Oncological and endocrinological outcomes for children and adolescents with testicular and ovarian sex cord-stromal tumors. Results of the TGM13 National Registry.

RATIONALE: Sex cord-stromal tumors (SCST) are hormonally active and rare. The aim was to describe their endocrinological presentation and outcomes. METHOD: Patients (< 19 years) registered in the TGM13 registry between 2014 and 2021 for SCST were selected. RESULTS: Sixty-three ovarian SCST (juvenile granulosa tumor (JGT) n = 34, Sertoli-Leydig cell tumor (SLCT) n = 17, other SCST n = 12) were included. Median age was 13.1 years (0.4-17.4). Germline DICER1 pathogenic variant was present in 9/17 SLCT. Sixty-one were FIGO stage I (IC n = 14). Adjuvant chemotherapy was administered for 15. Seven had recurrence (FIGO IA n = 3, IX n = 2, III n = 2), leading to one death. With a median follow-up of 42 months (2.5-92), the 3-year progression-free survival (PFS) was 89% (95% CI 76%-95%). Median age was 6.4 years (0.1-12.9) among the 15 testicular SCST (Leydig cell tumor n = 6, JGT n = 5, Sertoli cell tumor n = 3, mixed SCST n = 1). Tumor-nodes-metastases (TNM) stage was pSI in 14. Eight underwent a tumorectomy, 7 an orchiectomy. None experienced recurrence. Endocrinological data were reviewed for 41 patients (18 prepubescent). Endocrine symptoms were present at diagnosis in 29/34 females and 2/7 males (gynecomastia). After a median follow-up of 11 months, 15 patients had persistent endocrine abnormalities: gynecomastia/breast growth (2 males, 1 prepubescent female), precocious/advanced puberty (4 prepubescent females), and hirsutism/menstruation disorders/voice hoarseness/hot flashes (8 pubescent females). The mean height at the last follow-up was within normal ranges (+0.3 standard deviation). CONCLUSIONS: SCSTs have a favorable prognosis. Tumorectomy appears safe with testicular primary. Endocrinological disorders, common at diagnosis, may persist warranting endocrinological follow-up.

Detection of FOXL2 C134W Mutation Status by a Novel BaseScope In Situ Hybridization Assay is Highly Sensitive and Specific for Adult Granulosa Cell Tumors.

Adult granulosa cell tumors (AGCTs) are a molecularly distinct group of malignant ovarian sex cord-stromal tumors (SCSTs) characterized by a nearly ubiquitous c.402C>G/p.C134W mutation in FOXL2 (hereafter referred to as "C134W"). In some cases, AGCT exhibits marked morphologic overlap with other SCSTs and has an identical immunophenotype, and molecular testing may be necessary to help confirm the diagnosis. However, molecular testing is time consuming, relatively expensive, and unavailable in many pathology laboratories. We describe the development and validation of an in situ hybridization (ISH) custom BaseScope assay for the detection of the FOXL2 C134W mutation. We evaluated 106 ovarian SCSTs, including 78 AGCTs, 9 juvenile granulosa cell tumors, 18 fibromas (cellular and conventional), and 1 SCST, not otherwise specified, as well as 53 epithelial ovarian tumors (42 endometrioid carcinomas and 11 carcinosarcomas) and 1 STK11 adnexal tumor for the presence or absence of FOXL2 wild-type and FOXL2 C134W RNA expression via BaseScope-ISH. Fifty-one tumors had previously undergone DNA sequencing of the FOXL2 gene. Across the entire cohort, the FOXL2 C134W probe staining was positive in 77 of 78 (98.7%) AGCTs. Two of 81 (2.5%) non-AGCTs also showed positive staining, both of which were epithelial ovarian tumors. The assay worked in tissue from blocks >20 years old. There was 100% concordance between the FOXL2 sequencing and BaseScope-ISH results. Overall, assessment of FOXL2 mutation status by custom BaseScope-ISH demonstrated 98.7% sensitivity and 97.5% specificity for the diagnosis of AGCT. BaseScope-ISH for FOXL2 C134W represents a reasonable alternative to sequencing, is quicker and less expensive, and is more easily incorporated than molecular testing into many pathology laboratories. It also has the advantage of requiring less tissue, and the neoplastic cells can be directly visualized on stained sections.

