Testicular Sex Cord-stromal Tumors Research Articles

Frequency of Androgen Receptor Positivity in Tumors: A Study Evaluating More Than 18,000 Tumors.

Androgen receptor (AR) is a transcription factor expressed in various normal tissues and is a therapeutic target for prostate and possibly other cancers. A TMA containing 18,234 samples from 141 different tumor types/subtypes and 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry. AR positivity was found in 116 tumor types including 66 tumor types (46.8%) with ≥1 strongly positive tumor. Moderate/strong AR positivity was detected in testicular sex cord-stromal tumors (93.3-100%) and neoplasms of the prostate (79.3-98.7%), breast (25.0-75.5%), other gynecological tumors (0.9-100%), kidney (5.0-44.1%), and urinary bladder (5.4-24.2%). Low AR staining was associated with advanced tumor stage (pTa versus pT2-4; p < 0.0001) in urothelial carcinoma; advanced pT (p < 0.0001), high tumor grade (p < 0.0001), nodal metastasis (p < 0.0001), and reduced survival (p = 0.0024) in invasive breast carcinoma; high pT (p < 0.0001) and grade (p < 0.0001) in clear cell renal cell carcinoma (RCC); and high pT (p = 0.0055) as well as high grade (p < 0.05) in papillary RCC. AR staining was unrelated to histopathological/clinical features in 157 endometrial carcinomas and in 221 ovarian carcinomas. Our data suggest a limited role of AR immunohistochemistry for tumor distinction and a prognostic role in breast and clear cell RCC and highlight tumor entities that might benefit from AR-targeted therapy.

Familial syndromes associated with testicular and paratesticular neoplasms: a comprehensive review.

A syndromic association between a subset of testicular/paratesticular neoplasms is well established. Such examples include Carney complex and large cell calcifying Sertoli cell tumor, Peutz-Jeghers syndrome and intratubular large cell hyalinizing Sertoli cell neoplasia, and VHL syndrome and clear cell papillary cystadenoma of the epididymis.However, recent studies proposed potential novel links between some testicular and paratesticular neoplasms with certain tumor syndromes. While more studies are still needed to solidify these associations, recent research suggests that a subset of Leydig cell tumors may arise in patients with hereditary leiomyomatosis and renal cell carcinoma syndrome or that some seminomas may occur in Lynch syndrome patients. Additionally, an association between testicular sex cord stromal tumors and paratesticular sarcomas with Familial adenomatous polyposis syndrome and DICER1 syndrome, respectively, has been proposed as well. This review provides a comprehensive overview of the intricate relationship between familial syndromes and associated testicular and paratesticular tumors, shedding light on their clinicopathological and molecular characteristics.

β-Catenin alterations in testicular Leydig cell tumour: a immunohistochemical and molecular analysis.

Testicular Leydig cell tumours (LCTs) are the most common type of sex cord-stromal tumour in men, representing 1%-3% of all testicular neoplasms. Among testicular sex cord-stromal tumours, CTNNB1 mutations and nuclear expression of β-catenin have been typically associated with Sertoli cell tumour. Recent genomic analyses have shown that CTNNB1 variants are also identified in a subset of LCTs; however, the frequency and clinicopathologic associations of β-catenin alterations remain incompletely understood in this tumour type. In this study, we evaluated 32 LCTs (five malignant/metastasizing, 27 nonmetastasizing) using β-catenin immunohistochemistry and DNA sequencing. Immunohistochemistry revealed focal or multifocal nuclear β-catenin expression in 47% of the tumours. Diffuse nuclear β-catenin expression (in >50% of the tumour cells) was not detected in any of the cases analysed herein. Comparison of β-catenin-positive and β-catenin-negative cases did not show significant differences in the frequency of adverse histopathologic findings or malignant clinical behaviour. DNA sequencing performed de novo on a subset of seven cases revealed the presence of exon 3 CTNNB1 variants in four of them (4/7, 57%), with variant allele frequencies (VAF) ranging from 7 to 33%. Two additional β-catenin-positive cases that had been sequenced as part of a previous study harboured exon 3 CTNNB1 variants at VAF of 28% and 7%, respectively. These results demonstrate that β-catenin alterations are relatively common in LCT, most likely occurring as subclonal events that are not enriched in cases with aggressive features. Further studies are needed to clarify the oncogenic role of β-catenin in this tumour type.

