Single-cell transcriptomic analysis reveals that the APP-CD74 axis promotes immunosuppression and progression of testicular tumors.

Testicular tumors represent the most common malignancy among young men. Nevertheless, the pathogenesis and molecular underpinning of testicular tumors remain largely elusive. We aimed to delineate the intricate intra-tumoral heterogeneity and the network of intercellular communication within the tumor microenvironment. A total of 40,760 single-cell transcriptomes were analyzed, encompassing samples from six individuals with seminomas, two patients with mixed germ cell tumors, one patient with a Leydig cell tumor, and three healthy donors. Five distinct malignant subclusters were identified in the constructed landscape. Among them, malignant 1 and 3 subclusters were associated with a more immunosuppressive state and displayed worse disease-free survival. Further analysis identified that APP-CD74 interactions were significantly strengthened between malignant 1 and 3 subclusters and 14 types of immune subpopulations. In addition, we established an aberrant spermatogenesis trajectory and delineated the global gene alterations of somatic cells in seminoma testes. Sertoli cells were identified as the somatic cell type that differed the most from healthy donors to seminoma testes. Cellular communication between spermatogonial stem cells and Sertoli cells is disturbed in seminoma testes. Our study delineates the intra-tumoral heterogeneity and the tumor immune microenvironment in testicular tumors, offering novel insights for targeted therapy. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

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.

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.

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.

Ultrasound contrast-enhanced diagnosis of testicular Leydig cell tumor: A case report and literature review.

Leydig cell tumor (LCT) is a rare testicular tumor. We report a case of an elderly male patient who discovered a left testicular mass during a regular health examination four years ago. The patient did not experience any significant discomfort and opted for regular follow-up visits. During the most recent visit, we performed routine ultrasound and contrast-enhanced ultrasound (CEUS) examinations. By observing the lesion's location, echogenicity, margins, vascular distribution, as well as the rapid enhancement and slow washout characteristics on contrast-enhanced ultrasound, we arrived at a diagnosis of LCT. Subsequently, the patient underwent left inguinal orchiectomy. Postoperative pathology and immunohistochemistry confirmed the diagnosis of LCT. Additionally, we conducted a comprehensive review of LCT-related literature from PubMed and SCOPUS, summarizing the clinical features, follow-up duration, prognosis, and ultrasound characteristics associated with LCT.

An Ovarian Sertoli-Leydig Cell Tumor with Elevated Alpha-Fetoprotein in an Adolescent: A Rare Case Report and Literature Review.

An ovarian Sertoli-Leydig cell tumor is a rare type of sex cord-stromal tumor of the ovary. Typically, it presents as abdominal pain or androgenic manifestations in women in the second to third decade of life. While cases of ovarian Sertoli-Leydig cell tumor associated with increased levels of alpha-fetoprotein are rare, they are reported to be the most common alpha-fetoprotein-producing ovarian non-germ cell tumor. We report the case of a 16-year-old patient, who presented with complaints of amenorrhea that had lasted for one year. Transabdominal ultrasound revealed the presence of a tumor in the right ovary, measuring 9.3 × 5.8 cm in size. The laboratory investigation showed an increased level of alpha-fetoprotein. The patient underwent laparoscopic right salpingo-oophorectomy. Histopathological examination confirmed the presence of a moderately differentiated (G2) Sertoli-Leydig cell tumor in the right ovary. For reproductive-age patients with disease confined to the ovary, fertility-sparing surgery is recommended. According to the current recommendations, the administration of adjuvant chemotherapy is indicated in cases of the presence of heterologous elements, poorly differentiated tumors, or FIGO stages IB-IV. As there were no high-risk factors and no residual disease in this case, there were no indications for further treatment with adjuvant chemotherapy. A recent follow-up visit showed that the patient is in complete remission. This report presents a detailed description of the findings, differential diagnosis, clinical course, chosen treatment, and prognosis. Also, a comprehensive literature review of ovarian Sertoli-Leydig cell tumors, focusing on their clinical presentation, laboratory findings, macroscopic and histopathological features, genetics, clinical management, prognostic factors and follow-up, is provided.

Oncological outcomes among young women with non-epithelial ovarian cancer: the YOC-Care study (Young Ovarian Cancer - Care).