Molecular Biomarkers With Potential Clinical Application in Testicular Cancer.

Testicular germ cell tumors (TGCTs) and sex cord-stromal tumors (SCSTs) are the most common testicular neoplasms. The morphologic spectrum of such tumors is wide, with several histologic subtypes within each group. Testicular tumors often represent a diagnostic challenge, requiring proper identification of their biologic potential for accurate risk stratification and selection of therapy. In the era of precision medicine, molecular biomarkers are increasingly assuming a critical role in the management of patients with cancer. Given the overall rarity of certain types of testicular neoplasms, progress in biomarker research has been relatively slow. However, in recent years, we have witnessed a multitude of important contributions, including both tissue-based and liquid biopsy biomarkers, stemming from important discoveries of tumor pathobiology, accurate histopathological analysis, multi-institutional studies, and genome-wide molecular analyses of specific tumor subtypes. In this review, we provide an overview of the progress in molecular biomarkers of TGCTs and SCSTs, focusing on those with greatest potential for clinical application. In TGCTs, developmental biology has been the key to understanding these tumors and identifying clinically useful biomarkers (from classical serum tumor markers to pluripotency factors and circulating microRNAs of the 371-373 cluster). For SCSTs, studies have focused on tissue biomarkers only, and genome-wide investigations have recently contributed to a better understanding of rare phenotypes and the aggressive biological behavior of some tumors within this nosologic category. Several new biomarkers are moving toward clinical implementation in this field. Therefore, the practicing pathologist should be aware of their strengths and limitations in order to utilize them properly and maximize their clinical benefits.

Depression and anxiety in women with malignant ovarian germ cell (MOGCT) and sex cord stromal tumors (SCST): an analysis of the AGO-CORSETT database.

INTRODUCTION: The intention of this study was to evaluate the level of anxiety and depression of malignant ovarian germ cell (MOGCT) and sex cord stromal tumors (SCST) survivors and to identify possible alterable cofactors. METHODS: CORSETT was an observational, multicenter, mixed retrospective/prospective cohort study of the AGO Studygroup. Women who had been diagnosed with MOGCTs and SCSTs between 2001 and 2011 were asked to complete the Hospital Anxiety and Depression Scale (HADS) to evaluate distress. Predictors of distress (type of surgery, chemotherapy, time since diagnosis, recurrence, second tumor, pain) were investigated using multivariate linear regression analysis. RESULTS: 150 MOGCT and SCST patients with confirmed histological diagnosis completed the questionnaire median seven years after diagnosis. They had a HADS total score ≥ 13 indicating severe mental distress in 34% of cases. Patients after fertility-conserving surgery had lower probability of severe mental distress than those without fertility-conserving treatment (ß = - 3.1, p = 0.04). Pain was associated with the level of distress in uni- and multivariate analysis (coef 0.1, p < 0.01, coef. Beta 0.5). DISCUSSION: Severe mental distress was frequent in patients with MOGCT and SCST and the level of pain was associated with the level of distress. Fertility conserving therapy, however, was associated with less mental distress. Screening and treatment of pain and depression is required to improve mental well-being in survivors of MOGCT and SCST.

From diagnosis to treatment of androgen-secreting ovarian tumors: a practical approach.

