Sertoli-Leydig Cell Tumor Research Articles

BILATERAL MALIGNANT OVARIAN SERTOLI-LEYDIG CELLTUMOR :A CASE REPORT

Ovarian stromal and or sex cord tumors develop from the supportive tissue of the ovaries. Within this group of tumors, we distinguish granulosa tumors, androblastomas(Sertoli Leydig tumors), sex cord tumors with annular tubules, steroid cell tumors and fibrosarcomas. Most of these tumors synthesize ovarian hormones: estrogens, androgens and corticosteroids. Sertoli Leydig tumors are almost always benign, while others are malignant with locoregional recurrences. Their prognosis is uncertain. The poorly differentiated forms of Sertoli-Leydig tumors have a significant potential for malignancy. We report the case of a 45-year-old patientwith a large non-secreting ovarian tumor, whose biopsy suggested a Sertoli-Leydig tumor, of intermediate differentiation. We decided to perform surgical excision, which revealed a tumor at the stage of peritoneal carcinomatosis. And a cytoreductive procedure was performed. Surgery is the mainstay of treatment, and should be supplemented by chemotherapy in case of malignancy.

SWOG/NCI Phase II Dual Anti-CTLA-4/PD-1 Blockade in Rare Tumors (DART): Non-Epithelial Ovarian Cancer.

The role of dual checkpoint inhibition in advanced rare/ultra-rare non-epithelial ovarian cancers (NEOCs) is yet to be explored. DART is a prospective, multicenter (1,016 US sites), multi-cohort, single-arm phase II trial conducted through the Early Therapeutics and Rare Cancer SWOG/NCI Committee, assessing ipilimumab (anti-CTLA-4) (1mg/kg every 6 weeks) and nivolumab (anti-PD-1) (240mg every 2 weeks) in adults with advanced NEOCs who lack beneficial standard therapy. Primary outcome was overall response rate [ORR; complete response (CR)/partial response (PR)]; secondary outcomes were progression-free survival (PFS), overall survival (OS), clinical benefit rate [CBR; stable disease (SD) ≥6 months plus ORR], and toxicity. Seventeen patients (median age: 64; number of prior therapies ranged from 0-8 with no immunotherapy exposure; 8 granulosa, 6 carcinosarcomas, 1 Sertoli-Leydig, 1 yolk sac, 1 Wolffian) were evaluated. In granulosa cell tumors, ORR was 25% (n=2/8; 1 CR, 1 PR) and CBR, 50% (n=4/8); PFS of 58.3 (CR), 50.7+ (PR), 30.4 (SD), and 8.7 (SD) months. Median PFS was 3.5 months (95% confidence intervals (CI) 1.7-11.2 months); median OS, 42.5 months (95% CI 10.1 months-not reached). One Sertoli-Leydig cell tumor showed a 22% regression (PFS 11.2 months). Carcinosarcomas had no response. Three participants (18%) discontinued treatment due to grade 3-4 adverse events. Ipilimumab-nivolumab shows activity in treatment-refractory granulosa cell tumors, with 25% (n=2/8) of patients experiencing either CR or PR lasting over 4 years.​.

DICER1-Related Tumor Predisposition: Identification of At-risk Individuals and Recommended Surveillance Strategies.

DICER1-related tumor predisposition increases risk for a spectrum of benign and malignant tumors. In 2018, the International Pleuropulmonary Blastoma (PPB)/DICER1 Registry published guidelines for testing and imaging-based surveillance of individuals with a known or suspected germline DICER1 pathogenic or likely pathogenic (P/LP) variant. One of the Registry's goals is to continue to refine these guidelines as additional data becomes available. Individuals were enrolled in the International PPB/DICER1 Registry, the International Ovarian and Testicular Stromal Tumor Registry, and/or the National Cancer Institute Natural History of DICER1 Syndrome study. Review of participant records identified 713 participants with a germline DICER1 P/LP variant from 38 countries. To date, 5 cases of type I and 29 cases of type Ir PPB have been diagnosed by surveillance in enrolled individuals. One hundred and three individuals with a germline P/LP variant developed a primary ovarian Sertoli-Leydig cell tumor (SLCT) at a median age of 14 years (range: 11 months-66 years); 13% were diagnosed under age 8 years, the current age of onset of pelvic surveillance. Additionally, 4% of SLCTs were diagnosed before the age of 4 years. Ongoing data collection highlights the role of lung surveillance in the detection of early PPB and suggests that imaging-based detection and early resection may decrease the risk of advanced PPB. DICER1-related ovarian tumors were detected before age 8 years, prompting the Registry to recommend earlier initiation of ovarian surveillance with pelvic ultrasound beginning at the time of detection of a germline DICER1 P/LP variant.

