Development Of Testicular Tumors Research Articles

Persistent Mullerian Duct Syndrome- a Rare Case with Review of Literature

Persistent Mullerian Duct Syndrome (PMDS) is a rare type of male pseudohermaphroditism. It is brought on by an insufficiency of anti-mullerian hormone (AMH) or a malfunction of its receptor (type II). Approximately 150 adult cases of PMDS have been documented overall, with the majority from the Middle East, USA and Europe. 44 publications (49 individuals) with 3 testicular tumors linked to PMDS were found using the Medline/Pubmed search; the majority (59%) of the patients presented with a big abdominal mass. In our case, the abdomen mass that was identified as seminoma testis in a 22-year-old male patient with PMDS. Our goal in presenting this case is to highlight how uncommon it is for PMDS patients to have a testicular tumor, and how the presence of an undescended testis raises the risk of testicular tumor development in PMDS patients. The clinicians should be aware of rare entity while dealing with the cryptorchidism with inguinal hernia and necessary management should be done to offer proper treatment.

Cryptorchidism and testicular cancer in the dog: unresolved questions and challenges in translating insights from human studies†.

Cryptorchidism, the failure of one or both testes to descend into the scrotum, and testicular cancer show a strong correlation in both dogs and humans. Yet, long-standing medical debates persist about whether the location of undescended testes directly causes testicular cancer in humans or if both conditions stem from a common origin. Although testicular cancer is a prevalent disease in dogs, even less is known about its cause and correlation with testicular descent in this species. This review investigates the relation between these two disorders in dogs, drawing insights from human studies, and examines key biomarkers identified thus far. In addition, it explores potential causal links, including the impact of temperature on maturing testicular cells and a potential shared genetic origin. Notably, this literature review reveals significant differences between men and dogs in reproductive development, histological and molecular features of testicular tumors, and the prevalence of specific tumor types, such as Sertoli cell tumors in cryptorchid dogs and germ cell tumors in humans. These disparities caution against using dogs as models for human testicular cancer research and underscore the limitations when drawing comparisons between species. The paper concludes by suggesting specific research initiatives to enhance our understanding of the complex interplay between cryptorchidism and testicular cancer in dogs.

Effect of 900 MHz radiofrequency electromagnetic radiation emitted from mobile phone on testicular immunity and the associated risk of testicular germ cell tumor

The emission of radiofrequency electromagnetic radiation (RF-EMR) from mobile phones has been implicated in causing inflammatory changes in the testis. Nevertheless, the direct association of these changes with the development of testicular germ cell tumors (TGCT) remains unclear. Therefore, we purposed to investigate the effect of RF-EMR exposure on inflammatory changes in the testis, cytokine gene expression levels, and the incidence of TGCT. Twenty male Wistar albino rats were randomly assigned to either the study or control groups. The study group was exposed to RF-EMR at 900 MHz, 26 V/m, and a specific absorption rate (SAR) of 0.14 W/kg for 4 h/day over 8 weeks. Histopathological analysis, vitality analysis using Annexin V, and real-time polymerase chain reaction for the analysis of interleukin 1 (IL-1), IL-4, IL-10, tumor necrosis factor-alpha, and interferon-gamma (IFN-γ) cytokine gene expressions were performed on the testicular tissue. The median testis weight (163.0 g [133.0 – 183.0] vs. 179.0 g [134.0 – 195.0], P = 0.012) and volume (0.95 cm3 [0.800 – 1.400] vs. 1.100 cm3 [1.050 – 1.500], P = 0.031) of the study group were significantly lower compared to the control group. The seminiferous tubule damage (P < 0.001) and interstitial edema (P = 0.042) were significantly higher in the study group. The tunica albuginea thickness was significantly reduced in the study group (P < 0.001). The fold changes in the expression levels of IL-4 and IFN-γ increased significantly in the study group. Our findings indicate that RF-EMR exposure causes structural, histopathological, and inflammatory toxic effects on the testis. The observed elevation in gene expression levels of IL-4 and IFN-γ cytokines following RF-EMR exposure suggests their potential role as regulators of TGCT initiation, thereby offering a viable potential therapeutic target in combination with current treatments. Nonetheless, future well-designed studies are necessary to validate our findings.