About 5% of all ovarian tumors develop some form of hormonal activity. Only 1% of ovarian tumors will secrete androgens causing clinical hyperandrogenism. Most androgen-secreting neoplasms (ASN) derive from sex cord or stroma cells of the ovary and may affect both premenopausal and postmenopausal women. Typically, a patient will present reporting symptoms of rapidly increasing hyperandrogenization such as: hirsutism, acne, frontal/male pattern balding, and in severe cases even virilization. Sertoli-Leydig Cell Tumors are the most frequent ASN and constitute about 0.5% of all ovarian neoplasms. Typically affecting women under 30 years of age, these tumors are usually unilateral and benign. They are also the most common tumor in postmenopausal women suffering with hyperandrogenism. Other tumors originating from the sex-cord stroma are also known to develop in this population, but the incidence of these is much lower. Approaching suspected hyperandrogenemia and its related symptoms in a clinical setting can be a significant diagnostic challenge. When evaluating a patient for hyperandrogenism, it is important to assess the severity of symptoms but most of all it is critical to assess the time of onset and dynamics of symptom progression. Diagnostic tools including laboratory tests and imaging studies should also be engaged. When deriving a differential diagnosis for androgen-secreting ovarian tumors, adrenal gland tumors should be considered as well as typical endocrine pathologies including polycystic ovary syndrome, congenital adrenal hyperplasia, Cushing's disease, and acromegaly. Treatment options for an androgen-secreting ovarian tumors is mainly surgical, but in exceptional cases can involve pharmacotherapy alone.

"Chronic fatigue, quality of life and long-term side-effects of chemotherapy in patients treated for non-epithelial ovarian cancer: national case-control protocol study of the GINECO-Vivrovaire rare tumors INCa French network for rare malignant ovarian tumors".

BACKGROUND: Germ cell tumors and sex cord stromal tumors are rare cancers of the ovary. They mainly affect young women and are associated with a high survival rate. The standard treatment mainly involves conservative surgery combined with chemotherapy [bleomycin, etoposide and cisplatin (BEP)] depending on the stage and the prognostic factors, as for testicular cancers. As reported in testicular cancer survivors, chemotherapy may induce sequelae impacting quality of life, which has not yet been evaluated in survivors of germ cell tumors and sex cord stromal tumors. The GINECO-VIVROVAIRE-Rare tumor study is a two-step investigation aiming to assess i) chronic fatigue and quality of life and ii) long-term side-effects of chemotherapy with a focus on cardiovascular and pulmonary disorders. METHODS: Using self-reported questionnaires, chronic fatigue and quality of life are compared between 134 ovarian cancer survivors (cancer-free ≥2 years after treatment) treated with surgery and chemotherapy and 2 control groups (67 ovarian cancer survivors treated with surgery alone and 67 age-matched healthy women). Medical data are collected from patient records. In the second step evaluating the long-term side-effects of chemotherapy, a subgroup of 90 patients treated with chemotherapy and 45 controls undergo the following work-up: cardiovascular evaluation (clinical examination, non-invasive cardiovascular tests to explore heart disease, blood tests), pulmonary function testing, audiogram, metabolic and hormonal blood tests. Costs of sequelae will be also assessed. Patients are selected from the registry of the INCa French Network for Rare Malignant Ovarian Tumors, and healthy women by the 'Seintinelles' connected network (collaborative research platform). DISCUSSION: This study will provide important data on the potential long-term physical side-effects of chemotherapy in survivors of Germ Cell Tumors (GCT) and Sex Cord Stromal Tumors (SCST), especially cardiovascular and pulmonary disorders, and neurotoxicity. The identification of long-term side-effects can contribute to adjusting the treatment of ovarian GCT or SCST patients and to managing follow-up with adapted recommendations regarding practices and chemotherapy regimens, in order to reduce toxicity while maintaining efficacy. Based on the results, intervention strategies could be proposed to improve the management of these patients during their treatment and in the long term. TRIAL REGISTRATION: This trial was registered at clinicaltrials.gov : 03418844 , on 1 February 2018. This trial was registered on 25 October 2017 under the unique European identification number (ID-RCB): 2017-A03028-45. Recruitment Status: Recruiting. PROTOCOL VERSION: Version n° 4.2 dated from Feb 19, 2021. TRIAL SPONSOR: Centre François Baclesse, 3 avenue du Général Harris, F-14076 Caen cedex 05, France.

Consensus recommendations from the EXPeRT/PARTNER groups for the diagnosis and therapy of sex cord stromal tumors in children and adolescents.

