Sertoli – Leydigzelltumoren des Ovars: Analyse des Dicer1 – und Foxl2 – Mutationstatus

Purpose: Sertoli Leydig cell tumors (SLCT) are rare sex cord-stromal tumors of the ovary. Dicer1 mutations have been shown to be present in a majority of SLCT, while only few reported cases have harbored Foxl2 mutations. It was our aim to classify SLCTs according to their molecular profile and clinicopathological features. Methods: Formalin-fixed, paraffin-embedded tissue blocks from a cohort of 45 SLCT diagnosed between 1995 and 2016 were available after specialized gynecopathological review. Dicer1 mutation status was determined by Sanger Sequencing while Foxl2 402G>C mutation status was determined by TaqMan allelic discrimination assay. Clinical data sets were updated allowing for correlation with mutation status. Results: Dicer1 mutation analyses could be performed successfully in 44/45 SLCT, and 18/44 (41%) of cases were positive for at least 1 hotspot mutation. Dicer1 mutation-positive cases had a median age of 24,5 years (range 15-62 years). A majority (68,8%) of Dicer1 mutation-positive cases showed hyperandrogenic symptoms, and in 18,8% of patients, abnormal uterine bleeding was noted at presentation. Foxl2 mutation analyses was successfully done in all 45 cases, and 10/45 SLCT (22,2%) were 402G>C mutation positive. In this subgroup, the median age was 78,5 years (range 54-90 years). 4/5 (80%) of patients with Foxl2 mutation-positive SLCT had abnormal uterine bleeding at presentation. Conclusions: This study suggests that there are different molecular subtypes of SLCT. Dicer1 mutation-positive tumors occur in younger patients presenting with hyperandrogenic symptoms, whereas Foxl2 mutation-positive SLCT occur more frequently in postmenopausal women presenting with abnormal uterine bleeding

The effect of fertility-sparing surgery on sexuality and global quality of life in women with malignant ovarian germ cell and sex cord stromal tumors : an analysis of the CORSETT database of the AGO study group

Purpose Malignant ovarian germ cell (MOGCT) and sex cord stromal tumors (SCST) are ovarian neoplasms that affect disproportionally young women. Little is known about the impact of surgical and adjuvant management of these patient’s sexual life. This study investigated the effect of fertility-sparing surgery on sexual activity and global quality of life (gQoL) in women with MOGCT and SCST. Methods CORSETT was an observational, multicenter, mixed retrospective/prospective cohort study of the AGO study group. Women of any age who had been diagnosed with MOGCTs and SCSTs between 2001 and 2011 were asked to complete the Sexual Activity Questionnaire (SAQ) and the EORTC QLQ-C30. Results In total, 355 patients were included. Of these, 152 patients with confirmed histological diagnosis had completed the questionnaires. A total of 106 patients were diagnosed with SCST and 46 with MOGCT. Totally, 83 women (55%) were sexually active. After fertility-sparing surgery, patients had a 2.6 fold higher probability for being sexually active than after non-fertility-conserving treatment (unadjusted odds ratio (OR) 2.6, p = 0.01). After adjustment for age, time since diagnosis, FIGO stage, histology and phase of disease, the OR dropped to 1.8 (p = 0.22). Of the sexually active patients, 35 (42%) reported high levels of discomfort during intercourse; 38% after fertility-sparing; and 58% after non-fertility-sparing surgery (adjusted OR 2.8, p = 0.18). Women with fertility-conserving treatment reported a significantly better global QoL (Fadj 2.1, 6.2 points difference, p = 0.03) but not more pleasure during intercourse than women without fertility-sparing surgery (Fadj 0.4, p = 0.52). Conclusion Fertility preserving approaches should be offered to every patient, when oncologically acceptable

Adult-type granulosa cell tumor of the ovary : a FOXL2-centric disease

Adult-type granulosa cell tumors (aGCTs) account for 90% of malignant ovarian sex cord-stromal tumors and 2-5% of all ovarian cancers. These tumors are usually diagnosed at an early stage and are treated with surgery. However, one-third of patients relapse between 4 and 8 years after initial diagnosis, and there are currently no effective treatments other than surgery for these relapsed patients. As the majority of aGCTs (>95%) harbor a somatic mutation in FOXL2 (c.C402G; p.C134W), the aim of this study was to identify genetic mutations besides FOXL2 C402G in aGCTs that could explain the clinical diversity of this disease. Whole-genome sequencing of 10 aGCTs and their matched normal blood was performed to identify somatic mutations. From this analysis, a custom amplicon-based panel was designed to sequence 39 genes of interest in a validation cohort of 83 aGCTs collected internationally. KMT2D inactivating mutations were present in 10 of 93 aGCTs (10.8%), and the frequency of these mutations was similar between primary and recurrent aGCTs. Inactivating mutations, including a splice site mutation in candidate tumor suppressor WNK2 and nonsense mutations in PIK3R1 and NLRC5, were identified at a low frequency in our cohort. Missense mutations were identified in cell cycle-related genes TP53, CDKN2D, and CDK1. From these data, we conclude that aGCTs are comparatively a homogeneous group of tumors that arise from a limited set of genetic events and are characterized by the FOXL2 C402G mutation. Secondary mutations occur in a subset of patients but do not explain the diverse clinical behavior of this disease. As the FOXL2 C402G mutation remains the main driver of this disease, progress in the development of therapeutics for aGCT would likely come from understanding the functional consequences of the FOXL2 C402G mutation.Peer reviewe