JPC SYSTEMIC PATHOLOGY
REPRODUCTIVE SYSTEM
January 2022
R-N05

SLIDE A: Signalment (JPC #2643312):  Dog

HISTORY:  None

HISTOPATHOLOGIC DESCRIPTION:  Ovary (per contributor):  Extending to submitted margins and diffusely effacing normal ovarian tissue architecture is a multilobular, densely cellular neoplasm composed of polygonal cells arranged in islands and cords and frequently palisading along the fibrovascular stroma forming rosette-like structures that surround central eosinophilic secretory material (Call-Exner bodies).  Neoplastic cells have distinct cell borders, a moderate amount of pale eosinophilic, granular to vacuolated cytoplasm, and one to two round nuclei with finely-stippled chromatin and a distinct nucleolus.  The mitotic rate is 1 per 2.37mm^2.  Multifocally within the neoplasm there is fibrin, hemorrhage, edema, lakes of eosinophilic acellular material (secretory product), foamy macrophages, hemosiderophages, and cholesterol clefts. 

MORPHOLOGIC DIAGNOSIS:  Ovary (per contributor):  Granulosa cell tumor, breed unspecified, canine.

SLIDE B: Signalment (JPC #1848611):  30-year-old female Bornean orangutan (Pongo pygmaeus)

HISTORY:  None

HISTOPATHOLOGIC DESCRIPTION:  Ovary:  Extending to submitted margins and diffusely effacing normal ovarian tissue architecture is a multilobular, densely cellular neoplasm composed of polygonal cells arranged in islands and indistinct cords and frequently palisading along the fibrovascular stroma forming rosette-like structures that surround a central eosinophilic secretory globule (Call-Exner bodies).  Neoplastic cells have indistinct cell borders, a scant amount of pale eosinophilic cytoplasm, and one round to ovoid nucleus with finely-stippled chromatin and an indistinct nucleolus.  The mitotic rate is 1 per 2.37mm^2.  Multifocally, few islands or lobules contain lakes of eosinophilic proteinaceous material (secretory product) with, foamy macrophages, hemosiderophages, and few lymphocytes and there are areas of mild hemorrhage, fibrin, and edema.

MORPHOLOGIC DIANGOSIS:  Ovary:  Granulosa cell tumor, Bornean orangutan (Pongo pygmaeus), nonhuman primate.

SLIDE C: Signalment (JPC #4065007):  Horse

HISTORY:  None

HISTOPATHOLOGIC DESCRIPTION:  Ovary:  Diffusely expanding and effacing the ovarian tissue architecture and extending to submitted margins is an unencapsulated, well demarcated, densely cellular neoplasm composed of neoplastic granulosa cells that line multiple variably sized (up to 4mm diameter), tortuous, cystic structures arranged in a macrofollicular pattern, or palisade along the margin of solidly cellular trabecular or tubule like structures on a moderate to dense, often hemorrhagic, collagenous stroma.  Neoplastic cells have distinct cell borders, a moderate amount of pale eosinophilic to granular or vacuolated cytoplasm, and a round to ovoid nucleus with finely stippled chromatin and an indistinct nucleolus.  Anisocytosis and anisokaryosis are mild with 1 mitotic figure per 2.37mm^2.  Granulosa cells are surrounded by a layer of streaming spindle cells with indistinct cell borders, scant fibrillar eosinophilic cytoplasm, and a round to oval nucleus with finely stippled chromatin and indistinct nucleoli (theca cells).  Admixed with theca cells and/or adjacent to the margins of follicular structures are aggregates of large, polyhedral cells with variably distinct cell borders and abundant granular or vacuolated eosinophilic cytoplasm (resemble testosterone-producing Leydig cells).  Some cysts contain abundant hemorrhage or eosinophilic acellular material (secretory product) or few foamy macrophages.  Multifocally, the ovarian stroma contains hemosiderin-laden macrophages and low numbers of lymphocytes, multifocal hemorrhage, fibrin, and edema, and multiple ectatic lymphatic vessels.  Few macrophages contain phagocytized red blood cells and there is increased clear space separating collagenous tissue (edema).

