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Sertoli-Leydig cell tumors (SLCTs) are rare ovarian sex cord-stromal neoplasms. The only known recurrent genetic abnormality is DICER1 mutation, with rare mutations reported in FOXL2. We set out to establish a molecular classifier using DICER1 and FOXL2 somatic mutation status and clinicopathologic features in 42 SLCTs. Five tumors (12%) were well differentiated, 31 (74%) moderately differentiated, and 6 (14%) poorly differentiated. Eight (19%) had heterologous elements, and 2 (5%) showed retiform differentiation; all 10 were moderately differentiated. DICER1 RNase IIIb domain mutations were identified in 18/41 (44%; 17 moderately, 1 poorly differentiated), including all cases with retiform or heterologous elements. FOXL2 c.402CG (p.C134W) mutation was identified in 8/42 (19%) tumors (5 moderately, 3 poorly differentiated). DICER1 and FOXL2 mutations were mutually exclusive. Median age for the cohort was 47 years (range, 15 to 90 y). Patients with DICER1 mutations were younger (median, 24.5 y; range, 15 to 62 y) than patients with FOXL2 mutation (median, 79.5 y; range, 51 to 90 y) (P0.0001). Nine of 10 tumors with retiform or heterologous elements occurred in premenopausal patients (median, 26.5 y; range, 15 to 57 y). Patients with tumors that were wild type for DICER1 and FOXL2 (15/42, 37%) had an intermediate age (median, 51 y; range, 17 to 74 y). All tumors were FOXL2 positive by immunohistochemistry. Patients with FOXL2 mutation trended toward presenting more often with abnormal bleeding (P=0.13); DICER1-mutant patients trended toward having more androgenic symptoms (P=0.22). Our data suggest at least 3 molecular subtypes of SLCT with distinct clinicopathologic features: DICER1 mutant (younger, more androgenic symptoms, moderately/poorly differentiated, retiform or heterologous elements), FOXL2 mutant (postmenopausal, abnormal bleeding, moderately/poorly differentiated, no retiform or heterologous elements), and DICER1/FOXL2 wild type (intermediate age, no retiform or heterologous elements, including all well-differentiated tumors).

Background The sex cord-stromal tumors are relative rare, comprising 5-8% of all ovarian neoplasms. Methods The study androgen tumors and a description of three cases: Leydig tumor, steroid cell (NOS) tumor and Sertoli-Leydig tumor. Results Twelve patients were menopausal and one patient of reproductive age. In all cases, regardless of the histological variety, women presented symptoms of hyperandrogenism and virilization. All had increased values of total testosterone. In all cases surgical treatment was performed, with favorable clinical and biochemical evolution. Conclusions Sex cord stromal tumors of the ovary are rare, and can be characterized by virilization for most patients. The majority of the tumors are benign, with few cases having low-grade malignancy. The suspicion and correct evaluation of these women will lead to an early diagnosis and improve their quality of life.

Sex cord-stromal tumors of the ovary (SCSTO) comprise a heterogeneous and fascinating group of neoplasms with diverse clinicopathological features, including benign lesions as well as tumors with malignant potential. Clinically, SCSTO may be associated with hyperestrogenic or androgenic function as a result of steroid hormone production by the tumor cells.Histological diagnosis may be challenging due to complex and sometimes overlapping morphological features of the various tumor types. A panel of immunohistochemical sex cord markers (e. g. inhibin-α, calretinin) has proven to be helpful in confirming the cellular lineage of SCSTO and differentiating them from other sex cord-like ovarian lesions. Recently, molecular analysis of SCSTO has led to the discovery of specific molecular events such as FOXL2 and DICER1 mutations. In selected diagnostically challenging cases, mutation analysis of FOXL2 and DICER1 may be helpful in the differential diagnosis. Molecular analysis is also expected to help advance the classification of SCSTO, and it may hold prognostic potential and form the basis for future type-specific therapies.This review focuses on the clinicopathological as well as the molecular features of adult and juvenile granulosa cell tumors (AGCTs and JGCTs) as well as Sertoli-Leydig cell tumors (SLCTs), these being the most relevant lesions with malignant potential in the SCSTO category. In addition, recently published molecular findings among rare ovarian gynandroblastomas (GABs) are described, which may also impact the future classification of SCSTO.