Molecular Characterization of Patients with Cryptorchidism: Preliminary Search for an Expression Profile Related to That of Testicular Germ-Cell Tumors.

Cryptorchidism (CO) is a risk factor for the development of testicular germ-cell tumors (TGCT). This is supported by reports showing the persistence of gonocytes in CO patients. These cells are proposed to be related to the development of germ-cell neoplasia in situ (GCNIS), which is considered the precursor stage/lesion of TGCT. Therefore, it is proposed that some patients with CO could express some molecular markers related to TGCT. In this study, we analyzed testicular tissue samples from CO, TGCT, and controls. We determined the expression of POU5F1, PLAP, and KIT by immunohistochemistry and that of the hsa-miR-371-373 cluster, hsa-miR-367, and LATS2, PTEN, and IGFR1 genes by RT-qPCR. We then carried out a bioinformatic analysis to identify other possible candidate genes as tumor biomarkers. We found that 16.7% (2/12) of the CO patients presented increased expression of POU5F1, KIT, PLAP, hsa-miR-371-373, and hsa-miR-367 and decreased expression of LATS2 and IGF1R. Finally, the genes ARID4B, GALNT3, and KPNA6 were identified as other possible candidate tumor biomarkers. This is the first report describing the expression of the hsa-miR-371-373 cluster, hsa-miR-367, LATS2, and IGF1R in the testicular tissues of two CO patients with cells immune-positive to POU5F1, PLAP, and KIT, which is similar to what is observed in TGCT.

Prediagnostic Hormone Levels and Risk of Testicular Germ Cell Tumors: A Nested Case-Control Study in the Janus Serum Bank.

It has been hypothesized that poorly functioning Leydig and/or Sertoli cells of the testes, indicated by higher levels of serum gonadotropins and lower levels of androgens, are related to the development of testicular germ cell tumors (TGCT). To investigate this hypothesis, we conducted a nested case-control study within the Janus Serum Bank cohort. Men who developed TGCT (n = 182) were matched to men who did not (n = 364). Sex steroid hormones were measured using LC/MS. Sex hormone binding globulin, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) were quantified by direct immunoassay. Multivariable logistic regression was used to calculate ORs and 95% confidence intervals (CI) for associations between hormone levels and TGCT risk. Higher FSH levels [tertile (T) 3 vs. T2: OR = 2.89, 95% CI = 1.83-4.57] were associated with TGCT risk, but higher LH levels were not (OR = 1.26, 95% CI = 0.81-1.96). The only sex steroid hormone associated with risk was androstane-3α, 17β-diol-3G (3α-diol-3G; OR = 2.37, 95% CI = 1.46-3.83). Analysis by histology found that increased FSH levels were related to seminoma (OR = 3.55, 95% CI = 2.12-5.95) but not nonseminoma (OR = 1.19, 95% CI = 0.38-3.13). Increased levels of 3α-diol-3G were related to seminoma (OR = 2.29, 95% CI = 1.35-3.89) and nonsignificantly related to nonseminoma (OR = 2.71, 95% CI = 0.82-8.92). Higher FSH levels are consistent with the hypothesis that poorly functioning Sertoli cells are related to the development of TGCT. In contrast, higher levels of 3α-diol-3G do not support the hypothesis that insufficient androgenicity is related to risk of TGCT. Clarifying the role of sex hormones in the development of TGCT may stimulate new research hypotheses.

Temporal decline of sperm concentration: role of endocrine disruptors.

