Leydig Cell Tumor Research Articles

First Evidence of the Expression and Localization of Prothymosin α in Human Testis and Its Involvement in Testicular Cancers.

Prothymosin α (PTMA) is a phylogenetically conserved polypeptide in male gonads of Vertebrates. In Mammals, it is a ubiquitous protein, and, possessing a random-coil structure, it interacts with many other partners, in both cytoplasmic and nuclear compartments. PTMA has been widely studied during cell progression in different types of cancer because of its anti-apoptotic and proliferative properties. Here, we provided the first evidence of PTMA expression and localization in human testis and in two testicular cancers (TC): classic seminoma (CS) and Leydig cell tumor (LCT). Data showed that its protein level, together with that of proliferating cell nuclear antigen (PCNA), a cell cycle progression marker, increased in both CS and LCT samples, as compared to non-pathological (NP) tissue. Moreover, in the two-cancer tissue, a decreased apoptotic rate and an increased autophagic flux was also evidenced. Results confirmed the anti-apoptotic action of PTMA, also suggesting that it can act as a switcher from apoptosis to autophagy, to favor the survival of testicular cancer cells when they develop in adverse environments. Finally, the combined data, even if they need to be further validated, add new insight into the role of PTMA in human normal and pathological testicular tissue.

A rare case report: testicular leydig cell tumor with gynecomastia

Gynecomastia is the most common definition of breast tissue growth. It is common in urology due to androgen blockade used in prostate cancers. Clinically insignificant gynecomastia is present in 50% of men and there is no proliferation of breast tissue in ductus epithelium. Gynecomastia is rarely seen in primary testicular tumors such as Leydig Cell Tumors (LCT). Leyındg Cell Tumors are one of the rare sex cord stromal cell tumors of the testis . Although it is usually with endocrine changes, it is a painless mass or incidentally occurring tumor in the testis. In this case report, we examined the left testicle cell tumor of the gynecomastia at the age of 43 years. He had been admitted to our clinic for gynecomastia and breast pain for 6 years. The patient was followed-up by endocrinology due to the aforementioned complaints. The patient was suspected of prolactinoma. Physical examination revealed no MRI. MRI, heterogenous hyperintense in T2A with mild lobulated contoured T2A with a hypointense capsule in T2A with well limited T2A in the left intratesticular area, and heterogeneous isohaphy hyperintense internal T1A in the form of a nodular lesion (testicular tumor) showing intense and heterogeneous contrast enhancement commented. The patient underwent left inguinal orchiectomy and the pathology report was negative for the leyding cell tumor and surgical margin.
 Leydig cell tumors are the most common spermatic cord / stromal tumors. About 30% of patients present with gynecomastia. Ultrasonography is accepted as the first research method for the diagnosis of leydic cell tumor, but MRI is superior to ultrasonography in diagnosis. The gold standard treatment option is radical inguinal orchiectomy. The mechanism of hormonal disorders may be an overproduction of testosterone and estrogens by the tumor. As in our case, it is necessary to consider the possibility of LCT which is rarely seen in patients with gynecomastia and to provide differential diagnosis by performing the tests in this direction.

Arsenic compounds activate MAPK and inhibit Akt pathways to induce apoptosis in MA-10 mouse Leydig tumor cells.

Arsenic compounds have been applied treating acute promyelocytic 1eukemia and solid tumors with brief mechanism investigations. In fact, we have demonstrated that sodium arsenite plus dimethylarsenic acid could activate apoptosis in MA-10 mouse Leydig tumor cells by inducing caspase pathways. However, detail underlying mechanisms how caspase cascade is regulated remains elusive. Therefore, the apoptotic mechanism of sodium arsenite plus dimethylarsenic acid were examined in MA-10 cells in this study. Our results reveal that Fas/FasL protein expressions were stimulated by sodium arsenite plus dimethylarsenic acid in MA-10 cells. In addition, reactive oxygen species (ROS) generation, cytochrome C release, Bid truncation, and Bax translocation were induced in MA-10 cells by arsenic compounds. Moreover, activation of p38, JNK and ERK1/2, MAPK pathways was stimulated while Akt phosphorylated levels and Akt expression were decreased by sodium arsenite plus dimethylarsenic in MA-10 cells. In conclusion, sodium arsenite and dimethylarsenic acid did activate MAPK pathway plus ROS generation, but suppress Akt pathway, to modulate caspase pathway and then induce MA-10 cell apoptosis.