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

Sex cord-stromal tumors (SCST) are hormonally active and rare. The aim was to describe their endocrinological presentation and outcomes. Patients (<19 years) registered in the TGM13 registry between 2014 and 2021 for SCST were selected. 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). SCSTs have a favorable prognosis. Tumorectomy appears safe with testicular primary. Endocrinological disorders, common at diagnosis, may persist warranting endocrinological follow-up.

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.

Germline APC Alterations May Predispose to Testicular Sex Cord-Stromal Tumors.

Sertoli cell tumor is a type of testicular sex cord-stromal tumor (TSCST) typically driven by gain-of-function CTNNB1 variants. Recently, molecular studies have identified TSCSTs (including Sertoli cell tumors) with loss-of-function APC variants, raising the possibility that germline APC alterations may predispose to TSCSTs. In this study, we evaluated 4 TSCSTs from 4 individual patients, including 3 APC -mutant neoplasms identified in prior studies (1 in a patient with familial adenomatous polyposis [FAP] and 2 in patients with unknown syndromic status) and 1 tumor of unknown mutational status diagnosed in a patient with known FAP. Three neoplasms were typical Sertoli cell tumors, and 1 was a malignant unclassified TSCT. All neoplasms exhibited diffuse nuclear beta-catenin expression. Non-neoplastic tissue could be obtained for DNA sequencing in the 3 Sertoli cell tumors. Comparative assessment of non-neoplastic and lesional tissue in these cases suggested that germline APC variants with subsequent inactivation of the gene (loss of heterozygosity) were the likely oncogenic driver of these Sertoli cell tumors. In the malignant unclassified TSCSTs, APC inactivation was also interpreted as the most likely driver event, and the germline origin of the variant was inferred using a recently published method. The results of this study suggest that pathogenic germline APC alterations (eg, FAP and variants thereof) may predispose to TSCSTs.

A Boy with 46,XX Karyotype (SRY double-positive) having a Leydig Cell Tumor.

Leydig cell tumors are the most common type of testicular sex cord stromal tumors. Presence of Y chromosome is associated with tumor risk in sex development disorder (DSD), however tumor development without Y chromosome are extremely rare. A 16-year-old boy diagnosed with Leydig cell tumor due to a mass in the right testis was referred after the right orchiectomy. In physical examination, left testis was 10 ml, and a labium residue in penoscrotal region with bilateral gynecomastia was present. Karyotype was 46,XX, and SRY was double-positive in FISH analysis. Ifosfamide, carboplatin and etoposide chemotherapy was initiated due to Leydig cell tumor. Here, we report the first pediatric case having 46,XX, SRY double-positive testicular DSD with Leydig cell tumor.

An insight into metastatic Leydig cell tumors: A case report

Sex cord-stromal tumors comprise approximately 5% of all testicular tumors, while the remainder are of germ cell origin. Leydig cell tumors are the most common subtype of testicular sex cord-stromal tumors and account for 1%–2% of all testicular tumors. Leydig cell tumors are mostly benign but approximately 5%–10% of them have malignant potential. The commonest metastatic sites are regional lymph nodes, lung, liver, and bones. Here, we report a case of late metastatic relapsed Leydig cell disease in a 73-year-old male. The goal of this care report was to better understand manifestation and management of patients with late relapsed Leydig cell tumors and low-volume disease. Patients with metastatic Leydig cell tumors (or sex cord-stromal tumors) have poor prognosis, and standard treatment recommendations do not exist. Surgical resection of metastasis and/or chemotherapy with bleomycin, etoposide, and cisplatin should be discussed with patients, as some were reported to have complete remission after these interventions. Although there are few literature studies and data to support ideal management, this case has shown that there may be utility for local radiation therapy in unresectable low-volume metastatic Leydig cell disease. A limitation in this report is that we will need long-term follow-up regarding this case. Given the rare occurrence of this malignancy, more data collection going forward will assist in the optimal management of future patients, given this diagnosis.

