Back To Search Results

Granulosa Theca Cell Tumors of the Ovary

Editor: Charles J. Dunton Updated: 11/12/2023 11:11:45 PM

Introduction

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]

Etiology

Register For Free And Read The Full Article
Get the answers you need instantly with the StatPearls Clinical Decision Support tool. StatPearls spent the last decade developing the largest and most updated Point-of Care resource ever developed. Earn CME/CE by searching and reading articles.
  • Dropdown arrow Search engine and full access to all medical articles
  • Dropdown arrow 10 free questions in your specialty
  • Dropdown arrow Free CME/CE Activities
  • Dropdown arrow Free daily question in your email
  • Dropdown arrow Save favorite articles to your dashboard
  • Dropdown arrow Emails offering discounts

Learn more about a Subscription to StatPearls Point-of-Care

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.

Postoperative and Rehabilitation Care

Review of symptoms, physical examination, and serum tumor markers should be assessed every 2 to 4 months for the first 2 years and then every 6 months after that. Routine imaging studies are not recommended in postoperative surveillance unless directed by the onset of symptoms suggestive of recurrence. GCT tends to have a late recurrence, and once the tumor recurs, it is fatal in 80% of cases. There is a lack of high-quality data on the optimal management of recurrent disease. If the recurrent disease is resectable, several case series have reported a survival advantage for salvage surgery followed by platinum-based chemotherapy.[38][39]

Deterrence and Patient Education

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.

Enhancing Healthcare Team Outcomes

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. 

References


[1]

Li X, Tian B, Liu M, Miao C, Wang D. Adult-type granulosa cell tumor of the ovary. American journal of cancer research. 2022:12(8):3495-3511     [PubMed PMID: 36119817]


[2]

Kottarathil VD, Antony MA, Nair IR, Pavithran K. Recent advances in granulosa cell tumor ovary: a review. Indian journal of surgical oncology. 2013 Mar:4(1):37-47. doi: 10.1007/s13193-012-0201-z. Epub 2012 Dec 7     [PubMed PMID: 24426698]

Level 3 (low-level) evidence

[3]

Magoffin DA. Ovarian theca cell. The international journal of biochemistry & cell biology. 2005 Jul:37(7):1344-9     [PubMed PMID: 15833266]


[4]

Pilsworth JA, Cochrane DR, Neilson SJ, Moussavi BH, Lai D, Munzur AD, Senz J, Wang YK, Zareian S, Bashashati A, Wong A, Keul J, Staebler A, van Meurs HS, Horlings HM, Kommoss S, Kommoss F, Oliva E, Färkkilä AE, Gilks B, Huntsman DG. Adult-type granulosa cell tumor of the ovary: a FOXL2-centric disease. The journal of pathology. Clinical research. 2021 May:7(3):243-252. doi: 10.1002/cjp2.198. Epub 2021 Jan 11     [PubMed PMID: 33428330]


[5]

Boyce EA, Costaggini I, Vitonis A, Feltmate C, Muto M, Berkowitz R, Cramer D, Horowitz NS. The epidemiology of ovarian granulosa cell tumors: a case-control study. Gynecologic oncology. 2009 Nov:115(2):221-5. doi: 10.1016/j.ygyno.2009.06.040. Epub 2009 Aug 7     [PubMed PMID: 19664811]

Level 2 (mid-level) evidence

[6]

Quirk JT, Natarajan N. Ovarian cancer incidence in the United States, 1992-1999. Gynecologic oncology. 2005 May:97(2):519-23     [PubMed PMID: 15863154]


[7]

Ranganath R, Sridevi V, Shirley SS, Shantha V. Clinical and pathologic prognostic factors in adult granulosa cell tumors of the ovary. International journal of gynecological cancer : official journal of the International Gynecological Cancer Society. 2008 Sep-Oct:18(5):929-33     [PubMed PMID: 18081789]

Level 2 (mid-level) evidence

[8]

Mehta H, Trivedi P, Parikh B, Shukla K, Shah MJ. Clinicopathological prognostic factors of adult granulosa cell tumor of the ovary--a study of 37 cases. Indian journal of pathology & microbiology. 2005 Oct:48(4):439-43     [PubMed PMID: 16366090]

Level 2 (mid-level) evidence

[9]

Li J, Chu R, Chen Z, Meng J, Yao S, Song K, Kong B. Progress in the management of ovarian granulosa cell tumor: A review. Acta obstetricia et gynecologica Scandinavica. 2021 Oct:100(10):1771-1778. doi: 10.1111/aogs.14189. Epub 2021 Jul 16     [PubMed PMID: 34027996]