MORPHOLOGIC DIAGNOSIS:  Ovary:  Granulosa cell tumor, breed unspecified, equine.

SYNONYMS:  Sex cord-stromal tumor; granulosa-theca cell tumor; Sertoli cell tumor of the ovary

GENERAL DISCUSSION:

• Tumors with an ovarian tissue phenotype are divided into 3 categories:
  • Tumors of the epithelium of the ovary, including surface coelomic epithelium, the subsurface epithelial structures (SES), and the rete ovarii
  • Tumors of the sex-cords and gonadal stroma
  • Germ cell tumors
• Primary ovarian tumors occur most commonly in the bitch (often bilateral; from surface epithelium and SES), mare and cow (unilateral; gonadal-stromal); few neoplasms reported in cats and pigs; feline tumors similar to the bitch
• Sex-cord stromal tumors are tumors of granulosa and theca cells or their luteinized counterparts
  • Often produce hormones (estrogen, progesterone, inhibin, testosterone) with subunits A and B
  • Most are phenotype mixtures of granulosa cells and theca cells predominating and often co-existing within the same tumor (granulosa-theca tumor); less commonly, tumors contain only theca cells (thecoma or luteoma)
    • Typically, unilateral and non-malignant in any species
    • Incidence increases with age
  • Histologically, some resemble Sertoli cell testicular tumors and interstitial endocrine cell types
  • Frequently develop within ovarian remnants
  • Granular cell tumors (GCTs) are the most common neoplasm of the large animal ovary
  • Metastasis can occur to the regional lymph nodes and other organs via the blood
    • Metastasis of GCTs and is less common in the bitch
  • Conditions described in bitches associated with sex-cord stroma tumors: Pyometra, cystic endometrial hyperplasia and hyperadrenocorticism

PATHOGENESIS:

• Sex cord stromal tumors are derived from normal cellular components of the ovarian endocrine apparatus
• Granulosa cells produce the peptide hormone inhibin, which inhibits the release of follicle stimulating hormone (FSH), and may cause atrophy of the contralateral ovary, especially in mares

TYPICAL CLINICAL FINDINGS:

• Altered estrus cycles, including anestrus, continuous estrus, or intermittent estrus, or masculinization
• GCTs in the cat and dog are often associated with clinical signs of hyperestrogenism including continuous or intermittent estrus, anestrus, vulvar swelling, vaginal discharge, pyometra, and cystic endometrial hyperplasia
• GCTs in the horse are associated with 3 behavioral patterns: (1) anestrous; inhibin-producing (2) nymphomania; continuous or intermittent estrus (3) male behavior; androgen-producing; testosterone levels are elevated in most cases, but male behavior is only observed when serum testosterone levels are above 100 pg/mL
• Hypertrophic osteopathy (formerly hypertrophic pulmonary osteopathy, M-N05) can be associated with tumors of the ovary

TYPICAL GROSS FINDINGS:

• Firm tumors with smooth to nodular surface up to 20-30 cm in diameter
• White to yellow solid appearance, cystic or polycystic on cut surface; commonly cystic in the mare
• Uni- or bilateral, nodular or symmetrical ovarian enlargement +/- hemorrhagic necrosis; solid portion is white or yellow depending on lipid content
• Atrophy of the contralateral ovary; common in mares

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Variety of histologic patterns and named based upon their similarity to normal constituents of the ovarian endocrine apparatus; tumors often composed of more than one cell type
• Common patterns are micro/macrofollicular, insular, trabecular, and diffuse sheets
• Neoplastic granulosa cells have scant eosinophilic cytoplasm, round to spherical, hyperchromatic nuclei and distinct nucleoli
• Contain areas with characteristic glandular or rosette-like patterns in abortive follicles that may resemble ovum with eosinophilic secretory globules (Call-Exner bodies); some may have a tubular pattern with dense fibrous stroma similar to a Sertoli cell tumor
  • Call-Exner bodies are small, central, round to oval spaces containing eosinophilic follicular fluid surrounded by a collar of radially-arranged granulosa cells (diagnostic, but not always present); most commonly associated with macrofollicular pattern
• Cysts are lined by granulosa cells with surrounding thecal cells
• In mares, thecal component and follicular pattern are typically more prominent

