Multiple distinct malignancies in dogs_53 cases by Salah EL MOUSTAGHFIR

Multiple Distinct Malignancies in Dogs: 53 Cases Despite the clinical recognition of multiple distinct types of neoplasia in individual dogs, a detailed description of such cases has not recently been published. Canine oncology cases that were diagnosed with multiple, confirmed, distinct malignancies were prospectively collected for analysis. Approximately 3% of 1722 dogs that were presented to the oncology service at the Colorado State University Veterinary Medical Center were diagnosed with multiple distinct primary tumors. No significant breed or sex predisposition was apparent. Dogs with mast cell tumor, malignant melanoma, and thyroid carcinoma were significantly overrepresented and thus more likely to be diagnosed with multiple tumor types. These findings emphasize the importance of thorough, whole-body evaluation for dogs presented with mast cell tumor, malignant melanoma, and thyroid carcinoma. Furthermore, because approximately 33% of dogs that were presented with thyroid tumors were found to have additional distinct tumors, complete staging is justified 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)

From the Animal Cancer Center and Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, 300 West Drake Road, Fort Collins, Colorado 80523. 20

Introduction Despite the fact that some dogs are presented with tumors believed to carry a low metastatic potential, frequent recommendations are for these dogs to undergo advanced staging to rule out preexisting or concurrent neoplasia. In addition, staging for tumors believed to carry a high probability of metastasis sometimes leads to the discovery of incidental or confounding second malignancies. Several studies have reported a relatively high occurrence of second malignancies in dogs with endocrine, hepatocellular, and intracranial neoplasms.1-3 Yet, only a limited number of studies (the largest of which were published over 30 years ago) have directly examined the occurrence of multiple tumor types (MTT) in dogs.4,5 Therefore, it is not known how common second malignancies are clinically diagnosed using currently available staging modalities. Several breeds are reported to be overrepresented with regard to the development of certain distinct tumor types, and a heritable basis for some specific canine cancers has been strongly suggested.6-11 Multiple endocrine neoplasia is one of the most well-characterized syndromes of MTT in humans; it results from one of several genetic mutations that ultimately leads to multiple tumors of endocrine and nonendocrine origin.12 While a specific genetic aberration has not been identified in dogs, a similar syndrome has been described in a limited number of dogs.13-17 A recently identified germline mutation in the mesenchymal-epithelial transition factor (MET) proto-oncogene was found in approximately 70% of rottweilers, a breed believed to be predisposed to the development of several cancers.18 Breed also influences tumor karyotypes in canine appendicular osteosarcoma and gene expression patterns in canine hemangiosarcoma.19,20 Based on these recent findings, we questioned whether any particular breeds might be predisposed to the development of multiple distinct malignancies. Therefore, we set out to prospectively examine and report the occurrence of MTT in individual canine cancer cases in order to 1) determine JOURNAL of the American Animal Hospital Association

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Multiple Distinct Malignancies in Dogs

the occurrence of MTT in dogs; 2) determine whether any particular breeds may be overrepresented within this population of dogs; and 3) determine if any specific tumor types are commonly associated with previous, concurrent, or subsequent primary cancers.

Materials and Methods Case Selection Dogs that were presented to the oncology service at the Colorado State University Veterinary Medical Center (CSUVMC) between April 1, 2006 and December 31, 2007 with a newly diagnosed malignant tumor were eligible for inclusion. Dogs with histories of previous malignant tumor(s) or that received a diagnosis of synchronous malignant tumors (within 1 month) were prospectively collected for inclusion in this study. In addition, dogs diagnosed with a malignant tumor during this time period and that went on to develop a subsequent 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 with multiple, histologically or cytologically confirmed distinct malignancies were included in analyses.

Statistical Analysis Variables assessed included tumor histological type, breed, sex, and age and weight at diagnosis of first malignancy. Median age and weight at diagnosis were determined, and Fisherâ&#x20AC;&#x2122;s exact test was utilized to determine if histological type, breed, or sex were significantly overrepresented. A P value of <0.05 was considered significant for all analyses.