8661 A case of post-menopausal female with virilization due to Sertoli-Leydig cell ovarian tumor recurring in contralateral ovary 8 years later

Abstract Disclosure: M.S. Maharaul: None. J.L. Miller: None. Introduction: Sertoli-Leydig cell tumors (SLCTs) are rare androgen-secreting tumors of the ovaries, accounting for less than 0.5% of all ovarian tumors. Their incidence peaks in the second to third decade of life. New onset of severe hyperandrogenism with virilization in postmenopausal women is exceedingly rare, and the three most frequent causes are ovarian tumors, ovarian hyperthecosis and adrenal androgen producing tumors. We report one such case of ovarian androgen producing tumor which was further complicated by recurrence in the contralateral ovary. Case: A 66-year-old woman presented for evaluation of hyperandrogenism. Physical examination revealed evidence of virilization and clitoromegaly. Laboratory workup was remarkable for total serum testosterone level of 367 ng/dL with normal dehydroepiandrosterone sulfate and cortisol levels. A computerized scan of abdomen did not show any adrenal masses. Transvaginal ultrasound revealed uterine myomas but did not show any ovarian pathology. She underwent selective vein catheterization of her adrenal glands as well as ovaries and was noted to have right ovary secreting 3,982 ng/dL of testosterone whereas all other samples had total testosterone levels < 200 ng/dL. She underwent right salpingo-oophorectomy. Histopathologic examination revealed a 2.2 cm well differentiated Sertoli-Leydig cell tumor confined to the ovary; the fallopian tube was negative for tumor. Six weeks later, her serum total testosterone level was 18 ng/dL. 8 years later, she returns with recurrent symptoms of hyperandrogenism. Repeat workup revealed a total testosterone level of 662 ng/dL. A computerized scan of abdomen and transvaginal ultrasound revealed an unremarkable uterus and left ovary. Magnetic resonance imaging of the pelvis was done that showed a 1.2 cm enhancing mass in the left ovary. She then underwent left salpingo-oophorectomy and supracervical hysterectomy. Histopathologic examination revealed a 1.5 cm Sertoli-Leydig-cell tumor of the left ovary, the fallopian tube was negative for tumor. Six weeks later, her serum total testosterone level was 24 ng/dL and she felt significant improvement in her symptoms. Conclusion: We present an interesting case of virilization in a post-menopausal female due to Sertoli-Leydig cell tumor that resolved after unilateral oophorectomy but recurred 8 years later in the contralateral ovary with resolution after completion oophorectomy. Presentation: 6/2/2024

