Granulosa Theca Cell Cancer


Continuing Education Activity

Granulosa cell tumors are rare ovarian neoplasms derived from the sex cords/ovarian mesenchyme with an indolent course and long natural history. Unlike epithelial ovarian cancers, these tumors are detected early, often in young females that usually manifest with abdominal distension or pain or rarely with features of hyperestrogenism/virilization. There is a high chance of late recurrence, and hence lifelong follow-up is indicated. This activity reviews the evaluation and management of granulosa cell tumors of the ovary. It highlights the role of the interprofessional team in improving the care of patients with this condition.

Objectives:

  • Identify the etiology of granulosa cell tumors of the ovary.
  • Outline the appropriate evaluation of granulosa cell tumors of the ovary.
  • Discuss the management options available for granulosa cell tumors of the ovary.

Introduction

Granulosa theca cell cancers include ovarian tumors, which consist of granulosa cells, theca cells, and fibroblasts in variable combinations. Granulosa cells in the sex cords produce sex steroids and several peptides needed for folliculogenesis and ovulation. They also give rise to granulosa theca cell tumors (GCT), which form about 5 percent of ovarian neoplasms and are the commonest sex cord-stromal tumors of the ovary (70 percent). There are two distinct types of GCT -adult and juvenile forms- based on characteristic clinicopathologic features. The adult type is the commonest variety and manifests in peri- or post-menopausal women, while the juvenile type constitutes only 5 percent of cases and occurs in prepubertal girls and young women.

Theca cells are present in the ovarian stroma and play an essential role in fertility by producing the androgen substrate required for ovarian estrogen biosynthesis. Thecomas are uncommon and comprise less than 7 percent of sex cord-stromal tumors. They are usually benign and have an excellent prognosis. Malignant thecoma is rare and most often contains an element of granulosa cells, too, and hence the article focuses on GCTs unless otherwise specified. Finally, GCTs are distinct from epithelial ovarian cancers in that they are detected in the early stage, often in young females, and usually manifest with abdominal distension, pain, or rarely with features of hyperestrogenism/virilization.

The extra ovarian spread is to the omentum and peritoneum and occasionally to the lungs, liver, or brain via hematogenous spread. Lymph node metastases are uncommon. These tumors are treated by surgery alone and have a good prognosis. However, they tend to have an indolent progression that is prone to late recurrence that is seen in as many as up to 25 percent despite having curative surgery.[1][2]

Etiology

Aneuploidy of chromosome 12 (trisomy), 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 GCT. BRCA1 and BRCA 2 mutations do not imply an elevated risk of GCT, even though some studies have identified a family history of breast or ovarian cancer to be a significant risk factor. A case-control study by Boyce et al. suggested an independent association between non-white race and obesity in the development of GCT. At the same time, parity and oral contraceptive use were found to be protective. 

There are some tumor predisposition syndromes associated with GCT, such as Peutz Jeghers syndrome and Potters syndrome. Juvenile GCT seems to have an association with Ollier disease [enchondromatosis] and Maffucci disease. Certain medications, such as selective estrogen receptor modulators (SERM),  gonadotropins, and clomiphene citrate, have also been found to increase the risk of GCT.[1][3]

Epidemiology

Data from the SEER (Surveillance, Epidemiology, and End Results) database reveal an incidence of 0.2 per lakh women for sex cord-stromal tumors. Every year, about 1500 to 2000, new cases are diagnosed in the United States. Age-standardized incidence of granulosa theca cell cancer ranges from 0.58 to 1.6/100,000 women per year worldwide. The mean age at diagnosis was 50 years [a decade younger than epithelial ovarian cancer], and 57 percent were in the 30 to 60 year age group, with only 12 percent younger than 30 years old. The incidence also tends to be higher in black women than in white women [0.44 vs. 0.18 per lakh population].[4][5][6] 

Lee et al. reported the mean age at diagnosis of juvenile GCT to be 20 years (range 8 to 45 years) with more than 50 percent diagnosed before 20 years and 45.5 percent in the premenarchal group.[7] The worldwide incidence of this group of tumors remains the same, 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 resulted in two theories. The first one suggests the origin of these neoplasms from the genital ridge mesenchyme. The second theory suggests that these tumors originate from precursors within the mesonephric and coelomic epithelium. However, the exact pathophysiology has not been elucidated so far. Recent molecular genetic studies propose that these tumors have a somatic missense point mutation (C402G) in the FOXL2 gene, which was seen in 97% of adult GCT, 10 percent of juvenile GCT, and 21 percent of thecomas.[8]