[10]

Lee IH, Choi CH, Hong DG, Song JY, Kim YJ, Kim KT, Lee KW, Park IS, Bae DS, Kim TJ. Clinicopathologic characteristics of granulosa cell tumors of the ovary: a multicenter retrospective study. Journal of gynecologic oncology. 2011 Sep:22(3):188-95. doi: 10.3802/jgo.2011.22.3.188. Epub 2011 Sep 28     [PubMed PMID: 21998762]

Level 2 (mid-level) evidence

[11]

Shah SP, Köbel M, Senz J, Morin RD, Clarke BA, Wiegand KC, Leung G, Zayed A, Mehl E, Kalloger SE, Sun M, Giuliany R, Yorida E, Jones S, Varhol R, Swenerton KD, Miller D, Clement PB, Crane C, Madore J, Provencher D, Leung P, DeFazio A, Khattra J, Turashvili G, Zhao Y, Zeng T, Glover JN, Vanderhyden B, Zhao C, Parkinson CA, Jimenez-Linan M, Bowtell DD, Mes-Masson AM, Brenton JD, Aparicio SA, Boyd N, Hirst M, Gilks CB, Marra M, Huntsman DG. Mutation of FOXL2 in granulosa-cell tumors of the ovary. The New England journal of medicine. 2009 Jun 25:360(26):2719-29. doi: 10.1056/NEJMoa0902542. Epub 2009 Jun 10     [PubMed PMID: 19516027]


[12]

Da Cruz Paula A, da Silva EM, Segura SE, Pareja F, Bi R, Selenica P, Kim SH, Ferrando L, Vahdatinia M, Soslow RA, Vidal A, Gatius S, Przybycin CG, Abu-Rustum NR, Matias-Guiu X, Rubin BP, Reis-Filho JS, DeLair DF, Weigelt B. Genomic profiling of primary and recurrent adult granulosa cell tumors of the ovary. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 2020 Aug:33(8):1606-1617. doi: 10.1038/s41379-020-0514-3. Epub 2020 Mar 12     [PubMed PMID: 32203090]


[13]

Zhao C, Vinh TN, McManus K, Dabbs D, Barner R, Vang R. Identification of the most sensitive and robust immunohistochemical markers in different categories of ovarian sex cord-stromal tumors. The American journal of surgical pathology. 2009 Mar:33(3):354-66. doi: 10.1097/PAS.0b013e318188373d. Epub     [PubMed PMID: 19033865]


[14]

Zhang M, Cheung MK, Shin JY, Kapp DS, Husain A, Teng NN, Berek JS, Osann K, Chan JK. Prognostic factors responsible for survival in sex cord stromal tumors of the ovary--an analysis of 376 women. Gynecologic oncology. 2007 Feb:104(2):396-400     [PubMed PMID: 17030354]


[15]

Schumer ST, Cannistra SA. Granulosa cell tumor of the ovary. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2003 Mar 15:21(6):1180-9     [PubMed PMID: 12637488]


[16]

Nakashima N, Young RH, Scully RE. Androgenic granulosa cell tumors of the ovary. A clinicopathologic analysis of 17 cases and review of the literature. Archives of pathology & laboratory medicine. 1984 Oct:108(10):786-91     [PubMed PMID: 6548120]

Level 3 (low-level) evidence

[17]

Mom CH, Engelen MJ, Willemse PH, Gietema JA, ten Hoor KA, de Vries EG, van der Zee AG. Granulosa cell tumors of the ovary: the clinical value of serum inhibin A and B levels in a large single center cohort. Gynecologic oncology. 2007 May:105(2):365-72     [PubMed PMID: 17306349]

Level 2 (mid-level) evidence

[18]

Färkkilä A, Koskela S, Bryk S, Alfthan H, Bützow R, Leminen A, Puistola U, Tapanainen JS, Heikinheimo M, Anttonen M, Unkila-Kallio L. The clinical utility of serum anti-Müllerian hormone in the follow-up of ovarian adult-type granulosa cell tumors--A comparative study with inhibin B. International journal of cancer. 2015 Oct 1:137(7):1661-71. doi: 10.1002/ijc.29532. Epub 2015 Apr 11     [PubMed PMID: 25808251]

Level 2 (mid-level) evidence

[19]

Zanagnolo V, Pasinetti B, Sartori E. Clinical review of 63 cases of sex cord stromal tumors. European journal of gynaecological oncology. 2004:25(4):431-8     [PubMed PMID: 15285297]

