JPC SYSTEMIC PATHOLOGY

REPRODUCTIVE SYSTEM

January 2025

R-N07

 

Signalment (JPC# 997552): Rabbit

 

HISTORY: None 

 

HISTOPATHOLOGIC DESCRIPTION: Uterus: Multifocally and transmurally infiltrating and effacing the uterus is an unencapsulated, densely cellular, poorly demarcated neoplasm composed of polygonal cells arranged in tubules, acini, and solidly cellular areas on a variably dense collagenous to myxomatous or desmoplastic stroma. Neoplastic cells have indistinct cell borders, a small amount of eosinophilic cytoplasm, and a round to oval nucleus with finely stippled chromatin and indistinct nucleoli. There is moderate anisocytosis and anisokaryosis, and less than one mitotic figure per 2.37mm². Tubules are ectatic with fronds of neoplastic cells bulging into the lumen, and are often filled with eosinophilic proteinaceous and/or mucinous material admixed with variable amounts of necrotic cellular debris. Multifocally, there are neoplastic cells within uterine lymphatic vessels. There are multifocal areas of coagulative necrosis with loss of differential staining and retention of architecture, as well as multifocal areas of lytic necrosis characterized by loss of tissue architecture and replacement by eosinophilic cellular and karyorrhectic debris admixed with low numbers of lymphocytes, heterophils, and hemorrhage. Within several cross sections of the uterus, the endometrium is hyperplastic forming papillary projections often lined by epithelium that piles up two to three layers thick. Multifocally hyperplastic glands are markedly ectatic forming cystic structures up to 1.5mm diameter that are lined by attenuated epithelium (cystic endometrial hyperplasia).

 

MORPHOLOGIC DIAGNOSIS: 

1. Uterus: Adenocarcinoma, breed unspecified rabbit, lagomorph.

2. Uterus, endometrium: Hyperplasia, cystic, diffuse, moderate.

 

GENERAL DISCUSSION:

• Most common spontaneous tumor of the domestic rabbit (Oryctolagus cuniculi)
• Incidence greatly increases with age (4% at 2-3 years, 80% by 5-6 years)

• Decreased litter size may be an indicator of uterine malignancy 

• Often arises at multiple sites within the uterus, slow growing and often preceded by hyperplastic changes in the endometrium
• Metastasis to lung, liver, and serosa of abdominal organs is common
• Rare in other domestic animals

 

PATHOGENESIS: 

• Rabbits are induced ovulators and are commonly housed individually
• Adenocarcinoma may arise from endometrial tissue subjected to long periods of unopposed estrogen stimulation 

 

TYPICAL CLINICAL FINDINGS: 

• Hematuria or serosanguineous vaginal discharge
• Decreased fertility, reduced litter size, increased occurrence of fetal retention/resorption and stillbirths 

 

TYPICAL GROSS FINDINGS:

• Multicentric nodular enlargements of the uterine wall, usually involving both horns
• Firm, cauliflower-like masses that are often ulcerated, or papillary to polypoid masses that protrude into the uterine lumen
• May contain large areas of hemorrhage and/or necrosis (usually central region of the mass)
• Early metastasis to peritoneal cavity; later metastases to lungs, liver, and bone
• Thickened uterine wall without alterations to the luminal epithelium
• Characteristic fibrous tissue makes it firm and tough with localized constriction bands on the serosal surface

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Acinar/tubular structures lined by cuboidal cells on a myxomatous vascular stroma
• May protrude into the uterine lumen and/or invade the myometrium
• May secrete large amounts of mucus into uterine lumen
• Endometrial atrophy
• Desmoplastic response with deposition of large amounts of fibrosis is characteristic 
• Distinguished from normal endometrium by: Increase in size, pleomorphism and disarray of glandular epithelial cells w/ scirrhous reaction 

 

ADDITIONAL DIAGNOSTIC TESTS:

 

DIFFERENTIAL DIAGNOSIS:

Other causes of uterine enlargement:

• Endometrial hyperplasia
• Uterine polyps
• Endometrial venous aneurysms (R-M07)
• Leiomyoma/leiomyosarcoma 

 

COMPARATIVE PATHOLOGY:

• Uterine adenocarcinoma is rare in most domestic and wild species, except rabbits and cattle
• Cattle

• Uterine carcinoma is the most common primary uterine neoplasm and is frequently recognized at slaughter as single or multiple, firm, nodular masses in the uterine wall with a strong scirrhous response (it is rarely identified clinically) 

• Uterine lymphoma is the most common metastatic uterine neoplasm; in the cow the enzootic form is caused by the bovine leukemia retrovirus 

