Granulosa cell tumors arise from ovarian sex cords and make up an estimated 1% of all ovarian cancer cases but comprise more than 70% of all sex cord stromal tumors.
Granulosa cell tumors (GCTs) can be divided into adult and juvenile types. Adult GCTs are much more common, representing 95% of all GCTs. Women diagnosed with adult GCTs are typically younger as compared with those with epithelial ovarian cancer. The average age of diagnosis for adult GCTs is 50 years, and for women with juvenile GCTs, the average age at diagnosis is 20 years.
Granulosa cell tumors have been shown to be more common in nonwhite women, those with a high body mass index, and a family history of breast or ovarian cancer.1Adult GCTs can be associated with Peutz-Jeghers and Potter syndromes. Juvenile GCTs are exceedingly rare but can also be associated with mesodermal dysplastic syndromes characterized by the presence of enchondromatosis and hemangioma formation, such as Ollier disease or Maffucci syndrome.
Adult granulosa cell tumors are large, hormonally active tumors; typically secreting estrogen and associated with symptoms of hyperestrogenism. In one study, 55% of women with GCTs were reported to have hyperestrogenic findings such as breast tenderness, virulism, abnormal or postmenopausal bleeding, and hyperplasia, and those with juvenile GCTs may present with precocious puberty.2,3
In pregnancy, hormonal symptoms are temporized, thus the most common presentation is acute rupture. Initial evaluation of women with adult GCTs will reveal a palpable unilateral pelvic mass typically larger than 10cm. Juvenile and adult GCTs are unilateral in 95% of cases.4
In women presenting with a large adnexal mass, the appropriate initial clinical evaluation includes radiographic and laboratory studies. Endovaginal ultrasound typically reveals a large adnexal mass with heterogeneous solid and cystic components, areas of hemorrhage or necrosis and increased vascularity on Doppler. Juvenile GCTs have a more distinct appearance of solid growth with focal areas of follicular formation.
Laboratory findings suggestive of GCT include elevated inhibin-A, inhibin-B, anti-Mullerian hormone (AMH), and CA-125. Inhibin-B is the most commonly used tumor marker for the clinical monitoring of adult GCTs, but AMH may be the most specific.5 Lastly, an endometrial biopsy should be considered in all patients with abnormal uterine bleeding and in all postmenopausal women with an adnexal mass and an endometrial stripe greater than 5mm.6
Surgical staging for adult GCTs is the standard of care. For women who do not desire fertility, this includes total hysterectomy, bilateral salpingo-oophorectomy and removal of all gross disease. Comprehensive nodal dissection is not indicated except when necessary for complete cytoreduction. In contrast to epithelial ovarian cancer, approximately 80% of women with adult GCTs are diagnosed with stage I disease. For stage IA disease, treatment with surgery alone is sufficient, yet in women with stage II-IV disease or with tumors that are ruptured intraoperatively, platinum-based chemotherapy is recommended. The most common regimen is bleomycin, etoposide, and cisplatin, though there is increasing experience with an outpatient regimen of paclitaxel and carboplatin.
The gross appearance of both adult and juvenile GCTs are of a large, tan-yellow tumor with cystic, solid, and hemorrhagic components. Microscopically, juvenile GCTs are more distinct than that of adult GCTs. Whereas adult GCTs comprise diffuse cords or trabeculae and small follicles termed Call-Exner bodies of rounded cells with scant cytoplasm and pale “coffee-bean” nuclei, juvenile GCTs have nuclei that are rounded, hyperchromatic with moderate to abundant eosinophilic or vacuolated cytoplasm.
The prognosis of GCTs is largely dependent on the stage at diagnosis and presence of residual disease after debulking. Negative prognostic factors for recurrence include tumor size, rupture, atypia and increased mitotic activity.
There are distinct clinical, radiographic, and laboratory characteristics that may raise the suspicion of the practicing gynecologist for a GCT. In such cases, expedient referral for surgical exploration to a gynecologic oncologist is warranted. If the tumor is encountered inadvertently, intraoperative consultation from a gynecologic oncologist should be requested. If a gynecologic oncologist is not available, it is paramount to optimize surgical exposure to clearly document any abnormal pelvic or intra-abdominal findings, take care to prevent surgical spillage, and preserve fertility if indicated.
If referred appropriately and completely resected, the 5-year overall survival of stage IA disease can be upward of 90%. Recurrences are stage dependent with an average time to recurrence of just under 5 years. When recurrences occur, they tend to happen in the pelvis. All women with a history of GCT will require surveillance and monitoring.
References
1. Gynecol Oncol. 2005 May;97(2):519-23.
2. “ Rare and Uncommon Gynecological Cancers: A Clinical Guide ” (Heidelberg: Springer, 2011): Reed N.
3. Obstet Gynecol. 1980 Feb;55(2):231-8.
4. “Principles and Practice of Gynecologic Oncology” (Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins, 2013): Barakat R.
5. Indian J Surg Oncol. 2013 Mar;4(1):37-47.
6. “Uncommon Gynecologic Cancers” (Indianapolis: Wiley-Blackwell, 2014): Del Carmen M.
Dr. Gehrig is professor and director of gynecologic oncology at the University of North Carolina at Chapel Hill. Dr. Castellano is a resident physician in the obstetrics and gynecology program at the university. They reported having no relevant financial disclosures. To comment, email them at obnews@frontlinemedcom.com.