Sertoli Leydig cell tumor of the ovary, is a rare neoplasm from the group of sex cord-stromal tumors of the ovary, accounting for less than 1% of all ovarian tumors. Among the Sertoli Leydig cell tumors, we distinguish a separate group of tumors secreting α-fetoprotein (AFP). The young 24-year-old woman presented to the Clinical Department of Gynaecological Endocrinology at the University Hospital in Krakow due to secondary amenorrhea, hirsutism and worsening abdominal pain for several months. During the admission draws attention was drawn to the abnormal level of testosterone, AFP and the revised structure of the ovary in the ultrasound. After a preliminary diagnosis, expanded pelvic MRI was performed, which found an isolated tumor derived from Sertoli Leydig cells. The patient was enrolled to unilaterally remove the right ovary by laparotomy. Histopathological examination and immunohistochemical staining confirmed the diagnosis of Sertoli Leydig cells tumor, and in pathological examination we found glandular mucosa cells of the colon. Owing to scientific reports on the stromal tumors of the ovary, we decided to perform genetic testing and verify the patient’s karyotype. In the follow-up 90 days after the surgery, levels of testosterone and AFP were correct. In case of Sertoli Leydig cell tumors, especially in young women of childbearing potential, special attention should be paid to Anti-Mullerian hormone testing before surgery, as well as genetic diagnostics to exclude disorders of sex development.

Sex cord-stromal tumors (SCSTs ) are rare neoplasms derived from, or display differentiation towards primitive sex cords or stromal cells. The tumors in this category exhibit a great diversity of patterns with a long array of mimickers, and accordingly may pose a diagnostic challenge. Some of the derivative cells are involved in hormone production under physiologic conditions; therefore, many tumors under this category produce excess hormones, which may lead to the development of hormone-mediated syndromes. There are clear age-related differences in the incidence of several tumors in this category, with juvenile granulosa cell tumors, for example, occurring primarily in the

5547 Background: Sertoli-Leydig cell tumors (SLCT) are rare ovarian sex cord-stromal tumors which occur primarily in adolescents and young adults and are associated with DICER1 pathogenic variants. Methods: Informed consent for participation in the International PPB/ DICER1 or OTST Registry was obtained. When available, pathology was centrally reviewed. Staging was evaluated by Registry review using the International Federation of Gynecology and Obstetrics (FIGO) classification system. Results: Eighty-three patients with stage I SLCT were enrolled. Median age at diagnosis was 15 (range 1-60) years. Most (57/83) patients had germline DICER1 testing; 35/57 (61%) had germline pathogenic variants. Fifty-six patients had Ia and 27 had Ic SLCT. The distribution of patients receiving chemo based on histology and stage is displayed in Table. One patient with poorly differentiated stage Ia SLCT with sarcomatous elements and no chemo at diagnosis recurred 6 months after surgery and died of disease. Three patients with local diagnosis of stage Ia SLCT, with data unavailable for Registry confirmation of stage, developed a subsequent SLCT 33 to 74 months after diagnosis; of these, 2 died, and 1 remains in treatment for recurrence. Available records and molecular testing in these 3 cases have not provided a distinction between recurrent and metachronous disease. Excluding the latter 3 patients, 3-year overall survival was 97.3% for stage Ia SLCT. Six patients with stage Ic SLCT recurred (Stage Ic1=5 and Stage Ic2=1) with a median time to recurrence of 25 (range 3-53) months. In stage Ic1, 18% (2/11) recurred after upfront chemo compared to 33% (3/9) after surgery alone. Of the 5 patients with stage Ic1 disease that recurred, 4 had intermediate and 1 had poorly differentiated SLCT. One patient had sarcomatous elements and 2 received upfront chemo. Two of the 5 patients are alive, neither received upfront chemo. One patient with poorly differentiated stage Ic2 SLCT with sarcomatous elements and no upfront chemo recurred and died of disease. Three-year event free and overall survival were 86.9 and 88.6% for stage Ic SLCT. Four patients had metachronous SLCT in the contralateral ovary confirmed by clinical review or somatic testing at a median time from diagnosis of 33 (range 28-104) months. All 4 have germline pathogenic variants and no evidence of disease at last follow-up. Conclusions: Individuals with early stage SLCT generally fare well, however, ongoing surveillance for recurrence and metachronous disease is indicated. Novel therapies are needed to address recurrent SLCT.[Table: see text]

Rational: Ovarian sertoli-leydig cell tumor (OSLCT) is extremely rare. We reported a OSLCT case in whom postmenopausal vaginal bleeding was the first symptom. Patient concerns: The patient came to our hospital due to postmenopausal vaginal bleeding. Diagnoses: Serum tumor markers and color Doppler ultrasound for her pelvic cavity were negative. The patient was finally diagnosed with left OSLCT by pathology. It was difficult to make a definite diagnosis before operation, the diagnosis of OSLCT required postoperative pathology in the patients. Interventions: the patient underwent laparoscopic hysterectomy+bilateral adnexectomy+lysis of pelvic adhesions. Outcomes: Postoperative laboratory examinations were normal. The patient was discharged from our hospital on the seventh day after operation and came to our hospital for follow-up check in April 2020. Physical and laboratory examinations were normal. Lessons: OSLCT can show different endocrine abnormalities, which are related to the various types of tumor tissues. Missed diagnosis and misdiagnosis are likely to occur in the patients who only have elevated serum testosterone. For the menopausal women with elevated serum testosterone, ovarian tumor shoule be highly suspected after excluding adrenal gland-related diseases.