Clinicopathologic and molecular spectrum of testicular sex cord-stromal tumors not amenable to specific histopathologic subclassification

A subset of testicular sex cord-stromal tumors (SCST), which includes neoplasms with mixed histology, cannot be classified into a specific histologic subtype. This study evaluated the clinicopathologic, immunophenotypic and molecular features of 26 SCST not amenable to specific classification by expert uropathologists. Median age at diagnosis was 43 years and median tumor size was 2.4 cm. Follow-up information was available for 18 (69%) patients, with evidence of an aggressive clinical course in 6 patients (4 alive with disease, 2 dead of disease 3 months and 6 months after orchiectomy). Microscopically, SCST not amenable to specific classification demonstrated monophasic epithelioid (9/26, 35%), monophasic spindle cell (5/26, 19%), and biphasic or mixed histology (12/26, 46%). One or more aggressive histopathologic features were seen in 11 cases. DNA sequencing was successful in 22 tumors. Pathogenic CTNNB1 and APC alterations were seen in 7 (33%) and 2 (10%) cases, respectively, with additional variants (e.g., CDKN2A, RB1, TP53, BRCA2) being identified in individual cases. Combined evaluation of morphology, sequencing data and beta-catenin immunohistochemistry resulted in reclassification of 6 (23%) tumors as Sertoli cell tumor, not otherwise specified. This was supported by comparing the methylation profiles of a subset of these tumors and those of typical Sertoli cell tumors. Additionally, a subset of 5 neoplasms (19%) with spindle cell or biphasic histology and SMA expression was characterized by hyperdiploid genomes with recurrent chromosomal gains and absence of driver mutations, possibly representing a distinct tumor type. The SCST that remained not amenable to specific histologic classification (15/26, 58%) were enriched for aggressive histologic features and malignant clinical behavior. In conclusion, this study demonstrated that a subset of testicular SCST that were originally not amenable to specific classification could be reclassified by combined evaluation of morphology, immunohistochemistry and molecular data.

Malignant testicular unclassified sex cord stromal tumor: a case report

BackgroundMost testicular tumors are germ cell tumors; sex cord stromal tumors are infrequent, accounting for only 3–5% of testicular tumors. Unclassified sex cord stromal tumors are extremely rare. Generally, 10% of sex cord stromal tumors are malignant. We report a case of malignant unclassified sex cord stromal tumor with retroperitoneal lymph node metastasis at first visit and a corresponding literature review.Case presentationA 72-year-old Japanese man visited our department primarily for indolent right scrotum enlargement in September 2020. Blood biochemistry examination, urinalysis, and tumor markers (alpha-fetoprotein, human chorionic gonadotropin, and lactate dehydrogenase) showed no abnormal findings. Contrast-enhanced computed tomography showed enlarged para-aortic lymph node (18 × 16 and 10 × 102 mm); a 50 × 452 mm mass with uneven contents was found in the right testicle. The patient underwent inguinal orchiectomy in September 2020. As per immunohistochemistry, the tumor cells were diffusely positive for SF-1 and Ki-67, partially positive for inhibin, and negative for CAM5.2, CK7, CK20, C-KIT, CD30, LCA, GATA-3, TTF-1, and PAX8. Calretinin was expressed in approximately 5% of tumor cells; thus, sex cord/gonadal stroma components were considered to be involved. The final pathological diagnosis was unclassified malignant sex cord stromal tumor. The patient was diagnosed with pT1, N1, M0, S0, and tumor–node–metastasis stage IIA disease. The patient received postoperative chemotherapy with four courses of etoposide and cisplatin therapy from November 2020. Post-chemotherapeutic computed tomography showed new metastatic lesions including lung, liver, pancreas, and para-aortic lymphadenopathy, which increased in size. Disease progression was observed. Cancer genome research was performed using the OncoGuide National Cancer Center oncopanel system; however, no gene mutation for which the drug could be expected to be effective was found. The patient opted for best supportive care at a nearby hospital and died from cancer progression in January 2022.ConclusionWe encountered a case of malignant testicular unclassified sex cord stromal tumor pathologically diagnosed as testicular tumor with retroperitoneal lymph node metastasis in a patient who underwent inguinal orchiectomy. Future data collection is necessary to establish multimodality therapy for malignant testicular unclassified sex cord stromal tumor.

Sex Cord-Stromal Tumors of Testis: A Clinicopathologic and Follow-Up Study of 15 Cases in a High-Volume Institute of China.

