A 58-year-old woman presents with postmenopausal bleeding and is found to have an ovarian mass on gynecologic examination. Ultrasound shows a thickened endometrial stripe and a solid and cystic left ovarian mass. A total abdominal hysterectomy and bilateral salpingo-oophorectomy is performed.

The left ovarian mass measures 14.0 x 12.8 x 6.0 cm, has a smooth external surface, and is multicystic on cut section. The cysts are filled with serosanguinous fluid and the walls, which vary in thickness from 0.1–2.8 cm, are pink/tan to yellow.

Master List of Diagnoses

  • Adult granulosa cell tumor
  • Endometrioid adenocarcinoma
  • Juvenile granulosa cell tumor
  • Metastatic carcinoid tumor
  • Small cell carcinoma, hypercalcemic type
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This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2017, Case 12, and is adult granulosa cell tumor of the ovary.

Criteria for Diagnosis and Comments

Sections from the submitted mass show a highly cellular tumor arranged (depending on the slide received) in sheets, nests, trabeculae, and/or cords. Variably sized cystic spaces filled with eosinophilic material are prominent in some slides. The cells have scant to minimal cytoplasm with ovoid to round nuclei without pleomorphism. Mitotic activity is variable and, depending on the slide received, might be brisk. The histology is classic for adult granulosa cell tumor.

Adult granulosa cell tumor (AGCT) is considered a pure sex-cord tumor in the category of sex-cord stromal tumors of the ovary according to the most recent WHO classification. In comparison to epithelial ovarian tumors, it is uncommon, accounting for only 1%–2% of all ovarian tumors. The adult form represents 95% of granulosa cell tumors; the juvenile form, which occurs mainly in younger women and has different histopathologic features, comprises the remainder. AGCT typically occurs in perimenopausal or postmenopausal women and is the most common tumor associated with estrogenic manifestations. It is associated with endometrial carcinoma (usually well-differentiated) in approximately 5% of cases. Androgenic manifestations are typically associated with tumors that have an extensive cystic component. Most patients with AGCT present with unilateral tumors that are confined to the ovary; in approximately 10% of cases, the tumor is ruptured at the time of surgery. All AGCTs are considered to have malignant potential and patients typically have a hysterectomy and bilateral salpingo-oophorectomy. Late recurrences (sometimes decades after initial diagnosis) are not uncommon; spread to the abdominopelvic cavity is typical although distant metastases may be seen. Serum inhibin levels can be monitored to detect residual or recurrent disease.

On gross examination, AGCTs are typically solid and cystic with a mean diameter of 12.0 cm. Occasionally, they may be uniformly solid or entirely cystic/multicystic. The solid areas are typically tan to white to yellow and the cysts, if present, are often filled with serosanguinous fluid or clotted blood; hemorrhage is particularly conspicuous in tumors that have ruptured. Histologic examination may reveal a variety of often admixed patterns including diffuse (sheet-like), which is the most common, as well as cords, nests, trabeculae, and undulating ribbons. The microfollicular pattern, in which the tumor recapitulates the appearance of Call-Exner bodies, is actually uncommon and usually not conspicuous. Occasionally, as seen in some of the slides in this case, a macrofollicular pattern may be seen. In all patterns, tumor cells typically have scant amounts of cytoplasm and round-to-oval uniform nuclei. The presence of a nuclear groove, which imparts a “coffee bean” appearance to the nucleus, is a characteristic, but not necessarily prominent or common finding in all cases of AGCT. Rarely (approximately 2% of the time), tumors may focally contain cells with enlarged, pleomorphic and hyperchromatic nuclei. The stromal component of AGCTs, which is typically minor, may have a fibromatous appearance or contain theca-like cells. The tumor cells are typically positive for inhibin, calretinin, steroidogenic factor-1 (SF-1), FOXL2, WT-1, and CD 56. They are variably positive for cytokeratin (usually with a dot-like pattern) and are negative for epithelial membrane antigen. Tumor cells may also be positive for desmin, S100, and smooth muscle actin. Molecular genetic analysis of AGCT has shown that over 90% of tumors have a missense somatic point mutation in the FOXL2 gene.

Ovarian endometrioid adenocarcinomas, which also most commonly occur in perimenopausal and postmenopausal women, may occasionally have an insular, trabecular or microcystic growth pattern that can mimic an AGCT. Recognition as an endometrioid carcinoma is based on (1) areas characteristic of endometrioid differentiation, which are almost always present, such as classic endometrioid–type glands and squamous or mucinous differentiation, (2) lack of nuclear grooves, (3) greater degree of nuclear hyperchromasia, (4) lack of Call-Exner bodies, (5) lack of inhibin, SF-1, or FOXL2 immunoreactivity, and (6) positivity for epithelial membrane antigen.