As part of the European Union-funded project designated Paediatric Rare Tumours Network - European Registry (PARTNER), the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT) is continuously developing consensus recommendations in order to harmonize standard care for very rare solid tumors of children and adolescents. This paper presents the internationally recognized recommendations for the diagnosis and treatment of sex cord stromal tumors (SCST). The clinical approach to sex cord stromal tumors of the testis (TSCST) and ovary (OSCST) depends on histological differentiation and tumor stage. Virtually all TSCSTs present as localized nonmetastatic tumors, with excellent prognosis after complete resection. In contrast, the prognosis of OSCSTs may be adversely affected by tumor spillage during surgery or presence of metastases. In these cases, cisplatin-based chemotherapy is recommended. Of note, some SCSTs may develop in the context of tumor predisposition syndromes, for example, DICER-1, so that specific follow-up is indicated. SCSTs should be diagnosed and treated according to standardized recommendations that include reference pathology, genetic testing for tumor predisposition syndromes in selected cases, and stratified adjuvant chemotherapy in patients with unfavorable risk profile. To ensure high quality of diagnosis and therapy, patients should be enrolled into prospective registries.

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.

Gynecologic and reproductive health in patients with pathogenic germline variants in DICER1.

OBJECTIVE: Germline pathogenic variation in DICER1 underlies a tumor-predisposition disorder with increased risk for cervical embryonal rhabdomyosarcoma and ovarian sex-cord stromal tumors, particularly Sertoli-Leydig cell tumors. The gynecologic and reproductive health of these females has not yet been described. METHODS: All female subjects recruited from November 2011 to July 2018 participating in an epidemiologic study of families with pathogenic DICER1 germline variation were included in this cross-sectional analysis. Participant evaluation included obstetric-gynecologic history, physical examination, hormone testing, pelvic ultrasound and record review. RESULTS: Of 64 females aged 2-72 years, fifteen underwent treatment for pleuropulmonary blastoma as children and three were treated for cervical embryonal rhabdomyosarcoma. Of nine patients reporting a history of ovarian tumors, all presented with virilization or amenorrhea; eight occurred in adolescence. Post-pubertal females with no history of ovarian tumors experienced normal pubertal development, reported regular menstrual cycles, were fertile and underwent natural menopause at median age of 52 years. Thirty-two of 33 women who tried to conceive successfully delivered liveborn children. Of these 32, 10 experienced pregnancy-related thyroid enlargement resulting in thyroidectomy within one year of pregnancy; nine others had undergone pre-pregnancy thyroidectomy. CONCLUSION: In these DICER1-carrier females, DICER1-related gynecological tumors occurred during childhood or adolescence in some after which women generally experienced healthy reproductive lives. Individual education and screening for these tumors is warranted. The high rate of DICER1-related multinodular goiter resulting in pre- and post-pregnancy thyroidectomy underscores the importance of thyroid monitoring during pregnancy to ensure maternal and fetal wellbeing.

Results from a Monocentric Long-Term Analysis of 23 Patients with Ovarian Sertoli-Leydig Cell Tumors.