ObjectivesTo report the first series of testicular sex cord-stromal tumors (TSCSTs) with detailed clinicopathologic findings and long-term follow-up in the Chinese population.Patients and MethodsFrom 2008 to 2018, 15 patients with TSCST were included in our study. The tumors were analyzed for epidemiological parameters, clinical characteristics, tumor markers, therapy, and follow-up data.ResultsThe median age of the patients was 28 years (range, 13–80 years). Para-aortic lymph node metastases were detected in 2 patients after radiological evaluation. Orchiectomy was performed in all patients, and the median diameter of the tumor was 1.5 cm (range, 0.5–5.0 cm). Nine Leydig cell tumors (LCTs), 5 Sertoli cell tumors (SCTs), and 1 unclassified type were confirmed after pathologic evaluation. Thirteen patients (86.7%) were categorized as stage I, and 2 patients (13.3%) were categorized as stage II. The median clinical follow-up was 39.0 months (range, 5–97 months), which showed 10 alive patients, such as 1 patient with progression at 40 months after orchiectomy. The 3- and 5-year progression-free survivals were 100 and 90.0%, respectively.ConclusionTesticular sex cord-stromal tumor at stages I and II is a rare subtype with benign behavior and a favorable prognosis in the Chinese population. However, lymph node metastases may be the dominant risk factor for patients with TSCST.

Unclassified testicular sex cord-stromal tumors in children

We report a case of 12-year-old boy diagnosed with an unclassified sex cord stromal testicular tumor after a mild testicular trauma and the unclear ultrasound finding of a testicular mass. Physical examination was significant for a mass in the right testis. Scrotal magnetic resonance revealed an 8 millimeters nodular lesion suggestive of a Leydig cell tumor. Tumor markers were negative. The patient underwent a right radical orchiectomy plus implantation of a testicular prosthesis. Tumor cells expressed inhibin, WT 1, CD 56, CD99, vimentin and actin. Pathological diagnosis was unclassified sex cord stromal tumor confined to the testis. Metastatic workup by CT was negative. Unclassified sex cord-stromal tumors are infrequent and show an indeterminate differentiation of tumor cells that cannot be characterized with light microscopy towards Leydig, Sertoli, granulosa or theca cells. Immunohistochemistry helps in the differential diagnosis.Due to the risk of malignancy, local recurrence and uncertain biological behavior, radical orchiectomy is recommended, and a metastatic workup should be performed. Keywords: children; orchiectomy; sex cord-stromal tumor; scrotal ultrasound; testicular tumor

Promising Immunotherapy in Metastatic Testicular Sex Cord Stromal Tumours After First-Line Chemotherapy.

BackgroundTesticular sex cord stromal tumours (TSCSTs) are rare, with few studies focusing on the metastatic TSCST prognosis. The value of treatments, including radical orchiectomy (RO) and retroperitoneal lymph node dissection (RPLND), in preventing metastasis is controversial. Additionally, metastatic TSCSTs are resistant to chemotherapy. We aimed to assess the effectiveness and safety of immunotherapy in metastatic TSCSTs after first-line chemotherapy.MethodsWe retrospectively screened patients with testicular tumours undergoing testis surgery between January 2005 and January 2019. Patients with TSCSTs who had undergone testis-sparing surgery (TSS) or RO were identified. The malignant type was defined as metastasis confirmed by pathology. Treatment responses, progression-free survival (PFS), overall survival (OS) and safety were analysed.ResultsAmong the 494 testicular tumour patients who received TSS or RO, 11 (2.2%) patients with histologically proven TSCSTs were identified. At the last follow-up, 7 patients survived without tumours, and 4 patients developed metastasis and received first-line cisplatin-based chemotherapy, with 1 of them achieving an objective response. Their PFS times were 1.5, 2.2, 9.0, and 17.0 months, respectively. Two patients received immune checkpoint inhibitors (ICIs) after developing chemotherapy resistance and achieved a partial response up to the last follow-up; one of them experienced Grade 1 adverse events, and the other experienced Grade 2 adverse events during immunotherapy. The median OS time of the 4 patients with metastatic TSCSTs was 32 months.ConclusionsTSCSTs are rare, and most are benign with a good prognosis. ICIs represent a promising option for improving clinical outcomes in metastatic TSCSTs.