OBJECTIVE: To determine oncological outcomes and associated prognostic factors in women younger than 45 years diagnosed with non-epithelial ovarian cancer. METHODS: A retrospective, multicenter Spanish study was performed including women with non-epithelial ovarian cancer younger than 45 years between January 2010 and December 2019. All types of treatments and stages at diagnosis with at least 12 months of follow-up were collected. Women with missing data, epithelial cancers, borderline or Krukenberg tumors, and benign histology, as well as patients with previous or concomitant cancer, were excluded. RESULTS: A total of 150 patients were included in this study. The mean±SD age was 31.45±7.45 years. Histology subtypes were divided into germ cell (n=104, 69.3%), sex-cord (n=41, 27.3%), and other stromal tumors (n=5, 3.3%). Median follow-up time was 58.6 (range: 31.10-81.91) months. Nineteen (12.6%) patients presented with recurrent disease with a median time to recurrence of 19 (range: 6-76) months. Progression-free survival and overall survival did not significantly differ among histology subtypes (p=0.09 and 0.26, respectively) and International Federation of Gynecology and Obstetrics (FIGO) stage (I-II vs III-IV) with p=0.08 and p=0.67, respectively. Univariate analysis identified sex-cord histology with the lowest progression-free survival. Multivariate analysis showed that body mass index (BMI) (HR=1.01; 95% CI 1.00 to 1.01) and sex-cord histology (HR=3.6; 95% CI 1.17 to 10.9) remained important independent prognostic factors for progression-free survival. Independent prognostic factors for overall survival were BMI (HR=1.01; 95% CI 1.00 to 1.01) and residual disease (HR=7.16; 95% CI 1.39 to 36.97). CONCLUSIONS: Our study showed that BMI, residual disease, and sex-cord histology were prognostic factors associated with worse oncological outcomes in women younger than 45 years diagnosed with non-epithelial ovarian cancers. Even though the identification of prognostic factors is relevant to identify high-risk patients and guide adjuvant treatment, larger studies with international collaboration are essential to clarify oncological risk factors in this rare disease.

Sertoli-Leydig cell tumor: a clinicopathological analysis in a comprehensive, national cohort.

INTRODUCTION: Sertoli-Leydig cell tumors are rare tumors of the ovary. Moderate and poorly differentiated tumors can metastasize and have a poor outcome. A pathogenic variant in DICER1 is associated with an increased risk of developing these tumors along with other clinical phenotypes. We aimed to describe a national cohort of all Sertoli-Leydig cell tumors with regard to clinicopathological characteristics and frequency of DICER1 pathogenic variants. METHODS: In May 2018, all patients registered from January 1997 to December 2017 with the Systematized Nomenclature of Medicine code M86310 (Sertoli-Leydig cell tumor) were obtained from the Danish National Pathology Registry. Validation of the diagnosis depended on comments in the reports that two pathologists validated the initial diagnosis or revision of the pathology at another facility. We performed descriptive statistics to describe baseline characteristics, and cancer related survival was calculated using Kaplan-Meier analysis followed by a log rank test for differences between variables RESULTS: 41 women with Sertoli-Leydig cell tumors were identified. Median age was 41 years (range 6-79). The stages according to the International Federation of Gynecology and Obstetrics (FIGO) were: stage I, 85% (n=35), stage II, 2% (n=1), stage III, 5% (n=2), and stage IV, 7% (n=3). The 5 year cancer related survival was 100% for patients with localized disease (stages I-II) and 0% in advanced tumor stages (stages III-IV). Histological differentiation grade of the tumors was well differentiated in 29% (n=12), moderately differentiated in 56% (n=23), and poorly differentiated in 15% (n=6), and the 5 year cancer related survival was 100%, 96%, and 33%, respectively, according to grade. All patients underwent surgery. Twenty-two patients had fertility sparing surgery and four of these had given birth at the time of follow-up. Analysis of DICER1 was performed in eight women. Four carried a pathogenic variant. Four patients received adjuvant chemotherapy, three because of advanced tumor stage, and one because of a poorly differentiated Sertoli-Leydig cell tumor. CONCLUSION: The prognosis for women with Sertoli-Leydig cell tumors with localized disease is excellent. Women with advanced stages (III-IV) have a poor prognosis, regardless of adjuvant chemotherapy. Fertility sparing surgery seems to be a viable option for localized Sertoli-Leydig cell tumors. DICER1 screening was rarely performed in previous cohorts and concomitant organ screening programs are topics for discussion.

