A Genome-First Approach to Characterize DICER1 Pathogenic Variant Prevalence, Penetrance, and Phenotype.

Importance: Genetic disorders are historically defined through phenotype-first approaches. However, risk estimates derived from phenotype-linked ascertainment may overestimate severity and penetrance. Pathogenic variants in DICER1 are associated with increased risks of rare and common neoplasms and thyroid disease in adults and children. This study explored how effectively a genome-first approach could characterize the clinical traits associated with germline DICER1 putative loss-of-function (pLOF) variants in an unselected clinical cohort. Objective: To examine the prevalence, penetrance, and phenotypic characteristics of carriers of germline DICER1 pLOF variants via genome-first ascertainment. Design, Setting, and Participants: This cohort study classifies DICER1 variants in germline exome sequence data from 92 296 participants of the Geisinger MyCode Community Health Initiative. Data for each MyCode participant were used from the start of the Geisinger electronic health record to February 1, 2018. Main Outcomes and Measures: Prevalence of germline DICER1 variation; penetrance of malignant tumors and thyroid disease in carriers of germline DICER1 variation; structured, manual review of electronic health records; and DICER1 sequencing of available tumors from an associated cancer registry. Results: A total of 92 296 adults (mean [SD] age, 59 [18] years; 98% white; 60% female) participated in the study. Germline DICER1 pLOF variants were observed in 1 in 3700 to 1 in 4600 participants, more than double the expected prevalence. Malignant tumors (primarily thyroid carcinoma) were observed in 4 of 25 participants (16%) with DICER1 pLOF variants, which is comparable (by 50 years of age) to the frequency of neoplasms in the largest registry- and clinic-based (phenotype-first) DICER1 studies published to date. DICER1 pLOF variants were significantly associated with risks of thyroidectomy (odds ratio [OR], 6.0; 95% CI, 2.2-16.3; P = .007) and thyroid cancer (OR, 9.2; 95% CI, 2.1-34.7; P = .02) compared with controls, but there was not a significant increase in the risk of goiter (OR, 1.8; 95% CI, 0.7-4.9). A female patient in her 80s who was a carrier of a germline DICER1 hotspot variant was apparently healthy on electronic health record review. The term DICER1 did not appear in any of the medical records of the 25 participants with a pLOF DICER1 variant, even in those affected with a known DICER1-associated tumor or thyroid phenotype. Conclusions and Relevance: This cohort study was able to ascertain individuals with germline DICER1 variants based on a genome-first approach rather than through a previously established DICER1-related phenotype. Use of the genome-first approach may complement more traditional approaches to syndrome delineation and may be an efficient approach for risk estimation.

Ovarian Sertoli-Leydig and granulosa cell tumor: comparison of epidemiology and survival outcomes.

PURPOSE: To investigate the epidemiology, clinico-pathological characteristics and outcomes of patients diagnosed with malignant ovarian Sertoli-Leydig cell tumors (SLCTs) in comparison to granulosa cell tumors (GCTs). METHODS: The National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database were accessed and patients diagnosed with a malignant SLCT and GCT between 1988 and 2013 were selected. Demographic and clinico-pathological characteristics were compared using the Mann-Whitney and chi-square tests. Overall (OS) and cancer-specific survival (CSS) rates were estimated with the Kaplan-Meier method and compared with the log-rank test. Cox hazard models were constructed to control for confounders. RESULTS: A total of 175 and 1361 patients diagnosed with SLCT and GCT, respectively, were identified. Compared to patients with GCT, those with SLCT were younger (median age 32 vs. 51 years, p < 0.001) and more likely to present with larger tumors (median size 15 vs 9.5 cm, p < 0.001) confined to the ovary (77.5% vs 69.2%, p = 0.031). Patients with SLCTs had worse CSS compared to those with GCTs, p < 0.001 (5-year rate was 76.2% vs 90.7%). After controlling for the presence of extra-ovarian disease and tumor size (≤ 10 vs > 10 cm), SCLTs were associated with a worse cancer-specific mortality compared to GCTs. CONCLUSIONS: SLCTs are extremely rare, commonly arise in premenopausal patients. They are associated with a poorer prognosis compared to GCT.

Ovarian Sertoli-Leydig Cell Tumors: Epidemiological, Clinical and Prognostic Factors.