The high frequency of this mutation suggests that it may be specifically diagnostic for Adult GCT [with the only exception of well- or moderately differentiated Sertoli Leydig cell tumors of the ovary], and the absence of this mutation in juvenile GCT may 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 [which can be targeted in precision oncology] 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-kB (NFkB)
  • TNF-related apoptosis-inducing ligand (TRAIL; CD253)

Histopathology

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

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

Few important histologic clues are that androgenic GCTs tend to be large unilocular/multilocular cysts. At the same time, focal luteinization and edema, and disorderly arrangement are seen in GCT occurring in pregnancy. Juvenile GCT has a diffuse [commonest] or macrofollicular morphology, mucin positive interfollicular secretion, large cells with luteinization, a theca cell component, the paucity of nuclear grooves, and nuclear atypia with variable or high mitotic activity. Immunohistochemistry helps when the morphologic diagnosis is doubtful, and one of the most useful markers is the alpha subunit of Inhibin. It 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.[9] 

Other immunohistochemical markers include activin, anti-Mullerian hormone, and Melan-A. FOXL2 expressed in the tumor nuclei can prove to be of particular advantage in staining cells with scant cytoplasm (adult GCT and fibromas), especially since cytoplasmic stains like inhibin may not be positive in such cells. About 97 percent of adult GCT showed a mutation of FOXL2.[5][7][10][11]

History and Physical

Granulosa theca cell tumors affect teenagers to the elderly and are most common in postmenopausal women with an average age of 45 to 55 years. The presenting symptoms are usually nonspecific with abdominal pain (41.1%), distension (26.4 percent), or a palpable abdominopelvic mass that is usually unilateral. About 70 percent 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 while heavy menstrual bleeding (HMB), irregular menstrual bleeding patterns, or amenorrhea can be seen in premenopausal women along with breast enlargement /tenderness. Rare adult GCTs can secrete androgens and result in virilization in young women aged 15 to 35 years and manifest with hirsutism, clitoromegaly, deepening of the voice, or amenorrhea.

High Inhibin levels may result in infertility due to inhibition of FSH (follicle-stimulating hormone) secretion. Rarely these tumors can present during pregnancy. Complications like tumor rupture [seen in 10 percent] or torsion of the adnexal mass or intratumoral hemorrhage can present as a case of acute abdomen with hypotension. Some patients with thecoma have a Meigs-like syndrome, with ascites and hydrothorax.[7][12]

Evaluation

The most important is to feature in reaching the proper diagnosis of GCTs is to maintain a high index of suspicion in patients presenting with adnexal mass and endocrine effects([estrogen/androgen excess). Hence the workup typically includes lab tests for serum hormonal levels (total testosterone in case of virilization, estradiol if there is hyperestrogenism), and tumor markers like Inhibin A and B [Inhibin-B is more accurate than inhibin A).[13] Combining Anti Mullerian hormone levels with inhibin B estimation is shown to improve the detection of recurrent disease.[14] 

Imaging of the adnexal mass is with a pelvic ultrasound and other additional imaging studies like contrast-enhanced CT to evaluate the abdomen or other sites in patients with suspected metastatic disease. Radiographic studies usually reveal either 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 don’t have intracystic papillary projections. Furthermore, the chance of peritoneal spread is low, and these tumors are rarely bilateral. An enlarged uterus with a thickened endometrium is often noted due to estrogenic action. Endometrial sampling may detect endometrial hyperplasia/intraepithelial neoplasia in 25% to 50%, with granulosa cell tumors and carcinoma in another 5 to 10 percent. In patients with thecoma, carcinoma may be detected in 20 to 25 percent of patients, and another 15% may have a precursor lesion.[11][15] 

Ascites is very rarely seen. As in the workup of all adnexal masses, surgery is performed to resect and determine the histology if ultrasound findings suggest the risk of harboring malignancy, if there are other risks associated with the mass (e.g., torsion) or if the mass is causing symptoms.

Treatment / Management

The 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/biologic therapy is reserved for treating recurrent or metastatic disease. These treatment options may improve survival or increase the length of disease-free time before a recurrence.

After completing the treatment, individuals should continue to have regular visits with their providers to check for recurrences. These visits should include updating the medical history, performing a pelvic exam, and possibly requesting tumor markers. If there are any suspicious findings during these visits, an imaging test such as a CT scan may be done.[16]

Differential Diagnosis

If the presentation is with an incidentally detected adnexal mass, the differential diagnosis should consider pelvic masses from gastrointestinal or genitourinary organs or retroperitoneal masses or cysts. Differential diagnosis of patients with adnexal mass and abnormal uterine bleeding include benign pathologies like uterine fibroid/polyp and malignant causes like uterine cancer with ovarian metastases or epithelial ovarian cancer with metastases to endometrium or a synchronous endometrial and ovarian cancer. When patients present with a pelvic mass and endocrine abnormalities a polycystic ovary syndrome and adrenal tumors have to be excluded.