To explore the clinical features, imaging findings, and pathological manifestations of ovarian Sertoli-Leydig cell tumors (SLCTs). The clinical and pathological manifestations, tumor location, size, morphology, vascularity, computed tomography (CT) density, magnetic resonance imaging (MRI) signal intensity, and contrast enhancement patterns in five cases with SLCTs were retrospectively reviewed. SLCTs most commonly occurred in young women. Virilization was observed in three cases (60%). All five tumors were unilateral and oval or round, with a clear boundary. The solid part of the tumor was isoattenuated on the conventional CT scan, and showed isoattenuation or slight hypoattenuation relative to adjacent myometrium on T1 weighted imaging (T1WI) and T2 weighted imaging (T2WI). On contrast-enhanced images, three tumors showed marked enhancement. DICER1 hotspot mutations were commonly seen in SLCTs. A highly vascularized mass with low signal intensity (SI) of the solid part on T2WI and androgen overproduction symptoms may suggest an SLCT.

Key Points Question What are the prevalence, risk, and phenotypic spectrum of individuals with a germline putative loss-of-function (pLOF) variant in DICER1 according to a genome-first approach in a population-scale cohort? Findings In this cohort study, DICER1 pLOF variants were more than twice as common (even after adjustment for relatedness) than previously observed. Malignant tumors were observed in 16% of participants with a DICER1 pLOF variant, which is comparable to the frequency of neoplasms in the largest phenotype-first DICER1 studies published to date. Meaning The genome-first approach complements more traditional approaches to syndrome delineation and may be an efficient approach for risk estimation in monogenic disorders., 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., This cohort study examines the prevalence and penetrance of germline DICER1 putative loss-of-function variants via genome-first ascertainment.

The purpose of the current study was to compare prognostic outcomes between patients with high-grade ovarian Sertoli-Leydig cell tumors (SLCTs) and those with other low-grade SLCTs. We retrospectively reviewed medical records for 24 patients pathologically diagnosed with SLCTs between 2006 to 2019 at two institutions. The patients were grouped according to pathological grade: SLCT was classified as grade 1, well differentiated; grade 2, intermediated differentiated; or grade 3, poorly differentiated (Meyer's classification). Statistical analysis was performed to compare survival outcomes according to pathological grade. The median patient age was 42.5 years (range 16–75). Eighteen patients (75%) were International Federation of Gynecology and Obstetrics stage I, and none were diagnosed in stage IV. Nine patients (37.5%) were grade 3, and 15 patients (63.5%) were grades 1–2. When comparing clinical baseline characteristics of the grade 1–2 group with those of the grade 3 group, only serum CA125 level at diagnosis was significantly higher in the grade 3 group (38.34 vs. 382.29, p=0.002). Five patients experienced recurrence of grade 3 disease, while no recurrence was reported in grade 1–2 disease. Four of the five recurrent patients died. In result, grade 3 ovarian SLCT showed significantly poorer prognosis than grade 1–2 disease (overall survival, hazard ratio=14.25, 95% confidence interval=1.881–108.0; log-rank p=0.010). Our findings were consistent with the concept that patients with stage I/grade 1–2 tumors have a good prognosis without adjuvant chemotherapy. Since grade 3 ovarian SLCT appears to be relatively more fatal than grade 1 or 2, patients with grade 3 SLCT might require more aggressive surgical intervention and post-treatment surveillance.

Background DICER1 syndrome is a hereditary cancer predisposition syndrome which is related DICER1 gene and may present a variety of manifestations. Case A prepubertal girl with ovarian Sertoli-Leydig cell tumor, thyroid follicular carcinoma, embryonal rhabdomyosarcoma of the cervix and lung cyst is presented. Genetic analysis demonstrated mutation (c.3377delC, c.71delC) in 14q32.13 loci and confirmed the diagnosis of DICER1 syndrome. Conclusion The case is presented to emphasize the importance of early diagnosis of alterations in DICER1 gene and close follow-up for the development of DICER1 syndrome related pathologies, and necessity for genetic evaluation of the family.