Ovarian leydig cell tumor- A rare presentation without features of and rogenization

Leydig cell tumor is a rare benign tumor which belongs to the category of sex cord stromal tumors of ovary. Leydig cell tumor usually presents with androgenizing features like hirsutism, deepening of voice, or clitoromegaly and are often suspected only if such symptoms are present. Leydig cell tumors can however be estrogenizing or non-functional. We report an incidental finding of Leydig cell tumor in a patient who underwent hysterectomy for postmenopausal bleeding.

Multiparametric ultrasound for the diagnosis of Leydig cell tumours in non-palpable testicular lesions.

The widespread use of ultrasonography has led to an increased number of incidentally detected small non-palpable lesions, with Leydig cell tumours representing the majority of them. The ultrasonography, real-time elastography and contrast-enhanced ultrasonography features of a large series of non-palpable testicular lesions were evaluated, focusing on the differences between Leydig cell tumours and other testicular masses. Of the 4679 testicular ultrasonography examinations performed at the Authors' Institution between January 2009 and December 2018, 78 patients (1.7%) were incidentally diagnosed with at least one non-palpable lesion and were enrolled. Thirteen patients (16.6%) declined surgery and were thus excluded. The remaining 65 underwent surgical resection with frozen section analysis. The conventional ultrasonography, colour Doppler, real-time elastography and contrast-enhanced ultrasonography were performed by a radiologist having more than 10 years of experience. Demographic and clinical data were collected. Leydig cell tumours were detected in 32 patients, being the most frequent benign tumours (49.2%); of the non-Leydig cell tumours, 25 patients had malignant tumours, five non-neoplastic lesions and three other benign tumours. The Leydig cell tumour group had mostly infertility problems whereas the non-Leydig cell tumour group frequently experienced pain (p<0.001). Leydig cell tumours were all hypoechoic (32/32, 100%; p=0.002), more frequently presented with well-defined margins compared to non-Leydig cell tumours (30/32, 93.8%vs. 19/33, 57.6%; p=0.001) and tended to be smaller than non-Leydig cell tumours (5.3mm [standard deviation 2.7mm] vs. 10.6mm [standard deviation 3.8mm], respectively; p<0.001). The vascular pattern characterised by the rapid wash-in followed by the delayed wash-out observed during contrast-enhanced ultrasonography was significantly associated with the Leydig cell tumour histological diagnosis, even at multivariate analysis (odds ratio 480.5, p<0.001), and yielded a high diagnostic accuracy (area under the receiver operating characteristic curve 0.954, 95% confidence interval 0.903-1). Contrast-enhanced ultrasonography demonstrated high diagnostic accuracy in identifying benign testicular lesions, such as Leydig cell tumours; they are the most common non-palpable tumours detected in infertile men and may benefit from enucleation.

Leydig Cell Tumors of the Testis: An Update of the Imaging Characteristics of a Not So Rare Lesion

Simple SummaryStromal tumors of the testis are rare. However, among this group, Leydig cell tumors (LCT) are the most frequent, and recent studies suggest that LCTs account for up to 22% of small testicular nodules. It is now accepted that small LCTs can benefit from testis-sparing surgery or in some selected cases radiological surveillance. Since percutaneous testicular biopsy is still not recommended, the diagnosis of LCT rests on multimodal imaging techniques. Therefore, it is essential for the radiologist and the urologist to know the main imaging features of LCTs in ultrasound and MRI.Pre-operative testicular tumor characterization is a challenge for radiologists and urologists. New data concerning imaging approaches or immunochemistry markers improve the management of patients presenting with a testicular tumor, sometimes avoiding radical orchiectomy. In the past 20 years, imaging modalities, especially ultrasound (US) and magnetic resonance imaging (MRI), improved, allowing for great progress in lesion characterization. Leydig cell tumors (LCT) are rare testicular tumors developing from the stromal tissue, with relatively scarce literature, as most of the studies focus on the much more frequent germ cell tumors. However, with the increase in testicular sonography numbers, the incidence of LCT appears much higher than expected, with some studies reporting up to 22% of small testicular nodules. Multimodal ultrasound using Doppler, Elastography, or injection of contrast media can provide crucial arguments to differentiate LCT from germ cell tumors. Multiparametric MRI is a second intention exam, but it allows for extraction of quantifiable data to assess the diagnosis of LCT. The aims of this article are to review the latest data regarding LCT imaging features, using multimodal ultrasound and multiparametric MRI, and to focus on the peculiar aspect of the testis of patients with Klinefelter’s syndrome. The possibility of an LCT should be raised in front of a small hypoechoic tumor with a marked corbelling hypervascularization in an otherwise normal testicular pulp. Ultrasonographic modules, such as ultrasensitive Doppler, contrast-enhanced ultrasonography, or elastography, can be used to reinforce the suspicion of LCT. MRI provides objective data regarding vascularization and enhancement kinetics.

