JPC SYSTEMIC PATHOLOGY
ENDOCRINE SYSTEM
January 2022
R-N16

Signalment (JPC #4019837):  Female mouse (Mus musculus), age and strain not given.

HISTORY:  The left ovary was enlarged and hemorrhagic. (Incidental finding at sentinel health monitoring)

HISTOPATHOLOGIC DESCRIPTION:  Ovary: Expanding the ovary up to 4mm in diameter, peripheralizing compressed remaining ovarian stroma and follicles, and abutting a pre-existing corpus luteum is a hemorrhagic, cystic, paucicellular, well-demarcated, unencapsulated neoplasm composed of sheets of large, pleomorphic cells up to 200um diameter (trophoblast-like cells) with distinct cell borders, an abundant amount of eosinophilic, pale, finely vacuolated cytoplasm, and large, round to oval to irregular, often vesiculate nuclei up to 80um diameter with finely stippled or prominent, coarsely clumped chromatin and 1-7 dark, irregularly shaped, prominent nucleoli. Anisocytosis and anisokaryosis are marked, there are few binucleate cells (syncytiotrophoblast-like cells), and no mitoses are observed. Cells in the center of the lesion are variably pale with decreased differential staining and retention of architecture (coagulative necrosis). There is abundant central hemorrhage, fibrin and edema extending into the ovarian bursa.

Oviduct; uterus:  No significant findings.

MORPHOLOGIC DIAGNOSIS:  Ovary: Choriocarcinoma, mouse (Mus musculus), rodent.

GENERAL DISCUSSION:

• Germ cell origin (either gestational or nongestational, see below)
• Tumors of the ovary are divided into three groups based on tissue of origin:
  • Epithelial tumors – arise from surface epithelium, SES (in bitches), or, less commonly, the rete ovarii (at the hilus)
  • Sex cord stromal tumors – arise from endocrine cells in the ovary (theca, follicular granulosa, or luteinized derivatives)
  • Germ cell tumors – arise from germ cells; examples include teratoma, dysgerminoma, yolk sac carcinoma, and choriocarcinoma
    • Germ cells are originally located in the yolk sac (developing fetus) and migrate to the gonadal ridge; germ cells and sex cords associate within the developing ovary to form primary follicles
  • Rare in domestic animals; identified in the uterus or ovary of macaques, rabbits, rodents, and a potbellied pig
    • B6C3F1 mice may be overrepresented
    • Genetically engineered mouse model available with alterations in Brca2, Trp53, and RB (Szabova, Vet Pathol, 2019)
    • Single case report of mixed embryonal carcinoma and choriocarcinoma in a harvest mouse (Minoli, J Comp Pathol, 2020)

PATHOGENESIS:

• May be primary, originating from trophoblastic differentiation of a germ cell or a poorly differentiated endometrial carcinoma (nongestational) or in association with ovarian pregnancy (gestational); or may be secondary, a metastasis from a primary uterine choriocarcinoma arising during pregnancy (gestational)
• Mouse placentas have three types of trophoblastic cells: giant cells, cytotrophoblasts, and syncytiotrophoblasts; choriocarcinomas can contain one or more or a combination of those cell types
• It is possible that Tie2 induced deletion of Trp53 may play a role in development

TYPICAL CLINICAL FINDINGS: 

• Usually an incidental finding at necropsy

TYPICAL GROSS FINDINGS:

• Dark red/hemorrhagic cystic masses which efface or are attached to the ovary or uterine wall

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Biphasic population of cytotrophoblastic and syncytiotrophoblastic +/-trophoblastic giant cells effacing and replacing ovarian or uterine stroma
• Often associated with large cystic areas of hemorrhage
• Variable mitotic rate (often low to absent)
• Trophoblastic cells:
  • Markedly irregular shape; multinucleation common
  • Abundant amounts of eosinophilic finely granular to vacuolated cytoplasm
  • Abnormally large and irregularly shaped vesiculate nuclei with finely stippled chromatin and variable numbers of often irregularly shaped nucleoli

ADDITIONAL DIAGNOSTIC TESTS:

• Immunohistochemistry:
  • Positive for human chorionic gonadotropin (hCG), pan-cytokeratin, HSD83B1 (indicates trophoblastic origin), α-inhibin, CD146, folate binding protein
  • Negative for vimentin, OCT4, and α-fetoprotein (distinguishes from dysgerminoma, embryonal carcinoma, and yolk sac tumors)
  • May be positive for: human placental lactogen, p63, CD10
  • Ki-67 index is characteristically high
• PAS positive droplets in the cytoplasm of trophoblastic cells

DIFFERENTIAL DIAGNOSIS:

• Microscopic appearance of trophoblastic cells is characteristic
• Other tumors of germ cell origin: teratoma (contains 2 or more germ cell layers); dysgerminoma (female equivalent of testicular seminoma, composed of round cells – germ cells with no somatic differentiation); yolk sac carcinoma

REFERENCES:

1. Agnew DW, MacLachlan NJ. Tumors of the genital systems. In: Meuten DJ, ed. Tumors in Domestic Animals. 5^th Ames, IA: John Wiley & Sons, Inc.; 2017:690-700.
2. Alison RH, Lewis DJ, Montgomery CA. Ovarian choriocarcinoma in the mouse. Vet Pathol. 1987;24(3):226-230.
3. Castiglioni V, Farhand Ghahremani M, Goossens S, et al. Immunohistochemical description of nongestational ovarian choriocarcinoma in two female mice with conditional loss of Trp53 driven by the Tie2 promoter. Vet Pathol. 2015;52(4):752-756.
4. Elmore SA, Carreira V, Labriola CS, Mahapatra D, et al. Proceedings of the 2018 national toxicology program satellite symposium. Toxicol Pathol. 2018;46(8):865-897.
5. Hirata A, Miyazaki A, Sakai H, Imada N, et al. Choriocarcinoma-like tumor in a potbellied pig (Sus scrofa). J Vet Diagn Invest. 2014;26(1):163-166.
6. Minoli L, Assenmacher CA, Ranieri BN, et al. Mixed germ cell tumour with embryonal carcinoma and choriocarcinoma in a female Eurasian harvest mouse (Micromys minutus). J Comp Pathol. 2020;180:122-127.
7. Schlafer DH, Foster RA. Female genital system. In: Maxie MG, ed. Jubb Kennedy and Palmer’s Pathology of Domestic Animals. Vol 3. 6th ed. Philadelphia, PA: Elsevier Saunders; 2016:377-378.
8. Szabova L, Karim B, Gordon M, et al. A transplantable syngenic allograft mouse model for nongestational choriocarcinoma of the ovary. Vet Pathol. 2019;56(3):399-403.
9. Veiga-Parga T, La Perle KM, Newman SJ. Spontaneous reproductive pathology in female guinea pigs. J Vet Diagn Invest. 2016;28(6):656-661. 

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