Testicular Neoplasms With Sex Cord and Stromal Components Harbor a Recurrent Pattern of Chromosomal Gains.

A small subset of testicular sex cord-stromal tumors, designated as Sertoli-stromal cell tumors (SSCTs), comprises a mixture of Sertoli, spindle, and/or Leydig cells. The clinicopathologic features of these tumors have not been studied in any detail, and their molecular features are unknown. We, therefore, assessed the morphologic and genomic features of 14 SSCTs, including 1 tumor with features similar to the ovarian Sertoli-Leydig cell tumor (SLCT) with retiform tubules. The median age of the patients was 24 years (range, 10-55 years), and the median tumor size was 2.3 cm (range, 0.7-4.7 cm). All tumors showed Sertoli-like sex cord cells arranged in variably developed tubular structures, typically also forming nests and cords. These imperceptibly blended with a neoplastic spindle cell stroma or, in the SLCT, vacuolated to eosinophilic Leydig cells. Genomic analysis demonstrated the presence of a hotspot loss-of-function DICER1 mutation in the SLCT (patient 1) and hotspot gain-of-function CTNNB1 mutations in the tumors of patients 2 and 3, with both CTNNB1 variants being interpreted as possible subclonal events. The mutations were the only relevant findings in the tumors of patients 1 and 2, whereas the tumor of patient 3 harbored concurrent chromosomal arm-level and chromosome-level copy number gains. Among the remaining 11 tumors, all of those that had interpretable copy number data (9 tumors) harbored multiple recurrent chromosomal arm-level and chromosome-level copy number gains suggestive of a shift in ploidy without concurrent pathogenic mutations. The results of the present study suggest that CTNNB1 mutations (likely subclonal) are only rarely present in SSCTs; instead, most of them harbor genomic alterations similar to those seen in testicular sex cord-stromal tumors with pure or predominant spindle cell components. A notable exception was a testicular SLCT with morphologic features identical to the ovarian counterpart, which harbored a DICER1 mutation.

Lessons from genomic profiling: towards a molecular-based classification of ovarian Sertoli-Leydig cell tumour.

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.

Teratoma-associated and so-called pure Wilms tumour of the ovary represent two separate tumour types with distinct molecular features.

AIMS: Ovarian Wilms tumour (WT)/nephroblastoma is an extremely rare neoplasm that has been reported to occur in pure form or as a component of a teratomatous neoplasm. We hypothesized that teratoma-associated and pure ovarian WT may represent different tumour types with diverging molecular backgrounds. To test this hypothesis, we comprehensively characterized a series of five tumours originally diagnosed as ovarian WT. METHODS AND RESULTS: The five cases comprised three teratoma-associated (two mature and one immature) and two pure WTs. Two of the teratoma-associated WTs consisted of small nodular arrangements of "glandular"/epithelial structures, while the third consisted of both an epithelial and a diffuse spindle cell/blastemal component. The pure WTs consisted of "glandular" structures, which were positive for sex cord markers (including inhibin and SF1) together with a rhabdomyosarcomatous component. The two pure WTs harboured DICER1 pathogenic variants (PVs), while the three associated with teratomas were DICER1 wildtype. Panel-based DNA sequencing of four of the cases did not identify PVs in the other genes investigated. Analysis of the HA19/IGF2 imprinting region showed retention of imprinting in the pure WTs but loss of heterozygosity with hypomethylation of the ICR1 region in two of three teratoma-associated WTs. Furthermore, copy number variation and clustering-based whole-genome DNA methylation analyses identified divergent molecular profiles for pure and teratoma-associated WTs. CONCLUSION: Based on the morphological features, immunophenotype, and molecular findings (DICER1 PVs, copy number, and DNA methylation profiles), we suggest that the two cases diagnosed as pure primary ovarian WT represent moderately to poorly differentiated Sertoli Leydig cell tumours (SLCTs), while the tumours arising in teratomas represent true WTs. It is possible that at least some prior cases reported as pure primary ovarian WT represent SLCTs.

