of cases that may be suitablefor surgical management:

• Accurate localisation of the mass is essential.• Nature of tumour – only solitary and non-

invasive tumours are suitable• Site – a tumour that is on or near the surface of

the brain is accessible for surgical management.The cerebral hemispheres are the most suitablesite for surgical intervention. Significant mor-bidity may be associated with surgical removal oftumours of the caudal fossa or brain stem.

• Patient status – neurological function must becompatible with life.

Radiotherapy

Radiotherapy is probably the most widely usedtreatment for brain tumours in cats and dogs andmay either be used alone or in conjunction withsurgery or chemotherapy. External beam mega-voltage radiation provides a deeply penetrating X-ray beam of predictable configuration which allowsthe tumour volume to be targeted from severaltreatment ports, while sparing to some degree theadjacent normal tissue (Fig. 13.4). Careful treat-ment planning is essential, and this is aided by com-puter planning systems and good quality CT orMRI images of the brain. Brain tissue is quite sus-ceptible to late radiation toxicity resulting in brainnecrosis. The optimum fractionation schedule forradiotherapy of brain tumours in animals has notbeen established. Some authorities favour smalldaily fractions keeping the normal tissue dose

‘tumours’ in cats and dogs are not confirmedhistopathologically in life.

Recently a CT-guided stereotactic brain biopsysystem has been modified for use in cats and dogs(LeCouter et al. 1998) and offers an accurate meansof collecting biopsy samples from brain lesions witha low rate of complications.

Other

Several other techniques may be indicated in theevaluation of the patient with neurological signsbut none assist specifically in the diagnosis ofprimary brain tumours.

Cerebrospinal fluid (CSF) analysisCerebrospinal fluid (CSF) analysis may be indi-cated to rule out inflammatory diseases of CNS,for example granulomatous meningioenceph-alomyelitis (GME), which is an important differen-tial diagnosis for many of the clinical signs listedabove. However, it is unusual to find tumour cellsin the CSF and so CSF analysis rarely confirms the presence of a tumour. One possible exception is in the case of CNS lymphoma where the CSF may contain significant numbers of abnormal lym-phoid cells. Increased CSF protein and normal toincreased CSF white cell count are often reportedin cases with brain tumours as a result of necrosisor microabcessation associated with the tumourmass. CSF collection should not be performed inanimals with suspected brain tumours until afterimaging because of the risk that the technique canprecipitate herniation of the brain in cases withraised intracranial pressure.

Electrodiagnostic testingBrainstem auditory evoked potential (BAEP)testing and electroencephalography (EEG) may beused to assess function of the brain stem and thecerebrum, respectively, but neither are widely avail-able. Both techniques can help to locate the site ofa lesion but neither provide specific informationabout the cause of any abnormalities detected(Fischer & Obermaier 1994).

Staging

A clinical staging system has not been devised forprimary brain tumours.


below 50Gy (Gavin et al. 1995), whilst others havereported similar results with hypofractionatedradiotherapy to a total tumour dose of 38Gy(Brearley et al. 1999).

Chemotherapy

The role of chemotherapy in the treatment of braintumours has not really been established in cats and dogs. Many chemotherapeutic agents do not

achieve therapeutic concentrations in the brainbecause of limited passage of the blood brainbarrier. The lipophilic agents BiCNU (carmustine)and CCNU (lomustine) do pass into the CSF intherapeutic concentrations but only rare tumourssuch as teratoma and dysgerminoma are regardedas potentially curable by chemotherapy in humans.Few chemotherapy studies have been reported indogs with brain tumours and results have been variable. It is probable that different tumour types

Dorsoventralfield

Head

Brain

Tumour

Brass Wedge

Lateralfield

Mandible

Lateralfield

Fig. 13.4 Computer generated treatment plan for a dog with a brain tumour. (See also Colour plate 28, facing p. 162, the key of which follows on here: An MRI scan is digitised into the computer to provide a scaled linedrawing of the outline of the dog’s head (blue line) and mandibles (blue), the brain (outer red) and the tumour(inner red). The computer predicts the radiation dose deposition, shown as isodose contours (black lines; figuresindicate percentage applied radiation dose) based on an isocentric treatment using three portals: dorsoventral andright and left lateral, with brass wedges (green triangles) used to attenuate the lateral beams.)

Nervous System 199

managed palliatively as above, survival times postdiagnosis are short.

Where surgical resection of a brain tumour ispossible, e.g. meningioma in cats, long-term survivalis possible. In a study of 42 cats with surgicallyresected cerebral meningiomas, overall survival was 66% at one year and 50% at two years;however, 20% of patients died in the immediatepost-operative period (Gordon et al. 1994).

Results of radiotherapy for brain tumours indogs are variable with median survival timesranging from 20–43 weeks (Heidner et al. 1991;Brearley et al. 1999). It is likely that differenttumours may differ in their radiosensitivity and a recent study using hypofractionated radio-therapy has suggested that extra-axial tumours (byinference meningioma) carry a slightly morefavourable prognosis than intra-axial tumours (byinference glioma) and that overall, pituitary-basedtumours carry a significantly worse prongosis thaneither (Brearley et al. 1999). However, it should benoted that pituitary-based tumours have a veryvariable survival rate: those associated with severeneurological problems tend to have a short survivalwhereas those with mild signs can survive for longperiods following radiotherapy (M. Brearley pers.comm.)

differ in their chemosensitivity and there is someevidence that glial cell tumours may show aresponse to lomustine (Jeffery & Brearley 1993).While lymphoma is chemosensitive, treatment ofCNS lymphoma is hampered by drug delivery.

Other

Supportive, symptomatic therapy to control the sec-ondary effects of the tumour can greatly improvethe status of patients with brain tumours in theshort term.

• Anticonvulsant therapy – may be required tocontrol seizures

• Corticosteroid therapy – reduces tumour associated inflammation and swelling.

These treatments may be required for patientsundergoing surgery and/or radiotherapy.

Prognosis

Although many brain tumours are relatively slowgrowing, most are not diagnosed until they reach anadvanced stage and are associated with neurologi-cal signs. For those animals that are not treated, or

SPINAL CORD

Epidemiology

The spinal cord is not a common site for the devel-opment of tumours and only a small number of case series have been reported, making unreli-able figures for age, breed and sex predisposition.They can be seen in any age of cat and dog; in onestudy of 29 tumours 27% of animals were threeyears of age or less (Luttgen et al. 1980). No breedor sex predisposition has been reported in eitherspecies although large dogs appear to be at higherrisk.

Traditionally tumours affecting the spinal cordare classified according to their location withrespect to the cord and dura (Table 13.4).Extradural tumours are the most common, repre-senting up to 50% of all spinal tumours. Intradural-extramedullary tumours comprise up to 30% oftumours at this site.

Aetiology

With the exception of lymphoma in cats (Chapter15), the aetiology of tumours affecting the spinalcord in cats and dogs is unknown.

Pathology

Extradural

The most common extradural tumours in dogs arisefrom the vertebrae and include osteosarcoma andother primary bone tumours. The vertebral columnmay be the site for development of secondarytumours and may also be affected by more gener-alised neoplastic disease, e.g. multiple myeloma.Extradural liposarcoma and lymphoma have alsobeen reported in dogs. In cats osteosarcoma is the


most common extradural tumour; benign tumourssuch as osteochondroma may affect the vertebralcolumn and extradural lymphoma is of importance.Overall lymphoma is the most common spinaltumour in cats.

Intradural-extramedullary

In dogs meningioma and peripheral nerve sheathtumours are the most common tumours to occur at this site. (The term peripheral nerve sheathtumour encompasses all tumours arising fromSchwann cells, also termed neurinoma, neurile-moma, schwannoma, malignant schwannoma, neu-rofibroma, neurofibrosarcoma – see also Chapter5.) Neuroepithelioma (also called ependymoma,medulloepithelioma and spinal cord blastoma) hasbeen reported to arise in the T10-L2 segments ofthe spinal cord in young dogs, especially Germanshepherds and retrievers (Moissonnier & Abbott1993). Meningiomas are the most commonlyreported intradural-extramedullary tumours in catsbut lymphoma may also arise at this site.

Intramedullary

Intramedullary spinal tumours arise from compo-nents of the spinal cord and are uncommon in dogsand rare in cats. In dogs glial cell tumours (e.g.astrocytoma) are the most common tumours to

arise at this site. Haemangiosarcoma and othermalignant tumours may metastasise to the spinalcord, although this is unusual. The cord may also beaffected by lymphoma and occasionally by GME.


Many different patterns of behaviour may be asso-ciated with the diverse list of tumours that mayaffect the spinal cord. All tumours at this site resultin spinal cord compression. This may be gradual inthe case of a slowly growing extradural tumour butcould be acute, due to haemorrhage or ischaemiaor where tumour-associated osteolysis of a vertebraresults in a pathological fracture or collapse of thebone (Fig. 13.5).

While some of the tumours listed as affecting thespinal cord are malignant, the severity of the localeffects on the cord are usually of greater impor-tance than the longer term risk of metastasis.

Primary tumours of the spinal cord are notusually associated with paraneoplastic syndromes.

Presentation/signs

The clinical signs of a spinal tumour are variableand depend to some extent on the location of thelesion and on its rate of growth. The signs may be

Table 13.4 Classification of tumours affecting the spinal cord.

Site Location and origin Tumour types

Extradural Located outside the dura mater, arising from Primary bone tumoursmesenchymal elements in the adjacent (osteosarcoma, chondrosarcoma,spinal column fibrosarcoma, haemangiosarcoma)

Tumours metastatic to vertebrae(e.g. mammary or prostatic carcinoma)

Multiple myelomaLymphoma (in cats)

Intradural– Located outside the spinal cord but within Meningiomaextramedullary the dura mater, arising from connective Peripheral nerve sheath tumours

tissues of the dura Neuroepithelioma (= ependymoma)

Intramedullary Sited within the spinal cord, arising from Glial cell tumourscomponents of the spinal cord Undifferentiated sarcoma

Metastatic tumours(haemangiosarcoma, melanoma,mammary carcinoma)

Lymphoma

Nervous System 201

Imaging techniques

Plain radiographs of the vertebral column mayidentify an extradural lesion of the axial skeletonbut contrast myelography is usually required tolocate the lesion in terms of level of cord, site(extradural–intradural) and extent (Figs 13.6 and13.7). MRI and CT would provide superior detailof the tumour mass and its relationships with surrounding tissues, which would be valuable ifplanning a surgical approach.

Plain films of the chest and abdomen should betaken to look for primary or secondary tumours.

Biopsy/FNA

Definitive diagnosis of most neoplasms affectingthe spinal cord will require a biopsy of the lesion.However, as with tumours of the brain, most spinaltumours are not readily accessible for biopsy orFNA and, by force of necessity, collection of biopsymaterial becomes part of the therapeutic approach.

Other

CSF may be collected as part of the diagnostic workup, especially if myelography is performed. As withtumours of the brain, neoplastic cells are rarelyfound in CSF samples from animals with spinaltumours; non-specific changes in protein and cellcontent may occur in some cases.

gradual in onset and progress in severity over avariable period of time, but on occasion (for thereasons outlined above) the onset may be acute.

• Pain is a common feature of extradural and intradural-extramedullary tumours due toinvolvement of spinal nerves, nerve roots and/orbone.

• Neurological deficits will depend on the site ofthe lesion. There is usually a progressive loss of neurological function caudal to the lesion,leading to ataxia, paresis or paralysis. This progression can be rapid in the case ofintramedullary tumours.

Unilateral spinal cord compression may causedeficits in the opposite limb.

Investigations

A full neurological examination is necessary tolocate the site of the spinal lesion but unless thereis a large/palpable extradual mass this is unlikely toprovide much information on the nature of lesion.

Bloods

Routine haematological and biochemical analysesmay be indicated in the initial evaluation of apatient presenting with a potential spinal injury, butthere are no specific changes associated with mostspinal tumours. Hypercalcaemia and or hypergam-maglobulinaemia may be detected in dogs withmultiple myeloma.

Fig. 13.5 Collapse of an osteolytic myeloma lesion inthe lumbar vetebral body, leading to acute onset spinalpain and paresis.

Fig. 13.6 Extradural lesion. On the myelogram, thecontrast columns taper and converge slightly at thelevel of T3 (see arrows). At post mortem examinationan epidural mass was located at the level of T3–T4.(Courtesy of Radiology Department, Department ofClinical Veterinary Medicine, Cambridge.)


Staging

A clinical staging system has not been devised fortumours of the spinal cord.

Treatment

Surgery

Where possible surgery is the treatment of choicefor most extradural and intradural-exatramedullarytumours. The spinal cord may be approached andthe lesion visualised by a dorsal or hemilaminec-tomy. Complete removal of the tumour mass maybe possible at the time of surgery but in cases wherethis cannot be achieved surgery may still be bene-ficial for:

• Cytoreduction of the mass• Provision of biopsy material for histological

diagnosis• Decompression of the cord.

Radiotherapy

There are few reports in the literature concerningthe use of radiotherapy in the treatment of tumoursof the spinal cord.As with the brain, the spinal cordis reported to be susceptible to late radiation-induced necrosis and is not generally regarded as a good site for radiotherapy, although this maydepend on fractionation schedules and totalapplied dose. One series of nine dogs with assortedtumour types (including six meningioma) suggestedthat radiotherapy was a useful adjunct to decom-pressive surgery in these cases and reported amedian overall survival time of 17 months (Siegelet al. 1996). Radiotherapy has been used in thetreatment of spinal cord lymphoma, with or withoutchemotherapy. The exquisite sensitivity of lym-phoma to radiation permits effective treatment atlower radiation doses than would be required formost solid tumours.

Chemotherapy

With the exception of lymphoma, chemotherapyhas not been used in treatment of spinal cordtumours.

Other

Glucocorticoids may be used to reduce swelling orcompression of the cord in cases with acute onsetof problems.

Prognosis

The prognosis for tumours of the spinal cord is veryvariable depending on the nature and the extent ofthe lesions. What is clear from the limited literatureis that surgical management can be quite successfuland even if complete tumour removal is not possi-ble, post-operative radiotherapy can lead to a sig-nificant improvement in survival duration.

References

Brearley, M.J., Jeffery, N.D., Phillips, S.M. & Dennis, R.(1999) Hypofractionated radiation therapy of brainmasses in dogs: a retrospective anaysis of survival of 83cases (1991–1996). Journal of Veterinary Internal Medi-cine, (13), 408–12.

Fig. 13.7 Intradural lesion – myelogram of a dog pre-sented with hemiparesis. The dorsal column stops atC6, the ventral column at C7 (see arrow). The appear-ance suggests an intramedullary lesion. A nerve roottumour was found at post mortem examination. (Cour-tesy of Radiology Department, Department of ClinicalVeterinary Medicine, Cambridge.)

Nervous System 203

Fischer, A. & Obermaier, G. (1994) Brainstem auditory-evoked potentials and neuropathologic correlates in 26dogs with brain tumours. Journal of Veterinary InternalMedicine, (8), 363–9.

Gavin, P.R., Fike, J.R. & Hoopes, P.J. (1995) Centralnervous system tumours. Seminars in Veterinary Medi-cine & Surgery (Small animal), (10), 180–89.

Gordon, L.E., Thatcher, C., Matthiesen, D.T. et al. (1994)Results of craniotomy for treatment of cerebral menin-gioma in 42 cats. Veterinary Surgery, (23), 94–100.

Heidner, G.L., Kornegay, J.N., Page, J.N., Dodge, R.K. &Thrall, D.E. (1991) Analysis of survival in a retrospec-tive study of 86 dogs with brain tumours. Journal of Veterinary Internal Medicine, (5), 219–26.

Jeffery, N. & Brearley, M.J. (1993) Brain tumours in thedog: treatment of 10 cases and a review of recent litera-ture. Journal of Small Animal Practice, (34), 367.

LeCouteur, R.A. (1999) Current concepts in the diagno-sis and treatment of brain tumours in dogs and cats.Journal of Small Animal Practice, (40), 411–16.

LeCouteur, R.A., Koblik, P.D., Higgins, R.J., Fick, J.,Kortz, G.D., Vernau, K.M., Sturges, B.K. & Berry, W.L.(1998) Computed tomography CT-guided stereotacticbrain biopsy in 25 dogs and 10 cats using the PelorusMark III biopsy system. Journal of Veterinary InternalMedicine, (12), 207.

Luttgen, P.J., Braund, K.G., Brauner, W.R. et al. (1980) Aretrospective study of 29 spinal tumours in the dog andcat. Journal of Small Animal Practice, (21), 213–26.

Moissonnier, P. & Abbott, D.P. (1993) Canine neuroepi-thelioma: case report and literature review. Journalof the American Animal Hospital Association, (29),397–401.

Moore, M.P., Bagley, R.S., Harrington, M.L. & Gavin, P.R.(1996) Intracranial tumours. Veterinary Clinics of NorthAmerica: Small Animal Practice, (26), 759–77.

Siegel, S., Kornegay, J.N. & Thrall, D.E. (1996) Post-operative irradiation of spinal cord tumours in ninedogs. Veterinary Radiology and Ultrasound, (37),150–53.

14Endocrine System

not produce paraneoplastic syndromes and thesemay remain undetected. Conversely, someendocrinopathies, such as acromegaly in dogs, maybe caused by non-neoplastic events, making thediagnosis and management of these conditionsquite challenging.

This chapter deals with the tumours which occurin endocrine glands and the endocrinopathies asso-ciated with them (Table 14.1). Further informationon the medical aspects of these conditions is givenin specific medical or endocrinological texts. Otherparaneoplastic syndromes which are associatedwith non-endocrine tumours are discussed inChapter 2.

When tumours develop in endocrine glands, theirnormal function may be affected in one of twoways:

• Reduced hormone production/secretion mayoccur if normal tissue is destroyed

• Autonomous hormone secretion may occur if the feedback mechanisms controlling hormoneoutput are altered.

Both scenarios may result in metabolic disorders or‘paraneoplastic syndromes’ and the presentingsigns characteristic of these disorders should alertthe clinician to the possibility of underlying neo-plasia. Some endocrine gland tumours, however, do

� Thyroid gland, 204� Parathyroid gland, 210� Pituitary gland, 212� Adrenal gland, 216� Pancreas (endocrine), 221

204

THYROID GLAND

Thyroid neoplasms occur in both cats and dogs butthe pathological and biological aspects of thesetumours differ greatly between the two species.Thyroid tumours in cats are usually benign butfunctional with significant clinical signs associated

with hyperthyroidism. In dogs, thyroid tumours areusually non-functional, and the majority are carci-nomas, many of which invade local tissues andmetastasise rapidly.

Endocrine System 205

Hyperthyroidism/thyroid adenomas affect mid-dle-aged and old cats (mean age 13 years) but thereis no sex or breed predisposition. Thyroid carcino-mas, although rare, also occur in old cats (age range6–18 years), with males over-represented.

Aetiology

The aetiology of canine and feline thyroid tumoursis unclear. However, specific chromosome translo-cations and inversions involving the RET oncogene

Epidemiology

Thyroid tumours in dogs represent 1–2% of all neo-plasms. Old or middle-aged dogs (mean 10 years)are affected, particularly beagles, boxers or goldenretrievers, but there is no sex predisposition (Susa-neck 1983; Sullivan et al. 1987). Thyroid carcinomasin dogs may exist as solitary tumours or as part ofa multiple endocrine neoplasia (MEN) syndrome,in conjunction with other primary tumours such asphaeochromocytoma or parathyroid adenoma.

Table 14.1 Paraneoplastic syndromes resulting from tumours of endocrine origin.

Endocrine gland Syndrome Tumour(s) Comment

Thyroid Hyperthyroidism Thyroid adenoma (cats) Most commonThyroid adenocarcinoma endocrine disorder of

(dogs and occasionally cats. Much lesscats) common in dogs since

most tumours are non-functional

Parathyroid Hyperparathyroidism Parathyroid adenoma One of the less common(hypercalcaemia) (dogs and rarely cats) causes of

hypercalcaemiaPituitary Acromegaly Pituitary adenoma (cats) Acromegaly in dogs is

caused by highprogesterone(endogenous orexogenous) notneoplasia

Pituitary Hyperadrenocorticism Pituitary adenoma Most common endo-(pituitary dependent) (dogs and cats) crine disorder of dogs.

Pituitary dependentform accounts forapproximately 80–85%of cases of hyperadrenocorticismin dogs and cats

Adrenal Hyperadrenocorticism Adrenal adenoma Less common cause of(cortex) (adrenal dependent) Adrenal carcinoma hyperadrenocorticism

(dogs and cats)Adrenal Hypercatecholaminaemia/ Phaeochromocytoma Intermittent syndrome(medulla) hypertension (dogs and rarely cats) due to episodic release

of catecholaminesPancreas Hypoglycaemia Insulinoma (dogs and Episodic syndrome(islets) rarely cats) initially due to

fluctuating glucoselevels

Hypergastrinaemia Gastrinoma (dogs and(Zollinger-Ellison cats)

syndrome)Metabolic epidermal Glucagonoma (dogs) Also reported with liver

necrosis disease and diabetesmellitus


have been identified in human thyroid carcinomas(Rabbitts 1994).

Pathology

The normal thyroid in the dog and cat consists oftwo separate lobes which lie lateral to the trachea(approximately from rings three to eight), each lobebeing associated with an external parathyroid glandat the cranial pole and an internal parathyroidgland on the medial aspect. Accessory or ectopicthyroid tissue may occur in the pericardial sac,anterior to the heart or at the base of the tongue,and tumours may arise at any of these sites.

Canine thyroid tumours

In dogs, approximately 50–90% of thyroid tumoursare carcinomas and the remainder are adenomas.Most carcinomas are large, solid masses, easilynoticed by owners. Two thirds are unilateral atinitial presentation. Carcinomas are derived fromthe epithelial cells of the thyroid follicles andmicroscopically may appear solid, follicular or as amixture of both patterns. Less commonly, carcino-mas may arise from the parafollicular C cells(medullary thyroid carcinoma). Adenomas, on theother hand, are usually small and not readilydetected unless they become cystic. Microscopi-cally they are well defined within a capsule andappear distinct from the surrounding compressedparenchyma.

Feline thyroid tumours

The majority of feline thyroid tumours are adeno-mas (or nodular adenomatous hyperplasia/goitres).Carcinomas are rare in this species, accounting for1–2% of all thyroid tumours, and usually coexistwith adenomatous change. Follicular, papillary ormixed compact patterns of cells are recognised histologically. Pleomorphism, anaplasia and highmitotic rate are not typical of thyroid carcinomas incats and so degree of invasion, metastasis and bio-logical behaviour have to be used to differentiatethem from adenomas (Turrel et al. 1988).

Tumour behaviour

Although some thyroid carcinomas are encapsu-lated and non-invasive, most are large, aggressive

tumours which invade local tissues of the neck to aconsiderable extent, making surgical excision diffi-cult. They metastasise rapidly via lymphatics to theretropharyngeal lymph nodes, lungs, liver and cer-vical vertebrae and approximately half of all caseswill have metastasised by the time of presentation.Thyroid adenomas are small, mobile nodules whichdo not invade locally or metastasise.


Hyperthyroidism is the most common endocrinedisorder in cats and is reported with both thyroidadenomas and carcinomas. In contrast, hyperthy-roidsim in dogs is much less frequently associatedwith thyroid neoplasia. It is usually associated withcarcinomas, not adenomas in this species, andoccurs in approximately 6–10% of dogs withthyroid neoplasia. Most dogs with thyroid tumoursare euthyroid or if there is significant destruction ofnormal tissues, hypothyroid.

Medullary thyroid carcinomas may also be func-tional and secrete calcitonin, somatostatin, sero-tonin, adrenocorticotrophic hormone (ACTH) or prostaglandins. Calcium concentrations are unaffected, however, and patients are usually eucalcaemic.

Presentation/signs

Dogs and cats with thyroid tumours may presentwith either:

• The clinical signs of hyperthyroidism (Fig. 14.1)• A mass in the ventral neck (Figs 14.2 and 14.3).

Most cats present with hyperthyroidism, showingclinical signs such as weight loss, tachycardia, hyper-activity, muscle weakness, diarrhoea, polyuria, poly-dipsia and poylphagia (Table 14.2).A small, thyroidnodule(s) is often palpable in the ventral neck,sometimes as far as the thoracic inlet, but ownerswill rarely have noticed it.

Most dogs with thyroid carcinomas present witha firm, painless, mass in the mid-ventral neck whichmay be attached to underlying structures. Sub-mandibular and retropharyngeal lymph nodes maybe enlarged secondary to lymphatic obstruction ormetastasis, and coughing, dyspnoea, dysphagia orfacial oedema may also be noted if the mass isapplying pressure to the trachea or oesophagus.Weight loss, lethargy, anorexia or neck pain may


Fig. 14.1 Marked weight loss in this cat was due tohyperthyroidism (picture taken following thyroidec-tomy).

Fig. 14.2 Thyroid carcinoma presenting as a grossmass in the ventral neck of a dog.

Fig. 14.3 An unusually large thyroid mass in the neckof a cat.

Table 14.2 Clinical signs associated with hyperthyroidism in cats.

System Clinical signs Comment

Metabolic Weight loss despite polyphagia, heat intolerance Anorexia in 10% of casesUrinary Polyuria and polydipsiaNeuromuscular Restlessness, hyperactivity, weakness, muscle Depression in 10% of cases

wasting, muscle tremorsDermatologic Unkempt hair coat, alopeciaRespiratory/cardiovascular Panting, dyspnoea, tachycardia, gallop rhythm, Signs due to hypertrophic

cardiac murmur, congestive heart failure cardiomyopathyGastrointestinal Bulky faeces and steatorrhoea, vomiting,

diarrhoea


also occur. Signs of hyperthyroidism are relativelyrare and are less pronounced than in cats. Withmedullary thyroid carcinomas, diarrhoea is themain presenting sign.

Investigations

Bloods

No specific changes are usually noted on haemato-logical and biochemical analysis, but a stressleucogram may be detected in cats and raised liverenzymes in both species. Hypercalcaemia is uncom-mon but may be detected in both cats and dogs.

To demonstrate hyperthyroidism, specific testsfor thyroid function should be carried out. For cats,measurement of basal plasma thyroxine (T4) is ofmost diagnostic use with concentrations increasedin 90% of cases with suggestive clinical signs.Normal T4 concentrations may sometimes be foundin early cases and the T3 suppression test or TRHstimulation test may be needed to confirm the diag-nosis in these animals. In dogs, T4 measurementshould be performed if clinical signs are suggestiveof hyperthyroidism but in most cases this is not nec-essary to make a diagnosis of thyroid neoplasia.

Imaging techniques

Thoracic and abdominal radiography should beperformed in dogs to look for pulmonary, hepaticor other abdominal metastases. Thoracic radiogra-phy in cats (and dogs) may show cardiomegaly dueto hypertrophic cardiomyopathy, with or withoutsigns of congestive heart failure such as pulmonaryoedema or pleural effusion. Full assessment ofcardiac function, however, will require ECG andultrasonography.

High resolution ultrasonography can be useful indetermining whether one or both thyroid lobes areaffected in hyperthyroid cats, particularly if nonodule is palpable. For carcinomas in dogs, ultra-sonography of the neck will help determine theextent of tumour invasion, will differentiatebetween solid and cystic masses and will help guidefine needle aspirates.

Thyroid tumours may also be imaged usingsodium pertechnetate (99mTc) scintigraphy sincefunctional thyroid tissue concentrates the isotopeand increased uptake is seen with hyperthyroidism.

It is used frequently in hyperthyroid cats prior tothyroidectomy to demonstrate whether one or boththyroid lobes are affected, particularly if no thyroidenlargement can be palpated. It may also be usefulif hyperfunctional ectopic thyroid tissue is sus-pected although this may be confused with metas-tasis on the basis of the scan alone. Patchy orirregular uptake of 99mTc is seen with thyroid carci-nomas, possibly with extension down the neck.Scintigraphy is not usually necessary to diagnosethyroid tumours in dogs but increased uptake of99mTc is seen in hyperthyroid cases.

Radioiodine (123I or 131I) scintigraphy may also beused to image the thyroid with increased uptakeseen in hyperthyroid cats (and dogs) compared tonormal animals but it is more expensive and is asso-ciated with a higher radiation exposure.

Biopsy/FNA

Aspirate or biopsy is not usually performed forfeline thyroid neoplasia, but for dogs, fine needleaspirates may be useful to differentiate thyroid carcinomas from non-neoplastic lesions or othertumour types. Haemorrhage is a common problem,however, because thyroid tumours are so vascular,and poor aspirates may be obtained. Histologicalexamination of tumour tissue is the only way tomake a definitive diagnosis and to distinguish ade-nomas from carcinomas. Needle biopsies, like fineneedles aspirates, may provoke haemorrhage andso wedge biopsies are recommended.

Staging

A TNM staging system exists for thyroid tumours(Table 14.3) and group staging can also be per-formed (Table 14.4). Clinical and surgical examina-tion, along with radiography of the thorax andradio-isotope scanning, should be used to assess the primary tumour and look for regional (cervicalnode) and distant metastasis.

Treatment

The treatment options for feline thyroid tumoursinclude:

• Surgery• Radioactive iodine (131I) therapy• Antithyroid drug therapy.


they are functional or non-functional. Patients withfunctional tumours (hyperthyroidism) should bestabilised medically prior to the operation to min-imise the anaesthetic risk. Benign adenomas aregenerally well encapsulated and easily resected, asare mobile, non-invasive carcinomas (Klein et al.1995). Most malignant tumours, however, are invasive and in a third of cases they are bilateral,making clean surgical margins difficult to obtain.Surgery is complicated by the vascular nature ofmost carcinomas and the proximity of importantstructures such as the recurrent laryngeal nerves,parathyroid glands and major blood vessels. Evenif complete excision is unobtainable, surgicaldebulking is helpful as a palliative measure in manycases, and can be combined with other modalitiessuch as radiotherapy or chemotherapy.

Parathyroid tissue cannot usually be preservedwhen resecting an invasive thyroid carcinoma butif the tumour is unilateral, hypocalcaemia (andhypothyroidism) are rare complications. With bilateral tumours, both hypoparathyroidism andhypothyroidism must be addressed using calciumand vitamin D (see parathyroid tumours, p. 210)and thyroxine. Other post-operative complicationsof thyroidectomy may include Horner’s syndrome and laryngeal paralysis.

Feline thyroid tumoursThyroidectomy is also the treatment of choice forbenign adenomas in hyperthyroid cats if radioac-tive iodide therapy is not available (see below).Patients are often stabilised by medical treatmentfor several weeks prior to the operation to mini-mise the anaesthetic risk. Scintigraphy may also beperformed prior to surgery to see if unilateral or bilateral enlargement of the thyroid gland ispresent. An intracapsular dissection may be chosento try and preserve the external parathyroid gland at the cranial end of the thyroid lobe butrelapse rates may be worse than with extracapsularsurgery. As with thyroid surgery in dogs, unilateralor bilateral thyroidectomy can be performed butcareful monitoring of calcium levels is essentialpost-operatively to detect hypocalcaemia resulting from damaged/excised parathyroid glands. Acutehypocalcaemia will require immediate therapy (see parathyroid tumours, p. 210) but it may be pre-vented by monitoring plasma calcium concentra-tions regularly and if they fall below 1.8mmol/l,supplementing with calcium lactate or carbonate

The options for canine thyroid carcinoma areslightly more limited with surgery being the mainchoice, and radiotherapy or chemotherapy usedadjunctively.

Surgery

Canine thyroid tumoursSurgical resection is the treatment of choice forcanine thyroid tumours, irrespective of whether

Table 14.3 Clinical stages (TNM) of canine tumoursof the thyroid gland. Owen (1980).

T Primary tumour T0 No evidence of tumourT1 Tumour <2 cm maximum diameter

T1a Not fixedT1b Fixed

T2 Tumour 2–5cm maximum diameterT2a Not fixedT2b Fixed

T3 Tumour >5 cm maximum diameterT3a Not fixedT3b Fixed

N Regional lymph nodes (RLN)N0 No evidence of RLN involvementN1 Ipsilateral RLN involved


N2 Bilateral RLN involvedN2a Not fixedN2b Fixed


Table 14.4 Stage grouping of canine thyroidtumours. Owen (1980).

Stage grouping T N M

I T1a,b N0(-) M0N1a(-)N2a(-)

II T0 N1(+) M0T1a,b N1(+)T2a,b N0(+) or N1a(+)

III Any T3 Any N M0Any T Any Nb

IV Any T Any N M1

(-) histologically negative (+) histologically positive.


(50mg/kg/day) and dihydrotachysterol (0.01mg/kg/day). Thyroxine supplementation is necessaryafter bilateral and occasionally unilateral thyroidectomy.

Radiotherapy

External beam hypofractionated radiotherapyshould be considered for adjunctive use followingsurgical resection of an invasive thyroid carcinoma,and may have a palliative role without surgery, as a local treatment for invasive thyroid carcinoma in the dog (Brearley et al. 1999). Side-effects may include oesophagitis, laryngitis, dysphonia andhypothyroidism.

Radioactive iodine (131I) therapy is the treatmentof choice for feline thyroid adenomas and hyper-thyroidism, since it is a non-invasive procedurewhich selectively destroys hyperfunctioning thyroidtissue, while preserving the normal thyroid tissueand the parathyroid glands. However facilities arelimited to selected referral institutions, and catsmust be hospitalised for several weeks while receiv-ing treatment. Dogs with hyperfunctional thyroidtumours may also be treated with radioiodine but treatment is less successful than for cats.Although some canine non-functional tumoursmay concentrate radioiodine, it is not clear whetherthey will do so adequately to respond to (131I)therapy.

Chemotherapy

Large, bulky thyroid carcinomas are unlikely torespond to cytotoxic drug therapy, but the metasta-tic and invasive nature of most tumours means thatchemotherapy should be considered following sur-gical resection. Doxorubicin, cisplatin or a com-bination of doxorubicin, cyclophosphamide andvincristine (VAC – Table 5.4) have been usedadjunctively to surgery to treat thyroid carcinoma

in the dog, although controlled trials have not beenperformed.

Other

Medical management with the antithyroid drugs,methimazole and carbimazole (but not propylth-iouracil because of excessive side-effects), may beused to control hyperthyroidism in cats, either as analternative to surgery or for a period of stabilisa-tion prior to thyroidectomy or (131I) therapy. Theyare not cytotoxic, however, and will not affect thegrowth or metastasis of thyroid carcinomas in dogsor cats. Methimazole is associated with more side-effects than carbimazole and these may includeanorexia, vomiting, lethargy and haematologicalabnormalities.

Cardiac drugs such as propranolol or diltiazemmay be used in conjunction with antithyroid drugsto control the cardiovascular abnormalities inducedby hyperthyroidism.

Prognosis

For thyroid carcinomas in dogs, the histomorpho-logical grade based on the presence of invasion, cel-lular and nuclear pleomorphism and mitotic rate isthe most important prognostic factor. Tumour sizealso has prognostic significance with the rate ofmetastasis increasing with larger tumours (Leav etal. 1976). Mean survival times of 36 months havebeen reported for freely mobile carcinomas withoutlocal tissue invasion (Klein et al. 1995), whereasmost dogs with fixed, invasive tumours survive forless than 12 months (Carver et al. 1995).

Cats with thyroid adenomas and hyperthy-roidism have an excellent prognosis for returningto normal following thyroidectomy or radioiodinetreatment, although the complication of hypocal-caemia may arise with bilateral cases treated surgically.

PARATHYROID GLAND

Epidemiology

Parathyroid tumours are uncommon in dogs andrare in cats. They usually occur in older dogs (8–10

years) with a predilection for keeshonds (Berger &Feldman 1987). Older cats are also affected, with apossible predilection for females and Siamese cats(Kallet et al. 1991).


adenocarcinoma of the apocrine glands of the analsac, as detailed in Chapter 2.

Bloods

Raised serum calcium concentrations will bedetected on biochemical analysis but values areusually in the region of 3–4mmol/l rather than thevery high levels often noted with lymphoma.Phosphate levels are usually low or normal.

Once the more common causes of hypercal-caemia have been eliminated, a PTH assay shouldbe performed to look for increased secretion ofPTH. A raised PTH concentration with concurrenthypercalcaemia confirms the diagnosis of hyper-parathyroidism and is suggestive of a parathyroidadenoma or hyperplasia. A raised PTH concentra-tion is also present with secondary hyperparathy-roidism which may result from renal failure orcalcium deficiency during growth. However, inthese conditions total calcium is usually normal andionised calcium may be low; phosphate is usuallyelevated along with raised urea and creatinine.PTH concentrations are low in cases of hypercal-caemia of malignancy.

Imaging techniques

The parathyroid glands in normal dogs are not rou-tinely visible with ultrasonography, but an enlargedparathyroid gland due to hyperplasia or adenomacan often be detected close to or within thyroidtissue.

Biopsy/FNA

Surgical exploration of the neck to locate anenlarged parathyroid gland/adenoma can be per-formed as part of the diagnostic investigations ofhypercalcaemia, once other more common causeshave beeen excluded, or once a PTH assay has beenperformed. An excisional biopsy of the enlargedgland is usually performed for a histopathologicaldiagnosis of parathyroid neoplasia.

Staging

There is no specific staging system for parathyroidgland tumours.

