Granulosa Theca Cell Tumors of the Ovary

Etiology

Aneuploidy of chromosome 12 (trisomy) and 22 (monosomy) and deletion of chromosome 6 are detected in granulosa theca cell tumors. Cytogenetic studies report trisomy of chromosome 12 and deletion in chromosome 6q to be associated with juvenile GCTs. In contrast, more than 95% of adult GCTs have a mutation in the FOXL2 gene, and recent studies conclude that this is the primary driver of the adult-type disease.[4]

BRCA1 and BRCA2 mutations do not confer an elevated risk of GCT, though some studies have identified a family history of breast or ovarian cancer as a significant risk factor. One case-control study suggested an independent association between non-white race and obesity in the development of GCT.[5] Parity and oral contraceptive use were found to be protective. 

Some tumor predisposition syndromes are associated with GCT, such as Peutz-Jeghers syndrome and Potter syndrome. Juvenile GCT appears to be associated with Ollier disease (enchondromatosis) and Maffucci syndrome. Certain medications, such as selective estrogen receptor modulators, gonadotropins, and clomiphene citrate, have also been found to increase the risk of GCT.[2][5] There is debate, however, about whether infertility or its treatment is an independent risk factor.[1]

Epidemiology

The SEER (Surveillance, Epidemiology, and End Results) database reveals an incidence of 0.2 per 100 000 women for sex cord-stromal tumors. About 1500 to 2000 new cases are diagnosed yearly in the United States. Age-standardized incidence of granulosa theca cell cancer ranges from 0.58 to 1.6 per 100 000 women annually worldwide. The mean age at diagnosis is 50 years, a decade younger than patients with epithelial ovarian cancer. Fifty-seven percent of patients are in the 30 to 60-year age group, while only 12% are younger than 30 years. The incidence also tends to be higher in black women than in white women (0.44 vs. 0.18 per 100 000  population).[6][7][8][9]

A multicenter retrospective study reported the mean age at diagnosis of juvenile GCT to be 20 years (range 8 years to 45 years), with more than 50% of patients diagnosed before 20 years and 45.5% of patients premenarchal.[10] The incidence of this group of tumors remains comparable between countries, as evidenced by the similar incidence of these tumors in Japan, Sweden, and the West Indies.

Pathophysiology

Attempts to explain the etiology of sex cord-stromal tumors have resulted in 2 theories. The first one suggests these neoplasms originate from genital ridge mesenchyme. The second theory suggests that these tumors originate from precursors within the mesonephric and coelomic epithelium. However, the exact pathophysiology has yet to be elucidated. Recent molecular genetic studies propose that these tumors have a somatic missense point mutation (C402G) in the FOXL2 gene, seen in 97% of adult GCTs, 10% of juvenile GCTs, and 21% of thecomas.[11][12] The high frequency of this mutation suggests that it may be specifically diagnostic for adult GCT (with the exception of well- or moderately differentiated Sertoli-Leydig cell tumors), and the absence of this mutation in juvenile GCT might be because it is an entirely different tumor.

Alterations in various signal transduction pathways have also been found to be crucial in the pathogenesis of GCTs. Some of the major pathway alterations are:

• Adenyl cyclase/cAMP/protein kinase-A (PKA) pathway
• MAPK and phosphatidylinositol 3-kinase PI3K/AKT pathway
• Vascular endothelial growth factor (VEGF) and its receptors
• Estrogen receptors
• Nuclear factor kappa B (NF-kB)
• TNF-related apoptosis-inducing ligand (TRAIL; CD253)

Histopathology

Grossly, GCTs appear as large unilateral solid cystic masses with tan to yellow color cut surfaces (due to steroid production). GCTs can vary in size from 3 cm to 24 cm. Microscopy reveals small pale, round to oval cells with characteristic coffee-bean nuclei (longitudinal nuclear grooves). These tumors may be mistaken for endometrioid adenocarcinoma on frozen section, and in such situations, the nuclear features help to verify the diagnosis.

Granulosa cells tend to form small rings surrounding shrunken nuclei or eosinophilic fluid-filled spaces called Call- Exner bodies, which are seen in 30% of cases. Well-differentiated GCTs show a microfollicular pattern most commonly. Other patterns are the macrofollicular, solid tubular, hollow tubular, insular, and trabecular patterns. Poorly differentiated GCTs appear as undulating parallel (watered-silk) or zigzag (gyriform) rows of granulosa cells in a single file or as diffuse (sarcomatoid) patterns characterized by a monotonous appearance. A thecal cell component may also be present.