Bilateral Ovarian Sertoli-Leydig Cell Tumors Harboring DICER1 Germline and Distinct Somatic Mutations: Case Report and Literature Review.

Background: DICER1 tumor predisposition syndrome is characterized by an increased risk for development of pleuropulmonary blastoma, pituitary blastoma, multinodular thyroid goiter, thyroid carcinoma, sex cord stromal tumor, cystic nephroma, embryonal rhabdomyosarcoma, and tumors of the CNS, amongst others. Of this list, only pituitary blastoma is recognized as pathognomonic for the syndrome. Case report: We describe a 15-year-old female with bilateral, asynchronous Sertoli-Leydig cell tumors (SLCT). Both tumors harbored an identical germline frameshift mutation as well as unique somatic DICER1 hot-spot point mutations. Discussion: A review of bilateral SLCTs demonstrates that all patients with available DICER1 mutation status carried a germline DICER1 mutation (100%, 9 of 9). In cases with known somatic DICER1 status on bilateral tumors, all harbored distinct somatic mutations (100%, 5 of 5). Our findings support the notion that bilateral ovarian SLCTs are indeed separate events and do not represent recurrent or metastatic disease.

Ovarian Leydig Cell Tumor and Ovarian Hyperthecosis in a Postmenopausal Woman: A Case Report and Literature Review.

Ovarian Leydig cell tumor is a rare type of ovarian steroid cell neoplasms, presenting in only 0.1% of all ovarian tumor cases, and is generally androgen-secreting and unilateral. Although they are often malignant non-spreading tumors, which have excellent prognosis, benign ovarian Leydig cell tumors with low-risk malignancy can be also detected. Ovarian hyperthecosis is a rare non-neoplastic disorder, in most cases bilateral. Ovarian tumors and ovarian hyperthecosis are one of the main causes of hyperandrogenism in postmenopausal women, a condition strongly associated with both hormonal and metabolic changes. Here, we report a 65-year-old patient with complaints of excessive body hairiness and alopecia. The laboratory investigation showed increased levels of serum testosterone and dehydroepiandrosterone sulfate (DHEA-S). Imaging, including transvaginal ultrasound and pelvic MRI revealed the presence of two masses in the ovaries. The patient underwent a laparoscopic bilateral salpingo-oophorectomy due to the ovarian tumors unknown etiology, and histopathological examination revealed a unilateral benign left ovarian Leydig cell tumor with bilateral ovarian stromal hyperplasia and ovarian hyperthecosis. Making differential diagnosis between ovarian tumors and ovarian hyperthecosis is difficult. Bilateral salpingo-oophorectomy is the treatment of choice in postmenopausal women with benign Leydig cell ovarian tumor, as well as ovarian hyperthecosis, as it offers both a cure and diagnostic confirmation.

Fertility sparing surgery in sex-cord stromal tumors: oncological and reproductive outcomes.

Sex cord stromal tumors are rare neoplasms, frequently diagnosed in young women often as early-stage disease. In patients who desire to preserve fertility, when possible, unilateral salpingo-oophorectomy with peritoneal surgical staging is a safe alternative to radical treatment. In this review, we analyze the available literature on the obstetrical outcomes after fertility-sparing surgery in a total of 255 patients with sex cord stromal tumors. We found that the spontaneous conception rate in granulosa cells tumor is encouraging (88.5%). In particular, juvenile granulosa cell tumors are associated with a more successful pregnancy rate than adult granulosa cells tumors (11/26 (42.3%) in juvenile granulosa cells tumors compared with 28.5% in adult granulosa cell tumors, respectively.) On the other hand, the results of obstetrical outcomes in Sertoli-Leydig cells tumors are less promising (7/36 (19.4%)). Unfortunately, no evidence on this topic is available for sex cord tumor with annular tubules due to the low incidence. Regarding the oncological outcomes of 900 cases of sex cord stromal tumors treated conservatively, data are reassuring with comparable outcomes between patients treated with conservative and radical surgery. Given the limited available data on this rare tumor, further studies are needed to evaluate the safety of conservative approaches and to define the obstetrical outcomes in this patient population.

