JPC SYSTEMIC PATHOLOGY
ENDOCRINE SYSTEM
January 2022
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 (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 mild 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)
• Often arises at multiple sites within the uterus
• 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
• Variable presence of estrogen and progesterone receptors in uterine adenocarcinoma has been documented in Fischer 344 rats (Wilson, Tox Pathol. 2015)

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
• Early metastasis to peritoneal cavity; later metastases to lungs, liver, and bone

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

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

• 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
• Guinea pigs: Spontaneous uterine adenocarcinoma was found in 3 of 83 Guinea pigs in one study (Laik-Schandelmaier, J Comp Pathol. 2017)
• 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)

REFERENCES:

1. Barthold SW, Griffey SM, Percy DH. Pathology of Laboratory Rodents and Rabbits. 4th ed. Ames, IA: Blackwell Publishing; 2016:320.
2. 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.
3. 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.
4. Bertram CA, Muller K, Klopfleisch R. Gental Tact Pathology in Female Pet Rabbits (Oryctolagus cuniculus): Retrospective Study of 854 Necropsy Examinations and 152 Biopsy Samples. J Comp Pathol. 2018;164:17-26.
5. Dockweiler JC, Cossic B, McDonough SP, et al. Tumor collision of uterine adenocarcinoma and leiomyosarcoma in a goat. J Vet Diagn Invest. 2017;29(5):696-699.
6. Foster RA. Female Reproductive System and Mammae. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2017:1168, 1178.
7. 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.
8. Laik-Schandelmaier C, Klopfleisch R, Schoniger S, et al. Sponteneous Arising Tumors and Tumor-like Lesions of the Cervix and Uterus in 83 Pet Guinea Pigs (Cavia porcellus). J Comp Path. 2017;156(4):339-351.
9. 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.
10. 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.
11. Willson CJ, Herbert RA, Cline JM. Hormone receptor expression in spontaneous uterine adenocarcinoma in Fischer 344 rats. Toxicol Pathol. 2015;43(6):865-71.

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