REVIEW ARTICLE
Gynecologic Cancer InterGroup (GCIG) Consensus Review for Ovarian Sex Cord Stromal Tumors Isabelle Ray-Coquard, MD, PhD,* Jubilee Brown, MD,Þ Philipp Harter, MD,þ Diane M. Provencher, MD,§ Peter C. Fong, MD,|| Johanna Maenpaa, MD, PhD,¶ Jonathan A. Ledermann, MD, FRCP,# Gunter Emons, MD, PhD,** Dominique Berton Rigaud, MD,ÞÞ Rosalind M. Glasspool, PhD, MBBS, FRCP,þþ Delia Mezzanzanica, PhD,§§ and Nicoletta Colombo, MD||||
Sex cord stromal tumors (SCST) are rare cancers of the ovarian area in adults. They constitute a heterogeneous group of tumors that develop from the sex cords and the ovarian stroma. These tumors are detected typically at an early stage, and they may recur as late as 30 years after the initial treatment. Because 70% of the patients present with stage I tumors, surgery represents the most important therapeutic arm. There are no data to support any kind of postoperative adjuvant treatment for patients with stage IA or IB SCSTs, given the indolent nature of these neoplasms and the overall good prognosis. The long natural history of the disease may lead to repeated surgical procedure should a relapse occurs. Platinum-based chemotherapy is currently used for patients with advanced stage SCSTs or recurrent disease, with an overall response rate of 63% to 80%. The indolent nature of SCSTs with the tendency for late recurrence requires long-term follow-up. Key Words: Rare tumor, Sex cord stromal tumors, Molecular analysis, First-line treatment, Metastatic disease Received April 22, 2014, and in revised form July 23, 2014. Accepted for publication July 27, 2014. (Int J Gynecol Cancer 2014;24: S42YS47)
EPIDEMIOLOGY Sex cord stromal tumors (SCSTs) can occur as an isolated histological tumor type or in combination with other tumor types, but together, they account for only 7% of all ovarian malignancies. The yearly adjusted incidence rate for SCSTs is 2.1 per 1,000,000 women.1 They are more common in adult women and account for approximately 3% to 5 % of ovarian malignancies and for the majority of functioning tumors with clinical manifestations. Sex cord stromal tumors and steroid cell tumors occur over a wide range of age, and many are found in perimenopausal and postmenopausal women. Familial forms *Centre Le´on Be´rard, Lyon, France (GINECO); †MD Anderson Cancer Center, Houston, TX (GOG); ‡Kliniken-Essen-Mitte, Essen, Germany (AGO); §CHUM Hoˆpital Notre Dame, Montre´al, Que´bec, Canada (NCIC-CTG); ||FMHS, University of Auckland, Auckland, New Zealand (ANZGOG); ¶Tampere University Hospital, Tampere, Finland (NSGO); #UCL Cancer Institute, London, United Kingdom (NCRI MRC); **University Medecine, Go¨ttingen, Germany (AGO); Copyright * 2014 by IGCS and ESGO ISSN: 1048-891X DOI: 10.1097/IGC.0000000000000249
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have been described frequently and should be sought.2 The International Federation of Gynecology and Obstetrics (FIGO) stage3 and intraperitoneal tumor rupture are the most often reported prognostic factors. Patient age (950 years) and the size of the tumor (95 cm) have a less certain prognostic value.4 The majority of these tumors can be cured, but approximately 20% relapse or give rise to metastases that can be fatal.
DIAGNOSIS The initial signs and symptoms of SCST are usually a pelvic pain, feeling of pelvic pressure because of pelvic mass, ††Institut de Cance´rologie de l’Ouest Rene´ Gauducheau, Saint Herblain, France (GINECO); ‡‡Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom (SGCTG); §§Fondazione IRCCS Instituto Nazionale dei Tumori, Milan, Italy (MITO); and ||||University of MilanYBicocca, Milan, Italy (MaNGO) Address correspondence and reprint requests to Isabelle Ray-Coquard, MD, PhD, Centre Le´on Be´rard, 28, rue Laennec, 69373 Lyon Cedex 08, France. E-mail: [email protected] The authors declare no conflicts of interest.
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and menstrual irregularities. Diagnostics should include pelvic ultrasound and abdominopelvic computed tomography scan in selected cases. Serum human chorionic gonadotrophin, >fetoprotein titers and lactate dehydrogenase, inhibin (secreted by granulosa cell tumors [GCTs]), complete blood count, and liver and renal function tests should be performed especially in young patients.5 Antimu¨llerian hormone (AMH) or mu¨llerian-inhibiting substance has been studied more recently. This hormone is produced exclusively by granulosa cells in postnatal females and both prenatally and postnatally by the Sertoli cells in the male testis. Serum mu¨llerian-inhibiting substance/AMH may be a marker of ovarian reserve and typically disappears from the serum after menopause or bilateral oophorectomy. However, in patients with GCTs, levels have been shown to parallel the extent of disease.6,7 This marker is highly specific for GCT in postmenopausal or oophorectomized women, because it is not typically produced by other gonadal or extragonadal tumors in contrast to inhibin and estradiol levels. However, studies have been limited to retrospective trials. With widespread clinical availability of AMH testing, this marker may gain ground in the management of women with GCTs and perhaps could be a molecular target in the future. In case of suspected gonadoblastomas, a preoperative karyotype should be obtained on all premenarche girls because of the propensity of these tumors to arise in dysgenetic gonads. The staging system for ovarian SCTs is generally adopted from that of epithelial ovarian cancer as originally defined by FIGO.