Sertoli-Leydig cell tumors (SLCTs) are rare and heterogeneous group of ovarian neoplasms which belong to the sex cord-stromal category of tumors. SLCTs are classified into well, intermediate, and poorly differentiated types. Retiform growth pattern and heterologous elements are commonly found in moderately and poorly differentiated tumors. SLCTs are usually encountered in the third decade of life and patients most often present with virilization. Here, we report two cases of SLCTs of the ovary, both in 2-year-old girls without any hormonal symptoms. The first case was a retiform variant of Sertoli-Leydig cell tumor and the second was a well-differentiated SLCT. Because of its wide spectrum of morphology, several tumors enter in the differential diagnosis and the presence of heterologous elements further complicates the diagnosis. Here, we have described the morphological characteristics of these tumors and discussed their differential diagnoses. SF-1, WT1, and α-inhibin are useful immunostains in establishing the diagnosis and differentiating these from the more the common ovarian germ cell tumors in children.

Sertoli-Leydig Cell Tumors (SLCT) are very rare neoplasms of the ovary (0.2%) and they belong to the group of sex cord-stromal tumors. Of these, 20% of the cases show heterologous elements. We report a case of a 22-year-old woman who presented with complaints of lower abdominal pain and secondary amenorrhea for 10 months. Physical examination revealed right lower abdominal tenderness and fullness. Imaging showed a right ovarian mass. She underwent right salpingo-oophorectomy with bilateral pelvic lymphadenectomy and omentectomy. Microscopic examination revealed a neoplasm with varied histomorphological patterns. The predominant pattern was an atypical proliferative mucinous tumor with foci of microinvasion. The other component was that of moderately differentiated Sertoli-Leydig Cell Tumor. Focal areas resembling carcinoid were also noted. Immunohistochemistry was performed and the Sertoli-Leydig Cells were positive for CD56, calretinin, inhibin, vimentin, and ER. The glandular component was positive for CK20, EMA, CEA, and CDX2. Synaptophysin and chromogranin were positive within nests resembling carcinoid. With the given histomorphological features and immunohistochemistry findings, a diagnosis of moderately differentiated Sertoli-Leydig Cell Tumor of the ovary with associated mucinous carcinoma and carcinoid was rendered. The presence of heterologous elements in SLCTs has been reported to be associated with poor prognosis.

A 50-year-old peri-menopausal woman presented with hard palpable mass on her lower abdomen and anemia from heavy menstrual bleeding. Ultrasonography showed a 13×12 cm sized hypoechoic solid mass in pelvis and a 2.5×2 cm hypoechoic cystic mass in uterine endometrium. Abdomino-pelvic computed tomography revealed a hypodense pelvic mass without enhancement, suggesting a leiomyoma of intraligamentary type or sex cord tumor of right ovary with submucosal myoma of uterus. Laparoscopy revealed a large Sertoli-Leydig cell tumor of right ovary with a very rare entity of intra-endometrial uterine leiomyoma accompanied by adenomyosis. The final diagnosis of ovarian sex-cord tumor (Sertoli-Leydig cell), stage Ia with intra-endometrial leiomyoma with adenomyosis, was made. Considering the large size of the tumor and poorly differentiated nature, 6 cycles of chemotherapy with Taxol and Carboplatin regimen were administered. There is neither evidence of major complications nor recurrence during 20 months' follow-up.

Background Sertoli–Leydig cell tumors are rare sex-cord stromal tumors of the ovary that can present with a variety of histological elements, which may complicate diagnosis and treatment. Case A 40-year-old female presenting with pelvic pain is found to have a large complex right adnexal mass and elevated alpha-fetoprotein. The mass was diagnosed as a Sertoli–Leydig cell tumor with heterologous elements including carcinoid and hepatoid components. She was treated with surgical resection followed by adjuvant chemotherapy and remains clear of disease. Conclusion Prognostic indicators for Sertoli–Leydig cell tumors include degree and type of heterologous element differentiation. Thorough characterization of such elements is crucial for adequate diagnosis and treatment., Highlights • Varying histopathology of Sertoli–Leydig tumors presents a diagnostic challenge. • Degree of heterologous element differentiation is a prognostic indicator. • Alpha-fetoprotein expression is rare in Sertoli–Leydig cell tumors. • Accurate diagnosis is crucial for appropriate treatment selection.

Sertoli-Leydig cell tumor of the ovary is a kind of sex cord-stromal tumor, which occurs between teens and twenties with symptoms including abdominal pain and swelling. The incidence rate is infinitely rare comprising less than 0.5% of all ovarian tumor. The average age of “retiform Sertoli-Leydig cell tumor” is 17 years as compared to 25 years for Sertoli-Leydig cell tumors as a group. We have experienced this rare case of retiform Sertoli-Leydig cell tumor in a 25-year-old foreign patient with the complaint of palpable mass on the right lower quadrant and an irregular menstrual period. The patient underwent right salpingo-oophorectomy and tumor stage was FIGO stage 1A. We report with a brief review of literature.