Gonadal tumor risk in pediatric and adolescent phenotypic females with disorders of sex development and Y chromosomal constitution with different genetic etiologies.

ObjectivesThis retrospective study sought to investigate the risk and proportion of gonadal neoplasms in phenotypic female pediatric patients with DSD and the presence of the Y chromosome and different genetic backgrounds in a single Chinese center.Materials and MethodsFrom January 2012 to December 2020, pediatric and adolescent patients with DSD and the presence of the Y chromosome who had unambiguous female genitalia and underwent bilateral gonadectomy or gonadal biopsy were included in this study. Patients’ demographics, karyotype, laboratory test results, gross pathology, and histology of gonadal tissue were all collected. The patients were divided into three groups based on their different genetic backgrounds, and the percentage of gonadal tumors was calculated to assess the risk of gonadal tumor and malignancy by etiology.ResultsA total of 22 patients with DSD and an unambiguous female phenotype with a Y chromosome were recruited. The mean age was 10.91 ± 4.99 years (9 months to 19 years). Gonadal neoplasia was confirmed in six (27.3%) cases by pathological examination of surgical gonadal tissue samples. Among 44 gonadal samples from these 22 patients, the following were identified: five gonadoblastomas, three dysgerminomas, and two Leydig cell tumors. The youngest patient with a tumor was a 2-year-old girl with 46,XY complete gonadal dysgenesis (46,XY CGD or Swyer syndrome) and bilateral gonadoblastoma. Patients with 46,XY complete gonadal dysgenesis (4/6; 66.7%) had the highest tumor occurrence rate. Among 10 patients with Turner syndrome with the presence of the Y chromosome, only one patient was diagnosed with a gonadal tumor. Leydig cell tumor was diagnosed in only one of six patients with 46,XY androgen synthesis/action disorders.ConclusionPediatric patients with 46,XY complete gonadal dysgenesis had a significantly increased risk of developing gonadal tumors and underwent prophylactic gonadectomy as soon as the diagnosis was confirmed, whereas those with Turner syndrome with Y chromosome and 46,XY androgen synthesis/action disorders had a relatively low risk. In view of the limited number of patients, a large multicenter study with close follow-ups is needed to support these conclusions.

Paraneoplastic Erythropoiesis in Patients With Ovarian Sertoli Leydig Cell Tumors: Retrospective Study From Tertiary Care Institute.

To study the clinical, paraneoplastic hematological presentation of Sertoli Leydig cell tumor patients. This retrospective study involved women with Sertoli Leydig cell tumors treated at JIPMER from 2018 to 2021. We reviewed the hospital registry for the Sertoli Leydig cell tumor among all the ovarian tumors being treated in the department of obstetrics and gynecology. We retrieved the datasheets of patients with Sertoli Leydig cell tumor and studied their clinical and hematological presentation, their management, complications, and follow-up. We had 5 patients of Sertoli Leydig cell tumor of 390 ovarian tumors operated during the study period. The mean age at presentation was 31.6years. All 5 patients had hirsutism and menstrual irregularity. One patient presented with symptoms of polycythemia along with these complaints. Elevated serum testosterone was seen in all (mean being 688ng/ml). Mean preoperative hemoglobin was 15.84%, and mean hematocrit was 50.14%. Fertility-sparing surgery was performed in 3 of them and the rest had complete surgery. All patients were in Stage IA. Histologically, one had Pure Leydig cell, three had steroid cell tumor not otherwise specified and one was mixed Sertoli Leydig cell tumor. After the operation, the hematocrit and testosterone levels came down to the normal range. The virilizing manifestations regressed over 4-6months. With a follow-up period ranging from 1 to 4years, all 5 patients are alive, one patient had a disease recurrence in the ovary after 1year of primary surgery. She is disease-free following the second surgery. The rest of the patients had no disease recurrence and are disease-free following surgery. Virilizing ovarian tumors can have paraneoplastic polycythemia which needs to be looked into while evaluating these patients. Similarly, while evaluating polycythemia in young females, an androgen-secreting tumor has to be ruled out as it is reversible and completely treatable.

