JPC SYSTEMIC PATHOLOGY
REPRODUCTIVE SYSTEM
January 2022
R-N01

Signalment (JPC #1688540):  Dog

HISTORY:  None

HISTOPATHOLOGIC DESCRIPTION:  Penis: Focally expanding the superficial subepithelial connective tissue and effacing the overlying ulcerated mucosa is a broad-based, exophytic, unencapsulated, well-demarcated, densely cellular neoplasm composed of sheets of closely-packed round cells multifocally separated by fine strands of fibrous connective tissue. Neoplastic cells have distinct cell borders, a moderate amount of pale eosinophilic, finely granular to clear cytoplasm, and a central, round nucleus with coarsely-stippled chromatin and one prominent, magenta nucleolus. The mitotic rate averages 3 per 2.37 mm². There is a focally extensive area of lytic necrosis characterized by a loss of cellular architecture and replacement scattered eosinophilic cellular and karyorrhectic debris. Scattered throughout the neoplasm and perivascularly within the subjacent subepithelial connective tissue are few infiltrating lymphocytes and plasma cells and rare eosinophils.

MORPHOLOGIC DIAGNOSIS:  Penis:  Transmissible venereal tumor (TVT), breed unspecified, canine

SYNONYMS:  Sticker’s sarcoma, venereal lymphosarcoma, venereal histiocytoma, venereal granuloma, transmissible sarcoma

GENERAL DISCUSSION:

• A transplantable tumor of the external genitalia, oral, nasal, and conjunctival mucosa, and skin of both sexes of dogs; found worldwide, especially where dogs are allowed to roam;
• Usually transmitted by coitus; also transmitted by other canine social activities (i.e. sniffing and licking)
• Enzootic in the southern and midwestern United States, southeastern Europe, Central and South America, Japan, the Far and Middle East, portions of Africa
• Also transmissible to foxes, coyotes, jackals, and wolves

PATHOGENESIS:

• Contagious neoplasm; differs from other infectious tumors in that the neoplastic cells are transplanted and grow like a graft (xenotransplantation/transplantation) rather than retroviral or other infectious pathogenesis
• Thought to arise from genetic alteration of canine histiocytes (supported by immunopositivity for vimentin, CD-45, lysozyme, alpha-1-antitrypsin)
• Most tumor cells have a fairly constant karyotype of 57, 58, or 59 chromosomes; normal canine cells have 78 chromosomes
• A genetic marker within the c-myc oncogene has been documented in TVT cell; indicates a common origin for all canine transmissible tumors with transmission of a genetically identical (clonal) cell line to new hosts
• Growth is rapid for 1-2 months, after which the tumors usually regress spontaneously; tumors rarely persist more than 6 months unless the animal is immunosuppressed
• Regression, the result of humoral response (IgG), is followed by transplantation immunity
• Tumor cells initially evade detection by the immune system by downregulating MHC I molecules, and there is no MHC II activity due to secretion of inhibitory cytokines (TGF-beta 1 and IL-6)
  • Following proliferation, MHC I or II is expressed
  • Experimentally, MHC I and II expression increases after 12 weeks
• Class I and II MHC antigens are expressed by neoplastic cells only during tumor regression

TYPICAL CLINICAL FINDINGS:

• Clinical course in dogs with experimentally transmitted tumors is determined by immune response towards the tumor, with 3 possible outcomes:
  • Spontaneous regression within 6 months
  • Indolent local growth
  • Very rarely, progressive growth with metastasis (more common in immunosuppressed patients)
• Metastasis is infrequent and most commonly to the uterus and cervix in female dogs and regional lymph nodes in both male and female dogs; rarely local infiltration of the adjacent haired skin or metastasis to visceral organs
• Large tumors can induce polycythemia due to erythropoietin production

TYPICAL GROSS FINDINGS:

• Solitary or multiple, nodular to pedunculated or multi-lobulated masses on mucous membranes of penis, prepuce, vulva, and vagina, and/or skin and subcutis of head, neck, limbs, trunk, scrotum, perineum; extension to the uterus, cervix, oviducts possible
• In some animals, ocular lesions may be the only TVT manifestation, with TVTs growing on the conjunctiva and adjacent skin
• Often ulcerated, inflamed, and friable
• Early metastasis to inguinal lymph nodes may occur

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Uniformly round or oval neoplastic cells arranged in sheets or clusters
• Neoplastic cells have high N:C, pale blue cytoplasm that is finely granular to vacuolated, central round nucleus with coarsely stippled chromatin and a single prominent nucleolus
• Vacuolation more prominent on cytology
• Numerous mitotic figures (often up to 6-8 per high powered field [0.237mm²])
• Epitheliotropism is rare
• Variable appearance depending on the stage of growth and regression
• Scant (early in progression) to abundant (late) fibrovascular stroma
• Lymphocytes (primarily T-cells) and other leukocytes infiltrate as the tumor regresses