Background Ovarian tumors, although uncommon in children, can retain endocrine function that disrupts normal feedback mechanisms leading to amenorrhea. Inheritance of germline DICER1 mutations can lead to increased risk for development of ovarian Sertoli-Leydig cell tumors (SLCTs). Case We report, to our knowledge, the first case of secondary amenorrhea due to elevated inhibin B levels in a female adolescent with an ovarian SLCT. Summary and Conclusion Ovarian tumors should be included in the differential diagnosis for pediatric patients who present with menstrual irregularities. Early evaluation of the hypothalamic-pituitary-ovarian axis and inhibin levels is appropriate. Our case also emphasizes the need for testing for DICER1 mutations in pediatric patients with ovarian SLCTs.

Sertoli-Leydig cells tumors are rare ovarian neoplasms that can be managed with conservative resection given their generally excellent prognosis. Here we report a case of Sertoli-Leydig cell tumor mistakenly diagnosed as an invasive mucinous adenocarcinoma at time of intraoperative consultation because of its blue-mucinous appearance in the frozen section material. The patient subsequently underwent an extensive staging procedure revealing unilateral, ovarian confined disease. The mucinous features seen on frozen section were lost on the slides prepared from formalin fixed tissues. Immunohistochemical work up confirmed the diagnosis of a pure Sertoli-Leydig cell tumor. No heterologous elements were identified in this tumor. This case illustrates a hitherto unrecognized frozen section pitfall in evaluation of ovarian neoplasms. To the best of our knowledge, this is the first well documented case of pure Sertoli-Leydig cells tumor which resembled a well differentiated mucinous adenocarcinoma during frozen section.

Rationale: DICER1 syndrome is an autosomal-dominant tumor predisposition syndrome associated with numerous cancerous and noncancerous conditions. The most common sex cord-stromal tumor associated with DICER1 syndrome is Sertoli-Leydig cell tumor of the ovary (SLCT), which is extremely unusual and accounts for

Literature on virilising ovarian tumors (VOTs) is limited to case reports and series reporting single pathological type. We have analyzed the clinical, hormonal, radiological, histological, management and outcome data of VOT. This retrospective study was conducted at a tertiary health care center from Western India. Consecutive patients with VOT presenting to our endocrine center between 2002 and 2017 were included. Our study included 13 patients of VOT. Out of 13 patients, two were postmenopausal. All patients in the reproductive age group had secondary amenorrhea except one who presented with primary amenorrhea. Modified F and G score (mFG) at presentation was 24 ± 4.3 and all patients had severe hirsutism (mFG ≥15). Change in voice (n = 11) and clitoromegaly (n = 7) were the other most common virilising symptoms. Duration of symptoms varied from 4 to 48 months. Median serum total testosterone level at presentation was 5.6 ng/mL with severe hyperandrogenemia (serum testosterone ≥2 ng/mL) but unsuppressed gonadotropins in all patients. Transabdominal ultrasonography (TAS) detected VOT in all except one. Ten patients underwent unilateral salpingo-oophorectomy whereas three patients (peri- or postmenopausal) underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy. Seven patients had Sertoli Leydig cell tumor, three had steroid cell tumor and two had Leydig cell tumor and one had miscellaneous sex cord stromal tumor. All patients had normalization of serum testosterone after tumor excision. In conclusion, VOTs present with severe hyperandrogenism and hyperandrogenemia. Sertoli Leydig cell tumor is the most common histological subtype. Surgery is the treatment of choice with good surgical outcome.

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).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.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.SLCTs are extremely rare, commonly arise in premenopausal patients. They are associated with a poorer prognosis compared to GCT.