Diagnostic importance of hepatocyte nuclear factor 1 beta (HNF1β) in testicular tumors and its sensitivity for the detection of yolk sac tumors: an immunohistochemical analysis

Objectives: Testicular tumors are common solid malignancies in young fertile men, and most are germ cell tumors. In general, they originate from a single germ cell and transform into different tumor types or present with the coexistence of different morphological patterns. Due to the heterogeneity of these tumors, immunohistochemical markers are frequently used in their differential diagnosis. In recent years, some studies have indicated hepatocyte nuclear factor 1 beta (HNF1β) can be used in the differential diagnosis of testicular tumors, especially yolk sac tumors (YSTs). In this study, we aimed to investigate the general expression status of HNF1β in all testicular tumors and determine its importance in YST detection. Methods: A total of 144 testicular tumors treated with orchiectomy between 2011 and 2020 were included in our study. The pathological diagnosis reports of these cases were retrospectively reviewed and their general prognostic features were determined. HNF1β immunohistochemical staining was applied to the characteristic paraffin blocks representing the lesions. Staining was evaluated in terms of severity and prevalence. Results: Most cases (38.2%) were seminomas, followed by mixed germ cell tumors (34.0%, 49/144), embryonic carcinomas (7.6%), pure YSTs (4.9%), and others (Leydig cell tumors, mesenchymal tumors, lymphomas, etc.). No HNF1β immunostaining was observed in any of the seminomatous lesions. A high level of staining was present in almost all the pure YSTs and tumor areas with the YST component. HNF1β had a specificity of 95.1% and sensitivity of 87.1% in the detection of YSTs. Conclusions: HNF1β has high specificity and sensitivity in detecting YSTs among testicular tumors, and therefore we consider that it can be routinely used to detect the presence of YSTs, especially in patients with mixed germ cell tumors.

Imaging of Pediatric Testicular and Para-Testicular Tumors: A Pictural Review.

Simple SummaryPediatric testicular tumors are rare and represent 1% to 2% of all solid tumors in children. Germ-cell tumors are the most frequent etiology; most are benign in the pre-pubertal population, whereas post-pubertal testicular tumors are similar to those that occur in adults, with potential malignancy. The development of testis-sparing surgery for presumed benign lesions enhances the need for better pre-operative tumor characterization by imaging, among other tools. Ultrasonography (US) remains the first-line examination for scrotal pathology assessment, but other techniques such as contrast-enhanced US, elastography, or scrotal MRI are emerging modalities for scrotal evaluation both in children and adults. This review provides an overview of imaging features of the most frequent testicular and para-testicular tumor types in children and discusses the role of imaging in disease staging and monitoring children with testicular tumors or risk factors for testicular tumors.Pre- and post-pubertal testicular tumors are two distinct entities in terms of epidemiology, diagnosis and treatment. Most pre-pubertal tumors are benign; the most frequent are teratomas, and the most common malignant tumors are yolk-sac tumors. Post-pubertal tumors are similar to those found in adults and are more likely to be malignant. Imaging plays a pivotal role in the diagnosis, staging and follow-up. The appearance on ultrasonography (US) is especially helpful to differentiate benign lesions that could be candidates for testis-sparing surgery from malignant ones that require radical orchidectomy. Some specific imaging patterns are described for benign lesions: epidermoid cysts, mature cystic teratomas and Leydig-cell tumors. Benign tumors tend to be well-circumscribed, with decreased Doppler flow on US, but malignancy should be suspected when US shows an inhomogeneous, not-well-described lesion with internal blood flow. Imaging features should always be interpreted in combination with clinical and biological data including serum levels of tumor markers and even intra-operative frozen sections in case of conservative surgery to raise any concerns of malignity. This review provides an overview of imaging features of the most frequent testicular and para-testicular tumor types in children and the value of imaging in disease staging and monitoring children with testicular tumors or risk factors for testicular tumors.