Aetiology

There is no known aetiology for parathyroidtumours in the dog and cat.

Pathology

External and internal parathyroid glands are asso-ciated with each thyroid lobe and any one of thefour glands may be affected. Tumours derive fromthe parathormone (PTH) secreting chief cells andadenomas predominate. Multiple nodular hyper-plasia of the glands can occur but adenocarcinomasare rare. Ectopic parathyroid tissue may be foundin the anterior mediastinum.

Tumour behaviour

Parathyroid adenomas are benign, well encapsu-lated tumours, whereas adenocarcinomas have thepotential for local invasion and metastasis.


Parathyroid adenomas autonomously secrete PTHto produce hyperparathyroidism and this results in hypercalcaemia (Chapter 2). Hypercalcaemiahas also been reported with parathyroid adenocarcinoma.

Presentation/signs

Dogs and cats with functional parathyroid tumourspresent with the clinical signs associated withhypercalcaemia (see Chapter 2). Parathyroid adenomas are usually small nodules which arerarely palpable in the ventral neck and would go unnoticed if it were not for the signs of hypercalcaemia.

Investigations

Since animals present with hypercalcaemia, theinvestigation of such cases involves ruling out othermore common causes of raised calcium concentra-tions such as lymphoma, hypoadrenocorticism or


Treatment

Surgery

Surgery is the most appropriate treatment forparathyroid adenomas and adenocarcinomas. Theaffected parathyroid gland can be excised, leavingthe other glands to produce PTH. With multiplenodular hyperplasia, more than one gland may beaffected and all need to be removed. Calcium con-centrations should fall quickly to within the normalrange following surgery, although there is a risk ofhypocalcaemia initially because the unaffectedparathyroid glands will have been suppressed byexcess PTH secretion. Calcium concentrationsshould therefore be monitored carefully post-operatively and prophylactic treatment withvitamin D and calcium supplementation is recommended before hypocalcaemia occurs. Ifhypocalcaemia causes clinical signs, calcium sup-plementation should be used as follows:

• Restore normal calcium concentrations with10% calcium gluconate (0.5–1.5ml/kg) by i.v.infusion over 10–30 minutes, monitoring heartfunction by ECG.

• Maintain normocalcaemia with subcutaneouscalcium gluconate (diluted 50:50 with 0.9%sodium chloride) every six hours until oral sup-plementation becomes effective.

• Start oral vitamin D (dihydrotachysterol at 20–30mg/kg) and calcium carbonate (50–100mg/kg/day) or calcium lactate (25–50mg/kg) supplementation.

• Continue treatment for several weeks, maintain-ing calcium concentration at the lower end of thenormal range, then gradually reduce first vitaminD and then calcium supplementation.

There is a danger of inducing hypercalcaemia withdihydrotachysterol therapy and if clinical signs suchas polyuria and polydipsia arise, therapy should bediscontinued immediately.

Radiotherapy

Radiotherapy has not been used to treat parathy-roid tumours in animals.

Chemotherapy

Chemotherapy is not appropriate for treatingparathyroid tumours in animals.

Prognosis

The prognosis for parathyroid tumours is excellentsince most can be removed surgically. However,complications with post-operative hypocalcaemiamay be life-threatening if not recognised andtreated immediately.

PITUITARY GLAND

Pituitary gland neoplasms are classified as sec-ondary brain tumours since they affect the brain bylocal extension.They are discussed here rather thanwith the nervous system because of the endocrinefunction of the anterior and posterior lobes.

Epidemiology

Most pituitary adenomas are reported in associa-tion with pituitary-dependent hyperadrenocorti-cism. Dogs with this paraneoplastic syndrome areusually middle-aged or old (median age 10 years),but slightly younger than those with adrenal depen-dent hyperadrenocorticism. Poodles, dachshunds,beagles, boxers, German shepherd dogs and Bostonterriers are frequently affected but both sexes are

affected equally (Peterson 1986; Reusch &Feldman 1991). Cats with pituitary-dependenthyperadrenocorticism also tend to be middle agedor old. Females appear to be predisposed but noparticular breeds are affected (Feldman 1995). Catswith acromegaly caused by a pituitary tumour arealso middle-aged or old and of mixed breed.

Aetiology

The aetiology of pituitary tumours in animals is notknown.

Pathology/tumour behaviour

The pituitary gland consists of two parts:


carcinomas are much less common and are usuallynon-functional, large and invasive tumours whichinvade the brain and sphenoid bone, metastasisingto lymph nodes, spleen and liver.

In cats, tumours of the somatotrophic cells(which are acidophilic) of the anterior pituitary areoften functional and cause acromegaly.

During embryogenesis, the anterior lobe devel-ops from Rathke’s pouch, which is derived from the ectoderm of the oropharynx. Tumours whichdevelop from Rathke’s pouch are called cranio-pharyngiomas and they occur in young animals.They are often very large tumours which growalong the ventral aspect of the brain and involvecranial nerves, hypothalamus and thalamus.


A variety of paraneoplastic syndromes may accom-pany pituitary tumours, depending on whetherhormone production is increased or decreased (seeTable 14.5). The most common pituitary relatedparaneoplastic syndrome in the dog and cat is pitu-itary-dependent hyperadrenocorticism. The otherparaneoplastic syndrome of note, in the cat, isacromegaly.

• The anterior lobe (adenohypophysis) which is a neuroendocrine gland under control of hypo-thalamic hormones released into the hypothala-mic-hypophyseal portal system.

• The posterior lobe (neurohypophysis) which is a neurosecretory system with axons extendingdirectly from cell bodies in the hypothalamus.These release oxytocin and vasopressin.

The cells of the anterior lobe are classified accord-ing to their specific secretory products (Table 14.5).Over half are somatotrophs, secreting growthhormone (GH), with the remaining types each representing 5–15% of the gland. Primary tumoursmay derive from any of these cells but the pituitaryis also a possible site for metastatic tumours suchas melanoma, or mammary adenocarcinoma.

The most common pituitary tumour in the dogand cat is derived from corticotrophic (chromo-phobic) cells of the anterior lobe (pars distalis andpars intermedia) which produce adrenocorti-cotrophic hormone (ACTH). These are benigntumours which may be either microadenomas (lessthan 1cm in diameter) or macroadenomas (greaterthan 1cm in diameter). They are usually functional,resulting in hyperadrenocorticism, but non-functional tumours also occur. Chromophobe

Table 14.5 Endocrine disorders caused by tumours of the pituitary gland.

Cell type Hormone Disorder associated with Disorder associated withunderproduction overproduction

Anterior lobeCorticotrophs ACTH Secondary Hyperadrenocorticism

hypoadrenocorticism – (Cushing’s disease)hypocortisolaemia

Somatotrophs GH Possible alopecia due to atrophy Acromegaly (cats not dogs)of skin and adnexae*(not dwarfism in adults)

Thyrotrophs TSH Hypothyroidism Hyperthyroidism (not reported in dogs and cats)

Gonadotrophs LH/FSH Hypogonadism – anoestrus,testicular atrophy

Lactotrophs PRL Galactorrhoea

Posterior lobeVasopressin Diabetes insipidus Syndrome of

inappropriate diuresis(SIAD)

* Most ‘growth hormone responsive alopecia’ of adults is in fact an adrenocortical condition.


Presentation/signs

Pituitary tumours may present in one of three ways:

• Endocrinologically active tumours may presentwith specific metabolic disorders due to hormoneexcess, for example pituitary-dependent hypera-drenocorticism (Fig. 14.4) or acromegaly in cats(Tables 14.5 and 14.6).

• Endocrinologically inactive tumours may presentwith other metabolic disorders due to insuffi-ciency of one or more hormones. Large, expand-ing anterior lobe tumours may also reducehormone production by the posterior lobe if theycompress it.

• Other tumours may present as space-occupyinglesions with neurological signs due to com-pression or invasion of the brain. Dogs and catsmay present with depression, behaviouralchanges, disorders of thirst, appetite or tempera-ture regulation, pacing, head pressing and circling.

Investigations

Bloods

The presumptive diagnosis of an anterior pituitarytumour may be made on the measurement of

Fig. 14.4 Typical clinical appearance of hyperadreno-corticism in a female poodle (this dog was also dia-betic). (Picture courtesy of Mr M. Herrtage,Department of Clinical Veterinary Medicine, Univer-sity of Cambridge.)

Table 14.6 Clinical features of acromegaly in cats.

Type of change Clinical signs

Physical Hypertrophy of face and extremitiesWeight gainThickening of skin and development of folds

around the head and neckHypertrophy of tonguePrognathism and wide interdental spacesHypertrophy of thoracic and abdominal organs

Cardiac Congestive heart failureMetabolic Development of insulin resistance and diabetes

mellitusRenal failure

Haematological Increased red blood cell countBiochemical Raised concentrations of:

GlucoseLiver enzymesPhosphateTotal proteinCholesterol

Elevated basal concentrations of GH or IGF-I or failure to suppress GH concentrations in a glucose suppression test

Diagnostic imaging Presence of a pituitary mass on CT or MRI


Staging

No staging system for pituitary tumours has beendescribed.

Treatment

Surgery

Hypophysectomy has been used in the treatment of pituitary-dependent hyperadrenocorticism butthe technique does not allow the complete removal of very large pituitary tumours and is not widelypractised. With the improvement of diagnosticimaging and surgical techniques, it is possible thatin future more dogs may be treated this way andgiven lifelong supplementation with thyroxine andcortisone.

Radiotherapy

With careful planning of the radiation field basedon CT or MRI images, megavoltage irradiation canbe used to treat pituitary tumours in both cats anddogs, particularly macroadenomas or tumourscausing mild neurological signs (Fig. 14.6; see also Chapter 3) (Dow et al. 1990). Radiation willdecrease the size of the tumour and resolve neuro-logical signs, but functional tumours may requireadditional medical treatment, for example mitotaneto control hyperadrenocorticism. Radiation side-effects may include hair loss, impaired hearing and

peripheral hormone concentrations, for examplethyroxine or cortisol, and by stimulation tests withappropriate hypothalamic releasing hormones forassessment of growth hormone (GH), luteinisinghormone (LH), adrenocorticotrophic hormone(ACTH) and prolactin (PRL) responses. Inade-quate responses may suggest partial or totalhypopituitarism. If diabetes insipidus is suspected,plasma vasopressin during osmotic stimulation byhypertonic saline can be measured, or a waterdeprivation test performed.

Tests for hormone overproduction are numerous(see adrenal cortex tumours later in this chapter forhyperadrenocorticism).

Imaging techniques

Pituitary tumours can only be reliably identifiedwith sophisticated imaging techniques such as con-trast-enhanced computed tomography and mag-netic resonance imaging (Fig. 14.5).

Biopsy/FNA

Biopsy of pituitary tumours is not possible unlesshypophysectomy is attempted.

Fig. 14.5 MRI scan showing a pituitary tumour in an11 year old domestic short hair cat with a long historyof polydipsia and lethargy. The contrast enhanced,sagittal T1 weighed scan shows a large, irregularlyenhancing mass extending dorsally from the pituitaryfossa. (Picture courtesy of Ruth Dennis, Animal HealthTrust, Newmarket.)

Fig. 14.6 Radiotherapy set up for dog with a braintumour.


vestibular signs, although brain necrosis has alsobeen reported as a late radiation effect and thiscauses recurrence of neurological signs.

Chemotherapy

Chemotherapy with mitotane (o,p’-DDD) may beused for pituitary-dependent hyperadrenocorticismto destroy selectively the zona fasiculata and retic-ularis of the adrenal cortex (see tumours of theadrenal cortex, below).

Other

Anterior pituitary failure can be treated by sub-stituting for the deficient hormone, for examplethyroxine or cortisone, but this is usually only a temporary measure until neurological effectsdevelop due to tumour enlargement. Posterior pitu-itary failure can be treated with the vasopressinanalogue, desmopressin (DDAVP), administeredtopically into the conjunctiva.

Overproduction of hormones may be treated

using specific drugs where available, although manyare expensive. Cabergoline (galastop), a potentanti-prolactin drug, is licensed for management ofpseudopregnancy in bitches.The dopamine agonist,bromocriptine, has been used to counteract theeffects of excess prolactin but is only effective insome cases and is not reported to be very effectivein counteracting GH excess in acromegalic cats.The somatostatin analogue, octreotide, can be usedto lower GH levels, but it is expensive.

Prognosis

The prognosis for pituitary tumours is variabledepending on their clinical presentation andwhether accompanying endocrine disorders can be controlled. Medical treatment of pituitary-dependent hyperadrenocorticism in dogs can bequite successful with 10% of cases successfullymanaged for over four years (Peterson 1986). Sur-vival times for cats with acromegaly range from 8to 30 months.

ADRENAL GLAND

The adrenal gland has two functionally distinctendocrine parts, the medulla and cortex, both ofwhich may become neoplastic.

The adrenal cortex consists of three layers:

• Zona glomerulosa – produces mineralocorti-coids

• Zona fasciculata – produces glucocorticoids andandrogens

• Zona reticulata – produces androgens but alsoglucocorticoids.

Adrenocortical tumours of clinical significance arethose which over secrete glucocorticoids resultingin hyperadrenocorticism.

The adrenal medulla consists of chromaffin cellsof neuroectodermal origin which can be regardedas sympathetic postganglionic neurons withoutaxons. These secrete predominantly epinephrine(adrenaline), but also some norepinephrine,directly into the blood rather than across a synap-tic cleft.Tumours derived from the adrenal medullaare phaeochromocytomas.

Tumours of adrenal cortex


Adrenocortical tumours occur in both dogs andcats but there is no known aetiology. They accountfor 15–20% of cases of hyperadrenocorticism indogs and 20% in cats. Large breeds of dogs areaffected, particularly poodles, German shepherddogs, dachshunds and Labrador retrievers (Scavelliet al. 1986; Reusch & Feldman 1991). Females areaffected more than males.

Cats with hyperadrenocorticism are middle-agedor old (7–15 years). There is no particular breedassociation but more females than males areaffected (Nelson & Feldman 1988).


Adrenocortical tumours are usually unilateral andsolitary, although 10% of cases are bilateral (Fordet al. 1993). With functional unilateral tumours the


clinical signs of this disease are related to theactions of glucocorticoids and are listed in Table 14.7.

InvestigationsBloodsOn haematological analysis high levels of gluco-corticoids produce characteristic findings of leuco-cytosis, neutrophilia, lymphopenia and eosinopenia.Alkaline phosphatase is usually elevated on biochemical analysis in dogs due to the induction of an isoenzyme. ALT may be mildly elevated and raised cholesterol, bile salts and glucose may also be noted. Persistent hyperglycaemia ismore common in the cat and, before hypera-drenocorticism is considered, many are diagnosed with diabetes mellitus which is hard to stabilise.

Specific diagnosis of hyperadrenocorticism relieson the following tests for adrenal function:

• ACTH stimulation test – to establish the diagno-sis of hyperadrenocorticism (HAC) but false negatives may occur. It will distinguish iatrogenicfrom spontaneous hyperadrenocorticism and isthe most useful test for monitoring treatmentwith mitotane. ACTH (0.25mg/dog or 0.125mg/cat) is administered intramuscularly or intra-venously and plasma cortisol is measured one

opposite adrenal gland is atrophied. Both adeno-mas and carcinomas occur in approximately equalproportions, and some of the latter can be verylarge, containing areas of haemorrhage and necro-sis. They may compress adjacent organs or invadethe aorta or vena cava, leading to intra-abdominalhaemorrhage. Approximately 50% of cases haveliver metastases and invasion of the caudal venacava and other vessels. Adrenocortical tumoursmay occur concurrently with phaeochromocytomasin dogs.


Adrenocortical tumours may be functional andautonomously secrete glucocorticoids. This pro-duces the characteristic signs of hyperadreno-corticism or Cushing’s syndrome. Although appro-ximately 80% of Cushing’s syndrome cases in thedog and cat are caused by pituitary tumours and are therefore ACTH dependent, the details ofCushing’s syndrome are included here, rather thanwith pituitary tumours.

Presentation/signs

Non-functional tumours may be found incidentallyat post mortem examination. Functional tumours,however, present with Cushing’s syndrome. The

Table 14.7 Clinical signs of hyperadrenocorticism.

System Clinical signs Comment

Metabolic Polyphagia, hepatomegaly, obesity, Concurrent diabetes mellitus in 5–10% ofpendulous abdomen dogs and 80–100% of cats

Urinary Polyuria and polydipsia, urinarytract infections, glycosuria

Neuromuscular Muscle weakness and atrophy,exercise intolerance, lethargy

Dermatologic Bilaterally symmetrical alopecia, Full thickness skin defects in catspyoderma, seborrhea, skin thinning,hyperpigmentation, calcinosis cutis

Respiratory/cardiovascular Hypertension, pulmonarythromboembolism, congestiveheart failure

Reproductive Anoestrus, testicular atrophyNeurologic Facial nerve paralysis, pseudomyotonia, Less common

CNS signs


hour later (and 1.5 hours for cats). With HAC,cortisol is increased to a much greater extentthan in normal animals and exceeds the upperlimit of the normal range.

• Low-dose dexamethasone suppression test (dex-amethasone screening test) – a more sensitiveand less specific way to establish the diagnosis of hyperadrenocorticism. Dexamethasone (0.01mg/kg) is administered intravenously in themorning and plasma cortisol is measured eighthours later. This is depressed in normal animalsdue to feedback inhibition of ACTH, but is highin animals with hyperadrenocorticism.

• High dose dexamethasone suppression test – todistinguish between pituitary dependent hypera-drenocorticism and an adrenocortical tumour.Dexamethasone is used (0.1mg/kg in dogs or 1mg/kg in cats) and plasma cortisol is usuallymeasured four hours later. With such a high dose of dexamethasone, ACTH secretion can besuppressed in pituitary-dependent hyperadren-ocorticism resulting in a decline in baseline cortisol concentration by over 50%. Productionof cortisol by adrenocortical tumours, however,is unaffected.

• ACTH assay – if cortisol concentrations aredepressed by less than 50%, it is necessary tomeasure plasma ACTH to differentiate betweenan adrenocortical tumour and non-suppressibleform of pituitary dependent HAC.

UrinalysisGlycosuria is common in cats and also seen in5–10% of dogs with HAC. Bacteriuria, or highwhite cell counts, may be present, indicating urinaryinfection, and in these cases urine culture and sensitivity should be performed on a cystocentesissample. Specific gravity is usually low because ofpolyuria and polydipsia.

Urinary cortisol : creatinine ratio has been usedto screen for hyperadrenocorticism but it is not specific and therefore not recommended forroutine use.

Imaging techniquesAbdominal radiography may reveal changes due to hyperadrenocorticism such as an enlarged liver, pot-bellied appearance, osteopenia andbladder distension, and in some cases an enlargedor calcified adrenal gland may be detected.

(Adrenal calcification may be noted in normalcats.) Thoracic films may show pulmonary metas-tases or interstitial lung markings due to poor lunginflation.

Ultrasonography is preferable to survey radiog-raphy for visualising the adrenals, and should giveinformation about tumour size and invasion. Uni-lateral enlargement suggests an adrenal mass, par-ticularly if the contralateral adrenal is atrophied.Bilateral enlargement of the adrenals may be moresuggestive of pituitary-dependent hyperadrenocor-ticism than of bilateral adrenocortical tumours. CTor MRI give the most detailed imaging informationabout adrenal tumours but they are expensive tech-niques and not always available.

Biopsy/FNAA definitive diagnosis of adrenocortical tumourrequires histopathological examination. Tissue isusually obtained by excisional biopsy when thetumour is treated surgically.

Staging

A TNM staging system is used for the adrenal gland(Table 14.8). Tumours should be investigated surgically to assess the primary mass, regional(lumbar) lymph nodes and distant sites. Thoracicradiography should be perfomed to look for pul-monary metastases.

Table 14.8 Clinical stages (TNM) of canine tumoursof the adrenal gland. Owen (1980).

T Primary tumour T0 No evidence of tumourT1 Well-defined tumourT2 Tumour invading neighbouring structuresT3 Tumour invading blood vessels




laris of the cortex may be used as for treating pitu-itary dependent hyperadrenocorticism but higherdoses may be necessary. The drug is irritant to thegastrointestinal tract and may produce vomitingand so it is best administered with food. In dogs, theprotocol for mitotane is:

• Induction dose of 50–75mg/kg/day until inap-petance, depression, vomiting or diarrhoea orreduced water consumption (below 60ml/kg/day) occur

• Maintenance dose of 75–100mg/kg/week, usingthe ACTH stimulation test to monitor progressand aiming to keep cortisol levels to below thenormal pre-treatment range.

OtherKetoconazole (5mg/kg BID for seven days then 10mg/kg BID) may also be used to manage caninehyperadrenocorticism since at high doses it inhibitssteroid synthesis. However, it is more expensivethan mitotane and requires twice daily dosing,indefinitely. Its use in cats is more disappointing,with only partial responses observed. Side-effects indogs include anorexia, vomiting and icterus/hepaticnecrosis and in cats, depression, anorexia, tremors,low blood cortisol and severe hypoglycaemia.

Metyrapone, a drug which inhibits the conversionof 11b-deoxycortisol to cortisol, has been used suc-cessfully to treat hyperadrenocorticism in cats.

Prognosis

The prognosis for adrenocortical adenomas in dogsis very good if surgically removed, but surgicalresection of adenocarcinomas is less successful.Dogs treated medically may respond quite wellwith a mean survival time of 16 months in one study(Kintzer & Peterson 1994).

The prognosis for cats following adrenalectomyis variable, but a median survival time of 12 monthswas reported in one study (Duesberg et al. 1995).Cats with adrenal tumours have a better long-termsurvival following adrenalectomy than those withpituitary tumours.

TreatmentSurgerySurgical resection is the treatment of choice for uni-lateral adrenocortical tumours. It may be combinedwith medical treatment for a few months prior tosurgery in order to stabilise debilitated animalswhich are poor surgical candidates. Removal ofadenomas can resolve the hyperadrenocorticismpermanently and even with malignant tumours,palliation of the disease or even a surgical cure maybe possible. Complications following surgery maybe minimal or as high as 50% and may includecardiac arrest, pancreatitis or acute renal failure.There is a danger of post-operative hypoadreno-corticism because of atrophy of the contralateralgland, hence patients must be carefully moni-tored and supported initially with intravenous fluid therapy and glucocorticoids. Mineraloc-orticoid supplementation (deoxycorticosteroneacetate/pivalate or fludrocortisone acetate) mayalso be needed, but both glucocorticoids and min-eralocorticoids can be tapered over several months.Bilateral tumours may also be resected but longterm supplementation with mineralocorticoids isrequired.

In cats, unilateral adrenalectomy is the treatmentof choice for adrenal tumours and since theresponse to cytotoxic therapy is poor, bilateraladrenalectomy is the best option for hyperadreno-corticism caused by pituitary tumours. Cats withhyperadrenocorticism are often more debilitatedthan dogs and therefore pose more of a surgicalrisk. Concurrent diabetes mellitus may also be aproblem and so careful management of insulinrequirements is essential perioperatively.

RadiotherapyRadiotherapy has not been used to treat adreno-cortical tumours in animals.

ChemotherapyFor inoperable tumours or if owners refuse surgicaltreatment, it is possible to use medical managementin dogs. The condition is poorly responsive in cats.The cytotoxic drug, o,p¢-DDD (mitotane) whichselectively destroys the zona fasciculata and reticu-


anorexia, lethargy, depression, panting andpolyuria/polydipsia. Tachycardia or other cardiacabnormalities may also occur and an abdominalmass may be palpable in some cases. Occasionallyanimals may present with haemoperitoneum and abdominal distension due to tumour rupture.Most animals are hypertensive and this may cause retinal haemorrhage or detachment or neu-rologic abnormalities. The adrenal mass often contains a lot of haemorrhage, possibly due tohypertension.

InvestigationsBloodsAt present blood samples are not usually used fordiagnosing phaeochromocytomas in dogs and catssince they have not been properly evaluated. Basalcatecholamine measurements are of limited use asexcessive concentrations are only released inter-mittently. Measurement of urinary catecholamineconcentrations and their metabolites over a 24 hourperiod may be more useful (Twedt & Wheeler1984).

Blood pressureSystemic hypertension is the main clinical feature of phaeochromocytomas but it is often difficult to document because of its episodic nature. Blood pressure should be determined onseveral occasions if a phaeochromocytoma is suspected.

Imaging techniquesAbdominal radiographs and ultrasonography may be used to detect an enlarged adrenal gland or adrenal mass and to screen for abdominalmetastases. Thoracic films should be performed to evaluate cardiac size and signs of congestiveheart failure and to look for pulmonary metatases.Caudal vena caval angiography was previously used to detect tumour thrombi but has been sur-passed by ultrasonography, which is currently the technique of choice for evaluation of the local extent and anatomic relationships of adrenal tumours. Despite their expense, CT andMRI are being increasingly used and these provide more detailed images of the adrenal glands.

Tumours of adrenal medulla


Phaeochromocytomas are uncommon tumours indogs and very rare in cats. Older dogs (mean age10–11 years) and cats are usually affected andboxers may show an increased incidence. They maybe solitary tumours or occur with other endocrineand non-endocrine tumours (Barthez et al. 1997).There is no known aetiology.


Phaeochromocytomas derive from adrenomed-ullary chromaffin cells but they may coexist with tumours of the adrenal cortex. Extra-adrenal phaeochromocytomas (paraganglionas)have also been reported. Phaeochromocytomas are usually unilateral and the affected adrenalappears enlarged with little normal tissue remain-ing. They are usually slow growing and benign but malignant forms do occur and these may grow quite large. Large tumours may invade localtissues and vessels including the vena cava andproduce a tumour cell thrombosis. Distant metas-tasis to other abdominal organs may occur, par-ticularly the liver, regional lymph nodes, spleen and kidneys.


Functional phaeochromocytomas over producecatecholamines resulting in overstimulation ofadrenergic receptors in different tissues and a syndrome of hypertension and tachycardia (seebelow).

Presentation/signs

Many phaeochromocytomas go undetected clini-cally and are found incidentally at exploratoryceliotomy or on post mortem examination. Others,however, may present as an acute crisis with cardiovascular collapse or be a cause of suddendeath. The most common clinical signs are non-specific and intermittent such as weakness,


noxybenzamine) and b blockers (propranolol).Precise monitoring of blood pressure and cardiacfunction is essential to detect any hypertensive ortachycardic crises.

RadiotherapyRadiotherapy has not been used to treatphaeochromocytomas in animals.

ChemotherapyChemotherapy has not been used to treatphaeochromocytomas in animals.

OtherIf surgical resection is not possible, medical man-agement may be used to control blood pressure andcardiac arrhythmias. Cardiac arrhythmias may betreated with a b blocker such as propranolol butonly after administration of an a 1 adrenergicblocker to prevent hypertension.

Prognosis

The prognosis for phaeochromocytomas is guardedbecause of the difficulties associated with surgicaltreatment and the potential for life-threateninghypertensive and tachycardic events. If surgery issuccessful, however, long term survival may extendto three years since late metastasis is rare (Barthezet al. 1997).

Biopsy/FNAA definitive diagnosis of phaeochromocytomarequires histological examination of adrenal tissue.Excisional biopsy is usually performed as part ofsurgical treatment or tissue can be obtained at postmortem examination. Special stains such as chro-mogranin A and synatophysin may be used toconfirm chromaffin cell origin.

Staging

A TNM staging system is available for adrenaltumours (Table 14.8) but no group staging is used.Clinical and surgical examination of primarytumour, regional (lumbar) lymph nodes and otherabdominal organs should be performed as well asradiography of the thorax.

TreatmentSurgeryAdrenal phaeochromocytomas have been removedsuccessfully in dogs and cats although dissection isdifficult because of their vascular nature and thetendency to invade major blood vessels (Henry et al. 1993; Gilson et al. 1994). Care is needed toavoid intraoperative hypertension and postopera-tive hypotension by using a combination of a (phe-

PANCREAS (ENDOCRINE)

Neoplasia of the exocrine pancreas is included with tumours of the gastro-intestinal tract (Chapter8). Tumours of the endocrine pancreas derive fromthe Islets of Langerhans. In the dog and cat,these may be classified by immunohistochemicalstaining as:

• Insulinoma (B cell tumour)• Gastrinoma (D cell tumour)• Glucagonoma (A cell tumour)• Pancreatic polypeptidoma (F or P cell tumour –

only one case reported, Zerbe et al. 1989).

In reality, pancreatic endocrine tumours oftensecrete multiple hormones although one cell typeusually predominates. Each of the above tumours

is associated with a paraneoplastic syndrome (Table 14.1).

Insulinoma

Epidemiology

Insulinoma is the commonest tumour of the pan-creatic islet cells. It occurs in medium to large-breeddogs with a mean age of 8–9 years (range 4–13 years) but there is no particular sex or breed predisposition. Insulinoma is rare in cats, with only isolated reports in the literature (Hawks et al.1992).


ment, or if insulin release increases after a meal.The central nervous system depends on glucose tofunction properly and so as glucose concentrationsfall, clinical signs such as confusion and bizarrebehaviour may become apparent, progressing toepileptiform convulsions if insulinoma is not diag-nosed. Other common signs are episodic muscleweakness, tremors, ataxia, hind limb weakness andcollapse. Anxiety and restlessness are also reportedsince counter-regulatory hormones such as glu-cagon and catecholamines increase in response tohypoglycaemia.

No abnormalities are usually detected on physi-cal examination, apart from weight gain in someanimals. Rare cases may show a peripheral neu-ropathy (Schrauwen 1991; Van Ham et al. 1997).

Investigations

Although persistent hypoglycaemia is suggestive ofan insulinoma, other possible causes of hypogly-caemia such as hypoadrenocorticism, liver failure,renal failure or sepsis should be considered as dif-ferentials. In these diseases, however, hypogly-caemia is not usually the predominant clinicalfinding.

BloodsA diagnosis of insulinoma can be made if hypo-glycaemia is detected repeatedly on a fasting blood sample (glucose <3.0mmol/l) and if accom-panying insulin concentrations are high (>10mU/l).Insulin:glucose, amended insulin:glucose andglucose:insulin ratios may be calculated to confirmthe diagnosis but false positives and negatives mayoccur and use of a single sample to make a diag-nosis is often insufficient. A fasting test has beendescribed which measures glucose and insulin infour samples taken from a fasting animal (Siliart & Stambouli 1996). Provocative tests such asglucose and glucagon tolerance tests are unreliablemethods of diagnosis and may induce severe hypo-glycaemia. Routine haematological and biochemi-cal parameters are often within normal ranges inanimals with insulinoma.

Imaging techniquesAbdominal ultrasonography can be used to identifya pancreatic mass and look for metastases, and if

Aetiology

The aetiology of insulinoma is unknown.

Pathology

Insulinomas may be either benign or malignant,although most tumours in dogs are malignant.Insulinomas are usually solitary and discrete butmultiple tumours and diffuse infiltrates arereported. Adenomas are usually spherical noduleson the serosal surface of the pancreas, whereas car-cinomas are larger, multilobular masses whichinvade the parenchyma and contain areas of haem-orrhage and necrosis. Both lobes of the pancreasare equally affected in dogs (Caywood et al. 1988).

On immunohistochemical examination, insulino-mas stain for not only insulin, but also somatostatin,glucagon and pancreatic polypeptide.

Tumour behaviour

The behaviour of insulinomas is difficult to predictfrom their histological appearance and sometumours which appear histologically well dif-ferentiated may occasionally invade lymphatics.Malignant insulinomas invade surrounding tissues(mesentery and omentum) and metastasise vialymphatics to regional lymph nodes, and liver inapproximately 50% of cases.


Insulinomas autonomously produce insulin despite falling blood glucose concentrations andthis results in a paraneoplastic syndrome ofepisodic hypoglycaemia.

Presentation/signs

The clinical signs associated with insulinomas arecaused by intermittent hypoglycaemia. These maybe subtle at first and dismissed, but may becomemore obvious at times of increased glucose con-sumption such as fasting, exercise, stress or excite-


RadiotherapyRadiotherapy has not been used to treat insulino-mas in animals.

ChemotherapyStreptozotocin and alloxan are used to treat pan-creatic insulinomas in humans but these drugs are nephrotoxic and are not recommended to treat insulinomas in animals. Medical managementwith other drugs, however, is appropriate (seebelow).

OtherInsulinomas may be managed medically prior tosurgical resection or as a longer term treatmentover several years. Medical management mayinclude:

• Restriction of physical exercise and excitementto reduce the demand for glucose.

• Feeding of four to five small meals a day, of highquality but low carbohydrate content.

• Prednisolone (0.5–1.0mg/kg/day divided bid) ifhypoglycaemia persists or if convulsions occur.Dose may need to be increased gradually.

• Diazoxide (10–60mg/kg/day divided bid, withfood) for longer term management if pred-nisolone fails to control clinical signs or causesside-effects (hyperadrenocorticism). Diazoxideinhibits insulin secretion and peripheral use ofglucose but may cause anorexia, diarrhoea orvomiting, bone marrow suppression or cardiacarrhythmias.

• Octreotide (1mg/kg tid subcutaneously). This is asomatostatin analogue that inhibits secretion ofinsulin by normal and neoplastic cells but it isexpensive to use and its effectiveness in dogs hasnot been completely evaluated.

Prognosis

The long term prognosis for dogs with insulinomais guarded although mean survival times of 12months can be obtained with medical management.Approximately 40% of canine insulinomas willhave metastasised by the time surgical interventionis attempted.Although 10–20% of animals die fromsurgical complications such as pancreatitis, ap-proximately 40% of cases will survive for at leastsix months following surgical treatment and mean

available, more detailed information can be gainedby using CT or MRI.

Biopsy/FNAHistological diagnosis of insulinoma requiresbiopsy or excision of tumour tissue at exploratoryceliotomy but the procedure is not without risks(see surgical treatment below).

Staging

No TNM staging system has been described by theWHO for endocrine tumours of the pancreas, butother authors have used TNM and clinical stagingsystems (Caywood et al. 1988).

TreatmentSurgerySurgical resection is the preferred method of treat-ment for insulinomas since it allows a definitive his-tological diagnosis and better assessment of tumoursize and metastatic disease. Partial pancreatectomyis usually performed, however the procedurecarries considerable risks of hypoglycaemia andpancreatitis which may be life-threatening. Thesecan be minimised by:

• Intravenous infusion of 5% glucose solutionbefore, during and after surgery

• Hourly monitoring of blood glucose• Intravenous fluids continued for 48 hours after

surgery• Nil by mouth for 48 hours after surgery• Minimal manipulation of the pancreas during the

surgical procedure.

Some cases may become hyperglycaemic post-operatively and may require insulin therapy for afew days.

The abdomen should be examined carefully for metastases since 40–50% of tumours may have metastasised by the time of surgery and lymph node excision or partial hepatectomy may also be required. If hypoglycaemia persists after surgery, it suggests that resection of the tumour (and metastases) has been incomplete.


survival times of 12–18 months may occur (Melhaffet al. 1985; Caywood et al. 1988; Dunn et al. 1993).Metastases frequently develop with recurrence ofthe signs in most cases treated surgically. Poor prog-nostic factors for survival time include young age,high preoperative insulin concentrations and pres-ence of regional or distant metastases (Leifer et al.1986; Caywood et al. 1988).

Gastrinoma

Epidemiology

Gastrinomas are uncommon tumours in dogs andcats. Middle-aged and old animals are affected butthere is no sex or breed predisposition.


Although gastrin is also produced by G cells in the gastric and duodenal mucosa, most gastrin-secreting tumours occur in the pancreatic islets.Gastrinomas may be single or multiple and areoften firm to palpate because of fibrous connectivetissue in the stroma. They are usually malignant and metastasise to local lymph nodes and the liver.


Gastrinomas oversecrete gastrin which results in aspecific paraneoplastic syndrome, often calledZollinger-Ellison syndrome in humans.

Clinical signs

Gastrinomas are usually small and undetectedlesions until the clinical signs of excess gastrinbecome apparent. Gastric hyperacidity due toexcessive gastrin production results in anorexia,weight loss, chronic vomiting and diarrhoea. Refluxoesophagitis and gastroduodenal ulcers may occur,resulting in haematemesis, haematochezia ormelaena. Animals are often depressed, emaciatedand febrile and abdominal palpation is painful. Anabdominal mass is rarely palpable.

InvestigationsBloodsRegenerative anaemia and mild neutrophilic leucocytosis may be detected on haematologi-cal analysis. Biochemical evaluation often reveals hyperglycaemia and hypoproteinaemia(hypoalbuminaemia).

Plasma gastrin concentrations are usually signifi-cantly elevated but although this is suggestive of agastrinoma, it is not diagnostic since renal failure,liver disease, chronic gastritis and gastric outletobstruction may also raise gastrin concentrations.Various provocative diagnostic tests have thereforebeen described such as the secretin stimulation test,calcium stimulation test, or testing gastrin secretionfollowing a protein rich meal.

Imaging techniquesContrast radiography with barium may revealgastric or duodenal ulcers, thickened gastric rugalfolds and rapid intestinal transit. Endoscopy willalso reveal signs of gastric hyperacidity such asoesophagitis, hypertrophic gastritis and gastroduo-denal ulceration. Abdominal ultrasonography canbe used to identify a pancreatic mass and look formetastases, but more detailed information is gainedby using CT or MRI. Somatostatin receptor scintig-raphy with 111indium pentetreotide has also beendescribed (Altschul et al. 1997).

