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Granulosa cell tumors are rare ovarian neoplasms derived from sex cords and ovarian mesenchyme with an indolent course and long natural history. Unlike epithelial ovarian cancers, these tumors are detected early, can be seen in young females, and typically manifest with abdominal distension, pain, or rarely with features of hyperestrogenism or virilization. There is a high chance of late recurrence. Hence lifelong follow-up is indicated. This activity reviews the epidemiology, etiology, and molecular pathways involved in the development of granulosa cell tumors. The latest advances in diagnosis, classification, and management are highlighted, including optimal surgical approaches and adjuvant therapies. Participants learn about the challenges of treating recurrent disease. The collaborative role of the interprofessional team in effectively managing and improving outcomes in patients with granulosa theca cell tumors is emphasized. Objectives: Differentiate between granulosa theca cell tumors and other ovarian neoplasms based on histological characteristics and molecular markers. Implement evidence-based guidelines for the diagnosis and staging of granulosa theca cell tumors, including the use of imaging modalities and tumor markers. Select the most appropriate surgical approach for patients with granulosa theca cell tumors of the ovary, considering patient age, disease stage, and reproductive desires. Coordinate long-term follow-up care for patients with granulosa theca cell tumors, focusing on monitoring for late effects and recurrence. Access free multiple choice questions on this topic.

Granulosa theca cell cancers are ovarian tumors that consist of granulosa cells, theca cells, and fibroblasts in various combinations. Granulosa cells in the sex cords produce sex steroids, and peptides needed for folliculogenesis and ovulation. Granulosa cells also give rise to granulosa cell tumors (GCT), which account for approximately 5% of all ovarian neoplasms and 70% of all sex cord-stromal tumors of the ovary. There are 2 distinct types of GCT, adult and juvenile, based on characteristic clinicopathologic features. The adult type is the most typical variety and manifests in peri- or post-menopausal women. In contrast, the juvenile type constitutes only 5% of cases and occurs in prepubertal girls and young women.[1] Theca cells are present in the ovarian stroma and play an essential role in fertility by producing the androgen substrate required for estrogen biosynthesis in the ovaries. Thecomas, comprising less than 7% of sex cord-stromal tumors, are uncommon, usually benign, and have an excellent prognosis. Malignant thecomas are rare and most often also contain an element of granulosa cells, and hence this article focuses on GCTs unless otherwise specified. GCTs are distinct from epithelial ovarian cancers in that they are detected in the early stage, can occur in young females, and usually manifest with abdominal distension, pain, or rarely with features of hyperestrogenism or virilization. Extra-ovarian spread is to the omentum and peritoneum, with occasional hematogenous spread to the lungs, liver, or brain. Lymph node metastases are uncommon. These tumors are treated by surgery alone and have a good prognosis. However, GCTs tend to have an indolent progression prone to late recurrence, seen in up to 25% of cases despite having had curative surgery.[2][3]

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]

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.

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)

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]

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]

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 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]

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.

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]

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]

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]

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

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]

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.

There are no known means of preventing granulosa theca cell tumors of the ovary. Patients should be counseled preoperatively about the planned procedure for benign, malignant, or indeterminate intraoperative findings and issues regarding fertility preservation, which should be documented in the medical record. In patients who opt for fertility preservation, issues regarding incomplete staging and the potential need for further surgery should be discussed if the definitive diagnosis proves malignant. The need for life-long follow-up should be emphasized and thoroughly discussed with the patient, as these tumors have late recurrences, sometimes even after a disease-free interval of 30 years.

Unlike epithelial ovarian cancers, granulosa theca cell tumors have varied presentations and may initially present to multiple different specialists. For example, juvenile GCT may present first to pediatric clinicians for the evaluation of precocious puberty. In contrast, patients who present with amenorrhea and infertility due to androgen-secreting tumors or tumors associated with high serum inhibin levels may consult a reproductive endocrinologist. Women in the reproductive-age group who manifest menstrual abnormalities and women who experience postmenopausal bleeding are likely to consult a gynecologist. Finally, patients with an acute abdomen may seek care in the emergency department or with a general surgeon. It is paramount that all health care professionals have sound knowledge of the clinical presentation of GCTs and the need for accurate surgical staging, given that stage is the most important prognostic factor determining the outcome of this disease. Prompt referral to a surgical or gynecologic oncologist is advisable. While a preoperative diagnosis is often not possible, a detailed imaging assessment of the adnexal mass and discussion with radiologists may provide valuable clues to the probable diagnosis of GCT, thereby facilitating preoperative patient counseling regarding the extent of surgery and the possibility of fertility preservation. Close collaboration with an expert gynecologic pathologist is also crucial since an intraoperative frozen section may not always yield a definitive diagnosis. If the pathologist suspects an epithelial malignancy, the surgeon should consider comprehensive staging, including pelvic and para-aortic lymph node dissection, rather than the usually limited staging procedure performed for granulosa thecal cell tumors. Nurses are equally essential in providing patients with the necessary information regarding their disease throughout the process of diagnosis and management. Nurses should ensure the highest standard of care possible and assist the interprofessional team in reporting any adverse changes in the patient's general condition during treatment and follow-up. Effective communication and collaboration among interprofessional team members are critical for providing optimal care for patients with GCTs.