ADDITIONAL DIAGNOSTIC TESTS:

• Immunohistochemistry
  • Sex cord stromal tumors are positive for inhibin-α, vimentin, and cytokeratin
  • Granulosa cell component often positive for vimentin, S-100, and smooth muscle actin, +/- Melan-A
  • Stroma may be focally positive for desmin
• Endocrinology
  • Inhibin-α levels correlate to tumor mass and more often are elevated
  • Cows and mares: Serum anti-Mullerian hormone is a sensitive indicator of diagnosing granulosa cell tumors
  • Mares: Most have elevated testosterone levels, some have elevated estrogen levels
  • Bitches: High plasma luteinizing hormone (LH) may occur

DIFFERENTIAL DIAGNOSIS:

• Other sex cord stromal tumors:
  • Thecoma: Spindle cells that contain lipid (steroid hormones) and are loosely arranged in sheets or interlacing bundles
  • Luteoma: Large, round to polygonal cells that contain lipid vacuoles with round nuclei that resemble cells of the corpus luteum; neoplastic cells are separated by a well-vascularized connective tissue stroma
• Germ cell tumors:
  • Dysgerminoma (R-N06): Uniform population of large round cells with clear or light staining amphophilic cytoplasm that resemble primordial germ cells; analogous to seminoma in males
  • Teratoma (R-N08): Composed of 2 or 3 of the primordial germ cell lineages
    • Endoderm: Gastrointestinal tract (except oral cavity, pharynx and terminal rectum), respiratory epithelium, urinary bladder and urethra, auditory tubes and tympanic cavity, epithelial components of endocrine glands
    • Mesoderm: Collagen, muscle (skeletal, smooth, cardiac), bone, cartilage, blood vessels, renal tubular epithelium, mesothelium, erythrocytes
    • Ectoderm: Nervous system (brain, spinal cord, nerves), epidermis and melanocytes, tooth enamel, lining of oral cavity, pharynx, terminal rectum, dermal adnexa

COMPARATIVE PATHOLOGY:

• Cow: GCTs frequently demonstrate a solid pattern; malignancy variably reported; nymphomania manifests by mounting other animals in the herd; masculinization results in phenotypic changes such as bull-like thickening of the head and neck, elevation of the tail head, and bull-like vocalization and behavior; late metastasis can occur in bovine sex cord tumors
• Queen: Infrequent occurrence; metastasis relatively common
• Gerbil: Most common ovarian neoplasm in aged females; animal model for human disease; frequently bilateral, fleshy, cystic to lobulated
• Guinea pig: Uncommon; teratoma is the most common ovarian tumor
• Mouse: Transgenic mouse models have been developed to model human GCT, including:  Inhibin alpha-subunit knockout; SMAD-knockout; and a model that overexpresses luteinizing hormone; p53+/- mice have developed malignant GCTs
• Nonhuman primate (NHP): Most common sex-cord stromal tumor; GCTs in macaques are all considered malignant, many are biologically aggressive, and some produce estrogen; one or more concurrent lesions (i.e., endometrial hyperplasia, endometrial polyps, vaginal keratinization) may be present due to estrogen effects   
  • A recent comprehensive review of spontaneous genitourinary lesions in NHPs at 2 research centers identified GCT as the most common ovarian neoplasm (Kirejczyk S. et al., Vet Pathol. 2021)
• Giraffes: In a retrospective survey of neoplasia in managed giraffes, of 18 tumors identified one was a cystic GCT (Doden G. et al., J Zoo Wildl Med. 2021)
• Lizards: A recent retrospective review of neoplasms in captive lizards in the UK diagnosed the first testicular GCT in captive lizards (Kubiak M. et al., Vet Rec. 2020)
• Ovarian GCTs also reported in the following: Llamas, captive maned wolves and captive African wild dogs, rock hyraxes (single report), harbor porpoise, captive manatees (uncommon), snakes (benign), longjaw mudsucker, lesser bushbaby, pygmy slow loris, slender loris, whiptail lizards, green iguanas, and blue-tongued skink

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