Male infertility is a widespread disease with an etiology that is not always clear. A number of studies have reported a decrease in sperm production in the last forty years. Although the reasons are still undefined, the change in environmental conditions and the higher exposure to endocrine-disrupting chemicals (EDCs), namely bisphenol A, phthalates, polychlorinated biphenyls, polybrominated diphenyl esters, dichlorodiphenyl-dichloroethylene, pesticides, and herbicides, organophosphates, and heavy metals, starting from prenatal life may represent a possible factor justifying the temporal decline in sperm count. The aim of this study is to provide a comprehensive description of the effects of the exposure to EDCs on testicular development, spermatogenesis, the prevalence of malformations of the male genital tract (cryptorchidism, testicular dysgenesis, and hypospadias), testicular tumor, and the mechanisms of testicular EDC-mediated damage. Animal studies confirm the deleterious impact of EDCs on the male reproductive apparatus. EDCs can compromise male fertility by binding to hormone receptors, dysregulating the expression of receptors, disrupting steroidogenesis and hormonal metabolism, and altering the epigenetic mechanisms. In humans, exposure to EDCs has been associated with poor semen quality, increased sperm DNA fragmentation, increased gonadotropin levels, a slightly increased risk of structural abnormalities of the genital apparatus, such as cryptorchidism and hypospadias, and development of testicular tumor. Finally, maternal exposure to EDCs seems to predispose to the risk of developing testicular tumors. EDCs negatively impact the testicular function, as suggested by evidence in both experimental animals and humans. A prenatal and postnatal increase to EDC exposure compared to the past may likely represent one of the factors leading to the temporal decline in sperm counts.

HF01-14 DESCENDING THROUGH THE HISTORY OF CRYPTORCHIDISM AND TESTICULAR TUMORS

You have accessJournal of UrologyCME1 May 2022HF01-14 DESCENDING THROUGH THE HISTORY OF CRYPTORCHIDISM AND TESTICULAR TUMORS Alexis Steinmetz, Kit Yuen, David Diamond, and Ronald Rabinowitz Alexis SteinmetzAlexis Steinmetz More articles by this author , Kit YuenKit Yuen More articles by this author , David DiamondDavid Diamond More articles by this author , and Ronald RabinowitzRonald Rabinowitz More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002541.14AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: An appreciation for the association between aberrant testicular descent and testicular cancer has developed over the past two centuries. While the etiology is incompletely understood, cryptorchidism is a known risk factor for the development of testicular tumors—even in the contralateral descended testis. This report presents the history of the relationship between cryptorchidism and testis tumors. METHODS: The literature was reviewed for historical descriptions of cryptorchidism and testis tumors. RESULTS: While much of our understanding regarding testicular maldescent evolved over the last 200 years, cryptorchidism was described in the Mishnah, the 2nd century CE writing of Jewish oral law. Baron Albrecht von Haller identified the intra-abdominal location of the fetal testis in 1755. Seven years later, through postmortem dissection, John Hunter observed that testes descend during the 8th month of gestation. He also correctly hypothesized that testicles that failed to descend into the scrotum were intrinsically abnormal and that it was best to assist the testis in its passage. Surgical repair was attempted unsuccessfully in early 19th century Germany. James Adams and Thomas Curling are credited with the first orchidopexy on an infant in 1871 in London. Unfortunately, the patient developed a wound infection and died of sepsis. Using antiseptic technique, Thomas Annandale performed the first successful orchidopexy in Edinburgh in 1877. A growing appreciation of histological aberrations in the cryptorchid testis further supported the concept of surgical correction. In the US, Arthur Dean Bevan popularized the orchidopexy, reporting 400 orchidopexies with a 95% success rate in 1918. There were reports of carcinomas affecting undescended testes in the 1850s, and Max Schüller described their malignant potential in 1881. John Cunningham reported a testicular tumor following orchidopexy in 1921. Larger studies emerged by the 1940s documenting the increased incidence of testicular cancer in patients with cryptorchidism. It has since been established that approximately 10% of all germ cell tumors occur in maldescended testes. Early orchidopexy was initially believed to be beneficial by facilitating tumor detection, however more recent data have demonstrated that early repair reduces the risk of subsequent malignancy; histology worsens the longer the testis is undescended. The underlying mechanisms of increased tumorigenesis in this setting remain unclear. CONCLUSIONS: There is a rich history of the management of cryptorchidism and its relation to subsequent tumor formation. Source of Funding: N/A © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e216 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Alexis Steinmetz More articles by this author Kit Yuen More articles by this author David Diamond More articles by this author Ronald Rabinowitz More articles by this author Expand All Advertisement PDF DownloadLoading ...