Results Case Characteristics Fifty-three dogs met the criteria for inclusion. The sex, breed, age, and weight at diagnosis of affected dogs are summarized in Table 1. Within this population were 119 cytologically or histologically distinct tumors included in analysis. One dog was diagnosed with four distinct tumor types, nine dogs had three distinct tumor types, and the remaining 43 dogs each had two distinct malignant tumors. Prior Therapy Fourteen dogs received chemotherapy prior to being diagnosed with at least one neoplasm (median time from beginning of therapy was 8.6 months). Five dogs received radiation therapy prior to the development of additional neoplasms. Only one dog had a tumor arising near the irradiated field; the tumor was a hemangiosarcoma of the right atrium after undergoing three once-weekly 3-Gy fractions of radiation therapy to one hemithorax. Two dogs underwent investigational treatment with some form of immunotherapy prior to the development of subsequent neoplasms.

Observed Synchronous and Subsequent Tumors Twenty-one dogs with no previous history of cancer were presented with synchronous primary tumors; they represented

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

Castrated male

Intact female

Breed: Mixed-breed dog

Golden retriever

Labrador retriever

Bernese mountain dog

German shepherd dog

Shih tzu

Other (1 each)

Treatment prior to diagnosis of MTTâ&#x20AC; : Chemotherapy

Radiation therapy

Immunotherapy

* At diagnosis of first tumor â&#x20AC; MTT=multiple tumor types

approximately 1.2% of cases that were presented to the oncology service at the CSU-VMC during the study period [Table 2]. Three additional dogs were presented with synchronous primary tumors and histories of previously diagnosed third distinct malignancies (one malignant melanoma, one peripheral nerve sheath tumor, and one soft-tissue sarcoma) [Table 2]. The remaining 29 dogs were diagnosed with multiple subsequent tumors [Table 3].

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

Lymphoma

Mast cell tumor

Thyroid carcinoma

Melanoma

Pheochromocytoma

Transitional cell carcinoma

Thyroid carcinoma

Fibrosarcoma

Soft-tissue sarcoma

Osteosarcoma

Peripheral nerve sheath tumor

Thyroid carcinoma

Hepatocellular carcinoma

Mammary gland tumor

Hepatocellular carcinoma

Osteosarcoma

Thyroid carcinoma

Melanoma

Malignant histiocytosis

Anal sac adenocarcinoma

Tumor 3

Sex*

Labrador retriever

Golden retriever

Mixedbreed dog

Shih tzu

Golden retriever

Anatolian shepherd

Breed

26.4

21.5

31.6

5.2

11.8

13.16

9.1

10.8

12.6

9.9

NAâ&#x20AC;

36.4

9.25

40.2

Age at First Tumor (y)

Thyroid carcinoma, lung adenocarcinoma

Osteosarcoma, fibrosarcoma

Hepatocellular carcinoma, thyroid carcinoma

Mammary gland tumor, transitional cell carcinoma, thyroid carcinoma

Hepatocellular carcinoma, pheochromocytoma

Thyroid carcinoma, melanoma

Thyroid carcinoma, malignant histiocytosis

Osteosarcoma, mast cell tumor

Lymphoma, anal sac adenocarcinoma

Synchronous (within 1 mo)

12.25

Interval (mo)

(Continued on next page)

Peripheral nerve sheath tumor

Soft-tissue sarcoma

First Tumor

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Lung adenocarcinoma Thyroid carcinoma

Tumor 2

Tumor 1

Weight (kg)

Observed Cases of Synchronous Primary Tumors in Dogs

Table 2

22 January/February 2010, Vol. 46

Tumor 2

Mast cell tumor

Anal sac adenocarcinoma

Mammary gland tumor

Soft-tissue sarcoma

Fibrosarcoma

Osteosarcoma

Liposarcoma

Islet cell carcinoma

Mast cell tumor

Melanoma

Tumor 1

Lymphoma

Squamous cell carcinoma

Mast cell tumor

Liposarcoma

Melanoma

Thyroid carcinoma

Melanoma

Hemangiosarcoma

Mammary gland tumor

Soft-tissue sarcoma

Leiomyosarcoma

Soft-tissue sarcoma

Tumor 3

Sex*

Labrador retriever

German shepherd dog

Mixedbreed dog

Golden retriever

Mixedbreed dog

Golden retriever

Labrador retriever

Malamute

German shepherd dog

Boxer

Breed

32.4

23.2

40.6

Weight (kg)

11.7

8.4

12.2

14.7

11.25

11.6

9.6

11.8

10.1

8.75

Age at First Tumor (y)