Abstract LB144: Antagonism of SF-1 as a potential targeted therapy for malignant Leydig cell tumors

Abstract Leydig cell tumors (LCT), originating from androgen-producing interstitial Leydig cells of the testis, represent about 3% of all testicular cancers. LCT belong to the family of sex cord stromal tumors (SCST), a collection of tumors formed in the supporting tissue within the ovaries or testes. Although 90% of LCT are considered benign and can be cured by orchiectomy, in adult patients about 10% of LCT are malignant and metastasis is common. Non-resectable metastatic disease is poorly responsive to radiation and chemotherapy and patients are advised to seek clinical trials. Steroidogenic Factor 1 (SF-1, or NR5A1) is a transcription factor that is essential for the development of the adrenal gland and gonads. SF-1 mutations result in disorders of sexual development, ovarian failure, and adrenal insufficiency. SF-1 is necessary for development of fetal and adult Leydig cells and is strongly expressed in LCT. Significant data support the role of SF-1 in adrenocortical cancer (ACC). To address the need for a targeted therapy in ACC and other SF-1-dependent malignancies, Orphagen has identified potent small molecule antagonists to SF-1*. Here, using R2C, a rat Leydig tumor cell line, we demonstrate that small molecule antagonists of SF-1 inhibit Leydig tumor cell proliferation in vitro and in vivo. OR-449, an orally available inhibitor of SF-1 transcriptional activity (SF-1 Luc IC50 = 16 nM) and OR-907S, a probe SF-1 antagonist (SF-1 Luc IC50 = 22 nM), exhibit striking anti-proliferative activity in R2C cell cultures, inhibiting DNA synthesis by &amp;gt;90% at 1 μM with estimated IC50’s of 0.068 μM and 0.074 μM, respectively. OR-907R, the ~100-fold less active stereoisomer of OR-907S (SF-1 Luc IC50 = 2 μM) was significantly less active in the R2C proliferation assay (estimated IC50 &amp;gt;10 μM). Moreover, in cell lines lacking SF-1 expression, such as HEK293, SF-1 antagonists have no anti-proliferative activity up to 20 μM, suggesting that the anti-proliferative effect on R2C is SF-1-mediated and not due to cytotoxicity. Furthermore, OR-449 completely blocks R2C xenograft tumor growth in immunocompromised mice at an oral dose of 30 mg/kg/day. OR-449 also dose-dependently regulates expression of SF-1 responsive genes, a mRNA signature first identified in R2C culture by comparison of the activity of OR-907S and OR-907R at 1 μM. OR-449 has excellent pharmacokinetic properties and is well-tolerated in repeat dosing toxicity studies in rodents and non-rodents*. These results highlight SF-1 antagonism as a novel targeted therapeutic approach with potential utility in the treatment of LCT and other SCST. OR-449 is currently in IND-enabling studies in order to enter the clinic by the end of 2022. * P. Crowe, et al. A novel steroidogenic factor-1 antagonist, OR-449, as a targeted therapy for adrenocortical cancer. ENDO 2021: J Endocr Soc, Vol5, Supplement_1, A1010 Citation Format: Haiyan Tao, Emily Eastwood, Raymond G. Fox, Neil Raheja, Paul D. Crowe, Scott M. Thacher. Antagonism of SF-1 as a potential targeted therapy for malignant Leydig cell tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB144.

Reinke crystals: Hallmarks of adult Leydig cells in humans.

Reinke crystals are structures pathognomonic for Leydig cells, which have the important function of testosterone production and are vital for male reproductive health. These crystalline inclusions are thought to be of protein origin; however, the molecular composition has not yet been resolved. This review summarizes all available information regarding Reinke crystal's characteristics and aims to produce a comprehensive guide for research on this topic as well as to determine and discuss potential Reinke-protein candidates. Pubmed was thoroughly searched for all publications regarding Reinke crystals and 137 publications were identified. All publications were surveyed and all relevant information was included in the review. Along with the cytoplasm, structures that resemble Reinke crystals were also observed in the nucleus, suggesting that their formation depends only on protein concentration. Variations in tissue processing protocols could impact Reinke crystal microscopic visualization, which is an important factor in diagnosing Leydig cell disorders such as Leydig cell tumors. Reinke crystals appear to be hallmarks of normally differentiated, adult, Leydig or Leydig-like cells in humans, while some abnormal and nonhuman Leydig cells contain Reinke-like paracrystalline inclusions or crystalloids. These characteristics point to some differentially expressed proteins, which could be involved in Reinke crystal formation. Differential Reinke crystal and paracrystalline inclusion presence could also be due to small changes in protein structure or the cell environment. Further research is needed to solve the ongoing mystery of the Reinke crystal, which would enhance our knowledge of Leydig cell contribution in the pathogenesis of various male reproductive disorders and improve their diagnosis and treatment.