The Polymorphisms of Genes Encoding Catalytic Antioxidant Proteins Modulate the Susceptibility and Progression of Testicular Germ Cell Tumor.

Simple SummaryTesticular cancer is the most common malignancy in the population of young and reproductively active men. The risk factors for its occurrence are not fully elucidated. Undescended testicle remains the main risk factor; however, more precise molecular studies associate genetic variations with susceptibility to testicular tumor development and progression. In this study, we found that specific variations in genes encoding antioxidant defense proteins confer risks of testicular cancer development and progression and, therefore, helps to identify subjects at higher risk, as well as those requiring additional diagnostics and more intensive forms of treatment.The simultaneous analysis of redox biomarkers and polymorphisms encoding for regulatory and catalytic antioxidant proteins was performed in order to evaluate their potential role in the development of testicular germ cell tumor (GCT), as well as the progression of the disease. NRF2 (rs6721961), GSTM3 (rs1332018), SOD2 (rs4880) and GPX3 (rs8177412) polymorphisms were assessed in 88 patients with testicular GCT (52 with seminoma) and 88 age-matched controls. The plasma levels of 8-hydroxy-2′-deoxyguanosine (8-OHdG), thiol groups and the plasma activity of glutathione peroxidase were measured. A significant association between variant GPX3*TC+CC genotype and risk of overall testicular GCT, as well as seminoma development, was found. Moreover, carriers of variant SOD2*TT genotype were at almost 3-fold increased risk of seminoma development. Interestingly, combined SOD2*TT/GPX3*TC+CC genotype conferred a 7-fold higher risk for testicular GCT development. Finally, variant GSTM3*AC+CC genotype was associated with a higher risk for the development of advanced diseased. The presence of assessed genetic variants was not associated with significantly higher levels of redox biomarkers in both testicular GCT patients, as well as in those diagnosed with seminoma. In conclusion, the polymorphic expression of certain antioxidant enzymes might affect susceptibility toward testicular GCT development, as well as the progression of the disease.

Role of Hub Genes in the Occurrence and Development of Testicular Cancer Based on Bioinformatics.

BackgroundTesticular cancer severely affects male health, so finding effective diagnosis and prognostic indicators and exploring its pathogenesis are very important.PurposeThis study aims to explore the hub genes that play important roles in the occurrence and development of testicular germ cell tumor (TGCT).MethodsData were obtained from Gene Expression Omnibus datasets (GSE3218 and GSE1818) and verified in The Cancer Genome Atlas database and the Genotype-Tissue Expression database and the Human Protein Atlas database. A protein–protein interaction network was constructed to obtain hub genes. GEO2R, R software and packages were used to analyze differentially expressed genes (DEGs), receiver operating characteristic curve assessment, Cox regression analysis, Kaplan–Meier survival curve assessment, Gene Ontology analysis, Kyoto Encyclopedia of Genes and Genomes analysis, the relationship with clinicopathological information, gene set enrichment analysis, the correlation with immune cells’ infiltration, and the expression in pan-cancers of the hub genes.ResultsPLK4, TRIP13, TPR, KIF18A, CDKN3, HMMR, PBK, PTTG1, CKS2, SYCP1, HSPA2, and MKI67 were selected as the hub genes. mRNA of PLK4, TRIP13, CDKN3, SYCP1, HSPA2, and MKI67 had high diagnostic values, and higher expression of CDKN3 and HSPA2 mRNA were poor prognostic factors for progression-free interval of TGCT. The hub genes involved organelle division and cell cycle, chromosome and centromeric region, heat shock protein binding, and more. Downregulated TPR and PLK4 were selected as research targets for continued study, and they may participate in multiple signaling pathways. The expression of TPR and PLK4 correlated with the infiltration of a variety of immune cells and differed in pan-cancers.ConclusionThe mRNA levels of multiple hub genes have high diagnostic and prognostic values for TGCT. TPR and PLK4 may play a role in the occurrence and development of TGCT through cancer-related signaling pathways.