7452 A Diagnostically Challenging Case of Hyperandrogenism in Postmenopausal Woman

Abstract Disclosure: M.S. Hossain: None. S. Hossain: None. B. Gautam: None. H. liao: None. S.C. Kumar: None. D.S. Rosenthal: None. Background: The diagnosis of new-onset severe hyperandrogenism in postmenopausal women is rarely encountered, posing a unique challenge for clinicians. Ovarian hyperthecosis and androgen-secreting tumors are the usual suspects in post menopause. In our case ovarian hyperthecosis is the primary consideration but elevated 17-OH Progesterone (17-OHP) introduces the potential co-existence of Non classical congenial adrenal hyperplasia (NCCAH) or rare instances of Sertoli-Leydig Cell Tumor (SLCT). Case Presentation: A 70 years old female, with no past medical history, referred to the Endocrinology clinic for significantly elevated testosterone level. She reported excessive hair growth in various areas of her body since 2022, which required shaving almost every day. She also reported male pattern hair loss and weight loss of 15 lbs over the last three months. She denied headache, vision changes, deepening of voice, history of fertility problems and use of exogenous testosterone. Her vital sign were normal. On examination, she had clitoromegaly, terminal hair growth on her upper lip and chin, breast atrophy, male pattern baldness, but no cushingoid or acromegaly features. Blood tests showed significantly elevated total testosterone: 1422 ng/dl (2-45); free testosterone: 147.9 pg/ml (0.2-3.7) and Estradiol: 64 pg/ml (Postmenopausal <31) with low LH: 7.6 mIU/ml (Postmenopausal 10.0-54.7) and FSH: 22.2 mIU/mL (Postmenopausal 23-116). Her serum ACTH, DHEA Sulfate, 11-deoxycortisol, 17 OH pregnenolone, TSH, Free T4, prolactin, IGF-1 were normal while her 17-OHP: 396 ng/dl (<45 ng/dl) was significantly elevated. An ACTH stimulation test showed 17-OHP level of 734 ng/dl at 30 minutes and 901 ng/dl at 1 hour. Pelvic ultrasonography: right ovary of 2.3 x 1.6 x 1.9 cm and the left ovary of 3.1 x 1.8 x 3.0 cm. MRI showed normal adrenal glands but a prominent left ovary. Patient was referred to the Obstetrics department to undergo bilateral oophorectomy for the definitive diagnosis and treatment. Discussion: The current ACTH stimulation test for non-classical congenital adrenal hyperplasia is validated for premenopausal women but lacks standardization in post-menopausal state. In our case, distinguishing the source of elevated 17-OHP between adrenal (NCCAH) and ovarian (SLCT) was difficult. Unexpected asymmetry in ovarian size observed in our case further complicates the scenario, contrasting with the typical symmetrical enlargement seen in ovarian hyperthecosis. Pending surgical pathology will further guide the management. This case highlights the complexity of diagnosing hyperandrogenism in postmenopausal women, emphasizing the significance of thoroughly exploring differential diagnoses and meticulously analyzing laboratory results. Presentation: 6/2/2024

Characteristics and prognostic implications of a cohort of 50 Sertoli-Leydig cell tumors at a single center.

The aim of the study was to investigate the clinical characteristics, therapy strategies and prognosis of Sertoli-Leydig cell tumors (SLCTs). A total of 50 cases of ovarian SLCTs were retrospectively analyzed. We performed descriptive statistics to describe baseline characteristics. A total of 70% of SLCT patients were below the age of 45 years. The dominant pathologic types were poor (40%) and moderate (40%) differentiation. Retiform variant tumor is more aggressive and tends to appear in children. According to the 2014 FIGO (the International Federation of Gynecology and Obstetrics) classification, tumors were classified as Stage I (n = 46: well differentiated, n = 4; moderately differentiated, n = 19; poorly differentiated, n = 18; and retiform, n = 5), Stage II (n = 1, moderately differentiated), Stage III (n = 1, poorly differentiated), and Stage IV (n = 2: poorly differentiated, n = 1; and retiform, n = 1). Median follow-up was 58.1 months (2-132 months). A total of 45 patients (90%) achieved clinical remission. Four patients experienced a relapse (34.5 months, range: 7-58) and one patient died of the tumor at 10 months after initial treatment. All patients in grossly Stage IA achieved complete response, irrespective of the presence or absence of staging surgery or chemotherapy. After treatment, five patients successfully gave birth to healthy babies. The prognosis for women diagnosed with early stage (I-II) SLCT is generally favorable, especially Stage IA. while those with advanced stages, poorly differentiated, retiform variant, or tumors containing heterologous components exhibit a more aggressive clinical course. Fertility sparing surgery appears to represent a feasible treatment approach for early stage SLCTs.