MOLECULAR BIOLOGY Although the clinical management of SCST remains enigmatic, major advances in the understanding of the molecular biology of this group of tumors have occurred over the past few years. The etiology of GCT is unclear. Although the excessive stimulation by gonadotrophin in the context of treatment for infertility has been reported to increase the risk of developing GCT, this has not been shown in other studies.8 One approach to understanding the molecular pathogenesis of GCT is to take the available information about gene expression in normal cells as basis for analyzing signaling systems in these tumors. The patterns of many granulosa cell genes expressed through folliculogenesis have been characterized. The most active phase of granulosa cell proliferation occurs between the preantral and preovulatory stages. Proliferation is induced by follicle stimulating hormone, a response that requires both insulinlike growth factor I and estrogen action. It is also modulated by members of the transforming growth factor A superfamily. The mechanisms that regulate this phase of granulosa cell proliferation have been recently reviewed.9 Shah et al10,11 have recently reported the finding of the FOXL2 mutation in ovarian granulosa cell tumors. In the first article, the authors discovered a missense point mutation (402C -9 G) in the FOXL2 geneVa gene encoding a transcription factorVin 4 index adult-type granulosa cell tumors, 86 of 89 additional adult granulosa cell tumors, 3 of 14 thecomas, and 1 of 10 juvenile granulosa cell tumors. Subsequent reports have highlighted the utility of FOXL2 immunostaining and the finding that the FOXL2 mutation is virtually present
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in all adult granulosa cell tumors but absent in other pure subtypes within the SCST category.10,11 Recent publications also suggest a prognostic factor for the mutation status of FOXL2.12 The other major recent finding has been that of DICER1 mutations in SCST. Schultz et al13 reported that, among 296 kindreds including 325 children with pleuropulmonary blastoma (PPB), 3 children had both PPB and Sertoli-Leydig cell tumors. Among family members of PPB patients, they identified 6 SCSTs. Germline DICER1 mutations were identified in 4 of 6 patients with SCST from PPB kindreds and in 2 of 3 children with SCST and no personal or family history of PPB. In another report, Heravi-Moussavi et al14 found somatic DICER1 mutations in the RNase IIIb domain in 26 (60%) of 43 Sertoli-Leydig cell tumors, including 4 tumors with additional germline DICER1 mutations. Thus far, the finding of neither of these mutations has translated into a therapeutic target.15 Peutz-Jegher syndrome (PJS) is a rare autosomal dominant disorder characterized by mucocutaneous pigmentation, hamartomatous polyposis, and predisposition to benign and malignant tumors of the gastrointestinal tract, breast, ovary, uterine cervix, and testis. Germline-inactivating mutations in 1 allele of the STK11/ LKB1 gene at chromosome 19p13.3 have been found in most PJS patients. Although ovarian sex cord tumors with annular tubules (SCTATs) and minimal deviation adenocarcinomas (MDAs) of the uterine cervix are very rare in the general population, both tumor types occur with increased frequency in women with PJS. Connolly et al16 investigated the role of STK11 mutations and loss of heterozygosity (LOH) of the 19p13.3 region in 2 PJS-associated SCTATs and in 5 SCTATs and 8 MDAs of the uterine cervix, which occurred in patients lacking features of PJS (referred to here as ‘‘sporadic’’ cases). Germline mutations in the STK11 gene, accompanied by LOH of markers near the wild-type STK11 allele, were found in the 2 PJS-associated SCTATs. Somatic mutations were not found in any of the sporadic SCTATs or MDAs studied, although LOH of the 19p13.3 region was seen in 3 of 8 MDAs.16 These findings indicate that STK11, like other tumor suppressor genes, is affected by biallelic inactivation in gynecological tumors of PJS patients. In addition, although LOH of the 19p13.3 region was seen in sporadic MDAs, somatic STK11 mutations are rare. A yet-to-be-defined tumor suppressor gene in the 19p13.3 region may be the specific target of inactivation in these tumors.
PATHOLOGY Sex cord stromal and steroid cell tumors constitute a heterogeneous group of tumors (Table 1) and vary in their capacity to produce clinically significant amounts of steroid hormones. They usually expressed at least 1 of the following markers (inhibin, calretinin, and FOXL2), but in 15% of them, FOXL2 is the unique marker of sex cord differentiation. Granulosa cell tumors are the most frequent histological type. Granulosa cell tumor contains granulosa and thecal cells; the endocrine manifestations associated with them are often estrogenic. Two histological forms are known: juvenile (rare, young patients, early isosexuality, associated breast cancer, round nucleoli without grooves, high mitotic activity, good
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TABLE 1. Classification Ovarian stromal tumors with sex cord elements Adult granulosa cell tumor Juvenile granulosa cell tumor Sertoli-Leydig cell tumors Gynandroblastoma Sex cord tumor with annular tubules Others Pure stromal tumors Fibroma and thecoma; typical, cellular, and mitotically active Malignant tumors (fibrosarcoma) Other ovarian stromal tumors Ovarian stromal tumor with minor sex cord elements Sclerosing stromal tumor Signet ring stromal tumor Microcystic stromal tumor Ovarian myxoma Stromal-Leydig cell tumor Steroid cell tumors Stromal luteoma, Leydig cell tumor Steroid cell tumor, not otherwise specified
prognosis) and adult (hyperoestrogenism, grooved nuclei, associated with endometrial hyperplasia and uterine carcinoma, high tumor mass, which is the most common [95% of granulosa cell tumors]). Neoplasms of pure ovarian stroma are mostly benign, more than 50% of them being fibromas. In morphologically ambiguous cases, the reticulin stain, together with mutational analysis of FOXL2, is useful to distinguish adult granulosa cell tumor from fibrothecoma. Sertoli-Leydig cell tumors are derived from mesenchyme and sex cords, which regroup histologically all the embryonic phases of testicular development: from a diffuse stromal and undifferentiated cord appearance to well-differentiated Sertoli tubes. These tumors contain variable proportions of sertolian and leydigian elements. Tumors with only a sertolian component (Sertoli tumors) belong to the benign group. Tumors containing both types of components are classified into 3 groups as a function of the more or less differentiated character of the 2 constituents: (1) benign differentiated forms (androgenic, secretory in 60% of the cases); (2) intermediate differentiation (immature Sertoli cells); and (3) poorly differentiated forms (sarcomatoid or retiform). It is possible to see heterogeneous elements in the forms with poor or intermediate differentiation (primarily epithelial or mesenchymatous). These tumors typically produce androgens, and clinical virilization is noted in 70% to 85% of patients. Gynandroblastomas are extremely rare tumors that represent less than 1% of sex cord tumors and are probably derived from undifferentiated mesenchyme. This origin would explain their ‘‘bisexual’’ potential. These tumors contain variable but high proportions of granulosa cells and Sertoli (sex cord, nurse)YLeydig
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(interstitial stroma) cells. Because of the androgenic stimulation, signs of virilescence generally predominate over estrogenic effects. In the majority of cases, these tumors are benign; however, certain malignant tumors have been described in the literature, and they are usually large tumors, 7 to 10 cm in diameter, developing in women 30 to 50 years old. Clinically, they can be accompanied by signs of virilescence or hyperestrogenic manifestations. Because of estrogen secretion, endometrial hyperplasia is often associated and should be sought. Pure Leydig cell tumors are usually benign. In some cases, no evidence of ovarian or testicular differentiation is seen. These tumors belong either to the undifferentiated SCST or to the steroid cell tumors according to cell morphology. Some of them are malignant, but evolution remains unpredictable today.