Purpose ofinvestigation: Sertoli-Leydig cell tumors (SLCTs) of the ovary are rare, usually presenting as virilization in women in their second to third decade of life. Less than 10% of patients are older than age 50. The authors present a series of cases of SCLT managed at their institution.A retrospective review was performed of all cases of ovarian SLCT diagnosed at a tertiary care institution between 1990-2014. Demographic data, clinical presentation, pathological findings, and treatment modalities were col- lected.Of the 16 patients diagnosed with SCLT over a 24-year period, nine patients (56%) were postmenopausal at the time of diagnosis, with a median age of 52.5 years (IQR = 39.7 years). These nine patients had a median interval of 14.7 years (IQR = 15) since the onset of menopause. Hyperandrogenism was a presenting feature in only five of 16 (31%) [median age of 49 (IQR= 26.5)] whereas postmenopausal bleeding was noted in two of 16 (12%). At diagnosis, tumor grade varied from well- to poorly-differentiated lesions, and eight patients (15%) received adjuvant chemotherapy. Disease-free survival over a median follow up of 31.5 months (IQR = 73.5 months) was 100% without recurrence.The present patient population was noticeably older than what has been described in literature, with the majority being postmenopausal. To the authors' knowledge, this is the largest series of postmenopausal patients with SLCT. Hyperandrogenism was evident in only a small sub-group. While the definitive management of SLCT remains controversial and varied, prognosis and risk of recurrence are reassuring.

Sertoli-Leydig cell tumors are a group of tumors composed of variable proportions of Sertoli cells, Leydig cells, and sometimes heterologous elements. We describe the case of a 68-yr-old woman who presented with abdominal distention. A computed tomographic scan revealed a large right adnexal mass without evidence of intrahepatic tumors, and a complete cytoreductive surgery was performed. Pathologic examination revealed a moderately differentiated Sertoli-Leydig cell tumor with various heterologous elements, including gastrointestinal-type glands, insular carcinoid, and aggregations of hepatocytes without significant cytologic atypia. Moreover, adjacent to these hepatocytes, extensive overgrowth of highly atypical hepatocyte-like cells, providing a striking morphologic similarity to hepatocellular carcinoma of the liver, was identified. Both the heterologous hepatocytes and hepatocellular carcinomatous tumor cells were immunohistochemically positive for alpha-fetoprotein, hepatocyte paraffin 1, and arginase-1. Some Sertoli cells adjacent to the heterologous hepatocytes were also positive for alpha-fetoprotein and hepatocyte paraffin 1. The present case showed that a tumor morphologically and immunohistochemically analogous to hepatocellular carcinoma of the liver can arise in the ovary, in association with Sertoli-Leydig cell tumors.

Sertoli-Leydig cell tumour (SLCT) is a rare, androgen-secreting sex cord–stromal tumour of the ovary that usually occurs in young premenopausal women. The major clinical manifestations are virilisation and defeminisation. The following case describes an 88-year-old G1P1 woman, 40 years after menopause, who presented with flushing, hirsutism, voice changes and alopecia along with significantly elevated levels of testosterone. Postoperative report revealed a well-differentiated SLCT in the left ovary. This case is unique in that SLCT is a very rare cancer and even more so in an 88-year-old woman. Taking this case into consideration, it becomes reasonable to check androgen and oestrogen levels in postmenopausal women, not only in patients with signs of virilisation, but also in those with non-classical presentations, such as flushing or heat spells.

Our report details the workup and management of a 43-year-old woman with an identical twin who presented with 2 years of virilization and secondary amenorrhea. Serum total testosterone was elevated. An MRI did not identify adnexal or adrenal pathology. Subsequent ovarian vein sampling demonstrated unilateral testosterone elevation. The patient underwent laparoscopic unilateral oophorectomy resulting in the diagnosis of Sertoli-Leydig cell tumor (SLCT). Although SLCT is a rare sex-cord ovarian tumor, it is associated with endometrial hyperplasia and malignancy. Our goals are to review the workup of androgen-secreting tumors and discuss the clinical importance of the DICER1 mutation in the context of SLCT. In this case, an identical twin underwent DICER1 testing which was one of the essential steps in her clinical management.

To investigate the clinicopathologic prognostic factors in patients with malignant sex cord-stromal tumors (SCSTs) with lymph node dissection, and at the same time, to evaluate the influence of the log odds of positive lymph nodes (LODDS) on their survival.Patients diagnosed with malignant SCSTs who underwent lymph node dissection were extracted from the 1988-2013 Surveillance, Epidemiology, and End Results (SEER) database. Overall survival (OS) and cancer-specific survival (CSS) were estimated by Kaplan-Meier curves. The Cox proportional hazards regression model was used to identify independent predictors of survival.576 patients with malignant SCSTs and with lymphadenectomy were identified, including 468 (81.3%) patients with granulosa cell tumors (GCTs) and 80 (13.9%) patients with Sertoli-Leydig cell tumors (SLCTs). 399 (69.3%) patients and 118 (20.5%) patients were in the LODDS -1 group and -1 ≤ LODDS -0.5 group, respectively. The 10-year OS rate was 80.9% and CSS was 87.2% in the LODDS -0.5 group, whereas the survival rates for other groups were 68.5% and 73.3%. On multivariate analysis, age 50 years or less (p 0.001), tumor size of 10 cm or less (p 0.001), early-stage disease (p 0.001), and GCT histology (p ≤ 0.001) were the significant prognostic factors for improved survival. LODDS -0.5 was associated with a favorable prognosis (OS: p = 0.051; CSS:P = 0.055).Younger age, smaller tumor size, early stage, and GCT histologic type are independent prognostic factors for improved survival in patients with malignant SCST with lymphadenectomy. Stratified LODDS could be regarded as an effective value to assess the lymph node status, and to predict the survival status of patients.