Biopsy/FNAHistological confirmation of a gastrinoma requiresexamination of tissue which is usually obtained atexploratory celiotomy. This is the best method ofestablishing a definitive diagnosis.

Staging

A specific TNM staging system has not beendescribed for gastrinoma in dogs and cats.

TreatmentSurgerySurgical resection is the ideal treatment for gastri-nomas but it is rarely successful because of unre-sectable metastases and is therefore a palliativemeasure.


These may cause depression and reluctance towalk.

Investigations

A definitive diagnosis of glucagonoma requireshistopathological examination of tumour tissue and positive immunohistochemical staining forglucagon, although a tentative diagnosis can bemade if a pancreatic neoplasm can be detectedusing ultrasonography or other diagnostic imagingtechniques. Animals may have elevated plasmaglucagon levels but this can occur with other diseases such as liver failure as well as withglucagonoma.

Prognosis

The prognosis for dogs with glucagonoma appearsto be poor with euthanasia being the likelyoutcome. Successful excision of the pancreatictumour was carried out in one dog with subsequentresolution of the skin lesions (Torres et al. 1997).

References

Altschul, M., Simpson, K.W., Dykes, N.L., Mauldin, E.A.,Reubi, J.C. & Cummings, J.F. (1997) Evaluation ofsomatostatin analogues for the detection and treatmentof gastrinoma in a dog. Journal of Small Animal Prac-tice, (38), 286–91.

Barthez, P.Y., Marks, S.L., Woo, J., Feldman, E.C. & Matteucci, M. (1997) Phaeochromocytoma in dogs: 61

Radiotherapy/chemotherapyRadiotherapy and chemotherapy have not beenused to treat gastrinoma in dogs and cats.

OtherUnresectable gastrinomas may be managed medi-cally by inhibiting gastric acid secretion. Gastricparietal cells have receptors for histamine andacetylcholine as well as gastrin, and medical man-agement may therefore include:

• Histamine H2 receptor antagonists (cimetidine,ranitidine)

• Anticholinergics (probantheline bromide)• Somatostatin analogues (octreotide)• Proton pump inhibitors (omeprazole).

Gastro-intestinal protectants such as sucralfatemay also be used to minimise erosion and ulcera-tion of the mucosa.

Prognosis

The long-term prognosis for gastrinomas is poorbecause of the high metastatic rate and survivaltimes are short (less than six months).

Glucagonoma

Glucagon-producing tumours of the pancreas arerare, with only isolated cases (all carcinomas)reported in dogs and none reported in cats (Grosset al. 1990; Bond et al. 1995; Torres et al. 1997;Cerundolo et al. 1999). All of the dogs withglucagon secreting pancreatic carcinomas pre-sented with the paraneoplastic syndrome of meta-bolic epidermal necrosis which resembles thecondition of necrolytic migratory erythema, associ-ated with glucagonoma in humans. In dogs, meta-bolic epidermal necrosis has been more frequentlyreported with other diseases such as chronic liverdisease (hepatocutaneous syndrome) and diabetesmellitus, than with glucagonoma (Miller et al. 1990)(Fig. 14.7).

Clinical signs

The skin lesions characteristic of metabolic epider-mal necrosis are hyperkeratosis and fissuring of thefootpads, symmetrical erythema, and ulcerationand crusting of the face, feet and external genitalia.

Fig. 14.7 Hepatocutaneous syndrome. Hyperkeratosisand crusting dermatosis of the feet is characteristic ofhepatocutaneous syndrome.


cases (1984–1995). Journal of Veterinary Internal Medicine, (11), 272–8.

Berger, B. & Feldman, E.C. (1987) Primary hyper-parathyroidism in dogs: six cases (1982–1991). Journalof the American Veterinary Medical Association, (191),350–56.

Bond, R., McNeil, P.E., Evans, H. & Screbernik (1995)Metabolic epidermal necrosis in two dogs with dif-ferent underlying diseases. Veterinary Record, (136),466–71.

Brearley, M.J., Hayes, A.M. & Murphy, S. (1999)Hypofractionated radiation therapy for invasivethyroid carcinoma in dogs: a retrospective analysis ofsurvival. Journal of Small Animal Practice, (40), 206–10.

Carver, J.R., Kapatkin, A. & Patnaik, A.K. (1995) A com-parison of medullary thyroid carcinoma and thyroidadenocarcinoma in dogs: a retrospective study of 38cases. Veterinary Surgery, (24), 315–19.

Caywood, D.D., Klausner, J.S., O’Leary, T.P., Withrow, S.J.et al. (1988) Pancreatic insulin-secreting neoplasms:clinical, diagnostic and prognostic features in 73 dogs.Journal of the American Animal Hospital Association,(24), 577–84.

Cerundolo, R., McEvoy, F., McNeil, P.E. & Lloyd, D.H.(1999) Ultrasonographic detection of a pancreaticglucagon-secreting multihormonal islet cell tumour ina dachshund with metabolic epidermal necrosis. Veteri-nary Record, (145), 662–6.

Dow, S.W., LeCouteur, R.A., Rosychuk, R.A.W. et al.(1990) Response of dogs with functional pituitarymacroadenomas and macrocarcinomas to radiation.Journal of Small Animal Practice, (31), 287–94.

Duesberg, C.A., Nelson, R.W., Feldman, E.C. et al. (1995)Adrenalectomy for treatment of hyperadrenocorticismin cats: 10 cases (1988–1992). Journal of the AmericanVeterinary Medical Association, (207), 1066–70.

Dunn, J.K., Bostock, D.E., Herrtage, M.E., Jackson, K.F.& Walker, M.J. (1993) Insulin-secreting tumours of thecanine pancreas: clinical and pathological features of 11cases. Journal of Small Animal Practice, (34), 325–31.

Feldman, E.C. (1995) Hyperadrenocorticism. In:Textbook of Veterinary Internal Medicine, (eds S.J.Ettinger & E.C. Feldman), 1538–78. W.B. Saunders,Philadelphia.

Ford, S.L., Feldman, E.C. & Nelson, R.W. (1993) Hypera-drenocorticism caused by bilateral adrenocortical neoplasia in dogs: four cases (1983–1988). Journal of the American Veterinary Medical Association, (202),789–92.

Gilson, S.D., Withrow, S.J. & Orton, E.C. (1994) Surgicaltreatment of phaeochromocytoma; technique, compli-cations and results in six dogs. Veterinary Surgery, (23),195–200.

Gross, T.L., O’Brien, T.D., Davies, A.P. & Long, R.E.(1990) Glucagon-producing pancreatic endocrinetumors in two dogs with superficial necrolytic dermati-tis. Journal of the American Veterinary Medical Associ-ation, (197), 1619–22.

Hawks, D., Peterson, M.E., Hawkins, K.L. & Rosebury,W.S. (1992) Insulin-secreting pancreatic (islet cell) car-cinoma in a cat. Journal of Veterinary Internal Medicine,(6), 193–6.

Henry, C.J., Brewer, W.G., Montgomery, R.D., Groth,A.H., Cartee, R.E. & Griffin, K.S. (1993) Adrenalphaeochromocytoma. Journal of Veterinary InternalMedicine, (7), 199–201.

Kallet, A.J., Richter, K.P., Feldman, E.C. & Brum, D.E.(1991) Primary hyperparathyroidsim in cats: sevencases (1984–1989). Journal of the American VeterinaryMedical Association, (199), 1767–71.

Kintzer, P.P. & Peterson, M.E. (1994) Mitotane treatmentof 32 dogs with cortisol secreting adrenocortical neo-plasms. Journal of the American Veterinary MedicalAssociation, (205), 54–9.

Klein, M.K., Powers, B.E., Withrow, S.J. et al. (1995) Treat-ment of thyroid carcinoma in dogs by surgical resectionalone: 20 cases. Journal of the American VeterinaryMedical Association, (206), 1007–9.

Leav, I., Shiller, A.L. & Rijnberk, A. (1976) Adenomasand carcinomas of the canine and feline thyroid.American Journal of Pathology, (83), 61–93.

Leifer, C.E., Peterson, M.E. & Matus, R.E. (1986) Insulin-secreting tumor: diagnosis and medical and surgicalmanagement in 55 dogs. Journal of the American Veterinary Medical Association, (188), 60–64.

Melhaff, C.J., Peterson, M.E., Patnaik, A.K. & Carrillo,J.M. (1985) Insulin-producing islet cell neoplasms: sur-gical considerations and general management in 35dogs. Journal of the American Animal Hospital Associ-ation, (21), 607–12.

Miller, W.A., Scott, D.W., Buerger, R.G. et al. (1990)Necrolytic migratory erythema in dogs: a hepatocuta-neous syndrome. Journal of the American Animal Hos-pital Association, (26), 573–81.

Nelson, R.W. & Feldman, E.C. (1988) Hyperadrenocorti-cism in cats: seven cases (1978–1987). Journal of theAmerican Veterinary Medical Association, (193),245–50.


Peterson, M.E. (1986) Canine hyperadrenocorticism. In:Current Veterinary Therapy IX Small Animal Practice,(ed R.W. Kirk) pp. 963–72.W.B. Saunders, Philadelphia.

Rabbitts, T.H. (1994) Chromosomal translocations inhuman cancer. Nature, (372), 143–9.

Reusch, C.E. & Feldman, E.C. (1991) Canine hypera-drenocorticism due to adrenocortical neoplasia.Journal of Veterinary Internal Medicine, (5), 3–10.

Scavelli, T.D., Peterson, M.E. & Mattheisen, D.T. (1986)Results of surgical treatment for hyperadrenocorticismcaused by adrenocortical neoplasia in the dog: 25 cases (1980–1984). Journal of the American VeterinaryMedical Association, (189), 1360–64.

Schrauwen, E. (1991) Clinical peripheral neuropathyassociated with canine insulinoma. Veterinary Record,(128), 211–12.

Siliart, B. & Stambouli, F. (1996) Laboratory diagnosis ofinsulinoma in the dog: a retrospective study and a diag-nostic procedure. Journal of Small Animal Practice,(37), 367–70.

Torres, M.F., Caywood, D.D., O’Brien, T.D., O’Leary,T.P. & McKeever, P.J. (1997) Resolution of superficialnecrolytic dermatitis following excision of a glucagon-


Further reading

Marks, S.L., Koblik, P.D., Hornof, W.J. & Feldman, E.C.(1994) 99mTc pertechnetate imaging of thyroid tumorsin dogs: 29 cases (1980–1992). Journal of the AmericanVeterinary Medical Association, (204), 756–60.

Sullivan, M., Cox, F., Pead, M.J. & Mcneil, P. (1987)Thyroid tumours in the dog. Journal of Small AnimalPractice, (28), 505–12.

Susaneck, S. (1983) Thyroid tumors in the dog. Com-pendium of Continuing Education for the PractisingVeterinarian, (5), 35–9.

Wisner, E.R., Nyland, T.G., Feldman, E.C., Nelson,R.W. & Griffey, S.M. (1993) Ultrasonographic evaluation of the parathyroid glands in hypercalcaemicdogs. Veterinary Radiology and Ultrasound, (34),108–11.

secreting pancreatic neoplasm in a dog. Journal of the American Animal Hospital Association, (33), 313–19.

Turrel, J.M., Feldman, E.C., Nelson, R.W. et al. (1988)Thyroid carcinoma causing hyperthyroidism in cats: 14cases (1981–1986). Journal of the American VeterinaryMedical Association, (193), 359–64.

Twedt, D.C. & Wheeler, S.L. (1984) Phaeochromocytomain the dog. Veterinary Clinics of North America, SmallAnimal Practice, (14), 767–82.

Van Ham, L., Braund, K.G., Roels, S. & Putcuyps, I. (1997)Treatment of a dog with an insulinoma-related periph-eral polyneuropathy with corticosteroids. VeterinaryRecord, (141), 98–100.

Zerbe, C.A., Boosinger, T.R. & Grabau, J.H. (1989) Pancreatic polypeptide and insulin-secreting tumour in a dog with duodenal ulcers and hypertrophic gastritis. Journal of Veterinary Internal Medicine, (3),178–82.

15Haematopoietic System

lymphoid and non-lymphoid cell series. They aredescribed as:• Lymphoproliferative disease (LPD) – the term

used for tumours of solid lymphoid organs (lym-phoma) as well as for lymphoid tumours derivedfrom bone marrow (lymphoid leukaemias andmultiple myeloma).

• Myeloproliferative disease (MPD) – a spectrumof conditions derived from haematopoietic stemcells located in the bone marrow and includ-ing dysplastic or hyperplastic diseases such asmyelofibrosis and myelodysplastic syndromes, aswell as the non-lymphoid leukaemias.

Haematopoietic tumours are more common in thecat than the dog. Lymphoma is the commonesthaematopoietic tumour in both species, withleukaemia, other myeloproliferative disorders andmultiple myeloma occurring much less frequently.Haematopoietic neoplasms are the third mostcommon type of tumour diagnosed in the dog,accounting for approximately 8–9% of all canine malignant tumours. In the cat haematopoi-etic neoplasms are the most common tumour type, accounting for approximately one third of alltumours.

Haematopoietic neoplasms derive from the

� Lymphoma, 228� Leukaemia, 239� Multiple myeloma, 246

228

LYMPHOMA

This disease should strictly be referred to as ‘malignant’ lymphoma or ‘lymphosarcoma’, sinceby convention the ending ‘oma’ usually refers to a benign tumour. In most of the main oncologytexts, however, the term lymphoma is used to meanthe malignant lymphoproliferative disease and we have chosen to continue this nomenclature here.

Epidemiology

Lymphoma is the commonest haematopoietictumour in the dog, accounting for 80–90% of thesetumours and 5–7% of all canine neoplasms. Its inci-dence is reported as 13–24 cases/100 000 dogs/year(Dorn et al. 1968). Most cases are middle aged

Haematopoietic System 229

(often extranodal), either on its own or by coinfec-tion with FeLV (Shelton et al. 1990; Hutson et al.1991; Callanan et al. 1992; Poli et al. 1994). Ratherthan playing a direct role in tumourigenesis, FIVinfection probably induces immune dysfunctionand indirect development of lymphoma (Beatty et al. 1998).

Pathology

Lymphoma in the dog and cat may be classified byanatomical distribution, morphological cell typeand histological appearance, or immunophenotype.

Anatomical classification

Anatomically, tumours may be grouped as:

• Multicentric• Mediastinal• Alimentary• Cutaneous• Extranodal.

The clinical presentation of each group is discussedin the appropriate section below.

Histopathological classification

In an attempt to link cell type to prognosis, severalhistological classification schemes have beenapplied to canine lymphoma. The majority of theseare based on those used for human non-Hodgkinslymphoma (Tables 15.2, 15.3 and 15.4). The World

(mean 6–7 years), although young dogs may beaffected. ‘Histiocytic’ lymphoma often affects ayounger age group (mean four years). There is noobvious sex predisposition but breeds reported tobe at greater risk include Scottish terriers, boxers,basset hounds, bulldogs, Labrador retriever,Airedale terriers and St Bernards (Rosenthal1982).

In the cat, lymphoma accounts for 50–90% of allhaematopoietic neoplasms with an incidence of 200per 100 000 cats at risk (Essex & Francis 1976). Theage distribution is bimodal with the mean age ofaffected cats ranging from two to three years (FeLVpositive) to seven years (FeLV negative). Orientalbreeds may be more at risk.

Aetiology

Lymphoma is considered to be a multifactorialdisease with no clear aetiology confirmed in thedog. There may be a genetic component, since afamilial incidence has been reported in the bullmastiff (Onions 1984).

A C-type retrovirus, feline leukaemia virus(FeLV), is mainly responsible for the disease in thecat with up to 70% of cases testing positive for theviral antigen, p27. The percentage of cats found to be positive for the virus varies with the anatomi-cal site of the disease (Table 15.1). In general,multicentric and mediastinal forms are FeLV positive while cutaneous and alimentary forms are virus negative. Young cats are more frequentlyvirus positive than older cats. More details of FeLV infection are given in Chapter 1 and othertexts.

Feline immunodeficiency virus (FIV) may also be responsible for some cases of B cell lymphoma

Table 15.1 Variation in FeLV positivity withanatomical site of feline lymphoma. Jarratt (1994)and Vail et al. (1998).

Anatomical type % of cases positive Mean agefor FeLV (years)

Multicentric 30–60 4Mediastinal 70–80 2.5Alimentary 5–30 8Extranodal 20–60 8All sites 70

Table 15.2 Rappaport classification of non-Hodgkin’s lymphoma.

NodularLymphocytic well differentiatedLymphocytic poorly differentiatedMixed lymphocytic and histiocyticHistiocytic

DiffuseLymphocytic well differentiated (± plasmacytoid

features)Lymphocytic poorly differentiatedLymphoblasticMixed lymphocytic and histiocyticHistiocyticUndifferentiated


Health Organization scheme (Table 15.5) whichwas defined for the dog is rarely used. Usingschemes which assess the growth pattern (follicularor diffuse) within the node as well as cell type (lym-phocytic, lymphoblastic etc.), approximately 85%of canine lymphomas are classed as diffuse or minimally follicular. The Kiel and National CancerInstitute Working Formulation (WF) schemes areof most prognostic value and, using these schemes,the majority of canine lymphomas are found to

Table 15.3 Kiel Classification of lymphoma.

Low grade malignancyLymphocytic (CLL, MF, Sezary)Lymphoplasmacytic, lymphoplasmacytoidCentrocyticCentroblastic/centrocytic (follicular/diffuse)Unclassified

High grade malignancyCentroblasticLymphoblastic (Burkitt’s type, convoluted cell type)ImmunoblasticUnclassified

Table 15.4 National Cancer Institute Working For-mulation for lymphoma.

Low grade malignancySmall lymphocyticFollicular predominantly small cleavedFollicular mixed small cleaved and large cell

Intermediate grade malignancyFollicular predominantly large cellDiffuse small cleavedDiffuse mixed small cleaved and large cellDiffuse large cell (cleaved/noncleaved)

High grade malignancyImmunoblasticLymphoblastic (convoluted/nonconvoluted)Small noncleaved (Burkitt’s)

Table 15.5 World Health Organisation classifica-tion of canine lymphoma (Owen 1980).

Poorly differentiatedLymphoblasticLymphocytic and prolymphocyticHistiocytic, histioblastic, histiolymphocytic

be of high or intermediate grade malignancy andeither large cell (WF) or centroblastic (Kiel). TheNCI working formulation has been applied tofeline lymphoma with just over half of the casesclassified as high grade. One third of tumours areimmunoblastic cell type (Valli et al. 1989).

Immunophenotypic classification

Lymphoma may also be classified by immunophe-notype using serum from other species which crossreacts with dog tissue or, more recently, specificcanine monoclonal antibodies (Moore et al. 1992;Cobbold & Metcalfe 1994). The majority of caninelymphomas are derived from B cells with estimatesof T cell lymphomas accounting for between 10 and 38% of cases. There is no correlation betweenimmunophenotype and morphological cell typealthough T cell lymphomas are often of low or intermediate cytomorphological grade (Teske1993). Feline lymphomas may also be immunophe-notyped. Most feline thymic and multicentric lymphomas are T cell since they are caused by FeLV transformation. Most alimentary lym-phomas, however, are B cell derived and test FeLVnegative.

Tumour behaviour

Lymphoma arises from the neoplastic transfor-mation and subsequent proliferation of lym-phocytes in solid lymphoid organs. The disease may develop in multiple sites simultaneously or originate at one site and progress to others, although this is not metastasis as such.Neoplastic lymphoid cells may circulate in theblood and/or invade bone marrow, resulting inmyelosuppression.


The paraneoplastic diseases commonly seen withcanine lymphoma are hypercalcaemia and hyper-gammaglobulinaemia (see Chapter 2). Both alsooccur with feline lymphoma but much more rarelythan in the dog. Hypercalcaemia is present in10–40% of canine lymphoma cases and is oftenassociated with mediastinal forms and thosethought to be T cell derived. Hypergammaglobuli-naemia is less common than hypercalcaemia in thedog.


accompanied by pleural effusion and occasionallybone marrow infiltration. Although occasionally amass is seen as an incidental finding on thoracicradiography, animals usually present with coughing,dyspnoea, regurgitation or Horner’s syndrome andcaudal displacement of heart and lung sounds onauscultation. Hypercalcaemia is common with thisform of lymphoma in dogs and is often associatedwith T cell immunophenotype.

Alimentary

Alimentary lymphoma may present as solitary,diffuse or multifocal infiltration of the gastro-intestinal tract with or without mesenteric lym-phadenopathy (Fig. 15.2). Animals may presentwith vomiting, diarrhoea, anorexia, weight loss,dyschezia or tenesmus and occasionally peritonitissecondary to complete obstruction and rupture ofthe gut. An abdominal mass, enlarged mesenteric

Presentation/signs

The clinical presentation of lymphoma variesaccording to the anatomical type. Of the fouranatomical groups recognised, the multicentricform is most common in the dog and mediastinaland alimentary forms in the cat.

Multicentric

Animals present with a solitary or generalised lymphadenopathy which may be accompanied byhepatosplenomegaly, involvement of bone marrowor other organs (Fig. 15.1). Lymph nodes are mas-sively enlarged and hard, but usually non-painful topalpate.The majority of cases are clinically well butsome cases show non-specific signs such as weightloss, anorexia or lethargy. Approximately 20% ofcanine cases will show signs of hypercalcaemia suchas polydipsia, polyuria, anorexia, vomiting, consti-pation, depression, muscle weakness or cardiacarrhythmias. Fewer animals will show signs of amonoclonal gammopathy such as bleeding disor-ders, thromboembolism, ocular lesions (retinaldetachment, tortuous blood vessels), neurologicalsigns and infections.

Mediastinal

Cases with mediastinal (thymic) lymphoma have an anterior mediastinal lymphadenopathy, possibly

Fig. 15.1 Enlarged submandibular lymph nodes in aweimaraner with multicentric lymphoma.

Fig. 15.2 Intestinal lymphoma in a cat (post mortem).(Courtesy of Dr P. Nicholls.)


lymph nodes or thickened bowel loops may be palpable.

Cutaneous

The cutaneous form of lymphoma may be either:

• Primary, that is originating in the skin; or• Secondary, that is associated with lymphoma

found predominantly at other body sites.

Primary cutaneous lymphoma includes two forms,both of which are T cell derived and are discussedin detail in Chapter 4. Although these originate in the skin, they may later spread to abdominalviscera, lymph nodes and bone marrow (seeChapter 4). The two forms are:

• Epitheliotropic form – ‘mycosis fungoides’ has Tlymphocytes restricted to the epidermis. Casespresent with a chronic history of alopecia, depig-mentation, desquamation, pruritus and ery-thema. This progresses over months or years toplaque formation characterised by crusting andulceration, and finally to tumour formation(nodules or masses). Lesions are often aroundmucocutaneous junctions or in the oral cavity.

• Non-epitheliotropic (dermal) form – a moreaggressive disease, spreading rapidly from multi-ple cutaneous lesions to involve lymph nodes,abdominal viscera and bone marrow.

Secondary cutaneous lymphoma is also charac-terised by lymphoid cells in the dermis. These often have morphological features similar to thoseof histiocytes (histiocytic lymphoma) but theimmunophenotype may be B or T cell dependingon that of the lymphoma at the primary site.

Extranodal

The term extranodal lymphoma is used for lymphoma at sites which are not readily includedby the other anatomical classification groups, forexample:

• Renal• Nasopharyngeal• Ocular• Neural.

Renal lymphoma is relatively common in cats andclinical signs are related to renal failure since thedisease is usually bilateral (Fig. 15.3). Cats present

with emaciation and pallor (anaemia) and largeirregular kidneys may be palpated. Tumour pro-gression to the CNS is commonly found with renallymphoma.

Animals with nasopharyngeal lymphoma pre-sent with upper respiratory signs such as nasal dis-charge or sneezing and sometimes nasal deformity.Several cases of feline nasopharyngeal lymphomain our clinic have subsequently developed renallymphoma.

Ocular and neural lymphoma may be primary or accompany the multicentric form. Ocular lym-phoma is more common in cats than dogs and clini-cal signs associated with it include photophobia,blepharospasm, epiphora, hyphaema, hypopyon,ocular mass, anterior uveitis, chorioretinal involve-ment or retinal detachment (Fig. 15.4; see alsoChapter 16). Neural lymphoma may be solitary ordiffuse and involve central or peripheral nervoussystems. Presenting signs are variable and includeparalysis, paresis, lameness, muscle atrophy orcentral signs (Chapter 13).

Investigations

FeLV/FIV tests

All cats suspected of having lymphoma should be tested for FeLV and FIV. The most commonlyused screening test for FeLV is the enzyme-linkedimmunosorbent assay (ELISA) which detects freep27 antigen in the blood, but an immunofluorescent

Fig. 15.3 Renal lymphoma in a cat (post mortem).(Courtesy of Dr P. Nicholls.)


Imaging techniques

Radiography is necessary to help with the diagnosisin some anatomical forms of the disease such asmediastinal, renal, spinal or alimentary. Contrastradiography may be required such as a bariumseries, intravenous urography or myelography.Thoracic and abdominal radiography is also of vitalimportance to assess lymph node and organ involvement (liver, spleen, lungs etc.) in staging mul-ticentric forms of the disease (Figs 15.5 and 15.6).

Although radiography can show gross enlarge-ment or a change in shape of organs, ultrasonogra-phy is of more use for showing a definite infiltrationor change of architecture which may be useful forstaging the disease. Ultrasonography is also usefulfor guiding aspirates or biopsies to confirm thediagnosis.

Biopsy/FNA

The quickest and easiest way to confirm the diag-nosis of lymphoma is to take a fine needle aspirate

antibody test to detect p27 antigen in blood or bonemarrow cells may also be used. The ELISA is avail-able in kit form (CITE test) for use in general prac-tice and is much more sensitive, specific and quick.For a definitive test, virus isolation is necessary, butthis is expensive and time-consuming.

An ELISA test is also the most common methodused to diagnose FIV infection but the test detectsserum antibodies to the virus rather than viralantigen. Western blot and immunofluorescent anti-body tests may also be used.

Bloods

All cases of suspected lymphoma require routinehaematological analysis:

• To help stage the disease• To establish a base-line of haematological

parameters with which to compare futuresamples and assess the degree of myelosuppres-sion induced by treatment.

Haematological evaluation may be normal, or ifbone marrow involvement is present, may revealanaemia, thrombocytopenia, neutropenia, lym-phocytosis and the presence of immature lymphoidprecursors.

Biochemical evaluation should include liverenzymes (ALT and alkaline phosphatase) to detectliver dysfunction, BUN/creatinine to detect renaldysfunction, electrolytes to detect hypercalcaemia,and serum protein electrophoresis to detect a monoclonal gammopathy if the total protein levelis raised.

Fig. 15.4 Ocular involvement. This dog presented with sudden onset blindness due to intraocular haemorrhage.

Fig. 15.5 Lateral radiograph of thorax showing diffuseparenchymal involvement in case of multicentric lym-phoma (stage V).


for cytological evaluation from an enlarged lymphnode, mass or affected organ (Fig. 15.7). Alterna-tively, or additionally if there is any doubt about thecytological diagnosis, biopsy material can be exam-ined histologically. This is also needed for completehistological classification by cell type and growthpattern and also for immunophenotyping. A needleor incisional biopsy may be taken from a mass oraffected organ, but for the multicentric form, awhole lymph node (usually the popliteal) is bestsubmitted.

As part of the staging procedure, a bone marrowaspirate or biopsy should also be examined if there

is any evidence of haematological abnormalities.Ideally this should be performed for all cases, sinceit is possible for bone marrow infiltration to bepresent without obvious changes to haematologicalparameters.

Staging

A TNM staging system is not applicable to lym-phoma but a group staging system is used instead(Table 15.6). The extent of the disease must beassessed by clinical and radiographic examination,and by haematological and bone marrow evalua-tion. Most cases of multicentric lymphoma presentas stage III, IV or V.

Treatment

Surgery

Surgery is useful in the treatment of certain typesof lymphoma. In some cases of anterior mediasti-nal lymphoma where a diagnosis has not been con-firmed by aspirate or biopsy, a thoracotomy may be necessary to obtain tumour material for diag-nostic purposes and to remove the mass. Similarly,many cases of alimentary lymphoma will require aceliotomy to obtain biopsy material. For solitaryintestinal masses, surgical resection and anastomo-sis of the gut may be the best treatment option sincethere is a theoretical risk of gut perforation in caseswhere the tumour involves the full thickness of the

Fig. 15.6 Lateral radiograph of abdomen showinghepatomegaly and sublumbar lymphadenopathy incase of multicentric lymphoma (stage IV).

Fig. 15.7 Fine needle aspirate of lymph node from dog with multicentric lymphoma. Cytology reveals apopulation of large, neoplastic lymphoblasts. (See alsoColour plate 29, facing p. 162.)

Table 15.6 Clinical stages of lymphoma. Owen(1980).

Stage Extent of disease

I Involvement limited to a single node or lymphoid tissue in a single organ (excluding bone marrow)

II Involvement of many lymph nodes in a regional area (± tonsils)

III Generalised lymph node involvementIV Liver and/or spleen involvement (± stage III)V Manifestations in the blood and involvement

of bone marrow and/or other organ systems (± stages I–IV)

Subclassify each stage as (a) without systemic signs (b)with systemic signs.


gut wall and which are treated with cytotoxic drugs.Cases of spinal lymphoma or solitary skin massesmay also require surgical treatment. If it is likelythat not all tumour has been resected or that mul-ticentric disease may develop, surgery should befollowed by chemotherapy. A six month courseshould be sufficient if there is no gross evidence ofdisease at the start of treatment.

Radiotherapy

Lymphoma is a very radiosensitive tumour and intheory, radiotherapy should be highly successful in treating all forms of the disease. In animals,however, the side-effects associated with wholebody or half body radiation are such that multi-centric or widespread cutaneous disease is notusually treated in this way. Localised masses,however, can be treated very effectively and radio-therapy can be considered:

• As an alternative for solitary skin masses at sitesnot amenable to surgery

• For nasal lymphoma• For some cases of anterior mediastinal lym-

phoma.

We have also found radiotherapy effective in con-trolling oral lesions in cases of mycosis fungoideswhich present with predominantly oral and fewskin lesions.

Chemotherapy

The most common method of treatment for lym-phoma is combination chemotherapy. If chemo-therapy is intended, corticosteroids should not bestarted before the cytotoxic drugs, since they induceresistance to the cytotoxics and significantly lowerthe response rate and survival time. Before com-mencing drug therapy it is essential to establish a baseline of haematological parameters, for future monitoring of treatment associated myelo-suppression.

The aims of therapy for most cases of lymphomaare to:

• Induce remission with a chemotherapeuticregime

• Proceed to maintenance treatment once remis-sion is complete

• Intensify the regime if a complete response is notachieved.

The response of the disease to treatment is moni-tored by lymph node size or a reduction in visibletumour mass (Figs 15.8 and 15.9). Drug side-effectsare monitored by haematological parameters andother means specific to the drugs used. Most casesof lymphoma will eventually recur or relapsebecause treatment is stopped too soon or becauseof development of resistance to cytotoxic drugs. Atthis stage ‘rescue’ treatment is used.

Several combination chemotherapy protocolshave been described for treatment of cats and dogswith lymphoma. It is usually recommended to selecta protocol and to keep using the same one, in orderto familiarise oneself with the drugs and their tox-icities. The COAP and COP low dose proto-cols are often selected for induction because they

Fig. 15.8 Lateral thoracic radiograph of cat with medi-astinal lymphoma.

Fig. 15.9 The same cat after four weeks of COPchemotherapy.


are inexpensive and of low toxicity (Table 15.7),but other protocols based on a 21-day cycle or pulse therapy of a different drug each week are also available (Tables 15.8 and 15.9). For rescuetreatment, further protocols may be selected (Table15.10). For cats, the COP protocol (low or highdose) or pulse therapy (Table 15.9) are most oftenused. There is some evidence to suggest that pro-tocols including doxorubicin provide longerperiods of remission in cats with lymphoma (Mooreet al. 1996).

Other

Cases of lymphoma presenting with paraneoplasticsyndromes may require immediate supportivetreatment while the diagnosis is being confirmed.Prolonged hypercalcaemia results in irreversiblerenal damage and immediate steps should be taken

to lower serum calcium levels (Chapter 2). Hyper-gammaglobulinaemia will also require promptaction if severe.

Some forms of lymphoma, particularly the cutaneous ones, respond poorly to conventionalchemotherapy. Other options which have beentried with variable success for mycosis fun-goides include retinoids such as isotretinoin oretretinate (White et al. 1993) and photodynamictherapy.

A monoclonal antibody called CL/MAb 231(Synbiotics, California) is available in the USA foruse in combination with a non-immunosuppressivechemotherapy regime. The monoclonal acts viacomplement mediated or antibody dependent cellcytotoxicity (ADCC) pathways which require anintact host immune system. Initial trials showed a significantly increased median survival time com-pared to controls treated by chemotherapy alone

Table 15.7 Chemotherapy protocols for the treatment of lymphoma (continuous).

InductionCOAPCyclophosphamide 50 mg/m2 by mouth every 48 hours or for the first 4 days of each week*Vincristine 0.5 mg/m2 intravenously every 7 daysCytosine arabinoside 100 mg/m2 intravenously daily for first 4 days of protocol (in cats, use subcutaneously for

2 days)Prednisolone 40 mg/m2 by mouth daily for 7 days, then 20 mg/m2 by mouth every 48 hours (with

cyclophosphamide)

COP (low dose)Cyclophosphamide 50 mg/m2 by mouth every 48 hours or for the first 4 days of each week*Vincristine 0.5 mg/m2 intravenously every 7 daysPrednisolone 40 mg/m2 by mouth daily for 7 days, then 20 mg/m2 by mouth every 48 hours (with

cyclophosphamide)

MaintenanceCOPAfter 8 weeks of induction with COAP/COP, continue COP as alternate week treatment for 4 months, then 1 week

in 3 for 6 months, and reduce to 1 week in 4 after 1 year.

MOPAs for COP, but to reduce the risk of haemorrhagic cystitis, substitute melphalan (2–5 mg/m2 by mouth) for

cyclophosphamide after 6 months.

LMP/LPAfter 8–10 weeks of induction with COAP or COP, change to different drugs for maintenance, i.e. chlorambucil and

prednisolone ± methotrexateChlorambucil 20 mg/m2 by mouth every 14 daysMethotrexate 2.5 mg/m2 by mouth 2 to 3 times per weekPrednisolone 20 mg/m2 by mouth every 48 hours

* In cats, this regime is hard to achieve because cyclophosphamide is only available in the UK as 50 mg tablets whichshould not be broken. For an average cat of 3–4 kg, a 50 mg tablet is usually equivalent to four or five doses, so pulsedosing may be used – one tablet every 8–10 days. Alternatively, an intravenous dose may be used at 200 mg/m2 every2–3 weeks to suit the individual, or the COP (high dose) protocol.


Using large numbers of animals, and multivariatestatistical analysis a number of factors have beenshown to affect the prognosis for canine multi-centric lymphoma:

• Histological grade of malignancy appears to be the most reliable prognostic indicator withhigh grade tumours giving consistently poorerresponses. High grade tumours by the Kiel clas-sification have reduced attainment of completeresponse (CR) and shorter disease free interval(DFI), whereas high grade tumours by theWorking Formulation classification have shortersurvival time (Teske et al. 1994).

• T cell phenotype is also important and carries apoor prognosis regardless of histological grade(Teske 1993).

• In univariate studies, a higher clinical stagecarries a worse prognosis and substage (b) leadsto shorter DFI and survival, but the results are

(Jeglum 1991), but further trials have not been published.

Prognosis

Without therapy, the mean survival time for dogs orcats with lymphoma is only six to eight weeks. Withcorticosteroid therapy alone it may be extended to approximately three months, but with chemo-therapy it is usually six to nine months. A variety ofprotocols are available for treating lymphoma butregardless of which is used, approximately 70–80%of canine cases (65–75% of feline cases) with multi-centric lymphoma achieve remission and remain inremission for a mean of six to nine months.Survival times, however, may range from one weekto several years. Once relapse occurs, the prognosisworsens since fewer than 50% of cases respond torescue therapy.

Table 15.8 Chemotherapy protocols for the treatment of lymphoma (21 day cycles).

