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UNASSIGNED: DICER1-associated tumors are heterogeneous and affect several organs. DICER1-associated primary intracranial sarcoma is associated with histone H3 trimethylation on lysine 27 (H3K27me3) loss in nucleus by immunohistochemistry.
UNASSIGNED: We explored the H3K27me3 immunostaining pattern in other DICER1-associated tumors. Twelve tumors from eleven patients with confirmed DICER1 mutations (sporadic and germline) data from a pancancer next-generation sequencing panel, and four tumors of pleuropulmonary blastoma (PPB) were retrieved from our database and stained with anti-H3K27me3 antibody.
UNASSIGNED: The H3K27me3 expression in the nucleus showed heterogeneous mosaic loss in neoplastic Sertoli cell components in three of the five cases of moderately to poorly differentiated Sertoli-Leydig cell tumors. Among two tumors of DICER1-associated primary intracranial sarcoma, one showed complete loss of H3K27me3 in all neoplastic cells, whereas the other showed mosaic loss in the sarcomatous spindle cells. One DICER1-associated tumor with epithelial and mesenchymal differentiation, including pulmonary blastoma and PPB, showed mosaic loss of glandular epithelial and mesenchymal components. Four cases of type II PPB and a single case of type III PPB showed a similar mosaic loss of H3K27me3 staining restricted to large spindle cell components. All other components in all tumors-including Leydig cells; the areas of epithelial, cartilaginous, and rhabdomyomatous differentiation; and all cells of the remaining three cases (one papillary thyroid carcinoma and two cases of PPB type I)-demonstrated retained H3K27me3 staining.
UNASSIGNED: H3K27me3 expression is not universally lost in DICER1-associated tumors and thus is not predictive of DICER1 mutation status. The mosaic regional loss of H3K27me3 immunostaining is consistent in PPB type II and III, which can be a helpful diagnostic marker for these tumors and suggests a similarity to DICER1-associated intracranial sarcoma.

Sertoli-Leydig cell tumors (SLCTs) are rare sex cord-stromal tumors, representing <0.5% of all ovarian tumors. We sought to describe prognostic factors, treatment and outcomes for individuals with ovarian SLCT.
Individuals with SLCT were enrolled in the International Pleuropulmonary Blastoma/DICER1 Registry and/or the International Ovarian and Testicular Stromal Tumor Registry. Medical records were systematically abstracted, and pathology was centrally reviewed when available.
In total, 191 participants with ovarian SLCT enrolled, with most (92%, 175/191) presenting with FIGO stage I disease. Germline DICER1 results were available for 156 patients; of these 58% had a pathogenic or likely pathogenic germline variant. Somatic (tumor) DICER1 testing showed RNase IIIb hotspot variants in 97% (88/91) of intermediately and poorly differentiated tumors. Adjuvant chemotherapy was administered in 40% (77/191) of cases, and among these, nearly all patients received platinum-based regimens (95%, 73/77), and 30% (23/77) received regimens that included an alkylating agent. Three-year recurrence-free survival for patients with stage IA tumors was 93.6% (95% CI: 88.2-99.3%) compared to 67.1% (95% CI: 55.2-81.6%) for all stage IC and 60.6% (95% CI: 40.3-91.0%) for stage II-IV (p < .001) tumors. Among patients with FIGO stage I tumors, those with mesenchymal heterologous elements treated with surgery alone were at higher risk for recurrence (HR: 74.18, 95% CI: 17.99-305.85).
Most individuals with SLCT fare well, though specific risk factors such as mesenchymal heterologous elements are associated with poor prognosis. We also highlight the role of DICER1 surveillance in early detection of SLCT, facilitating stage IA resection.

OBJECTIVE: Sertoli-Leydig cell tumors (SLCTs) are rare neoplasms occurring in young women with 60% associated with DICER1 mutations. This is only the second published case series of patients with SLCTs with associated DICER1 gene alterations. DICER1 syndrome is a rare inherited tumor-susceptibility syndrome affecting organs such as the ovaries. We use this case series to inform readers on this increasingly important condition in gynecology.
RESULTS: We present three young females presenting with secondary amenorrhoea, hirsutism, acne and in one case tonic-clonic seizures. All cases had high testosterone levels and an adnexal mass on ultrasound. Following surgical removal, pathology confirmed SLCTs and genetic testing followed. All three patients had DICER1 syndrome with two patients subsequently found to be related.
CONCLUSIONS: The prevalence of DICER1 syndrome in the population is estimated to be 1 in 10 000 with a spectrum of sex cord stromal tumors affecting young women. The associated pathological classifications and management. This paper describes the DICER1 gene and the associated tumor predisposition syndrome alongside a surveillance protocol for use in clinical practice. It promotes discussion over the importance of early clinical genetics involvement in sex-cord stromal tumors and the associated difficulties in counseling in a young patient population. Genetic testing and early detection are imperative for targeted surveillance of at-risk organs to be performed but despite this there is no international guidance. The cases highlight the psychological impact of tumors in young patients and provokes an ethical discussion over DICER1 gene\'s inclusion in preimplantation genetics.
CONCLUSIONS: DICER1 syndrome is a rare but increasingly important condition in pediatric and adolescent gynecology with a paucity of published data and case reports. This makes international consensus on management and surveillance difficult.