Level 2 (mid-level) evidence

[20]

Aust S, Eberst L, Tredan O, Rousset-Jablonski C, Treilleux I, Méeus P, Chopin N, Beurrier F, Charreton A, Véronique D, Hallouz A, Coulon A, Ricoeur A, Mastier C, Bouhamama A, Racadot S, Devouassoux-Shisheboran M, Haddad V, Ray-Coquard I. Detailed overview on rare malignant ovarian tumors. Bulletin du cancer. 2020 Mar:107(3):385-390. doi: 10.1016/j.bulcan.2020.01.011. Epub 2020 Feb 27     [PubMed PMID: 32115180]

Level 3 (low-level) evidence

[21]

Levin G, Zigron R, Haj-Yahya R, Matan LS, Rottenstreich A. Granulosa cell tumor of ovary: A systematic review of recent evidence. European journal of obstetrics, gynecology, and reproductive biology. 2018 Jun:225():57-61. doi: 10.1016/j.ejogrb.2018.04.002. Epub 2018 Apr 11     [PubMed PMID: 29665458]

Level 1 (high-level) evidence

[22]

Rinne N, Farthing A, Borley J. Fertility sparing surgery in advanced and recurrent granulosa cell tumours of the ovary. Journal of obstetrics and gynaecology : the journal of the Institute of Obstetrics and Gynaecology. 2018 Jan:38(1):143-145. doi: 10.1080/01443615.2017.1332579. Epub 2017 Aug 7     [PubMed PMID: 28780898]


[23]

Armstrong DK, Alvarez RD, Backes FJ, Bakkum-Gamez JN, Barroilhet L, Behbakht K, Berchuck A, Chen LM, Chitiyo VC, Cristea M, DeRosa M, Eisenhauer EL, Gershenson DM, Gray HJ, Grisham R, Hakam A, Jain A, Karam A, Konecny GE, Leath CA III, Leiserowitz G, Liu J, Martin L, Matei D, McHale M, McLean K, Miller DS, Percac-Lima S, Remmenga SW, Schorge J, Stewart D, Thaker PH, Vargas R, Hendrickson AW, Werner TL, Zsiros E, Dwyer MA, Hang L. NCCN Guidelines® Insights: Ovarian Cancer, Version 3.2022. Journal of the National Comprehensive Cancer Network : JNCCN. 2022 Sep:20(9):972-980. doi: 10.6004/jnccn.2022.0047. Epub     [PubMed PMID: 36075393]


[24]

Wolf JK, Mullen J, Eifel PJ, Burke TW, Levenback C, Gershenson DM. Radiation treatment of advanced or recurrent granulosa cell tumor of the ovary. Gynecologic oncology. 1999 Apr:73(1):35-41     [PubMed PMID: 10094877]

Level 2 (mid-level) evidence

[25]

Uygun K, Aydiner A, Saip P, Kocak Z, Basaran M, Dincer M, Topuz E. Clinical parameters and treatment results in recurrent granulosa cell tumor of the ovary. Gynecologic oncology. 2003 Mar:88(3):400-3     [PubMed PMID: 12648593]

Level 2 (mid-level) evidence

[26]

Al-Badawi IA, Brasher PM, Ghatage P, Nation JG, Schepansky A, Stuart GC. Postoperative chemotherapy in advanced ovarian granulosa cell tumors. International journal of gynecological cancer : official journal of the International Gynecological Cancer Society. 2002 Jan-Feb:12(1):119-23     [PubMed PMID: 11860546]

Level 2 (mid-level) evidence

[27]

Brown J, Shvartsman HS, Deavers MT, Ramondetta LM, Burke TW, Munsell MF, Gershenson DM. The activity of taxanes compared with bleomycin, etoposide, and cisplatin in the treatment of sex cord-stromal ovarian tumors. Gynecologic oncology. 2005 May:97(2):489-96     [PubMed PMID: 15863149]

Level 2 (mid-level) evidence

[28]

Mangili G, Ottolina J, Cormio G, Loizzi V, De Iaco P, Pellegrini DA, Candiani M, Giorda G, Scarfone G, Cecere SC, Frigerio L, Gadducci A, Marchetti C, Ferrandina G. Adjuvant chemotherapy does not improve disease-free survival in FIGO stage IC ovarian granulosa cell tumors: The MITO-9 study. Gynecologic oncology. 2016 Nov:143(2):276-280. doi: 10.1016/j.ygyno.2016.08.316. Epub 2016 Sep 3     [PubMed PMID: 27597380]


[29]