Sex Cord-Stromal Tumors of the Ovary: An Update and Review. Part II - Pure Sex Cord and Sex Cord-Stromal Tumors.

We review the time honored but still frequently challenging features of ovarian sex cord-stromal tumors and also emphasize new developments, including unusual morphologic appearances that, despite the relative rarity of many of the tumors, result in a disproportionate number of differential diagnostic problems, variant immunohistochemical profiles, and specific molecular and syndromic associations. These neoplasms are also of historical interest as current knowledge is still based in significant part to the contributions of 2 giants of gynecologic pathology, Dr Robert Meyer and Dr. Robert E. Scully. In part I, we reviewed the pure ovarian stromal tumors. Now, in part II, we present the major clinical, pathologic, and genomic features of pure sex cord and sex cord-stromal tumors.

Contemporary Updates on Sex Cord-stromal Tumors of the Testis.

Testicular sex cord-stromal tumors (TSCSTs) are relatively rare, representing ~5% of testicular neoplasms overall. Historically, TSCSTs have been classified into 3 major entities: Leydig cell tumor, Sertoli cell tumor, and granulosa cell tumor. In recent years, immunophenotypic and molecular analyses have led to a more detailed understanding of the biological and genomic features of these neoplasms, resulting in the description of new entities, some of which have been included in the latest WHO classification. This review summarizes novel histopathologic, clinical, and molecular findings that may lead to a reappraisal of established concepts and help improve the diagnosis and clinical management of TSCSTs in the coming years.

Sex Cord-Stromal Tumors of the Ovary: An Update and Review. Part I - Pure Ovarian Stromal Tumors.

In two separate reviews, we review the time-honored but still frequently challenging features of ovarian sex cord-stromal tumors, and also emphasize new developments including unusual morphologic appearances that, despite the relative rarity of many of the tumors, result in a disproportionate number of differential diagnostic problems, variant immunohistochemical profiles, and specific molecular and syndromic associations. These neoplasms are also of historical interest as current knowledge is still based in significant part on the contributions of 2 giants of gynecologic pathology, Dr Robert Meyer and Dr Robert E. Scully. In part I, we present the major clinical, pathologic, and genomic features of the pure ovarian stromal tumors including comments on differential diagnosis and briefly note significant historical contributions. In part II we will discuss pure sex cord and sex cord-stromal tumors.

Outcomes in ovarian Sertoli-Leydig cell tumor: A report from the International Pleuropulmonary Blastoma/DICER1 and Ovarian and Testicular Stromal Tumor Registries.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

FOXL2 Mutation Status in Sex Cord-stromal Tumors Cannot be Predicted by Morphology.

Granulosa-cell tumors (GCTs) are the most common type of malignant ovarian sex cord-stromal tumor (SCST). The histopathologic diagnosis of these tumors can be challenging. A recurrent somatic mutation of the forkhead box L2 (FOXL2) gene has been identified in adult GCT. In this retrospective single-center study of 44 SCST, a morphologic review together with analysis of FOXL2 C134W was evaluated in relation to tumor morphology. In addition, TERT promoter mutation testing was performed. Twelve of 36 cases got an altered diagnosis based on morphology alone. The overarching architectural growth pattern in 32/44 (72.7%) tumors was diffuse/solid with several tumors showing markedly heterogeneous architecture. In correlation to FOXL2 C134W mutation status, cytoplasmic color, and nuclear shape, differed between the FOXL2 C134W positive and FOXL2 C134 W negative groups, but these differences were not significant when comparing them separately. Nineteen of 44 cases underwent TERT promoter sequencing with a positive result in 3 cases; 2 adult GCTs and 1 cellular fibroma. Three patients developed a recurrence of which 2 were FOXL2 C134W positive adult GCTs and the third was an unclassified SCST. In conclusion, the morphologic and immunohistochemical diagnosis of different SCSTs is challenging and one cannot reliably identify FOXL2 mutation-positive tumors solely by morphologic features. Therefore, broad use of molecular analysis of the FOXL2 C134W mutation is suggested for SCSTs, and further studies are needed to evaluate the clinical outcome of these tumors as well as the diagnostic and prognostic implications of TERT promoter mutations.