Soft-tissue sarcoma, melanoma

Mammary gland tumor, mast cell tumor

Hemangiosarcoma, islet cell carcinoma

Melanoma, liposarcoma

Thyroid carcinoma, osteosarcoma

Fibrosarcoma, leiomyosarcoma

Liposarcoma, soft-tissue sarcoma

Mast cell tumor, mammary gland tumor

Squamous cell carcinoma, anal sac adenocarcinoma

Mast cell tumor, lymphoma, soft-tissue sarcoma

Synchronous (within 1 mo)

Observed Cases of Synchronous Primary Tumors in Dogs

Table 2 (contâ&#x20AC;&#x2122;d)

6.5

Interval (mo)

(Continued on next page)

Melanoma

First Tumor

January/February 2010, Vol. 46 Multiple Distinct Malignancies in Dogs 23

Chondrosarcoma

Lung adenocarcinoma

Lymphoma

Mast cell tumor

Hepatocellular carcinoma

Salivary adenocarcinoma

Liposarcoma

Osteosarcoma

Synovial cell sarcoma

Lymphoma

* SF=spayed female; CM=castrated male â&#x20AC; NA=not available

Tumor 2

Tumor 1

Anaplastic sarcoma

Tumor 3

Sex*

Mixedbreed dog

Labrador retriever

Bernese mountain dog

Mixedbreed dog

Labrador retriever

Breed

40.1

26.8

Weight (kg)

11.25

15.8

9.2

Age at First Tumor (y)

Lymphoma, hepatocellular carcinoma

Mast cell tumor, synovial cell sarcoma

Osteosarcoma, lymphoma

Liposarcoma, lung adenocarcinoma

Salivary adenocarcinoma, chondrosarcoma

Synchronous (within 1 mo)

Observed Cases of Synchronous Primary Tumors in Dogs

Table 2 (contâ&#x20AC;&#x2122;d)

First Tumor

3.5

Interval (mo)

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

Tumor 2

Osteosarcoma

Chondrosarcoma

Transitional cell carcinoma

Osteosarcoma

Hemangiosarcoma

Melanoma

Lymphoma

Schwannoma

Thyroid carcinoma

Intestinal adenocarcinoma

Transitional cell carcinoma

Mast cell tumor

Tumor 1

Mast cell tumor

Melanoma

Mast cell tumor

Mammary gland tumor

Peripheral nerve sheath tumor

Lymphoma

Mast cell tumor

Osteosarcoma

Adrenal adenocarcinoma

Renal cell carcinoma

Lymphoma

Osteosarcoma

Prostate carcinoma

Tumor 3

Thyroid carcinoma

Tumor 4

Mixed-breed dog

Bernese mountain dog

Welsh springer spaniel

Mixed-breed dog

Rottweiler

Mixed-breed dog

Labrador retriever

Great Pyrenees

Elkhound

Bloodhound

Golden retriever

Sex* Breed

34.1

30.5

23.75

28.6

47.1

39.5

8.2

8.25

12.25

13.7

7.5

5.1

5.8

11.5

NA‡

28.2

8.9

6.7

5.4

8.6

8.25

8.75

7.5

48.5

Age at First Interval† Tumor (y) (mos)

50.1

Weight (kg)

Carboplatin/ doxorubicin

CHOP/GS-9219

Doxorubicin/ valproic acid

Carboplatin/ doxorubicin

Prednisone

CHOP§

Vinblastine

Prior Chemotherapy

(Continued on next page)

Prior Radiation Therapy

Observed Cases of Subsequent Primary Tumors Following Diagnosis of Initial Tumor

Table 3

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Lung adenocarcinoma

Hemangiosarcoma

Mammary gland tumor

Hemangiosarcoma

Soft-tissue sarcoma Transitional cell carcinoma

Squamous cell carcinoma

Hemangiosarcoma

Malignant histiocytosis

Hemangiosarcoma

Nasal sarcoma

Lymphoma

Osteosarcoma

Mast cell tumor

Melanoma

Mast cell tumor

Fibrosarcoma

Thyroid carcinoma Lymphoma

Chemodectoma

Lymphoma

Mixed-breed dog

Beagle

Golden retriever

Husky

Scottish terrier

Pomeranian

Labrador retriever

Golden retriever

Mixed-breed dog

Australian shepherd

Keeshond

Golden retriever

Sex* Breed

Tumor 4

25.4

9.6

15.3

31.4

22.4

35.5

9.9

9.6

7.9

13.6

8.6

8.75

12.13

9.8

10.3

25.5

10.25

1.5

4.75

2.75

2.5

Age at First Interval† Tumor (y) (mos)