Testicular Tumors: A Contemporary Update on Morphologic, Immunohistochemical and Molecular Features

Testicular tumors are incredibly diverse and one of the most challenging areas in surgical pathology. Because of the rarity and overlapping features with numerous entities occurring in the testis and paratestis, these tumors pose a diagnostic challenge even to the most experienced general pathologists. In 2016, the latest "World Health Organization (WHO) classification of testicular tumors" was released, which incorporated several updates to the previous 2004 classification system. These updates involved several entities, including germ cell tumors, sex cord-stromal tumors, tumors containing both germ cells and sex-cord stromal cells, a miscellaneous group of testicular tumors and paratesticular tumors. In addition, significant changes were also introduced in the 2018 AJCC TNM staging (8th edition) regarding testicular tumors. The germ cell tumors are divided into 2 major groups; tumors derived from germ cell neoplasia in situ (GCNIS) and those unrelated to GCNIS. The GCNIS associated tumors include seminomatous and nonseminomatous germ cell tumors, which constitute a heterogeneous group of tumors. Non-GCNIS-associated tumors include prepubertal-type teratoma, prepubertal yolk sac tumor, mixed prepubertal-type teratoma and yolk sac tumor and spermatocytic seminoma. In the sex cord-stromal category, the tumors are classified based on their cells of origin. Most are Leydig cell tumors and Sertoli cell tumors; however, several mixed and diverse entities based on cell types are included in this group. Gonadoblastoma is the only tumor in the mixed germ cell and sex cord-stromal tumor category. Because of recent advances in molecular techniques, abundant new genetic information has emerged which helped classify the tumors based on the molecular alterations and provided insights into the tumor pathogenesis. This review focused on the updates related to testicular germ cell tumors and sex cord-stromal tumors and described the morphologic, immunohistochemical and molecular characteristics with an aim to provide a practical diagnostic approach and an update on relevant recent molecular advances.

Immunohistochemical Characterization of 120 Testicular Sex Cord-Stromal Tumors With an Emphasis on the Diagnostic Utility of SOX9, FOXL2, and SF-1

Sex cord-stromal tumors (SCSTs) account for the second most common category of testicular neoplasms and include several entities that may show overlapping morphologies and present diagnostic challenges. We analyzed a cohort of 120 testicular SCSTs and investigated the diagnostic utility of SRY-box transcription factor 9 (SOX9), forkhead box protein L2 (FOXL2), and steroidogenic factor 1 (SF-1) immunohistochemical stains. The results were compared with the more commonly used SCST markers, inhibin α, calretinin, and Wilms' tumor 1 (WT1). SF-1 was overall the most sensitive stain (91%), followed by inhibin α (70%), calretinin (52%), FOXL2 (50%), SOX9 (47%), and WT1 (37%), but sensitivities varied by tumor type. SOX9 and calretinin were more commonly positive in sex cord elements versus stromal elements (62% vs. 27% and 47% vs. 9%, respectively), whereas FOXL2 was more commonly positive in stromal elements versus sex cord elements (100% vs. 55%) when excluding Leydig cell tumors from the stromal category. Although no individual stain was diagnostically specific, some immunophenotypic patterns were noted that may help in the subclassification of SCSTs. We conclude that SOX9, FOXL2, and SF-1 are useful immunohistochemical stains for confirming sex cord-stromal differentiation in testicular tumors and provide increased sensitivity as well as additional diagnostic information, especially when combined with the more commonly used inhibin α, calretinin, and WT1 immunostains. Although morphology is paramount for subclassification of SCSTs, knowledge of certain immunohistochemical patterns may be helpful for diagnostically challenging cases.

