Signalment:  

31-year-old female Rhesus macaque (Macaca mulatta)Used in an aging study examining neuropatholgical and behavioral changes related to age. Euthanized at end of study.

Gross Description:  

The right ovary is enlarged (5 x 6 cm) with multiple, large multiloculated cysts, the largest measuring approximately 3.5 to 4cm in diameter. On cut section, the cysts are demarcated by thin walls and contain an orange to red, proteinaceous material. Vagina, cervix and uterus are normal. The left ovary is twice enlarged and contains a solid mass. 

Histopathologic Description:

The right ovary contains two distinct tumors (a cystadenoma and a granulosa cell tumor) that replace the normal ovarian tissue. The cystadenoma is composed of numerous large cysts filled with eosinophilic homogenous material (proteinaceous fluid), lined by flat cuboidal epithelium with small basophilic nuclei, minimal eosinophilic cytoplasm, separated by and growing along dense collagenous connective tissue. The neoplastic cells form papillary projections into the cysts and in the surrounding interstitium. Mitoses are rare. The granulosa cell tumor is composed of a population of neoplastic cells arranged in stratified layers of polygonal cells with small basophilic nuclei and scant cytoplasm lining spaces with flocculent amphophilic material and growing along a fibrovascular stroma. This population of cells occasionally forms rings of pallisading cells at the center of which is deeply eosinophilic material (Call-Exner bodies). Nests and packets of these cells infiltrate the thin rim of dense ovarian stromal tissue at the periphery. Primary follicles are rare consistent with the monkeys age. Deeply basophilic irregular material (mineral) is multifocally present. Mitoses are rare. 

Morphologic Diagnosis:  

Ovary: Papillary serous cystadenoma and Granulosa cell tumor, macrofollicular (coincident in the same ovary)

Condition:  

Granulosa cell tumor; papillary serous cystadenoma

Contributor Comment:  

Ovarian masses can be separated into cysts and neoplasms. Cysts within the ovary are identified by dilatations not involving gonadal or stromal tissue. Serous inclusion cysts have been reported in the bitch and cystic rete tubules have been reported in the bitch and queen. Cysts involving the gonadal stroma are typically cycle dependent and include: cystic graffian follicles, follicular cysts, anovulatory luteinized cysts, and cystic corpus luteum. These are frequently associated with cows and sows.¹ In humans, cystic follicles are so frequent they can be considered physiologic originating from graffian follicles.²

Ovarian neoplasms account for 6% of all cancers in the female and are the fifth most common form of cancer in women in the United States (excluding skin cancer). Due to the difficult rate of early detection, these neoplasms are responsible for almost half of the deaths from cancer of the female genital tract. There are numerous types of ovarian tumors, both benign and malignant. About 80% are benign, and these occur mostly in young women between the ages of 20 and 45 years. The malignant tumors are more common in older women between the ages of 40 and 65 years.²

Ovarian neoplasms are generally broken into four categories-�-�germ cell, sex cord stromal, surface epithelial, and mesenchymal. A summary of diagnostic criteria can be found in the Histological Classification of Tumors of the Genital System of Domestic Animals, AFIP Second Series, Volume VI.³

We classified this ovary as having a component of a granulosa cell tumor based on its morphologic appearance of cells containing spherical-to-oval, hyperchromatic nuclei, distinct nucleoli, and scant eosinophilic cytoplasm. The Call-Exner bodies supported this diagnosis. The other cystic component of this ovary is composed of infoldings and papillary projections of subsurface small cuboidal epithelium, scant connective tissue stroma, and rare mitoses consistent with cystadenocarcinoma. Immunohistochemistry for the cystic tissue was strongly positive for confirming its epithelial origin. The granulosa cell component was positive for inhibin. 

Dual ovarian tumors in non-human primates have not been reported.⁵ Dual tumors in ovaries have been reported in humans, but are generally rare.^6,7 The pathogenesis for dual tumors is unknown, but postulated theories include: collision neoplasm, in which two tumors develop spontaneously; a heterologous differentiation within a granulosa cell tumor; or a teratomatous neoplasm with a bidirectional differentiation. Recently, a case of mucinous cystadenoma and granulosa cell tumor was reported in a 57-year-old woman.⁷ The immunohistochemical profile of this tumor demonstrated diffuse positive CK7 and focal weak CK20 within the mucinous component. The granulosa cell component was strongly alpha-inhibin positive and diffuse calretinin positive while being negative for epithelial membrane antigen (EMA) and anticytokeratin antibody AE1/3.