Sertoli-Leydig cell tumours (SLCTs) are rare, mixed sex-cord stromal tumours composed of varying proportions of both Sertoli and Leydig cells, which account for <0.5% of all ovarian tumours. The cytomorphologic features of SLCTs are not well described in literature. Herein, we describe the cytomorphologic features of an SLCT at an uncommon metastatic site in a young female. Sertoli-Leydig cell tumours (SLCTs) are rare, mixed sex-cord stromal tumours composed of varying proportions of both Sertoli and Leydig cells, which account for <0.5% of all ovarian tumours. The cytomorphologic features of SLCTs are not well described in literature. Herein, we describe the cytomorphologic features of an SLCT at an uncommon metastatic site in a young female.

A Sertoli-Leydig cell tumor (SLCT) is a rare ovarian tumor that often excessively secretes testosterone and its precursor, leading to virilization in females. We present a case of a female patient with persistent, severe hyperandrogenism. Our patient had a history of left oophorectomy due to an ectopic pregnancy and initially presented with amenorrhea at the age of 30. Biochemical evaluations suggested ovarian hyperandrogenism. Despite the absence of an ovarian mass, she underwent a right oophorectomy and remained hyperandrogenic postoperatively. When she established care with our endocrinology clinic at the age of 58, she had more virilizing features and total testosterone levels ranging from 10.1 to 12.0 nmol/L (292-346 ng/dL; normal reference range for women: 0.07-1.56 nmol/L; 2-45 ng/dL). While biochemical evaluations were consistent with tumorous ovarian hyperandrogenism, ultrasound and computed tomography again failed to identify the source. Finally, an 18F-fluorodeoxyglucose-positron emission tomography/computed tomography revealed a mass in the left adnexa, and she underwent removal of the mass. The final pathology confirmed SLCT. The case highlights that SLCT may be small and slow-growing and not readily visible on conventional imaging modalities.

Virilizing ovarian tumors are rare but a clinically important diagnosis in a patient presenting with hyperandrogenism. Workup of hyperandrogenism is challenging with a broad range of differentials, including adrenal and ovarian pathology, tumoral or nontumoral in nature. Baseline follicular-phase 17-hydroxyprogesterone (17OHP) measurement is part of the investigation algorithm, and elevated levels are often associated with nonclassic congenital adrenal hyperplasia (NCCAH), which can have its first presentation in adolescence or adulthood. This case describes a young adult woman of reproductive age presenting with menstrual irregularity, raised testosterone, and 17OHP. After extensive workup and serial follow-up, she was found to have a Sertoli-Leydig cell tumor of the left ovary and underwent successful laparoscopic salpingo-oophorectomy with normalization of her menstrual irregularity and biochemical resolution of her testosterone and 17OHP levels.

DICER1 syndrome is a rare genetic disorder predisposing young patients to multiple types of cancer. A 17-year-old woman with a history of mixed Sertoli-Leydig cell tumor and juvenile granulosa cell tumor of the left ovary at age 14 presented with a pelvic mass. She underwent fertility preservation cytoreductive surgery and the pathology showed high-grade sarcoma with rhabdomyosarcomatous differentiation. After the surgery, patient received one cycle of chemotherapy but her disease continued to progress. She therefore underwent total hysterectomy, right salpingo-oophorectomy and hyperthermic intraperitoneal chemotherapy followed by consolidation chemotherapy. Magnetic resonance imaging revealed no evidence of the disease before and after the completion of her chemotherapy. Genetic testing confirmed the DICER1 pathogenic variant. However, she presented again with a recurrence of the disease 6 months later and ultimately died of the disease 11 months after the surgery. Our case demonstrates the challenging management of this rare disease in a young patient and the need for new and effective treatments.

BACKGROUND: Sex cord-stromal tumors (SCST) are hormonally active and rare. The aim was to describe their endocrinological presentation and outcomes.
METHODS: 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.

Currently available molecular data support a dichotomous classification of Sertoli-Leydig cell tumours (SLCTs) based on DICER1 mutational status. This correspondence suggests a possible roadmap towards a molecular-based classification of SLCT.