Adult-type granulosa cell tumor is a clinically and molecularly unique subtype of ovarian cancer. These tumors originate from the sex cord stromal cells of the ovary and represent 3-5% of all ovarian cancers. The majority of adult-type granulosa cell tumors are diagnosed at an early stage with an indolent prognosis. Surgery is the cornerstone for the treatment of both primary and relapsed tumor, while chemotherapy is applied only for advanced or non-resectable cases. Tumor stage is the only factor consistently associated with prognosis. However, every third of the patients relapse, typically in 4-7 years from diagnosis, leading to death in 50% of these patients. Anti-Müllerian Hormone and inhibin B are currently the most accurate circulating biomarkers. Adult-type granulosa cell tumors are molecularly characterized by a pathognomonic somatic missense point mutation 402C->G (C134W) in the transcription factor FOXL2. The FOXL2 402C->G mutation leads to increased proliferation and survival of granulosa cells, and promotes hormonal changes. Histological diagnosis of adult-type granulosa cell tumor is challenging, therefore testing for the FOXL2 mutation is crucial for differential diagnosis. Large international collaborations utilizing molecularly defined cohorts are essential to improve and validate new treatment strategies for patients with high-risk or relapsed adult-type granulosa cell tumor. Key Messages: Adult-type granulosa cell tumor is a unique ovarian cancer with an indolent, albeit unpredictable disease course. Adult-type granulosa cell tumors harbor a pathognomonic somatic missense mutation in transcription factor FOXL2. The key challenges in the treatment of patients with adult-type granulosa cell tumor lie in the identification and management of patients with high-risk or relapsed disease.

Adult-type granulosa cell tumors (AGCTs) are sex-cord derived neoplasms with a propensity for late relapse. Hormonal modulators have been used empirically in the treatment of recurrent AGCT, albeit with limited success. To provide a more rigorous foundation for hormonal therapy in AGCT, we used a multimodal approach to characterize the expressions of key hormone biomarkers in 175 tumor specimens and 51 serum samples using RNA sequencing, immunohistochemistry, RNA in situ hybridization, quantitative PCR, and circulating biomarker analysis, and correlated these results with clinical data. We show that FSH receptor and estrogen receptor beta (ERβ) are highly expressed in the majority of AGCTs, whereas the expressions of estrogen receptor alpha (ERα) and G-protein coupled estrogen receptor 1 are less prominent. ERβ protein expression is further increased in recurrent tumors. Aromatase expression levels show high variability between tumors. None of the markers examined served as prognostic biomarkers for progression-free or overall survival. In functional experiments, we assessed the effects of FSH, estradiol (E2), and the aromatase inhibitor letrozole on AGCT cell viability using 2 in vitro models: KGN cells and primary cultures of AGCT cells. FSH increased cell viability in a subset of primary AGCT cells, whereas E2 had no effect on cell viability at physiological concentrations. Letrozole suppressed E2 production in AGCTs; however, it did not impact cell viability. We did not find preclinical evidence to support the clinical use of aromatase inhibitors in AGCT treatment, and thus randomized, prospective clinical studies are needed to clarify the role of hormonal treatments in AGCTs.

ObjectiveThe surgical staging system for endometrial carcinoma developed by International Federation of Gynecology and Obstetrics (FIGO) in 1988 was revised in 2009. Given the importance of continuous validation of the prognostic performance of staging systems, we analyzed the disease specific survival for patients with endometrial carcinoma using FIGO 1988 and 2009 systems. Further, the stage distribution of endometrioid and nonendometrioid carcinomas was studied.MethodsEight hundred twenty-one women with endometrial carcinoma were retrospectively staged using FIGO 1988 and 2009 systems.ResultsFIGO 1988 IC was associated with an inferior survival compared with IA-IB. Survival overlapped for 1988 IA and IB, for 1988 IC and IIA, and for 2009 IB and II. FIGO 2009 IA-II patients with negative peritoneal cytology had a superior survival compared with 1988 IIIA patients with positive cytology only. The survival was similar for 1988 IIIA with positive cytology only and for 2009 IIIA. Cox proportional hazards model recognized grade 3 endometrioid and nonendometrioid histology, tumor spread beyond the uterine corpus and cervix, and positive peritoneal cytology as significant predictors of death. Among 2009 IIIC substages, the proportion of IIIC2 tumors was higher for nonendometrioid than for endometrioid carcinomas (p=0.003).ConclusionStage I with deep myometrial invasion and stage II endometrial carcinoma seem to have similar survival outcomes. Although positive peritoneal cytology does not alter the stage according to the FIGO 2009 system, it should be considered a poor prognostic sign. The high proportion of nonendometrioid carcinomas in the stage IIIC2 category may reflect different patterns of retroperitoneal spread among tumors with different histologic subtypes.