Multiple distinct malignancies in dogs_53 cases

Multiple Distinct Malignancies in Dogs:53 Cases

Despite the clinical recognition of multiple distinct types of neoplasia in individual dogs, adetailed description of such cases has not recently been published. Canine oncology cases thatwere diagnosed with multiple, confirmed, distinct malignancies were prospectively collected foranalysis. Approximately 3% of 1722 dogs that were presented to the oncology service at theColorado State University Veterinary Medical Center were diagnosed with multiple distinct pri-mary tumors. No significant breed or sex predisposition was apparent. Dogs with mast celltumor, malignant melanoma, and thyroid carcinoma were significantly overrepresented and thusmore likely to be diagnosed with multiple tumor types. These findings emphasize the impor-tance of thorough, whole-body evaluation for dogs presented with mast cell tumor, malignantmelanoma, and thyroid carcinoma. Furthermore, because approximately 33% of dogs that werepresented with thyroid tumors were found to have additional distinct tumors, complete staging isjustified in all dogs presented with thyroid tumors. J Am Anim Hosp Assoc 2010;46:20-30.

Robert B. Rebhun, DVM, PhD,Diplomate ACVIM (Oncology)

Douglas H. Thamm, VMD,Diplomate ACVIM (Oncology)

IntroductionDespite the fact that some dogs are presented with tumors believed tocarry a low metastatic potential, frequent recommendations are for thesedogs to undergo advanced staging to rule out preexisting or concurrentneoplasia. In addition, staging for tumors believed to carry a high proba-bility of metastasis sometimes leads to the discovery of incidental or con-founding second malignancies. Several studies have reported a relativelyhigh occurrence of second malignancies in dogs with endocrine, hepato-cellular, and intracranial neoplasms.1-3 Yet, only a limited number ofstudies (the largest of which were published over 30 years ago) havedirectly examined the occurrence of multiple tumor types (MTT) indogs.4,5 Therefore, it is not known how common second malignancies areclinically diagnosed using currently available staging modalities.

Several breeds are reported to be overrepresented with regard to thedevelopment of certain distinct tumor types, and a heritable basis forsome specific canine cancers has been strongly suggested.6-11 Multipleendocrine neoplasia is one of the most well-characterized syndromes ofMTT in humans; it results from one of several genetic mutations that ulti-mately leads to multiple tumors of endocrine and nonendocrine origin.12

While a specific genetic aberration has not been identified in dogs, a sim-ilar syndrome has been described in a limited number of dogs.13-17 Arecently identified germline mutation in the mesenchymal-epithelial tran-sition factor (MET) proto-oncogene was found in approximately 70% ofrottweilers, a breed believed to be predisposed to the development of sev-eral cancers.18 Breed also influences tumor karyotypes in canine appen-dicular osteosarcoma and gene expression patterns in caninehemangiosarcoma.19,20 Based on these recent findings, we questionedwhether any particular breeds might be predisposed to the developmentof multiple distinct malignancies.

Therefore, we set out to prospectively examine and report the occur-rence of MTT in individual canine cancer cases in order to 1) determine

RS

20 JOURNAL of the American Animal Hospital Association

From the Animal Cancer Centerand Department of Clinical Sciences,

College of Veterinary Medicine andBiomedical Sciences,

Colorado State University,300 West Drake Road,

Fort Collins, Colorado 80523.

the occurrence of MTT in dogs; 2) determine whether anyparticular breeds may be overrepresented within this popu-lation of dogs; and 3) determine if any specific tumor typesare commonly associated with previous, concurrent, or sub-sequent primary cancers.

Materials and MethodsCase SelectionDogs that were presented to the oncology service at theColorado State University Veterinary Medical Center (CSU-VMC) between April 1, 2006 and December 31, 2007 witha newly diagnosed malignant tumor were eligible for inclu-sion. Dogs with histories of previous malignant tumor(s) orthat received a diagnosis of synchronous malignant tumors(within 1 month) were prospectively collected for inclusionin this study. In addition, dogs diagnosed with a malignanttumor during this time period and that went on to develop asubsequent distinct malignant tumor(s) were also included.Case criteria collected included tumor histological type,breed, sex, age and weight at diagnosis of first malignancy,and history of prior anticancer therapy. Only cases withmultiple, histologically or cytologically confirmed distinctmalignancies were included in analyses.

Statistical AnalysisVariables assessed included tumor histological type, breed,sex, and age and weight at diagnosis of first malignancy.Median age and weight at diagnosis were determined, andFisher’s exact test was utilized to determine if histologicaltype, breed, or sex were significantly overrepresented. A Pvalue of <0.05 was considered significant for all analyses.