A Case of Uterine Tumor Resembling Ovarian Sex Cord Tumor With Prominent Myxoid Features.

Uterine tumor resembling ovarian sex cord tumor (UTROSCT) is a rare tumor with low malignant potential that commonly occurs in middle age. Although more than 100 cases have been reported to date, myxoid morphology is not well documented. Here, we present a 75-yr-old woman with abnormal vaginal bleeding, with an 8-cm mass in the uterine corpus detected by irregular, high-intensity signaling on T2-weighted imaging. The uterine mass had a glistening mucinous appearance on gross examination. Microscopically, most of the tumor cells were floating in the myxoid stroma. The tumor cells formed clusters or nests with abundant cytoplasm, while some exhibited trabecular or rhabdoid appearances. Immunohistochemically, tumor cells were positive for pancytokeratin (AE1/AE3), α-smooth muscle actin, CD10, progesterone receptor, and some sex cord markers such as calretinin, inhibin, CD56, steroidogenic factor-1. Electron microscopy demonstrated epithelial and sex cord differentiation. This tumor was negative for JAZF1-JJAZ1 fusion gene that is frequently found in low-grade endometrial stromal sarcoma. Fusion genes related to UTROSCT, including NCOA2/3 , were not detected by reverse transcription polymerase chain reaction. The present case suggests that UTROSCT should be included in the differential diagnosis of myxoid uterine tumors.

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.

Moderately-differentiated Ovarian Sertoli-Leydig Cell Tumor With a Concurrent Serous Borderline Tumor in a 16-year-old Girl.

Sertoli-Leydig cell tumors (SLCT) are rare tumors of the ovary with a peak incidence in the second to third decade of life. Serous borderline tumors (SBT) are epithelial ovarian neoplasms which occur at a median age of 50 years. A co-occurrence of SLCT and SBT has not yet been reported. Here, we describe a case of a 16-year-old girl who presented with irregular menses, virilization, and an abdominopelvic mass. The mass was surgically removed and an intraoperative consultation revealed an 18.5 cm solid and cystic ovarian mass with the presence of co-existing SLCT and SBT. The diagnosis was confirmed on permanent sections after extensive sampling and immunohistochemical stains. The SLCT showed positive staining for calretinin, inhibin, CD99, and androgen receptor. MART-1 immunostain highlighted the Leydig cells. The SBT showed classic features including hierarchically branching papillae lined by stratified serous epithelium. This pediatric case is the first reported case of a Sertoli-Leydig cell tumor arising in association with a serous borderline tumor.

Imaging in gynecological disease (27): clinical and ultrasound characteristics of recurrent ovarian stromal cell tumors.

