JPC SYSTEMIC PATHOLOGY
Signalment (Slide A, JPC #2643312): Dog
HISTOPATHOLOGIC DESCRIPTION: Ovary (per contributor): Extending to submitted margins and diffusely effacing normal ovarian tissue is a multilobular, densely-cellular neoplasm composed of polygonal cells arranged in islands and cords which frequently palisade along the fibrovascular stroma forming rosette-like structures that surround a central eosinophilic secretory globule (Call-Exner bodies). Neoplastic cells have distinct cell borders, a moderate amount of pale eosinophilic, granular to fibrillar cytoplasm, one to two round nuclei, finely-stippled chromatin and a distinct nucleolus. The mitotic rate is 1 per 40x HPF. Multifocally within the neoplasm there is fibrin, hemorrhage, edema and lakes of an eosinophilic acellular material (secretory product).
MORPHOLOGIC DIAGNOSIS: Ovary (per contributor): Granulosa cell tumor, breed unspecified, canine.
Signalment (Slide B, JPC #1848611): 30-year-old female Bornean orangutan (Pongo pygmaeus)
HISTOPATHOLOGIC DESCRIPTION: Ovary: Extending to submitted margins and diffusely effacing normal ovarian tissue is a multilobular, densely-cellular neoplasm composed of polygonal cells arranged in islands and cords and frequently palisade 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, one round to ovoid nucleus, finely-stippled chromatin and an indistinct nucleolus. The mitotic rate is 1 per 40x HPF. Multifocally, few lobules contain lakes of eosinophilic acellular material (secretory product).
MORPHOLOGIC DIANGOSIS: Ovary: Granulosa cell tumor, Bornean orangutan (Pongo pygmaeus), nonhuman primate.
Signalment (Slide C, JPC #4065007): Horse
HISTOPATHOLOGIC DESCRIPTION: Ovary: Diffusely expanding and effacing the ovarian tissue and extending to submitted margins is an unencapsulated, well demarcated, densely cellular neoplasm composed of neoplastic granulosa cells that line multiple variably sized 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, and often hemorrhagic, collagenous stroma. Neoplastic cells have distinct cell borders, a moderate amount of pale eosinophilic to granular or vacuolated cytoplasm, a round to ovoid nucleus with finely-stippled chromatin and an indistinct nucleolus. Anisocytosis and anisokarryosis are mild with 1 mitotic figure per 10 40X HPF. Granulosa cells are surrounded by a layer of streaming spindle cells with indistinct cell borders, scant fibrillar eosinophilic cytoplasm, 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). Rarely, neoplastic granulosa cells surround pale eosinophilic secretory globules (Call-Exner bodies). Cysts contain abundant hemorrhage or eosinophilic acellular material (secretory product). 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.
MORPHOLOGIC DIAGNOSIS: Ovary: Granulosa cell tumor, breed unspecified, equine.
- Sex cord-stromal tumor; granulosa-theca cell tumor; Sertoli cell tumor of the ovary
- Tumors with an ovarian tissue phenotype are divided into 3 categories:
- Tumors of the epithelium of the ovary, including surface celomic 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)
- Most are phenotype mixtures of granulosa cells and theca cells predominating and often co-existing within the same tumor (granulosa-theca tumor)
- Typically, unilateral and non-malignant in any species
- Incidence increases with age
- Less commonly, tumors contain only theca cells (thecoma or luteoma)
- Histologically, some resemble Sertoli cell testicular tumors and interstitial endocrine cell types
- Frequently develop within ovarian remnants
- 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
- Granulosa cell tumors 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
- High plasma luteinizing hormone (LH) may occur in the bitch
- Hypertrophic pulmonary osteopathy is 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
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
- Contain areas with characteristic glandular or rosette-like patterns in abortive follicles; some may have a tubular pattern with dense fibrous stroma similar to a Sertoli cell tumor
- Neoplastic granulosa cells have scant eosinophilic cytoplasm, round to spherical, hyperchromatic nuclei and distinct nucleoli
- Common patterns are micro/macrofollicular, insular, trabecular and diffuse sheets
- Cysts are lined by granulosa cells with surrounding thecal cells
- 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
ADDITIONAL DIAGNOSTIC TESTS:
- Immunohistochemical findings for sex cord stromal tumors include positivity for inhibin-α, vimentin and cytokeratin
- Granulosa cell component often vimentin, S-100 and smooth muscle actin positive and inconsistently label with Melan-A
- Stroma may be focally positive for desmin
- Inhibin-α levels correlate to tumor mass and more often are elevated
- Cows and mares: Serum anti-Mullerian hormone can be used in cows and mares as a sensitive indicator of diagnosing granulosa cell 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: Uniform population of large round cells with clear or light staining amphophilic cytoplasm that resemble primordial germ cells; analogous to seminoma in males
- Teratoma: Neoplasm 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
- Most often benign; thecal component and follicular pattern usually are more prominent
- Three recognized behavioral patterns: (1) anestrous; inhibin-producing (2) continuous or intermittent estrus (3) male behavior; androgen-producing
- Testosterone levels are elevated in most cases; male behavior is only observed when hormone levels are above 100 pg/mL; some mares have elevated estrogen levels
- Atrophy of the opposite ovary occurs commonly
- Cow: 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
- Queen: Infrequent occurrence; metastasis relatively common
- Gerbil: Most common ovarian neoplasm in aged females; animal model for human disease; frequently bilateral
- Guinea pig: Uncommon; teratoma is the most common ovarian tumor
- Mouse: Transgenic mouse models have been developed to model human granulosa cell tumor, including: Inhibin alpha-subunit knockout; SMAD-knockout; and a model that overexpresses luteinizing hormone; p53+/- mice have developed malignant granulosa cell tumors
- Nonhuman primate: Most common sex-cord stromal tumor; granulosa cell tumors in macaques are all considered malignant, and many are biologically aggressive
- Manatee: Uncommon
- Agnew DW, MacLachlan NJ. In: Tumors of the genital system. In: Meuten DJ, ed. Tumors in Domestic Animals. 5th ed. Ames, IA: John Wiley & Sons, Inc.; 2017:690-698.
- Banco B, Antuofermo E, Borzacchiello G, Cossu-Rocca P, Grieco V. Canine ovarian tumors: an immunohistochemical study with HBME-1 antibody. J Vet Diagn Invest. 2011;23(5):977-981.
- Barthold SW, Griffey SM, Percy DH. Pathology of Laboratory Rodents and Rabbits. 4th ed. Ames, IA: Blackwell Publishing; 2016:115, 210, 251,
- Buijtels JJ, de Gier J, Kooistra HS, Kroeze EJ, Okkens AC. Alterations of the pituitary-ovarian axis in dogs with a functional granulosa cell tumor. Theriogenology. 2010;73(1):11-19.
- Crabtree J. Review of seven cases of granulosa cell tumour of the equine ovary. Vet Rec. 2011;169(10):251.
- Durkes A, Garner M, Juan-Salles C, Ramos-Vara J. Immunohistochemical characterization of nonhuman primate ovarian sex cord-stromal tumors. Vet Pathol. 2012;49(5):834-838.
- Fernandes TR, Grandi F, Monteiro LN, Salgado BS, Rocha NS. What is your diagnosis? Unilateral ovarian mass in a mare. Vet Clin Pathol. 2011;40(3):399-400.
- Foster RA. Female reproductive system and mammae. In: McGavin MD, Zachary JF, eds. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2017:1161-1162.
- Guzman-Silva MA, Costa-Neves M. Incipient spontaneous granulosa cell tumor in the gerbil, Meriones unguiculatus. Lab Anim. 2006;40(1):96-101.
- Jamieson S, Fuller PJ. Molecular pathogenesis of granulosa cell tumors of the ovary. Endocr Rev. 2012;33(1):109-144.
- Kennedy PC, Cullen JM, Edwards JF, et al. Histological Classification of Tumors of the Genital System of Domestic Animals. 2nd series. Volume IV. Washington, DC: Armed Forces Institute of Pathology; 1998.
- Masserdotti C, De Lorenzi D, Gasparotto L. Cytological detection of Call-Exner bodies in Sertoli cell tumors from 2 dogs. Vet Clin Pathol. 2008;37(1):112-114.
- McInnes ER, Ernst H, Germann PG. Spontaneous neoplastic lesions in control Syrian hamsters in 6-, 12-, and 24-month short-term and carcinogenicity studies. Toxicol Pathol. 2013;41(1):86-97.
- Schlafer DH, Foster RA. Female genital system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 3. 6th ed. Louis: Elsevier; 2016:375-379.
- Smith LN, Rotstein DS, Ball RL, et al. Reproductive neoplasms in wild and long-term captive female Florida manatees (Trichechus manatus latirostris). J Zoo Wildl Med. 2015;46(4):895-903.
- Spoor MS, Flesner BK, Trzil JE, et al. What is your diagnosis? Intra-abdominal mass in a female spayed dog. Vet Clin Path. 2014;43(1):109-110.