Medullary bone in male budgerigars (Melopsittacus undulatus) with testicular neoplasms.

Medullary bone is a calcium-rich, labile bone normally occurring in female birds with each egg-laying cycle. The stimulus for formation of medullary bone is, in part, the cyclic increase in serum estrogens produced by preovulatory ovarian follicles. Increased bone density due to formation of medullary bone, particularly in pneumatic bones, has been termed polyostotic hyperostosis, even if physiologic. This study investigated the formation of medullary bone in nonpneumatic (femur) and pneumatic (humerus) bones in sexually mature male budgerigars submitted for autopsy. Of the 21 sexually mature male budgerigars submitted for autopsy, 7 (33%) had medullary bone in 1 or more bones examined. All 7 male budgerigars with medullary bone had a testicular neoplasm, which was morphologically consistent with a testicular sustentacular cell tumor, seminoma, or interstitial cell tumor. Medullary bone was not present in the 14 cases with other diseases. Medullary bone formation in pneumatic and nonpneumatic bones can occur in male budgerigars with testicular neoplasms. Radiographic increases in medullary bone density, particularly in the humerus, could provide antemortem indication of testicular neoplasia in male budgerigars.

Complete androgen insensitivity syndrome - rare case of malignancy of dysgenetic gonads.

OBJECTIVE: A case report of a young patient with primary amenorrhea who was diagnosed with agenesis of the uterus and was genetically confirmed for complete androgen insensitivity syndrome with already developed malignancy of dysgenetic gonads. CASE REPORT: The 17-year-old patient visited a gynecological clinic for primary amenorrhea. Both ultrasound and vaginal examination revealed suspicion of uterine agenesis, which was subsequently verified during diagnostic laparoscopy. Genetic testing showed karyotype 46,XY, and a rare diagnosis - complete androgen insensitivity syndrome. A secondary finding from a left gonadal biopsy was a Sertoli-Leydig cell tumor. The patient underwent bilateral gonadectomy and was given estrogen replacement therapy. She is now regularly examined by a pediatric oncologist. CONCLUSION: Complete androgen insensitivity syndrome is a rare genetic disease characterized by varying degrees of feminization in individuals with a male karyotype. It should not be neglected, especially in the differential diagnostic work-up of primary amenorrhea. Genetic testing of the karyotype should be performed whenever uterine agenesis is suspected.

Thoracic Sertoli-Leydig cell tumor: An alternative type of pleuropulmonary blastoma associated with DICER1 variation.

A 2-year-old boy presented with a large cystic and solid chest mass arising from the lung, radiographically consistent with pleuropulmonary blastoma (PPB). He underwent right lower lobectomy with resection of a well-circumscribed, mixed solid and cystic mass. The solid areas were composed of cords and nests of tumor cells in the myxoid stroma and retiform foci whose pathologic and immunophenotypic findings were consistent with a sex cord-stromal tumor with features of a Sertoli-Leydig cell tumor. Tumor testing showed a pathogenic variant in the DICER1 RNase IIIb hotspot domain. Family history was suggestive of DICER1 germline pathogenic DICER1 variation in absence of a detectable germline variant. He received 12 cycles of chemotherapy with ifosfamide, vincristine, dactinomycin and doxorubicin (IVADo) and surgery with complete response. One year after completion of chemotherapy, imaging studies showed concern for recurrence confirmed by thorascopic biopsy of a pleural-based mass. He is currently receiving cisplatin-based chemotherapy with reduction in tumor size. Review of the literature showed no similar cases; however, review of our pathology files revealed a single similar case of anterior mediastinal Sertoli cell tumor in a 3-year-old girl.

Occult symptomatic bilateral pure Leydig cell tumors in a postmenopausal woman: a case report.