ResultsCase CharacteristicsFifty-three dogs met the criteria for inclusion. The sex,breed, age, and weight at diagnosis of affected dogs aresummarized in Table 1. Within this population were 119cytologically or histologically distinct tumors included inanalysis. One dog was diagnosed with four distinct tumortypes, nine dogs had three distinct tumor types, and theremaining 43 dogs each had two distinct malignant tumors.

Prior Therapy

Fourteen dogs received chemotherapy prior to being diag-nosed with at least one neoplasm (median time from begin-ning of therapy was 8.6 months). Five dogs receivedradiation therapy prior to the development of additional neo-plasms. Only one dog had a tumor arising near the irradiatedfield; the tumor was a hemangiosarcoma of the right atriumafter undergoing three once-weekly 3-Gy fractions of radia-tion therapy to one hemithorax. Two dogs underwent inves-tigational treatment with some form of immunotherapy priorto the development of subsequent neoplasms.

Observed Synchronous and Subsequent TumorsTwenty-one dogs with no previous history of cancer were pre-sented with synchronous primary tumors; they represented

approximately 1.2% of cases that were presented to the oncol-ogy service at the CSU-VMC during the study period [Table2]. Three additional dogs were presented with synchronousprimary tumors and histories of previously diagnosed thirddistinct malignancies (one malignant melanoma, one periph-eral nerve sheath tumor, and one soft-tissue sarcoma) [Table2]. The remaining 29 dogs were diagnosed with multiple sub-sequent tumors [Table 3].

Prevalence of Distinct Tumor TypesDuring the study period, 1722 dogs were presented for anew appointment to the oncology service at the CSU-VMC,and approximately 3% of these dogs were diagnosed withMTT. Of dogs with tumor types that could be statisticallyevaluated (soft-tissue sarcomas were not able to be evaluat-ed because of inconsistent coding within the database),those having thyroid carcinoma, malignant melanoma, ormast cell tumor were significantly overrepresented withinthe population of MTT dogs [Table 4]. No significant breed

January/February 2010, Vol. 46 Multiple Distinct Malignancies in Dogs 21

Table 1

Case Characteristics

* Age (y) median (range) 9.9 (5.1-15.8)

* Weight (kg) median (range) 31 (5.2-50.1)

Sex:

Spayed female 31

Castrated male 21

Intact female 1

Breed:

Mixed-breed dog 16

Golden retriever 9

Labrador retriever 7

Bernese mountain dog 2

German shepherd dog 3

Shih tzu 2

Other (1 each) 14

Treatment prior to diagnosis of MTT†:

Chemotherapy 14

Radiation therapy 5

Immunotherapy 2

* At diagnosis of first tumor† MTT=multiple tumor types

22 JOURNAL of the American Animal Hospital Association January/February 2010, Vol. 46

Table2

Obs

erve

dC

ases

ofS

ynch

rono

usP

rimar

yTu

mor

sin

Dog

s

Ageat

Weight

First

Synchronous

First

Interval

Tumor1

Tumor2

Tumor3

Sex

*Breed

(kg)

Tumor(y)

(within1mo)

Tumor

(mo)

Sof

t-tis

sue

sarc

oma

Lym

phom

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nals

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cell

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A†

9.9

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ver

mas

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mor

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iphe

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Thy

roid

carc

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alig

nant

CM

Gol

den

36.4

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hyro

idca

rcin

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Per

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erve

29sh

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tum

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nant

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212

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mel

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a

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mar

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and

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sitio

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ell

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roid

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Mix

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tum

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tum

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oma

carc

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dog

tran

sitio

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a,th

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aden

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roid

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or33

11.8

Thy

roid

carc

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lung

aden

ocar

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ma

(Continued

onnextpage)


Table2(cont’d)

Obs

erve

dC

ases

ofS

ynch

rono

usP

rimar

yTu

mor

sin

Dog

s

Ageat

Weight

First

Synchronous

First

Interval

Tumor1

Tumor2

Tumor3

Sex

*Breed

(kg)

Tumor(y)

(within1mo)

Tumor

(mo)

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ast

cell

tum

orS

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8.75

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Table2(cont’d)

Obs

erve

dC

ases

ofS

ynch

rono

usP

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mor

sin

Dog

s

Ageat

Weight

First

Synchronous

First

Interval

Tumor1

Tumor2

Tumor3

Sex

*Breed

(kg)

Tumor(y)

(within1mo)

Tumor

(mo)