Domestic use of pesticides during early periods of development and risk of testicular germ cell tumors in adulthood: a French nationwide case-control study

BackgroundTesticular germ cell tumours (TGCT) are the most frequent cancers in young men in developed countries and their incidence rate has doubled worldwide over the past 40 years. Early life exposures to pesticides are suspected to increase TGCT risk. Our research aimed at estimating adult TGCT risk associated with parental domestic use of pesticides during early periods of child development.MethodsWe conducted a case-control study of 304 TGCT cases, aged 18–45 years old, recruited in 20 French university hospitals, and 274 controls frequency-matched on hospital and birth year. Participants’ mothers provided information on their domestic use of pesticides from 1 year before start of pregnancy to 1 year after their son’s birth, for gardening activities, treatment of indoor plants, pets, wood and mold, and pest control. Odds ratios (OR) for TGCT (overall and by histological subtype) and 95% confidence intervals (CI) were estimated using conditional logistic regression.ResultsPrevalence of reported domestic use of pesticides was 77.3% for insecticides, 15.9% for fungicides and 12.1% for herbicides. While no association was found for any use of insecticides (OR = 1.27, CI = 0.80–2.01) or herbicides (OR = 1.15, CI = 0.67–2.00), elevated risks of TGCT overall (OR = 1.73, CI = 1.04–2.87) and non-seminoma subtype (OR = 2.44, CI = 1.26–4.74) were observed for any use of fungicides. When specific purposes were examined, using fungicides and/or insecticides for woodwork (OR = 2.35, CI = 1.06–5.20) and using insecticides on cats and dogs (OR = 1.95, CI = 1.12–3.40) were associated with increased risk of non-seminoma subtype. We found no association for seminoma subtype.ConclusionsAlthough recall bias may partially explain the elevated ORs, our study provides some evidence of a positive association between domestic use of pesticides during early periods of development, particularly fungicides and risk of adult TGCT and non-seminoma. Given the common domestic use of pesticides in France, further research on TGCT risk is warranted.

Intra-abdominal seminoma in undescended testis with retroperitoneal nodal metastasis: A case report

Undescended testis or cryptorchidism is the most common predisposing factor in the development of testicular germ cell tumors with seminoma being the most common type. Therefore, testicular malignancy should be ruled out in case of an abdominal mass in a cryptorchid patient. Here, we present a case of intra-abdominal seminoma transformation of the undescended right testis with retroperitoneal nodal metastasis in a 54-year-old male which was clinically manifested as a gradually enlarging intra-abdominal mass and dull aching lower abdominal pain. He was managed with surgical removal, followed by chemotherapy.

Le cancer des organes génitaux externes de l’homme dans le département de l’Hérault: résultats de 30 ans d’enregistrement du registre des tumeurs de l’Hérault (1987–2016)

The objective of this study is to present the history of cancers of the external genital organs of male in Hérault using data from the Hérault tumor register (RTH) over a period of 30 years. Using the RTH database, we studied the development of testicular germ cell tumors (TGCT) and penile cancer (PC) over 30 years, from 1987 to 2016. We analyzed the incidence and mortality data for these tumors. We compared these results to French, European and global data. In 30 years of registration we have recorded 725 cases of TGCT and 175 cases of PC. The age standardized incidence rate (ASR) of TGCT has doubled between 1987 and 2016 (4.2 per 100,000 in 1987 and 9.3 per 100,000 in 2016). It was multiplied by 2.63 in the population of patients aged 30 to 44. There is a decrease of the mortality rate with a ASR of 0.8 deaths per 100,000 in 1987, and 0.4/100 000 in 2016. The PC incidence ASR was stable between 1987 and 2016 (0.4-0.9/100,000). Mortality is stable with a ASR between 0.1 and 0.3 deaths per 100,000 between 1987 and 2016. The incidence of TGCT has increased sharply in the Hérault over the past 30years, while a decrease in mortality has been observed. The proportion of seminomas is increasing; it has gone from 53% to 60% in 30years in the Hérault. The incidence and mortality of PC shows a stability in the Hérault over the past 30years.