Mixed ovarian tumors in the veterinary literature are also extremely rare. A brief literature review shows key ovarian neoplasms documented in veterinary species include:

Equine	Granulosa cell tumor (almost always unilateral, slow growing, and benign; elevated inhibin in 90%) Cystadenoma-�-�most common tumor of surface epithelium
Bovine	Granulosa cell tumor
Feline	Malignant granulosa cell tumor
Canine	Papillary cystadenocarcinoma, malignant granulosa cell tumor; malignant teratoma
Murine	typically irradiation induced, all types; spontaneous cystadenoma and granulosa cell tumors have been reported.
Rat	Osborne-Mende strain 330, 33% of rats > 18months develop granulosa cell tumors; Sprague Dawley predisposed to a variety of histological subtypes
NHP	Granulosa cell tumor, teratoma, and cystadenocarcinoma have been reported in baboons, recently choriocarcinomas have been reported in macaques
Ferret	Sex cord stromal resulting in alopecia (Comp Med 2003)
fish	Ovarian carcinoma in a koi carp (Aus Vet J, 2006)
Poultry	Adenocarcinoma of turkeys and chickens in intensive-laying conditions. Cornell has C strain genetically predisposed to epithelial cancer
Snake	Granulosa cell tumor (especially garter snakes)
Lizard	Teratomas (especially iguanas)

For more information, the reader is directed to previous ovarian neoplasm submissions to AFIP as well as the following websites:
Radiology UCHC
PubMed

JPC Diagnosis:  

1. Ovary: Papillary serous cystadenocarcinoma, Rhesus macaque (Macaca mulatta), nonhuman primate.
2. Ovary: Granulosa cell tumor.

Conference Comment:  

Granulosa cell tumors are the most common ovarian tumor in large animals. They are generally benign in the cow and horse but are often malignant in dogs and cats.¹ Sex cord-stromal tumors may be hormonally active and produce varying amounts of progesterone, estrogen, testosterone, and inhibin.⁴ Anestrus, nymphomania, or stallion-like behavior are often seen in the mare, while the bitch may develop prolonged estrus or pyometra.

Epithelial tumors of the ovary generally arise from the surface epithelium, rete ovarii, and from the subsurface epithelial structures (SES) of the bitch. The bitch is unique in that the canine is the only domestic animal to contain SES, resulting in tumors of the ovary being common only in the bitch. This case was studied in consultation with pathologists in the Department of Gynecologic and Breast Pathology of the Armed Forces Institute of Pathology who agree that the epithelial portion of the neoplasm exhibited areas of low-grade carcinoma. Multifocally neoplastic epithelial cells exhibited moderate cellular atypia and pile up to 5 cell layers thick. Features of malignancy without evidence of metastasis or vascular invasion include a larger size, necrosis, hemorrhage, cellular atypia, piling up of neoplastic cells, increased mitotic index, and stromal invasion.⁴

Classification of ovarian tumors³

Sex cord-stromal (gonadostromal) tumors	Granulosa cell tumor (granulose-theca cell tumor) Thecoma (theca cell tumor) Interstitial cell tumor (luteoma, lipid cell tumor, steroid cell tumor)
Germ cell tumors	Dysgerminoma Teratoma Embryonal carcinoma
Epithelial tumors	Papillary adenoma, papillary cystadenoma Papillary adenocarcinoma Rete adenoma
Mesenchymal tumors	Hemangioma Leiomyoma

References:

1. Foster RA: Female reproductive system. In: Pathologic Basis of Veterinary Disease, eds. McGavin MD, Zachary JF, 4th ed., pp. 1280-1281. Elsevier, St. Louis, MO, 2007
2. Crum CP: The Female Genital Tract, Ovarian Tumors. In: Robbins and Cotran Pathologic Basis of Disease, eds. Kumar V, Abbas, AK, Fausto N, 7th ed., pp. 1093-1104. Elsevier Saunders, Philadelphia, PA, 2005
3. Kennedy PC, Cullen JM, Edwards JF, Goldschmidt MH, Larsen S, Munson L, Nielson S: Histological Classification of Tumors of the Genital System of Domestic Animals, vol. 4, pp. 24-25, 56-63. Armed Forces Institute of Pathology, Washington, D.C., 1998
4. Maclachlan NJ, Kennedy PC: Tumors of the genital systems. In: Tumors in Domestic Animals, ed. Meuten DJ, 4th ed., pp. 547-557. Blackwell Publishing, Ames, IA, 2002 5. Moore CM, Hubbard GB, Leland MM, Dunn BG, Best RG: Spontaneous ovarian tumors in twelve baboons: a review of ovarian neoplasms in non-human primates. J Med Primatol 32:48-56, 2003
6. Moid FY, Jones RV: Granulosa cell tumor and mucinous cystadenoma arising in a mature cystic teratoma of the ovary: a unique case report and review of literature. Ann Diag Path 8:96-101, 2004
7. McKenna M, Kenny B, Dorman G, McCluggage WG: Combined adult granulosa cell tumor and mucinous cystadenoma of the ovary: granulosa cell tumor with heterologous mucinous elements. Inter J Gyne Path 24:224-227, 2005
8. Schlafer DH, Miller RB: Female genital system. In: Jubb, Kennedy, and Palmers Pathology of Domestic Animals, ed. Maxie MG, 5th ed., vol. 3, pp. 450-453. Elsevier Limited, St. Louis, MO, 2007

A virtual slide is not available for this case.

---