ULTRASTRUCTURAL FINDINGS:

• Interdigitating cellular membranes (not normally evident with round cell tumors; compatible with lymphoreticular cell origin)
• On EM, growing tumor cells are round, with microvilli; regressing tumor cells are more spindled (suggestive of differentiation toward fibroblasts)

ADDITIONAL DIAGNOSTIC TESTS:

• Cytology: Highly cellular aspirates; medium-sized round cells with large nuclei and moderate amounts of light to dark blue cytoplasm; coarse chromatin and large, round nucleoli; often distinct, 1-2 um diameter, punctate, intracytoplasmic vacuoles present; frequent mitotic figures; during regressive stage, many lymphocytes, few neutrophils and macrophages
• Immunohistochemistry: Neoplastic cells are immunoreactive to lysozyme and alpha-1-antitrypsin; variably positive for vimentin and CD18 (Agnew, Tumors in Domestic Animals, 2017); negative for pancytokeratin, S100, and CD3

DIFFERENTIAL DIAGNOSIS:

Other canine external genital and/or round cell neoplasms:

• Squamous cell carcinoma: Cords and trabeculae of cytokeratin-positive polygonal cells
• Mast cell tumor: Round cells with variable amounts of metachromatic cytoplasmic granules (giemsa, cKit, toluidine-blue positive) & eosinophils
• Histiocytoma: round cells, tends to be more epitheliotropic, lymphocytic infiltrate late and at the tumor base; CD18, E-cadherin or IBA1 positive
• Plasmacytoma: Round cells, eccentric nuclei, bi/multinucleate cells, “helmet” cells, prominent anisocytosis and anisokaryosis; MUM1/methyl-green-pyronine positive
• Lymphoma: Dense sheets of round cells, CD3 or CD79a/PAX5 positive cytoplasm, occasionally with cerebriform nuclei, +/- eosinophils, may have epitheliotropism
• Papilloma: Papilliferous projections of cytokeratin-positive epithelial cells on variable amount of fibrovascular core
• Melanoma: Polygonal to spindle cells, variable amounts of intracytoplasmic uniformly-sized melanin granules, junctional activity, melan-A/S100-positive
• Hemangioma/hemangiosarcoma: Spindle cells forming vascular channels, wrapping collagen, protruding into vessel lumina

COMPARATIVE PATHOLOGY:

• NOD/SCID murine model for canine transmissible venereal tumor
• Other transmissible tumors:
  • Devil facial tumor disease of Tasmanian devil: The only other transmissible tumor in animals that spreads via transplantation; causes contagious tumors around mouth and face; transmitted by fighting/facial biting; tumors have fairly constant karyotype of 13 chromosomes while normal devil cells have 14 chromosomes
    • Schwann cell origin; cells are immunoreactive for periaxin
  • Fibropapilloma of cattle: Caused by papillomavirus; tumors of vagina and vulva of young heifers and penis of young bulls
  • Transmissible genital papilloma of the pig: Papillomavirus particles are present in tumors but recently a poxvirus has been suggested as the cause; tumors occur in the preputial diverticulum of boars and vagina and vulva of sows
  • Viral papilloma: Caused by papillomavirus; affects many species, especially the horse

REFERENCES:

1. Agnew DW, MacLachlan NJ. Tumors of the genital system. In: Meuten DJ, ed. Tumors in Domestic Animals. 5^th Ames, IA: John Wiley & Sons; 2017:718-721.
2. Foster RA. Female reproductive system and mammae. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2017:1190-1191.
3. Foster RA. Male genital system. In: Maxie MG, ed. Jubb, Kennedy, and Palmers Pathology of Domestic Animals. Vol 3. 6th ed. St Louis, MO: Elsevier; 2016:509-510.
4. Foster RA. Male reproductive system. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2017:1221-1222.
5. Gross TL, Ihrke PJ, Walder EJ, Affolter VK. Skin Diseases of the Dog and Cat. 2nd ed. Oxford, UK: Blackwell Publishing; 2005:800-803.
6. Hendrick, MJ. Mesenchymal Tumors of the Skin and Soft Tissues. In: Meuten DJ, ed. Tumors in Domestic Animals. 5^th Ames, IA: John Wiley & Sons; 2017:173-174.
7. Komnenou AT, Thomas AL, Kyriazis AP, Poutahidis T, Papzoglou LG. Ocular manifestations of canine transmissible venereal tumour: a retrospective study of 25 cases in Greece. Vet Rec. 2015; 176(20):523-528.
8. Pye RJ, Woods GM, Kreiss A. Devil Facial Tumor Disease. Vet Pathol. 2016;53(4):726-736.
9. Schlafer DH, Foster RA. Female genital system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 3. 6th ed. St. Louis, MO: Elsevier; 2016:448-449.

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