OBJECTIVE: To describe the clinical and ultrasound characteristics of recurrent granulosa cell and Sertoli-Leydig cell tumors. METHODS: This was a retrospective observational study performed at Fondazione Policlinico Universitario A. Gemelli, Istituto di Ricovero e Cura a Carattere Scientifico, IRCCS, Rome (Gemelli center), Italy. Patients with a histological diagnosis of recurrent granulosa cell tumor or Sertoli-Leydig cell tumor were identified from the database of the Department of Gynecological Oncology. Those who had undergone a preoperative ultrasound examination at the Gemelli center between 2012 and 2020 were included, and the data retrieved from the original ultrasound reports. In all of these reports, the recurrent tumors were described using International Ovarian Tumor Analysis (IOTA) terminology. If a patient had more than one episode of relapse, information from all episodes was collected. If there was more than one recurrent tumor at the same ultrasound examination, all tumors were included. One expert sonographer also reviewed all available ultrasound images to identify typical ultrasound patterns using pattern recognition. RESULTS: We identified 30 patients with a histological diagnosis of recurrent granulosa cell tumor (25 patients, 55 tumors) or Sertoli-Leydig cell tumor (five patients, seven tumors). All 30 had undergone at least one preoperative ultrasound examination at the Gemelli center and were included. These women had a total of 66 episodes of relapse, of which a preoperative ultrasound examination had been performed at the Gemelli center in 34, revealing 62 recurrent lesions: one in 22/34 (64.7%) episodes of relapse, two in 4/34 (11.8%) episodes and three or more in 8/34 (23.5%) episodes. Most recurrent granulosa cell tumors (38/55, 69.1%) and recurrent Sertoli-Leydig tumors (6/7, 85.7%) were classified as solid or multilocular-solid tumors, while 8/55 (14.5%) recurrent granulosa cell tumors and 1/7 (14.3%) recurrent Sertoli-Leydig cell tumors were unilocular cysts and 9/55 (16.4%) recurrent granulosa cell tumors were multilocular cysts. The nine unilocular cysts had contents that were anechoic (n = 2) or had low-level echogenicity (n = 7), had either smooth (n = 4) or irregular (n = 5) internal cyst walls, and ranged in largest diameter from 8 to 38 mm, with three being < 20 mm and five being 20-30 mm. On retrospective review of the images, two typical ultrasound patterns were described: small solid tumor measuring < 2 cm (15/62, 24.2%) and tumor with vascularized echogenic ground-glass-like content (12/62, 19.4%). CONCLUSIONS: Some granulosa cell and Sertoli-Leydig cell recurrences manifest one of two typical ultrasound patterns, while some appear as unilocular cysts. These are usually classified as benign, but in patients being followed up for a granulosa cell tumor or Sertoli-Leydig cell tumor, a unilocular cyst should be considered suspicious of recurrence. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

An open-label, single-arm, prospective, multi-center, tandem two-stage designed phase II study to evaluate the efficacy of fulvestrant in women with recurrent/metastatic estrogen receptor-positive gynecological malignancies (FUCHSia study).

OBJECTIVE: This study aimed to evaluate fulvestrant efficacy in women with estrogen receptor-positive low-grade gynecological cancers. The primary objective was to determine the response rate. Secondary objectives were progression-free survival, clinical benefit, duration of response, safety, tolerability, and quality of life. METHODS: FUCHSia is an open-label, single-arm, prospective, multi-center phase II study. The study population included patients with recurrent/metastatic low-grade gynecological malignancies with estrogen receptor positivity who received a maximum of two lines of previous hormonal therapy. Patients received fulvestrant (FASLODEX, AstraZeneca) via two intramuscular injections (250 mg/5 mL each) in the gluteal muscle on day 1, day 15, day 29, and then every 28 days thereafter until disease progression, withdrawal from the trial due to any unacceptable adverse event, or withdrawal of patient consent. RESULTS: A total of 15 patients (uterine sarcoma n=4; sex cord-stromal ovarian tumors n=3; endometrial carcinoma n=4; serous ovarian cancer n=4) were enrolled. Median follow-up was 48 weeks (interquartile range (IQR) 26-122) in the uterine sarcoma cohort, 63 weeks (IQR 28-77) for sex cord-stromal tumors, 19 weeks (IQR 17-21) for endometrial carcinoma, and 60 weeks (IQR 40-119) for serous ovarian cancer. One partial response according to Response Evaluation Criteria in Solid Tumors v1.1 was observed in one uterine sarcoma patient. No responses were observed in the other cohorts. However, stable disease was observed in three uterine sarcomas (median duration 12 weeks), three sex cord-stromal tumors (median duration 32 weeks), and four low-grade serous ovarian cancer patients (median duration 20 weeks), leading to a disease control rate of 100% for these tumor types. All patients with endometrial carcinoma showed progressive disease. CONCLUSION: Fulvestrant may control tumor growth in recurrent/metastatic estrogen receptor-positive low-grade gynecological malignancies of specific histology. Further studies are needed to confirm these results.

Ovarian sclerosing stromal tumor mimicking malignancy: case series and literature review.