Sertoli-Leydig tumors and the psychological impact on the patient - Case report

Sertoli-Leydig tumors and the psychological impact on the patient - Case report

Challenges in diagnosing ovarian sertoli-leydig cell tumors:<br /> A Peruvian case series

Challenges in diagnosing ovarian sertoli-leydig cell tumors:<br /> A Peruvian case series

The role of stathmin expression in the differential diagnosis, prognosis, and potential treatment of ovarian sex cord-stromal tumors

BackgroundStathmin, a cytosolic microtubule-destabilizing phosphoprotein involved in the regulation of mitosis, is widely expressed in various malignancies and acts as an adverse prognostic factor. Our research analyzed its immunohistochemical expression on a large cohort of ovarian sex cord-stromal tumors, evaluating its potential utility in differential diagnosis, prognosis, and therapeutic application.MethodsWe examined 390 cases of ovarian sex cord-stromal tumors including 281 adult granulosa cell tumors (AGCT), 5 juvenile granulosa cell tumors (JGCT), 33 Sertoli-Leydig cell tumors (SLCT), 50 fibromas/thecomas (F/T), 11 Leydig cell tumors/steroid cell tumors (LCT/SterCT), 5 sex-cord stromal tumors NOS (SCST-NOS), 3 Sertoli cell tumors (SCT), and 2 sclerosing stromal tumors (ScST). Immunohistochemical analysis was performed using TMAs.ResultsStrong expression (> 50%) was observed in all cases of AGCT, JGCT, SLCT, SCST-NOS, SCT and 1 ScST. The other case of ScST exhibited mild expression (5–10%). The negative cases included exclusively F/T and LCT/SterCT, with F/T showing 24% of negative cases and LCT/SterCT comprising 64% of negative cases.ConclusionThe results of our study indicate that stathmin is neither a prognostic marker nor suitable for the differential diagnosis of challenging cases of ovarian sex cord-stromal tumors. However, its predictive value may be theoretically significant, as a decrease in stathmin expression potentialy influences response to chemotherapy treatment.

STK11 (LKB1) immunohistochemistry is a sensitive and specific marker for STK11 adnexal tumours.

STK11 adnexal tumour is a rare, recently described malignant neoplasm that is associated with Peutz-Jeghers syndrome. [Correction added on 3 October 2024, after first online publication: 'ST11' in preceding sentence has been corrected to 'STK11' in this version.] It predominantly originates from the para-adnexal soft tissues and often shows secondary involvement of the fallopian tube and ovary. STK11 adnexal tumours have a broad differential diagnosis due to their variable morphology and non-specific immunoprofile, and diagnostic confirmation currently requires sequencing to identify an STK11 mutation. We investigate the diagnostic utility of STK11 (LKB1) immunohistochemistry (IHC) in a cohort of STK11 adnexal tumours and morphological mimics. IHC for STK11 was performed on 122 tumours, including 17 STK11 adnexal tumours and 105 morphological mimics (10 female adnexal tumours of Wolffian origin, 22 adult granulosa cell tumours, 10 juvenile granulosa cell tumours, four Sertoli-Leydig cell tumours, two Leydig cell tumours, one Sertoli cell tumour, one steroid cell tumour, four extra-ovarian sex cord-stromal tumours, 16 ovarian endometrioid carcinomas, eight tubo-ovarian high-grade serous carcinomas, five ovarian mesonephric-like adenocarcinomas, 14 ovarian carcinosarcomas, five peritoneal malignant mesotheliomas, two pelvic plexiform leiomyomata and one ovarian solid pseudopapillary tumour). All STK11 adnexal tumours showed complete loss of cytoplasmic staining for STK11. All other tumour types showed retained cytoplasmic staining, except for one endometrioid carcinoma with mucinous differentiation which showed complete loss of STK11 expression and a high-grade serous carcinoma with subclonal loss. STK11 is a highly sensitive and specific immunohistochemical marker for distinguishing STK11 adnexal tumour from its histological mimics, and can obviate the need for confirmatory molecular studies in the appropriate morphological context.