BACKGROUND: Sertoli-Leydig cell tumors (SLCTs) represent less than 0.5% of ovarian tumors. Because of the rarity of this tumor and its peak in frequency at around 25 years of age, this study aimed to describe SLCT management strategies. OBJECTIVE: The objective of this study was to determine the management (i.e., conservative surgery and adjuvant chemotherapy) of ovarian SLCTs. RESULTS: This retrospective analysis included 23 patients treated for ovarian SLCTs. A centralized pathologic review of the tumors was conducted. Patients were referred to or treated in our institution for an ovarian SLCT between 1994 and 2015. The median age at diagnosis was 33 years (range, 4-82 years). According to the 2014 Federation of Gynecology and Obstetrics classification, tumors were classified as stage Ia (n = 15: well differentiated, n = 1; of intermediate differentiation, n = 8; undifferentiated, n = 4; and undefined, n = 2), stage Ib (n = 1), stage Ic1 (n = 5), stage IIb (n = 1), and stage IIIc (n = 1). Surgery was conservative in 13 patients (Ia, n = 7; Ib, n = 1; Ic1, n = 5) and radical in 10 patients (Ia, n = 8; IIb, n = 1; IIIc, n = 1). Seven patients received adjuvant chemotherapy with a cisplatin-based regimen (Ia, n = 2; Ic1, n = 3; IIb, n = 1) or docetaxel + gemcitabine (IIIc, n = 1). Median follow-up was 61 months (range, 15-252 months). Eight patients experienced a relapse (Ia, n = 2; Ib, n = 1; Ic1, n = 3; IIb, n = 1; IIIc, n = 1). Of these, six had at least one peritoneal carcinomatosis, and four died (Ic1, n = 2; IIb, n = 1; and Ia, n = 1). Two patients had a local relapse (one uterus and one ovary) and survived without disease after relapse treatment. The median time between the initial treatment and relapse was 28 months (range 9-70). CONCLUSION: Conservative surgery was safe for patients with stage Ia ovarian SLCTs. The place of conservative surgery for stage Ic1 remains to be defined. The best chemotherapy regimen remains to be defined. IMPLICATIONS FOR PRACTICE: For stage Ia disease, conservative surgery (in women of reproductive age) was safe and effective for treating ovarian Seroli-Leydig cell tumors. Adjuvant chemotherapy should be proposed for stage Ia when poor prognostic factors are present (poor differentiation, retiform pattern, or heterologous elements). For stage Ic1 and more severe stages, radical surgery and adjuvant chemotherapy should be considered. The combination of bleomycin, etoposide, and cisplatin was the most frequently used regimen, but the best chemotherapy regimen remains to be defined.

Detection of Aristaless-related homeobox protein in ovarian sex cord-stromal tumors.

OBJECTIVE: To examine the potential of ARX as a novel biomarker of ovarian endometriosis and other ovarian pathologies. METHODS: The mRNA level of ARX in ovarian endometriosis and normal endometrium samples was determined by real-time PCR, while the protein level was determined by Western blotting and immunohistochemical staining. Immunohistochemical analysis was performed on nearly 200 tissue samples of different ovarian pathologies. GraphPad Prism was used for statistical analysis. RESULTS: The expression of ARX was significantly increased in ovarian endometriosis samples as compared to normal endometrium. Also Western blotting data showed higher ARX levels in the ovarian endometriosis samples versus normal endometrium. Immunohistochemical analysis revealed that the protein is localized in the ovarian stroma and does not originate from endometriosis. Further immunohistochemical analysis performed on several different non-neoplastic and neoplastic ovarian tissue samples revealed that in the non-neoplastic ovary ARX protein is present only in the stromal cells and their derivates (luteinized stromal cells, theca and Leydig cells) and not in granulosa cells, oocites, surface epithelium or rete ovarii, while all stromal and sex cord tumors showed strong nuclear staining for ARX. All other primary or metastatic epithelial tumors of the ovary were ARX negative. CONCLUSIONS: ARX is not associated with endometriosis and cannot be used as a biomarker for ovarian endometriosis. ARX is present in ovarian stroma and cells derived from ovarian stroma as well as in all types of sex cord-stromal tumors of the ovary and could thus be used as a marker for sex cord-stromal differentiation in ovarian tumors.

[Fibrothecoma of the testis: A case report in an adult]. / Fibrothécome testiculaire : à propos d'un cas chez un adulte.

Fibrothecal tumors belong to sex cord/stromal tumors (SCSTS). They represent 1 to 4.7 % of the organics tumors of ovary (Chechia et al., 2008) but are extremely rare in the testis, with only a few cases described in the literature. We report a new case of a fibrothecoma in the testis in an adult. The extemporaneous diagnosis was made in the same time of the surgical intervention. The castration has been avoided.

Prevalence of lymph node metastasis and prognostic significance of lymphadenectomy in apparent early-stage malignant ovarian sex cord-stromal tumors.