Role of Constitutive STAR in Mitochondrial Structure and Function in MA-10 Leydig Cells.

The steroidogenic acute regulatory protein (STAR; STARD1) is critical for the transport of cholesterol into the mitochondria for hormone-induced steroidogenesis. Steroidogenic cells express STAR under control conditions (constitutive STAR). On hormonal stimulation, STAR localizes to the outer mitochondrial membrane (OMM) where it facilitates cholesterol transport and where it is processed to its mature form. Here, we show that knockout of Star in MA-10 mouse tumor Leydig cells (STARKO1) causes defects in mitochondrial structure and function under basal conditions. We also show that overexpression of Star in STARKO1 cells exacerbates, rather than recovers, mitochondrial structure and function, which further disrupts the processing of STAR at the OMM. Our findings suggest that constitutive STAR is necessary for proper mitochondrial structure and function and that mitochondrial dysfunction leads to defective STAR processing at the OMM.

Modulatory Effects of Estradiol and Its Mixtures with Ligands of GPER and PPAR on MAPK and PI3K/Akt Signaling Pathways and Tumorigenic Factors in Mouse Testis Explants and Mouse Tumor Leydig Cells.

The present study was designed to evaluate how estradiol alone or in combination with G protein-coupled estrogen receptor (GPER) agonists and GPER and peroxisome proliferator-activated receptor (PPAR) antagonists alter the expression of tumor growth factor β (TGF-β), cyclooxygenase-2 (COX-2), hypoxia inducible factor 1-alpha (HIF-1α), and vascular endothelial growth factor (VEGF) in mouse testis explants and MA-10 mouse tumor Leydig cells. In order to define the hormone-associated signaling pathway, the expression of MAPK and PI3K/Akt was also examined. Tissue explants and cells were treated with estradiol as well as GPER agonist (ICI 182,780), GPER antagonist (G-15), PPARα antagonist (GW6471), and PPARγ antagonist (T00709072) in various combinations. First, we showed that in testis explants GPER and PPARα expressions were activated by the GPER agonist and estradiol (either alone or in mixtures), whereas PPARγ expression was activated only by GPER agonist. Second, increased TGF-β expression and decreased COX-2 expression were found in all experimental groups of testicular explants and MA-10 cells, except for up-regulated COX-2 expression in estradiol-treated cells, compared to respective controls. Third, estradiol treatment led to elevated expression of HIF-1α and VEGF, while their lower levels versus control were noted in the remaining groups of explants. Finally, we demonstrated the up-regulation of MAPK and PI3Kp85/Akt expressions in estradiol-treated groups of both ex vivo and in vitro models, whereas estradiol in mixtures with compounds of agonistic or antagonistic properties either up-regulated or down-regulated signaling kinase expression levels. Our results suggest that a balanced estrogen level and its action together with proper GPER and PPAR signaling play a key role in the maintenance of testis homeostasis. Moreover, changes in TGF-β and COX-2 expressions (that disrupted estrogen pathway) as well as disturbed GPER-PPAR signaling observed after estradiol treatment may be involved in testicular tumorigenesis.

Testicular cancer among Saudi adults: Hands on a nationwide Cancer Registry over 10 years

ABSTRACT Background/objective Testicular cancer (TC) is one of the most curable solid malignancies affecting young adults. The objective of this study was to identify factors affecting survival of Saudi adults who were diagnosed with testicular cancer over 10 years. Methods This was a retrospective study with data extracted from the Saudi Cancer Registry for Saudi Adults diagnosed with TC from 2008 to 2017. We collected demographic information, including age, marital status, region of residency, year of diagnosis, and the survival status. In addition, the tumor factors included the basis of diagnosis, the origin of the tumor, histopathological group and subtype, and tumor behavior, stage, and laterality were collected. Results A total of 869 patients were included, with a median age of 30 (IQR: 25–38). The highest percentage of the cases was 37.5% (326) in the Central region, followed by the Western region 24.6% (214). The primary site of the tumor was the testis 96.9% (842), 3.1% (27) in the undescended testis. The histopathological examination revealed seminoma in 44.8% (389), 33.5% (291) mixed germ cell tumor, 8.4% (73) embryonal carcinoma, 6.1% (53) teratoma, 2.6% (23) yolk sac tumor, 1.6% (14) choriocarcinoma, 0.3% (3) Leydig cell tumor, and 2.6% (23) sarcomas. Kaplan-Meier analysis revealed significant association between survival and the age groups (p = 0.001), histopathology group (p 0.04), histopathology subtypes (p = 0.01), and the stage of the tumor (p < 0.001). Conclusions A notable increase in the incidence of TC among Saudi adults was seen, with a mortality rate of 5.4% over a period of 10 years. Longer survival was associated with age groups, seminomatous germ cell tumor, and lower tumor stage.