INITIAL TREATMENT Surgery Because 70% of the patients present with stage I tumors, surgery represents the most important therapeutic arm.4 Surgical approach can be performed through open route or, in selected cases, by laparoscopy as recent emerging reports (but limited data) indicate that minimally invasive surgery for either primary surgery or surgical restaging is feasible and safe in selected patients with SCST.17 A careful examination of the abdominal cavity is required. Staging procedure includes infracolic omentectomy, biopsy of the diaphragmatic peritoneum, paracolic gutters, pelvic peritoneum, and peritoneal washings. Conservative surgery seems to be the appropriate approach in young patients for stage I SCST disease. In postmenopausal women and in patients with advanced stage disease, abdominal hysterectomy and bilateral salpingooophorectomy should be performed with careful surgical staging.18 There is no consensus about the role of systematic lymphadenectomy. A recent report by Thrall et al19 confirms previous reports and strengthens the principle that routine lymphadenectomy is unnecessary in the primary surgical management of SCST.20,21 Node dissection should be performed only in cases with evidence of nodal abnormality. The retroperitoneal evaluation is not mandatory because of the very low incidence of retroperitoneal metastases in early stage.20 For young women who can be offered conservative therapy, uterine curettage should be performed before surgery, because of the frequent association of granulosa cell tumors with endometrial hyperplasia (55%) or endometrial adenocarcinoma (4%Y20%).22
Adjuvant Treatment for Early Stage The majority of SCSTs (60%Y95%) are diagnosed at an early stage. Stage IA granulosa cell tumors have an excellent prognosis after surgery alone and do not require adjuvant therapy. There are no data to support any kind of postoperative adjuvant treatment for patients with stage I SCSTs, given the indolent nature of these neoplasms and the overall good prognosis (5% risk of relapse). Some authors would suggest adjuvant therapy for stage IC patients with high mitotic index.23 For Sertoli-Leydig cell tumors, postoperative adjuvant chemotherapy should be considered for those patients with stage I poorly differentiated or with heterologous elements.17 * 2014 IGCS and ESGO
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The most commonly used regimen is the BEP (bleomycin, etoposide, cisplatin) combination (3 cycles).15,24 The indolent nature of SCSTs with the tendency for late recurrence (the median time to relapse is approximately 4Y6 years) requires long-term follow-up. Several reports describe relapses occurring more than 20 years (up to 37 years) after diagnosis. Common sites of recurrence are the upper abdomen (55%Y70%) and the pelvis (30%Y45%). Follow-up visit must include history, physical examination with pelvic examination, and tumor markers (inhibin dosage could be considered as an option) every 4 months for the first 2 years, every 6 months during years 3, 4, and 5 or until progression. Because of very late relapse, some experts recommend prolonged follow-up until 10 or 15 years. Pelvic ultrasound needs to be performed every 6 months in those patients who have undergone fertility-sparing surgery, whereas computed tomography scan of the abdomen and pelvis is usually performed yearly. The use of positron emission tomography scan for follow-up is not well established yet. Because the risk of breast cancer in these patients is not negligible, especially those with the juvenile form, clinical monitoring and regular mammograms could be performed.22,25
ADVANCED/METASTATIC PHASE AND RELAPSE The long natural history of the disease may lead to repeated surgical procedure should a relapse occur. Debulking surgery, whenever feasible, remains the most effective treatment for metastatic or recurrent granulosa cell tumors. Adjuvant chemotherapy should be reserved for advanced (stage II to IV) and recurrent disease not able to be completely resected with surgery.26 Platinum-based chemotherapy is currently used for patients with advanced stage SCSTs or recurrent disease, with an overall response rate of 63% to 80%. BEP regimen for 3 to 6 cycles (last 2 without bleomycin) or carboplatin/paclitaxel is currently potentially recommended for adjuvant postoperative chemotherapy and for patients with advanced stage or with recurrent SCSTs.27,28 However, the efficacy of systemic therapy in advanced or recurrent granulosa cell tumor after complete resection is still undefined, and careful follow-up might be an option in selected cases. Unfortunately, the majority of patients with advanced disease do not have a durable remission. Patients with advanced gynandroblastoma have poor prognosis and are therefore treated with adjuvant therapy, although the data are very limited. Patients with steroid cell tumors who have tumors that are pleomorphic, have an increased mitotic count, are large, or are at an advanced stage should be treated with additional postoperative platinum-based chemotherapy, either BEP if not previously used or a taxaneplatinum combination. The Gynecologic Oncology Group is currently conducting a randomized phase II trial of BEP versus the combination of paclitaxel and carboplatin for patients with newly diagnosed and chemonaive recurrent metastatic SCSTs of the ovary. Additional options for the management of recurrent disease include hormonal therapies for adult granulosa cell tumors and other types of chemotherapy for all SCST subtypes. Alternative chemotherapy options include etoposide plus cisplatin; cyclophosphamide, doxorubicin, and cisplatin;
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paclitaxel and carboplatin; or platinum agent alone.29 Given the functional hormonal nature of granulosa cell tumors that express steroid hormone receptors, there is some rationale for a hormone-based approach. Response to gonadotropin-releasing hormone agonists, tamoxifen, progestins, and aromatase inhibitors has been reported in several case series.30 Some cases of advanced metastatic patients with partial response to radiotherapy are also published.