CHOP

Immunotherapy

CHOP

Carboplatin/ piroxicam

Prior Chemotherapy

(Continued on next page)

18 × 3 Gy

6 × 6 Gy

3 × 3 Gy

6 × 6 Gy

Prior Radiation Therapy

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Thyroid carcinoma Melanoma

Peripheral nerve sheath tumor

Thyroid carcinoma

Mast cell tumor

Tumor 3

Tumor 2

Tumor 1

Weight (kg)

Observed Cases of Subsequent Primary Tumors Following Diagnosis of Initial Tumor

Table 3 (cont’d)

26 January/February 2010, Vol. 46

* † ‡ §

SF=spayed female; CM=castrated male; IF=intact female Interval between diagnosis of first and second tumor NA=not available CHOP=cyclophosphamide, doxorubicin, vincristine, prednisone

Lymphoma

Mast cell tumor

Mixed-breed dog

German shepherd dog

Shih tzu

Sex* Breed

Lymphoma

Tumor 4

Soft-tissue sarcoma

Mast cell tumor

Tumor 3

Thyroid carcinoma Leiomyosarcoma

Tumor 2

Tumor 1

21.5

10.6

Weight (kg)

7.4

6.5

13.25

7.9

4.5

4.25

2.75

Age at First Interval† Tumor (y) (mos)

Prior Radiation Therapy

Observed Cases of Subsequent Primary Tumors Following Diagnosis of Initial Tumor

Table 3 (cont’d)

CHOP

Carboplatin/ doxorubicin

Vinblastine

Prior Chemotherapy

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January/February 2010, Vol. 46

Table 4 Occurrence of Select Distinct Tumor Types in Dogs Affected With Multiple Tumors No. of Dogs With MTT*

Total Dogs Diagnosed

% of All Oncology Cases

% of All Dogs Diagnosed

P Value

Mast cell tumor

3.4

25.4

<0.001

Melanoma

2.1

<0.001

Osteosarcoma

278

16.1

3.2

>0.05

Hepatocellular carcinoma

1.5

11.5

>0.05

Hemangiosarcoma

136

7.9

4.4

>0.05

Lymphoma

268

15.6

4.5

>0.05

Thyroid carcinoma

2.2

32.4

<0.001

* MTT=multiple tumor types

or sex predilection was found when comparisons were made to the general population of dogs presented as new appointments to the oncology service.

Discussion We set out to prospectively evaluate client-owned dogs that developed multiple distinct malignant tumors in order to 1) determine the percentage of dogs affected by MTT; 2) determine whether any particular breeds were overrepresented; and 3) determine if any specific primary tumors are commonly associated with previous, concurrent, or subsequent primary cancers. Analysis of this population of dogs revealed that approximately 3% of new cases presented to the oncology service at the CSU-VMC were diagnosed with MTT; however, no significant breed or sex predisposition was apparent. Interestingly, several distinct tumor types were overrepresented within the population of MTT dogs; they included thyroid carcinoma, mast cell tumors, and malignant melanoma. Because several breeds are predisposed to individual cancers, we questioned whether any breeds may be predisposed to the development of multiple distinct primary tumors. A recently described MET proto-oncogene mutation in the vast majority of rottweilers certainly lends credence to the possibility that distinct hereditary predispositions may exist among specific canine breeds, and such mutations could potentially give rise to multiple distinct malignancies within affected dogs. In fact, no breed

predisposition was identified, with approximately 30% of affected dogs being of mixed-breed backgrounds. While spayed females were numerically highest within this population, this finding was also not statistically significant (P=0.21). Previous treatment with cyclophosphamide in both dogs and humans has been associated with the development of transitional cell carcinoma (TCC) of the urinary bladder, and treatment with alkylating agents or topoisomerase inhibitors can be associated with the development of human leukemias.21-25 Therefore, it was critical to evaluate and report whether dogs had received any chemotherapy prior to the development of subsequent primary tumors. Fourteen dogs received some form of chemotherapy prior to the development of subsequent tumors. The median time from first chemotherapy treatment to the development of a subsequent tumor was 8.6 months in this population of dogs. Only four dogs within this study were diagnosed with TCC of the urinary bladder. Two of these dogs had not received prior chemotherapy; one dog had received vinblastine (48.5 months prior to development of TCC); and the remaining dog had previously been treated with a multidrug lymphoma chemotherapy protocol that included cyclophosphamide (approximately 8 months prior to diagnosis of TCC). The development of secondary sarcomas resulting from definitive megavoltage radiation therapy has been reported in dogs; however, the resulting tumors were diagnosed long after (5.2 and 8.7 years) undergoing radiation therapy.26