Surgical Oncology

Primary surgery is usually curative due to the early stage of the disease and unilateral involvement in most cases. Unilateral salpingo-oophorectomy suffices for children and pre-menopausal females since only 2 percent of cases are bilateral at presentation.

If the intraoperative frozen section suggests GCT, then a limited staging procedure is carried out. First, the contralateral ovary is assessed, and it should be biopsied if enlarged. Next, peritoneal washings, infra-colic omentectomy, careful palpation of the peritoneum and retroperitoneal nodes, and biopsy of any suspicious lesions are carried out. Complete cytoreduction is of paramount importance if there is a 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 done to rule out the possibility of co-existing endometrial adenocarcinoma. Pelvic or para-aortic lymphadenectomy is of limited value, particularly in early-stage disease, and is currently not recommended.[17] 

Enlarged or suspicious nodes are removed to allow evaluation and to ensure maximal cytoreduction. Rinne et al. reported that fertility-sparing surgery, including unilateral salpingo-oophorectomy, omentectomy, and stripping of the pelvic peritoneum, was safe and allowed future pregnancies in women with stage 2B-3C disease. Pregnancy did not appear to be detrimental to disease progression.[18]

Radiation Oncology

Currently, 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 one review of 34 patients treated at MD Anderson Cancer Centre in the US over a 40-year period with radiation alone, 3 of the 14 (21%) who were treated for the measurable disease were alive without disease progression after 10 to 21 years.[19]

Medical Oncology

NCCN (the National Comprehensive Cancer Network) 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.[20] However, an overall survival benefit has not been demonstrated.[21] 

Regarding stage I disease, there is no evidence that adjuvant chemotherapy will prevent recurrence or improve survival. The MITO 9 study was a retrospective multi-institutional review of patients with GCT of the ovary at FIGO stage IC designed to assess the efficacy of first-line postoperative chemotherapy. Still, it failed to show any disease-free survival advantage.[22] Regarding the choice of regimen, bleomycin, etoposide, and cisplatin (BEP) are preferred for patients younger than 40 years old; while for those who are more than 40 years old, paclitaxel and carboplatin (TC) is recommended, given better tolerability than with BEP in this older population.[23] 

Although there is limited data, angiogenesis inhibitors [bevacizumab], hormonal therapy (including gonadotropin-releasing hormone agonists, tamoxifen, or the aromatase inhibitors) have also demonstrated activity, especially for the treatment of adult-type granulosa cell tumors.[11][24][25][26] Lastly, for patients who are inoperable (either due to performance status or the extent of the disease) or those who experience multiple recurrences, medical therapy alone is recommended.

Staging

GCTs are staged based on findings at surgical exploration and follow the FIGO (Federation International of Gynecology and Obstetrics) system for staging ovarian malignancies, which was last revised in 2014.[27] It can be broadly summarised as follows:

Stage I: Tumor is confined to the ovaries

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

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

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

Stage IV: Distant metastasis

Prognosis

The stage is the most important prognostic factor, followed by tumor rupture [indicates worse prognosis]. Large size (more than 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 do not correlate with clinical outcome. Homozygous FOXL2 mutation, higher FOXL2 mRNA expression, and chromosomal imbalance are associated with early relapse and worse outcomes.[28][29] Higher levels of SMAD3 expression is a novel predictor of recurrence in early-stage disease.[30]

Complications

As many as 10% to 15% of the cases can be complicated by ovarian torsion [the large sizes to which these tumors grow to predispose to torsion], tumor rupture (especially in large thin-walled cysts), and intratumoral hemorrhage. This can result in the presentation as an acute abdomen, which may be accompanied by hemoperitoneum and consequent hypotension. Hormonally active granulosa theca cell cancers can also result in infertility (high inhibin levels suppressing FSH levels) and endometrial carcinoma (due to unopposed estrogen stimulation of endometrium).

Postoperative and Rehabilitation Care

Review of symptoms and physical examination and serum tumor markers should be assessed every 2% to 4% for the first two years and then every six months thereafter. Routine imaging studies are not recommended in postoperative surveillance unless directed by the onset of symptoms suggestive of recurrence. GCT tends to late recurrence, and once the tumor recurs, it is fatal in 80 percent of cases.