Important clinicopathologic clues can aid in the differentiation of tumor types. Androgenic GCTs tend to be large unilocular or multilocular cysts. Focal luteinization, edema, and disorderly arrangements are seen in GCTs in pregnancy. Juvenile GCTs have a diffuse (most common) or macrofollicular morphology, mucin-positive interfollicular secretion, large cells with luteinization, a theca cell component, a lack of nuclear grooves, and nuclear atypia with variable or high mitotic activity. Immunohistochemistry helps when the morphologic diagnosis is questionable, and one of the most useful markers is the alpha subunit of inhibin. Inhibin stains all sex cord-stromal tumors, sex cord-like elements of other gynecologic tumors, and most trophoblastic tumors. Inhibin negativity, however, does not rule out a diagnosis of GCT. Calretinin is more sensitive than inhibin but less specific. The most sensitive marker for GCT and all sex cord-stromal tumors is SF1.[13] Other immunohistochemical markers include activin, antimullerian hormone, and Melan-A. FOXL2 expressed in the tumor nuclei can be advantageous in staining cells with scant cytoplasm (adult GCTs and fibromas), especially since cytoplasmic stains like inhibin may not be positive in such cells. About 97% of adult GCTs show a mutation of FOXL2.[7][10][14][15]

History and Physical

Granulosa theca cell tumors affect children to older adults and are most common in postmenopausal women aged 45 to 55 years. The presenting symptoms are usually nonspecific, with abdominal pain, distension, or a palpable, usually unilateral abdominopelvic mass.

About 70% of these tumors are hormonally active, and the manifestations of hyperestrogenism depend on age and menstrual status. Postmenopausal bleeding is the usual presentation in older women. In contrast, heavy menstrual bleeding, irregular menstrual bleeding patterns, or amenorrhea can be seen in premenopausal women, along with breast enlargement and/or tenderness. Rare adult GCTs can secrete androgens resulting in virilization in young women aged 15 to 35 years and manifest with hirsutism, clitoromegaly, deepening of the voice, and/or amenorrhea. High inhibin levels may result in infertility due to inhibition of follicle-stimulating hormone (FSH) secretion. Rarely these tumors can present during pregnancy.

Complications like tumor rupture (seen in 10% of cases), torsion of the adnexal mass, or intratumoral hemorrhage can present as a case of acute abdomen with hypotension. Some patients with a thecoma have a Meigs-like syndrome, with ascites and hydrothorax.[10][16][9][1]

Evaluation

The most important aspect in reaching the proper diagnosis of GCT is maintaining a high index of suspicion in patients presenting with an adnexal mass and endocrine effects, specifically estrogen or androgen excess. The workup typically includes laboratory tests for serum hormonal levels (total testosterone in the case of virilization, estradiol for hyperestrogenism) and tumor markers such as inhibin A and B. Inhibin B is more accurate than inhibin A.[17] Combining antimullerian hormone levels with inhibin B estimation improves the detection of recurrent disease.[18] 

Pelvic ultrasound and/or contrast-enhanced CT scan are performed to evaluate the abdomen or other sites in patients with suspected metastatic disease. Radiologic studies usually reveal a solid mass with hemorrhagic or fibrotic changes, a multilocular cyst, or an entirely cystic tumor. The key differentiating features from epithelial ovarian tumors are that GCTs are usually confined to the ovary at diagnosis and do not have intracystic papillary projections. Furthermore, the chance of peritoneal spread is low, and GCTs are rarely bilateral. An enlarged uterus with a thickened endometrium is often noted due to an estrogenic effect. Endometrial sampling may detect endometrial hyperplasia in 25% to 50% of patients with GCTs and endometrial carcinoma in another 5% to 10%. In patients with thecoma, carcinoma may be detected in 20% to 25% of patients, and another 15% of patients may have a precursor lesion.[15][19] 

Ascites is very rarely seen in patients with GCTs. As with all adnexal masses, if ultrasound findings suggest the possibility of malignancy, if there are other risks associated with the mass (eg, torsion), or if the mass is causing symptoms, surgery is performed to resect the mass and to obtain a histologic diagnosis. 

Treatment / Management

Treatment depends on the age of the patient and the extent of the disease. Surgery alone is sufficient primary treatment for most patients, and chemotherapy, radiotherapy, and biologic therapy are reserved for treating recurrent or metastatic disease. These additional treatment options may improve survival or increase the length of disease-free intervals before a recurrence.

After completing treatment, individuals should continue to have regular visits with their clinical team to check for recurrences. These visits should include updating the medical history, performing a pelvic exam, and possibly ordering tumor markers. If there are any suspicious findings during these visits, an imaging test such as a CT scan should be performed.[20](B3)

Differential Diagnosis

If the patient presents with an incidentally detected adnexal mass, the differential diagnosis should consider pelvic masses from gastrointestinal or genitourinary organs, retroperitoneal masses, or cysts. Differential diagnoses of patients with an adnexal mass and abnormal uterine bleeding include benign pathologies such as uterine fibroids and polyps and malignant causes such as uterine cancer with ovarian metastases or epithelial ovarian cancer with metastases to endometrium or a synchronous endometrial and ovarian cancer. Polycystic ovary syndrome and adrenal tumors must be excluded when patients present with a pelvic mass and endocrine abnormalities.