PERSPECTIVES From a therapeutic point of view, as with epithelial ovarian cancers, targeted agents are of interest in the management of metastatic SCST. Antiangiogenic agents have been investigated in patients with recurrent adult granulosa cell tumor, because of the overexpression of vascular endothelial growth factor and vascularity of these tumors. Tao et al31 reported antiangiogenic activity among 8 patients with granulosa cell tumors treated with bevacizumab. A recent experience at the MD Anderson Cancer Center seems to confirm potential activity of bevacizumab, even though in a very limited number of patients. The Gynecologic Oncology Group conducted a phase II trial of bevacizumab for women with recurrent sex cord stromal ovarian tumors. This clinical trial reports a response rate of 16.7% and a median progression-free survival of 9.3 months.32 The GINECO is currently evaluating in a GCIG (Gynecologic Cancer InterGroup) randomized phase II trial the combination of weekly paclitaxel plus bevacizumab versus weekly paclitaxel alone then bevacizumab. In addition, besides surgical resection, the therapeutic options are poor. Endocrine therapy, in particular, has been unrewarding. The identification of aberrant signaling in granulosa cellYspecific pathways could provide existing targets for the development of novel relatively specific therapeutic agents. Two experiences could be reported, one with vorinostat (histone deacetylase inhibitor) with excellent PR for patient with granulosa tumor,33 partial responses were also reported with another pan-histone deacetylase inhibitor (panobinostat) in SCSTs34 and hyperexpression of epidermal growth factor receptor 1 to 4 in juvenile granulosa tumor.35
ACKNOWLEDGEMENTS The authors thank all participants of the London meeting validating all GCIG reviews in November 2013. Isabelle Ray Coquard (GINECO), Jonathan Ledermann (MRC NCRI), Monica Bacon (GCIG Canada), Eric PujadeLauraine (GINECO), Michael Quinn (ANZGOG), William Small (RTOG), Gavin Stuart (NCIC CTG), and Jan Vermorken (EORTC). AGOAu: Regina Berger, Christian Marth, Karl Tamussino AGO De: Klaus Baumann, Jacobus Pfisterer, Alexander Reuss, Gabriele Elser, Philip Harter ANZGOG: Alison Brand, Linda Mileshkin, Clare Scott COGi: Jonathan Berek, Ashley Powell, Wendy Fantl DGOG: Rudd Bekkers, Carien Creutzberg, Els Witteveen GEICO: Andres Poveda, Ignacio Romero GICOM: David Isla, Dolores Gallardo GINECO: Benedicte Votan, Emmanuel Kurtz, Fabrice Lecuru, Florence Joly
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GOG: Mark Brady, David Gershenson, David Miller GOTIC: Keiichi Fujiwara, Kosei Hasegawa, Yuji Takei ICORG: Dearbhaile O’Donnell, Noreen Gleeson, Paula Calvert JGOG: Satoru Sagae, Aikou Okamoto, Tadao Takano KGOG: Jae Weon Kim, Byung HO Nam, Sang Ryu MaNGO: Nicoletta Colombo, Roldano Fossati, Dionyssios Katsaros MITO: Domenica Lorusso, Georgia Mangili, Delia Mezzanzanica, Jane Bryce MRC-NCRI: Charles Gourley, Iain McNeish, Melanie Powell, Max Parmar NCIC CTG: Hal Hirte, Marie Plante, Diane Provencher NOGGO: Jalid Sehouli, Elena Braicu, Mani Nassir NSGO: Gunnar Kristensen, Johanna Maenpaa, Mansoor Mirza PMHC: Amit Oza, Helen MacKay, Steven Welch RTOG: Patricia Eifel, Anuja Jhingran, Jubilee Brown SGCTG: Rosalind Glasspool, David Millan, Nick Reed, Jim Paul NCI-US: Thomas Gross, Elise Kohn ISSTD: Michael Seckl
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11. Shah SP, Kobel M, Senz J, et al. Mutation of FOXL2 in granulosa-cell tumors of the ovary. N Engl J Med. 2009;360:2719Y2729. 12. D’Angelo E, Mozos A, Nakayama D, et al. Prognostic significance of FOXL2 mutation and mRNA expression in adult and juvenile granulosa cell tumors of the ovary. Mod Pathol. 2011;24:1360Y1367. 13. Schultz KA, Pacheco MC, Yang J, et al. Ovarian sex cordYstromal tumors, pleuropulmonary blastoma and DICER1 mutations: a report from the International Pleuropulmonary Blastoma Registry. Gynecol Oncol. 2011;122:246Y250. 14. Heravi-Moussavi A, Anglesio MS, Cheng SW, et al. Recurrent somatic DICER1 mutations in nonepithelial ovarian cancers. N Engl J Med. 2012;366:234Y242. 15. Gershenson DM. Current advances in the management of malignant germ cell and sex cordYstromal tumors of the ovary. Gynecol Oncol. 2012;125:515Y517. 16. Connolly DC, Katabuchi H, Cliby WA, et al. Somatic mutations in the STK11/LKB1 gene are uncommon in rare gynecological tumor types associated with Peutz-Jegher’s syndrome. Am J Pathol. 2000;156:339Y345. 17. Colombo N, Peiretti M, Garbi A, et al. Non-epithelial ovarian cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2012;23(suppl 7):vii20Yvii26. 18. Pankratz E, Boyes DA, White GW, et al. Granulosa cell tumors. A clinical review of 61 cases. Obstet Gynecol. 1978;52:718Y723. 19. Thrall MM, Paley P, et al. Patterns of spread and recurrence of sex cordYstromal tumors of the ovary. Gynecol Oncol. 2011;122:242Y245. 20. Bu-Rustum NR, Restivo A, Ivy J, et al. Retroperitoneal nodal metastasis in primary and recurrent granulosa cell tumors of the ovary. Gynecol Oncol. 2006;103:31Y34. 21. Brown J, Sood AK, Deavers MT, et al. Patterns of metastasis in sex cordYstromal tumors of the ovary: can routine staging lymphadenectomy be omitted? Gynecol Oncol. 2009;113:86Y90. 22. Evans AT, Gaffey TA, Malkasian GDJ, et al. Clinicopathologic review of 118 granulosa and 82 theca cell tumors. Obstet Gynecol. 1980;55:231Y238. 23. Schneider DT, Calaminus G, Wessalowski R, et al. Ovarian sex cordYstromal tumors in children and adolescents. J Clin Oncol. 2003;21:2357Y2363. 24. Pautier P, Gutierrez-Bonnaire M, Rey A, et al. Combination of bleomycin, etoposide, and cisplatin for the treatment of advanced ovarian granulosa cell tumors. Int J Gynecol Cancer. 2008;18:446Y452. 25. Burger HG, Fuller PJ, Chu S, et al. The inhibins and ovarian cancer. Mol Cell Endocrinol. 2001;180:145Y148. 26. Mangili G, Sigismondi C, Frigerio L, et al. Recurrent granulosa cell tumors (GCTs) of the ovary: a MITO-9 retrospective study. Gynecol Oncol. 2013;130:38Y42. 27. Brown J, Shvartsman HS, Deavers MT, et al. The activity of taxanes in the treatment of sex cordYstromal ovarian tumors. J Clin Oncol. 2004;22:3517Y3523. 28. Cecchetto G, Ferrari A, Bernini G, et al. Sex cord stromal tumors of the ovary in children: a clinicopathological report from the Italian TREP project. Pediatr Blood Cancer. 2011;56:1062Y1067. 29. Colombo N, Parma G, Zanagnolo V, et al. Management of ovarian stromal cell tumors. J Clin Oncol. 2007;25:2944Y2951. * 2014 IGCS and ESGO
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30. Hardy RD, Bell JG, Nicely CJ, et al. Hormonal treatment of a recurrent granulosa cell tumor of the ovary: case report and review of the literature. Gynecol Oncol. 2005;96:865Y869. 31. Tao X, Sood AK, Deavers MT, et al. Anti-angiogenesis therapy with bevacizumab for patients with ovarian granulosa cell tumors. Gynecol Oncol. 2009;114:431Y436. 32. Brown J, Brady WE, Schink J, et al. Efficacy and safety of bevacizumab in recurrent sex cordYstromal ovarian tumors: results of a phase 2 trial of the Gynecologic Oncology Group. Cancer. 2014;120:344Y351.