Sal

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Mix

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26.8

15.8

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astic

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spay

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cast

rate

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not

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Table3

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Prior

Weight

First

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Prior

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Sex

*Breed

(kg)

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Therapy

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otherapy

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(Continued

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Table3(cont’d)

Obs

erve

dC

ases

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ubse

quen

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Prior

Weight

First

Interval

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Prior

Tumor1

Tumor2

Tumor3

Tumor4

Sex

*Breed

(kg)

Tumor(y)(mos)

Therapy

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otherapy

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518

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(Continued

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Table3(cont’d)

Obs

erve

dC

ases

ofS

ubse

quen

tP

rimar

yTu

mor

sF

ollo

win

gD

iagn

osis

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itial

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Ageat

Prior

Weight

First

Interval

†Radiation

Prior

Tumor1

Tumor2

Tumor3

Tumor4

Sex

*Breed

(kg)

Tumor(y)(mos)

Therapy

Chem

otherapy

Mas

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e

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4.25

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atin

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cell

tum

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FM

ixed

-bre

ed35

6.5

4.5

CH

OP

dog

Mas

tce

lltu

mor

Lym

phom

aC

MM

ixed

-bre

ed39

7.4

6do

g

*S

F=

spay

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mal

e;C

M=

cast

rate

dm

ale;

IF=

inta

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e†

Inte

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een

diag

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first

and

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A=

not

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labl

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=cy

clop

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ham

ide,

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cin,

vinc

ristin

e,pr

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sone

or sex predilection was found when comparisons were madeto the general population of dogs presented as new appoint-ments to the oncology service.

DiscussionWe set out to prospectively evaluate client-owned dogs thatdeveloped multiple distinct malignant tumors in order to 1)determine the percentage of dogs affected by MTT; 2) deter-mine whether any particular breeds were overrepresented;and 3) determine if any specific primary tumors are com-monly associated with previous, concurrent, or subsequentprimary cancers. Analysis of this population of dogsrevealed that approximately 3% of new cases presented tothe oncology service at the CSU-VMC were diagnosed withMTT; however, no significant breed or sex predispositionwas apparent. Interestingly, several distinct tumor typeswere overrepresented within the population of MTT dogs;they included thyroid carcinoma, mast cell tumors, andmalignant melanoma.

Because several breeds are predisposed to individualcancers, we questioned whether any breeds may be predis-posed to the development of multiple distinct primarytumors. A recently described MET proto-oncogene muta-tion in the vast majority of rottweilers certainly lends cre-dence to the possibility that distinct hereditarypredispositions may exist among specific canine breeds, andsuch mutations could potentially give rise to multiple dis-tinct malignancies within affected dogs. In fact, no breed

predisposition was identified, with approximately 30% ofaffected dogs being of mixed-breed backgrounds. Whilespayed females were numerically highest within this popu-lation, this finding was also not statistically significant(P=0.21).

Previous treatment with cyclophosphamide in both dogsand humans has been associated with the development oftransitional cell carcinoma (TCC) of the urinary bladder,and treatment with alkylating agents or topoisomeraseinhibitors can be associated with the development of humanleukemias.21-25 Therefore, it was critical to evaluate andreport whether dogs had received any chemotherapy prior tothe development of subsequent primary tumors. Fourteendogs received some form of chemotherapy prior to thedevelopment of subsequent tumors. The median time fromfirst chemotherapy treatment to the development of a subse-quent tumor was 8.6 months in this population of dogs.Only four dogs within this study were diagnosed with TCCof the urinary bladder. Two of these dogs had not receivedprior chemotherapy; one dog had received vinblastine (48.5months prior to development of TCC); and the remainingdog had previously been treated with a multidrug lymphomachemotherapy protocol that included cyclophosphamide(approximately 8 months prior to diagnosis of TCC).

The development of secondary sarcomas resulting fromdefinitive megavoltage radiation therapy has been reportedin dogs; however, the resulting tumors were diagnosed longafter (5.2 and 8.7 years) undergoing radiation therapy.26


Table 4

Occurrence of Select Distinct Tumor Types in Dogs Affected With Multiple Tumors

No. of % of All % of AllDogsWith Total Dogs Oncology DogsMTT* Diagnosed Cases Diagnosed P Value