DICER1-sarcomas of GYN tract: Expanding on an emerging entity

Tumors with pathogenic DICER1 mutation are rare and encompass sporadic or hereditary benign, intermediate and malignant tumors. DICER1-associated sarcomas are heterogeneous; however, the prototypical ones in the GYN-tract include embryonal rhabdomyosarcoma, adenosarcoma and moderately to poorly differentiated Sertoli-Leydig tumor. In this report, we present three unique uterine sarcomas with DICER1 mutation and remarkable diffuse round/spindle cell morphology. The tumors occurred in cervix (n = 1), and uterine corpus (n = 2). The patient ages were 30, 37 and 59 years with tumor size of 8.8, 10 and 8.6 cm, respectively. Morphologically all three tumors were characterized by distinct spindle/round cell morphology and various amounts of neuroectodermal differentiation (yolk sac-like tubules, blastomatous areas and rosette formation). Other morphologic features of DICER1-sarcoma reported in the literature including cambium layer, focal or diffuse anaplasia, solid and cystic architecture, and chondroid/osteoid areas were absent. All three sarcomas were positive for SALL4 and had variable neuroendocrine marker expression. Whole genome methylation analysis was performed on one of the uterine sarcomas, which clustered the tumor with embryonal tumor with multilayered rosettes. Follow up information was available on all three cases. Two patients were alive with no evidence of disease 13 and 14 months post operation, while one patient had imaging evidence of local recurrence 4 months post operation. In summary, we describe three unique DICER1-sarcomas and expand the phenotypic spectrum of this emerging entity, particularly with GYN-tract origin.

Sidonia and Nicu de Barcsy: a famous mother with post-partum hirsutism after giving birth to a famous son with idiopathic short stature.

At the end of the 19th century, an 18-year-old lady gave birth to a well-proportioned, though very small, son. After delivery, the mother developed a full-grown beard, whereas the son always remained of small stature. The mother developed diabetes mellitus and died, aged 59, from a complicated severe cold. The son died at the age of 91 because of chronic kidney disease. The differential diagnosis in the son is isolated growth hormone deficiency. The mother might have suffered luteoma of pregnancy, polycystic ovary syndrome (PCOS), or Sertoli-Leydig cell tumor(s). The two cases are apparently coincidental/not related in pathophysiology. Hirsutism occurring directly postpartum can have several causes. Patients with isolated growth hormone deficiency can live a long life without the substitution of growth hormone. Coincidence does not necessarily imply correlation. In the past, patients with endocrine disorders like severe hirsutism or small stature were employed at circuses and fairs to entertain the audience as curiosities.

DICER1 Tumor Syndrome: A Retrospective Review and Future Perspectives

DICER1 syndrome, a rare autosomal dominant genetic disorder, stems from mutations in the DICER1 gene, disrupting RNA interference and leading to various tumors. These tumors, affecting organs like the lung, kidney, ovaries, and brain, pose diagnostic challenges due to diverse presentations. Understanding DICER1-associated tumors, including pleuropulmonary blastoma, ovarian Sertoli–Leydig cell tumors, and others, is vital for early detection and management. Surgical resection, chemotherapy, and targeted therapies are primary treatment modalities, with genetic counseling playing a crucial role. Multidisciplinary care is essential for optimal management, offering hope for improved outcomes in affected individuals.

45MO Management of stage I ovarian Sertoli-Leydig cell tumors: Prognostic factors from a multicenter international retrospective study

45MO Management of stage I ovarian Sertoli-Leydig cell tumors: Prognostic factors from a multicenter international retrospective study

Sertoli-Leydig Cell Tumour in a Patient with Ambiguous Genitalia and Congenital Adrenal Hyperplasia