BACKGROUND: Sclerosing stromal tumors (SST) are rare ovarian neoplasms that often appear as solid unilateral tumors of the ovary with no specific clinical or radiological presentation. The definitive treatment is surgical removal. CASE PRESENTATION: Our article presents four cases of female patients with sclerosing stromal ovarian tumor with clinical characteristics mimicking malignant ovarian lesions. Interestingly, two of our cases had elevated levels of inhibin B. All patients were treated with surgery (oophorectomy) and had no disease recurrence. CONCLUSION: Tumors' macroscopic features are usually non-specific and often suggestive of possible malignancy, therefore diagnosis is always based on histopathological report.

Uterine Tumors Resembling Ovarian Sex Cord Tumors (UTROSCTs): A Scoping Review of 511 Cases, Including 2 New Cases.

Uterine Tumors Resembling Ovarian Sex Cord Tumors (UTROSCTs) are rare uterine mesenchymal neoplasms with uncertain biological potential. These tumors, which affect both premenopausal and postmenopausal women, usually have a benign clinical course. Nevertheless, local recurrences and distant metastases have been described. By analyzing 511 cases retrieved from individual reports and cases series, we provide here the most comprehensive overview of UTROSCT cases available in the literature, supplemented by two new cases of UTROSCTs. Case 1 was an asymptomatic 31-year-old woman who underwent a laparoscopic resection of a presumed leiomyoma. Case 2 was a 58-year-old postmenopausal woman with abnormal vaginal bleeding who underwent an outpatient hysteroscopic biopsy of a suspicious endometrial area. In both cases, immunohistochemical positivity for Calretinin and Inhibin was noted, typical for a sex cord differentiation. In both cases, total laparoscopic hysterectomy with bilateral salpingo-oophorectomy was performed. In light of the available literature, no pathognomonic clinical or imaging finding can be attributed to UTROSCT. Patients usually present with abnormal uterine bleeding or pelvic discomfort, but 20% of them are asymptomatic. In most cases, a simple hysterectomy appears to be the appropriate treatment, but for women who wish to become pregnant, uterus-preserving approaches should be discussed after excluding risk factors. Age, tumor size, lymphovascular space invasion, nuclear atypia, and cervical involvement are not reliable prognostic factors in UTROSCT. The current research suggests that aggressive cases (with extrauterine spread or recurrence) can be identified based on a distinct genetic and immunohistochemical phenotype. For instance, UTROSCTs characterized by GREB1::NCOA1-3 fusions and PD-L1 molecule expression appear to be predisposed to more aggressive behaviors and recurrence, with GREB1::NCOA2 being the most common gene fusion in recurrent tumors. Hence, redefining the criteria for UTROSCTs may allow a better selection of women suitable for fertility-sparing treatments or requiring more aggressive treatments in the future.

Molecular Correlates of Aggressive Behavior and Biological Progression in Testicular Sertoli Cell Tumors.

Sertoli cell tumor (SCT) is the second most common type of sex cord-stromal tumor in men, and ∼10% exhibit malignant behavior. Although CTNNB1 variants have been described in SCTs, only a limited number of metastatic cases have been analyzed, and the molecular alterations associated with aggressive behavior remain largely unexplored. This study evaluated a series of nonmetastasizing and metastasizing SCTs using next-generation DNA sequencing to further characterize their genomic landscape. Twenty-two tumors from 21 patients were analyzed. Cases were divided into metastasizing SCTs and nonmetastasizing SCTs. Nonmetastasizing tumors were considered to have aggressive histopathologic features if they exhibited ≥1 of the following: size >2.4 cm, necrosis, lymphovascular invasion, ≥3 mitoses per 10 high-power fields, severe nuclear atypia, or invasive growth. Six patients had metastasizing SCTs, and the remaining 15 patients had nonmetastasizing SCTs; 5 nonmetastasizing tumors had ≥1 aggressive histopathologic feature(s). Gain-of-function CTNNB1 or inactivating APC variants were highly recurrent in nonmetastasizing SCTs (combined frequency >90%), with arm-level/chromosome-level copy number variants, loss of 1p, and CTNNB1 loss of heterozygosity occurring exclusively in CTNNB1-mutant tumors with aggressive histopathologic features or size >1.5 cm. Nonmetastasizing SCTs were almost invariably driven by WNT pathway activation. In contrast, only 50% of metastasizing SCTs harbored gain-of-function CTNNB1 variants. The remaining 50% of metastasizing SCTs were CTNNB1-wild-type and harbored alterations in the TP53, MDM2, CDKN2A/CDKN2B, and TERT pathways. These findings suggest that ∼50% of aggressive SCTs represent progression of CTNNB1-mutant benign SCTs, whereas the remaining ones are CTNNB1-wild-type neoplasms that exhibit alterations in genes of the TP53, cell cycle regulation, and telomere maintenance pathways.