OBJECTIVE: The aim of this retrospective population-based study was to investigate the prevalence of lymph node metastasis in patients with apparent early stage malignant sex cord-stromal tumors (SCSTs) and the effect of regional lymph node sampling/lymphadenectomy (LND) on their survival. METHODS: A cohort of patients diagnosed with malignant SCSTs between 1988 and 2012 was drawn from the National Cancer Institute's Surveillance, Epidemiology, and End Results database. Overall and Cancer Specific Survival, stratified by performance of LND, were calculated following generation of Kaplan-Meier curves. Comparisons were made using the log-rank and Breslow tests. A multivariate Cox proportional analysis was performed to determine the effect of LND on overall mortality. RESULTS: A total of 1156 patients with SCST met the inclusion criteria; 1000 (86.5%) and 156 (13.5%) patients had apparent stage I and II disease, respectively. LND was performed in 572 (49.5%) patients. Lymph node metastases were pathologically confirmed in 19 patients (3.3%). Five-year cancer specific survival (CSS) was similar, 92.7% and 94.7%, for patients who did or did not undergo LND, respectively. According to multivariate analysis overall mortality did not differ between the two groups after controlling for age, histology and apparent stage. CONCLUSIONS: Regional lymphatic mode metastasis in patients with apparent early stage SCSTs is uncommon and lymphadenectomy did not confer a survival benefit in this cohort.

Sex-Cord Stromal Tumors in Children and Teenagers: Results of the TGM-95 Study.

BACKGROUND: We present the results of the TGM-95 study for gonadal sex-cord stromal tumors (SCT). METHODS: Between 1995 and 2005, children (<18 years) with gonadal SCT were prospectively registered. Primary gonadal resection was recommended whenever feasible. Patients with disseminated disease or an incomplete resection received neoadjuvant or adjuvant VIP chemotherapy (etoposide, ifosfamide, cisplatinum). RESULTS: Thirty-eight children with ovarian SCT were registered. Median age was 10.7y. Endocrine symptoms were present in 21 cases. The histological diagnoses were as follows: juvenile (23) and adult (3) granulosa cell tumors, Sertoli-Leydig cell tumors (11), and mixed germ cell SCT (1). An initial oophorectomy ± salpingectomy led to complete resection in 23 patients who did not receive adjuvant treatment; two of them relapsed: one achieved second complete remission whereas the other one died of disease. Fifteen patients had tumor rupture and/or malignant ascites: 11 received chemotherapy and did not relapse, four did not receive chemotherapy and relapsed with a fatal outcome in two cases. With a median follow-up of 5.9y, the 5-y EFS and OS rates were respectively 85% and 94%. Eleven patients had localized testicular tumors (median age 0.83y): juvenile granulosa cell tumors (4), Sertoli or Leydig cell tumors (5) and not otherwise specified SCT (2). Treatment was surgery alone with an inguinal orchiectomy. None have relapsed (median follow-up: 5.4y). CONCLUSIONS: Childhood SCT carry favorable prognosis. In ovarian SCT, surgery should be complete and non-mutilating. Adjuvant chemotherapy efficiently prevents recurrences in cases of tumor rupture. In childhood testicular SCT, the prognosis is excellent with an inguinal orchiectomy, prompting the debate on testis-sparing surgery.

Ovarian steroid cell tumor, not otherwise specified: a clinicopathological and immunohistochemical experience of 12 cases.

AIM: Ovarian steroid cell tumors, not otherwise specified (SCT-NOS) are very rare neoplasms. No large study has been performed in Pakistan to establish the clinicopathological spectrum and immunohistochemical behavior in our region. The purpose of our study was to determine the various clinicopathological and immunohistochemical features of ovarian SCT-NOS along with follow-up in our institution. METHODS: This was a retrospective observational study. The study was conducted in the Section of Histopathology, Aga Khan University Hospital, Karachi, Pakistan. All reported cases of ovarian SCT-NOS occurring during January 1992 to August 2013 were retrieved. The slides were reviewed and patient demographics, and clinical and pathological features were noted with proforma software. SPSS version 19 was used for all analyses. Data is expressed as absolute values and percentages. RESULTS: A total of 12 SCT-NOS (2.3%) out of 528 ovarian sex cord stromal tumors were retrieved. The age range was 3-70 years, with mean of 40.75 years. The tumors ranged 2.5-13 cm in size, with a mean size of 6.1 cm. One patient had bilateral tumors. All of the tumors were positive for inhibin and calretinin. Four tumors were negative for Mic-2 (CD99). In two patients, the tumor recurred. Only one patient who had worse pathological features received adjuvant chemotherapy. CONCLUSION: Steroid cell tumors are very rare ovarian tumors in the Pakistani population, mostly presenting in adulthood. Diverse histological differentials exist so special stains and immunohistochemical stains are needed to distinguish these from other tumors.