InductionCOP (high dose)Cyclophosphamide 250–300 mg/m2 by mouth every 21 daysVincristine 0.75 mg/m2 intravenously every 7 days for 4 weeks, then every 21 daysPrednisolone 1 mg/kg by mouth daily for 4 weeks, then every 48 hours

COPAAs for COP, except use:Doxorubicin 30 mg/m2 intravenously in place of cyclophosphamide every third cycle, i.e. every

ninth week

CHOPCyclophosphamide 100–150 mg/m2 intravenously on day 1Doxorubicin 30 mg/m2 intravenously on day 1Vincristine 0.75 mg/m2 intravenously on days 8 and 15Prednisolone 40 mg/m2 daily for 7 days, then 20 mg/m2 every 48 hours, days 8–21(Potentiated sulphonamides) Protocol very myelosuppressive, therefore antibiotic cover advised

PACOPrednisolone 20 mg/m2 by mouth every 48 hoursActinomycin D 0.75 mg/m2 intravenously on day 1Cyclophosphamide 250–300 mg/m2 by mouth on day 10Vincristine 0.75 mg/m2 intravenously on days 8 and 15

repeat every 21 days

MaintenanceCOP/COPAAfter 1 year of induction with COP (high dose) or COPA, use the same cycle every 4 weeks for another 6 months

COP/LMPAfter 12 weeks of induction with CHOP, change to low dose COP or LMP for maintenance (see Table 15.7)

PALAfter 12 weeks induction with PACO, change to different drugs, i.e. PAL for maintenance:Prednisolone 20 mg/m2 by mouth every 48 hoursCytosine arabinoside 200 mg/m2 subcutaneously every 7 daysChlorambucil 20 mg/m2 every 14 days

}


Table 15.9 Chemotherapy protocols for treatment of lymphoma (weekly pulse therapy/cyclic combinationtherapy).

InductionWeek 1 (day 1) Vincristine 0.5–0.75 mg/m2 intravenously

L-Asparaginase 400 IU/kg intramuscularly± Prednisolone 2.0 mg/kg by mouth daily

Week 2 (day 8) Cyclophosphamide 200 mg/m2 intravenously or by mouth± Prednisolone 1.5 mg/kg by mouth daily

Week 3 (day 15) Vincristine 0.5–0.75 mg/m2 intravenously± Prednisolone 1.0 mg/kg by mouth daily

Week 4 (day 22) Doxorubicin* 30 mg/m2 intravenously± Prednisolone 0.5 mg/kg by mouth daily

Week 5 (day 29) Vincristine 0.5–0.75 mg/m2 intravenouslyWeek 6 (day 36) Cyclophosphamide** 200 mg/m2 intravenously or by mouthWeek 7 (day 43) Vincristine 0.5–0.75 mg/m2 intravenouslyWeek 8 (day 50) Doxorubicin* 30 mg/m2 intravenously

or Methotrexate 0.6–0.8 mg/kg (10–15 mg/m2) intravenouslyWeek 9 (day 57) No treatment

MaintenanceRepeat the 8 week cycle twice with an interval of 2 weeks between each drug administration and then another twicewith an interval of 3 weeks between each drug administration. Chlorambucil (1.4 mg/kg by mouth) may besubstituted for cyclophosphamide during maintenance cycles

* In cats, methotrexate is often used in weeks 4 and 8. If Doxorubicin is alternated with methotrexate, the dose is 20 mg/m2 rather than 30 mg/m2.** For renal lymphoma in cats, because of the risk of CNS spread, substitute cytosine arabinoside 600 mg/m2

(30 mg/kg) subcutaneously divided into 4 doses at 12 hour intervals over 48 hours.

Table 15.10 Rescue chemotherapy for relapsed cases of lymphoma.

If response to initial treatment was good, return to original induction protocol until remission achieved and then usemaintenance protocolCOAP Table 15.7COP (low or high dose) Tables 15.7 and 15.8COPA Table 15.8CHOP Table 15.8PACO Table 15.8Cyclic combination Table 15.9

If response to initial treatment was slow or for a second relapse, change to new drugs for rescue. Return tomaintenance once remission complete

Single agentsDoxorubicin 30 mg/m2 (dogs) or 20 mg/m2 (cats) intravenously every 21 daysL-Asparaginase 10 000–20 000 IU/m2 intramuscularly every 14–21 days

ADICDoxorubicin 30 mg/m2 (dogs) or 20 mg/m2 (cats) intravenously every 21 daysDacarbazine 1000 mg/m2 intravenous infusion (over 6–8 hours) every 21 daysCHOP Table 15.8PACO Table 15.8


calcaemia per se, although many hypercalcaemiccases are of the T cell phenotype and have a worseprognosis because of this.

In cats, stage of disease is considered importantfor prognosis, along with the severity of haemato-logical and biochemical abnormalities and overallclinical condition. FeLV and FIV status are alsoimportant since FeLV related disorders other thanneoplasia can influence survival (Mooney et al.1989).

often inconsistent. Within the T cell lymphomas,however, clinical stage does appear to be impor-tant, with higher stages performing worse.

• Of all the proliferation markers available, onlyAgNOR counts seem to be of prognostic valuewith a higher count indicating a shorter survivaltime in some studies.

Age, sex and weight of animals have no prognosticsignificance and neither does the presence of hyper-

LEUKAEMIA

The term leukaemia is restricted to haematopoietictumours which are derived from bone marrow andthese may be of lymphoid or non-lymphoid origin.They may be classified according to the degree ofmaturity of the cell type involved as either:

• Acute; or• Chronic.

Acute leukaemias arise from the neoplastic trans-formation and subsequent proliferation of earlyhaematopoietic precursor cells, leading to the arrestof normal cell lineage differentiation. Chronicleukaemias arise from the neoplastic transforma-tion of late precursor cells leading to proliferationof fairly well differentiated cells. Thus, leukaemiaderived from lymphoid series can be classified aseither acute lymphoblastic leukaemia (ALL) orchronic lymphocytic leukaemia (CLL). Leukaemiaderived from the non-lymphoid series is more vari-able and difficult to classify, particularly in cats. Thedisease frequently evolves from one line to anotherso that one, several or all non-lymphoid cell linesmay be affected. Although terms such as acutemyeloid leukaemia (AML) and chronic granulo-cytic leukaemia (CGL) are used, the non-lymphoidleukaemias are often grouped together under theterm ‘myeloproliferative disease’.

Lymphoid and myeloid leukaemias

The leukaemias included in this section are ALLand CLL, AML and CGL and the monocytic andmyelomonocytic leukaemias.

Epidemiology

Acute leukaemias account for less than 10% of all canine haematopoietic neoplasms with acute

myeloid cases exceeding acute lymphoid cases in a3 : 1 ratio (Couto 1992). Affected dogs are usuallyyoung to middle aged (mean 5–6 years for ALL)but the range is wide (1–12 years). More males thanfemales may be affected (3 : 2 ratio) but there is nobreed predisposition. Chronic leukaemias are lesscommon than acute leukaemias in dogs, with casesof chronic lymphocytic leukaemia (CLL) dramati-cally exceeding those of chronic granulocyticleukaemia (CGL). Most animals are middle-agedto old (mean 9.4 years for CLL) and although a sexratio of male to females of 2 : 1 is reported for CLL,there is no breed predisposition.

In cats, leukaemias are more common, account-ing for approximately one third of haematopoietictumours (Theilen & Madewell 1987). Approxi-mately two thirds of cases are myeloid (Couto1992). Of the lymphoid leukaemias, ALL predomi-nates with CLL occurring more rarely.

Aetiology

The aetiology of canine leukaemias is unknownalthough a lentivirus has been isolated from oneleukaemic dog (Safran et al. 1992). Ionising radia-tion and benzene exposure are proposed for humanALL (Leifer & Matus 1985) and genetic factors for human CLL. There is also an association ofhuman CLL with auto-immune disease suggestingan immunological aberration (Leifer & Matus1985, 1986).

In cats, FeLV plays an important role in leukae-mogenesis since 90% of lymphoid and myeloidleukaemias are FeLV positive. Other factors may beinvolved, however, since experimental infectionwith FeLV only causes a low incidence of myelo-proliferative disease. Chromosomal aberrationshave been reported in feline leukaemia, in both


FeLV positive and FeLV negative cells (Grindem &Bouen 1989; Gulino 1992). It has been proposedthat virus infection may cause proliferation ofhaematopoietic cells, which increases the risk ofchromosomal aberrations occurring and it is thesewhich trigger cell transformation. FIV may also beresponsible for some cases of myeloproliferativedisease, on its own or in conjunction with FeLV(Hutson et al. 1991).

Pathology

Acute and chronic leukaemias may arise from lymphoid or non-lymphoid cell lineages (Table15.11). The distinction between acute and chronic forms is not always precise and some lymphoidleukaemias with predominantly well differentiatedcells may also have immature forms, making it diffi-cult to predict how the disease may progress.

For many acute leukaemias, the cells may appearso undifferentiated that it is impossible to decidewhether they are lymphoid or myeloid withoutresorting to special cytochemical or immunocyto-chemical stains or flow cytometric studies. Use of such stains has shown that many leukaemias previously thought to be lymphoid are, in fact,myeloid and that many myeloid leukaemias showmonocytic differentiation. Depending on the celltype involved, acute myeloid leukaemias can be

divided into acute myelogenous without differen-tiation (AML), acute monocytic/monoblastic(AMoL) or acute myelomonocytic (AMML)leukaemias.

In cats, the involvement of multiple haemato-poietic cell lines is common and the distinctionbetween myeloid leukaemia and other myelopro-liferative diseases is less clear. This is undoubtedlyrelated to the fact that cell lines derive from acommon pluripotent myeloid stem cell which maydifferentiate along various pathways. Erythremicmyelosis, for example, may progress to either ery-throleukaemia or AML in the cat.

Tumour behaviour

Acute leukaemias are characterised by aggressivebiological behaviour and rapid progression. Theearly blast cells proliferate in the bone marrow atthe expense of normal haematopoiesis, spilling overinto the blood and infiltrating peripheral organs,e.g. spleen, liver, lymph nodes, bone and nerves.Massive leucocytosis may cause signs of hypervis-cosity due to aggregate formation and thrombosisin brain and lungs. Occasionally, neoplastic cells are restricted to the marrow and are not seen inperipheral blood. This is known as an aleukaemicor smouldering leukaemia. Acute leukaemias areusually characterised by severe myelosuppression,i.e. anaemia, thrombocytopenia and lymphopeniaor granulocytopenia, and increased susceptibility to infection due to reduced humoral and cellularimmunity.

Chronic leukaemias, on the other hand, are char-acterised by slow progression and relatively mildclinical signs. As for acute leukaemias, the neo-plastic cells proliferate in the bone marrow at theexpense of normal haematopoiesis, enter the bloodand infiltrate peripheral organs, but the degree ofmyelosuppression is much milder. With CGL, pro-liferation of blast cells rather than mature cells (a blast cell crisis) may occur as a terminal event,months to years after diagnosis. Secondary infec-tions due to reduced humoral and cellular immu-nity may also occur.


A monoclonal gammopathy is associated with 25%of cases of canine CLL although 10% of cases mayhave reduced immunoglobulin levels. A hypervis-

Table 15.11 Classification of leukaemias.

Acute Chronic

LymphoidAcute lymphoblastic Chronic lymphocytic

leukaemia leukaemia

Non-lymphoidAcute myeloid leukaemia Chronic granulocytic

leukaemiaAcute myelomonocytic

leukaemiaAcute monocytic leukaemiaErythremic myelosis Primary erythrocytosis

(erythroleukaemia) (polycythemia vera)Megakaryocytic leukaemia Primary (essential)

thrombocythemiaBasophilic leukaemiaEosinophilic leukaemiaMast cell leukaemia


cosity syndrome is associated with polycythemiavera.

Presentation/signs

Acute leukaemias present with:

• Non-specific signs including weakness, lethargy,anorexia, vomiting and diarrhoea, pyrexia (morecommon in AML) or pallor

• Mild lymphadenopathy (much less obvious thanwith lymphoma), splenomegaly or hepatomegalymay be noted

• Haematological complications may cause bleed-ing, bruising, joint swelling (haemarthrosis) orDIC (more common in AML).

Other possible signs include:

• Shifting lameness, bone pain (more common inAML)

• Ocular lesions such as retinal and conjunctivalhaemorrhage, hyphaema, glaucoma, retinal infiltrates (more common in AML)

• Neurological signs, neuropathies, paresis (morecommon in ALL)

• Secondary infections, e.g. skin lesions.

Half of all cases of CLL may be asymptomatic and only detected on haematological examination.The remaining cases of CLL and all of CGL showmild, progressive disease with vague signs such aslethargy, anorexia, vomiting, pyrexia, polyuria,polydipsia, weight loss, pallor, mild lymphadeno-pathy (more common in CLL), splenomegaly orhepatomegaly, skin infiltration or hyperviscositysyndrome.

Investigations

A tentative diagnosis of leukaemia may be made,based on clinical signs and haematological assess-ment (Fig. 15.13), but a definitive diagnosis requiresexamination of the bone marrow to demonstrateneoplastic changes in one or more of thehaematopoietic cell series (Figs 15.10, 15.11 and15.12).

FeLV/FIV testsAll cats suspected of having leukaemia/myelopro-liferative disease should be tested for FeLV antigenand FIV antibodies.

Fig. 15.10 Bone marrow aspirate from dog with AML,showing large undifferentiated myeloblasts. (See alsoColour plate 30, facing p. 162.)

Fig. 15.11 Bone marrow aspirate from dog with ALL.The smear is dominated by medium to large lym-phoblasts with very little normal erythroid or myeloidactivity. (See also Colour plate 31, facing p. 162.)

BloodsHaematological evaluation is needed to detect non-regenerative anaemia, thrombocytopenia orneutropenia resulting from myelosuppression(usually more severe cytopenias in acute thanchronic leukaemias). Atypical neoplastic cells maybe detected in the circulation, i.e. lymphoblasts in ALL, myeloblasts in AML, monoblasts in AMoL, and increased numbers of lymphocytes inCLL or granulocytes in CGL with a left shift to myelocytes or occasionally myeloblasts. Withacute leukaemia, a coagulation profile should becarried out to assess clotting function and to lookfor DIC.


Fig. 15.12 Bone marrow aspirate from dog with CLL.The marrow contains unusually high numbers of smalllymphoid cells but normal erythroid and myeloid pre-cursors are also present. (See also Colour plate 32,facing p. 162.)

Fig. 15.13 Capillary tubes showing high buffy coatlayer; massive leucocytosis may be a feature of somecases of leukaemia.

Biochemical evaluation should include elec-trolytes to detect hypercalcaemia, liver enzymes to detect liver dysfunction and BUN/creatinine to detect renal dysfunction. Total protein levels and serum electrophoresis are required to detectmonoclonal gammopathy in CLL.

Imaging techniquesAbdominal radiography and ultrasonography areuseful to confirm hepatosplenomegaly but fineneedle aspirates or biopsy are necessary to see ifthis is due to a neoplastic infiltrate.

Biopsy/FNACytological examination of bone marrow aspiratesfrom leukaemic cases is essential to:

• Confirm the diagnosis of leukaemia• Assess the degree of normal haematopoiesis• Determine whether there is a predominance of

blast cells (acute leukaemia) or a proliferation of mature lymphoid or myeloid cells (chronicleukaemia).

Special cytochemical and immunocytochemicalstains are essential to differentiate blast cell lineagein acute leukaemia since many leukaemias diag-nosed as lymphoid are often found to be myeloid on the basis of such stains. The immunopheno-type of leukaemias may also be determined by immunocytochemical staining and flow cytometricstudies of blood or marrow aspirates (Vernau &Moore 1999).

Staging

No specific staging system is used for leukaemiccases.

TreatmentSurgerySurgery is not generally indicated for leukaemiccases.

RadiotherapyRadiotherapy is not generally indicated forleukaemic cases. Irradiation of the bone marrow isassociated with side-effects considered unaccept-able in animals.


improvements in the treatment of acuteleukaemias, but as yet these agents are not avail-able commercially.

Drugs recommended for ALL are similar tothose for lymphoma, i.e. vincristine and pred-nisolone plus an alkylating agent or another drug. Treatment of AML, however, is based on cytosine arabinoside to encourage differentiationof the blast cells, with either prednisolone, mercap-topurine or thioguanine. Induction protocols foracute leukaemia are given in Table 15.12. These are used until the white blood cell count returns to within the normal range and blast cells are nolonger seen in peripheral blood. In theory, drugdoses and frequencies can then be reduced to main-tenance levels, but in practice this is rarelyachieved.

Treatment with cytotoxic drugs is usually recom-mended for chronic leukaemia although frequent

ChemotherapyChemotherapy is the treatment of choice forleukaemia although the response to treatmentvaries considerably with the type of leukaemia.Specific therapy is aimed at destroying theleukaemic cells and allowing normal haemato-poiesis to resume and this is more readily achieved with chronic than acute leukaemias. Thedegree of myelosuppression which is present with most acute leukaemias restricts the use of chemotherapeutic drugs because of the inability to preserve sufficient levels of normalblood cells during treatment. Intensive medicalcare, bone marrow transplants and extracorporealtreatment of bone marrow are used in human medicine but are not available, nor are they deemed acceptable, for veterinary use. The development of canine and feline recombinant G-CSF and GM-CSF could lead to significant

Table 15.12 Chemotherapy protocols for the treatment of acute leukaemia.

Acute lymphoblastic leukaemia (ALL)

Basic induction protocolVincristine 0.5 mg/m2 intravenously every 7 daysPrednisolone 40 mg/m2 by mouth daily for 7 days, then 20 mg/m2 every 48 hours

Additional agentsCyclophosphamide 50 mg/m2 by mouth every 48 hours* (see Table 15.7)Cyclophosphamide and 50 mg/m2 by mouth every 48 hours* (see Table 15.7)

cytosine arabinoside 100 mg/m2 subcutaneously or intravenously daily for 2 days (cats) or 4 days (dogs) (use divided doses if given intravenously)

L-Asparaginase 10 000–20 000 IU/m2 intramuscularly every 2–3 weeks

Acute myeloid leukaemia (AML)

Basic protocolCytosine arabinoside 100 mg/m2 subcutaneously or intravenously daily for 2–6 days

Additional agentsPrednisolone 40 mg/m2 by mouth daily for 7 days, then 20 mg/m2 every 48 hours6-Thioguanine 50 mg/m2 by mouth daily or every 48 hours6-Thioguanine and 50 mg/m2 by mouth daily or every 48 hours

doxorubicin 10 mg/m2 intravenously every 7 daysMercaptopurine 50 mg/m2 by mouth daily or every 48 hours

Alternative protocolsCytosine arabinoside 5–10 mg/m2 subcutaneously twice daily for 2–3 weeks, then on alternate weeksDoxorubicin 30 mg/m2 (dogs) or 20 mg/m2 (cats) intravenously every 3 weeks or 10 mg/m2 every 7 days

MaintenanceAny of the above combinations of drugs used for induction reduced to a dose and frequency which maintain whiteblood cell counts within the normal range


monitoring and haematological screens withoutactual therapy may be sufficient for asymptomaticcases of CLL. The alkylating agent chlorambucilcombined with prednisolone is the usual therapyfor CLL, whereas the drug of choice for CGL iseither hydroxyurea or busulphan (Table 15.13).Theaim is to restore the peripheral blood counts towithin the normal range and response to treatmentis monitored by haematological findings. Onceremission is achieved, maintenance therapy is con-tinued at reduced doses and frequencies of theappropriate drugs, in order to keep the white bloodcell counts within the normal range.

OtherParaneoplastic complications such as hypercal-caemia and hypergammaglobulinaemia may needto be addressed before specific chemotherapy commences (see Chapter 2). In addition, varioussupportive measures may be needed for acuteleukamias such as fluid therapy for dehydration oranorexia, blood transfusion for severe loss of red

cells or platelets, and antibiotic therapy for sec-ondary infections.

Prognosis

The prognosis for all acute leukaemias is poor dueto:

• Failure to induce and maintain remission• Organ failure which enhances the cytotoxic

effects of the drugs• Septicaemia secondary to the disease or

treatment• DIC.

The prognosis for dogs with ALL is slightly betterthan for AML; 20–40% of cases of ALL go intoremission, usually with short survival timesbetween one and three months (Couto 1992) butoccasionally for longer (MacEwen et al. 1977;Matus et al. 1983; Gorman & White 1987). Survivaltimes for AML rarely exceed three months (Couto1985; Grindem et al. 1985). The prognosis for

Table 15.13 Chemotherapy protocols for chronic leukaemia.

Chronic lymphocytic leukaemia (CLL)

Basic induction protocolChlorambucil 2–5 mg/m2 by mouth daily for 7–14 days, then 2 mg/m2 every 48 hours or 20 mg/m2 by

mouth as a single dose every 14 days± Prednisolone 40 mg/m2 by mouth daily for 7 days, then 20 mg/m2 every 48 hours

Additional agentVincristine 0.5 mg/m2 intravenously every 7 days

Alternative protocolsVincristine 0.5 mg/m2 intravenously every 7 daysCyclophosphamide 50 mg/m2 by mouth every 48 hours*Prednisolone 40 mg/m2 by mouth daily for 7 days, then 20 mg/m2 every 48 hoursVincristine 0.5 mg/m2 intravenously every 14 days (weeks 2 and 4)Cyclophosphamide 200–300 mg/m2 by mouth or intravenously every 14 days (weeks 1 and 3)Prednisolone 40 mg/m2 by mouth daily for 7 days, then 20 mg/m2 every 48 hours

Chronic myeloid leukaemia (CML)Hydroxyurea 50 mg/kg by mouth daily for 1–2 weeks, then every 48 hours, or 80 mg/kg by mouth every

3 days until remission achieved, or 1 g/m2 by mouth daily until remission achievedBusulphan 2–6 mg/m2 by mouth daily until remission achieved

MaintenanceAny of the above combinations of drugs used for induction reduced to a dose and frequency which maintain whiteblood cell counts within the normal range

* see Table 15.7.


and polycythaemia vera which is rare in both dogs and cats. Erythremic myelosis is character-ised by excessive proliferation of early erythroid precursors and nucleated red blood cells in bone marrow with severe anaemia, increasednumbers of circulating nucleated red blood cells, moderate to marked anisocytosis, andincreased mean corpuscular volume. Transforma-tion of erythremic myelosis to erythroleukaemiamay occur. Essentially, this is very similar to erythremic myelosis but myeloblasts are present in low numbers along with the erythroid precursors.

Polycythemia vera or primary erythrocytosis israre in both cats and dogs and must be distin-guished from relative and secondary absolute polycythemia and is characterised by persistentlyelevated PCV (65–85%) with low or normal ery-thropoietin activity. There is proliferation of theerythroid series with differentiation to mature redblood cells. Repeated phlebotomy and replacementof blood with colloids and electrolyte solutions maybe necessary (see Chapter 2) but a more gradualreduction in the PCV can be obtained usinghydroxyurea.

Myelodysplastic syndromes(preleukaemia)

Myelodysplastic syndromes are vague clinical con-ditions presenting as lethargy, anorexia, depressionand pyrexia and are associated with bone marrowwhich is normocellular or hypercellular but notovertly neoplastic. They are relatively common incats (80% FeLV positive) but less common in dogs.Maturation arrest of granulocytes and increasednumbers of immature precursors are seen. Thebone marrow changes may be reflected by haema-tological abnormalities such as cytopenias or presence of bizarre cells in the blood and physical findings may include pallor, hepatosplenomegaly,lymphadenopathy, recurrent infections or weightloss. These changes may wax and wane, withoutever progressing, but a proportion of cases willdevelop into aleukaemic leukaemia or overtmyeloid leukaemia eventually. In cats, this is lesslikely since many are euthanased because of theirFeLV status.

Treatment of such preleukaemic conditions with

chronic leukaemias in dogs is much morefavourable than for acute leukaemias. Mean andmedian survival times for CLL may exceed oneyear (Leifer & Matus 1985, 1986) but are usuallyshorter for CGL, which has a greater risk of blastcell crisis.

In cats, fewer cases of leukaemia (27%) than lymphoma (64%) respond to chemotherapy whengiven a COP protocol (Cotter 1983). In general, sur-vival times are better for ALL (one to sevenmonths) than AML (two to ten weeks) (Couto1992). Responses to treatment for CLL are goodbut reports of CGL are scarse.

Other myeloproliferative diseases

Eosinophilic and basophilic leukaemia

Eosinophilic and basophilic leukaemias are rarelyreported in the dog and cat but are characterisedby high white blood cell counts with a high proportion of either basophils or eosinophils.Eosinophilic leukaemias are difficult to distinguishfrom other hypereosinophilic syndromes andbasophilic leukaemias are often confused with mastcell leukaemias. Treatment of both leukaemias iswith corticosteroids or hydroxyurea.

Megakaryoblastic leukaemia/primarythrombocytosis

Megakaryoblastic or megakaryocytic leukaemia israre in dogs and cats and may be associated withplatelet dysfunction. Abnormal megakaryocytichyperplasia is seen in the bone marrow and throm-bocytosis or thrombocytopenia may be present.Primary thrombocytosis or essential thrombo-cythemia has also been infrequently reported, andis characterised by excessively high platelet counts,bizarre giant platelets with abnormal granulationand increased numbers of megakaryocytes in thebone marrow. It must be distinguished from sec-ondary or reactive thrombocytosis.

Erythroid leukaemias

These include erythremic myelosis and erythro-leukaemia which are relatively common in cats,


chemotherapy is contraversial since not all willprogress to full leukaemia, but regular monitoringand supportive therapy with fluids and antibiotics

is recommended. Differentiating agents (cytosinearabinoside), haematopoietic growth factors oranabolic steroids may also be tried.

MULTIPLE MYELOMA

Epidemiology

Multiple myeloma accounts for 8% of haematopoi-etic tumours and 4% of all bone tumours but lessthan 1% of all canine malignant tumours. It occursin older dogs (mean 8.3 years, range 2–15 years) butthere is no sex or breed predisposition.

Plasma cell myeloma is very rare in the cat andrepresent less than 1% of all haematopoietictumours. Affected cats are generally old (range6–13 years) but there is no sex predisposition.

Aetiology

No aetiology has been proposed for multiplemyeloma in the dog or cat although chronic antigenstimulation associated with desensitisation of aller-gies has been implicated in man. C type retroviruseshave been implicated in mice but not cats, andfeline cases are generally FeLV negative (MacEwen& Hurvitz 1977; Matus & Leifer 1985).

Pathology and tumour behaviour

Multiple myeloma arises from the neoplastic proliferation of plasma cells (B lymphocytes) pre-dominantly in bone marrow (Fig. 15.14), althoughspill over into blood and infiltration of peripherallymphoid organs may occur. In classical cases theplasma cells retain their secretory function andproduce monoclonal immunoglobulin (sometimescalled the M protein). IgA and IgG have equalprevalence in canine multiple myeloma (Hammer& Couto 1994) whereas production of IgM is oftencalled primary macroglobulinaemia.

Abnormal immunoglobulin coats red blood cellscausing a Coombs’ positive anaemia and occasion-ally haemolysis. Antibody coating of platelets leadsto poor platelet aggregation, release of plateletfactor 3 and inhibition of coagulation protein func-tion resulting in bleeding disorders and hypervis-cosity syndrome. Hyperviscosity is usually

associated with IgM which is the largestimmunoglobulin molecule, or with IgA dimerswhich can polymerise. As well as inhibitinghaemostasis, increased blood viscosity reducesoxygen perfusion due to sludging of blood vesselsin the vasculature, and interferes with cardiac func-tion due to increased peripheral resistance. Normalimmunoglobulin levels are depressed in multiplemyeloma and this results in impaired phagocytosis,granulocytopenia and depressed cell mediatedimmunity, which cause an increased susceptibilityto infection.

Immunoglobulin light chains, known as Bence-Jones proteins, are excreted in urine, and later in the disease albumin is also lost as glomerulardamage proceeds. Renal tubular damage may becaused by several mechanisms such as directplasma cell infiltration or hypercalcaemia, but mostdamage results from reabsorption and catabolismof immunoglobulin molecules by the tubular cells.As tubules are damaged and more light chainsexcreted, they precipitate to form casts whichimpair renal function even more. Pyelonephritis iscommon due to an increased susceptibility to infec-

Fig. 15.14 Bone marrow aspirate from dog with mul-tiple myeloma, showing a cluster of plasma cells, somewith secretory vacuoles in their cytoplasm. (See alsoColour plate 33, facing p. 162.)


tion but glomerular amyloidosis, although presentin humans, is rare in dogs.

Proliferation of neoplastic plasma cells in themarrow may cause myelosuppression resulting inanaemia, thrombocytopenia and leucopenia. It mayalso produce skeletal lesions, usually in long bonesor vertebrae, due to increased osteoclast activity.Occasionally a solid plasma cell mass may occur, forexample in the extra-dural space, leading to spinalcompression.


Numerous paraneoplastic syndromes may accom-pany multiple myeloma. Hypergammaglobuli-naemia causes bleeding disorders in a third ofcanine cases and hyperviscosity syndrome in 20%of cases. Hypercalcaemia may occur in 15–20% ofcases and polyneuropathy has also been reported(Villiers & Dobson 1998).

Presentation/signs

Affected animals usually present with non-specificsigns including pyrexia, pallor, lethargy or depres-sion. They may have a mild lymphadenopathy orhepatosplenomegaly. Cases with bleeding disordersmay have epistaxis, gingival bleeding, bruising,petechiae, echymoses or gastro-intestinal bleeding(Figs 15.15 and 15.16) while those with hypervis-cosity may also show:

• Cerebral dysfunction (ataxia, dementia, coma)• Ocular changes or sudden blindness (retinal

detachment, venous dilation and tortuosity)• Congestive heart failure (exercise intolerance,

syncope, cyanosis).

Some animals may present with signs of hypercal-caemia (Chapter 2) or renal failure, while otherswith skeletal lesions (over 50% of cases) may showlameness, pain, paresis or pathological fracture.

Investigations

Bloods

Haematological evaluation is essential for cases ofsuspected multiple myeloma. Abnormalities likelyto be detected include a mild to moderate non-

regenerative anaemia (70% canine cases) or aCoombs’ positive anaemia, leucopenia (25% caninecases), thrombocytopenia (16–30% canine cases) orperipheral plasmacytosis (10% canine cases). Coag-ulation parameters should also be assessed todetect bleeding diatheses.

Hyperproteinaemia will invariably be detectedon biochemical evaluation and an assessment of thealbumin : globulin ratio will give an indication of the

Fig. 15.15 Retinal haemorrhages may be a feature of myeloma as a result of hyperviscosity or thrombo-cytopenia. (Courtesy of Mr M. Herrtage, Departmentof Clinical Veterinary Medicine, Cambridge) (See alsoColour plate 34, facing p. 162.)

Fig. 15.16 Petechiation of mucous membranes due tothrombocytopenia associated with multiple myeloma.(See also Colour plate 35, facing p. 162.)


degree of immunoglobulin secretion and albuminloss. Serum protein electrophoresis should be doneto differentiate a monoclonal from a polyclonalgammopathy. BUN and creatinine are needed toassess renal function which is impaired in a third ofcases, and electrolyte analysis should be performedto look for hypercalcaemia.

Urinalysis

Urinalysis is necessary to look for proteinuriacaused by renal damage and Bence Jones proteins.Although albumin is detected using a dipstick,Bence Jones light chains must be detected by a heat precipitation test. The chains precipitate at40–60°C, dissolve on boiling and reform a precipi-tate on cooling. Urine electrophoresis should reflectthe monoclonal gammopathy seen on serum electrophoresis.

Imaging techniques

Radiography is useful in multiple myeloma cases toscreen vertebrae, pelvis and long bones for skeletallesions. These may appear as localised multiplepunctate lesions or generalised osteoporosis (Fig. 15.17).

Biopsy/FNA

Cytological examination of bone marrow aspiratesis necessary to look for sheets of neoplastic plasmacells and to assess the degree of myelosuppression.In cases of multiple myeloma, plasma cells usuallyaccount for 5–10% of bone marrow cells.

None of the above investigations are satisfactory

Fig. 15.17 Lateral radiograph of the lumbar spine of adog with multiple myeloma, showing punched outosteoltic lesions.

on their own to make a diagnosis of multiplemyeloma. A definitive diagnosis requires three ofthe following four parameters:

• Plasma cells in the bone marrow• Osteolytic bone lesions• Monoclonal immunoglobulin in serum or urine• Bence-Jones proteinuria.

Staging

There is no TNM or clinical staging system for mul-tiple myeloma.

Treatment

Surgery

Surgical treatment is not usually needed for multiple myeloma except to repair pathologicalfractures.

Radiotherapy

Radiotherapy may be used to treat localised bonelesions and give pain relief but there is a danger ofinducing a pathological fracture if the bone is verylytic.

Chemotherapy

Specific treatment for multiple myeloma uses com-bination chemotherapy based on alkylating agents(melphalan or cyclophosphamide) and corticos-teroids to target the neoplastic plasma cells (Table15.14). The response to treatment is assessed bymonitoring total protein levels and the presence of a monoclonal spike on serum protein elec-trophoresis. Examination of bone marrow aspiratesmay also be used. Once the immunoglobulin concentration is within normal limits, drug dosesand frequency are reduced to a maintenance level which keeps the immunoglobulin within theselimits.

Other

For cases presenting with hypercalcaemia, immedi-ate supportive therapy may be needed to maintain


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Table 15.14 Chemotherapy protocols for the treatment of multiple myeloma.

Induction

Basic protocolMelphalan 2.0 mg/m2 by mouth daily for 7–14 days, then every 48 hours**Prednisolone 40 mg/m2 by mouth daily for 7–14 days, then 20 mg/m2 every 48 hours

Additional agent(if response is inadequate)

Vincristine 0.5 mg/m2 intravenously every 7 days

Alternative protocols(if response is inadequate)

Cyclophosphamide 50 mg/m2 by mouth every 48 hours*Prednisolone 40 mg/m2 by mouth daily for 7–14 days, then 20 mg/m2 every 48 hours± Vincristine 0.5 mg/m2 intravenously every 7 daysorChlorambucil 2–5 mg/m2 by mouth every 48 hoursPrednisolone 40 mg/m2 by mouth daily for 7–14 days, then 20 mg/m2 every 48 hours± Vincristine 0.5 mg/m2 intravenously every 7 days

MaintenanceUse prednisolone in combination with either melphalan, cyclophosphamide or chlorambucil at a dose rate andfrequency sufficient to maintain plasma immunoglobulin concentration within normal limits

* see Table 15.7.** Alternative dose for cats is 0.1 mg/kg orally for 10 days, then 0.05 mg/kg daily.

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Further reading

Carter, R.F., Harris, C.K., Withrow, S.J., Valli, V.E.O. &Susaneck, S.J. (1987) Chemotherapy of canine lym-phoma with histopathological correlation: doxorubicinalone compared to COP as first treatment regimen.Journal of the American Animal Hospital Association,(23), 587–96.

Cotter, S.M. (1983) Treatment of lymphoma and leukemiawith cyclophosphamide, vincristine, and prednisolone:I. Treatment of dogs. Journal of the American AnimalHospital Association, (19), 159–65.

Cotter, S.M. (1986) Clinical management of lymphopro-liferative, myeloproliferative, and plasma cell neopla-sia. In: Contemporary Issues in Small Animal Practice6, Oncology, (ed. N.T. Gorman), pp. 169–94. ChurchillLivingstone, London.

Couto, C.G. (1985) Canine lymphomas: something old,something new. The Compendium of Continuing Edu-cation for the Practising Veterinarian, (7), 291–302.

Couto, C.G., Rutgers, H.C., Sherding, R.G. & Rojko, J.(1989) Gastrointestinal lymphoma in 20 dogs. Journalof Veterinary Internal Medicine, (3), 73–8.

Crow, S.E. (1982) Lymphosarcoma (malignant lym-phoma) in the dog: diagnosis and treatment. The Com-pendium of Continuing Education for the PractisingVeterinarian, (4), 283–92.

Dobson, J.M. & Gorman, N.T. (1993) Canine multicentriclymphoma 1: Clinicopathological presentation of the disease. Journal of Small Animal Practice, (34),594–8.

Facklam, N.R. & Kociba, G.J. (1986) Cytochemical char-acterisation of feline leukemic cells. Veterinary Pathol-ogy, (23), 155–61.

Grindem, C.B., Perman, V. & Stevens, J.B. (1985) Mor-

phological classification and clinical and pathologicalcharacteristics of spontaneous leukemia in 10 cats.Journal of the American Animal Hospital Association,(21), 227–36.

Hahn, K.A., Richardson, R.C., Teclaw, R.F., Cline, J.M.,Carlton, W.W., DeNicola, D.B. & Bonney, P.L. (1992) Ismaintenance chemotherapy appropriate for the man-agement of canine malignant lymphoma? Journal ofVeterinary Internal Medicine, (6), 3–10.

Hardy, W.D. (1981) Haematopoietic tumors of cats.Journal of the American Animal Hospital Association,(17), 921–40.

Jeglum, A.K., Whereat, A. & Young, K. (1987)Chemotherapy of lymphoma in 75 cats. Journal of the American Veterinary Medical Association, (190),174–8.

Leifer, C.E. & Matus, R.E. (1986) Canine lymphoma:clinical considerations. Seminars in Veterinary Medicineand Surgery (Small Animal), (1), 43–50.

Loar, A.S. (984) The management of feline lympho-sarcoma. Veterinary Clinics of North America: SmallAnimal Practice, (14), 1299–330.

MacEwen, E.G., Brown, N.O., Patnaik, A.K., Hayes, A.A.& Passe, S. (1981) Cyclic combination chemotherapy ofcanine lymphosarcoma. Journal of the American Veteri-nary Medical Association, (178), 1178–81.

Madewell, B.R. (1975) Chemotherapy for canine lym-phosarcoma. American Journal of Veterinary Research,(36), 1525–8.