Background: Hyperandrogenism, characterized by elevated levels of male hormones such as testosterone, presents various clinical manifestations including secondary amenorrhea, hirsutism, and clitoromegaly. While often associated with polycystic ovarian syndrome, other differentials such as Sertoli-Leydig cell tumors and Congenital Adrenal Hyperplasia (CAH) are critical to consider. These conditions can manifest at different life stages and are seldom seen together. Objective: This case study aims to explore the rare co-presentation of CAH and a Sertoli-Leydig cell tumor in a patient presenting with secondary amenorrhea and ambiguous genitalia, and to discuss the diagnostic challenges and management strategies involved. Methods: A 16-year-old female presented with irregular menstrual cycles and secondary amenorrhea, alongside symptoms of hyperandrogenism such as voice deepening and hirsutism. Diagnostic procedures included physical examinations, ultrasound imaging, and hormone level assessments. A detailed ultrasound revealed a large right-sided ovarian mass, and biopsies confirmed a Sertoli-Leydig cell tumor. Surgical intervention involved the excision of the mass, with subsequent histopathological examination. The patient underwent three cycles of chemotherapy and was scheduled for reconstructive surgery. Results: Ultrasound dimensions of the ovarian mass were 7.2 x 13.4 x 16 cm, with the post-surgical tumor measuring 18 x 17 cm. Laboratory findings included testosterone levels above 200 ng/ml, and elevated alpha-fetoprotein levels. The histopathological report confirmed a poorly differentiated Sertoli-Leydig cell tumor (FIGO stage 1a). Post-treatment follow-up showed a marked reduction in androgen levels and stabilization of the patient's menstrual cycle. Conclusion: The coexistence of CAH and a Sertoli-Leydig cell tumor presents unique diagnostic and therapeutic challenges. This case emphasizes the importance of a thorough evaluation and a multidisciplinary approach in the management of complex hyperandrogenic states to achieve optimal clinical outcomes.

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

ObjectiveSertoli-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. MethodsIndividuals 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. ResultsIn 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). ConclusionMost 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.

Histone H3 trimethylation on lysine 27 immunostaining pattern in DICER1-associated tumors.

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. 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. 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. 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.

Abstract 5463: Germline DICER1 loss promotes rhabdomyosarcoma via innate immune system

Abstract DICER1 syndrome is a cancer predisposition syndrome where affected patients have increased risk of neoplasms including pleuropulmonary blastoma, Sertoli-Leydig cell tumor, and fusion-negative rhabdomyosarcoma (FN-RMS). This syndrome is defined by germline heterozygous loss of function mutations in the gene DICER1, but it remains unclear exactly how these mutations predispose children to develop cancer. One would expect the germline loss of one allele to provide a sensitized background in the tumor cell to acquire a second hit mutation. To gain insight into the role of Dicer1 loss in FN-RMS, we deleted the Dicer1 gene both globally in the germline and conditionally in the tumor cell in our previously established mouse model of FN-RMS. Surprisingly, we observed faster tumor onset and increased penetrance in mice with germline heterozygous Dicer1 loss (Dicer1+/-) but not in mice where Dicer1 loss was restricted to the tumor cells, demonstrating that Dicer1 functions as a non-cell autonomous haploinsufficient tumor suppressor. Single cell RNA sequencing (scRNA-Seq) revealed massive expansion of immature neutrophils in Dicer1+/- tumors, which were enriched for proteases associated with neutrophil extracellular traps (NETs). NETs are webs of chromatin and proteases released when neutrophils undergo NETosis in response to inflammatory stimuli. These NETs are known to cause significant damage to the local extracellular matrix (ECM) and have been implicated in tumor promotion. In addition to the neutrophil enriched immunophenotype, we found that Dicer1+/- tumors show significant ECM remodeling and are enriched for C5a, the potent neutrophil chemoattractant and NET-priming factor. Taken together, these results suggest NETosis is upregulated in Dicer1+/- FN-RMS tumors. Performing iTALK ligand-receptor pair analysis on the scRNA-Seq data revealed a putative interaction between a NET-derived ligand and EGFR and IGF1R on tumor cells, suggesting direct tumor promoting signaling from NET-to-tumor. We validated this novel FN-RMS promotion mechanism in vitro using human FN-RMS cell lines and observed that this NET-derived ligand promoted FN-RMS growth in a dose-dependent manner and could function through both EGFR and IGF1R signaling. Finally, we incorporated a Padi4-/- allele into our tumor model to genetically block NETosis and observed complete rescue of the accelerated tumor onset and increased penetrance observed in Dicer1+/- mice, demonstrating that NETosis promotes the growth of Dicer1+/- FN-RMS tumors. Importantly, these findings may be applicable to many DICER1 syndrome-associated cancers, as neutrophils which get converted to tumor promoters by heterozygous DICER1 loss are present in DICER1 syndrome patients regardless of tumor type. Citation Format: Randolph Larsen, Jason Hanna, Kristin Reed, Hongjian Jin, Wood Kimbrough, Kyna Vuong, Myron Evans, Casey Langdon, Catherine Drummond, Matthew Garcia, David Finkelstein, Patrick Schreiner, Jerold Rehg, Mark Hatley. Germline DICER1 loss promotes rhabdomyosarcoma via innate immune system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5463.