Testicular Juvenile Granulosa Cell Tumors Demonstrate Recurrent Loss of Chromosome 10 and Absence of Molecular Alterations Described in Ovarian Counterparts.

Testicular juvenile granulosa cell tumors (JGCTs) are a rare type of sex cord-stromal tumor, accounting for <5% of all neoplasms of the prepubertal testis. Previous reports have demonstrated sex chromosome anomalies in a small subset of cases, but the molecular alterations associated with JGCTs remain largely undescribed. We evaluated 18 JGCTs using massive parallel DNA and RNA sequencing panels. The median patient age was <1 month (range, newborn to 5 months). The patients presented with scrotal or intra-abdominal masses/enlargement, and all underwent radical orchiectomy (17 unilateral and 1 bilateral). The median tumor size was 1.8 cm (range, 1.3-10.5 cm). Histologically, the tumors were purely cystic/follicular or mixed (ie, solid and cystic/follicular). All cases were predominantly epithelioid, with 2 exhibiting prominent spindle cell components. Nuclear atypia was mild or absent, and the median number of mitoses was 0.4/mm2 (range, 0-10/mm2). Tumors frequently expressed SF-1 (11/12 cases, 92%), inhibin (6/7 cases, 86%), calretinin (3/4 cases, 75%), and keratins (2/4 cases, 50%). Single-nucleotide variant analysis demonstrated the absence of recurrent mutations. RNA sequencing did not detect gene fusions in 3 cases that were sequenced successfully. Recurrent monosomy 10 was identified in 8 of 14 cases (57%) with interpretable copy number variant data, and multiple whole-chromosome gains were present in the 2 cases with significant spindle cell components. This study demonstrated that testicular JGCTs harbor recurrent loss of chromosome 10 and lack the GNAS and AKT1 variants described in their ovarian counterparts.

Myoid gonadal stromal tumours are characterised by recurrent chromosome-level copy number gains: molecular assessment of a multi-institutional series.

Myoid gonadal stromal tumours (MGST) represent a rare type of testicular sex cord-stromal tumour that has recently been recognised as a distinct entity by the World Health Organization (WHO) classification of genitourinary tumours. MGSTs affect adult men and have been reported to behave in an indolent fashion. Histologically, MGSTs are pure spindle cell neoplasms that coexpress SMA and S100 protein. Given that the molecular features of these neoplasms remain largely undescribed, we evaluated a multi-institutional series of MGSTs using DNA and RNA sequencing. This study included 12 tumours from 12 patients aged 28 to 57 years. Tumour sizes ranged from 0.6 to 4.3 cm. Aggressive histologic features, such as vascular invasion, necrosis, invasive growth, and atypical mitoses were invariably absent. Mitotic activity was low, with a median of less than 1 mitosis per 10 high power fields (HPF; maximum: 3 mitoses per 10 HPF). Molecular analyses did not identify recurrent mutations or gene fusions. All cases with interpretable copy number variant data (9/10 cases sequenced successfully) demonstrated a consistent pattern of chromosome arm-level and whole-chromosome-level copy number gains indicative of ploidy shifts, with recurrent gains involving chromosomes 3, 6, 7, 8, 9, 11, 12, 14q, 15q, 17, 18q, 20, and 21q. Similar findings have also been recognised in pure spindle cell and spindle-cell predominant sex cord-stromal tumours without S100 protein expression. MGSTs are characterised by ploidy shifts and may be part of a larger spectrum of spindle cell-predominant sex cord-stromal tumours, including cases without S100 protein expression.