A phosphodiesterase 11 (Pde11a) knockout mouse expressed functional but reduced Pde11a: Phenotype and impact on adrenocortical function

Phosphodiesterases catalyze the hydrolysis of cyclic nucleotides and maintain physiologic levels of intracellular concentrations of cyclic adenosine and guanosine mono-phosphate (cAMP and cGMP, respectively). Increased cAMP signaling has been associated with adrenocortical tumors and Cushing syndrome. Genetic defects in phosphodiesterase 11A (PDE11A) may lead to increased cAMP signaling and have been found to predispose to the development of adrenocortical, prostate, and testicular tumors. A previously reported Pde11a knockout (Pde11a−/−) mouse line was studied and found to express PDE11A mRNA and protein still, albeit at reduced levels; functional studies in various tissues showed increased cAMP levels and reduced PDE11A activity. Since patients with PDE11A defects and Cushing syndrome have PDE11A haploinsufficiency, it was particularly pertinent to study this hypomorphic mouse line. Indeed, Pde11a−/− mice failed to suppress corticosterone secretion in response to low dose dexamethasone, and in addition exhibited adrenal subcapsular hyperplasia with predominant fetal-like features in the inner adrenal cortex, mimicking other mouse models of increased cAMP signaling in the adrenal cortex. We conclude that a previously reported Pde11a−/− mouse showed continuing expression and function of PDE11A in most tissues. Nevertheless, Pde11a partial inactivation in mice led to an adrenocortical phenotype that was consistent with what we see in patients with PDE11A haploinsufficiency.

Cryptorchidism and Testicular Tumor: Comprehensive Analysis of Common Clinical Features and Search of SNVs in the KIT and AR Genes

Allelic variants in genes implicated in the development of testicular germ cell tumor (TGCT) could be present in patients with cryptorchidism (CO). Currently; the mechanisms explaining this relationship are still unknown. In this study the common clinical features in patients with CO and TGCT and 6 variants of KIT and AR genes associated to TGCT were analyzed. Population analyzed included 328 individuals: 91 patients with CO; 79 with TGCT, 13 of them with previous CO diagnosis, and 158 healthy males. Of the 13 patients with TGCT and history of CO, one patient (7.7%) presented the heterozygous form of the variant rs121913507 and two patients (15.4%) presented homozygote genotype for the variant rs121913506 in KIT gene. Interestingly, the heterozygous form for the variant rs121913506 of KIT gene was identifying in all of 13 patients. The rs201934623, rs774171864, and rs12014709 variants of the AR gene did not show any clinical association. Our results strongly support that genetic component in CO could be conditioning for the development of TGCT. Notably, KIT gene variants might be determinants in the pathological association between TGCT and CO.

Empty hemiscrotum and a giant abdominal mass case report

Testicular germ cell tumors are the most common adult male malignancy among men 20–35 years, having a favorable prognosis when detected at early stages. Testicular teratomas are derived from embryonic tissue within gonads and tend to exhibit locally invasive and chemo resistant behavior. Cryptorchidism is a significant risk factor for the development of testicular germ cell tumors, therefore, patients with undescended testicles should be closely monitored. Pre-pubertal orchiopexy should be considered to reduce the risk of germ cell tumors and improve its early detection. We report a 26-year-old male with an empty hemiscrotum who incidentally presented with a large intraabdominal mass after being evaluated for a broken jaw. He was lost to follow-up and re-presented with a 19 cm intraabdominal mass and alpha-fetoprotein of 5,310 ng/mL, beta-human chorionic gonadotrophin of 0.5 MIU/mL, and a lactate dehydrogenase of 846 U/L. After completion of four cycles of paclitaxel, ifosfamide, and cisplatin chemotherapy, he underwent a left orchiectomy, bilateral full template retroperitoneal lymph node dissection, and a partial cystectomy. Final pathology revealed a malignant mixed germ cell tumor consisting of 75% immature teratoma, 25% mature teratoma, and involvement in zero of twenty-three retroperitoneal lymph nodes. The patient recovered well with no signs of recurrence. This case highlights the importance of proper genitourinary assessment during routine physical examinations and close follow-up of adult patients with cryptorchidism.

Environmental Pollution as a Risk Factor in Testicular Tumour Development: Focus on the Interaction between Bisphenol A and the Associated Immune Response.