Objective – The aim was to report a case of a 17-year-old girl with marked virilization and secondary amenorrhea due to androgen producing Sertoli-Leydig cell tumor (SLCT). We also provided a brief review of the literature with insight into clinical picture, pathological features and treatment of patients with this rare tumor. Case report − We present a 17-year-old girl with SLCT, who developed clinical symptoms of severe virilization. The tumor secreted testosterone and alpha fetoprotein (AFP). The imaging revealed tumor of the right ovary which histologically corresponded to intermediate-grade SLCT with low mitotic rate. Furthermore, it was stage IA according to International Federation of Gynecology and Obstetrics. Laparoscopic right salpingo-oophorectomy was preformed, resulting in regression of virilization symptoms and normalization of serum testosterone and AFP levels. Conclusion − Due to rarity of SLCT in children and adolescents, gathering information from available case reports is necessary to establish guidelines regarding optimal management, including type of surgery and adjuvant chemotherapy. New knowledge regarding related diseases in SLCT survivors emphasize the need for long-term follow up of these patients.

ObjectiveFamilial multinodular goiter (MNG), with or without ovarian Sertoli-Leydig cell tumor (SLCT), has been linked to DICER1 syndrome. We aimed to search for the presence of a germlineDICER1mutation in a large family with a remarkable history of MNG and SLCT, and to further explore the relevance of the identified mutation.Design and methodsSanger sequencing, Fluidigm Access Array and multiplex ligation-dependent probe amplification (MLPA) techniques were used to screen forDICER1mutations in germline DNA from 16 family members. Where available, tumor DNA was also studied. mRNA and protein extracted from carriers’ lymphocytes were used to characterize the expression of the mutant DICER1.ResultsNine of 16 tested individuals carried a germline, in-frameDICER1deletion (c.4207-41_5364+1034del), which resulted in the loss of exons 23 and 24 from the cDNA. The mutant transcript does not undergo nonsense-mediated decay and the protein is devoid of specific metal ion-binding amino acids (p.E1705 and p.D1709) in the RNase IIIb domain. In addition, characteristic somatic ‘second hit’ mutations in this region were found on the other allele in tumors.ConclusionsPatients with DICER1 syndrome usually present a combination of a typically truncating germlineDICER1mutation and a tumor-specific hotspot missense mutation within the sequence encoding the RNase IIIb domain. The in-frame deletion found in this family suggests that the germline absence of p.E1705 and p.D1709, which are crucial for RNase IIIb activity, may be enough to permit DICER1 syndrome to occur.

Sertoli-Leydig cell tumor of the ovary represents less than 0.5% of all ovary neoplasms. It is a tumor that affects predominantly young woman, who most of the times associate signs of virilization. It has recently been associated with mutations in DICER1. In this report, we describe a case of Sertoli-Leydig cell tumor in an asymptomatic 61- year-oldwoman who underwent a laparoscopic bilateral anexectomy for a heterogenous cystic lesion found in her left ovary. The microscopic examination of the lesion, showed a solid-cystic tumoral proliferation in the region identified as ovarian hilum, formed by two distinct and intermixed cell populations (Leydig cells and Sertoli cells). The prognosis of this kind of tumor is usually good, unless it shows poor differentiation and/or heterologous elements or retiforme pattern. So, the recommended treatment of these tumors, is a conservative approach. In our case, the anexectomy was performed by expressed desire of the patient.