Impact of a second opinion using expression and molecular analysis of FOXL2 for sex cord-stromal tumors. A study of the GINECO group & the TMRO network.

OBJECTIVE: Ovarian sex cord-stromal tumors (SCSTs) are rare and their diagnosis is often difficult to establish. Recently, immunostaining and molecular analysis for Forkhead box L2 (FOXL2) have been developed in this pathology. This study aims to assess the benefit of an algorithm incorporating these new tools for a better diagnosis and classification of SCSTs METHODS: Seventy-two tumors with a potential diagnosis of SCSTs were addressed by 37 different pathologists to one French rare ovarian tumor expert center, member of the Rare Malignant Ovarian Tumor network (TMRO). Then a "second opinion" (SO) through an algorithm incorporating immunostaining (IHC) and molecular analysis of FOXL2 was performed for all these cases. This algorithm was then validated by all pathologists of the TMRO network. RESULTS: After a second opinion including molecular analysis and immunostaining for FOXL2 the initial diagnosis was changed in 15 of 72 samples (21%). FOXL2 mutation was present in 44 out of 47 adult granulosa cell tumors (94%), in 3 out of 8 Thecomas (37%), in 1 out of 10 Sertoli-Leydig cell tumors (SLSTs) (10%) and in 3 out of 5 undifferentiated-SCSTs (Und-SCSTs) (60%). Immunoexpression of FOXL2 was available in 45 cases of SCSTs: FOXL2 was expressed in 44 of them (98%). CONCLUSIONS: A second opinion in an expert center for all cases of SCSTs is fundamental to get an optimal classification of these rare tumors. This second opinion could be performed with an algorithm which integrates FOXL2 mutation and expression status of FOXL2 in order to standardize the practice.

Intrauterine factors and risk of nonepithelial ovarian cancers.

OBJECTIVE: The majority of ovarian tumors in girls and young women are nonepithelial in origin. The etiology of nonepithelial ovarian tumors remains largely unknown, and intrauterine exposures may play an important role. We examined the association of perinatal factors with risk of nonepithelial ovarian tumors in girls and young women. METHODS: National cohort study of 1,536,057 women born in Sweden during 1973-2004 and followed for diagnoses of nonepithelial ovarian tumors through 2009 (attained ages 5-37 years). Perinatal and maternal characteristics and cancer diagnoses were ascertained using nationwide health registry data. RESULTS: 147 women were diagnosed with nonepithelial ovarian tumors in 31.6 million person-years of follow-up, including 94 with germ cell tumors and 53 with sex-cord stromal tumors. Women born preterm (<37 weeks of gestation) had a significantly increased risk of developing nonepithelial ovarian tumors (adjusted hazard ratio 1.86, 95% CI 1.03-3.37; p=0.04). Histological subgroup analyses showed that preterm birth was associated with increased risk of sex-cord stromal tumors (4.39, 2.12-9.10; p<0.001), but not germ cell tumors (0.68, 0.21-2.15; p=0.51). No significant associations were found with fetal growth, birth order, and maternal age at birth. CONCLUSIONS: This large cohort study provides the first evidence that preterm birth is a risk factor for developing sex cord-stromal tumors. Ovarian hyperstimulation in response to high gonadotropin levels in preterm girls could mediate disease risk through the proliferative and steroidogenic effects of FSH and LH on granulosa and theca cells, from which most sex-cord stromal tumors are derived.

CT-based radiomic analysis for categorization of ovarian sex cord-stromal tumors and epithelial ovarian cancers.