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33. Rubin EH, Agrawal NG, Friedman EJ, et al. A study to determine the effects of food and multiple dosing on the pharmacokinetics of vorinostat given orally to patients with advanced cancer. Clin Cancer Res. 2006;12:7039Y7045. 34. Cassier PA, Lefranc A, Amela EY, et al. A phase II trial of panobinostat in patients with advanced pretreated soft tissue sarcoma. A study from the French Sarcoma Group. Br J Cancer. 2013;109:909Y914. 35. Leibl S, Bodo K, Gogg-Kammerer M, et al. Ovarian granulosa cell tumors frequently express EGFR (Her-1), Her-3, and Her-4: an immunohistochemical study. Gynecol Oncol. 2006;101:18Y23.
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Gynecologic Cancer InterGroup (GCIG) Consensus Review for Ovarian Sex Cord Stromal Tumors Isabelle Ray-Coquard, MD, PhD,* Jubilee Brown, MD,Þ Philipp Harter, MD,þ Diane M. Provencher, MD,§ Peter C. Fong, MD,|| Johanna Maenpaa, MD, PhD,¶ Jonathan A. Ledermann, MD, FRCP,# Gunter Emons, MD, PhD,** Dominique Berton Rigaud, MD,ÞÞ Rosalind M. Glasspool, PhD, MBBS, FRCP,þþ Delia Mezzanzanica, PhD,§§ and Nicoletta Colombo, MD||||
Sex cord stromal tumors (SCST) are rare cancers of the ovarian area in adults. They constitute a heterogeneous group of tumors that develop from the sex cords and the ovarian stroma. These tumors are detected typically at an early stage, and they may recur as late as 30 years after the initial treatment. Because 70% of the patients present with stage I tumors, surgery represents the most important therapeutic arm. There are no data to support any kind of postoperative adjuvant treatment for patients with stage IA or IB SCSTs, given the indolent nature of these neoplasms and the overall good prognosis. The long natural history of the disease may lead to repeated surgical procedure should a relapse occurs. Platinum-based chemotherapy is currently used for patients with advanced stage SCSTs or recurrent disease, with an overall response rate of 63% to 80%. The indolent nature of SCSTs with the tendency for late recurrence requires long-term follow-up. Key Words: Rare tumor, Sex cord stromal tumors, Molecular analysis, First-line treatment, Metastatic disease Received April 22, 2014, and in revised form July 23, 2014. Accepted for publication July 27, 2014. (Int J Gynecol Cancer 2014;24: S42YS47)
EPIDEMIOLOGY Sex cord stromal tumors (SCSTs) can occur as an isolated histological tumor type or in combination with other tumor types, but together, they account for only 7% of all ovarian malignancies. The yearly adjusted incidence rate for SCSTs is 2.1 per 1,000,000 women.1 They are more common in adult women and account for approximately 3% to 5 % of ovarian malignancies and for the majority of functioning tumors with clinical manifestations. Sex cord stromal tumors and steroid cell tumors occur over a wide range of age, and many are found in perimenopausal and postmenopausal women. Familial forms *Centre Le´on Be´rard, Lyon, France (GINECO); †MD Anderson Cancer Center, Houston, TX (GOG); ‡Kliniken-Essen-Mitte, Essen, Germany (AGO); §CHUM Hoˆpital Notre Dame, Montre´al, Que´bec, Canada (NCIC-CTG); ||FMHS, University of Auckland, Auckland, New Zealand (ANZGOG); ¶Tampere University Hospital, Tampere, Finland (NSGO); #UCL Cancer Institute, London, United Kingdom (NCRI MRC); **University Medecine, Go¨ttingen, Germany (AGO); Copyright * 2014 by IGCS and ESGO ISSN: 1048-891X DOI: 10.1097/IGC.0000000000000249
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have been described frequently and should be sought.2 The International Federation of Gynecology and Obstetrics (FIGO) stage3 and intraperitoneal tumor rupture are the most often reported prognostic factors. Patient age (950 years) and the size of the tumor (95 cm) have a less certain prognostic value.4 The majority of these tumors can be cured, but approximately 20% relapse or give rise to metastases that can be fatal.
DIAGNOSIS The initial signs and symptoms of SCST are usually a pelvic pain, feeling of pelvic pressure because of pelvic mass, ††Institut de Cance´rologie de l’Ouest Rene´ Gauducheau, Saint Herblain, France (GINECO); ‡‡Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom (SGCTG); §§Fondazione IRCCS Instituto Nazionale dei Tumori, Milan, Italy (MITO); and ||||University of MilanYBicocca, Milan, Italy (MaNGO) Address correspondence and reprint requests to Isabelle Ray-Coquard, MD, PhD, Centre Le´on Be´rard, 28, rue Laennec, 69373 Lyon Cedex 08, France. E-mail: [email protected] The authors declare no conflicts of interest.