Mooney, S.C., Hayes,A.A., Matus, R.E. & MacEwen, E.G.(1987) Renal lymphoma in cats: 28 cases (1977–1984).Journal of the American Veterinary Medical Associa-tion, (191), 1473–7.

Ogilvie, G.K. (1993) Recent advances in cancer,chemotherapy and medical management of the geri-atric cat. Veterinary International, (5), 3–12.

Price, G.S., Page, R.L., Fischer, B.M., Levine, J.F. & Gerig,T.M. (1991) Efficacy and toxicity of doxorubicin/cyclophosphamide maintenance therapy in dogs with multicentric lymphosarcoma. Journal of VeterinaryInternal Medicine, (5), 259–62.

Rosenthal, R.C. & MacEwen, E.G. (1990) Treatment oflymphoma in dogs. Journal of the American VeterinaryMedical Association, (196), 774–81.

Weller, R.E. & Stann, S.E. (1983) Renal lymphosarcomain the cat. Journal of the American Animal HospitalAssociation, (19), 363–7.

16The Eye and Orbit

may also be a site for secondary tumours or may beinvolved in systemic neoplastic disease, e.g. multi-centric lymphoma.

Aetiology

The aetiology of most ocular tumours is not known.Prolonged exposure to sunlight is important in thedevelopment of SCC of the eyelids in white catsand possibly in some dogs, as previously described(Chapter 1). Previous trauma and/or chronicinflammation have been reported to incite invasiveocular sarcomas in cats (Dubielzig et al. 1990).Genetic factors are known to be important in thedevelopment of retinoblastoma in children wherethe role of the hereditary retinoblastoma gene (Rb)is well documented. However retinoblastoma isvery rare in domestic species.

Epidemiology

The eye is not a common site for development oftumours in cats and dogs, neither are tumours acommon cause of ocular disease in these species.Nevertheless, tumours of the eye and surroundingstructures are important because of the threat theymay pose to the patient’s vision, quality of life andsurvival. The eyelids are the most common site forocular tumours in the dog and the majority of thesetumours are benign. Tumours of the eyelids andconjunctiva are less common in cats but there is ahigher incidence of malignant tumours, especiallySCC. Tumours of the third eyelid are rare in bothcats and dogs. Primary intraocular tumours are notcommon in either species, although a variety oftumours have been described affecting the cornea,sclera, iris and ciliary body (Table 16.1). The eye

� Tumours of the eyelid and conjunctiva, 252� Tumours of the orbit, 256� Ocular tumours, 258

252

TUMOURS OF THE EYELID AND CONJUNCTIVA

Pathology

Meibomian (sebaceous) gland adenomas are themost common tumour affecting the eyelids in the

dog, accounting for 60% of eyelid tumours in onestudy (Roberts et al. 1986).They tend to affect olderanimals; no sex predisposition has been reported.These tumours arise from the meibomian glandssited at the eyelid margin. Most are benign,

The Eye and Orbit 253

although occasionally meibomian gland adenocar-cinoma is reported. Viral papillomas may occur inyounger dogs and SCC in older animals. SCC is themost common tumour of the eyelid in cats. Othertumours of the skin, for example mast cell tumours,basal cell tumours and melanoma, may affect theskin of the eyelids and epitheliotrophic lymphomamay affect the mucocutaneous junction of the lidmargin (Chapters 4 and 15).

Tumours of the third eyelid and conjunctivae arerare but melanoma, haemangioma, histiocytoma,adenoma, adenocarcinoma and basal and squa-mous cell tumours may arise at this site, as may,rarely, mast cell tumours. Secondary involvementfrom multicentric lymphosarcoma may be seen asa bilateral nodular form affecting the third eyelid(Fig. 16.1) or a more diffuse inflamed and swollen

Table 16.1 Summary of tumours affecting the eye and orbit.

Site

Extraocular Eyelids SCC and BCC – cats and dogsMeibomian/sebaceous gland adenoma (adenocarcinoma) – dogsMelanomaMCT and other skin tumours

Third eyelid Primary tumoursMelanomaHaemangiomaBCC and SCCAdenoma/adenocarcinomaViral papilloma

SecondaryLymphoma

Conjunctiva SCCMelanomaSystemic histiocytosis

Orbit Primary connective tissue tumours, e.g. rhabdomyosarcoma, fibrosarcomaPrimary tumours of skull, e.g. multilobular osteochondrosarcomaLocal invasion by tumours of nasal cavity, frontal sinus and caudal maxilla

Optic nerve Optic nerve meningioma

Ocular Cornea and sclera Melanoma (limbal or epibulbar)SCC

Iris and ciliary body Ciliary body adenoma/adenocarcinomaMulticentric lymphomaMelanomaMedulloepitheliomaMetastatic tumours (mammary carcinoma, haemangiosarcoma, malignant

melanoma)Retina and choroid (Retinoblastoma)

(Melanoma)

Fig. 16.1 Lymphoma presenting as raised nodules onthe third eyelid in a dog.


conjunctiva (Fig. 16.2). Ocular signs are also seen in systemic histiocytosis, a rare familial condition inthe Bernese mountain dog. In addition to skinlesions (Chapter 4) affected animals often showsigns of scleritis, episcleritis and conjunctivitis.Conjunctival biopsies show a diffuse infiltrate ofhistiocytic cells.

Presentation/tumour behaviour/paraneoplastic syndromes

Meibomian gland tumours usually arise on themargin of the eyelid but often extend into theeyelid where they present as a bulging of the con-junctiva (Fig. 16.3). These are slowly growingtumours that range in size from 1–10mm.They maycause ocular irritation or discomfort leading toocular discharge and blepharospasm and may ulti-mately lead to corneal damage and ulceration.Meibomian gland tumours are mostly adenomaswhich are non-invasive and follow a benign course.

SCC of the eyelids is an invasive tumour oftenpresenting as an ulcerated mass causing distortionand destruction of adjacent soft tissues (Figs 16.4and 16.5). Although locally aggressive, the rate ofmetastasis is low.

Melanoma of the eyelid may follow a benigncourse, especially if the tumour is cutaneous,heavily pigmented and well differentiated histolog-ically.Tumours sited at the mucocutaneous junction

of the lid and tumours affecting the conjunctivaetend to be more anaplastic morphologically andmalignant in their behaviour with a high rate ofdistant (haematogenous) metastasis.

Paraneoplastic syndromes are not commonlyassociated with primary tumours of the eyelids.

Fig. 16.2 A dog with multicentric lymphoma withocular involvement causing inflammation of the con-juctiva and sclera.

Fig. 16.3 Meibomian gland adenoma in an Englishspringer spaniel. (Courtesy of Dr S. Petersen-Jones,Department of Small Animal Clinical Sciences, Veteri-nary Medical Centre, Michigan State University.)

Fig. 16.4 A large squamous cell carcinoma affectingthe upper eyelid in a dog.


presentation and as they are non-invasive an exci-sional biopsy would be justified in such cases. Inci-sional or punch biopsies are indicated for ulcerativelesions, suspicious of SCC or other malignanttumours, and for multiple or diffuse lesions prior totreatment.

Staging

There is no staging system specific to the eyelids butthe clinical staging system for tumours of the skin(Table 4.2) is applicable to this site.

Treatment

Surgery

Most solitary tumours of the eyelids are amenableto surgical resection. Cryosurgery may be preferredfor treatment of small, benign lesions as this mayprovide better preservation of the eyelid margin.Cryosurgery may also be used for early, superficial,non-invasive SCC in the cat. In any tumour of theeyelid it is preferable to treat early, upon initialdetection of the problem. Smaller tumours can beresected with minimal damage to the lids; removalof larger tumours may require substantial recon-structive eyelid surgery. In the case of meibomiangland adenoma the surgical resection needs toinclude any extension of the tumour into the con-juctiva. Larger benign tumours that involve lessthan 25% of the margin, may be excised by a par-tial or full thickness wedge resection. Radical sur-gical resection is required for carcinomas and other malignant tumours of the eyelid and this will require complex reconstructive techniques(Bedford 1999). Removal of the eye may be con-sidered as a salvage procedure for treatment ofadvanced tumours or those with extensive con-junctival involvement.

Radiotherapy

External beam radiation is rarely used in the treat-ment of periocular tumours because of the damag-ing effects of radiation on the tissues of the eye(Chapter 3). Brachytherapy offers a more localisedform of radiotherapy that may have a role in themanagement of periocular carcinomas. Implanta-tion techniques are not widely used in small animals

Investigations

In the case of meibomian gland tumours and otherprimary tumours of the eyelids a presumptive diagnosis of a neoplasia may be made on clinicalexamination. Lymphoma of the third eyelid or con-junctiva may be confused with inflammatory con-ditions of these tissues.

Bloods

These are not generally indicated in the diagnosisof primary tumours of the eyelids, although theywould be included in the work-up of cases with lymphoma.

Imaging techniques

Radiography/ultrasonography of the primarytumour is not necessary. Thoracic films are impor-tant to look for metastases in cases of malignanttumours, but most tumours at this site have lowmetastatic potential.

Biopsy/FNA

FNAs may be difficult to perform safely at this siteunless the patient is anaesthetised, in which case itis probably preferable to collect a total excisionalbiopsy of the lesion for histological diagnosis. Cyto-logical preparations from impression smears andtissue scrapings are of limited diagnostic value.Many meibomian gland tumours are small at initial

Fig. 16.5 An ulcerated squamous cell carcinoma ofthe third eyelid in a cat.


due to lack of specialist containment facilities,although irridium brachytherapy is used in treat-ment of periocular SCC in horses (Fig. 3.7).Strontium 90 provides a superficial source of radio-therapy which could be applied to perioribitaltumours, but this technique has not been widelyused in small animals.

Chemotherapy

The main indication for chemotherapy in the treat-ment of eyelid tumours is in the management oflymphoma as described in Chapter 15. A creamcontaining a 5% solution of the antimetabolite 5-Fluorouracil is available for topical treatment ofsuperficial squamous and basal cell tumours andhas been used for SCC of the third eyelid in horses.This agent must not be used (even topically) in cats.

Other

Manual expression of meibomian gland adenomasmay release trapped secretions and provide short

term alleviation of ocular discomfort prior to sur-gical management. Photodynamic therapy mayoffer an alternative to surgical excision or cryo-surgery for treatment of early, superficial SCC(Chapter 3).

Prognosis

The prognosis for tumours of the eyelids dependson the histological type. Most meibomian glandtumours are benign and the prognosis followingsurgical resection or cyrosurgery is very good. Theprognosis for early SCC (in both cats and dogs) fol-lowing surgery is also favourable due to the lowrate of metastasis from this site. More advanced andinvasive SCC carry a guarded prognosis as localrecurrence may result from inability to achieve adequate margins of excision. The prognosis formelanoma of the eyelid is guarded because whilemost are benign, a proportion of such tumoursfollow a malignant course with haematogenousmetastasis.

TUMOURS OF THE ORBIT

Tumours of the orbit are not common but neopla-sia is the most common cause of orbital disease.Tumours affecting the orbit may be:

• Primary, usually soft tissue tumours, e.g. fibrosar-coma, mast cell tumour, arising within the retro-bulbar space

• Tumours of the adjacent skull, e.g. osteosarcoma,multilobular osteochondrosarcoma, whichextend into the orbit

• Local extension of tumours arising in the nasalcavity and paranasal sinuses (e.g. nasal carcinoma– dog) and local extension of tumours of the oralcavity (e.g. squamous cell carcinoma – cat).

Most tumours of the orbit are thus malignant.


The behaviour of tumours which may affect theorbit has been discussed in previous chapters:Chapter 4, Skin; Chapter 5, Soft tissues; Chapter 6,Skeletal system; Chapter 7, Head and neck. Para-

neoplastic syndromes are not commonly associatedwith most of these tumours.

Presentation/signs

Most orbital or retrobulbar tumours are relativelyslow growing and usually present as gradual onsetexophthalmos with or without conjunctival swellingor chemosis. This may first be noticed as a widen-ing of the palpebral fissure and is clinicallydetectable as a reduced ability to retropulse theaffected eye. As the globe is gradually displaced bythe increasing retrobulbar mass, deviation of theeye from its normal axis will result in strabismus. Incases where the tumour is anterior to the midpointof the globe its growth may cause enophthalmos,but this would be unusual. Conjunctival swellingand oedema may be marked and in some cases mayobscure the globe. Unless there are secondary com-plications (e.g. corneal ulceration or glaucoma) theeye is not usually painful and this lack of pain is auseful sign to distinguish retrobulbar neoplasiafrom a retrobulbar abscess. However, some retro-


bulbar tumours, e.g. carcinomas that erode into the orbit from adjacent sites, may be more acute inonset than outlined above and these may be asso-ciated with considerable pain. Retrobulbar mastcell tumours can also have a more acute presen-tation due to inflammation mediated through local release of histamine with sporadic massive chemosis.

Investigations

A complete ophthalmic examination with pupildilation is important in the investigation of casespresenting with exophthalmos, as is a full examina-tion of the head and mouth. The main differentialdiagnoses for exophthalmos are:

• Retrobulbar abscess• Foreign body• Cellulitis• Zygomatic salivary gland inflammation or

mucocele.

Bloods

These are not generally indicated in the diagnosisof tumours of the orbit. A neutrophilia with a leftshift might support a differential diagnosis of infec-tion or abscessation, but a similar picture may occurin tumours containing areas of necrosis.

Imaging techniques

Radiography of the skull including the nasal andparanasal sinuses, the orbit and the maxilla may beuseful in the evaluation of tumours involving thesesites. Ultrasound is a more useful technique forevaluation of the soft tissues of the orbit andretrobulbar space (Fig. 16.6). CT or MRI imagescan provide excellent detail of the eye and adjacentstructures (Fig. 16.7).

Biopsy/FNA

FNA is a useful technique in investigation of anorbital lesion. Cytological examination of FNAsamples may at least differentiate between inflam-matory and neoplastic conditions and in some casesprovide a cytological diagnosis (Boydell 1991).Ultrasound guidance for aspirate collection isuseful both to direct the needle to the abnormal

Fig. 16.6 Ultrasonogram of the eye and retrobulbarmass, showing a discrete hyopechoic mass in themedial aspect of the orbit. (Courtesy of Ruth Dennis,Animal Health Trust, Newmarket, previously publishedin Journal of Small Animal Practice (2000), (41),145–55, with permission.)

Fig. 16.7 Contrast enhanced, dorsal plane T1W MRIscan of a cat with an orbital mass. Enhancement offrontal lobe tissue indicates intracranial extension ofthe tumour. The final diagnosis was lymphoma. (Cour-tesy of Ruth Dennis, Animal Health Trust, Newmarket,previously published in Journal of Small Animal Prac-tice (2000), (41), 145–55, with permission.)


tissue and to aid avoidance of the globe, optic nerveand major blood vessels. A needle biopsy (e.g. tru-cut) may be considered if there is a large mass toprovide tissue for histological diagnosis but anexploratory orbitotomy may be preferable for pro-viding representative biopsy material (Slatter &Abdelbaki 1979).

Staging

There is no clinical staging system described fortumours of the orbit in cats or dogs.

Treatment

Surgery

Surgical resection is the theoretical treatment ofchoice for most primary tumours of the orbit, e.g.fibrosarcoma (Gilger et al. 1994). The surgicalapproach will often necessitate removal of the eyeand supporting structures but because of the rela-tively advanced stage of many tumours by the timeof diagnosis, it may not be possible to achieve themargins required for complete eradication of thetumour. Surgical resection of tumours which haveinvaded into the orbit from the nasal or oral cavityis rarely feasible.

Radiotherapy

The use of radiotherapy in the orbit is limited bythe sensitivity of the eye to radiation (Chapter 3).

Radiotherapy may have a role as an adjunct tocytoreductive surgery (including removal of theeye) in the management of locally invasive retro-bulbar tumours, especially soft tissue sarcomas.Radiotherapy has been used alone for treatment ofcarcinomas of the nasal and paranasal sinuses withretrobulbar involvement, but such treatment is onlypalliative and carries a high risk of radiation-induced keratitis, keratoconjunctivitis sicca andcorneal ulceration.

Chemotherapy

With the exception of lymphoma, most tumoursinvolving the orbit are not amenable to chemotherapy.

Prognosis

Irrespective of tumour type, most tumours affect-ing the orbit carry a guarded to poor prognosisbecause:

• Most tumours at this site are malignant andalthough distant metastasis is not usually a major problem, the locally invasive nature oftheir growth precludes adequate surgical resection.

• Diagnosis is often delayed until the tumour hasreached a relatively advanced stage.

• Treatment is complicated by the proximity ofcritical structures such as the eye and brain.

OCULAR TUMOURS

Melanoma and lymphoma are the two most impor-tant tumours of the globe in cats and in dogs.Melanoma is the most common primary tumour in both species and usually affects the iris and cili-ary body (i.e. intra-ocular melanoma). In dogsmelanoma may also be limbal (epibulbar) and inrare cases, arise in the choroid. Ocular lymphomais usually a manifestation of systemic or multi-centric disease which may involve the conjunctiva,the iris, the choroid and the retina. Primary epi-thelial tumours of the iris and ciliary body are notcommon in either species although adenoma andadenocarcinoma have been reported and rarely, inyoung dogs, medulloepithelioma (Dubielzig 1990;

Dubielzig et al. 1998). In cats an invasive soft tissuesarcoma may arise secondary to lens ruptureseveral years following ocular trauma. Primarytumours of the choroid and retina are rare in thecat and the dog.

Presentation/signs

Primary ocular tumours are usually unilateral.In dogs ocular melanoma usually presents as a

nodular pigmented lesion. Epibulbar or limbaltumours may be detected by the owner as a non-painful, pigmented mass bulging from the sclera,


visible in the pupil, as a result of distortion of theiris or as a result of secondary ocular changes. Incats, spindle cell sarcoma and osteosarcoma havebeen reported in animals with a history of oculartrauma, 1–10 years prior to the onset of tumour.Post-traumatic sarcomas present as a firm, swollen,opaque, usually non-painful globe (Dubielzig et al.1990).

In cats and dogs with lymphoma, ocular involve-ment is more likely to be bilateral and diffuse innature. Infiltration of the iris may lead to adetectable change in the eye, the iris becomingpaler and assuming a swollen appearance. Moreoften, though, such cases present with signs of ante-rior uveitis, hyphema or hypopyon (Fig. 16.10).Other tumours which metastasise to the eye, e.g.haemangiosarcoma, are also more likely to show abilateral presentation and intraocular haemorrhageas a common feature.


While the biological behaviour of an ocular tumourin terms of malignancy is important for overall

adjacent to the cornea (Fig. 16.8).An increased inci-dence of epibulbar melanoma has been reported inGerman shepherd dogs and other breeds, e.g.cocker spaniel, standard schnauzer and poodle, mayalso be predisposed (Diters et al. 1983). Intra-ocularmelanomas affect the iris and ciliary body. Most butnot all tumours at these sites are heavily pigmentedlesions causing thickening of the iris and irregular-ity of the pupil. Blindness, ocular pain and glau-coma may result from the expanding tumour massrestricting aqueous drainage, or from tumour infiltration.

Feline ocular melanoma usually presents in amore diffuse form, with tumour infiltration causinga diffuse darkening, thickening and distortion of the iris (Fig. 16.9). Secondary glaucoma, due to infil-tration of the filtration apparatus, is common.Feline melanoma can present as a solitary masswhich may be difficult to differentiate from abenign naevus.

Other primary iridociliary epithelial tumoursmay present as a white, pink, red or pigmented mass

Fig. 16.8 Epibulbar or limbal melanoma in a threeyear old German shepherd dog. (Courtesy of Dr S.Petersen-Jones, Department of Small Animal ClinicalSciences, Veterinary Medical Centre, Michigan StateUniversity.)

Fig. 16.9 Diffuse iris melanoma in a cat. (Courtesy of Dr S. Petersen-Jones, Department of Small AnimalClinical Sciences, Veterinary Medical Centre, Michi-gan State University.)


prognosis it is important to appreciate that evenbenign intra-ocular tumours can cause severe intra-ocular damage and blindness due to space occupy-ing and pressure effects.

Canine ocular melanomas may be described asbenign or malignant according to histological crite-ria (e.g. cellular anaplasia, presence of mitoses);however, local infiltration and progressive destruc-tion of the eye are features common to both benignand malignant variants. Although there was apopular perception of canine ocular melanoma asa malignant tumour with a high risk of systemicmetastasis, clinical studies have shown that limbaland benign uveal melanomas do not metastasise.Even in those tumours with histological features ofmalignancy, the actual incidence of metastasis is low(Wilcock & Peiffer 1986). In contrast, feline ocularmelanomas are truly malignant tumours; they arelocally destructive of adjacent ocular structures andthe development of systemic metastases, especiallyto the liver, has been documented (Acland et al.1980).

Benign and malignant variants of iridociliaryepithelial tumours have been described. Invasivebehaviour is one criterion used to make this distinction, with tumours demonstrating scleralinvasion being designated as malignant (i.e. adeno-carcinoma) although the actual rate of metastasis insuch cases appeared to be very low in one study, ifit occurred at all (Dubielzig et al. 1998).

Feline ocular sarcomas are aggressive, infiltratingtumours that invade the retina and optic nerve

early in the course of the disease.Tumour extensionalong the course of the optic nerve may lead toinvolvement of the optic chiasm, thus affectingvision in the other eye. Orbital extension of thetumour is also possible.

Investigations

A complete ophthalmic examination with pupildilation is important in the investigation of casespresenting with an ocular mass, or with less specificsigns of ocular disease.

Bloods

These are not generally indicated in the diagnosisof ocular tumours, although would be indicated inthe investigation of animals with lymphoma and are important in pre-surgical assessment of thepatient.

Imaging techniques

Radiography is of little value in the evaluation ofocular tumours, but thoracic and abdominal filmswould be required in the evaluation of animals withmalignant or systemic tumours. Ultrasound is amore useful technique for evaluation of the eye andcan provide detail on the size and position of a massand its relationship with adjacent structures. CT orMRI images can be useful where orbital extensionis possible.

Biopsy/FNA

While FNA or biopsy via iridectomy might assist inthe diagnosis of some ocular tumours, most oculartumours are diagnosed following either an exci-sional biopsy or, in more advanced cases, followingenucleation of the eye.

Staging

There is no clinical staging system described forocular tumours in cats or dogs. In animals with lym-phoma, ocular involvement would signify stage Vdisease according to the WHO stage grouping(Owen 1980).

Fig. 16.10 Ocular lymphoma with cellular infiltrateand haemorrhage in the anterior chamber. (Courtesyof Mr D. E. Bostock.)


carry a favourable prognosis following enucleation.In contrast most feline ocular melanomas aremalignant and the prognosis for such cases is poordue to a high risk of systemic metastasis.

The prognosis for iridociliary epithelial tumoursis favourable in both species but feline ocular sar-comas are aggressive tumours and are unlikely tobe cured by surgical resection.

The prognosis for ocular lymphoma is poor forthe reasons outlined above.

References

Acland, G.M., McLean, I.W., Aguirre, G.D. et al. (1980)Diffuse iris melanoma in cats. Journal of the AmericanVeterinary Medical Association, (176), 52–6.

Bedford, P.G.G. (1999) Diseases and surgery of the canineeyelids. In: Veterinary Ophthalmology, 3rd edn, (ed.K.N. Gelatt), pp. 535–68. Williams & Wilkins, Lipincott.Chapter 14.

Boydell, P. (1991) Fine needle aspiration biopsy in thediagnosis of exophthalmos. Journal of Small AnimalPractice, (32), 542–6.

Cook, C.S. & Wilkie, D.A. (1999) Treatment of presumediris melanoma in dogs by diode laser photocoagulation:23 cases. Veterinary Ophthalmology, (2), 217–25.

Diters, R.W., Dubielzig, R.R., Aguirre, G.D. et al. (1983)Primary ocular melanoms in dogs. Veterinary Pathol-ogy, (20), 379–95.

Dubielzig, R.R. (1990) Ocular neoplasma in smallanimals. In: Small Animal Ophthalmology, VeterinaryClinics of North America, Small Animal Practice, (edsN.J. Millichamp & J. Dziezyc), 20 (3), 837–48. W.B.Saunders, Philadelphia.

Dubielzig, R.R., Everitt, J., Shadduck, J.A. et al. (1990)Clinical and morphological features of post-traumaticocular sarcomas in cats. Veterinary Pathology, (27),62–5.

Dubielzig, R.R., Steinbery, H., Garvin, H., Deehr, A.J. &Fischer, B. (1998) Iridociliary epithelial tumours in 100dogs and 17 cats: a morphological study. VeterinaryOphthalmology, 1 (4), 223–31.

Gilger, B.C., Whitley, R.D. & Mc Laughlin, S.A. (1994)Modified lateral orbitotomy for removal of orbital neo-plasms in two dogs. Veterinary Surgery, (23), 53–8.

Owen, L.N. (1980) TNM Classification of Tumors inDomestic Animals. World Health Organization,Geneva.

Roberts, S.M., Severin, G.A. & Lavach, J.D. (1986) Preva-lence and treatment of palpebral neoplasms in the dog:200 cases (1975–1983) Journal of the American Veteri-nary Medical Association, (189), 1355–9.

Slatter, D.H. & Abdelbakl, Y. (1979) Lateral orbitotomyby zygomatic arch resection in the dog. Journal of Veterinary Medical Association, (175), 1179–82.

Wilcock, B.P. & Peiffer, R.L. (1986) Morphology andbehaviour of primary ocular melanomas in 91 dogs.Veterinary Pathology, (23), 418–24.

Treatment

Surgery

Surgical resection is the treatment of choice formost primary ocular tumours. In some cases,small, localised lesions of the iris can be excised successfully without loss of the eye. Limbalmelanomas in dogs and cats may also be treated bylocal surgical excision. Most cases, however, willrequire at least enucleation of the eye and in caseswhere the tumour has invaded the sclera andextraocular tissues, exenteration of the orbit is recommended.

Radiotherapy

Most ocular tumours are not amenable to radio-therapy although radiotherapy may have a role asan adjunct to cytoreductive surgery (includingremoval of the eye) in the management of locallyinvasive tumours, such as ocular sarcomas.

Chemotherapy

With the exception of lymphoma, ocular tumoursare not amenable to chemotherapy. In dogs and catswith multicentric lymphoma, ocular lesions mayimprove following systemic chemotherapy with anyof the protocols described in Chapter 15, althoughthe prognosis for animals with ocular involvement(i.e. stage V lymphoma) is very guarded. Survivaltimes tend to be shorter than those for stage III orIV lymphoma and recurrence of ocular signs oftenheralds systemic relapse.

Other

Non-invasive diode laser photocoagulation hasbeen used for treatment of solitary lesions of theiris in dogs, presumed to be melanoma, and thiswould appear to be a safe and effective alternativefor isolated lesions (Cook & Wilkie 1999).

Prognosis

The prognosis for ocular tumours depends on his-tological type and species. Irrespective of whetherthe tumour is described as benign and malignant itwould seem that most canine ocular melanomas

17Miscellaneous Tumours

tumours arising at specific sites have not been con-sidered. This chapter draws these together.

Most neoplasms of cats and dogs have beenincluded within the body systems presented in thepreceding chapters. However, a small number of

� Thymoma, 262� Cardiac tumours, 266� Mesothelioma, 270� Splenic toumours, 272� Malignant (and systemic) histiocytosis, 275

262

THYMOMA

Epidemiology

Thymoma is an uncommon tumour in dogs and catsand there are few population-based reports on theincidence of this tumour. In one study of cats anddogs with ‘thymic disease’, thymoma was diagnosedin 5 of 30 cats and 18 of 36 dogs (Day 1997).Thymoma is usually a disease of the older animal,affecting medium to large breeds of dog, with afemale predisposition. However in Day’s study the18 dogs were aged from 10 months to 12 years witha mean of 7.5 years. Labradors, Labrador-crossesand German shepherd dogs were over represented,as were females. The five cats in the same studywere aged from 5 to 14 years (mean 9.10 years),four were male, three were domestic short hair, onedomestic long hair and one Siamese.

Aetiology

The aetiology of thymoma in cats and dogs isunknown.

Pathology

The thymus is sited in the cranial mediastinum andthis is the site of development of the tumour mass.The normal thymus consists of two cell types:

• Epithelial cells derived from the embryonic pharyngeal pouches

• T-lymphocytes.

In thymoma the epithelial cells are the neoplasticelement but are accompanied by a benign prolifera-tion of small, well differentiated, mature lymphoidcells. Thymoma may be predominantly epithelial

Miscellaneous Tumours 263

but such signs may also be a manifestation ofmyasthenia.

Those animals with paraneoplastic myastheniagravis may present with signs of:

• Muscle weakness• Regurgitation and possibly aspiration pneumo-

nia due to megaoesophagus (dogs).

On auscultation the chest is dull cranially and ven-trally, and heart sounds are muffled and often dis-

or predominantly lymphoid according to the rela-tive proportions of the two cell types. Subclassifica-tion of thymoma according to the organization of the epithelial elements (spindle cell, epithelial,pseudorosette) has not been shown to be of prog-nostic value in animal tumours.


Thymoma is typically a slowly growing tumour ofrelatively benign behaviour. Most tumours arequite well encapsulated but some may be locallyinvasive of adjacent structures. Metastasis is rare.

Thymoma may be associated with autoimmuneparaneoplastic syndromes, in particular myastheniagravis and occasionally polymyositis, and with anincreased incidence of non-thymic neoplasms(lymphoma, pulmonary adenocarcinoma and hae-mangiosarcoma) (Aronsohn 1985a). The associa-tion between thymoma and myasthenia gravis iswell recognised in dogs, especially German shep-herd dogs and thymoma associated myasthenia hasalso been reported in the cat (Scott-Moncrieff et al.1990; Rusbridge et al. 1996). On occasion, myasthe-nia gravis has been observed to develop after sur-gical resection of thymoma in humans, dogs andcats (Gores et al. 1994). Paraneoplastic hypercal-caemia is rare in dogs with thymoma.

Presentation/signs

As a result of the slow growth rate of most thymo-mas, clinical signs may not be apparent until thetumour has reached massive proportions (Fig.17.1). The most common clinical signs result fromthe presence of a large mass in the cranial medi-astinum causing pressure on adjacent organs andstructures. These include:

• Respiratory – cough, dyspnoea• Cardiovascular – obstruction of the cranial vena

cava, impairing venous return to the heartleading to ‘precaval syndrome’ with facial and/orforelimb oedema (Fig. 17.2) and enlarged, promi-nent jugular veins

• Salivation, regurgitation or vomiting could result from direct pressure on the oseophagus,

Fig. 17.1 Lateral thoracic radiograph of dog with alarge cranial medistinal mass, causing elevation of thetrachea and caudal displacement of the heart. Themass was diagnosed as a lymphocytic thymoma fol-lowing surgical excision.

Fig. 17.2 Oedematous swelling of the head and neck,anterior caval syndrome.


placed caudally. In cats there may be reduced com-pressibility of the cranial chest.

Investigations

Further investigations are indicated in order to:

• Confirm the presence of a mediastinal mass• Determine the histological type.

The main differential diagnoses for a mediastinalmass are listed in Table 17.1. Lymphoma is the mostcommon tumour at this site in dogs and cats andcan be difficult to distinguish from lymphocyticthymoma.

Bloods

Routine haematological/biochemical analyses arenot generally very helpful in establishing a defini-tive diagnosis of thymoma. Lymphocytosis has beenreported but this is neither a consistent nor a spe-cific finding (Atwater et al. 1994). However, suchinvestigations would be indicated to rule out con-current problems and in the pretreatment evalua-tion of older animals. Leucocytosis with a left shift may occur in the presence of aspiration pneumonia.

Imaging techniques

On plain lateral thoracic radiographs animals withthymoma usually have an obvious soft tissue massin the cranial mediastinum (Fig. 17.1). The tumouris usually of sufficient size to cause dorsal dis-

placement of the trachea and caudo-dorsal dis-placement of the heart. A pleural effusion may bepresent but this is not a consistent finding. Megaoe-sophagus and aspiration pneumonia may also beapparent on plain radiographs in dogs with myas-thenia gravis.

Tracheo-bronchial lymph nodes are not usuallyenlarged in cases with thymoma, an observationthat may assist in differentiation between thymomaand mediastinal lymphoma.

Ultrasound may be useful to distinguish betweenfluid and soft tissue in cases with pleural effusion,but although some thymomas may contain cysticclefts and cavities as opposed to the more homo-geneous appearance of lymphoma, the texture ofthese tumours varies considerably and ultrasounddoes not provide a definitive guide to the likely his-tology of the mass. Ultrasound is useful to assessthe capsule of the tumour for local invasion, toassess relationships with adjacent structures and toaid collection of biopsy or aspirate material.

Biopsy/FNA

Fine needle aspiration is the least invasive methodof obtaining cytological material from a mediasti-nal mass and with the aid of ultrasound guidancethis is a relatively safe technique. However,although cytology can be useful in the diagnosis of mediastinal lymphoma (on the basis of findinglarge numbers of lymphoblasts) it is not a reliablemethod for diagnosis of thymoma. Thymomas donot exfoliate very well and samples collected byFNA may yield non-diagnostic material or tend tocontain predominantly lymphocytes (and oftenmast cells) rather than the epithelial component ofthe tumour.

Definitive diagnosis of thymoma depends onexamination of biopsy material. Tumour materialmay be collected under ultrasound guidance by a transthoracic needle biopsy technique, or at thoracotomy.

Other

Diagnosis of generalised myasthenia gravis may beconfirmed by observing a rapid reversal of clinicalsigns following administration of a test dose of ananticholinesterase drug e.g. edrophonium. Alterna-tively acetylcholine receptor autoantibodies maybe detected in the patient’s serum (Hopkins 1993).

Table 17.1 Differential diagnoses of a cranial medi-astinal mass.

NeoplasticLymphomaChemodectoma (aortic/carotid body tumours)Ectopic thyroid tumourEctopic parathyroid tumourThymoma(Soft tissue sarcoma)(Tumour metastasis in mediastinal/presternal lymph

node)

Non-neoplasticAbscessGranuloma


Radiotherapy

There is little information on the use of radiother-apy in the treatment of canine or feline thymoma,although in theory radiation might be expected toreduce the lymphoid component of the tumourmass. In human patients with invasive or metasta-tic tumours radical surgery followed by radiationhas been shown to produce longer survival timesthan surgery alone and it is possible that this wouldbe the case in animals.

Chemotherapy

Chemotherapy has not been used successfully intreatment of canine or feline thymoma. Indeedbecause of the difficulty encountered in some casesin distinguishing between thymic lymphoma andlymphocytic thymoma without resorting to inci-sional biopsy, on occasion response to chemother-apy may be used to assist the diagnosis. Themajority of thymic lymphomas will respond rapidlyto chemotherapy, and thymoma should thereforebe suspected in cases where the thymic massremains relatively unchanged after two to threeweeks of combination chemotherapy.

Other

If myasthenia gravis is present this should be treated with immunosuppressive doses of prednisolone and anticholinesterase therapy (pyridostigmine).

Staging

Clinical staging of thymoma requires assessment ofthe tumour capsule, tumour invasion into adjacenttissues/structures and the presence of metastasis.Ultrasound is the most useful technique for clinicalstaging of a thymic tumour prior to thoracotomyand gross inspection. A clinically relevant stagingsystem for canine thymoma based on human andveterinary literature was proposed by Aronsohn(1985a) as shown in Table 17.2.

Treatment

Surgery

Surgical resection, thymectomy, is the definitivetreatment for thymoma and is the treatment ofchoice for stage I and II tumours. Median ster-notomy is the favoured approach to give best expo-sure, especially for larger tumours and those withpericapsular invasion. The feasibility of completetumour resection can often only be assessed at thetime of surgery when tumour adhesion to majorveins, the pericardium and oesophagus becomeapparent. Surgical debulking of unresectabletumours is often not very successful and may leadto considerable post-operative morbidity. Thus it isadvisable to discuss the possibility of inability toremove the tumour with the client prior to surgeryand to formulate a plan for such an eventuality. Ifthe tumour is not resectable and further treatments(see below) are to be attempted a reasonable sizedbiopsy should be collected from the tumour massprior to closure.

Table 17.2 Clinical staging of canine thymoma.

Stage Description

I Growth completely within intact thymic capsuleII Pericapsular growth into mediastinal fat tissue, adjacent pleura

and/or pericardiumIII Invasion into surrounding organs and/or intrathoracic metastasesIV Extrathoracic metastases

The presence and extent of the paraneoplastic syndrome can be indicated by:P0 – no evidence of paraneoplastic syndromeP1 – myasthenia gravisP2 – non-thymic malignant tumour


Prognosis

The prognosis for thymoma depends on the feasi-bility of surgical resection and the presence of paraneoplastic myasthenia gravis. The prognosis for stage I uncomplicated thymoma is good withlong term remissions or even cure likely to beachieved following thymectomy. In one study a one year survival rate of 83% was reported for dogs with a resectable tumour and without megaoe-

sophagus (Atwater et al. 1994). Surgical resec-tion of thymoma in cats also appears to lead to a favourable prognosis with median survivalapproaching two years in one study (Gores et al.1994). Stage III and IV tumours carry a guarded topoor prognosis due to lack of effective treatmentbut because of the slow growth rate some animalsmay survive many months untreated. The presenceof myasthenia gravis, megaoesophagus and aspira-tion pneumonia all lead to an increasingly guardedprognosis.