Sertoli-Leydig cell tumors are characterized by the presence of somatic DICER1 hotspot mutations. In this study, we sought to define the association between DICER1 hotspot mutations and different morphologic subtypes of ovarian Sertoli-Leydig cell tumors. Furthermore, we aimed to assess whether DICER1 hotspot mutations occur in other ovarian sex cord-stromal tumors, testicular sex cord-stromal tumors, or other female genital tract tumors with rhabdomyosarcomatous differentiation. We subjected a series of ovarian Sertoli-Leydig cell tumors (n=32), Sertoli cell tumors (n=5) and gynandroblastomas (n=5), testicular sex cord-stromal tumors (n=15) and a diverse group of female genital tract tumors with rhabdomyosarcomatous morphology (n=10) to DICER1 hotspot mutation analysis using Sanger sequencing. We also tested two gynandroblastomas for the presence of FOXL2 hotspot mutations (p.C134W; c.402C>G). Twenty of 32 (63%) Sertoli-Leydig cell tumors harbored a DICER1 hotspot mutation, of which 80% had the p.E1705K mutation. No association was found between DICER1 mutation status and the presence of heterologous or retiform differentiation in Sertoli-Leydig cell tumors. DICER1 mutations were found at similar frequencies in gynandroblastoma (2/5; 40%) and ovarian Sertoli cell tumors (5/8; 63%; P>0.1), and all mutated tumors harbored a p.E1705K mutation. DICER1 hotspot mutations were also identified in a single cervical rhabdomyosarcoma and in the rhabdomyosarcomatous component of a uterine carcinosarcoma. No DICER1 mutations were detected in testicular sex cord-stromal tumors. Two DICER1 wild-type gynandroblastomas harbored a p.C134W FOXL2 hotspot mutation in both tumor components. In this study we confirmed that DICER1 hotspot mutations occur in over half of ovarian Sertoli-Leydig cell tumors, and are unrelated to tumor differentiation. We also widened the spectrum of ovarian sex cord-stromal tumors with sertoliform differentiation, in which DICER1 mutations are known to occur, to include Sertoli cell tumors and gynandroblastomas. Our results suggest that DICER1 mutations may not have a role in testicular sex cord-stromal tumorigenesis.

DICER1, an endoribonuclease required for microRNA (miRNA) biogenesis, is essential for embryogenesis and the development of many organs including ovaries. We have recently identified somatic hotspot mutations in RNase IIIb domain of DICER1 in half of ovarian Sertoli-Leydig cell tumors, a rare class of sex-cord stromal cell tumors in young women. These hotspot mutations lost IIIb cleavage activity of DICER1 in vitro and failed to produce 5p-derived miRNAs in mouse Dicer1-null ES cells. However, the oncogenic potential of these hotspot DICER1 mutations has not been studied. Here, we further revealed that the global expression of 5p-derived miRNAs was dramatically reduced in ovarian Sertoli-Leydig cell tumors carrying DICER1 hotspot mutations compared with those without DICER1 hotspot mutation. The miRNA production defect was associated with the deregulation of genes controlling cell proliferation and the cell fate. Using an immortalized human granulosa cell line, SVOG3e, we determined that the D1709N-DICER1 hotspot mutation failed to produce 5p-derived miRNAs, deregulated the expression of several genes that control gonadal differentiation and cell proliferation, and promoted cell growth. Re-expression of let-7 significantly inhibited the growth of D1709N-DICER1 SVOG3e cells, accompanied by the suppression of key regulators of cell cycle control and ovarian gonad differentiation. Taken together, our data revealed that DICER1 hotspot mutations cause systemic loss of 5p-miRNAs that can both drive pseudodifferentiation of testicular elements and cause oncogenic transformation in the ovary.

International audience; AIMS: FOXL2 mutation has been consistently identified in adult granulosa cell tumours (A-GCTs). DICER1 mutations have been described predominantly in Sertoli-Leydig cell tumours (SLCTs). The prognostic implication of these mutations remains uncertain, as moderately sized studies have yielded variable outcomes. Our aim was to determine the implications of DICER1 and FOXL2 mutations in 156 ovarian sex cord-stromal tumours (SCSTs). METHODS AND RESULTS: FOXL2 mutations were found in 94% of pathologically confirmed A-GCTs (95/101), in one of eight juvenile granulosa cell tumours (J-GCTs), and in two of 19 SLCTs. DICER1 mutations in the RNase IIIb domain were found in six of 19 SLCTs, two of eight J-GCTs, and one of 12 undifferentiated SCSTs (Und-SCSTs). Comparison of DICER1-mutated SLCTs with DICER1-non-mutated SLCTs showed that patient age at diagnosis was lower and oestrogen receptor expression was more frequent in DICER1-mutated tumours. With a median follow-up of 22 months, two of five DICER1-mutated SLCTs relapsed, in contrast to none of eight DICER1-non-mutated tumours. CONCLUSIONS: Our results suggest that, in contrast to FOXL2 mutations in A-GCT, DICER1 mutations in SLCT might be more useful for prognosis than for diagnosis. However, study of a larger cohort of patients is necessary to establish this. Identification of genetic alterations in SCST offers promising therapeutic options

Sertoli-Leydig cell tumor (SLCT) of the ovary is an exceedingly unusual neoplasm that belongs to a group of sex-cord-stromal tumors of ovary and accounts for