Histone H4 acetylation is dysregulated in active seminiferous tubules adjacent to testicular tumours.

Is histone H4 acetylation (H4ac) altered in the seminiferous tubules of patients affected by testicular tumours? A considerable dysregulation of H4ac was detected in the cells of the seminiferous tubules adjacent to testicular tumours of different aetiology and prior to any treatment, while no comparable alterations were observed in patients with disrupted spermatogenesis. Altered H4ac levels have been associated with a variety of testicular pathological conditions. However, no information has been available regarding potential alterations in the spermatogenic cells adjacent to the neoplasia in testicular tumour patients. A retrospective analysis using testicular sections from 33 men aged between 21 and 74 years old was performed. Three study groups were defined and subjected to double-blind evaluation: a control group with normal spermatogenesis (n = 6), patients with testicular tumours (n = 18) and patients with spermatogenic impairments (n = 8). One additional sample with normal spermatogenesis was used as a technical internal control in all evaluations. Immunohistochemistry against H4ac and, when needed, Placental-like alkaline phosphatase and CD117, was performed on testicular sections. The H4ac H-score, based on the percentage of detection and signal intensity, was used as the scoring method for statistical analyses. Protein expression data from the Human Protein Atlas were used to compare the expression levels of predicted secreted proteins from testicular tumours with those present in the normal tissue. We revealed, for the first time, a dramatic disruption of the spermatogenic H4ac pattern in unaffected seminiferous tubule cells from different testicular tumour patients prior to any antineoplastic treatment, as compared to controls (P < 0.05). Since no similar alterations were associated with spermatogenic impairments and the in silico analysis revealed proteins potentially secreted by the tumour to the testicular stroma, we propose a potential paracrine effect of the neoplasia as a mechanistic hypothesis for this dysregulation. Statistical analyses were not performed on the hypospermatogenesis and Leydig cell tumour groups due to limited availability of samples. To the best of our knowledge, this is the first report showing an epigenetic alteration in cells from active seminiferous tubules adjacent to tumour cells in testicular tumour patients. Our results suggest that, despite presenting spermatogenic activity, the global epigenetic dysregulation found in the testicular tumour patients could lead to molecular alterations of the male germ cells. Since testicular tumours are normally diagnosed in men at reproductive age, H4ac alterations might have an impact when these testicular tumour patients express a desire for fatherhood. This work was supported by the European Union Marie Curie European Training Network actions and by grants to R.O. from the 'Ministerio de Economía y Competividad (Spain)' (fondos FEDER 'una manera de hacer Europa', PI13/00699, PI16/00346 and PI20/00936) and from EU-FP7-PEOPLE-2011-ITN289880. J.C. was supported by the Sara Borrell Postdoctoral Fellowship, Acción Estratégica en Salud, CD17/00109. J.C. is a Serra Húnter fellow (Universitat de Barcelona, Generalitat de Catalunya). F.B. has received grants from the Ministerio de Educación, Cultura y Deporte para la Formación de Profesorado Universitario (Spain) (FPU15/02306). A.d.l.I. is supported by a fellowship of the Ministerio de Economía, Industria y Competitividad (Spain) (PFIS, FI17/00224). M.J. is supported by the Government of Catalonia (Generalitat de Catalunya, pla estratègic de recerca i innovació en salut, PERIS 2016-2020, SLT002/16/00337). The authors have no conflicts of interest to declare. N/A.