BACKGROUND: Pure Leydig cell tumors (LCTs) represent 0.1% of ovarian masses. Postmenopausal patients typically present with virilization. Although LCTs can be challenging to locate on conventional imaging, positron emission tomography (PET) has been demonstrated to be effective. CASE: A 64-year-old postmenopausal woman presented with alopecia, facial hirsutism, and clitoromegaly. Laboratory findings included elevated testosterone and androstenedione. Ultrasound, computed tomography, and magnetic resonance imaging showed no adnexal masses. PET did not demonstrate ovarian fludeoxyglucose-avidity. Histopathology after bilateral salpingo-oophorectomy revealed bilateral Leydig cell tumors. Her testosterone normalized 2 weeks postoperatively. CONCLUSION: We describe the occult, symptomatic, bilateral ovarian Leydig cell tumors, an occurrence that has not been described in the literature. Virilizing tumors must be considered in patients with evidence of hyperandrogenism, even without pelvic masses on imaging.

Preliminary Investigation on the Involvement of Cytoskeleton-Related Proteins, DAAM1 and PREP, in Human Testicular Disorders.

Herein, for the first time, the potential relationships between the cytoskeleton-associated proteins DAAM1 and PREP with different testicular disorders, such as classic seminoma (CS), Leydig cell tumor (LCT), and Sertoli cell-only syndrome (SOS), were evaluated. Six CS, two LCT, and two SOS tissue samples were obtained during inguinal exploration in patients with a suspect testis tumor based on clinical examination and ultrasonography. DAAM1 and PREP protein levels and immunofluorescent localization were analyzed. An increased DAAM1 protein level in CS and SOS as compared to non-pathological (NP) tissue was observed, while LCT showed no significant differences. Conversely, PREP protein level increased in LCT, while it decreased in CS and SOS compared to NP tissue. These results were strongly supported by the immunofluorescence staining, revealing an altered localization and signal intensity of DAAM1 and PREP in the analyzed samples, highlighting a perturbed cytoarchitecture. Interestingly, in LCT spermatogonia, a specific DAAM1 nuclear localization was found, probably due to an enhanced testosterone production, as confirmed by the increased protein levels of steroidogenic enzymes. Finally, although further studies are needed to verify the involvement of other formins and microtubule-associated proteins, this report raised the opportunity to indicate DAAM1 and PREP as new potential markers, supporting the cytoskeleton dynamics changes occurring during normal and/or pathological cell differentiation.

Risk Factors and Treatment Outcomes of 1,375 Patients with Testicular Leydig Cell Tumors: Analysis of Published Case Series Data.

PURPOSE: Leydig cell tumors are rare but they are the most common nongerm cell testicular tumors. Only limited evidence exists for reliably differentiating between benign and malignant Leydig cell tumors and for optimally managing the different types and stages of this rare disease. In this review we synthesize the available evidence on the clinical presentation and clinicopathological characteristics associated with Leydig cell tumor malignancy and management. MATERIALS AND METHODS: We analyzed published case series data on Leydig cell tumors. The association between clinicopathological variables and the presence of metastatic disease was assessed using regression analyses. RESULTS: We included 357 reports, reviewing available data from 1,375 patients (median age 34 years). Testis sparing surgery was performed in 463 patients. Local recurrence after testis sparing surgery occurred in 8 of 121 (7%) patients with available followup information. Metastases were found in 101 patients and were most often located in the retroperitoneal lymph nodes (60%), lungs (38%) and/or liver (29%). The multivariable models with or without multiple imputation predicting metastatic disease included older age, larger tumor size, presence of any adverse factor (larger tumor diameter, necrosis, angiolymphatic invasion, pleomorphism, high mitotic index, atypia) and any protective factor (Reinke crystals, lipofuscin pigments, gynecomastia) with model AUCs of 0.93. Durable remission after resection of metastases or use of platinum based chemotherapy was rarely seen. CONCLUSIONS: Our risk tables using clinicopathological parameters can help identify patients with malignant tumors. These patients should undergo disease staging and be followed or receive further treatment. In some patients with metastatic disease surgical and systemic treatment might result in disease control.

Pediatric ovarian Sertoli-Leydig cell tumors with heterologous rhabdomyosarcoma elements: Clinical case series and review of the literature.