Leydig Cell Tumours: a Case Series from a Single Irish Centre

Leydig cell tumours (LCT) are rare testicular neoplasms that usually follow a benign clinical course. Due to the aggressive, difficult-to-treat nature of metastatic disease arising from a small percentage of LCTs, it is imperative to understand and recognize how to identify those tumours which exhibit features that predict malignant behaviour in order to guide initial surgical and oncological management. By using the well-described high-risk histopathological features of Leydig cell tumours as guidance, the management of LCTs has evolved to commonly include testis-sparing surgery (TSS), in patients who historically would have undergone a complete orchidectomy. Thus, assessment of the clinicopathological features of Leydig cell tumours allows for optimal management of this rare disease, whilst modern technologies and surgical techniques have altered the potential treatment landscape. This does not replace the need for the urologist and medical oncologist to remain vigilant in the risk-stratification of patients presenting with these rare testicular sex cord stromal tumours. We present three cases of patients diagnosed with Leydig cell tumours in a single institution in Dublin, Ireland, between 2016 and 2020 and discuss how the clinicopathological features dictate the management and subsequent follow-up for patients presenting with these rare tumours.

Clinical outcome of patients diagnosed with testicular sex cord stromal tumors.

e17055 Background: Testicular Sex Cord Stromal Tumors (TSCST) are rare representing approximately 5% of testicular cancers. Leydig Cell Tumours (LCT) constitute 1-3% of testicular tumours, occur commonly in third to sixth decade and are up to 50mm in diameter. Sertoli Cell Tumours(SCT) constitute less than 1%, occur commonly in the fourth decade and have an average diameter of 35mm. High-risk histological features include; tumour size, increased mitotic activity, pleomorphic nuclei, necrosis, vascular invasion and rete testis invasion. Management is surgical with no standard chemotherapy or radiotherapy in adjuvant or metastatic setting. Methods: A retrospective review of epidemiology, radiological staging, histopathological features, relapse rate and treatment in 82 patients diagnosed with TSCST between 4/12/2001 -27/12/2018 at a tertiary referral centre. Results: 2,170 testicular cancer patients were diagnosed in this period of whom 82 patients (3.8%) had TSCST. 65 patients (2.9% ) had LCT,13 patients (0.59%) had SCT, 3 patients had Unclassified SCST and 1 patient had Mixed SCST. Median patient age for LCT was 43 years, SCT was 29 years, unclassified SCST was 46 years and for mixed SCST was 49 years (age range of TSCST was 18 - 82 years). Median size of LCT was 11mm (range 4 – 28 mm) in 43 patients and of SCT was 16mm (range 7 – 60mm) in 10 patients. 79 patients (3.6% ) presented with stage 1 disease. One patient with LCT and 4 high risk histological features on initial diagnosis had local retroperitoneal recurrence 4 years later and underwent surgical resection with 1year distant disease-free survival. On distant relapse, he was treated with mitotane. One patient presented with metastatic SCT with 4 histological high risk features. He was treated with carboplatin and etoposide. Median survival in the metastatic disease was 10.5 months. Conclusions: TSCST have an excellent prognosis with over 98% of patients are free of disease post-surgery. Our relapse rate is 1.2% which is lower than previously reported and is confined to patients with high risk features. Metastatic LCT and SCT are resistant to chemotherapy with poor survival.

A comparison of stage-specific all-cause mortality between testicular sex cord stromal tumors and germ cell tumors: results from the National Cancer Database

BackgroundTesticular sex cord stromal tumors (SCSTs) are managed similarly to germ cell tumors (GCTs); however, few studies have directly compared outcomes between these tumor types. Using the National Cancer Database (NCDB), we sought to compare overall and stage-specific all-cause mortality (ACM) between SCSTs versus GCTs.MethodsNCDB was queried for patients diagnosed with SCSTs and GCTs between 2004 and 2013. Descriptive statistics were used to compare sociodemographic and clinical characteristics between groups. Univariable and multivariable Cox proportional hazards regression analyses were used to assess associations with ACM.ResultsWe identified 42,192 patients diagnosed with testicular cancer between 2004 and 2013, with 280 having SCSTs and 41,912 patients having GCTs. Median age for SCSTs and GCTs was 45 (interquartile range [IQR] 34–59) and 34 (IQR 27–43), respectively (p < 0.001). Median follow-up was 39 and 52 months, respectively. Overall, patients with SCSTs had greater risk of ACM compared to those with GCTs (HR 1.69, 95% CI 1.14–2.50). Private insurance, greater education, and fewer comorbidities were associated with reduced risk of ACM (p < 0.05 for all). Among those with stage I disease, tumor type was not associated with ACM on multivariable analysis. Among those with stage II/III disease, patients with SCSTs had increased risk of ACM compared to patients with GCTs (HR 3.29, 95% CI 1.89–5.72).ConclusionsPatients with advanced SCSTs had worse survival outcomes compared to those with advanced GCTs. These data suggest a need for further investigation to ascertain effective management recommendations for SCSTs.