Juvenile granulosa cell tumor occurs in a younger age group than AGCT and predominantly affects children and young adults less than 30 years of age (mean age 15 years). These tumors are indistinguishable from AGCT on gross examination; however, histologically, they typically show solid (diffuse or nodular) and follicular growth, the latter having follicles of varying size and shape containing eosinophilic or basophilic secretions. In contrast to AGCT, the cells have ample eosinophilic to vacuolated cytoplasm and rounded nuclei without grooves. These tumors do not have FOXL2 point mutations.

Small cell carcinoma, hypercalcemic type may be mistaken for an AGCT since both are characterized by the presence of follicle-like spaces and tumor cells with scanty cytoplasm. Small cell carcinoma is distinguished from AGCT by the following:

  1. the presence of paraendocrine hypercalcemia in approximately two-thirds of patients
  2. its occurrence in a younger age population (mean age third decade)
  3. its greater propensity for spread beyond the ovary at the time of presentation
  4. its lack of estrogenic manifestations
  5. its greater degree of nuclear hyperchromasia
  6. more frequent mitoses
  7. lack of nuclear grooves
  8. lack of inhibin immunoreactivity
  9. epithelial membrane antigen positivity, if present (can be variable)

Metastatic carcinoid tumor contains acini that may be mistaken for Call-Exner bodies. Besides histologic features that would suggest a metastatic process to the ovary (including bilaterality, nodular appearance, superficial cortical involvement, and lymphatic/vascular invasion), carcinoid tumors have characteristic coarse nuclear chromatin, may contain cytoplasmic granules, and are positive for neuroendocrine markers.

  1. Which tumor is most commonly associated with estrogenic manifestations and typically occurs in women more than 30 years of age?
    1. Adult granulosa cell tumor
    2. Endometrioid adenocarcinoma
    3. Juvenile granulosa cell tumor
    4. Metastatic carcinoid tumor
    5. Small cell carcinoma, hypercalcemic type
  2. Which entity most often has spread beyond the ovary at the time of presentation and typically occurs in young women?
    1. Adult granulosa cell tumor
    2. Endometrioid adenocarcinoma
    3. Juvenile granulosa cell tumor
    4. Metastatic carcinoid tumor
    5. Small cell carcinoma, hypercalcemic type
  3. Which entity is associated with FOXL2 mutations in over 90% of cases?
    1. Adult granulosa cell tumor
    2. Endometrioid adenocarcinoma
    3. Juvenile granulosa cell tumor
    4. Metastatic carcinoid tumor
    5. Small cell carcinoma, hypercalcemic type

References

  1. Al-Agha OM, Huwait HF, Chow C, et al. FOXL2 is a sensitive and specific marker for sex-cord stromal tumors of the ovary. Am J Surg Pathol. 2011;35:484-494.
  2. Evans AT 3rd, Gaffey TA, Malkasian GD Jr, Annegers JF. Clinicopathologic review of 118 granulosa and 83 theca cell tumors. Obstet Gynecol. 1980; 55:231-237.
  3. Köbel M, Gilks CB, Huntsman DG. Adult-type granulosa cell tumors and FOXL2 mutation. Cancer Res. 2009;69:9160-9162.
  4. Scully RE, Young RH, Clement PB. Granulosa cell tumors. In: Atlas of Tumor Pathology: Tumors of the Ovary Maldeveloped Gonads, Fallopian Tube, and Broad Ligament. Third Series, Fascicle 23. Washington, DC: Armed Forces Institute of Pathology; 1996.
  5. Young RH, Oliva E, Scully RE. Small cell carcinoma of the ovary, hypercalcemic type. A clinicopathologic analysis of 150 cases. Am J Surg Pathol. 1994;18:1102-1116.
  6. Young RH, Prat J, Scully RE. Ovarian endometrioid carcinomas resembling sex cord-stromal tumors. A clinicopathologic analysis of 13 cases. Am J Surg Pathol. 1982;6:513-522.

Author

Marisa R. Nucci, M.D.
Surgical Pathology Committee
Brigham and Women’s Hospital
Boston, MA

Answer Key

  1. Adult granulosa cell tumor (a)
  2. Small cell carcinoma, hypercalcemic type (e)
  3. Adult granulosa cell tumor (a)