There is a paucity of high-quality data on the optimal management of the recurrent disease. If the recurrent disease is resectable, few case series have reported a survival advantage for salvage surgery followed by platinum-based chemotherapy.[31][32]

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 records. In patients who opt for fertility preservation, issues regarding incomplete staging, and the potential need for further surgery if the definitive diagnosis is malignant, should be discussed. The need for life-long follow-up should be emphasized and thoroughly discussed with the patient, as these tumors tend to 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 can have varied presentations and may initially present to different specialists. For example, juvenile GCT may present first to pediatric care providers for 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 with menstrual abnormalities and women who experience postmenopausal bleeding are likely to consult a general gynecologic service provider. Finally, a presentation with an acute abdomen leads to an emergency general surgery consultation.

Given the above-stated, it is of paramount importance that all these providers have a sound knowledge of the clinical presentation of GCTs and the need for accurate surgical staging since the stage is the most important prognostic factor determining the outcome of this disease. Only then will prompt referral to a surgical/gynecologic oncologist be possible via effective inter-professional communication. Even though 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 and thereby facilitate patient counseling regarding the extent of surgery and possibility of fertility preservation.

Close collaboration with an expert gynecologic pathologist is crucial since an intraoperative frozen section may not always yield a definitive diagnosis. Instead, if the pathologist suspects an epithelial malignancy, the surgeon should consider a comprehensive staging including pelvic and para-aortic lymph node dissection rather than the usually limited staging procedure done for granulosa thecal cell tumors.

Nurses play a crucial role in providing patients with the required information regarding their disease during the diagnosis and management process. The nurse should ensure the provision of the best standard of care possible to women with GCT. The nurse should assist the interprofessional team in reporting any untoward changes in the general condition of the woman. Effective communication and collaboration among the interprofessional team members are crucial for the provision of the best possible standard of care for women with GCT and their families. [Level 5]


Article Details

Article Author

Shafeek Shamsudeen

Article Editor:

Heba Mahdy

Updated:

2/25/2021 5:46:07 PM

References

[1]

Kottarathil VD,Antony MA,Nair IR,Pavithran K, Recent advances in granulosa cell tumor ovary: a review. Indian journal of surgical oncology. 2013 Mar;     [PubMed PMID: 24426698]

[2]

Magoffin DA, Ovarian theca cell. The international journal of biochemistry     [PubMed PMID: 15833266]

[3]

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;     [PubMed PMID: 19664811]

[4]

Quirk JT,Natarajan N, Ovarian cancer incidence in the United States, 1992-1999. Gynecologic oncology. 2005 May;     [PubMed PMID: 15863154]

[5]

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;     [PubMed PMID: 18081789]

[6]

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     [PubMed PMID: 16366090]

[7]

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;     [PubMed PMID: 21998762]

[8]

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;     [PubMed PMID: 19516027]

[9]

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;     [PubMed PMID: 19033865]

[10]

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;     [PubMed PMID: 17030354]

[11]

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;     [PubMed PMID: 12637488]

[12]

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     [PubMed PMID: 6548120]

[13]

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;     [PubMed PMID: 17306349]

[14]

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;     [PubMed PMID: 25808251]

[15]

Zanagnolo V,Pasinetti B,Sartori E, Clinical review of 63 cases of sex cord stromal tumors. European journal of gynaecological oncology. 2004;     [PubMed PMID: 15285297]

[16]

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     [PubMed PMID: 32115180]

[17]

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;     [PubMed PMID: 29665458]

[18]

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;     [PubMed PMID: 28780898]

[19]

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;     [PubMed PMID: 10094877]

[20]

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;     [PubMed PMID: 12648593]

[21]

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;     [PubMed PMID: 11860546]

[22]

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;     [PubMed PMID: 27597380]

[23]

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;     [PubMed PMID: 15863149]

[24]

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

[25]

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;     [PubMed PMID: 22136798]

[26]

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;     [PubMed PMID: 24166194]

[27]

Prat J, 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;     [PubMed PMID: 24219974]

[28]

Kraus F,Dremaux J,Altakfi W,Goux M,Pontois L,Sevestre H,Trudel S, {i}FOXL2{/i} homozygous genotype and chromosome instability are associated with recurrence in adult granulosa cell tumors of the ovary. Oncotarget. 2020 Jan 28;     [PubMed PMID: 32064045]

[29]

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;     [PubMed PMID: 21623383]

[30]

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;     [PubMed PMID: 28727617]

[31]

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;     [PubMed PMID: 15154651]

[32]

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;     [PubMed PMID: 23623833]