NKX3.1 and Prostein Expression in Testicular Tissue and Sex Cord-stromal Tumors.

Prostate cancer is well known to metastasize to the testis and is not an uncommon finding on castration performed for advanced disease. Although germ cell tumors make up the majority of testis neoplasms, there are more rare tumors, such as rete testis adenocarcinoma, that can mimic metastatic disease. NKX3.1 and prostein (P501S) are antibodies highly specific for prostate origin. Relatively little is known of the expression of these markers in testicular tissue. We investigated the expression of NKX3.1 and P501S in testicular tissues, sex cord-stromal tumors, germ cell tumors, and rete testis adenocarcinoma. We found strong diffuse nuclear staining for NKX3.1 in Sertoli cells of the testis. Expression of NKX3.1 was seen in 0/3 ovarian Sertoli cell tumors, 1/4 testicular Sertoli cell tumors, and in the Sertoli cell component of 1/12 ovarian Sertoli-Leydig cell tumors. We found moderate, diffuse cytoplasmic positivity for P501S in rete testis epithelium and in testicular Leydig cells. P501S also highlighted Leydig cells in 9/12 Sertoli-Leydig cell tumors of the ovary. Two of 3 Leydig cell tumors of the testis showed weak to moderate, diffuse cytoplasmic staining for P501S. All cases of embryonal carcinoma and pure seminoma were negative for both NKX3.1 and P501S. One case of rete testis adenocarcinoma showed patchy positivity for both NKX3.1 and P501S. In conclusion, NKX3.1 shows routine expression in Sertoli cells and P501S shows routine expression in Leydig cells and rete testis epithelium. In addition, these markers can be positive in sex cord-stromal tumors and rete testis adenocarcinoma.

Genomic Features of Metastatic Testicular Sex Cord Stromal Tumors

BackgroundMetastatic testicular sex cord stromal tumors of the testis (MSCSTs) comprise an extremely uncommon form of genitourinary malignancy. ObjectiveTo perform comprehensive genomic profiling (CGP) to enable the search for potential therapy targets. Design, setting, and participantsTen patients with testicular Leydig cell tumors (LCTs), six with Sertoli cell tumors (SCTs), and three with undifferentiated sex cord stromal tumors (USCSTs) and a comparison group of 366 patients with ovarian sex cord stromal tumors (SCSTs) underwent hybrid-capture–based CGP to evaluate all classes of genomic alterations (GAs). The tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA, and microsatellite instability (MSI) was determined on 114 loci. InterventionCGP on tumor samples. Outcome measurements and statistical analysisDescriptive analyses and differences between histological subgroups were reported. Results and limitationsIn these patients, all of whom had metastatic disease at the time of sequencing, the primary testis tumor was sequenced in six (32%) patients and a metastatic site in 13 (68%) patients. The overall frequencies of GAs were similar in LCTs, SCTs, and USCSTs, ranging from 3.0 to 3.5 GAs/tumor. The most frequent untargetable GAs included CTNNB1 and CDKN2A/B, both ranging from 20% to 33% of cases. Targetable GAs were uncommon in all MSCST subgroups, but several tumors showed potential for cell-cycle inhibitors (CDK4 in LCTs), mTOR inhibitors (RICTOR, NF2, and PTEN in all three tumor types), hedgehog inhibitors (PTCH1 in LCTs), and poly(ADP-ribose) polymerase inhibitors (BAP1 in SCTs). No MSI-high status was identified. The TMB was also low in all MSCST groups, and tumors featuring a TMB of ≥10 mutations/Mb were not identified. GA findings from ovarian SCSTs largely recapitulated those from MSCSTs. A lack of clinical outcome correlation is a limitation of the present analyses. ConclusionsRare cases of testicular MSCSTs have GAs linked to potential targeted therapy benefits on CGP. In contrast, the lack of MSI-high status and an overall low TMB indicate a likely lack of benefit for immunotherapies. Patient summaryGenomic profiling can guide clinical research and disclose therapeutic opportunities for patients with rare testicular cancers for which standard therapies are lacking.