OBJECTIVE: To describe a series of cases of ovarian Sertoli-Leydig cell tumors (SLCTs). METHODS: Retrospective review of 12 cases of SLCT treated at the Hospital do Câncer de Barretos, Barretos, state of São Paulo, Brazil, between October 2009 and August 2017. RESULTS: The median age of the patients was 31 years old (15-71 years old). A total of 9 patients (75.0%) presented symptoms: 8 (66.7%) presented with abdominal pain, 5 (41.7%) presented with abdominal enlargement, 2 (16.7%) presented with virilizing signs, 2 (16.7%) presented with abnormal uterine bleeding, 1 (8.3%) presented with dyspareunia, and 1 (8.3%) presented with weight loss. The median preoperative lactate dehydrogenase (LDH) was 504.5 U/L (138-569 U/L), alpha-fetoprotein (AFP) was 2.0 ng/ml (1.1-11.3 ng/ml), human chorionic gonadotropin (ß-hCG) was 0.6 mUI/ml (0.0-2.3 mUI/ml), carcinoembryonic antigen (CEA) was 0.9 ng/ml (0.7-3.4 ng/ml), and cancer antigen 125 (CA-125) was 26.0 U/ml (19.1-147.0 U/ml). All of the tumors were unilateral and surgically treated. Lymphadenectomy was performed in 3 (25.0%) patients, but none of the three patients submitted to lymphadenectomy presented lymph node involvement. In the anatomopathological exam, 1 (8.3%) tumor was well-differentiated, 8 (66.7%) were moderately differentiated, and 3 (25.0%) were poorly differentiated. A total of 5 (55.6%) tumors were solid-cystic, 2 (22.2%) were purely cystic, 1 (11.1%) was cystic with vegetations, and 1 (11.1%) was purely solid, but for 3 patients this information was not available. The median lesion size was 14.2 cm (3.2-23.5 cm). All of the tumors were at stage IA of the 2014 classification of the International Federation of Gynecology and Obstetrics (FIGO). A total of 2 (16.7%) patients received adjuvant treatment; 1 of them underwent 3 cycles of paclitaxel and carboplatin every 21 days, and the other underwent 4 cycles of ifosfamide, cisplatin and etoposide every 21 days. None of all of the patients had recurrence, and one death related to complications after surgical staging occurred. CONCLUSION: Abdominal pain was the most frequent presentation. There was no ultrasonographic pattern. All of the SLCTs were at stage IA, and most of them were moderately differentiated. Relapses did not occur, but one death related to the surgical staging occurred.

OBJETIVO: Descrever uma série de casos de tumores de células de Sertoli-Leydig (TCSLs) ovarianos. MéTODOS: Revisão retrospectiva de 12 casos de TCSL tratados no Hospital de Câncer de Barretos entre outubro de 2009 e agosto de 2017. RESULTADOS: A mediana de idade foi 31 anos (15­71 anos). Um total de 9 pacientes (75,0%) apresentaram sintomas: 8 (66,7%) apresentaram dor abdominal, 5 (41,7%) apresentaram aumento abdominal, 2 (16,7%) apresentaram virilização, 2 (16,7%) apresentaram sangramento uterino anormal, 1 (8,3%) apresentou dispareunia, e 1 (8,3%) apresentou emagrecimento. A mediana de desidrogenase láctica (DHL) foi 504,5 U/L (138­569 U/L), alfafetoproteína (AFP) foi 2,0 ng/ml (1,1­11,3 ng/ml), gonadotrofina coriônica humana (ß-hCG) foi 0,6 mUI/ml (0,0­2,3 mUI/ml), antígeno carcinoembrionário (CEA) foi 0,9 ng/ml (0,7­3,4) ng/ml, e antígeno cancerígeno 125 (CA-125) foi 26,0 U/ml (19,1­147,0 U/ml), todos pré-operatórios. Todos os tumores foram unilaterais e tratados cirurgicamente. Realizou-se linfadenectomia em 3 (25,0%) pacientes, porém, nenhuma das três apresentou acometimento linfonodal. No exame anatomopatológico, 1 tumor (8,3%) era bem diferenciado, 8 (66,7%) eram moderadamente diferenciados, e 3 (25,0%) eram pouco diferenciados. Um total de 5 (55,6%) tumores eram sólido-císticos, 2 (22,2%) eram puramente císticos, 1 (11,1%) era cístico com vegetações, e 1 (11,1%) era puramente sólido, mas para 3 pacientes estas informações não estavam disponíveis. A mediana da dimensão da lesão foi 14,2 cm (3,2­23,5 cm). Todos os tumores eram estádio IA de acordo com a classificação de 2014 da Federação Internacional de Ginecologia e Obstetrícia (FIGO, na sigla em inglês). Duas (16,7%) pacientes receberam adjuvância; uma realizou 3 ciclos de paclitaxel e carboplatina a cada 21 dias, e a outra 4 ciclos de ifosfamida, cisplatina e etoposide a cada 21 dias. Dentre todas as pacientes, nenhuma apresentou recidiva e houve um óbito relacionado a complicações após estadiamento cirúrgico. CONCLUSãO: Dor abdominal foi a apresentação mais frequente. Todos os TCSLs eram estádio IA e a maioria era moderadamente diferenciada. Não ocorreram recidivas, mas ocorreu um óbito relacionado ao estadiamento cirúrgico.

