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45-year-old woman presents with abnormal vaginal bleeding and an ovarian mass is found on pelvic examination. The oophorectomy specimen contains a 12.0 x 10.0 x 8.0 cm yellow, solid and cystic tumor.
Archive Case and Diagnosis:
This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2010, case 18, and is an adult granulosa cell tumor.
Criteria for Diagnosis and Comments:
Sections of the ovary demonstrate a tumor with solid and trabecular patterns in a fibromatous background. The cells are uniform with relatively scant cytoplasm and round to oval nuclei, some of which have longitudinal grooves. There is minimal cytologic atypia and a low mitotic rate. These features are consistent with an adult granulosa cell tumor (AGCT).
AGCT is one of the most frequent sex cord tumors, accounting for approximately 2-3% of primary ovarian tumors. It can occur at any age, but is most frequent in peri- and postmenopausal women, with a median age of approximately 50 years. AGCT is the most common estrogen producing ovarian tumor, so patients are at risk for concurrent endometrial hyperplasia and adenocarcinoma and can present with menometrorrhagia or postmenopausal bleeding. In prepubertal patients, the most common manifestation is isosexual pseudoprecocity. Less often, AGCT is androgenic and can be virilizing. Other common presentations include abdominal pain and the presence of a pelvic mass. The majority (>95%) of AGCT are unilateral and range from incidental microscopic findings to 30.0 cm in maximum dimension, with an average size of 12.0 cm. They are predominantly solid or solid and cystic with a yellow to white cut surface. Occasional tumors consist of uni- or multilocular cysts filled with serous or serosanguinous fluid.
The granulosa cells can be arranged in a number of different patterns and frequently there is a combination of patterns in the same tumor. A diffuse growth of cells is most frequent, followed by trabecular, microfollicular, macrofollicular, insular, gyriform, and watered silk patterns. Call-Exner bodies, the hallmark of the microfollicular pattern, are microcystic spaces that contain deeply eosinophilic basal lamina material. They can be helpful in the diagnosis of the cystic variant of AGCT. The granulosa cell proliferation frequently has a fibrothecomatous background, which can be prominent in some cases. By definition, the granulosa cells must make up at least 10% of the tumor for a diagnosis of AGCT; otherwise it is classified as a fibroma, or fibrothecoma, with a minor sex cord element. The granulosa cells generally have scant cytoplasm and round to oval or angular nuclei with a longitudinal groove. Nuclear grooves, however, are not limited to AGCT and may be present only in scattered cells in some cases. Mitotic activity is variable, but typically is less than five mitoses per ten high power fields.
Rarely, AGCT may have focal bizarre nuclei or luteinization of the granulosa cells. Reticulin staining demonstrates well defined fibers surrounding aggregates of tumor cells and can be helpful for distinguishing AGCT from some other tumors, such as cellular fibroma. Calretinin and inhibin are sensitive markers of AGCT, and WT1 (nuclear) and CD99 also stain the majority of tumors.
Pankeratin, smooth muscle actin, desmin, S100, ER, and PR are variably positive. CD56 is also reported to be positive in AGCT. EMA and cytokeratin 7 are typically negative.
The most important prognostic indicator in AGCT is stage. Patients with stage I tumors have a ten year survival rate of approximately 85% compared to 38-60% for those with advanced stage disease. There is a propensity for late recurrences, with an average time to recurrence of five years and some developing up to thirty years after initial diagnosis. Serum levels of inhibin can be used to monitor tumor recurrences. Pathologic factors such as size (> 5.0 cm), mitotic activity (> 5 mitoses/10HPF), and tumor rupture have been associated with a worse prognosis in some studies.
AGCTs with trabecular, insular, and microfollicular patterns may resemble an endometrioid adenocarcinoma. However, AGCTs lack the squamous or mucinous differentiation and associated endometriosis that can be seen in some endometrioid adenocarcinomas. Additionally, positive calretinin and inhibin immunohistochemical stains, and negative EMA and cytokeratin 7 stains help rule out an endometrioid adenocarcinoma. AGCT with a diffuse or solid pattern can be mistaken for benign sex cord-stromal tumors, such as thecoma or cellular fibroma. Reticulin staining is important in making this distinction because thecomas and cellular fibromas are also positive for calretinin and inhibin; in contrast to distinct reticulum fibers surrounding large groups of granulosa cells in AGCT, thecomas and fibromas have small fibers surrounding many individual cells. AGCT with a diffuse pattern can also mimic undifferentiated carcinoma. The presence of relatively uniform nuclei with grooves, a relatively low mitotic rate, absence of staining for EMA, and tumor limited to the ovary help to exclude undifferentiated carcinoma.