Steroidogenic Acute Regulatory Protein Is a Useful Marker for Sex-Cord-Stroma Tumors and Normal and Neoplastic Adrenocortical Tissue.

Steroidogenic acute regulatory (StAR) protein is a mitochondrial transport protein with a critical regulatory role for steroid hormone production. The tissue distribution of StAR expression is limited to few human normal tissues. To assess the diagnostic and prognostic value of StAR immunohistochemistry analysis. A tissue microarray containing 19 202 samples from 152 different tumor types and subtypes and 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry. StAR immunostaining occurred in 198 (1.2%) of the 17 135 analyzable tumors. StAR expression was observed in 27 of 152 tumor categories, 9 of which included at least 1 strongly positive case. The highest rate of StAR positivity occurred in Leydig cell tumors of the testis and the ovary (100%), steroid cell tumors of the ovary (100%), adrenocortical carcinomas (93%) and adenomas (87%), Sertoli-Leydig cell tumors (67%) and granulosa cell tumors of the ovary (56%), as well as seminomas (7%). Nineteen other tumor entities showed-a usually weak-StAR positivity in less than 6% of cases. A comparison with preexisting Melan-A (a melanocyte antigen) data revealed that StAR was more often positive in adrenocortical neoplasms and in Leydig cell tumors while StAR (but not Melan-A) was negative in Sertoli cell tumors. Our data provide a comprehensive overview on the patterns of StAR immunostaining in human tumors and suggest a diagnostic utility of StAR immunohistochemistry for supporting a diagnosis of Leydig cell tumors or of normal or neoplastic adrenocortical tissue.

Histopathological and Immunohistochemical Evaluation of Malignant Ovarian Tumours

Objective: To determine the frequency and histological types of malignant ovarian tumours using morphological features and immunohistochemistry. Study Design: Cross-sectional study. Place and Duration of Study: Department of Histopathology, Army Medical College, Rawalpindi Pakistan, Jan 2016 to Dec 2018. Methodology: Newly diagnosed cases of malignant ovarian tumour who had not received chemotherapy were included. Cases of benign ovarian tumours and those who were treated with pre-surgical chemotherapy were excluded. Results: In total, 118 cases of malignant ovarian tumours were evaluated. High-grade serous carcinomas were 61(51.7%), which outnumber others, followed by granulosa cell tumours 17(14.4%), germ cell tumours 13(11%), endometrioid carcinoma 9(7.6%), clear cell carcinoma 4(3.4%), mucinous carcinoma 4(3.4%), low-grade serous carcinoma 2(1.7%) and carcinosarcoma in one case (0.8%). Cancer in the ovary was metastatic in 7(5.9%) cases. No Sertoli Leydig cell tumour, malignant Brenner tumour, embryonal carcinoma or immature teratomas were diagnosed. Conclusion: Surface epithelial tumours were the most common malignancy, followed by granulosa cell tumours and dysgerminoma. An increase in the frequency of ovarian tumours in younger age groups was also noted. Immunohistochemistry was a useful adjuvant diagnostic tool in cases of ovarian malignancy. Metastases to the ovary were mostly gastrointestinal in origin.