Ovarian sertoli-leydig cell tumors: epidemiological, clinical and prognostic factors / Tumores de células de Sertoli-Leydig ovarianos: fatores epidemiológicos, clínicos e prognósticos

Abstract Objective To describe a series of cases of ovarian Sertoli-Leydig cell tumors (SLCTs). Methods Retrospective review of 12 cases of SLCT treated at the Hospital do Câncer de Barretos, Barretos, state of São Paulo, Brazil, between October 2009 and August 2017. Results The median age of the patients was 31 years old (15-71 years old). A total of 9 patients (75.0%) presented symptoms: 8 (66.7%) presented with abdominal pain, 5 (41.7%) presented with abdominal enlargement, 2 (16.7%) presentedwith virilizing signs, 2 (16.7%) presented with abnormal uterine bleeding, 1 (8.3%) presented with dyspareunia, and 1 (8.3%) presented with weight loss. The median preoperative lactate dehydrogenase (LDH) was 504.5 U/L (138-569 U/L), alpha-fetoprotein (AFP) was 2.0 ng/ml (1.1-11.3 ng/ml), human chorionic gonadotropin (β-hCG) was 0.6 mUI/ml (0.0-2.3 mUI/ml), carcinoembryonic antigen (CEA) was 0.9 ng/ml (0.7-3.4 ng/ml), and cancer antigen 125 (CA-125) was 26.0 U/ml (19.1-147.0 U/ml). All of the tumors were unilateral and surgically treated. Lymphadenectomy was performed in 3 (25.0%) patients, but none of the three patients submitted to lymphadenectomy presented lymph node involvement. In the anatomopathological exam, 1 (8.3%) tumor was well-differentiated, 8 (66.7%) were moderately differentiated, and 3 (25.0%) were poorly differentiated. A total of 5 (55.6%) tumors were solid-cystic, 2 (22.2%) were purely cystic, 1 (11.1%) was cystic with vegetations, and 1 (11.1%) was purely solid, but for 3 patients this information was not available. The median lesion size was 14.2 cm (3.2-23.5 cm). All of the tumors were at stage IA of the 2014 classification of the International Federation ofGynecology andObstetrics (FIGO). A total of 2 (16.7%) patients received adjuvant treatment; 1 of themunderwent 3 cycles of paclitaxel and carboplatin every 21days, and the other underwent 4 cycles of ifosfamide, cisplatin and etoposide every 21 days. None of all of the patients had recurrence, and one death related to complications after surgical staging occurred. Conclusion Abdominal pain was the most frequent presentation. There was no ultrasonographic pattern. All of the SLCTs were at stage IA, and most of them were moderately differentiated. Relapses did not occur, but one death related to the surgical staging occurred.