Bisphenol A (BPA) is an endocrine disruptor to which animals and humans are highly exposed. Many reports have established a relationship between BPA exposure and breast cancer incidence, especially during critical periods of development. However, its effects on the immune response in testicular tumour growth have not yet been described. Thus, we wanted to analyse the effect of perinatal BPA exposure in pregnant female mice and the immune response modulation and tumour growth in an intratesticular cancer model in offspring male mice. Pregnant female mice were exposed to a dose of 250 mg/kg/day/body weight of BPA in their drinking water. In adulthood, male offspring underwent intrascrotal inoculation with 4T1 cancer cells. On day 21 after inoculation, mice were euthanised, and serum was obtained to measure BPA levels using HPLC coupled to mass spectrometry. The percentages of immune cell populations in peripheral lymph nodes (PLN), the spleen and tumours were evaluated by flow cytometry. In addition, the tumour expression of IL-10, TNF-α and TGF-β was analysed by RT-PCR. Of note, we found detectable circulating levels of BPA in the offspring of mothers exposed to it while pregnant. Remarkably, BPA treatment promoted tumour growth by about 75% compared to mice coming from female mice that did not receive the compound. Perinatal exposure to BPA modulated the percentages of different immune cells in the spleen and PLN. In addition, the expression of inflammatory-related cytokines (IL-10 and TNF-α) in the tumours was significantly enhanced compared to control and vehicle groups. In conclusion, the perinatal BPA administration in pregnant female mice modulated different cellular and molecular immune components that resulted in outstanding testicular tumour size in male offspring.

On the Origin of Testicular Germ Cell Tumors: From Gonocytes to Testicular Cancer.

Human primordial germ cells (PGCs) have been described in the yolk sac wall around the beginning of the third week. From week 4 to 5, they migrate under control of SCF/c-KIT signaling pathway to the genital ridge, where they become gonocytes. PGCs and gonocytes express classic pluripotency markers, such as KIT, NANOG, and OCT3/4 that, during spermatogonia differentiation, are gradually suppressed, and substituted by the expression of some germ cell specific genes, such as VASA, SOX17, and TSPY. These genes, during normal development of germ cells, are tightly regulated by epigenetic modification, in terms of microRNA expression and DNA methylation. In adolescents and young adults, testicular germ cell tumors (TGCT) have a common precursor, the germ cell neoplasia in situ (GCNIS); the hypothesis of their origin from PGCs or gonocytes, whose maturation is altered, is widely accepted. The origin of TGCT, probably starting at early stages of embryogenesis, seems to be a part of the Testicular Dysgenesis Syndrome (TDS) where some early PGC/gonocytes, for still unclear reasons, are blocked in their differentiation, retaining their early marker profile. In this paper, current knowledge on the combination of epidemiological and genomic factors, involved in the development of testicular germ cell tumors, is reviewed.

Aging and Senescence in Canine Testes.

Senescent cells accumulate with age but tissue-based studies of senescent cells are limited to selected organs from humans, mice, and primates. Cell culture and xenograft studies have indicated that senescent cells in the microenvironment may play a role in tumor proliferation via paracrine activities. Dogs develop age-related conditions, including in the testis, but cellular senescence has not been confirmed. We hypothesized that senescent cells accumulate with age in canine testes and in the microenvironment of testicular tumors. We tested the expression of the established senescence markers γH2AX and p21 on normal formalin-fixed, paraffin-embedded testes from 15 young dogs (<18 months of age) and 15 old dogs (7-15 years of age) and correlated the findings with age-dependent morphological changes. A statistically significant age-dependent increase in the percentage of p21-expressing cells was observed for testicular fibroblasts (4-fold) and Leydig cells (8-fold). However, p21-expressing cells were still a rare event. In contrast, the percentage of γH2AX-positive cells did not increase with age. P21- and γH2AX-expressing cells were rare in the microenvironments of tumors. Age-dependent morphological changes included an increased mean number of Leydig cells per intertubular triangle (2.95-fold) and a decreased spermatogenesis score. To our surprise, no age-related changes were recorded for interstitial collagen content, mean tubular diameter, and epithelial area. Opposed to our expectations based on previous in vitro data, we did not identify evidence of a correlation between age-associated accumulation of senescent cells and testicular tumor development. Understanding the role of the microenvironment in senescence obviously remains a challenging task.