International Journal of Gynecological Cancer
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and menstrual irregularities. Diagnostics should include pelvic ultrasound and abdominopelvic computed tomography scan in selected cases. Serum human chorionic gonadotrophin, >fetoprotein titers and lactate dehydrogenase, inhibin (secreted by granulosa cell tumors [GCTs]), complete blood count, and liver and renal function tests should be performed especially in young patients.5 Antimu¨llerian hormone (AMH) or mu¨llerian-inhibiting substance has been studied more recently. This hormone is produced exclusively by granulosa cells in postnatal females and both prenatally and postnatally by the Sertoli cells in the male testis. Serum mu¨llerian-inhibiting substance/AMH may be a marker of ovarian reserve and typically disappears from the serum after menopause or bilateral oophorectomy. However, in patients with GCTs, levels have been shown to parallel the extent of disease.6,7 This marker is highly specific for GCT in postmenopausal or oophorectomized women, because it is not typically produced by other gonadal or extragonadal tumors in contrast to inhibin and estradiol levels. However, studies have been limited to retrospective trials. With widespread clinical availability of AMH testing, this marker may gain ground in the management of women with GCTs and perhaps could be a molecular target in the future. In case of suspected gonadoblastomas, a preoperative karyotype should be obtained on all premenarche girls because of the propensity of these tumors to arise in dysgenetic gonads. The staging system for ovarian SCTs is generally adopted from that of epithelial ovarian cancer as originally defined by FIGO.
MOLECULAR BIOLOGY Although the clinical management of SCST remains enigmatic, major advances in the understanding of the molecular biology of this group of tumors have occurred over the past few years. The etiology of GCT is unclear. Although the excessive stimulation by gonadotrophin in the context of treatment for infertility has been reported to increase the risk of developing GCT, this has not been shown in other studies.8 One approach to understanding the molecular pathogenesis of GCT is to take the available information about gene expression in normal cells as basis for analyzing signaling systems in these tumors. The patterns of many granulosa cell genes expressed through folliculogenesis have been characterized. The most active phase of granulosa cell proliferation occurs between the preantral and preovulatory stages. Proliferation is induced by follicle stimulating hormone, a response that requires both insulinlike growth factor I and estrogen action. It is also modulated by members of the transforming growth factor A superfamily. The mechanisms that regulate this phase of granulosa cell proliferation have been recently reviewed.9 Shah et al10,11 have recently reported the finding of the FOXL2 mutation in ovarian granulosa cell tumors. In the first article, the authors discovered a missense point mutation (402C -9 G) in the FOXL2 geneVa gene encoding a transcription factorVin 4 index adult-type granulosa cell tumors, 86 of 89 additional adult granulosa cell tumors, 3 of 14 thecomas, and 1 of 10 juvenile granulosa cell tumors. Subsequent reports have highlighted the utility of FOXL2 immunostaining and the finding that the FOXL2 mutation is virtually present
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in all adult granulosa cell tumors but absent in other pure subtypes within the SCST category.10,11 Recent publications also suggest a prognostic factor for the mutation status of FOXL2.12 The other major recent finding has been that of DICER1 mutations in SCST. Schultz et al13 reported that, among 296 kindreds including 325 children with pleuropulmonary blastoma (PPB), 3 children had both PPB and Sertoli-Leydig cell tumors. Among family members of PPB patients, they identified 6 SCSTs. Germline DICER1 mutations were identified in 4 of 6 patients with SCST from PPB kindreds and in 2 of 3 children with SCST and no personal or family history of PPB. In another report, Heravi-Moussavi et al14 found somatic DICER1 mutations in the RNase IIIb domain in 26 (60%) of 43 Sertoli-Leydig cell tumors, including 4 tumors with additional germline DICER1 mutations. Thus far, the finding of neither of these mutations has translated into a therapeutic target.15 Peutz-Jegher syndrome (PJS) is a rare autosomal dominant disorder characterized by mucocutaneous pigmentation, hamartomatous polyposis, and predisposition to benign and malignant tumors of the gastrointestinal tract, breast, ovary, uterine cervix, and testis. Germline-inactivating mutations in 1 allele of the STK11/ LKB1 gene at chromosome 19p13.3 have been found in most PJS patients. Although ovarian sex cord tumors with annular tubules (SCTATs) and minimal deviation adenocarcinomas (MDAs) of the uterine cervix are very rare in the general population, both tumor types occur with increased frequency in women with PJS. Connolly et al16 investigated the role of STK11 mutations and loss of heterozygosity (LOH) of the 19p13.3 region in 2 PJS-associated SCTATs and in 5 SCTATs and 8 MDAs of the uterine cervix, which occurred in patients lacking features of PJS (referred to here as ‘‘sporadic’’ cases). Germline mutations in the STK11 gene, accompanied by LOH of markers near the wild-type STK11 allele, were found in the 2 PJS-associated SCTATs. Somatic mutations were not found in any of the sporadic SCTATs or MDAs studied, although LOH of the 19p13.3 region was seen in 3 of 8 MDAs.16 These findings indicate that STK11, like other tumor suppressor genes, is affected by biallelic inactivation in gynecological tumors of PJS patients. In addition, although LOH of the 19p13.3 region was seen in sporadic MDAs, somatic STK11 mutations are rare. A yet-to-be-defined tumor suppressor gene in the 19p13.3 region may be the specific target of inactivation in these tumors.