Large cell calcifying Sertoli cell tumour: molecular and immunohistochemical assessment of a series comprising non-metastasising and metastasising neoplasms.

Large cell calcifying Sertoli cell tumour (LCCSCT) is a type of testicular sex cord-stromal tumour that may occur sporadically or in the context of Carney complex and other genetic syndromes. A subset is clinically malignant, and the molecular mechanisms that drive such aggressive behaviour remain unknown. METHODS AND RESULTS: We analysed 21 samples from 20 patients with LCCSCT (12 non-metastasising and eight metastasising) using PRKAR1A immunohistochemistry (IHC) and next-generation sequencing. All tumours except two (cases 17 and 20, both metastasising) demonstrated loss of PRKAR1A expression. Among 11 cases with interpretable sequencing results, all harboured pathogenic single nucleotide variants of PRKAR1A. Evidence of loss of heterozygosity (LOH) of PRKAR1A was present in all tumours with interpretable zygosity data, but the mechanisms of LOH were different for non-metastasising and metastasising tumours. Non-metastasising tumours demonstrated only copy-neutral LOH, while metastasising tumours demonstrated a spectrum of mechanisms of LOH, including copy-loss LOH, two concurrent mutations or copy-neutral LOH. Relevant molecular findings in non-metastasising LCCSCT were limited to PRKAR1A variants. In contrast, all metastasising LCCSCTs with interpretable data harboured additional pathogenic variants, including (but not restricted to) BRCA2 mutations with evidence of LOH and bi-allelic CDKN2A/B deletions. Three patients harboured PRKAR1A variants of inferred germline origin, including one with Carney complex and two without known syndromic features. CONCLUSIONS: This study further confirms that PRKAR1A IHC is a useful diagnostic tool for both non-metastasising and metastasising tumours and suggests that molecular analyses can be helpful to identify non-metastasising tumours with malignant potential in selected patients. Importantly, these results highlight that germline assessment could be beneficial for all patients presenting with LCCSCT.

Impact of surgery and chemotherapy in ovarian sex cord-stromal tumors from the multicentric Salomé study including 469 patients. A TMRG and GINECO group study.

OBJECTIVE: Identifying prognostic factors and evaluating the impact of adjuvant chemotherapy in patients with sex cord stromal tumors (SCST) is crucial. In this study, we aimed to address these challenges. METHODS: We conducted a retrospective analysis of data from 13 centers of the French Rare malignant gynecological tumors (TMRG) network. We enrolled 469 adult patients with malignant SCST who received upfront surgery since 2011 to July 2015. RESULTS: 75% were diagnosed with adult Granulosa cell tumors, and 23% had another subtype. With a median follow-up of 6.4 years, 154 patients (33%) developed a first recurrence, 82 (17%) two recurrences, and 49 (10%) three recurrences. Adjuvant chemotherapy was administered in 14.7% of patients at initial diagnosis. In relapse, perioperative chemotherapy was administered in 58.5%, 28.2%, and 23.8% of patients, respectively, in the first, second, and third relapse. In the first-line therapy, age under 70 years, FIGO stage, and complete surgery were associated with longer progression-free survival (PFS). Chemotherapy had no impact on PFS in early-stage disease (FIGO I-II). The PFS was similar using BEP or other chemotherapy regimens (HR 0.88 [0.43; 1.81]) in the first-line therapy. In case of recurrence, PFS was statistically prolonged by complete surgery, but perioperative chemotherapy use did not impact PFS. CONCLUSION: Chemotherapy use did not impact survival in the first-line or relapse setting in SCST. Only surgery and its quality demonstrated benefit for PFS in ovarian SCST in any lines of treatment.