Resumo Objetivo Descrever uma série de casos de tumores de células de Sertoli-Leydig (TCSLs) ovarianos. Métodos Revisão retrospectiva de 12 casos de TCSL tratados no Hospital de Câncer de Barretos entre outubro de 2009 e agosto de 2017. Resultados A mediana de idade foi 31 anos (15-71 anos). Um total de 9 pacientes (75,0%) apresentaram sintomas: 8 (66,7%) apresentaram dor abdominal, 5 (41,7%) apresentaram aumento abdominal, 2 (16,7%) apresentaram virilização, 2 (16,7%) apresentaram sangramento uterino anormal, 1 (8,3%) apresentou dispareunia, e 1 (8,3%) apresentou emagrecimento. A mediana de desidrogenase láctica (DHL) foi 504,5 U/L (138-569 U/L), alfafetoproteína (AFP) foi 2,0 ng/ml (1,1-11,3 ng/ml), gonadotrofina coriônica humana (β-hCG) foi 0,6 mUI/ml (0,0-2,3 mUI/ml), antígeno carcinoembrionário (CEA) foi 0,9 ng/ml (0,7-3,4) ng/ml, e antígeno cancerígeno 125 (CA-125) foi 26,0 U/ml (19,1-147,0 U/ml), todos pré-operatórios. Todos os tumores foram unilaterais e tratados cirurgicamente. Realizou-se linfadenectomia em 3 (25,0%) pacientes, por em, nenhuma das tr^es apresentou acometimento linfonodal. No exame anatomopatológico, 1 tumor (8,3%) era bem diferenciado, 8 (66,7%) eram moderadamente diferenciados, e 3 (25,0%) eram pouco diferenciados. Um total de 5 (55,6%) tumores eram sólido-císticos, 2 (22,2%) eram puramente císticos, 1 (11,1%) era cístico com vegetações, e 1 (11,1%) era puramente sólido, mas para 3 pacientes estas informações não estavam disponíveis. A mediana da dimensão da lesão foi 14,2 cm (3,2-23,5 cm). Todos os tumores eram estádio IA de acordo com a classificação de 2014 da Federação Internacional de Ginecologia e Obstetrícia (FIGO, na sigla em inglês). Duas (16,7%) pacientes receberam adjuvância; uma realizou 3 ciclos de paclitaxel e carboplatina a cada 21 dias, e a outra 4 ciclos de ifosfamida, cisplatina e etoposide a cada 21 dias. Dentre todas as pacientes, nenhuma apresentou recidiva e houve um óbito relacionado a complicações após estadiamento cirúrgico. Conclusão Dor abdominal foi a apresentação mais frequente. Todos os TCSLs eram estádio IA e a maioria era moderadamente diferenciada. Não ocorreram recidivas, mas ocorreu um óbito relacionado ao estadiamento cirúrgico.

Sex cord stromal tumours of the ovary, experience at Shifa International Hospital Islamabad.

This descriptive study was carried out at Pathology Department, Shifa International Hospital from 2007 to 2016; all sex cord stromal tumours diagnosed during this time period were included. Epithelial, germ cell and metastatic tumours were excluded from the study. A total of 1254 Ovarian tumours were brought to Shifa of which47 (4%) were labeled as sex cord stromal tumours. Of these 36( 76 %)were granulosa cell tumour (adult33, juvenile3), 7 were labeled as sertoli leydig cell tumours (15%), 3 as thecoma/ fibroma group (7%)and only one case was labeled as microcystic stromal tumour of the ovary (2%). Overall age range for sex cord stromal tumours was 42 (12-71). Immunohistochemistry was done in 41 out of 47 cases. Sex cord stromal tumours of the ovary are rare tumours comprising 4% of the total. Adult Granulosa cell tumour is the commonest tumour seen in our study.

The prevalence of DICER1 pathogenic variation in population databases.

The DICER1 syndrome is associated with a variety of rare benign and malignant tumors, including pleuropulmonary blastoma (PPB), cystic nephroma (CN) and Sertoli-Leydig cell tumor (SLCT). The prevalence and penetrance of pathogenic DICER1 variation in the general population is unknown. We examined three publicly-available germline whole exome sequence datasets: Exome Aggregation Consortium (ExAC), 1,000 Genomes (1,000 G) and the Exome Sequencing Project (ESP). To avoid over-estimation of pathogenic DICER1 variation from cancer-associated exomes, we excluded The Cancer Genome Atlas (TCGA) variants from ExAC. All datasets were annotated with snpEff and ANNOVAR and variants were classified into four categories: likely benign (LB), unknown significance (VUS), likely pathogenic (LP), or pathogenic (P). The prevalence of DICER1 P/LP variants was 1:870 to 1:2,529 in ExAC-nonTCGA (53,105 exomes) estimated by metaSVM and REVEL/CADD, respectively. A more stringent prevalence calculation considering only loss-of-function and previously-published pathogenic variants detected in ExAC-nonTCGA, yielded a prevalence of 1:10,600. Despite the rarity of most DICER1 syndrome tumors, pathogenic DICER1 variation is more common than expected. If confirmed, these findings may inform future sequencing-based newborn screening programs for PPB, CN and SLCT, in which early detection improves prognosis.

Pediatric Gynecologic Cancers.