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While five dogs within our study underwent some form of external-beam megavoltage radiation therapy prior to the development of subsequent tumors, only one dog developed a tumor near or within the radiation field. This particular dog underwent an investigational clinical trial evaluating the safety and efficacy of immunotherapy combined with external-beam radiation therapy for metastatic pulmonary osteosarcoma. Therefore, this dog received three, 3-Gy fractions of external-beam radiation to one hemithorax. Necropsy performed on this dog revealed primary hemangiosarcoma of the right auricle; however, the tumor was unlikely to have arisen secondary to radiation, because the total dose received (9 Gy) was quite low, and the diagnosis was made within 2.5 months after receiving the first 3-Gy dose. While 3% of dogs represents a relatively small subpopulation overall, several tumor types were found to be significantly overrepresented within affected dogs. Tumor types included mast cell tumors, malignant melanoma, and thyroid carcinoma [Table 4]. Several breeds have a predisposition for the development of mast cell tumors, and previous studies report that up to 31% of dogs diagnosed with a single mast cell tumor will go on to develop additional mast cell tumors.6,27 In the present study, 25% of dogs diagnosed with mast cell tumors had or went on to develop additional distinct tumors that were not mast cell malignancies. The high risk of developing additional tumors in dogs with mast cell tumors is noteworthy; however, it must be cautioned that the dogs within this study likely represent a selective population of large or aggressive mast cell tumors for which referral is pursued. Alternatively, because mast cell tumors represent the most common skin malignancy of dogs, the high incidence of mast cell tumors within this study is possibly a result of incidentally diagnosed tumors when the dogs were presented to an oncologist for evaluation or treatment of different tumor types.6 In humans, approximately 7% of patients diagnosed with thyroid tumors and 10% diagnosed with melanoma will go on to develop additional distinct malignancies.28 Malignant melanoma and thyroid carcinoma were statistically overrepresented in dogs diagnosed with MTT. Activating mutations in the rearranged during transfection (RET) gene have been associated with the familial form of medullary thyroid carcinoma in humans, and although a dog pedigree with an apparent familial medullary thyroid cancer has been reported, no such mutation was identified within the affected dogs.11 Boxers, beagles, and golden retrievers are reported to be at increased risk of developing thyroid tumors; however, the overrepresentation of thyroid tumors within this report cannot be explained based upon breed predisposition, since only two golden retrievers and one beagle with MTT were diagnosed with thyroid tumors.29 Several dogs that were suspected to have MTT were excluded from analysis because of lack of cytological or histological confirmation. Combined with the fact that not all dogs underwent complete necropsy is the likelihood that the true prevalence of multiple distinct tumor types in dogs is slightly higher than reported. Also worth noting is that

Multiple Distinct Malignancies in Dogs

certain tumor sites may have a propensity to be underrepresented in a prospective clinical study because of the inherent difficulty associated with obtaining adequate diagnostic tissue from those sites (i.e., heart base, brain, or lung). In fact, one previous postmortem study reported concurrent unrelated tumors in 23% of dogs diagnosed with primary intracranial neoplasia.2 However, we felt it critical to include only dogs with confirmed multiple distinct malignancies in analysis. An additional deficiency within this report was our inability to statistically evaluate the total number of soft-tissue sarcomas diagnosed at the CSU-VMC because of the inconsistent coding of medical records. While this deficiency in no way affects the collection of prospective cases, nor does it impact the statistical analysis of other tumor types, it does preclude the ability to determine whether soft-tissue sarcomas may be overrepresented in this population of canine cancer cases.

Conclusion The diagnosis of multiple distinct malignancies in dogs was made in approximately 3% of the dogs that were presented to the oncology service at the CSU-VMC. Despite numerical differences, no statistically significant sex or breed predilection was identified. Dogs with mast cell tumor, malignant melanoma, and thyroid carcinoma were overrepresented and thus more likely to be diagnosed with MTT. For the practicing veterinarian, such information should alert clinicians to the possibility of multiple distinct malignancies in dogs. Also, more extensive staging and workup for dogs diagnosed with a thyroid tumor, mast cell tumor, or malignant melanoma may be justified.

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