Re-Assessment of the Plant Protection Product PROMAN – with the Active Ingredient Metobromuron [Edition 2

Proman is a broad spectrum selective herbicide for potatoes grown outdoors, containing the active substance metobromuron. VKM’s Panel on Plant Protection Products has previously discussed questions concerning Proman raised by The Norwegian Food Safety Authority, and stated its opinion in a report of 21. January 2015 (http://www.vkm.no/dav/3c64afe035.pdf). &#x0D; Following this report, The Norwegian Food Safety Authority turned down the application to register Proman as a plant protection product in Norway. The applicant filed a complaint on this decision, and the VKM Panel has been asked to reassess its previous opinion in light of the information given by the applicant in the complaint. &#x0D; The VKM Panel has discussed the arguments put forward in the complaint. The arguments did not change the Panel’s main conclusions in the original assessment. Some changes in the wording of the conclusions were however done, in order to put more emphasis on areas of uncertainty. &#x0D; These are the standing conclusions of VKM’s Panel on Plant Protection Products:&#x0D; &#x0D; On the relevance of the carcinogenic effects observed in the rat carcinogenicity study; fibrosarcomas in females and pheochromocytomas and Leydig cell tumours in males: &#x0D; It is the opinion of VKM’s Panel for Plant Protection Products that the relevance of the observed incidences of mammary gland tumours and Leydig cell tumours in the rat carcinogenicity study is strengthened by the fact that the increases in tumours associated with exposure to metobromuron are observed in hormone responsive tissues. The panel concludes that the carcinogenic effects observed in the rat carcinogenicity study could be relevant for tumour induction in humans. &#x0D; Higher incidences of still dumbbell-shaped centres of thoracic vertebrae and nonossification of the 13th rib observed in the rat developmental toxicity study and whether these are considered to be malformations: &#x0D; VKM’s Panel on Plant Protection Products has discussed the classification of the different types of incomplete ossifications and concluded that incomplete ossification of sternebrae and non-ossification of the 13th rib in rats should by itself be considered to be variations, and not adverse developmental effects. On the other hand, the Panel agrees with ECHA that the “thoracic vertebral centres still dumbbell-shaped” should be considered as malformations, due to limited data and understanding of the mechanism underlying the observed slow reversal of these anomalies. Furthermore, it is the view of the Panel that the different types of retarded ossification induced by the exposure should be considered as a whole when assessing for developmental effects. &#x0D; Establishment of the NOAEL for the developmental toxicity study in rats and the reference value (ARfD): &#x0D; VKM’s Panel on Plant Protection Products supports the proposal of an ADI value of 0.008 mg/kg bw/day based on a NOAEL of 0.8 mg/kg bw/day from the 2-year study in mouse, and AOEL of 0.016 mg/kg bw/day based on the NOAEL of 1.6 mg/kg bw/day from the 1-year feeding study in dog. The panel suggests an alternative ARfD value of 0.03 mg/kg bw based on a LOAEL of 10 mg/kg bw /day for the observations of incomplete ossification in the rat developmental study. &#x0D; The anti-androgenic potential of metobromuron: &#x0D; The rat carcinogenicity study indicates that metobromuron may interact with the endocrine system. The data from the Hershberger in vivo rat study, the in vitro studies, as well as the comparison with demonstrated effects and mechanisms for flutamide and linuron is suggestive of an anti-androgenic effect. Thus, it is the opinion of the VKM Panel on Plant Protection Products that an anti-androgenic effect of metobromuron cannot be excluded.

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.

Precocious puberty related to Leydig cell testicular tumor: the diagnostic imaging keys

BackgroundWe report the challenging case of a 6-year-old boy with precocious puberty related to histologically proven Leydig cell tumor.Case presentationMultiparametric ultrasound and magnetic resonance imaging (MRI) was performed. Interesting findings were scarcely or never reported in children and differed from adults Leydig cell tumors s such as the hyperechogenic halo surrounding the lesion and the dominant central vascularization using ultrasensitive Doppler. MRI revealed an enlarged testicle with strong enhancement of a tumor, a tumor apparent diffusion coefficient (ADC) of 600 × 10−3 mm2/s and a lower ADC value of the non-tumor parenchyma compared to the contralateral testis (ADC = 800 × 10−3 mm2/s vs 1100 × 10−3 mm2/s), attributed to the spermatogenesis induced by hormonal impregnation.ConclusionWe illustrate multiparametric US and MRI findings of a pediatric Leydig cell tumor, including the imaging changes attributed to local hormone secretion, which may be helpful in similar cases.

The endocrine disruptor Benzo[a]Pyrene inhibits gonadotropin-mediated steroidogenesis in a mouse Leydig tumor cell line

The endocrine disruptor Benzo[a]Pyrene inhibits gonadotropin-mediated steroidogenesis in a mouse Leydig tumor cell line