CARDIAC TUMOURS

Neoplasia is not a common cause of heart diseasein cats or dogs but cardiac muscle, vessels and con-nective tissues may be the site for development ofboth primary and secondary tumours. Such lesionsmay be intracavitary, intramural or pericardial inlocation.

Epidemiology

Primary cardiac tumours are uncommon in dogsand rare in cats. The most common cardiac tumourin the dog is haemangiosarcoma, to which theGerman shepherd dog appears predisposed. Aorticbody tumours (chemodectoma) are the secondmost common canine cardiac tumour; these tend tooccur in older (10–15 years) brachycephalic dogs,with males at greater risk. Primary cardiac tumoursare so rarely reported in cats that no age, sex orbreed associations have been observed.

Aetiology

The aetiology of primary cardiac tumours isunknown, although the breed/type predispositionsnoted above might suggest a genetic influence incertain breeds or types of dog.

Pathology

Primary tumours of the heart may be benign ormalignant. As already stated, haemangiosarcoma isthe most common primary cardiac tumour in thedog. In most cases the tumour is sited in the rightatrium or the right auricle, or both (Aronsohn

1985b). Chemodectoma of the aortic body arises atthe base of the heart (‘heart-base tumour’) and isusually located either at the base of the aorta orbetween the aorta and pulmonary artery. (Carotidbody tumours, also chemodectoma, arise near thebifurcation of the carotid artery in the neck andpresent as a cranial cervical mass.) Isolated casereports have documented the occurrence of anumber of other primary cardiac tumours in thedog, as listed in Table 17.3.

Primary cardiac tumours are extremely rare in cats, two cases of chemodectoma have beenreported (Tilley et al. 1981). Mesothelioma mayaffect the pericardium in both cats and dogs, as dis-cussed in a later section.

Cardiac muscle and the pericardium may also bethe site for development of secondary, metastatictumours including lymphoma, as listed in Table17.4. Lymphoma is the most common tumouraffecting the heart in cats.

Table 17.3 Cardiac tumours – primary tumoursreported in the dog.

HaemangiosarcomaChemodectomaFibromaFibrosarcomaHaemangiomaRhabdomyosarcomaChondromaChondrosarcomaMyxomaTeratomaGranular cell tumour


Haemangiosarcoma is usually sited in the rightatrium/auricle. Presenting signs may include:

• Sudden death from rupture of the tumour orcardiac dysrhythmia

• Pericardial haemorrhage, cardiac tamponade andsigns of right-sided heart failure:– Dyspnoea, cough– Exercise intolerance– Syncope– Ascites, possibly pleural effusion– Muffled heart sounds– Dysrhythmias and pulse deficits– Weight loss

• Haemorrhagic diathesis due to disseminatedintravascular coagulation.

Chemodectoma usually causes signs of right-sidedcongestive heart failure due to pressure on theaorta and/or vena cava, although it may also beassociated with pericardial effusion.

Myocardial infiltration by lymphoma or me-tastatic tumours is likely to cause rhythm disturbances.

Investigations

The diagnosis of a cardiac tumour may be difficult,as the clinical signs are non-specific and usuallyonly indicate the presence of heart disease. In manycases a definitive diagnosis may not be possiblebefore exploratory thoracotomy or necropsy.

Bloods

Routine haematological/biochemical analyses arenot generally very helpful in establishing a defini-tive diagnosis of cardiac tumours, although suchinvestigations may be helpful in ruling out differ-ential diagnoses. Clotting studies would be indi-cated if there were a suspicion of DIC.

Imaging techniques

Plain thoracic radiography may be normal or mayindicate non-specific changes associated with heartdisease:

• Cardiomegaly• Globular cardiac silhouette with pericardial

effusion• Pulmonary oedema.


The behaviour of cardiac tumours varies accordingto tumour type, but irrespective of the degree ofmalignancy, all tumours at this site have potentiallylife-threatening consequences through interferencewith cardiac function.

Haemangiosarcoma is a highly malignant tumourand widespread haematological disseminationoccurs early in the course of the disease. Theprimary tumour or the presence of metastases mayact as a trigger for disseminated intravascular coag-ulation (Chapter 2).

Chemodectoma is less aggressive than haeman-giosarcoma and some tumours follow a benigncourse. However 40–50% of tumours display localinvasion and infiltration, and metastasis (to thelungs, mediastinal lymph nodes, left atrium, peri-cardium, kidney, liver, spleen and other distantsites) may occur in up to 22% of cases (Patnaiket al. 1975). The histological appearance of thetumour does not appear to correlate with clinicalbehaviour. Chemoreceptors are part of the para-sympathetic nervous system but tumours in cats and dogs do not appear to be functional. However,concurrent endocrine tumours (including testicular,thyroid and pancreatic tumours) appear to be quitecommon in dogs with chemodectoma (Owen et al.1996).

Presentation/signs

Most animals with cardiac tumours present as aresult of the effects of the tumour on the functionof the heart. Clinical signs can be variable anddepend on the size and location of the primarytumour.

Table 17.4 Canine and feline cardiac tumours –tumours reported to have metastasised to the heart.

HaemangiosarcomaLymphomaMammary carcinomaPulmonary carcinomaSalivary adenocarcinomaMalignant melanomaMast cell tumour


Heart-base tumours may be visualised on plainradiographs as a soft tissue mass extending from thebase of the heart into the cranial mediastinum,causing dorsal displacement of the trachea (Fig.17.3). Contrast techniques, e.g. angiography, mayassist better definition of a tumour mass. In caseswith pericardal effusion, pneumopericardiographymay be performed following drainage of the effu-sion to outline a right atrial mass. However, suchtechniques have been superseded by ultrasonogra-phy. Plain thoracic radiographs are indicated forevaluation of metastases.

Ultrasound, echocardiography, is the most useful,non-invasive technique to define the presence,location and size of cardiac masses and to con-firm the presence of pericardial effusion or myocar-dial infiltration. Echocardiography can also pro-vide information on the effect of the tumour on the haemodynamics and function of the heart.Although echocardiography cannot provide adefinitive diagnosis of tumour type, the site of acardiac mass is an important indicator of its likelyhistogenesis. Ultrasound may also be used to assessfeasibility of surgical excision of a solitary mass andto examine local lymph nodes as potential sites ofmetastasis.

Biopsy/FNA

Histological diagnosis of cardiac tumours is usuallymade on tissue collected at exploratory thoraco-tomy or at post mortem examination. Fine needleaspiration and non-surgical biopsy of suspectedvascular tumours carry high risks and are notadvised. In cases with pericardial effusions, cyto-logical examination of pericardial fluid is of limiteddiagnostic value (Sisson et al. 1984).

Other

Electrocardiography may show a number of abnormalities:

• Low voltage QRS complexes and electrical alter-nans associated with pericardial effusion

• Dysrhythmias associated with myocardialdisease, which may correlate with the specificlocation of the tumour or be secondary tomyocardial ischaemia and hypoxia.

Fig. 17.3 (a) Lateral thoracic radiograph of a dog,demonstrating a large soft tissue mass sited at the baseof the heart which is extending into the cranial medi-astinum and elevating the trachea. (b) Gross appear-ance of this same heart base tumour at post mortemexamination.

(b)

(a)


although in humans radiation may be used as a palliative measure in patients with inoperable orrecurrent chemodectoma. Four dogs with aorticbody tumours were reported to respond well toradiotherapy (Turrell 1987) but further studies arenecessary to evaluate the efficacy of radiotherapyin such tumours.

Chemotherapy

Chemotherapy with doxorubicin alone or com-bined with cyclophosphamide and vincristine (VAC protocol, Table 5.4) is used to treat haeman-giosarcoma at other sites, often in an adjuvantsetting following surgical resection of the primarytumour. Reports on the use of chemotherapy for cardiac haemangiosarcoma are few but com-bination chemotherapy with vincristine, doxoru-bicin and cyclophosphamide produced a partialremission of a right atrial haemangiosarcoma in one dog and resulted in resolution of an associ-ated pericardial effusion. However, the dog suc-cumbed to pulmonary metastasis and died after 20 weeks (de Madron et al. 1987). There is no evidence that chemodectoma is sensitive tochemotherapy.

Other

In most cases treatment is limited to symptomaticmedical management of cardiac failure and dysrhythmias.

Prognosis

The prognosis for many animals with cardiactumours is poor. Surgical resection of the tumour isnot possible in most cases and these do not usuallyrespond well to medical management.

Haemangiosarcoma is a highly malignant tumourand even if the primary tumour can be treated sur-gically, the prognosis remains poor due to earlyonset metastatic disease. In one study of 38 dogswith right atrial haemangiosarcoma it was possibleto resect the tumour by removing part of the right atrium in nine cases but the surgery was notwithout complications that requiried prolongedhospitalisation and the mean survival time for this

Staging

Clinical staging of cardiac tumours requires assess-ment of the primary tumour and evaluation of possible sites of lymphatic and haematogenousmetastasis. Ultrasonography and radiography mayboth contribute to this process. A clinical stagingsystem for canine haemangiosarcoma which isapplicable to cardiac tumours has been described(Brown et al. 1985; Table 17.5).

Treatment

Surgery

Surgical resection of cardiac tumours is only suc-cessful in a small number of cases with non-invasive primary tumours. Considerable skill andexpertise is required in the surgical procedure andin the perioperative care of the patient (Aronsohn1985b).

Radiotherapy

There are few reports on the use of radiotherapy in the treatment of cardiac tumours in animals,

Table 17.5 Clinical staging for canine haeman-giosarcoma.

T Primary tumourT0 = no evidence of tumourT1 = tumour confined to primary siteT2 = tumour confined to primary site but rupturedT3 = tumour invading adjacent structures

N Lymph nodes*N0 = no evidence of lymph node involvementN1 = regional lymph node involvementN2 = distant lymph node involvement

M MetastasisM0 = no evidence of metastatic diseaseM1 = metastasis in same body cavity as primary tumourM2 = distant metastasis

StageI = T0 or T1, N0, M0II = T1 or T2, N0 or N1, M1III = T2 or T3, N1 or N2, M2

* Haemangiosarcoma usually metastasises via thehaematogenous route. Local or regional lymph nodeinvolvement is uncommon.


group was only four months (Aronsohn 1985b).None of these animals were treated with adjuvantchemotherapy.

affected body cavity. Tumours may spread by localextension and invasion. Pleural mesothelioma has been reported to metastasise beyond thepleural cavity (Morrison & Trigo 1984). No para-neoplastic syndromes are commonly associatedwith mesothelioma.

Presentation/signs

Mesothelioma is a highly effusive tumour and it isthe effusion that is the most common presentingsign:

• Pleural effusion – dyspnoea• Pericardial effusion – cardiac tamponade and

signs of right-sided heart failure• Peritoneal effusion – abdominal distension.

Investigations

The diagnosis of mesothelioma can be challenging.In most cases investigations will be directedtowards establishing the cause of the presentingeffusion and because mesothelioma is one of theless common causes of this (Table 17.6), the suspi-cion of mesothelioma may only be reached follow-

MESOTHELIOMA

Epidemiology

Mesothelioma is a rare tumour in cats and dogs.Although this tumour usually arises in olderanimals, a juvenile form is recognised in ruminants.No breed or sex predispositions have been estab-lished in cats and dogs.

Aetiology

In humans, mesothelioma is associated with occu-pational exposure to airborne asbestos fibres andasbestos may be implicated in the aetiology of sometumours in dogs. Dogs with pleural mesotheliomawere shown to have higher levels of asbestos intheir lungs than normal controls and their ownersoften had a history of contact with asbestos (Glick-man et al. 1983). The aetiology of mesothelioma atother sites is not known.

Pathology

Mesothelioma arises from the serosal lining of bodycavities. Pleural, pericardial and peritoneal sites arethose most frequently affected in cats and dogs butthe tumour can also occur in the scrotum and tunicavaginalis in dogs.

Grossly the tumour forms a diffuse, oftennodular proliferation covering the surface of thebody cavity; this is usually associated with a signif-icant effusion into the affected cavity. The effusionis usually haemorrhagic in nature, but may becomechylous if the tumour causes lymphatic obstruction.

Normal mesothelial cells are of mesodermalorigin although their morphological appearance isepithelial. Histologically epithelial, mesenchymal,sclerosing and mixed types of mesothelioma aredescribed.


Mesothelioma is considered to be malignantbecause of its ability to seed throughout the

Local invasion often prevents surgical manage-ment of aortic body tumours and studies on post-operative survival times are not available.

Table 17.6 Major differential diagnosis for mesothe-lioma.

Pleural effusionHaemangiosarcomaMetastatic carcinomaFeline infectious peritonitisInfections (pyothorax)

Pericardial effusionPericardial cystTraumatic pericardial haemorrhageCoagulopathyHaemangiosarcomaIdiopathic pericardial haemorrhage

Peritoneal effusionPeritonitisFeline infectious peritonitis


of representative tissue usually requires ex-ploratory thoracotomy or celiotomy to allow directvisualisation of the lesion. The techniques of thora-coscopy and laparasocopy may provide a less inva-sive alternative in the future.

Staging

By virtue of the diffuse and effusive nature ofmesothelioma, it is usually assumed that theaffected body cavity is contaminated with tumourand no clinical staging systems have beendescribed.

Treatment

An effective method for treatment of mesothe-lioma has not been established.

Surgery

Treatment of pericardial mesothelioma by peri-cardiectomy has been described (Closa et al. 1999)but surgical resection is not possible in most casesdue to the widespread nature of mesothelioma.

Radiotherapy

Radiotherapy is not a realistic option in most casesas irradiation of the entire thorax or abdomenwould cause unacceptable toxicity.

Chemotherapy

Chemotherapy with cisplatin or other agents mayhave a role in the management of mesothelioma.Intracavitary administration of cisplatin was usefulin palliation of mesothelioma in a small number of cases by controlling the malignant effusion andretarding tumour progression without undue toxic-ity (Moore et al. 1991).

Prognosis

In the absence of a successful method of treatment,the prognosis for mesothelioma is poor. Survivalfigures are sparse as many animals are euthanasedupon diagnosis. On the basis of small numbers of

ing exclusion of more common causes or persistentrecurrence of the effusion.

Bloods

Routine haematological/biochemical analyses arenot generally very helpful in establishing a diagno-sis of mesothelioma although such investiga-tions may be helpful in ruling out other causes ofeffusions.

Imaging techniques

Survey radiographs of the thorax and abdomen willindicate the presence of fluid in the affected cavity,or a pericardial effusion, but are unlikely to showevidence of the tumour.

Pleural, pericardial or peritoneal masses may bevisualised on ultrasound but can be difficult todetect in early cases or where the tumour is verydiffuse.

Biopsy/FNA

Analysis of the fluid collected by pleural, pericar-dial or peritoneal drainage can be useful to establish:

• The nature of the fluid – in dogs the effusionassociated with mesothelioma is most commonlyhaemorrhagic, sterile and non-clotting. In catsthe nature of the fluid is more variable, rangingfrom haemorrhagic to chylous.

• Cell content – cytological examination of theeffusion can be very useful to diagnose or ruleout other effusive conditions, e.g. lymphoma,infection. However, the cytology of the effusionis of limited value in the diagnosis of mesothe-lioma because, although neoplastic mesothelialcells readily exfoliate into the fluid, it is very difficult to distinguish between neoplastic andreactive mesothelial cells on the basis of cell morphology. Reactive mesothelial cells are com-monly found in effusions and are often of bizarreappearance.

Where a mass is visible on ultrasonography, fineneedle aspirates of the lesion may provide ade-quate samples for cytological diagnosis within thelimitations set out above. In most cases, definitivediagnosis of mesothelioma depends on histopatho-logical examination of biopsy samples. Collection


animals, intracavitary chemotherapy does appear tobe of palliative value with survival times from 129

days to 27 months (Moore et al. 1991; Closa et al.1999).

SPLENIC TUMOURS

As one of the major reticuloendothelial organs ofthe body, the spleen is an important site for thedevelopment of primary tumours and is also acommon site for development of metastatictumours and tumours of the haematopoieticsystem. Although most of these tumours have beencovered elsewhere, splenic haemangiosarcoma andsplenic sarcoma warrant individual consideration.Tumours affecting the spleen are summarised inTable 17.7 (canine) and 17.8 (feline).

Epidemiology

Splenic abnormality, most commonly spleno-megaly, is frequently recognised in dogs, and patho-logical reviews of splenic biopsies/splenectomiessuggest that neoplasia is the cause of the abnor-mality in between 43–75% of such cases (Frey &Betts 1977; Day et al. 1995). Haemangiosarcoma isthe most common tumour of the canine spleen. Itaffects older dogs and the German shepherd is atgreater risk than other breeds. Non-angiomatousmesenchymal tumours (splenic sarcoma – seebelow) are also recognised with some frequency in

the spleen of older dogs, especially retriever breeds(Spangler et al. 1994).

Tumours of the spleen are less common in cats.A splenic form of mast cell tumour (lymphoreticu-lar MCT – Chapter 4) is the most common tumourof the feline spleen and accounts for 15% of splenicdisease in this species (Spangler & Culbertson1992).

Aetiology

In general the aetiology of splenic tumours is notknown. Breed predisposition for haemangiosar-coma and possibly splenic sarcoma in dogs might implicate genetic factors. In cats FeLV isimplicated in the aetiology of lymphoma and forms of leukaemia which may affect the spleen(Chapter 15).

Pathology

Tables 17.7 and 17.8 demonstrate the diversity oftumours that may arise in the spleen. Most of thesetumours have been considered elsewhere and donot require further discussion.

Haemangiosarcoma is the most important

Table 17.7 Tumours of the canine spleen.

Primary tumoursHaemangiomaHaemangiosarcomaSarcoma – various – see text

Secondary or multicentric tumoursLymphoproliferative and myeloproliferative conditions

including lymphomaHaemangiosarcomaMast cell tumourOther malignant tumours with widespread metastases,

e.g. melanoma

Non-neoplastic causes of splenomegaly or splenic massNodular hyperplasiaHaematomaThrombosis and infarctionCongestionExtramedullary haematopoiesisTorsion

Table 17.8 Tumours of the feline spleen.

Primary tumoursMast cell tumourHaemangiosarcomaSarcoma – various

Secondary or multicentric tumoursLymphoproliferative and myeloproliferative conditions,

including lymphomaHaemangiosarcomaOther malignant tumours with widespread metastases,

e.g. adenocarcinoma

Non-neoplastic causes of splenomegaly or splenic massNodular hyperplasiaHaematomaCongestionExtramedullary haematopoiesis



Haemangiosarcoma is a highly malignant tumourwith haematogenous metastasis occurring early inthe course of the disease. Rupture of the primarytumour can lead to acute and fatal haemorrhage(see below). Primary or secondary tumours may beassociated with DIC. In contrast, haemangioma ofthe spleen is a slowly growing tumour and canattain large proportions before diagnosis. Metasta-sis does not occur.

Primary mesenchymal tumours of the spleen canbe divided into three categories on the basis of theirbiological behaviour (Spangler et al. 1994):

• Benign, non-invasive tumours (leiomyoma,lipoma) – these do not metastasise and are asso-ciated with long patient survival times

• Intermediate tumours (mesenchymoma) –median survival period of 12 months with 50%one year survival

• Malignant tumours (fibrosarcoma, leiomyosar-coma, undifferentiated sarcoma, histiocyticsarcoma) – these are capable of metastasis andare associated with relatively short post-operative survival times (median survival fourmonths, 80–100% mortality after 12 months).

Presentation/signs

For low grade and benign tumours abdominal dis-tension due to the enlarging tumour mass may bethe first sign of the problem or the mass may bedetected during routine clinical examination. Suchtumours can reach large proportions withoutcausing clinical signs. Splenic sarcomas may causenon-specific signs of malaise but are also most oftendetected on clinical examination, radiography orultrasound or at the time of exploratory celiotomy.

In contrast the presenting signs of splenic hae-mangiosarcoma may be dramatic:

• Acute collapse may follow rupture of theprimary mass leading to a haemoperitoneum

• Less specific signs of lethargy, weakness, pallorand anorexia may be detected prior to a majorabdominal bleed

• Bleeding due to DIC may be a presenting sign insome cases

tumour of the canine spleen, but haemangioma andhaematoma are also quite common at this site andsometimes it can be difficult to differentiate theseconditions clinically and histopathologically, forexample when major haemorrhage occurs within a haemangiosarcoma. It may be necessary toexamine multiple sections from the lesion before acertain diagnosis can be reached. Haemangiomaand haemangiosarcoma may both present as asingle mass or as multiple nodules within thespleen. Haemangiosarcoma arising at other sitesmay also metastasise to the spleen. It is a matter fordebate as to whether the heart or the spleen is themost common site for development of haeman-giosarcoma in the dog. In some cases with wide-spread tumour metastases it is difficult to be certainwhich location is the primary focus or whether thetumour might be multicentric.

The spleen may also be a site for development ofprimary tumours of mesenchymal origin, ‘sarcomas’(Fig. 17.4). Some such tumours are well differenti-ated and can be classified according to their mor-phology on haematoxylin and eosin (H&E)sections, for example, liposarcoma. However, manylack such clear differentiation leading to diagnosesof ‘undifferentiated sarcoma’. When more detailedimmunohistochemical staining is performed onthese tumours it appears that they, along withsplenic fibrosarcoma and leiomyosarcoma, mightshare a common origin from smooth muscle orsplenic myofibroblasts (Spangler et al. 1994).

Fig. 17.4 Primary splenic sarcoma from a flat-coatedretriever. This tumour was diagnosed as a histiocyticsarcoma.


• Splenic haemangiosarcoma may also be detectedas an incidental finding in the absence of overtclinical signs.

Investigations

Bloods

In cases of splenic haemangiosarcoma thehaemogram may show a number of changes:

• Anaemia – may be regenerative if due to bloodloss, or microangiopathic due to fragmentation ofred blood cells during passage through a mesh-work of fibrin in the microvascular network ofthe tumour.

• Acanthocytes (damaged red cells) and schisto-cytes (red blood cell fragments) – highly indica-tive of haemangiosarcoma.

• Thrombocytopenia – due to bleeding, seques-tration of platelets within the microvascularnetwork of the tumour or DIC.

In cases with DIC, clotting studies will revealabnormalities in both primary and secondaryhaemostasis, fibrin degradation products will beelevated and fibrinogen and antithrombin IIIdecreased.

Imaging techniques

Splenomegaly or a splenic mass may be detected onplain radiographs of the abdomen, and these mayalso show evidence of abdominal fluid in cases withhaemorrhage. Ultrasonography can provide usefulinformation about the structure of a splenic massor masses and their relationship with normalspleen. The vascular nature of haemangiosarcomamay be seen on ultrasound as a mixed or non-homogeneous mass with echolucent areas in con-trast to the more homogeneous denser structure ofnormal spleen.

Radiography of the thorax and ultrasonographyof other abdominal organs, especially the liver andkidneys, is indicated to detect metastases.

Biopsy/FNA

Fine needle aspirates may assist in cytological diag-nosis in cases of generalised splenomegaly or wheresplenic lesions appear solid on ultrasonography. It

is not advisable to attempt FNA in cases wheresplenic lesions have a vascular appearance on ultra-sound. It is unlikely that the resulting sampleswould be diagnostic; usually blood is all that is col-lected from such lesions but, more importantly, theprocedure carries a significant risk of causing haem-orrhage into the abdomen and possible seeding oftumour cells.

Splenic biopsy may be indicated in cases withdiffuse splenomegaly or multinodular splenicdisease. Needle biopsy techniques may be usedunder ultrasound guidance or incisional biopsiescollected at celiotomy. The latter allows visualisa-tion of the whole spleen and thus better selectionof representative lesions for biopsy.

In cases where there is a distinct mass in thespleen, excisional biopsy by splenectomy is prefer-able. Not only is this technically easier to performbut also provides the pathologist with sufficientmaterial to achieve the correct diagnosis. This isparticularly important for differentiating haeman-gioma and haemangiosarcoma.

Staging

The clinical staging system for canine haeman-giosarcoma is shown in Table 17.5. In both splenichaemangiosarcoma and splenic sarcoma, the extentof the tumour within the spleen is of less impor-tance than whether the tumour has invadedthrough the splenic capsule. Nodal metastases are uncommon but radiography and ultrasono-graphy are required to evaluate the patient forhaematogenous metastases.

Treatment

Surgery

Surgical removal of the tumour by splenectomy isthe treatment of choice for splenic haemangiosar-coma and splenic sarcoma. Unfortunately this is nota curative treatment for most splenic sarcomas. Inthe case of haemangiosarcoma, survival times fol-lowing splenectomy range from 19 to 143 days(Wood et al. 1998) and most dogs die as a result ofmetastasis. For splenic sarcomas a median survivaltime of four months has been reported and metas-tases were a frequent reason for euthanasia in thesepatients (Spangler et al. 1994).


treatment for dogs with splenic sarcoma, but less isknown about the chemosensitivity of such tumours.Larger scale clinical trials are required to betterdefine the role of chemotherapy in the manage-ment of splenic tumours.

Prognosis

As outlined above the prognosis for dogs withsplenic haemangiosarcoma is poor. There appearsto be little difference in survival for those animalswith stage I versus stage II disease, i.e. rupture ofthe tumour does not appear to affect prognosis(Wood et al. 1998). The prognosis for splenicsarcoma is also poor, although there is a widerrange of survival times for such tumours. Mitoticindex has been shown to be of prognostic impor-tance in this group of tumours: those tumours witha mitotic index <9 showed significantly longer sur-vival than those with a mitotic index >9 (Spangleret al. 1994).

Radiotherapy

Radiotherapy is not indicated in the treatment ofsplenic tumours.

Chemotherapy

In most cases of splenic haemangiosarcomamicrometastases are present at the time of diagno-sis of the primary tumour; these progress rapidlyand are the reason for poor survival times follow-ing splenectomy. Post-operative chemotherapy is indicated in an attempt to prevent or delay the progression of this micrometastatic disease.Chemotherapy protocols based on doxorubicinwith cyclophosphamide and vincristine have beenused in this adjuvant setting with median survivaltimes from 141–179 days (Hammer et al. 1991;Sorenmo et al. 1993). Doxorubicin used as a singleagent has been reported to achieve similar survivaltimes (Ogilvie et al. 1996).

Post-operative chemotherapy would be a logical

MALIGNANT (AND SYSTEMIC) HISTIOCYTOSIS

Malignant histiocytosis is characterised by neoplas-tic proliferation of cells of histiocytic (monocyte)lineage. Several disorders of histiocytes have beendescribed in animals (see Chapter 4) but of theseonly canine cutaneous histiocytoma is common.There is still uncertainty about the precise natureof this group of tumours.

Epidemiology

Malignant histiocytosis is a rare tumour first recog-nised in the Bernese mountain dog and still stronglyassociated with this breed, although it has also beenreported in the golden retriever, rottweiler, dober-mann, English springer spaniel and flat-coatedretriever (Kerlin & Hendrick 1996). In the Berneseit typically affects older dogs, seven to eight yearsof age, and is more common in males. Malignanthistiocytosis has been documented in cats.

Systemic histiocytosis is another rare histiocyticdisorder affecting the Bernese mountain dog butthis is a condition of younger animals, with age ofonset at three to four years (Paterson et al. 1995).

Although the clinical signs and presentation of

these two conditions differ, the fact that they areboth disorders of histiocytic cells and are both rela-tively common in the Bernese mountain dog has ledto the suggestion that they may be manifestationsof a common underlying defect (Moore & Rosin1986).

Aetiology

There are indications that histiocytosis is an inher-ited disease in the Bernese mountain dog and it hasbeen suggested that the mode of inheritance ispolygenic rather than a simple autosomal recessiveor dominant trait (Padgett et al. 1995).

Pathology

Malignant histiocytosis is characterised by thedevelopment of solid tumour masses in a variety oforgans (Fig. 17.5a,b). The most common sites forthe tumour are:

• Spleen• Liver


• Lymph nodes• Lungs.

Involvement of the spinal column has also beenreported (Ramsey et al. 1996). In contrast to sys-temic histiocytosis, the eyes and skin are rarelyinvolved.

The tumours consist of sheets of large, pleomor-phic cells with foamy cytoplasm often showing evidence of erythrophagocytosis. Mitotic activity is

high and abnormal mitotic figures are oftenpresent. Interspersed between these cells are multinucleate giant cells, and an infiltrate of lymphocytes and neutrophils is often present.Immunostaining for tissue-specific enzymes (espe-cially lysozyme) is necessary to distinguish thisanaplastic tumour from poorly differentiated sar-comas or carcinomas.


Malignant histiocytosis is a highly malignant andvery aggressive disease that runs a rapid and fatalcourse. Affected animals usually present with mul-tiple lesions, often involving several organs.

Systemic histiocytosis is a more chronic diseaseinvolving the skin, peripheral lymph nodes, eyesand other tissues and is characterised by a fluctuat-ing course.

Presentation/signs

In malignant histiocytosis most tumours are sitedinternally. In many cases the clinical signs are non-specific, for example:

• Anorexia• Weight loss• Lethargy, depression• Anaemia.

In other cases the signs may reflect the organsinvolved, for example:

• Cough or dyspnoea may be indicative of a lungmass

• Lameness and paresis, spinal cord involvement.

The clinical signs and presentation of systemic his-tiocytosis have been discussed in Chapter 4.

Investigations

Bloods

A severe (often regenerative) anaemia is acommon finding in dogs with malignant histiocyto-sis. Bone marrow aspirates may assist in the diag-nosis of such cases to demonstrate malignanthistiocytic proliferation with erythrophagocytosis.

Fig. 17.5 (a) Lateral thoracic radiograph of a Bernesemountain dog showing a large soft tissue mass in theventral thorax, displacing the heart dorsally. A softtissue opacity around the bifurcation of the tracheasuggests an enlargement of the tracheobronchiallymph nodes. (Previously published in VeterinaryRecord (1996), (138), 440–44, with permission) (b) Gross appearance of the mass at post mortem examination.

(b)

(a)


Aronsohn, M. (1985a) Canine thymoma. VeterinaryClinics of North America, 15 (4), 755–67.

Aronsohn, M. (1985b) Cardiac haemangiosarcoma in thedog: a review of 38 cases. Journal of the American Vet-erinary Medical Association, (187), 922–6.

Brown, N.O., Patnaik, A.K., MacEwan, E.G. (1985)Canine haemangiosarcoma. Journal of the AmericanVeterinary Medical Association, (186), 56–8.

Closa, J.M., Font, A. & Mascort, J. (1999) Pericardialmesothelioma in a dog: long-term survival after peri-cardiectomy in combination with chemotherapy.Journal of Small Animal Practice, (40), 383–6.

Day, M.J., Lucke, V.M. & Pearson, H. (1995) A review ofpathological diagnoses made from 87 canine splenicbiopsies. Journal of Small Animal Practice, (36), 426–33.

Day, M.J. (1997) Review of thymic pathology in 30 catsand 36 dogs. Journal of Small Animal Practice, (38),393–403.

Frey, A.J. & Bets, C.W. (1977) A retrospective survey ofsplenectomy in the dog. Journal of the AmericanAnimal Hospital Association, (13), 730–34.

Glickman, L.T., Domanski, L.M., Maguire, T.G. et al.(1983) Mesothelioma in pet dogs associated with ex-posure of their owners to asbestos. EnvironmentalResearch, (32), 305.

Gores, B.R., Berg, J., Carpenter, J.L. et al. (1994) Surgicaltreatment of thymoma in cats: 12 cases (1987–1992).Journal of the American Veterinary Medical Associa-tion, (204), 1782–5.

Hammer, A.S., Couto, C.G., Filppi, J. et al. (1991) Efficacyand toxicity of VAC chemotherapy (vincristine, dox-orubicin and cyclophosphamide) in dogs with haeman-giosarcoma. Journal of Veterinary Internal Medicine,(5), 160–66.

Hopkins, A.L. (1993) Canine myasthenia gravis. Journalof Small Animal Practice, (33), 477–84.

Kerlin, R.L. & Hendrick, M.J. (1996) Malignant fibroushistiocytoma and malignant histiocytosis in the dog –convergent or divergent phenotypic differentiation?Veterinary Pathology, (33), 713–16.

de Madron, E., Helfand, S.C. & Stebbins, K.E. (1987) Useof chemotherapy for the treatment of cardiac haeman-giosarcoma in a dog. Journal of the American VeterinaryMedical Association, (190), 887–91.

Moore, A.S., Kirk, C. & Cardona, A. (1991) Intracavitarycisplatin chemotherapy experience in six dogs. Journalof Veterinary Internal Medicine, (5), 227–31.

Moore, P.F. & Rosin, A. (1986) Malignant histiocytosis of Bernese mountain dogs. Veterinary Pathology, (23),1–10.

Morrison, W.B. & Trigo, F.J. (1984) Clinical characterisa-tion of pleural mesothelioma in seven dogs. Com-pendium on Continuing Education, (6), 342–8.

Ogilvie, G.K., Powers, B.E., Mallinckrodt, C.H. et al.(1996) Surgery and doxorubicin in dogs with heman-giosarcoma. Journal of Veterinary Internal Medicine,(6), 379–84.


Owen,T.J., Bruyette, D.S. & Layton, C.E. (1996) Chemod-

Biochemical parameters may demonstrateabnormalities related to failure of specific organs.

Imaging techniques

Plain survey radiographs of the thorax andabdomen may demonstrate the presence of a softtissue mass or masses or enlargement of abdominalorgans. Ultrasonographic examination of the liverand spleen may show evidence of lesions withinthese tissues. Further, more detailed studies may beindicated according to preliminary findings.

Biopsy/FNA

If lesions are accessible for fine needle aspiration,the finding of anaplastic mononuclear cells withvacuolated cytoplasm, multinucleated cells andbizarre mitotic figures may provide cytological evidence of a malignant, anaplastic tumour.However, the diagnosis of malignant histiocytosiswill usually depend on histological examination of biopsy material or material collected at postmortem examination.

Staging

There is no clinical staging system described formalignant histiocytosis.


Although chemotherapy has been attempted notreatment has proved effective in the managementof malignant histiocytosis. This is an aggressive andrapidly fatal disease and the prognosis is grave.

Systemic histiocytosis is a chronic progressivedisease that fluctuates with periods of improvementand recrudescence. Immunosuppressive therapydoes not appear to alter the course of the disease.The disease is rarely fatal but euthanasia is oftenrequested by the owners due to the debilitatingnature of the condition.

References

Atwater, S.W., Powers, B.E., Park, R.D. et al. (1994)Canine thymoma: 23 cases (1980–1991). Journal of the American Veterinary Medical Association, (205),1007–13.


ectoma in dogs. Compendium on Continuing Educa-tion, (18), 253–65.

Paterson, S., Boydell, P. & Pike, P. (1995) Systemic histio-cytosis in the Bernese mountain dog. Journal of SmallAnimal Practice, (36), 233.

Padgett, G.A., Madewell, B.R., Kellert, E.T. et al. (1995)Inheritance of histiocytosis in Bernese mountain dogs.Journal of Small Animal Practice, (36), 93–8.

Patnaik, A.K., Lui, S.K., Hurvitz, A.I. et al. (1975) Caninechemodectoma (extra-adrenal paragangliomas) – acomparative study. Journal of Small Animal Practice,(16), 785–801.

Ramsey, I.K., McKay, J.S., Rudorf, H. & Dobson, J.M.(1996) Malignant histiocytosis in three Bernese moun-tain dogs. Veterinary Record, (138), 440–44.

Rusbridge, C., White, R.N., Elwood, C.M. & Wheeler, S.J.(1996) Treatment of acquired myasthenia gravis asso-ciated with thymoma in two dogs. Journal of SmallAnimal Practice, (36), 376–80.

Scott-Moncrieff, J.C., Cook, J.R. & Lantz, G.C. (1990)Acquired myasthenia gravis in a cat with thymoma.Journal of the American Veterinary Medical Associa-tion, (196), 1291–3.

Sisson, D., Thomas, W.P., Ruehl, W.W. et al. (1984) Diag-nostic value of pericardial fluid analysis in the dog.Journal of the American Veterinary Medical Associa-tion, (184), 51–5.

Sorenmo, K.U., Jeglum, K.A. & Helfand, S.C. (1993)Chemotherapy of canine haemangiosarcoma with dox-orubicin and cyclophosphamide. Journal of VeterinaryInternal Medicine, (7), 370–76.

Spangler,W.L. & Culbertson, M.R. (1992) Prevalence andtype of splenic diseases in cats: 455 cases (1985–1991).Journal of the American Veterinary Medical Associa-tion, (201), 773–6.

Spangler, W.L., Culbertson, M.R. & Kass, P.H. (1994)Primary mesenchymal (nonangiomatous/nonlym-phomatous) neoplasms occuring in the canine spleen:anatomic classification, immunohistochemistry andmitotic activity correlated with patient survival. Veteri-nary Pathology, (31), 37–47.

Tilley, L.P., Band, B., Patnaik,A.K. & Liu, S.K. (1981) Car-diovascular tumours in the cat. Journal of the AmericanAnimal Hospital Association, (17), 1009–21.

