Sertoli-Leydig cell tumor: a clinicopathological analysis in a comprehensive, national cohort.

INTRODUCTION: Sertoli-Leydig cell tumors are rare tumors of the ovary. Moderate and poorly differentiated tumors can metastasize and have a poor outcome. A pathogenic variant in DICER1 is associated with an increased risk of developing these tumors along with other clinical phenotypes. We aimed to describe a national cohort of all Sertoli-Leydig cell tumors with regard to clinicopathological characteristics and frequency of DICER1 pathogenic variants. METHODS: In May 2018, all patients registered from January 1997 to December 2017 with the Systematized Nomenclature of Medicine code M86310 (Sertoli-Leydig cell tumor) were obtained from the Danish National Pathology Registry. Validation of the diagnosis depended on comments in the reports that two pathologists validated the initial diagnosis or revision of the pathology at another facility. We performed descriptive statistics to describe baseline characteristics, and cancer related survival was calculated using Kaplan-Meier analysis followed by a log rank test for differences between variables RESULTS: 41 women with Sertoli-Leydig cell tumors were identified. Median age was 41 years (range 6-79). The stages according to the International Federation of Gynecology and Obstetrics (FIGO) were: stage I, 85% (n=35), stage II, 2% (n=1), stage III, 5% (n=2), and stage IV, 7% (n=3). The 5 year cancer related survival was 100% for patients with localized disease (stages I-II) and 0% in advanced tumor stages (stages III-IV). Histological differentiation grade of the tumors was well differentiated in 29% (n=12), moderately differentiated in 56% (n=23), and poorly differentiated in 15% (n=6), and the 5 year cancer related survival was 100%, 96%, and 33%, respectively, according to grade. All patients underwent surgery. Twenty-two patients had fertility sparing surgery and four of these had given birth at the time of follow-up. Analysis of DICER1 was performed in eight women. Four carried a pathogenic variant. Four patients received adjuvant chemotherapy, three because of advanced tumor stage, and one because of a poorly differentiated Sertoli-Leydig cell tumor. CONCLUSION: The prognosis for women with Sertoli-Leydig cell tumors with localized disease is excellent. Women with advanced stages (III-IV) have a poor prognosis, regardless of adjuvant chemotherapy. Fertility sparing surgery seems to be a viable option for localized Sertoli-Leydig cell tumors. DICER1 screening was rarely performed in previous cohorts and concomitant organ screening programs are topics for discussion.

Carboplatin re-treatment in platinum-resistant epithelial ovarian cancer patients.

PURPOSE: Treatment of multi-resistant epithelial ovarian cancer represents a clinical challenge with limited choices. Anti-angiogenic therapy has shown great potential in combination with frontline-therapy. Studies investigating heavily pre-treated patients are few. This study investigated the effect of re-treating patients with carboplatin combined with bevacizumab and cell-free DNA (cfDNA) as a potential predictor of outcome. METHODS: This single-center study enrolled 73 multi-resistant ovarian cancer patients from 2008 to 2015. Patients were treated with a combination of bevacizumab (10 mg/kg) and carboplatin (AUC5) every 3 weeks. Baseline plasma samples were analyzed for cfDNA levels. Treatment response was evaluated based on the Response Evaluation Criteria in Solid Tumors (RECIST) criteria and CA125 blood values. RESULTS: The response rate according to RECIST and/or CA125 was 57%. Median number of cycles was 6. The median progression-free survival and overall survival was 5.0 and 11.2 months, respectively. Eighteen patients developed allergic reactions to carboplatin. Patients were grouped into two cfDNA-groups according to median value. The cfDNA value was correlated to progression-free survival (PFS, p = 0.015), but not to overall survival (OS, p = 0.067) in the univariate analysis. In the multivariate analysis both PFS and OS were highly correlated to the levels of cfDNA (PFS, hazard ratio = 1.87, p = 0.012; OS, hazard ratio = 1.67, p = 0.037) with patients with high levels of cfDNA having poorest outcome. CONCLUSION: Our results might provide guidance in cases with heavily pre-treated patients, where alternatives are limited. Carboplatin and bevacizumab treatment should be weighed against best supportive care, current non-platinum therapies and experimental treatment. cfDNA seems to offer prognostic insight.

Revised Danish guidelines for the cancer surveillance of patients with Cowden Syndrome.

INTRODUCTION: Cowden syndrome is a cancer predisposition syndrome caused by pathogenic variants in PTEN. The affected patients possess an increased risk of breast, thyroid, renal, colorectal, endometrial cancers as well as malignant melanoma. Thus prophylactic surveillance and follow up is crucial for these patients. METHODS: A review of the literature including existing guidelines from the years 1996 until 2017 was carried out. In total, 2078 scientific papers were identified through database searches on Cowden syndrome. Among these, 11 manuscripts were included based on scientific relevance and quality. Expert consensus was reached to define management guidelines. RESULTS: The literature revealed a high risk of cancer in specific organs for patients diagnosed with Cowden Syndrome. Alternative management guidelines were proposed and discussed. CONCLUSIONS: Here we propose a revised set of management guidelines for patients with Cowden syndrome in Denmark to address the increased risk of various cancer types.

Prognostic importance of vascular endothelial growth factor-A expression and vascular endothelial growth factor polymorphisms in epithelial ovarian cancer.

INTRODUCTION: Vascular endothelial growth factors (VEGFs) play a central role in angiogenesis and consequently, in various steps of ovarian carcinogenesis. Gene polymorphisms within the VEGF system have revealed a correlation with prognosis in some malignancies. The aim of the present study was to examine the possible importance of 2 VEGF polymorphisms and VEGF-A expression in ovarian cancer. METHODS: We investigated 2 single nucleotide polymorphisms VEGF +405G/C and VEGF -460C/T by polymerase chain reaction and also analyzed VEGF-A expression by immunohistochemistry in 159 women with ovarian cancer. RESULTS: Vascular endothelial growth factor-A expression revealed a significant correlation with survival in a Cox proportional hazards regression model (P = 0.012). Germline polymorphisms were not correlated with clinicopathological parameters such as stage, type, and histology. Heterozygous genotype in VEGF +405G/C predicted a better survival compared with homozygous genotypes (P = 0.034), and the heterozygous genotype in VEGF -460C/T pointed to the same direction. A multivariate analysis also indicated that heterozygosity of either of the 2 polymorphisms held independent prognostic significance (P = 0.001). CONCLUSIONS: Vascular endothelial growth factor polymorphisms +405G/C and VEGF expression seem to have independent prognostic importance.