• Enzootic lymphoma in cattle commonly affects the heart, abomasum, lymph nodes, and uterus

• Rats: BDII/Han, DA/Han, Donryu, and Wistar/Han rats have high incidence of endometrial adenocarcinoma
• Chinese hamsters: also have high spontaneous incidence
• Asian elephants: Uterine neoplasia is common in managed Asian elephants; uterine adenocarcinoma is second in frequency to the more common myometrial leiyomyoma (Gottdenker, Vet Pathol. 2021)
• Goats: The occurrence of metastases in distant sites such as lungs, kidneys and liver has been described in goats with uterine adenocarcinoma. (Consalter, J. Comp. Pathol, 2022)
• Cats: Rare but uterine adenocarcinomas are reportedly the most common feline uterine neoplasm
• Chickens: Adenomas in the oviduct and adenocarcinomas in the ovary and oviduct are frequently found in older egg-laying chickens

• Oviductal tumors are usually located in the magnum, but also rarely in the infundibulum and shell gland
• Adenocarcinomas occur simultaneously in the ovary and oviduct more frequently than in either organ alone
• Unknown if reproductive tract adenocarcinomas arise at a single site and spread to other tissues by metastasis, or if they arise simultaneously in multiple sites (synchronous or multicentric origin)
• Hens with advanced reproductive tract adenocarcinomas have moderate to marked ascites, weight loss, metastatic tumors in the liver and lungs, and generalized serosal tumors involving the intestinal peritoneal cavity (carcinomatosis)

 

REFERENCES:

1. Barnes HJ, Fletcher OJ, Abdul-Aziz T. Chapter 13: Reproductive System. In: Abdul-Aziz T, Fletcher OJ, Barns HJ, eds. Avian Histopathology. 4th ed. Madison, WI: Omnipress; 2016: 590-593.
2. Barthold SW, Griffey SM, Percy DH. Pathology of Laboratory Rodents and Rabbits. 4th ed. Ames, IA: Blackwell Publishing; 2016:320.
3. Baum B. Not Just Uterine Adenocarcinoma-Neoplastic and Non-Neoplastic Masses in Domestic Pet Rabbits (Oryctolagus cuniculus): A Review. Vet Pathol. 2021;58(5):890-900.
4. Bertram CA, Bertram B, Bartel A, et al. Neoplasia and Tumor-Like Lesions in Pet Rabbits (Oryctolagus cuniculus): A Retrospective Analysis of Cases Between 1995 and 2019. Vet Pathol. 2021;58(5):901-911.
5. Camus MS, Allison RW, Miller D. Female Reproductive Tract. In: Valenciano AC, Cowell RL, eds. Diagnostic Cytology and Hematology of the Dog and Cat. 5th ed. St. Louis, MO: Elsevier Mosby; 2014:424-438. 
6. Consalter A, Balaro MFA, Nascimento NT, Waterloo MML, Batista BP, Ferreira AMR, Leite JS. Intramedullary Metastatic Endometrial Adenocarcinoma in a Goat. J Comp Pathol. 2022;192:18-22.
7. Delaney MA, Treuting PM, Rothenburger JL. Lagomorpha. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London, UK: Academic Press; 2018:486-487.
8. Foster RA, Premanandan C. Female Reproductive System and Mammae. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:1293.
9. Gottdenker NL, Ellis AE, Rech RR, Han S, Lowenstine LJ, Agnew D, Garner MM, McAloose D, Hollinger C, St Leger J, Terrell SP, Duncan M, Pessier AP. Reproductive tract neoplasia in adult female Asian elephants (Elephas maximus). Vet Pathol. 2021;58(6):1131-1141.
10. Pare JA, Paul-Murphy J. Disorders of the reproductive and urinary systems. In: Quesenberry KE, Carpenter JW, eds. Ferrets, Rabbits and Rodents: Clinical Medicine and Surgery. 2nd ed. Philadelphia, PA: W. B. Saunders; 2004:183-184. 
11. Paździor-Czapula K, Mikiewicz M, Fiedorowicz J, Otrocka-Domagała I. Mammary and reproductive tract tumours and tumour-like lesions of 286 small pet mammals: a retrospective study. J Comp Pathol. 2024;213:46-58.
12. 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: 449-450.
13. Schmidt R, Reavill DR, Phalen DN. Pathology of Pet and Aviary Birds. 2nd ed. Ames, IA: John Wiley & Sons, Inc.; 2015:155.
14. Vielmo A, Santos IR, Piva MM, Bandinelli MB, Pavarini SP, Panziera W, Driemeier D. Histological and immunohistochemical features of carcinomas with pulmonary involvement in cattle. Vet Pathol. 2024;61(2):179-189.

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