Turrell, J.M. (1987) Principles of radiation therapy. IIClinical Applications. In: Veterinary Cancer Medicine,(eds G.H. Theilen & B.R. Madewell), pp. 148–56. Lea& Febiger, Philadelphia.

Wood, C.A., Moore, A.S, Gliatto, J.M. et al. (1998) Prog-nosis for dogs with Stage I or II splenic haemangiosar-coma treated by splenectomy alone: 32 cases(1991–1993). Journal of the American Animal HospitalAssociation, (34), 417–21.

Appendices

Morrison, W.B. (1998) Cancer in Dogs and Cats. Medi-cal & Surgical Management. Williams & Wilkins,Pennsylvania.

Moulton, J.E. (ed.) (1990) Tumours in Domestic Animals,3rd edn. University of California Press.

Ogilvie, G.K. & Moore, A.S. (1995) Managing the Veteri-nary Cancer Patient (A Practice Manual). VeterinaryLearning Systems Co., Inc., Trenton, New Jersey.

Pavletic, M.M. (1999) Atlas of Small Animal Reconstruc-tive Surgery, 2nd edn. W.B. Saunders Company,Philadelphia.

Rijnberk, A. (ed.) (1996) Clinical Endocrinology of Dogsand Cats, Kluwer Academic Publishers, Dordrecht,Boston, London.

Slatter, D. (1993) Textbook of Small Animal Surgery, 2ndedn. W.B. Saunders Company, Philadelphia.

Theilen, G.H. & Madewell, B.R. (1987) Veterinary CancerMedicine, 2nd edn. Lea & Febiger, Philadelphia.

White, R.A.S. (ed.) (1991) BSAVA Manual of SmallAnimal Oncology. British Small Animal VeterinaryAssociation Publications, Cheltenham.

Withrow, S.J. & MacEwen, E.G. (1996) Small Animal Clinical Oncology, 2nd edn. J.B. Lippincott Company,Philadelphia.

Allwood, M. & Wright, P. (eds) (1993) The CytotoxicsHandbook, 2nd edn. Radcliffe Medical Press, Oxford.

Brown, N.O. (ed.) (1985) Clinical Veterinary Oncology.The Veterinary Clinics of North America series, 15 (3).W.B. Saunders, Philadelphia.

Brown, N.O. (ed.) (1985) Canine HaematopoieticTumours. The Veterinary Clinics of North Americaseries, 15 (4). W.B. Saunders, Philadelphia.

Chabner, B.A. & Collins, J.M. (eds) (1990) CancerChemotherapy. J.B. Lippincott, Philadelphia.

Dobson, J.M. & Gorman, N.T. (1993) Cancer Chemo-therapy in Small Animal Practice. Library of VeterinaryPractice Series, Blackwell Science Ltd, Oxford.

Feldman, E.C. & Nelson, R.W. (1996) Canine & FelineEndocrinology and Reproduction, 2nd edn. W.B.Saunders Company, Philadelphia.


Goute C.G. (ed.) (1990) Clinical Management of theCancer Patient. The Veterinary Clinics of NorthAmerica series, 20 (4). W.B. Saunders, Philadelphia.

Hahn, K. & Richarson, R.C. (ed.) (1995) CancerChemotherapy. A Veterinary Handbook. Williams &Wilkins, Pennsylvania.

279

I GENERAL READING LIST

� I General reading list� II Actions, indications and toxicity of cytotoxic

agents used in veterinary practice� III Body weight:surface area conversions� IV Protocols for administration of doxorubicin

and cisplatin� V Glossary of drugs and dosages included in

text

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II ACTIONS, INDICATIONS AND TOXICITY OF CYTOTOXIC AGENTS USED IN VETERINARY PRACTICE

1. ALKYLATING AGENTSAction: Substitute alkyl radicals (R-CH2-CH3) for hydrogen atoms in the DNA molecule. Alkylation of nucleotide bases causes breaks, cross-linkages and

abnormal base pairing in DNA, all of which interfere with replication of DNA and transcription of RNA. These actions are not cell cycle specific.Toxicity: All agents may cause: Myelosuppression

Gastrointestinal toxicity, anorexia, vomiting, diarrhoea.May also affect gametogenesis and cause alopecia or thinning of coat in some breeds of dog.

Individual agents/dose Indications Specific toxicity

Nitrogen mustard derivatives Cyclophosphamide Lymphoma and leukaemia Urologic – haemorrhagic cystitisEndoxanaTM (Cytoxan – US) Multiple myeloma50 mg/m2 po every other day, or daily (sarcomas/carcinomas in

for first 4 days of each week or combination protocols)250–300 mg/m2 po or iv every 3 Immunosuppressionweeks (do not exceed 250 mg/m2

in dogs)Chlorambucil Chronic lymphocytic leukaemia Myelosuppression – mildLeukeranTM Multiple myeloma2–10 mg/m2 po daily or every other Lymphoma (maintenance)

day (Polycythaemia vera)(Immunosuppression)

Melphalan Multiple myeloma Myelosuppression – may be delayedAlkeranTM Lymphoma in onset1–5 mg/m2 po daily or every other (Carcinomas and sarcomas in

day combination protocols)

Ethenamine derivatives Thiotepa Malignant effusions by instillation Myelosuppression – can follow local(triethylenethiophosphoramide) into body cavities instillation

see specific protocols Carcinoma of bladder by instillation

Alkyl suphonates Busulphan Chronic granulocytic leukaemia Pulmonary fibrosisMyleranTM Polycythaemia vera Endocrinological disorders2–6 mg/m2 po daily Ocular – lens changes

All rare

Triazine derivatives Dacarbazine Lymphoma Irritant – perivascular reactionsIn addition to alkylating actions, DTIC-DomeTM (Hepatotoxicity)

also inhibits DNA and 100 mg/m2 iv every 7 days orprotein synthesis 200–250 mg/m2 daily on days

1–5 repeating every 21–28 days

Nitrosureas Carmustine Brain tumours – malignant Myelosuppression: cumulative andLipophilic agents, pass into BiCNUTM glioma delayed due to stem cell toxicity

cerebrospinal fluid 50 mg/m2 iv every 3–6 weeks (Pulmonary fibrosis)Lomustine Brain tumours – as above Myelosuppression as aboveCCNUTM (?Mast cell tumours) Neurological reactions60–90 mg/m2 po every 3–6 weeks

Appendices

281

2. ANTI-METABOLITESAction:These agents are structural analogues of metabolites required for purine and/or pyrimidine synthesis.They interfere with DNA and RNA synthesis

by enzyme inhibition or by causing synthesis of non-functional molecules.Antimetabolites are cell cycle specific, acting during the S phase of the cell cycle.Toxicity: All agents may cause: Myelosuppression

Gastrointestinal toxicity (anorexia, vomiting, diarrhoea).Some agents may cause renal or neurological toxicity as noted

Individual agents/dose Specific indications Specific toxicity

Antifolates Methotrexate Lymphoma and leukaemia Renal tubular necrosisMaxtrexTM TVT1–3 mg/m2 po daily (Sertoli cell tumour)(see specific protocols) (Soft tissue sarcoma and osteosarcoma)

Pyrimidine analogues 5-Fluorouracil Carcinomas – especially mammary Neurological toxicity – cerebellar150–200 mg/m2 iv every 7 days Topical – basal and squamous cell ataxia and seizures(EfudixTM – topical preparation) carcinoma of the skin Do not use in cats

Cytarabine/Cytosine arabinoside Lymphoma and leukaemia100 mg/m2 iv or sc daily for 2–4 days or Especially in acute leukaemias

75 mg/m2 by infusion over 24 hours

Purine analogues 6-Mercaptopurine Lymphoma and leukaemiaPuri-netholTM

50 mg/m2 po daily or every other day

6-Thioguanine Lymphoma and leukaemiaLanvisTM

50 mg/m2 po daily or every other day

Azathioprine Immunosuppression (Hepatic toxicity reported in humans)AzamuneTM, BerkaprineTM, ImuranTM Use with care in cats1–2 mg/kg po every 24–48 hours (continued on p. 282.)

II Continued.

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3. ANTI-TUMOUR ANTIBIOTICSAction: These compounds, which are derived from soil fungi, form stable complexes with DNA, thus inhibiting DNA synthesis and transcription. These

actions are not cell cycle specific. This group contains some of the most potent and broad spectrum anti-cancer agents indentified to date.Toxicity: Myelosuppression is the major, dose-limiting toxicity (except bleomycin)

Gastro-intestinal toxicity – dose relatedAlso cause a diverse range of selective toxicities as detailed below.

Individual agents/dose Specific indications Specific toxicity

Doxorubicin Lymphoma and leukaemia Hypersensitivity(formerly Adriamycin) Soft tissue and osteogenic sarcoma Vesicant – perivascular reactionDogs (Carcinomas) Cardiac toxicity (acute and chronic/30 mg/m2 iv every 21 days or 10 mg/m2 cumulative)

iv every 7 days Nephrotoxic in catsCats Alopecia20 mg/m2 po every 3–6 weeks

Epirubicin As above Hypersensitivity(PharmorubicinTM) Vesicant – perivascular reaction30 mg/m2 iv every 21 days Cardiac toxicity (acute and chronic/

cumulative – less than doxorubicin)Alopecia

Mitozantrone Lymphoma and leukaemia Irritant – perivascular reaction(NovantroneTM) ?Soft tissue sarcoma Cardiac toxicity (less than doxorubicin)3–5 mg/m2 iv every 21 days ?Carcinomas Seizures reported in cats

Actinomycin D Lymphoproliferative disorders Alopecia(dactinomycin) Vesicant – perivascular reaction0.75 mg/m2 iv every 21 days

4. VINCA ALKALOIDSAction: Vinca alkaloids bind specifically to microtubular proteins (tubulin) and inhibit the formation of the mitotic spindle, thus blocking mitosis and

causing a metaphase arrest. These actions are cell cycle specific, acting during the M phase.Toxicity: see below


Vincristine Lymphoma and leukaemia Vesicant – perivascular reaction(OncovinTM) ?Mast cell tumours Peripheral and autonomic neuropathies0.5–0.75 mg/m2 iv every 7 days TVT Alopecia – mild

(Thrombocytopenia)

Vinblastine Lymphoma and leukaemia Myelosuppression(VelbeTM, VelbanTM) (Mammary and testicular carcinomas) Vesicant – perivascular reaction2.0–2.5 mg/m2 iv every 7 days Neurological

Gastro-intestinal

II Continued.

Appendices

283

5. MISCELLANEOUSPLATINUM CO-ORDINATION COMPOUNDSAction: Inhibit protein synthesis by the formation of both inter and intra cross links in the strands of DNA. The N7 atom of guanine is particularly reactive

and platinum cross-links between adjacent guanine bases on the same DNA strand are most readily demonstrated. These agents also act with other nucleophiles such as the sulphydryl groups of proteins and these reactions may produce some of the toxic effects.

Toxicity: Severe toxicity has limited veterinary use of these drugs.Gastro-intestinal toxicity is common with acute and severe vomiting mediated by direct actions on the chemoreceptor trigger zone.Nephrotoxicity is the main concern.


Cisplatin Osteogenic sarcoma Nephrotoxicity – acute proximal tubular necrosis(PlatinolTM) Carcinomas50–70 mg/m2 iv every 4 weeks Gastrointestinal tract – vomiting

(Vesicant)(Myelosuppression)Do not use in cats

Carboplatin Osteogenic sarcoma Myelosuppression(ParaplatinTM) Carcinomas Nephrotoxic – less than cisplatin300 mg/m2 iv every 3–4 weeks Nausea and vomiting – less than cisplatin

Irritant – perivascular reaction

L-asparaginase – cristantaspase Lymphoproliferative disease Hypersensitivity reactions(ErwinaseTM) (?mast cell tumours) GastrointestinalAction: An enzyme which hydrolyses Dose rate: 10 000–40 000 IU/m2 Haemorrhagic pancreatitis has been reported in

asparagine. Most normal mammalian im every 7 days the dogtissues synthesise sufficient asparagine forprotein synthesis. Lymphoid tumours do not have this ability and are therefore susceptible to the actions of asparaginase.

Hydroxyurea Polycythaemia vera MyelosuppressionAction: Inhibits DNA synthesis. Acts by Chronic granulocytic leukaemia

inhibiting the enzyme ribonucleoside Dose rate: 50 mg/m2 daily to effect ordiphosphate reductase. This enzyme acts 80 mg/kg every 3 daysat a critical and rate limiting step in thebiosynthesis of DNA. This action is cellcycle specific (S phase).

Mitotane Hyperadrenocorticism Nausea, vomitingAction: o.p’DDD is a derivative of the 50 mg/kg daily to effect then weekly Hypoadrenocorticism

chlorinated hydrocarbon insecticides. Itcauses destruction of the zona fasiculataand reticularis of the adrenal cortex,through actions on cytochrome P450

dependent enzymes in adrenocortical cells.

II Continued.


III BODY WEIGHT: SURFACE AREA CONVERSIONS

Table for conversion of body weight to surface area(dogs).

kg M2 kg M2

0.5 0.06 26.0 0.881.0 0.10 27.0 0.902.0 0.15 28.0 0.923.0 0.20 29.0 0.944.0 0.25 30.0 0.965.0 0.29 31.0 0.996.0 0.33 32.0 1.017.0 0.36 33.0 1.038.0 0.40 34.0 1.059.0 0.43 35.0 1.0710.0 0.46 36.0 1.0911.0 0.49 37.0 1.1112.0 0.52 38.0 1.1313.0 0.55 39.0 1.1514.0 0.58 40.0 1.1715.0 0.60 41.0 1.1916.0 0.63 42.0 1.2117.0 0.66 43.0 1.2318.0 0.69 44.0 1.2519.0 0.71 45.0 1.2620.0 0.74 46.0 1.2821.0 0.76 47.0 1.3022.0 0.78 48.0 1.3223.0 0.81 49.0 1.3424.0 0.83 50.0 1.3625.0 0.85

Table for conversion of body weight to surface area(cats).

kg M2 kg M2

2.0 0.159 3.6 0.2352.2 0.169 3.8 0.2442.4 0.179 4.0 0.2522.6 0.189 4.2 0.2602.8 0.199 4.4 0.2693.0 0.208 4.6 0.2773.2 0.217 4.8 0.2853.4 0.226 5.0 0.292

Appendices 285

IV PROTOCOLS FOR ADMINISTRATION OF DOXORUBICIN AND CISPLATIN

Doxorubicin administration

(1) Calculate required dose of drug according to body weight:surface area conversion. Usual dose = 30 mg/m2.(2) Reconstitute doxorubicin according to manufacturer’s instructions with water for injection or with saline, ideally

in biological safety cabinet. Load drug into syringe for administration. NB: Gloves, face mask and protectiveclothing should be used.

(3) Place an intravenous catheter into the cephalic vein and tape firmly in place, making sure it is patent and flusheseasily with saline. Connect 500 ml 0.9% saline via giving set and luer locking three-way tap.

(4) Pre-medicate with anti-histamine, e.g. chlorpheniramine.(5) Set saline to fast drip rate and administer the doxorubicin into the side port of the giving set over a 20–30

minute period, monitoring heart rate and rhythm, integrity of vein and observing for any adverse reactions.Discontinue the infusion if any problems occur.

(6) Flush through the catheter and distal end of the giving set with saline prior to disconnecting. Dispose of thebag, giving set, catheter and all other contaminated materials as cytotoxic waste, i.e. double bag and destroy byhigh temperature incineration.

(7) Continue to monitor the patient for the next 30–60 minutes for any delayed reaction.

NB: Gloves and face protection should be worn at all times and great care should be taken not to spill any doxorubicinor contaminate work surfacesIn the event of extravasation of doxorubicin or epirubicin the following action is recommended:Infiltrate the area with 2–5 ml 2.1% sodium bicarbonate, leave for 2 min and aspirate off. Paint DMSO topically tothe extravasated area, 2-hourly. Apply hydrocortisone cream and cold compresses.

Cisplatin administration

(for actual protocols see Chapter 6, Table 6.4)(1) Check haematology and renal function (BUN/creatinine).(2) Calculate required dose of drug according to body weight:surface area conversion – usual dose = 70 mg/m2.(3) Place an intravenous catheter into the cephalic vein and tape firmly in place, making sure it is patent and flushes

easily with saline.(4) Calculate required volume of saline per hour and drip rate necessary to administer it. Connect up bag of 0.9%

saline, and administer subsequent bags as needed. Monitor urine production – allow plenty of opportunities tourinate.

(5) If using mannitol, add required volume to a 500 ml bag of saline (empty some saline out of bag first to allow forextra volume) and change drip to this bag, approximately 30 minutes before cisplatin is due.

(6) Add required dose of cisplatin to a 500 ml bag of saline (empty some saline out of bag first). NB: Face mask,gloves, eye protection and over-clothing should be used.

(7) Pre-medicate with anti-emetic, e.g. metoclopramide (1 mg/kg im) and then connect cisplatin bag. Infuse slowlyover 15–30 minutes.

(8) Disconnect cisplatin bag and dispose of carefully as cytotoxic waste. Reconnect 0.9% saline and completeinfusion protocol.

NB: All urine should be regarded as contaminated for 24 hours after administration and protective clothing and glovesshould be worn to handle the patient during this period.In the event of extravasation of cisplatin the following action is recommended:Infiltrate the area with 2–5 ml of 3% sodium thiosulphate, aspirate off. Give 1500 units hyaluronidase around the areaand apply heat and compression.

In the event of extravasation of vincristine or vinblastine the following action is recommended:Infiltrate the area with 1500 units of hyaluronidase and apply heat and compression.

Indications: Potent antitussive. Suppression ofmild to moderate pain.

Forms: Injectable 10mg/ml solution, oral 1mg,5mg, 10mg tablets.

Dose: For analgesia: Dogs: 0.3–0.4mg/kg iv, im,sc, q 6–8 hours

Cats: 0.05–0.6mg/kg im, scq 6–8 hours.

Cabergoline (GalastopTM) POM

Action: Ergoline derivative with potent and selective inhibitory effect on prolactin secretion.

Indications: Treatment of pseudopregnancy inbitches and termination of lactation.

Forms: Oral: aqueous solution, 50mg/ml.Dose: Bitches for pseudopregnancy: 5mg/kg po

every 24 hours for 4–6 days.

Calcium carbonate (CanovelTM calciumtablets) GSL

Indications: Calcium supplementation, also usedas intestinal phosphate binder to reduce phos-phate absorption in patients with renal failureand as an antacid.

Forms: Oral: 420mg calcium carbonate tablet.Dose: Dogs and cats: 20–100mg/kg po q 8 hours.

Carbimazole (Neo-MercazoleTM) POM*

Action: Carbimazole is metabolised to the activedrug methimazole which intereferes with the synthesis of thyroid hormones.

Indications: To control thyroid hormone levels incats with hyperthyroidism.

Forms: Oral: 5mg tablet.Dose: 5mg/cat po every 8 hours.

Chlorpheniramine (PiritonTM) P*

Action: Antihistamine H1 antagonist.Indications: Used in the management/prevention

of allergies and anaphylactic reactions.Forms: Injectable 10mg/ml solution

Oral: 4gm tablet, 2mg/5ml oral syrup.Dose: Dogs: Small – medium 2.5–5mg im q 12

hours (or as premedication)


V GLOSSARY OF DRUGS AND DOSAGES INCLUDED IN TEXT

* Signifies human medicinal product not licensedfor veterinary use.

Alendronate (FosamaxTM) POM*

Forms: Oral 10mg tablet.Dose: Dogs: 10mg q 24 hours po.

Bismuth subsalicylate (PeptoBismolTM)GSL*

Actions: Cytoprotectant and anti-inflammatoryactions on GIT

Indications: Prevention/treatment of doxorubicininduced enterocolitis.

Form: Oral suspension.Dose: 3–15ml po q 6–8 hours.

Bisphosphonates

Action: Bisphosphonates are adsorbed ontohydroxyapatite crystals, slowing their rate of formation and dissolution.

Indications: Used for symptomatic treatment of hypercalcaemia, when other therapies are noteffective. (Possible palliative role in treatment of bone tumours.)

Bromocriptine (Bromocriptine,ParodelTM) POM*

Action: Dopamine agonist which inhibits releaseof prolactin and growth hormone by the pituitarygland.

Indications: Has been used in the management of pituitary-dependent hyperadrenocorticism(PDH) in dogs, although not very effective.Possible use for counteracting excess growthhormone in acromegaly in cats, again not veryeffective.

Forms: Oral: 1mg, 2.5mg tablets, 5mg, 10mg capsules.

Dose: PDH in dogs: 0.05mg/kg po every 12 hours.

Butorphanol (TorbugesicTM, TorbutrolTM)POM

Action: Mixed agonist/antagonist opioid withmedium duration of action.

Appendices 287

Medium – large 5–10mg im q 12hours (or as premedication)

(Cats: 2–4mg/cat po q 8–12 hours).Note: Maximum recommended dose is 0.5mg/kg

q 12 hours in both cats and dogs.

Cimetidine (TagametTM) POM*

Action: Histamine (H2) receptor antagonist.Indications: Prevention and management of

gastric and duodenal ulceration.Forms: Injectable: 100mg/ml solution.

Intravenous infusion: 4mg/ml in NaCl.Oral: 200mg, 400mg, 800mg tablets,

40mg/ml syrup.Dose: Dogs: 5–10mg/kg iv, im, po q 6–8 hours.

Cats: 2.5–5mg/kg iv, im, po q 8–12 hours.Note: Retards oxidative hepatic drug metabolism

by binding to P450. This may increase the plasmalevels of some drugs and could exacerbate side-effects such as leucopenia.

Clodronate (BonefosTM, LoronTM) POM*

Forms: Injectable 30mg/ml, 60mg/ml, oral 400mgcapsule.

Dose: Dogs: 5–14mg/kg q 24 hours iv. or 10–30mg/kg q 8–12 hours po.

Cyproheptadine (PeriactinTM) P*

Action: Antihistamine and serotonin antagonist.Indications: Various indications described includ-

ing symptomatic relief in cases of allergic skindisease. Used in oncological patients as anappetite stimulant.

Forms: Oral: 4mg tablet.Dose: For appetite stimulation: cats and dogs:

0.1–0.5mg/kg po q 8–12 hours.Deoxycortone acetate/pivalate

Deoxycortone acetate/pivalate

Action: Steroid secreted by the adrenal cortexwhich has primarily mineralocorticoid activityand no significant glucocortioid action.

Indications: Treatment of adrenal insufficiency.Forms: Solution for injection.Dose: Dogs: starting dose of 2.2mg/kg by deep im

injection every 4 weeks.

Desmopressin (DDAVP) POM*

Action: Analogue of vasopressin.Indications: Diagnosis and treatment of central

diabetes insipidus.Forms: Intranasal drops: 100mg/ml solution

(for topical use).Injectable: 4mg/ml solution.

Dose: For treatment of diabetes insipidusCats: 5mg/cat topically onto the conjunctiva every 8–24 hoursDogs: 5–40mg/dog topically onto the conjunctiva every 8–24 hours.

Diazoxide (EudemineTM) POM*

Actions: Benzothiazide diuretic which alsoinhibits insulin secretion by blocking calciummobilisation.

Indications: In the management of hypogly-caemia associated with insulinoma.

Forms: Oral 50mg tablet.Dose: Dogs: hypoglycaemia: 3.3mg/kg po every 8

hours, increasing to 20mg/kg po every 8 hours.

Dihydrotachysterol

Action: Vitamin D analogue, influences calciumand phosphorus metabolism. Raises serumcalcium within 1–7 days.

Indications: Hypocalcaemia.Forms: Oral: 0.25mg/ml aqueous liquid.Dose: 0.01–0.03mg/kg po every 24 hours initially

then 0.01–0.02mg/kg every 24–48 hours for maintenance.

Dimethylsulphoxide (DMSO) POM*

Actions: Various pharmacological actions includ-ing free radical scavenging, membrane stabilisa-tion, analgesia and anti-inflammatory actions.

Indications: Various but including topical use inthe management of cyclophosphamide inducedhaemorrhagic cystitis.

Forms: 50%, 90% liquid.Dose: For topical application to urinary bladder.

10ml of 50% solution, diluted in equal volume of sterile water, instilled into bladder for 20minutes. Repeat at weekly intervals if necessary.

Notes: Solution is very hygroscopic and should be

Forms: Oral: 0.1mg tablet.Dose: Dogs and cats start at 0.01mg/kg po every

24 hours. Monitor sodium and potassium levelsand adjust dose accordingly.

Frusemide (DiurideTM, FrusecareTM,LasixTM) POM

Actions: ‘Loop diuretic’, inhibits reabsorption ofchloride and sodium in the ascending loop ofHenle and thus promotes naturesis and reduceswater reabsorption.

Indications: Diuresis, e.g. hypercalcuricnephropathy.

Forms: Injectable: 50mg/ml solutionOral: 20mg, 40mg, 1g tablets.

Dose: Standard dose 2mg/kg po q 8–12 hours.For hypercalcaemic nephropathy may give up to5mg/kg bolus iv then begin 5mg/kg/hour infu-sion. Maintain hydration and electrolyte balancewith normal saline and added KCl. Monitor urineoutput and calcium.

Note: Ensure patient is hydrated before therapy.

Isotretinoin (RoaccutaneTM)*(Hospital only)

Acitretin (NeotigasonTM)* (Hospital only)

Action: Vitamin A derivatives used in treatmentof severe acne in human patients.

Indications: Possible therapeutic benefit in treat-ment of epitheliotrophic lymphoma.

Forms: 5mg, 25mg capsules.Dose: Isotretinoin: 1.7–3.7mg/kg po daily

Acitretin: 0.7–1.0mg/kg po daily.Note: These agents are teratogenic and will only

be supplied on a named patient basis.

Ketoconazole (NizoralTM) POM*

Actions: Broad spectrum imidazole antifungalagent. Also inhibits cytochrome P450 dependentenzymes which results in decreased synthesis ofadrenal and gonadal steroids.

Indications: In addition to antifungal properties,has been used in the treatment of hyperadreno-corticism (HAC) in dogs.

Forms: Oral: 200mg tablet, 100ml, 5ml oral suspension.

Dose: Dogs: for HAC 5mg/kg po every 12 hours


kept in tightly closed container. DMSO is rapidlyabsorbed through intact skin; handle with careand wear gloves. Do not mix with potentiallytoxic compounds as DMSO may promote theirsystemic absorption.

Edrophonium chloride (Edrophonium,CamsilonTM) POM*

Actions: Rapid and short-acting anticholines-terase drug.

Indications: In the diagnosis of myasthenia gravis.Forms: Injectable: 10mg/ml solution.Dose: Dogs: 0.11–0.22mg/kg iv

Cats: 2.5mg/cat ivImprovement should be noted within 30 seconds and wane within 5 minutes.

Note: Atropine should be available (0.05mg/kg)to control cholinergic side-effects.

Etidronate (DidronelTM) POM*

Forms: Injectable 50mg/ml, 60mg/ml, oral 200mgtablet.

Dose: Dogs: 7.5mg/kg q 24 hours iv for 3 days or 20mg/kg q 24 hours po. (?Efficacy of oral route.)

G-CSF: Filgrastim (Neupogen) POM,Lenograstim (Granocyte) POM*

Actions: Human recombinant granulocyte colonystimulating factors (rHuG-CSF), stimulates gran-ulocyte production.

Indications: Management of chemotherapy-induced neutropenia, neutrophil counts risewithin 24 hours of treatment.

Forms: Filgrastim: Injectable: 300mg/ml (30million units per ml) solution.Lenograstim: Injectable 263mg powder in vial forreconstitution.

Dose: Filgrastim: Cats, dogs: 5–20mg/kg sc q 12–24hours for 1–2 weeks.Lenograstim: Cats, dogs; insufficient information.

Fludrocortisone acetate (FlorinefTM)POM*

Actions: Mineralocorticoid with weak glucocorti-coid activity.

Indications: Treatment of hypoadrenocorticism.

Appendices 289

for 7 days increasing to 10mg/kg q 12 hours if noadverse effects seen.

Lithium carbonate (Camcolit) POM*

Actions: Stimulates bone marrow stem cells.Indications: May be of value in the treatment of

cytotoxic drug-induced myelosuppression, aplas-tic anaemia, cyclic haematopoiesis.

Forms: Oral: 250mg, 400mg tablets.Dose: Dogs: 10mg/kg po q 12 hours.Note: Avoid concurrent use with diuretics,

NSAIDs, ACE inhibitors and calcium channelblockers.

Medroxyprogesterone acetate(Promone-ETM, PerlutexTM) POM

Actions: Long acting progestogen.Indications: Various including control of oestrus

in queen and bitch, management of prostatichypertrophy, treatment of feline miliary dermatitis.

Forms: Injectable: 25mg/ml, 50mg/ml suspensionOral: 5mg tablet.

Dose: Depends on indication. For prostatichypertrophy in dogs 50–100mg/dog sc every 3–6months.

Megoestrol acetate (OvaridTM) POM

Actions: Oral progestagen.Indications: Prevention and postponement of

oestrus in the bitch and queen and managementof pseudopregnancy. ?Treatment of oestrogen-dependent mammary tumours.

Forms: Oral: 5mg, 20mg tablets.Dose: Depends on indication.

Metoclopramide (EmequellTM,Maxalon*) POM

Actions: Anti-emetic and upper GI tract stimu-lant. Inhibits vomiting by blocking dopamine atthe chemoreceptor trigger zone, also inhibits thevomiting reflex peripherally by: increasing oeso-phageal sphincter pressure, gastric tone and con-tractions and peristaltic activity in the upper smallintestine and by relaxing the pyloric sphincter.

Indications: Treatment/prevention of vomiting.

Forms: Injectable: 5mg/ml solutionOral: 10mg tablet (Emequell), 1mg/ml syrup (Maxalon).

Dose: Cats and dogs: 0.5–1mg/kg im, sc po q 6–8hours, or 1–2mg/kg as a slow iv infusion over 24hours.

Note: May cause sedation, extrapyramidal effectsand changes in behaviour especially if adminis-tered iv. Also reduces renal blood flow which may exacerbate pre-existing renal disease (seecisplatin administration).

Metyrapone (Metopirone) POM*

Action: Reduces cortisol synthesis by competitiveinhibition of 11b-hydroxylation, thereby block-ing the conversion of 11-deoxycortisol to cortisol.

Indication: In humans may be used as a test ofanterior pituitary function. May have a role in themedical management of hyperadrenocorticism incats (see text).

Forms: Oral: 250mg capsules.Dose: Cats: 65mg/kg every 8–12 hours.

Note: Potential side-effects include, depression,tremors, ataxia, hypocortisolaemia.

Octreotide (SandostatinTM) POM*

Action: Somatostatin analogue.Indications: To decrease growth hormone levels

in acromegaly. Also inhibits secretion of insulinby normal and neoplastic cells and thus may beuseful in the management of insulinoma.

Forms: Injectable: 50, 200, 500ug/ml solution.Dose: 1mg/kg sc q 8 hours. Information on the use

of this drug in cats and dogs is limited.

Omeprazole (LosecTM) POM*

Actions: Proton pump inhibitor, potent inhibitorof gastric acid secretion.

Indications: Treatment of gastric hyperacidity andulceration, especially associated with gastrin producing tumours (gastrinoma) and mast celltumours.

Forms: Oral 10mg, 20mg, 40mg capsules.Dose: Dogs: 0.5–1.5mg/kg po every 24 hours.

Ondansetron (ZofranTM) POM*

Actions: 5HT3 antagonist.Indications: Prevention and treatment of radia-

tion or chemotherapy induced emesis.

Forms: Oral: 15mg tablet.Dose: GI indications: 0.25mg/kg po q 8–12

hours.

Propranolol (Inderal, Propranolol)POM*

Actions: Beta adrenoceptor antagonist, antago-nises chronotropic and inotropic effects of beta 1 adrenoceptors on the heart and blocksvasodilatory actions of beta 2 adrenoceptors.

Indications: In the treatment of cardiac arrhyth-mias and tachycardia,hypertension,and to reducesome of the cardiac effects of hyperthyroidismprior to surgery.

Forms: Oral 10mg, 40mg, 80mg, 160mg tablets.Dose: Cats: 2.5–5mg/cat po every 8 hours.

Pyridostigmine (Mestinon) POM*

Actions: Long acting anticholinesterase agent.Indications: Used in the treatment of myasthenia

gravis.Forms: Oral 60mg tablets.Dose: Dogs: 0.2–5mg/kg po every 8–12 hours.Note: May cause cholinergic effects necessitating

dose reduction.

Ranitidine (ZantacTM) POM*

Action: Histamine (H2) receptor antagonist.Indications: Prevention and management of

gastric and duodenal ulceration.Forms: Injectable: 25mg/ml solution.

Oral: 150mg, 300mg tablets, 12.5mg/mlsyrup.

Dose: Dogs: Ranitidine: 2mg/kg slow iv sc po q8–12 hours.

Cats: Ranitidine: 2mg/kg/day constant ivinfusion, 2.5mg/kg slow iv q 12 hours,3.5mg/kg po q 12 hours.

Note: Retards oxidative hepatic drug metabolismby binding to P450. This may increase the plasmalevels of some drugs and could exacerbate side-effects such as leucopenia.

Sucralfate (AntepsinTM) POM*

Actions: Complex of aluminium hydroxide and sulphated sucrose, binds to proteinaceous exu-date in GI tract thus protecting against furthererosion. Also stimulates mucosal defences andrepair mechanisms.


Forms: Injection 2mg/mlOral: 4mg, 8mg tablets (very expensive),

syrup 4mg/5ml (Suppositories: 16mg).Dose: 0.1mg/kg iv immediately before

chemotherapy and every 6 hours thereafter.

Pamidronate (ArediaTM) POM*

Forms: Injectable 50mg/ml, 60mg/vial, powderfor reconstitution.

Dose: Dogs: 0.9–1.3mg/kg infusion over 24 hours,once.

Notes: Adverse effects may include: nausea, vom-iting, hypocalaemia, hypophosphataemia, hypo-magnesaemia and hypersensitivity reactions.

Phenoxybenzamine (Dibenyline) POM*

Actions: Alpha adrenergic blocker.Indications: In the treatment of hypertension in

animals with phaeochromocytoma prior tosurgery (in conjunction with a beta blocker).Alsoused for treatment of reflex dyssynergia.

Forms: Oral 10mg capsule.Dose: Dogs: hypertension associated with

phaeochromocytoma: 0.2–1.5mg/kg po every 12hours, starting at a low dosage and increasinguntil the hypertension is controlled.

Note: Should be used in conjunction with a betablocker for treatment of phaeochromocytoma toavoid possible hypertensive crisis.

Piroxicam POM*

Actions: NSAID which inhibits cyclo-oxygenase-1. Anti-inflammatory, antipyretic and analgesiceffects.

Indications: In addition to standard NSAIDeffects, piroxicam has been used for palliativetreatment of transitional cell carcinoma of thecanine urinary bladder.

Forms: Oral 10mg, 20mg capsules.Dose: Dogs: 0.3mg/kg po q 24 hours.Note: Possible gastro-intestinal and renal toxicity.

Propantheline bromide (Pro-Banthine)POM*

Actions: Anti-muscarinic, anti-cholinergic agent.Indications: Various including, peripherally acting

anti-emetic and antispasmodic.

Appendices 291

Indications: Oesophageal, gastric and duodenalulceration.

Forms: Oral: 1g tablet, 0.2g/ml suspension.Dose: Cats: 250mg/cat po q 8–12 hours.

Dogs: <20kg, 500mg/dog po q 6–8 hours,>20kg 1–2g/dog po q 6–8 hours.

Note: Sucralfate may decrease bioavailability ofH2 antagonists and interfere with absorption offluoroquinolones.

Tamoxifen (Tamoxifen, NolvadexTM)POM*

Action: Tamoxifen is an oestrogen receptorantagonist.

Indications: Adjuvant, hormonal treatment forbreast cancer in post-menopausal women at highrisk of metastatic disease following surgical man-agement of primary tumour. Efficacy of this drugin bitches is unproven (see Chapter 12).

Forms: 10mg, 20mg and 40mg tablets.Dose: Women: 20mg daily

Therapeutic dose not established in thebitch.

Tetracosactrin (ACTH) (Synacthen)POM*

Action: Analogue of adrenocorticotrophic hor-mone (ACTH).

Indications: Used to stimulate cortisol productionfor the diagnosis of hyperadrenocorticism.

Forms: Injectable: 0.25mg/ml solution.Dose: Cats and dogs < 5kg body weight, 0.125mg

iv. Dogs > 5kg body weight 0.25mg iv.

For further details on ACTH stimulation test andinterpretation of results see texts on endocrinology.

Thyroxine (L-thyroxine, soloxine) POM

Action: Levothyroxine is a synthetic form of thyroxine.

Indications: HypothyroidismForms: Oral: 0.05mg, 0.1mg, 0.2mg, 0.3mg,

0.5mg, 0.8mg tablets.Dose: Cats and dogs, 0.02–0.04mg/kg/day po.

Monitor serum T4 levels.

Please note: page numbers in boldrefer to tables.