Surgical Oncology

Primary surgery is usually curative due to the early stage of the disease. Unilateral salpingo-oophorectomy suffices for children and premenopausal females since only 2% of cases are bilateral at presentation.

If the intraoperative frozen section suggests GCT, a limited staging procedure is performed. The contralateral ovary is assessed and should be biopsied if enlarged. Peritoneal washings, infracolic omentectomy, careful palpation of the peritoneum and retroperitoneal nodes, and biopsy of any suspicious lesions are then completed. Full cytoreduction is paramount if there is metastatic disease in the abdomen since these tumors are slow-growing and do not respond well to chemotherapy. If the uterus is left in situ in premenopausal patients, a dilatation and curettage of the uterus should be performed to rule out the possibility of coexisting endometrial adenocarcinoma. Pelvic or para-aortic lymphadenectomy is of limited value, particularly in early-stage disease, and is currently not recommended.[21] 

Enlarged or suspicious nodes are removed to allow evaluation and to ensure maximal cytoreduction. Case reports show fertility-sparing surgery, including unilateral salpingo-oophorectomy, omentectomy, and stripping of the pelvic peritoneum, are safe and allow future pregnancies in women with stage IIB to IIIC disease. Pregnancy does not appear to be detrimental to disease progression.[22][23]

Radiation Oncology

There is no robust evidence to recommend adjuvant radiation therapy for GCTs. However, radiotherapy may help to palliate isolated pelvic recurrence and attain occasional long-term remission in such cases. In a  review of 34 patients treated with radiation alone in the US over 40 years, 3 of the 14 patients (21%) treated for measurable disease were alive without disease progression after 10 to 21 years.[24]

Medical Oncology

The National Comprehensive Cancer Network (NCCN) guidelines recommend adjuvant chemotherapy for completely resected stage II to IV granulosa theca cell tumors based on retrospective data showing a progression-free survival benefit.[25] However, an overall survival benefit has not been demonstrated.[26][23] Regarding the choice of regimen, bleomycin, etoposide, and cisplatin (BEP) are preferred for patients younger than 40 years; while for those who are older than 40 years, paclitaxel and carboplatin (TC) are recommended, given better tolerability in the older population.[27] Regarding stage I disease, there is no evidence that adjuvant chemotherapy will prevent recurrence or improve survival. Retrospective studies involving patients with stage IC GCT of the ovary investigated the efficacy of first-line postoperative chemotherapy and failed to show any disease-free survival advantage.[28][29] 

Although there is limited data, bevacizumab, an angiogenesis inhibitor, and hormonal therapy (including gonadotropin-releasing hormone agonists, tamoxifen, or aromatase inhibitors) have demonstrated antitumor activity, especially for the treatment of adult-type granulosa cell tumors.[15][30][31][32] Lastly, medical therapy alone is recommended for inoperable patients (either due to performance status or the extent of disease) and patients with multiple recurrences. A recent review of systemic therapy demonstrated overall response rates of 30% for chemotherapy regimens. Similarly, anti-hormonal therapy shows an overall response rate of 30%.[33] 

Staging

GCTs are staged based on findings at surgical exploration and follow the International Federation of Gynecology and Obstetrics (FIGO) system for staging ovarian malignancies, which was last revised in 2014.[34] The staging  can be broadly summarised as follows:

Stage I: The tumor is confined to the ovaries

• IA - limited to 1 ovary
• IB - involves both ovaries
• IC - stage IA or IB with an intraoperative surgical spill or tumor on the external surface of ovaries or malignant cells in ascites/peritoneal washings

Stage II: Tumor involves 1 or both ovaries, with pelvic extension

Stage III: Tumor involves 1 or both ovaries, with peritoneal implants outside the pelvis and/or positive retroperitoneal lymph nodes

Stage IV: Distant metastasis

Prognosis

Stage is the most important prognostic factor, followed by tumor rupture, which indicates a worse prognosis. Large size (>15 cm) and bilaterality are unfavorable prognostic factors; however, the prognostic impact of size disappears when corrected for the stage. Mitotic activity or nuclear atypia does not correlate with clinical outcomes. Homozygous FOXL2 mutation, higher FOXL2 mRNA expression, and chromosomal imbalance are associated with early relapse and worse outcomes.[35][36] Higher levels of SMAD3 expression are a novel predictor of recurrence in early-stage disease.[37]

Complications

As many as 10% to 15% of cases can be complicated by ovarian torsion or tumor rupture, especially in large thin-walled cysts and intratumoral hemorrhage. This can result in the presentation of an acute abdomen, which may be accompanied by hemoperitoneum and consequent hypotension. The large sizes to which these tumors grow also predispose to torsion.

Hormonally active granulosa theca cell cancers can result in infertility, with high inhibin levels suppressing FSH levels and endometrial carcinoma due to unopposed estrogen stimulation of endometrium.