Nasioudis D, Ko EM, Haggerty AF, Giuntoli RL 2nd, Burger RA, Morgan MA, Latif NA. Role of adjuvant chemotherapy in the management of stage IC ovarian granulosa cell tumors. Gynecologic oncology reports. 2019 May:28():145-148. doi: 10.1016/j.gore.2019.04.004. Epub 2019 Apr 17     [PubMed PMID: 31192990]


[30]

Martikainen H, Penttinen J, Huhtaniemi I, Kauppila A. Gonadotropin-releasing hormone agonist analog therapy effective in ovarian granulosa cell malignancy. Gynecologic oncology. 1989 Dec:35(3):406-8     [PubMed PMID: 2532171]

Level 3 (low-level) evidence

[31]

Alhilli MM, Long HJ, Podratz KC, Bakkum-Gamez JN. Aromatase inhibitors in the treatment of recurrent ovarian granulosa cell tumors: brief report and review of the literature. The journal of obstetrics and gynaecology research. 2012 Jan:38(1):340-4. doi: 10.1111/j.1447-0756.2011.01698.x. Epub 2011 Dec 5     [PubMed PMID: 22136798]

Level 3 (low-level) evidence

[32]

Brown J, Brady WE, Schink J, Van Le L, Leitao M, Yamada SD, de Geest K, Gershenson DM. Efficacy and safety of bevacizumab in recurrent sex cord-stromal ovarian tumors: results of a phase 2 trial of the Gynecologic Oncology Group. Cancer. 2014 Feb 1:120(3):344-51. doi: 10.1002/cncr.28421. Epub 2013 Oct 24     [PubMed PMID: 24166194]


[33]

Brink GJ, Groeneweg JW, Hooft L, Zweemer RP, Witteveen PO. Response to Systemic Therapies in Ovarian Adult Granulosa Cell Tumors: A Literature Review. Cancers. 2022 Jun 17:14(12):. doi: 10.3390/cancers14122998. Epub 2022 Jun 17     [PubMed PMID: 35740663]


[34]

Prat J, FIGO Committee on Gynecologic Oncology. Staging classification for cancer of the ovary, fallopian tube, and peritoneum. International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics. 2014 Jan:124(1):1-5. doi: 10.1016/j.ijgo.2013.10.001. Epub 2013 Oct 22     [PubMed PMID: 24219974]


[35]

Kraus F, Dremaux J, Altakfi W, Goux M, Pontois L, Sevestre H, Trudel S. FOXL2 homozygous genotype and chromosome instability are associated with recurrence in adult granulosa cell tumors of the ovary. Oncotarget. 2020 Jan 28:11(4):419-428. doi: 10.18632/oncotarget.27447. Epub 2020 Jan 28     [PubMed PMID: 32064045]


[36]

D'Angelo E, Mozos A, Nakayama D, Espinosa I, Catasus L, Muñoz J, Prat J. Prognostic significance of FOXL2 mutation and mRNA expression in adult and juvenile granulosa cell tumors of the ovary. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 2011 Oct:24(10):1360-7. doi: 10.1038/modpathol.2011.95. Epub 2011 May 27     [PubMed PMID: 21623383]


[37]

Sakr S, Abdulfatah E, Thomas S, Al-Wahab Z, Beydoun R, Morris R, Ali-Fehmi R, Bandyopadhyay S. Granulosa Cell Tumors: Novel Predictors of Recurrence in Early-stage Patients. International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists. 2017 May:36(3):240-252. doi: 10.1097/PGP.0000000000000325. Epub     [PubMed PMID: 28727617]

Level 2 (mid-level) evidence

[38]

Sehouli J, Drescher FS, Mustea A, Elling D, Friedmann W, Kühn W, Nehmzow M, Opri F, Klare P, Dietel M, Lichtenegger W. Granulosa cell tumor of the ovary: 10 years follow-up data of 65 patients. Anticancer research. 2004 Mar-Apr:24(2C):1223-9     [PubMed PMID: 15154651]

Level 2 (mid-level) evidence

[39]

Mangili G, Sigismondi C, Frigerio L, Candiani M, Savarese A, Giorda G, Lauria R, Tamberi S, Greggi S, Lorusso D. Recurrent granulosa cell tumors (GCTs) of the ovary: a MITO-9 retrospective study. Gynecologic oncology. 2013 Jul:130(1):38-42. doi: 10.1016/j.ygyno.2013.04.047. Epub 2013 Apr 25     [PubMed PMID: 23623833]

Level 2 (mid-level) evidence