AC protocol for sarcomas, 76acromegaly, 205, 213, 214acanthomatous epulis, oral, see basal

cell carcinomaacemannan, 48, 76ACTH, see adrenocorticotrophic

hormoneACTH stimulation test, 217–18actinomycin D, 157, 237acute leukaemia, 239acutely transforming viruses, 8adamantinoma, 108adenocarcinoma

of the anal sac, see peri-anal tumoursof the intestine, 131–5of the nasal cavity, 98of the ovary, 166–9of the prostate, 180–83of the stomach, 127–30radiosensitivity of, 36

adenohypophysis, 213adjunctive chemotherapy, 41administration of cytotoxic drugs, 46adnexal tumours, 54–5adrenal tumours, 216–21

cortical, 216–19epidemiology/aetiology, 216investigations, 217–18paraneoplastic syndromes, 217pathology/tumour behaviour,

216–17presentation/signs, 217prognosis, 219staging, 218treatment, 219

medullary, 220–21adrenocorticotrophic hormone

from anterior pituitary, 213from medullary thyroid carcinoma,

206adriamycin, see doxorubicinAgNORs, agrophilic nucleolar

organiser regions, 17

air pollution, as cause of cancer, 10alimentary system, as site of tumour

development, 1see also gastro-intestinal tract,

tumours ofalkylating agents, 39ameloblastoma, 110anaemia, from myelosuppression, 42

Coomb’s positive, 246–7see also haematological

complications of tumoursanal sac tumours, see peri-anal tumoursanaplastic sarcoma, see soft tissue

sarcomaanatomical classification of tumours,

see stagingangiogenesis by tumours, 42anorexia

chemotherapy induced, 42tumour induced, 25

antibiotics, anti-tumour, 39antibiotic therapy for chemotherapy

induced infection, 43anti-metabolites, 39anti-oestrogen therapy, 9anti-tumour antibiotics, see antibiotics,

anti-tumourapocrine gland tumours, see peri-anal

tumoursappendicular osteosarcoma, see

osteosarcoma, long boneasparaginase, 39, 43, 65, 238, 243aspergillus serology, 99astrocytoma, 193, 200aural tumours, see ear tumoursautogenous vaccination, 47

BCG immune stimulation, 48, 190basal cell carcinoma

cutaneous, 54oral, 109–10

Bence-Jones proteins, 246, 248bile duct tumours, 138biological approaches to cancer

therapy, see novel methods ofcancer therapy

biopsy techniques, 16–17for bone tumours (jamshidi core

technique), 85for nasal tumours, 101

bisphosphonates, 29, 249bladder tumours, 158–62

aetiology, 159epidemiology, 158–9investigations, 160–61paraneoplastic syndromes, 159pathology, 159presentation/signs, 160prognosis, 162staging, 161treatment, 161–2tumour behaviour, 159

blast cell crisis, 240bleeding disorders

in acute leukaemia, 241in multiple myeloma, 246–7in splenic haemangiosarcoma, 273–

4body weight to body surface area

conversion, 41bone marrow aspirates, 242, 234, 248bone marrow suppression, see

myelosuppressionbone (and cartilage) tumours, 78–89

aetiology, 78–9epidemiology, 78investigations, 83–5pathology, 79–81paraneoplastic syndromes, 82–3presentation/signs, 83prognosis, 88–9staging, 85treatment, 85–8tumour behaviour, 81–2

brain tumours, 192–9aetiology, 192classification of, 193epidemiology, 192investigations, 195–7magnetic resonance imaging of,

195–6pathology, 192–3

Index

292

Index 293

presentation/signs, 194–5prognosis, 199staging, 197treatment, 197–9tumour behaviour/paraneoplastic

syndromes, 193–4see also pituitary tumours

brainstem auditory evoked potential,197

busulphan, 244

cachexia, 25calcitonin

for treatment of hypercalcaemia, 29from medullary thyroid tumours, 206

calcium, 26–9for treatment of

hypoparathyroidism, 209, 212cancer

causes of, 4–10definition of, 4incidence of, 1impaired cell differentiation in, 4inherited/familial, 10molecular changes in, 5multistep process in, 4pathogenesis of, 4–10

canine cutaneous histiocytoma, 66carbimazole, 210cardiac tumours, 266–70

aetiology, 266epidemiology, 266investigations, 267–8paraneoplastic syndromes, 267pathology, 266presentation/signs, 267prognosis, 269–70staging, 269treatment, 269tumour behaviour, 267

capsules, safe handling, 45carmustine, 198carboplatin, 39, 44, 76

for blader carcinoma, 162for osteosarcoma, 87

carcinomabasal cell, 54of the bladder, 159–62gastric, 127–30hepatocellular, 138intestinal, 130–35of the lung, 148–53mammary, 184–90nasal, 98–104pancreatic, 141–2prostatic, 180–83thyroid, 205–10transitional cell, see transitional cell

tumourcardiotoxicity, doxorubicin induced, 45cell

communication and adhesion,alteration of, 4

cycle, 35differentiation, 16

neoplastic transformation, 4oxygenation, 35pleomorphism, 16

central nervous system, tumours of, seenervous system

cerebrospinal fluid, analysis of, 197, 210ceruminous gland adenocarcinoma,

119–21chemical factors, see carcinogenschemodectoma, 266–70chemoreceptor trigger zone, 42chemotherapy, 39–46

adjunctive therapy, 41combination therapy, 41complications of, 41–5dosage and timing, 41indications for use, 41principles of, 39safe handling of, 45–6stages of (induction, maintenance,

rescue), 40see also cytotoxic drugs and specific

drug nameschlorambucil, 244, 236, 237chlorpheniramine, 29, 43cholangiocellular

adenoma/adenocarcinoma, 138chondroma, (chondroma rodens),

79–80chondrosarcoma, see bone (and

cartilage) tumourschromosomal abnormalities causing

cancer, 5–7chromosome analysis in transmissible

venereal tumour, 179chronic inflammation, as cause of

cancer, 10, 70chronic leukaemia, 239clinical tumour staging systems, see

stagingcimetidine

therapy in mast cell tumour, 29therapy in melanoma, 48

cisplatin, 39, 44for carcinomas, 153, 162, 190, 210intracavitary/peritoneal lavage, 169,

271nephrotoxicity, 45for osteosarcoma, 87

CL/Mab, 231, see monoclonal antibodyCOAP therapy for lymphoma, 235colony stimulating factors, 42, 243computed tomography

in staging, 20–21for brain tumours, 195–6for nasal tumours, 101

COP therapy for lymphoma, 235COPA therapy for lymphoma, 236corticosteroids, see glucocorticoidscraniomandibular osteopathy, 117–18craniopharyngioma, 213Cushing’s syndrome, 217–19

see also hyperadrenocorticismcutaneous

histiocytoma, 66

histiocytosis, 66–7lymphoma, 63–5, 232manifestations of tumours, 27tumours, see skin tumours

cyclophosphamide, 39, 76for carcinomas, 153, 157, 162, 190,

210in combination chemotherapy,

236–8, 243–4, 248, 269, 275haemorrhagic cystitis induced by, 44

cystadenoma/adenocarcinoma of ovary,166

cystic endometrial hyperplasia, 168, 172cytarabine, see cytosine arabinosidecytokines

production by tumour, 25for treatment of neutropenia, 35for immunostimulation, 48

cytology, 17cytosine arabinoside, 243, 236–7cytotoxic drugs

mode of action, 39principle of administration, 40safe handling of, 45–6

dacarbazine, 76, 238dexamethasone tests for

hyperadrenocorticism, 218diagnosis of tumours, 15–17

cytology, 17histology, 15–17

diagnostic evaluation of cancer patient,29

diagnostic imaging, see computedtomography; magneticresonance imaging; radiography;radioisotope imaging; andultrasonography

diazoxide, 223disseminated intravascular coagulation,

23in acute leukaemia, 241in haemangiosarcoma, 267, 273heparin therapy for, 23

DNA ploidy, 16DNA tumour viruses, see virusesdoxorubicin, 39, 44, 92

administration, 45for carcinomas, 153, 157, 190, 210cardiotoxicity, 45for leukaemia, 243for lymphoma, 237–8for soft tissue sarcoma, 76, 269, 275

drug resistance, 39multidrug resistance, 40

dysgerminoma, 167–9

ear tumours, 118–21aetiology, 119epidemiology, 118investigations, 120pathology, 119prognosis, 120–21staging, 120treatment, 120

294 Index

gall baldder tumours, 138gastric tumours, 127–30

aetiology, 127classification of, 127epidemiology, 127investigations, 128–9paraneoplastic syndromes, 128pathology, 127–8presentation/signs, 128prognosis, 130staging, 129treatment, 129–30tumour behaviour, 128

gastrinoma, 224–5gastrointestinal toxicity, chemotherapy

induced, 42gastrointestinal tract, tumours of,

125–42see also gastric; hepatic; intestinal;

oseophageal; pancreatic; andperi-anal tumours

geneticbasis of cancer, 4–10

inherited events, 10–11spontaneous events, 5–7

genital tract tumours, 166–83see also ovarian; penile and

preputial; prostatic; testicular;uterine and cervical; vaginal andvulval tumours

giant cell tumour of bone, 80glial cell tumour, 193, 200glioma, 192glucagonoma, 225–6glucocorticoid therapy

for brain tumours, 199for haemorrhagic cystitis, 44in hypercalcaemia, 28in hyperhistaminaemia, 29for hypoadrenocorticism, 219

granular cell myoblastoma, 116granulocyte colony stimulating factor,

42granulocyte/monocyte colony

stimulating factor, 42granulocytic leukaemia, see leukaemiagranulomatous/histiocytic skin

conditions, 66–7granulosa cell tumour, 167–9growth fraction, 35, 40growth factor receptors, 48

haemangiopericytoma, see soft tissuetumours

haemangioma, see soft tissue tumourshaemangiosarcoma

of right atrium, 266–70of spleen, 272–5see also soft tissue tumours

haematological assessment of cancerpatitent, 24

haematological complications oftumours, 22–4

haematopoietic growth factors, 243, 246see also colony stimulating factors

haematopoietic system, tumours of,

228–49see also leukaemia; lymphoma;

multiple myelomahaematopoietic tissues as site of

cancer, 1haemorrhagic cystitis from

cyclophosphamide therapy, 44hair follicle tumours, 54hepatic tumours, 137–40

aetiology, 137classification of, 138epidemiology, 137investigations, 139–40paraneoplastic syndromes, 139pathology, 137–9presentation/signs, 139prognosis, 140staging, 140treatment, 140tumour behaviour, 139

hepatocellularadenoma/adenocarcinoma, 138

hepatocutaneous syndrome, 27, 225hepatoid galnd tumours, see peri-anal

tumourshistamine release from mast cell

tumours, 29histiocytoma, cutaneous, 66histiocytosis

cutaneous, 66–7malignant, see malignant (and

systemic) histiocytosis; softtissue tumours

sytemic, see malignant (andsystemic) histiocytosis

histological examination of tumour,15–17

histological features of malignancy, 16histological grading of sarcomas, 73hormonal causes of cancer, 9hormone therapy, 9hydroxyurea, 244–5hyperadrenocorticism

adrenal dependent, 25, 216–19pituitary dependent, 25, 212–16

hypercalcaemia, cancer associated,26–9

clinical signs of, 26diagnosis of, 26–7investigation of, 28treatment of, 28–9

hypergammaglobulinaemia, 23–4in chronic lymphocytic leukaemia,

240–45in multiple myeloma, 246–9

hypergastrinaemia, 25, 224–5hyperhistaminaemia, 26, 29hyperparathyroidism, 25, 211–12hyperproteinaemia, 247hypersensitivity reactions of cytotoxic

drugs, 43hypertension, 205, 220–21hyperthyroidism, 25, 204–10hyperthermia, 47hypertrophic (pulmonary) osteopathy,

27, 149–50

tumour behaviour/paraneoplasticsyndromes, 119

effusion, differential diagnosis of, 270electrocardiography, 268electroencephalography, 197enchondroma, 80endocrine complications of tumours,

24–30endocrine system, tumours of, 204–26

see also adrenal; pancreatic;parathyroid; pituitary; andthyroid tumours

endoscopy of diagnosis and staging, 19eosinophilic ganuloma, 94ependymoma, 193, 200epirubicin, 39, 44epithelial tumours, skin, 53–8epitheliotropic lymphoma, 64, 232epulides, 108–10epulis

oral acanthomatous, see basal cellcarcinoma

fibromatous/ossifying, see peripheralodontogenic fibroma

erythremic myelosis, 245erythroleukaemia, 245erythropoietin, 24excisional biopsy, 16external causes of cancer

chemicals, 10hormones, 9parasites, 8–9, 70radiation, 9–10, 70trauma/chronic inflammation, 10, 70UV light, 9, 50, 57, 94viruses, 7–8, 70

eye tumours, 252–61aetiology, 252epidemiology, 252see also ocular tumours; orbital

tumourseyelid and conjunctival tumours, 252–6

classification of, 253investigations, 255paraneoplastic syndromes, 254pathology, 252presentation/signs, 254prognosis, 256staging, 255treatment, 255tumour behaviour, 254

feline immunodeficiency virusdiagnostic tests, 232–3in leukaemia/lymphoma, 229, 240

feline leukaemia virusoncogenesis, 7–8diagnostic tests, 232–3in leukaemia/lymphoma, 229, 239–40

feminising syndrome, canine, 176fibroma, of uterus and vagina, 169–74

see also soft tissue tumoursfibrosarcoma, of oral cavity, 112–13

see also soft tissue tumoursfine needle aspiration, 175-fluoruracil, 39, 153, 157, 162, 190, 256

Index 295

hyperviscosity, 23–4, 241, 246–9hypocalcaemia, treatment of, 209–12hypoglycaemia, 25–6, 139hypoparathyroidism, 209hypothyroidism, 209, 213

immunoglobulin production byneoplastic cells, seehypergammaglobulinaemia

immunotherapy, 47–8incidence of cancer, 1–2induction and maintenance therapy, see

chemotherapy; and lymphoma,treatment of

incisional biopsy, 16infection following chemotherapy, 42inflammation as cause of cancer, 10injectable solution (safe handling), 46insulinoma, 222–4intracutaneous cornifying epithelioma,

54interferon, 25, 48interstitial cell tumour of testis, 175intestinal tumours, 130–35

aetiology, 130classification, 131epidemiology, 130investigations, 132–3paraneoplastic syndromes, 132pathology, 131–2presentation/signs, 132prognosis, 134–5staging, 133treatment, 133–4tumour behaviour, 132

joint and joint associated tumours,89–92

aetiology, 89classification of, 90epidemiology, 89investigations, 90–91paraneoplastic syndromes, 90pathology, 89presentation/signs, 90prognosis, 92staging, 91treatment, 91–2tumour behaviour, 89

ketoconazole therapy forhyperadrenocorticism, 219

kidney tumours, see renal tumours

L-asparaginase, see asparaginaselaryngeal tumours, 144–6

aetiology, 144epidemiology, 144investigations, 145–6pathology, 144paraneoplastic syndromes, 145presentation/signs, 145prognosis, 146–7staging, 146treatment, 146tumour behaviour, 145

leiomyoma of uterus and vagina,169–72

see also soft tissue tumoursleiomyosarcoma, see soft tissue

tumoursleukaemia, 239–45

acute lymphoblastic, 239myeloid, 239monocytic/myelomonocytic, 240

chronic granulocytic, 239lymphocytic, 239

lymphoid and myeloid leukaemiasaetiology, 239–40epidemiology, 239investigations, 241–2paraneoplastic syndromes, 240–41pathology, 240presentation/signs, 241prognosis, 244–5staging, 242treatment, 242–4tumour behaviour, 240

eosinophilic and basophilic, 245erythroid, 245megakaryoblastic, 245preleukaemia/myelodysplastic

syndromes, 245Leydig cell tumours, 175–7limb salvage in osteosarcoma, 86lingual tumours, 115–16lipoma, infiltrating, 71liposarcoma, see soft tissue tumoursliver tumours, see hepatic tumourslomustine, 198–9lung tumours, 148–53

aetiology, 148epidemiology, 148investigations, 150–51paraneoplastic syndromes, 149pathology, 148–9presentation/signs, 149prognosis, 153staging, 152treatment, 152–3tumour behaviour, 149

lymph node, evaluation of, 20lymphoma, 228–39

aetiology, 229alimentary, 231–2

see also gastro-intestinal tumoursclassification

anatomical, 229histopathological, 229–30immunophenotypic, 230

cutaneous, 63–5, 232epidemiology, 228–9extranodal, 232intra-ocular, 258–61investigations, 232–4mediastinal/thymic, 231multicentric, 231paraneoplastic syndromes, 230pathology, 229–30presentation/signs, 231prognosis, 237–9renal, 232

see also renal tumoursstaging, 234treatment, 234–7tumour behaviour, 230

lymphoproliferative disease, 228lymphosarcoma, see lymphomalymphomatoid granulomatosis, 65

magnetic resonance imaging, instaging, 20–21

brain tumours, 195–6nasal and paranasal tumours, 101ocular tumours, 257

malignant lymphoma, see lymphomamalignant fibrous histiocytoma, see soft

tissue tumoursmalignant (and systemic) histiocytosis,

71, 275–7aetiology, 275epidemiology, 275investigations, 276–7pathology, 275–6presentation/signs, 276prognosis, 277staging, 277treatment, 277tumour behaviour, 276

mammary tumours, 184–90aetiology, 184classification of,epidemiology, 184investigations, 187–8tumour behaviour, 186paraneoplastic syndromes, 187pathology, 184–6presentation/signs, 187prognosis, 190staging, 188treatment, 188–90

Marie’s disease, see hypertrophic(pulmonary) osteopathy

mast cell tumours, 59–62canine, 59–61

investigations, 60of the orbit, 256–7paraneoplastic syndromes, 29, 60of prepuce and scrotum, 178presentation/signs, 59prognosis, 61staging, 60treatment, 60–61tumour behaviour, 59

feline, 61–2systemic, 62visceral (intestinal, splenic), 62,

132, 272mediastinal tumours, 264meibomian gland adenoma, 252–6melanoma

cutaneous, 58eyelid, 254–6prepuce and scrotum, 178

intra-ocular, 258–61oral, 114–15

melphalan, 39, 236, 248meningioma, 192, 200

296 Index

mercaptopurine, 243mesothelioma, 270–72

aetiology, 270epidemiology, 270investigations, 270–71paraneoplastic syndromes, 270pathology, 270presentation/signs, 270prognosis, 271–2staging, 271treatment, 271tumour behaviour, 270

metabolic effects of tumours, 22–30metabolic epidermal necorsis, 27,

225metalloproteinases, 48metastases, 11–12

detection of, 20–21lung patterns, 151mechanisms of, 12sites of, 12methimazole, 210

methotrexate, 236–8mineralocorticoid therapy for

hypoadrenocorticism, 219mithramycin, 29, 249mitotane, see o,p’DDDmitotic rate, 16mitotic spindle, 39mitozantrone, 39, 44, 76, 153molecular changes in cancer, 5monoclonal antibody (CL/Mab231), 48,

236–7monoclonal gammopathy, see

hypergammablobulinaemiamultidrug resistance, 40multilobular osteochondrosarcoma, 80,

117multiple cartilagenous exostoses, 79–81multiple endocrine neoplasia

syndrome, 205multiple myeloma, 65, 246–9

aetiology, 246epidemiology, 246investigations, 247–8paraneoplastic syndromes

(hypergammaglobulinaemia),247

pathology/tumour behaviour, 246–7presentation/signs, 247prognosis, 249staging, 248treatment, 248–9

muramyl tripeptide phosphatidylethanolamine (MTP-PE), 48

liposome encapsulated forosteosarcoma, 88

mutations, genetic, 4–10myasthenia gravis, 27, 263–6mycosis fungoides, 64, 232myelodysplastic syndromes, 245–6myeloproliferative disease, 228myelosuppression, chemotherapy

induced, 42myelotoxicity, oestrogen induced, 176

myxoma/myxosarcoma, see soft tissuetumours

nasal and paranasal sinus tumours,98–104

aetiology, 98classification, 98epidemiology, 98investigations, 99–101paraneoplastic syndromes, 99pathology, 98presentation/signs, 99prognosis, 1034staging, 101treatment, 101–3tumour behaviour, 98

nasal planum tumours, 94–8aetiology, 94epidemiology, 94investigations, 95–6paraneoplastic syndromes, 95pathology, 94presentation/signs, 95prognosis, 97staging, 96treatment, 96–7tumour behaviour, 95

needle core biopsy, 16for bone tumours, 85

neoplasmsbenign, malignant, 11definition of, 4see also cancer, tumours

nephroblastoma, 155–7nephrotoxicity, cisplatin induced, 45nervous system, 192–202

see also brain tumours; spinal cordtumours

neurilemmoma, 193, 200see also soft tissue tumours

neuroblastoma, 193neuroepithelioma, 200neurofibroma/neurofibrosarcoma, 200

see also soft tissue tumoursneurohypophysis, 213neurological effects of tumour, 27neutropenia, due to myelosuppression,

42nitrogen mustard, 64nodular dermatofibrosis, 27novel methods of cancer therapy, 46–8

ocular tumours, 258–61investigations, 260presentation/signs, 258–9prognosis, 261staging, 260treatment, 261tumour behaviour, 259–60

oesophageal tumours, 125–7aetiology, 125epidemiology, 125investigations, 126paraneoplastic syndromes, 126pathology, 125

presentation/signs, 126prognosis, 127staging, 126treatment, 126–7tumour behaviour, 125–6

oestrogen receptors in mammarytumours, 184

oligodendroglioma, 193oncocytoma, 144oncogenes, 4–8o,p’DDD, 216, 219oral tumours, 104–17

aetiology, 104classification, 105epidemiology, 104investigations, 105–6paraneoplastic syndromes, 105pathology, 104presentation/signs, 104–5staging, 106treatment, 106–8see also individual tumour types

orbital tumours, 256–8investigations, 257–8paraneoplastic syndromes, 256presentation/signs, 256–7prognosis, 258staging, 258treatment, 258tumour behaviour, 256

osteochondroma, 79–80osteogenic sarcoma, see osteosarcomaosteoma, 79osteomyelitis, as cause of cancer, 10osteosarcoma

appendicular (long bone), 83axial, 83mandibular (and skull), 117–18see also bone tumours

ovarian tumours, 166–9aetiology, 166classification, 167epidemiology, 166investigations, 168paraneoplastic syndromespathology, 166–7presentation/signs, 168prognosis, 169staging, 168treatment, 169tumour behaviour, 167–8

p53, 5–6, 10, 11P-glycoprotein, 40pancreatic tumours

endocrine (gastrinoma, glucagonoma,insulinoma), 221–6

exocrine, 140–42papillomatosis/papillomas of skin,

53–4, 178, 253DNA viruses in, 50

paraneoplastic syndromes, 22–30see also endocrine system, tumours of

parathyroid hormone, 26, 211related protein, 26

Index 297

parathyroid tumours, 210–12aetiology, 211epidemiology, 210investigations, 211paraneoplastic syndromes, 211pathology, 211presentation/signs, 211prognosis, 212staging, 212treatment, 212tumour behaviour, 211

parosteal osteosarcoma, see bonetumours

pathogenesis, of cancer, 4–10penile and preputial tumours, 178–80

aetiology, 178epidemiology, 177–8investigations, 179paraneoplastic syndromes, 178pathology, 178presentation/signs, 178prognosis, 180staging, 179treatment, 179–80tumour behaviour, 178

peri-anal tumours (apocrine gland),135–7

aetiology, 135epidemiology, 135investigations, 136paraneoplastic syndromes, 135pathology, 135presentation/signs, 135prognosis, 137staging, 136treatment, 136–7tumour behaviour, 135

peri-anal gland tumours, 55–6of prepuce and scrotum, 178

peripheral nerve sheath tumours, seesoft tissue tumours

peripheral odontogenic fibroma, 108–9phaeochromocytoma, 205, 220–21phlebitis, chemotherapy induced, 44phlebotomy for hyperviscosity

syndromes, 23photodynamic therapy, 47, 57, 97pinna, tumours of, 118piroxicam, as immunostimulant, 48

for treatment of bladder tumours, 162pituitary gland tumours, 212–15

aetiology, 212epidemiology, 212investigations, 213–14paraneoplastic syndromes, 213pathology/tumour behaviour, 212–13presentation/signs, 213prognosis, 215staging, 214treatment, 214–15see also brain tumours

plasma cell myeloma, see multiplemyeloma

plasmacytoma/plasma cell tumour, 65see also gastro-intestinal tumours

plasmapheresis for hyperviscositysyndromes, 24

polycythaemia rubra vera, 23–4, 245polymyositis, 263polyp

gastric, 127intestinal/rectal, 131–5nasopharyngeal, 117progression to malignancy, 4, 132

prednisolone, in combinationchemotherapy, 236–8, 243–4

see also glucocorticoid therapypreleukaemia, 245preputial tumours, see penile and

preputial tumoursprimary erythrocytosis, 245primary tumour, evaluation of, 18–20progestagen therapy, 184progesterone receptors in mammary

tumours, 184prostatic tumours, 180–83

aetiology, 180epidemiology, 180investigations, 181–2paraneoplastic syndromes, 181pathology, 180presentation/signs, 181prognosis, 183staging, 182treatment, 182–3tumour behaviour, 180

quality of life, 2

radiationas cause of cancer, 9, 70biology, 35–6sickness, 36treatment for cancer, 34

radiography, in stagingof metastases, 21of tumour, 19

radioisotope imaging, in staging, 20for gastrinoma, 224for thyroid tumours, 208, 210

radiotherapy, 34–8brachytherapy, 34–5, 255–6of brain tumours, 197–8, 215combination with surgery, 38fractionation of dose, 36indications for, 37–8of nasal and para-nasal tumours,

102–3side-effects, 36–7teletherapy, 34–5tumour radiosensitivity, 35, 36types of ionising radiation, 34see also individual tumour types

ranitidine therapy in mast celltumours, 29

reconstitution of cytotoxic drugs, 46renal tumours, 154–7

aetiology, 154classification of, 155epidemiology, 154

investigations, 156–7paraneoplastic syndromes, 156pathology, 154–5presentation/signs, 156prognosis, 157staging, 157treatment, 157tumour behaviour, 155–6

respiratory tract, tumours of, 144–53see also laryngeal; lung; and tracheal

tumoursretinoblastoma, 11, 253retinoids (etretinate, isotretinoin), 65,

236retroviruses, 7–8rhabdomyoma, see soft tissue tumoursrhabdomyosarcoma,

embryonal/botryoid, 159see also soft tissue tumours

RNA viruses, see virusesround cell tumours, see soft tissue

tumours

safe-handling of cytotoxic drugs, 45–6salivary gland tumours, 121–3

aetiology, 121epidemiology, 121investigations, 122–3pathology, 121presentation/signs, 121–2staging, 123treatment/prognosis, 123tumour behaviour/paraneoplastic

syndromes, 121sarcoma of oral cavity, 113–14

see also soft tissue tumoursschwannoma, malignant schwannoma,

200see also soft tissue tumours

scintigraphy, see radioisotope imagingsebaceous gland tumours, 54seminoma, 175–7sertoli cell tumour, 175–7skeletal system, tumours of, 78–92

see also bone and cartilage tumours;joint and joint associatedtumours

skin, as site of cancer, 1skin tumours, 50–67

aetiology, 50classification of, 52epidemiology, 50epithelial, 53–8investigations, 51–3histiocytic and granulomatous

conditions, 66–7multifocal/diffuse, 63–5pathology, 50–51tumour behaviour/paraneoplastic

syndromes, 51see also individual tumour types

skull tumours, 117–18soft tissue tumours, 69–76

aetiology, 70classification of, 71

298 Index

epidemiology, 69investigations, 73–4pathology, 70–71paraneoplastic syndromes, 73presentation/signs, 71prognosis, 76staging, 74–5treatment, 75–6tumour behaviour, 71–3

spinal tumours, 199–202aetiology, 199classification of, 200epidemiology, 199–200investigations, 201paraneoplastic syndromes, 200pathology, 199–200presentation/signs, 200–01prognosis, 202staging, 202treatment, 202tumour behaviour, 200

splenic tumours, 272–5aetiology, 272epidemiology, 272investigations, 274paraneoplastic syndromes, 273pathology, 272–3presentation/signs, 273–4prognosis, 275staging, 274treatment, 274–5tumour behaviour, 273

spindle cell sarcoma, see soft tissuetumours

squamous cell carcinomacutaneous (including digit), 56–8of eyelid, 254–6gingival, 110–11labial, 111–12lingual, 115–16of nasal planum, 94–7of tonsil, 116–17

staging of tumours, 17–22see also individual tumour types

sterile panniculitis, 66stomach tumours, see gastric tumourssurgery, 31–4

approaches of, 32–3biopsy techniques, 16–17combined with other techniques, 38cytoreductive, 38in pain management, 31principles of, 32prophylaxis, 31use of skin flaps, 33see also individual tumour types

synovial tumours, see joint and jointassociated tumours

tablet handling, 45teratoma, 167, 175testicular tumours, 174–83

aetiology, 174epidemiology, 174investigations, 176–7

paraneoplastic syndromes, 176pathology, 174–5presentation/signs, 176prognosis, 177staging, 177treatment, 177tumour behaviour, 175

thioguanine, 243thiotepa, see

triethylenethiophosphoramidethrombocytopenia, due to

myleosuppression, 42see also haematological

complications of tumoursthymoma, 262–6

aetiology, 262epidemiology, 262investigations, 264pathology, 262–3presentation/signs, 263–4prognosis, 266staging, 265treatment, 265tumour behaviour/paraneoplastic

syndromes, 263thyroid tumours, 204–10

aetiology, 205–6epidemiology, 205investigations, 208paraneoplastic syndromes, 206pathology, 206presentation/signs, 206–8prognosis, 210radioisotope imaging, 208, 210staging, 208treatment, 208–10tumour behaviour, 206

tissue exudate/imprint/scrape/smear, 17tissue necrosis, 16, 44tongue tumours, 115–16tonsillar tumours, 116–17tracheal tumours, 147–8transitional cell tumour, 154, 155, 159,

98, 180transmissible venereal tumour, 172, 178trauma, as cause of cancer, 10triethylenethiophosphoramide, 162tumour

angiogenesis, 48biology, 11–12cell kill, 35degree of invasion, 16diagnosis, 15–17distribution of tumour types, 1growth effects of, 23growth fraction, 35, 40metastasis, see metastasesnecrosis, 16necrosis factor, 25progression, 4related complications, 22–30staging, see stagingstromal reaction in, 16suppressor genes, 4type and grade, 11, 16, 70

ultrasonography, in staging, 19–21ureteric tumours, 158urethral tumours, 162–4

aetiology, 162epidemiology, 162investigations, 163paraneoplastic syndromes, 163pathology, 163presentation/signs, 163prognosis, 164staging, 163treatment, 164tumour behaviour, 163

urinary tract, tumours of, 154–64see also bladder; renal; ureteric; and

urethral tumoursuterine and cervical tumours, 169–71

aetiology, 169epidemiology, 169investigations, 170–71paraneoplastic syndromes, 170pathology, 169–70presentation/signs, 170prognosis, 171staging, 171treatment, 171tumour behaviour, 170

UV light, as cause of cancer, 9, 50, 57,94

VAC therapy for soft tissue sarcoma,76, 269, 275

vaccine induced sarcomas, 70vaginal and vulval tumours, 171–4

aetiology, 171epidemiology, 171investigations, 173tumour behaviour, 172paraneoplastic syndromes, 172pathology, 171–2presentation/signs, 172prognosis, 174staging, 173treatment, 173–4

vertebral tumours, 199–200vinblastine, 39, 44vinca alkaloids, 39vincristine, 39, 44

for transmissible venereal tumour,174, 180

in combination chemotherapy, 76,210, 236–7, 243–4, 269, 275

virusesacutely transforming, 8DNA or RNA containing, 7–8in papillomatosis, 50retroviruses, 7–8in sarcoma formation, 70

vitamin D therapy, 212vomiting, chemotherapy induced, 42

waste disposal, 46Wilm’s tumour, 11, 155

Zollinger-Ellison syndrome, 25, 224–5

Plate 1 Hybridisation of dog chromosome 1 paint toa metaphase from a canine sarcoma. Chromosome 1paint is labelled with the fluorescent dye Cy3 (pink)and the other chromosomes are counterstained withDAPI (blue). One normal copy of chromosome 1 (largearrow) is present in the metaphase, but the other copy(small arrow) has split and translocated to a third chromosome (arrow head). This shows that there is atranslocation involving chromosome 1 and another as yet unidentified chromosome in this sarcoma. (Chromosome paint as from Yang et al. 1999.)Plate 2 Acute radiation skin reaction – erythema of theskin and moist desquamation of the nasal planum fol-lowing treatment of a SCC of the nasal planum.Plate 3 Post radiation alopecia.Plate 4 Local tissue damage following perivascularleakage of vincristine.Plate 5 Red light source being used to treat superficialSCC on cat’s nose.

Plate 1

Plate 3

Plate 2

Plate 4

Plate 5

Plate 6 Sweat gland adenocarcinoma, infiltratingwidely throughout the skin.Plate 7 Perianal gland adenoma.

Plate 6

Plate 7

Plate 8

Plate 9

Plate 8 Perianal gland adenocarcinoma. (Courtesy ofDr R.A.S. White, Department of Clinical VeterinaryMedicine, Cambridge.)Plate 9 SCC nasal planum – cat.

Plates 10 and 11 SCC of the pinna in a cat. Plate 10Early stage lesion with erythema and crusting is seenon the right ear. Plate 11 A more advanced, ulceratedand invasive tumour is affecting the left pinna of thesame cat.

Plate 12 Cytological appearance of a mast celltumour. Mast cells may be recognised by the charac-teristic heavily staining cytoplasmic granules. (NeatStain – Haematology and Gram – Guest Medical.)Plate 13 Primary cutaneous T cell lymphoma, gener-alised erythematous plaques and nodules.Plate 14 Primary cutaneous T cell lymphoma. Closeup of erythematous nodule from a different dog. Noteinfiltration of surrounding skin.

Plate 10

Plate 11

Plate 12

Plate 13

Plate 14

Plates 17 and 18 Epitheliotropic lymphoma (Plate 17)shows generalised nature of skin lesions (Plate 18)close up showing erythematous crusting nature oflesions.Plate 19 Epitheliotropic lymphoma affecting oralmucocutaneous junctions and mucosae.

Plate 15 Histological appearance of primary cutane-nous lymphoma. The tumour infiltrate affects thedermis, the epidermis is intact.Plate 16 Histological appearance of epitheliotropiclymphoma. In contrast to Plate 15, the tumour cellinfiltrate is in the epidermis.

Plate 15

Plate 16

Plate 17

Plate 18

Plate 19

Plates 20 and 21 Cutaneous histiocytosis/pyogranulo-matous skin condition in a retriever. Plate 20 The dogpresented with a soft tissue swelling over the bridge ofthe nose. Plate 21 Several other dermal masses werenoted.Plate 22 Early crusting lesion of carcinoma on cat’snose.Plate 23 Minimally invasive, early SCC of nasalplanum.Plate 24 Invasive SCC of nasal planum in cat.Plate 25 Invasive and destructive SCC of nasal planumin a dog.

Plate 20

Plate 22

Plate 23

Plate 24

Plate 21

Plate 25

Dorsoventralfield

Head

Brain

Tumour

Brass Wedge

Lateralfield

Mandible

Lateralfield

Plate 26

Plate 27

Plate 28 Computer generated treatment plan for a dog with a brain tumour. An MRI scan is digitised into thecomputer to provide a scaled line drawing of the outline of the dog’s head (blue line) and mandibles (blue), thebrain (outer red) and the tumour (inner red). The computer predicts the radiation dose deposition, shown as isodosecontours (black lines; figures indicate percentage applied radiation dose) based on an isocentric treatment usingthree portals: dorsoventral and right and left lateral, with brass wedges (green triangles) used to attenuate thelateral beams.

Plate 26 Endoscopic view of a gastric carcinoma sitednear the pylorus in a rough collie.Plate 27 Cytology of urine sediment showing neo-plastic cells, leading to diagnosis of a transitional cellcarcinoma. (Courtesy of Ms K. Tennant, Department of Clinical Veterinary Medicine, University of Cambridge.)

Plate 29 Fine needle aspirate of lymph node from dogwith multicentric lymphoma. Cytology reveals a popu-lation of large, neoplastic lymphoblasts.Plate 30 Bone marrow aspirate from dog with AML.Showing large undifferentiated myeloblasts.Plate 31 Bone marrow aspirate from dog with ALL. Thesmear is dominated by medium to large lymphoblastswith very little normal erythroid or myeloid activity.

Plate 29

Plate 30

Plate 31

Plate 32 Bone marrow aspirate from dog with CLL.The marrow contains unusually high numbers of smalllymphoid cells but normal erythroid and myeloid pre-cursors are also present.Plate 33 Bone marrow aspirate from dog with multi-ple myeloma, showing a cluster of plasma cells, somewith secretory vacuoles in their cytoplasm.

Plate 32

Plate 33

Plate 35 Petechiation of mucous membranes due tothrombocytopenia associated with multiple myeloma.

Plate 34

Plate 35

Plate 34 Retinal haemorrhages may be a feature ofmyeloma as a result of hyperviscosity or thrombocy-topenia.

small animal oncology

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