PATHOLOGY Sex cord stromal and steroid cell tumors constitute a heterogeneous group of tumors (Table 1) and vary in their capacity to produce clinically significant amounts of steroid hormones. They usually expressed at least 1 of the following markers (inhibin, calretinin, and FOXL2), but in 15% of them, FOXL2 is the unique marker of sex cord differentiation. Granulosa cell tumors are the most frequent histological type. Granulosa cell tumor contains granulosa and thecal cells; the endocrine manifestations associated with them are often estrogenic. Two histological forms are known: juvenile (rare, young patients, early isosexuality, associated breast cancer, round nucleoli without grooves, high mitotic activity, good
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TABLE 1. Classification Ovarian stromal tumors with sex cord elements Adult granulosa cell tumor Juvenile granulosa cell tumor Sertoli-Leydig cell tumors Gynandroblastoma Sex cord tumor with annular tubules Others Pure stromal tumors Fibroma and thecoma; typical, cellular, and mitotically active Malignant tumors (fibrosarcoma) Other ovarian stromal tumors Ovarian stromal tumor with minor sex cord elements Sclerosing stromal tumor Signet ring stromal tumor Microcystic stromal tumor Ovarian myxoma Stromal-Leydig cell tumor Steroid cell tumors Stromal luteoma, Leydig cell tumor Steroid cell tumor, not otherwise specified
prognosis) and adult (hyperoestrogenism, grooved nuclei, associated with endometrial hyperplasia and uterine carcinoma, high tumor mass, which is the most common [95% of granulosa cell tumors]). Neoplasms of pure ovarian stroma are mostly benign, more than 50% of them being fibromas. In morphologically ambiguous cases, the reticulin stain, together with mutational analysis of FOXL2, is useful to distinguish adult granulosa cell tumor from fibrothecoma. Sertoli-Leydig cell tumors are derived from mesenchyme and sex cords, which regroup histologically all the embryonic phases of testicular development: from a diffuse stromal and undifferentiated cord appearance to well-differentiated Sertoli tubes. These tumors contain variable proportions of sertolian and leydigian elements. Tumors with only a sertolian component (Sertoli tumors) belong to the benign group. Tumors containing both types of components are classified into 3 groups as a function of the more or less differentiated character of the 2 constituents: (1) benign differentiated forms (androgenic, secretory in 60% of the cases); (2) intermediate differentiation (immature Sertoli cells); and (3) poorly differentiated forms (sarcomatoid or retiform). It is possible to see heterogeneous elements in the forms with poor or intermediate differentiation (primarily epithelial or mesenchymatous). These tumors typically produce androgens, and clinical virilization is noted in 70% to 85% of patients. Gynandroblastomas are extremely rare tumors that represent less than 1% of sex cord tumors and are probably derived from undifferentiated mesenchyme. This origin would explain their ‘‘bisexual’’ potential. These tumors contain variable but high proportions of granulosa cells and Sertoli (sex cord, nurse)YLeydig
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(interstitial stroma) cells. Because of the androgenic stimulation, signs of virilescence generally predominate over estrogenic effects. In the majority of cases, these tumors are benign; however, certain malignant tumors have been described in the literature, and they are usually large tumors, 7 to 10 cm in diameter, developing in women 30 to 50 years old. Clinically, they can be accompanied by signs of virilescence or hyperestrogenic manifestations. Because of estrogen secretion, endometrial hyperplasia is often associated and should be sought. Pure Leydig cell tumors are usually benign. In some cases, no evidence of ovarian or testicular differentiation is seen. These tumors belong either to the undifferentiated SCST or to the steroid cell tumors according to cell morphology. Some of them are malignant, but evolution remains unpredictable today.
INITIAL TREATMENT Surgery Because 70% of the patients present with stage I tumors, surgery represents the most important therapeutic arm.4 Surgical approach can be performed through open route or, in selected cases, by laparoscopy as recent emerging reports (but limited data) indicate that minimally invasive surgery for either primary surgery or surgical restaging is feasible and safe in selected patients with SCST.17 A careful examination of the abdominal cavity is required. Staging procedure includes infracolic omentectomy, biopsy of the diaphragmatic peritoneum, paracolic gutters, pelvic peritoneum, and peritoneal washings. Conservative surgery seems to be the appropriate approach in young patients for stage I SCST disease. In postmenopausal women and in patients with advanced stage disease, abdominal hysterectomy and bilateral salpingooophorectomy should be performed with careful surgical staging.18 There is no consensus about the role of systematic lymphadenectomy. A recent report by Thrall et al19 confirms previous reports and strengthens the principle that routine lymphadenectomy is unnecessary in the primary surgical management of SCST.20,21 Node dissection should be performed only in cases with evidence of nodal abnormality. The retroperitoneal evaluation is not mandatory because of the very low incidence of retroperitoneal metastases in early stage.20 For young women who can be offered conservative therapy, uterine curettage should be performed before surgery, because of the frequent association of granulosa cell tumors with endometrial hyperplasia (55%) or endometrial adenocarcinoma (4%Y20%).22
Adjuvant Treatment for Early Stage The majority of SCSTs (60%Y95%) are diagnosed at an early stage. Stage IA granulosa cell tumors have an excellent prognosis after surgery alone and do not require adjuvant therapy. There are no data to support any kind of postoperative adjuvant treatment for patients with stage I SCSTs, given the indolent nature of these neoplasms and the overall good prognosis (5% risk of relapse). Some authors would suggest adjuvant therapy for stage IC patients with high mitotic index.23 For Sertoli-Leydig cell tumors, postoperative adjuvant chemotherapy should be considered for those patients with stage I poorly differentiated or with heterologous elements.17 * 2014 IGCS and ESGO
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The most commonly used regimen is the BEP (bleomycin, etoposide, cisplatin) combination (3 cycles).15,24 The indolent nature of SCSTs with the tendency for late recurrence (the median time to relapse is approximately 4Y6 years) requires long-term follow-up. Several reports describe relapses occurring more than 20 years (up to 37 years) after diagnosis. Common sites of recurrence are the upper abdomen (55%Y70%) and the pelvis (30%Y45%). Follow-up visit must include history, physical examination with pelvic examination, and tumor markers (inhibin dosage could be considered as an option) every 4 months for the first 2 years, every 6 months during years 3, 4, and 5 or until progression. Because of very late relapse, some experts recommend prolonged follow-up until 10 or 15 years. Pelvic ultrasound needs to be performed every 6 months in those patients who have undergone fertility-sparing surgery, whereas computed tomography scan of the abdomen and pelvis is usually performed yearly. The use of positron emission tomography scan for follow-up is not well established yet. Because the risk of breast cancer in these patients is not negligible, especially those with the juvenile form, clinical monitoring and regular mammograms could be performed.22,25
ADVANCED/METASTATIC PHASE AND RELAPSE The long natural history of the disease may lead to repeated surgical procedure should a relapse occur. Debulking surgery, whenever feasible, remains the most effective treatment for metastatic or recurrent granulosa cell tumors. Adjuvant chemotherapy should be reserved for advanced (stage II to IV) and recurrent disease not able to be completely resected with surgery.26 Platinum-based chemotherapy is currently used for patients with advanced stage SCSTs or recurrent disease, with an overall response rate of 63% to 80%. BEP regimen for 3 to 6 cycles (last 2 without bleomycin) or carboplatin/paclitaxel is currently potentially recommended for adjuvant postoperative chemotherapy and for patients with advanced stage or with recurrent SCSTs.27,28 However, the efficacy of systemic therapy in advanced or recurrent granulosa cell tumor after complete resection is still undefined, and careful follow-up might be an option in selected cases. Unfortunately, the majority of patients with advanced disease do not have a durable remission. Patients with advanced gynandroblastoma have poor prognosis and are therefore treated with adjuvant therapy, although the data are very limited. Patients with steroid cell tumors who have tumors that are pleomorphic, have an increased mitotic count, are large, or are at an advanced stage should be treated with additional postoperative platinum-based chemotherapy, either BEP if not previously used or a taxaneplatinum combination. The Gynecologic Oncology Group is currently conducting a randomized phase II trial of BEP versus the combination of paclitaxel and carboplatin for patients with newly diagnosed and chemonaive recurrent metastatic SCSTs of the ovary. Additional options for the management of recurrent disease include hormonal therapies for adult granulosa cell tumors and other types of chemotherapy for all SCST subtypes. Alternative chemotherapy options include etoposide plus cisplatin; cyclophosphamide, doxorubicin, and cisplatin;
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paclitaxel and carboplatin; or platinum agent alone.29 Given the functional hormonal nature of granulosa cell tumors that express steroid hormone receptors, there is some rationale for a hormone-based approach. Response to gonadotropin-releasing hormone agonists, tamoxifen, progestins, and aromatase inhibitors has been reported in several case series.30 Some cases of advanced metastatic patients with partial response to radiotherapy are also published.