Sertoli-Leydig cell tumors (SLCTs) are rare ovarian neoplasms in pediatric patients. More exceedingly rare are SLCTs that also contain heterologous rhabdomyosarcoma (RMS) elements. For these patients, there is no standardized treatment. We report four cases of pediatric SLCT with heterologous RMS elements that were successfully treated with surgical resection and adjuvant chemotherapy. All four patients are alive and remain in remission.

Ovarian Sertoli-Leydig and granulosa cell tumor: comparison of epidemiology and survival outcomes.

PURPOSE: To investigate the epidemiology, clinico-pathological characteristics and outcomes of patients diagnosed with malignant ovarian Sertoli-Leydig cell tumors (SLCTs) in comparison to granulosa cell tumors (GCTs). METHODS: The National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database were accessed and patients diagnosed with a malignant SLCT and GCT between 1988 and 2013 were selected. Demographic and clinico-pathological characteristics were compared using the Mann-Whitney and chi-square tests. Overall (OS) and cancer-specific survival (CSS) rates were estimated with the Kaplan-Meier method and compared with the log-rank test. Cox hazard models were constructed to control for confounders. RESULTS: A total of 175 and 1361 patients diagnosed with SLCT and GCT, respectively, were identified. Compared to patients with GCT, those with SLCT were younger (median age 32 vs. 51 years, p < 0.001) and more likely to present with larger tumors (median size 15 vs 9.5 cm, p < 0.001) confined to the ovary (77.5% vs 69.2%, p = 0.031). Patients with SLCTs had worse CSS compared to those with GCTs, p < 0.001 (5-year rate was 76.2% vs 90.7%). After controlling for the presence of extra-ovarian disease and tumor size (≤ 10 vs > 10 cm), SCLTs were associated with a worse cancer-specific mortality compared to GCTs. CONCLUSIONS: SLCTs are extremely rare, commonly arise in premenopausal patients. They are associated with a poorer prognosis compared to GCT.

Interstitial Leydig Cell Tumorigenesis-Leptin and Adiponectin Signaling in Relation to Aromatase Expression in the Human Testis.

Although epidemiological studies from the last years report an increase in the incidences of Leydig cell tumors (previously thought to be a rare disease), the biochemical characteristics of that tumor important for understanding its etiology, diagnosis, and therapy still remains not completely characterized. Our prior studies reported G-protein coupled estrogen receptor signaling and estrogen level disturbances in Leydig cell tumors. In addition, we found that expressions of multi-level-acting lipid balance- and steroidogenesis-controlling proteins including peroxisome proliferator-activated receptor are altered in this tumor. In order to get deeper into the other molecular mechanisms that regulate lipid homeostasis in the Leydig cell tumor, here we investigate the presence and expression of newly-described hormones responsible for lipid homeostasis balancing (leptin and adiponectin), together with expression of estrogen synthase (aromatase). Samples of Leydig cell tumors (n = 20) were obtained from patients (31-45 years old) and used for light and transmission electron microscopic, western blotting, and immunohistochemical analyses. In addition, body mass index (BMI) was calculated. In tumor mass, abundant lipid accumulation in Leydig cells and various alterations of Leydig cell shape, as well as the presence of adipocyte-like cells, were observed. Marked lipid content and various lipid droplet size, especially in obese patients, may indicate alterations in lipid homeostasis, lipid processing, and steroidogenic organelle function in response to interstitial tissue pathological changes. We revealed significantly increased expression of leptin, adiponectin and their receptors, as well as aromatase in Leydig cell tumors in comparison to control. The majority of patients (n = 13) were overweight as indicated by their BMI. Moreover, a significant increase in expression of phospholipase C (PLC), and kinases Raf, ERK which are part of adipokine transductional pathways, was demonstrated. These data expand our previous findings suggesting that in human Leydig cell tumors, estrogen level and signaling, together with lipid status, are related to each other. Increased BMI may contribute to certain biochemical characteristics and function of the Leydig cell in infertile patients with a tumor. In addition, altered adipokine-estrogen microenvironment can have an effect on proliferation, growth, and metastasis of tumor cells. We report here various targets (receptors, enzymes, hormones) controlling lipid balance and estrogen action in Leydig cell tumors indicating their possible usefulness for diagnostics and therapy.