PURPOSE: To evaluate the diagnostic potential of radiomic analyses based on machine learning that rely on contrast-enhanced computerized tomography (CT) for categorizing ovarian sex cord-stromal tumors (SCSTs) and epithelial ovarian cancers (EOCs). METHODS: We included a total of 225 patients with 230 tumors, who were randomly divided into training and test cohorts with a ratio of 8:2. Radiomic features were extracted from each tumor and dimensionally reduced using LASSO. We used univariate and multivariate analyses to identify independent predictors from clinical features and conventional CT parameters. Clinic-radiological model, radiomics model and mixed model were constructed respectively. We evaluated model performance via analysis of the receiver operating characteristic (ROC) curve and area under ROC curves (AUCs), and compared it across models using the Delong test. RESULTS: We selected a support vector machine as the best classifier. Both radiomic and mixed model achieved good classification accuracy with AUC values of 0.923/0.930 in the training cohort, and 0.879/0.909 in the test cohort. The mixed model performed significantly better than the model based on clinical radiological information, with AUC values of 0.930 versus 0.826 (p = 0.000) in the training cohort and 0.905 versus 0.788 (p = 0.042) in the test cohort. CONCLUSION: Radiomic analysis based on CT images is a reliable and noninvasive tool for identifying SCSTs and EOCs, outperforming experience radiologists.

A Sertoli-Leydig ovarian tumor presenting as ovarian torsion: A case report.

Torsion occurs as a complication in 10% of cases of ovarian tumors. It predominantly occurs in benign ones, while malignant tumors are less prone to torsion. Sertoli-Leydig cell tumors are highly unusual sex cord-stromal tumors of the ovary, accounting for less than 0.2% of all ovarian cancers. A 39-year-old patient presented to the emergency department with a Sertoli-Leydig cell tumor diagnosed due to ovarian torsion. The clinical presentation was characterized by abdominal pain. Ultrasound indicated signs of torsion, and torsion of the right ovary was subsequently confirmed during laparotomy. A salpingo-oophorectomy was performed, and histological examination revealed a moderately differentiated Sertoli-Leydig cell tumor. Sertoli-Leydig cell tumors often present with hormone-related or non-hormonal symptoms. Surgery plays a crucial role in both diagnosis and treatment. Postoperative treatment is not necessary for well-differentiated Sertoli-Leydig cell tumors in stage IA-IB. However, patients with grade 2-3 disease, advanced stage, or heterologous elements may consider adjuvant treatment. As these tumors are rare, this case contributes to the documentation of Sertoli-Leydig cell tumors, with a case diagnosed due to ovarian torsion. The case highlights the importance of establishing international registries of Sertoli-Leydig cell tumor cases for standardized management.

An extensive immunohistochemical analysis of 290 ovarian adult granulosa cell tumors with 29 markers.

The current knowledge about the immunohistochemical features of adult granulosa cell tumor (AGCT) is mostly limited to the "traditional" immunohistochemical markers of sex cord differentiation, such as inhibin, calretinin, FOXL2, SF1, and CD99. Knowledge about the immunohistochemical markers possibly used for predictive purpose is limited. In our study, we focused on the immunohistochemical examination of 290 cases of AGCT classified based on strict diagnostic criteria, including molecular testing. The antibodies used included 12 of the "diagnostic" antibodies already examined in previous studies, 10 antibodies whose expression has not yet been examined in AGCT, and 7 antibodies with possible predictive significance, including the expression of HER2, PD-L1, CTLA4, and 4 mismatch repair (MMR) proteins. The results of our study showed expression of FOXL2, SF1, CD99, inhibin A, calretinin, ER, PR, AR, CKAE1/3, and CAIX in 98%, 100%, 90%, 78%, 45%, 41%, 94%, 82%, 26%, and 9% of AGCT, respectively. GATA3, SATB2, napsin A, MUC4, TTF1, and CD44 were all negative. PTEN showed a loss of expression in 71% of cases and DPC4 in 4% of cases. The aberrant staining pattern (overexpression) of p53 was found in 1% (3/268) of cases, 2 primary tumors, and 1 recurrent case. Concerning the predictive markers, the results of our study showed that AGCT is microsatellite stable, do not express PD-L1, and are HER2 negative. The CTLA4 expression was found in almost 70% of AGCT tumor cells.