PERSPECTIVES From a therapeutic point of view, as with epithelial ovarian cancers, targeted agents are of interest in the management of metastatic SCST. Antiangiogenic agents have been investigated in patients with recurrent adult granulosa cell tumor, because of the overexpression of vascular endothelial growth factor and vascularity of these tumors. Tao et al31 reported antiangiogenic activity among 8 patients with granulosa cell tumors treated with bevacizumab. A recent experience at the MD Anderson Cancer Center seems to confirm potential activity of bevacizumab, even though in a very limited number of patients. The Gynecologic Oncology Group conducted a phase II trial of bevacizumab for women with recurrent sex cord stromal ovarian tumors. This clinical trial reports a response rate of 16.7% and a median progression-free survival of 9.3 months.32 The GINECO is currently evaluating in a GCIG (Gynecologic Cancer InterGroup) randomized phase II trial the combination of weekly paclitaxel plus bevacizumab versus weekly paclitaxel alone then bevacizumab. In addition, besides surgical resection, the therapeutic options are poor. Endocrine therapy, in particular, has been unrewarding. The identification of aberrant signaling in granulosa cellYspecific pathways could provide existing targets for the development of novel relatively specific therapeutic agents. Two experiences could be reported, one with vorinostat (histone deacetylase inhibitor) with excellent PR for patient with granulosa tumor,33 partial responses were also reported with another pan-histone deacetylase inhibitor (panobinostat) in SCSTs34 and hyperexpression of epidermal growth factor receptor 1 to 4 in juvenile granulosa tumor.35
ACKNOWLEDGEMENTS The authors thank all participants of the London meeting validating all GCIG reviews in November 2013. Isabelle Ray Coquard (GINECO), Jonathan Ledermann (MRC NCRI), Monica Bacon (GCIG Canada), Eric PujadeLauraine (GINECO), Michael Quinn (ANZGOG), William Small (RTOG), Gavin Stuart (NCIC CTG), and Jan Vermorken (EORTC). AGOAu: Regina Berger, Christian Marth, Karl Tamussino AGO De: Klaus Baumann, Jacobus Pfisterer, Alexander Reuss, Gabriele Elser, Philip Harter ANZGOG: Alison Brand, Linda Mileshkin, Clare Scott COGi: Jonathan Berek, Ashley Powell, Wendy Fantl DGOG: Rudd Bekkers, Carien Creutzberg, Els Witteveen GEICO: Andres Poveda, Ignacio Romero GICOM: David Isla, Dolores Gallardo GINECO: Benedicte Votan, Emmanuel Kurtz, Fabrice Lecuru, Florence Joly
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GOG: Mark Brady, David Gershenson, David Miller GOTIC: Keiichi Fujiwara, Kosei Hasegawa, Yuji Takei ICORG: Dearbhaile O’Donnell, Noreen Gleeson, Paula Calvert JGOG: Satoru Sagae, Aikou Okamoto, Tadao Takano KGOG: Jae Weon Kim, Byung HO Nam, Sang Ryu MaNGO: Nicoletta Colombo, Roldano Fossati, Dionyssios Katsaros MITO: Domenica Lorusso, Georgia Mangili, Delia Mezzanzanica, Jane Bryce MRC-NCRI: Charles Gourley, Iain McNeish, Melanie Powell, Max Parmar NCIC CTG: Hal Hirte, Marie Plante, Diane Provencher NOGGO: Jalid Sehouli, Elena Braicu, Mani Nassir NSGO: Gunnar Kristensen, Johanna Maenpaa, Mansoor Mirza PMHC: Amit Oza, Helen MacKay, Steven Welch RTOG: Patricia Eifel, Anuja Jhingran, Jubilee Brown SGCTG: Rosalind Glasspool, David Millan, Nick Reed, Jim Paul NCI-US: Thomas Gross, Elise Kohn ISSTD: Michael Seckl
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30. Hardy RD, Bell JG, Nicely CJ, et al. Hormonal treatment of a recurrent granulosa cell tumor of the ovary: case report and review of the literature. Gynecol Oncol. 2005;96:865Y869. 31. Tao X, Sood AK, Deavers MT, et al. Anti-angiogenesis therapy with bevacizumab for patients with ovarian granulosa cell tumors. Gynecol Oncol. 2009;114:431Y436. 32. Brown J, Brady WE, Schink J, et al. Efficacy and safety of bevacizumab in recurrent sex cordYstromal ovarian tumors: results of a phase 2 trial of the Gynecologic Oncology Group. Cancer. 2014;120:344Y351.
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33. Rubin EH, Agrawal NG, Friedman EJ, et al. A study to determine the effects of food and multiple dosing on the pharmacokinetics of vorinostat given orally to patients with advanced cancer. Clin Cancer Res. 2006;12:7039Y7045. 34. Cassier PA, Lefranc A, Amela EY, et al. A phase II trial of panobinostat in patients with advanced pretreated soft tissue sarcoma. A study from the French Sarcoma Group. Br J Cancer. 2013;109:909Y914. 35. Leibl S, Bodo K, Gogg-Kammerer M, et al. Ovarian granulosa cell tumors frequently express EGFR (Her-1), Her-3, and Her-4: an immunohistochemical study. Gynecol Oncol. 2006;101:18Y23.
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