PURPOSE OF REVIEW: Three primary categories of gynecologic cancer are found in pediatric and adolescent patients: stromal carcinomas including juvenile granulosa cell tumors and Sertoli-Leydig cell tumors, rhabdomyosarcomas arising from the vagina and cervix (sarcoma botryoides), and ovarian germ cell tumors which comprise a wide range of histologies. These entities are rare and treatment approaches have focused on decreasing late effects of chemotherapy treatment. Here, we review presentation, histologic classifications, diagnosis, and treatment recommendations for pediatric gynecologic cancers. RECENT FINDINGS: Event-free and overall survival for these cancers is high, and the goals of treatment are minimization of morbidity and preservation of fertility with unilateral salpingo-oophorectomies and limited staging. Surveillance of tumor markers after surgery is helpful in monitoring for disease progression and adjuvant chemotherapy is often reserved for patients at recurrence. Recent literature supports avoiding chemotherapy even in high-grade germ cell tumors in the pediatric population.

Ovarian Sertoli-Leydig cell tumours: How typical is their typical presentation?

Ovarian Sertoli-Leydig cell tumours (OSLCT) are rare and typically present with androgenic manifestations in women of the 2nd-3rd decade. Out of 228 diagnoses of ovarian sex cord-stromal tumours recorded at an academic institution during a 14-year period, eight women were surgically treated for OSLCT. Patient mean age was 54.8 years (range 19-81), five women being in the postmenopausal stage (62.5%). Only one woman presented with androgenic manifestations (12.5%), four with abnormal/postmenopausal uterine bleeding (50%), and three with abdominal pain (37.5%). Fertility sparing or radical surgery was performed depending on patient age and stage of disease. The only patient with an advanced disease (FIGO stage IV) was referred to palliative care postoperatively. The other seven were at FIGO stage I. Five of them were free from disease at a mean follow-up of 67 months, while the remaining two were lost at follow-up. The youngest woman of the series, treated with fertility-preserving unilateral salpingo-oophorectomy at the age of 19, had two spontaneous pregnancies and deliveries of healthy babies during a 10-year follow-up period. In conclusion, our single institution 14-year experience demonstrates that the diagnosis of OSLCT is particularly challenging since many patients are older than expected and lack androgenic manifestations. Impact statement • What is already known on this subjectOvarian Sertoli-Leydig cell tumours (OSLCT) are rare and are thought to typically present with androgenic manifestations in women of the 2nd-3rd decade. • What the results of this study addOur single institution 14-year experience shows that a high proportion of women with ovarian Sertoli-Leydig cell tumours may not present with androgenic manifestations, and many of them also are in the postmenopausal stage. Most patients have a good prognosis and fertility-preserving surgery in younger women can lead to spontaneous pregnancies and deliveries of healthy children after treatment. • What are the implications of these findings for clinical practice and/or further researchThe diagnosis of OSLCT is particularly challenging and therefore not reached before surgery in most of the cases. However, while hysterectomy with bilateral salpingo-oophorectomy and surgical staging are recommended for women with higher stage or no fertility wish, fertility-sparing surgery should be considered in younger women with early disease. Therefore, further research should focus on non-invasive diagnosis possibly by means of laboratory or imaging techniques.

Mouse ovarian tumors--a review including classification and induction of neoplastic lesions and description of several previously unreported types.

The purpose of this study is to review the pertinent literature on the incidence, methods of induction and pathogenesis of ovarian tumors of mice. Strains of mice with a high incidence of spontaneously occurring granulosa cell tumors (gct) and tubular adenomas (ta) are the C3HeB/Fe and C3HeB/De; strain HAN:NMRI developed Sertoli cell tumors and (DBA x Ce)F1 hybrids had a high incidence gct. Ninety-five percent of hybrid (C57BL/6J x C3H/HeJ)F1 WxWv mice which lack germ cells develop complex tubular adenomas. Strain LT, in which a high percentage of ovarian ova develop parthenogenetically, develops has a high incidence of teratomas. The use of hormones, castration and transplantation of the ovaries in a number of inbred strains results in a high incidence of ovarian tumors; in strain Maf/Sp gct and luteomas were induced in 82%. Irradiation with gamma rays produced a similar incidence of ovarian tumors in (C57L x A)F1 hybrids. The chemical inducing the highest incidence (92%) of ovarian tumors of mice is 9,10 Dimethyl 1,2 benzanthracene (DMBA). Recently, 4-Vinylcyclohexene was shown to induce a high incidence of ovarian tumors. A number of rare ovarian tumors were reported. Described are five androblastomas composed of either Leydig or Sertoli cells or a combination of the two cell types and a single undifferentiated androblastoma. Seven teratomas were described, three of which contained large amounts of neural tissue; another was classified as a teratoma with a parieto-visceral yolk-sac carcinoma component.