Mast cell tumor 15 59 3.4 25.4 <0.001

Melanoma 9 36 2.1 25 <0.001

Osteosarcoma 9 278 16.1 3.2 >0.05

Hepatocellular carcinoma 3 26 1.5 11.5 >0.05

Hemangiosarcoma 6 136 7.9 4.4 >0.05

Lymphoma 12 268 15.6 4.5 >0.05

Thyroid carcinoma 12 37 2.2 32.4 <0.001

* MTT=multiple tumor types

While five dogs within our study underwent some form ofexternal-beam megavoltage radiation therapy prior to thedevelopment of subsequent tumors, only one dog developeda tumor near or within the radiation field. This particulardog underwent an investigational clinical trial evaluating thesafety and efficacy of immunotherapy combined with exter-nal-beam radiation therapy for metastatic pulmonaryosteosarcoma. Therefore, this dog received three, 3-Gy frac-tions of external-beam radiation to one hemithorax. Necropsyperformed on this dog revealed primary hemangiosarcoma ofthe right auricle; however, the tumor was unlikely to havearisen secondary to radiation, because the total dose received(9 Gy) was quite low, and the diagnosis was made within 2.5months after receiving the first 3-Gy dose.

While 3% of dogs represents a relatively small subpopu-lation overall, several tumor types were found to be signifi-cantly overrepresented within affected dogs. Tumor typesincluded mast cell tumors, malignant melanoma, and thy-roid carcinoma [Table 4]. Several breeds have a predisposi-tion for the development of mast cell tumors, and previousstudies report that up to 31% of dogs diagnosed with a sin-gle mast cell tumor will go on to develop additional mastcell tumors.6,27 In the present study, 25% of dogs diagnosedwith mast cell tumors had or went on to develop additionaldistinct tumors that were not mast cell malignancies. Thehigh risk of developing additional tumors in dogs with mastcell tumors is noteworthy; however, it must be cautionedthat the dogs within this study likely represent a selectivepopulation of large or aggressive mast cell tumors for whichreferral is pursued. Alternatively, because mast cell tumorsrepresent the most common skin malignancy of dogs, thehigh incidence of mast cell tumors within this study is pos-sibly a result of incidentally diagnosed tumors when thedogs were presented to an oncologist for evaluation or treat-ment of different tumor types.6

In humans, approximately 7% of patients diagnosed withthyroid tumors and 10% diagnosed with melanoma will goon to develop additional distinct malignancies.28 Malignantmelanoma and thyroid carcinoma were statistically overrep-resented in dogs diagnosed with MTT. Activating mutationsin the rearranged during transfection (RET) gene have beenassociated with the familial form of medullary thyroid car-cinoma in humans, and although a dog pedigree with anapparent familial medullary thyroid cancer has been report-ed, no such mutation was identified within the affecteddogs.11 Boxers, beagles, and golden retrievers are reportedto be at increased risk of developing thyroid tumors; how-ever, the overrepresentation of thyroid tumors within thisreport cannot be explained based upon breed predisposition,since only two golden retrievers and one beagle with MTTwere diagnosed with thyroid tumors.29

Several dogs that were suspected to have MTT wereexcluded from analysis because of lack of cytological orhistological confirmation. Combined with the fact that notall dogs underwent complete necropsy is the likelihood thatthe true prevalence of multiple distinct tumor types in dogsis slightly higher than reported. Also worth noting is that

certain tumor sites may have a propensity to be underrepre-sented in a prospective clinical study because of the inher-ent difficulty associated with obtaining adequate diagnostictissue from those sites (i.e., heart base, brain, or lung). Infact, one previous postmortem study reported concurrentunrelated tumors in 23% of dogs diagnosed with primaryintracranial neoplasia.2 However, we felt it critical toinclude only dogs with confirmed multiple distinct malig-nancies in analysis. An additional deficiency within thisreport was our inability to statistically evaluate the totalnumber of soft-tissue sarcomas diagnosed at the CSU-VMCbecause of the inconsistent coding of medical records.While this deficiency in no way affects the collection ofprospective cases, nor does it impact the statistical analysisof other tumor types, it does preclude the ability to deter-mine whether soft-tissue sarcomas may be overrepresentedin this population of canine cancer cases.

ConclusionThe diagnosis of multiple distinct malignancies in dogs wasmade in approximately 3% of the dogs that were presentedto the oncology service at the CSU-VMC. Despite numeri-cal differences, no statistically significant sex or breedpredilection was identified. Dogs with mast cell tumor,malignant melanoma, and thyroid carcinoma were overrep-resented and thus more likely to be diagnosed with MTT.For the practicing veterinarian, such information shouldalert clinicians to the possibility of multiple distinct malig-nancies in dogs. Also, more extensive staging and workupfor dogs diagnosed with a thyroid tumor, mast cell tumor, ormalignant melanoma may be justified.

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