Rare presentation of a seminoma with mixed germ cell tumor in undescended inguinal testis

Cryptorchidism is the most common predisposing factor in the development of testicular germ cell tumors. Seminoma is the most common malignancy developing in a cryptorchid testis. A rare case of seminoma with mixed germ cell tumor in an undescended testis is reported here. A 35-year-old male patient presented with swelling in left inguinal region science 1.5year. This was smooth, firm to hard in consistency, restricted mobility and his left scrotum was empty. Serological markers α-FP, β-HCG, LDH were raised. Sonography and CT scan revealed a testicular tumor in undescended left inguinal testis. High inguinal orchidectomy was done. Patient had an uneventful recovery. The histopathology report of biopsy revealed a seminoma with mixed germ cell tumor. Early diagnosis and management of the undescended testicle are needed to preserve fertility and improve early detection of testicular malignancy. Therapy should begin between six months and two years of age and may consist of hormone or surgical treatment.

Association of Inherited Pathogenic Variants in Checkpoint Kinase 2 (CHEK2) With Susceptibility to Testicular Germ Cell Tumors

ImportanceApproximately 50% of the risk for the development of testicular germ cell tumors (TGCTs) is estimated to be heritable, but no mendelian TGCT predisposition genes have yet been identified. It is hypothesized that inherited pathogenic DNA repair gene (DRG) alterations may drive susceptibility to TGCTs.ObjectiveTo systematically evaluate the enrichment of germline pathogenic variants in the mendelian cancer predisposition DRGs in patients with TGCTs vs healthy controls.Design, Setting, and ParticipantsA case-control enrichment analysis was performed from January 2016 to May 2018 to screen for 48 DRGs in 205 unselected men with TGCT and 27 173 ancestry-matched cancer-free individuals from the Exome Aggregation Consortium cohort in the discovery stage. Significant findings were selectively replicated in independent cohorts of 448 unselected men with TGCTs and 442 population-matched controls, as well as 231 high-risk men with TGCTs and 3090 ancestry-matched controls. Statistical analysis took place from January to May 2018.Main Outcomes and MeasuresGene-level enrichment analysis of germline pathogenic variants in individuals with TGCTs relative to cancer-free controls.ResultsAmong 205 unselected men with TGCTs (mean [SD] age, 33.04 [9.67] years), 22 pathogenic germline DRG variants, one-third of which were in CHEK2 (OMIM 604373), were identified in 20 men (9.8%; 95% CI, 6.1%-14.7%). Unselected men with TGCTs were approximately 4 times more likely to carry germline loss-of-function CHEK2 variants compared with cancer-free individuals from the Exome Aggregation Consortium cohort (odds ratio [OR], 3.87; 95% CI, 1.65-8.86; nominal P = .006; q = 0.018). Similar enrichment was also seen in an independent cohort of 448 unselected Croatian men with TGCTs (mean [SD] age, 31.98 [8.11] years) vs 442 unselected Croatian men without TGCTs (at least 50 years of age at time of sample collection) (OR, >1.4; P = .03) and 231 high-risk men with TGCTs (mean [SD] age, 31.54 [9.24] years) vs 3090 men (all older than 50 years) from the Penn Medicine Biobank (OR, 6.30; 95% CI, 2.34-17.31; P = .001). The low-penetrance CHEK2 variant (p.Ile157Thr) was found to be a Croatian founder TGCT risk variant (OR, 3.93; 95% CI, 1.53-9.95; P = .002). Individuals with the pathogenic CHEK2 loss-of-function variants developed TGCTs 6 years earlier than individuals with CHEK2 wild-type alleles (5.95 years; 95% CI, 1.48-10.42; P = .009).Conclusions and RelevanceThis multicenter case-control analysis of men with or without TGCTs provides evidence for CHEK2 as a novel moderate-penetrance TGCT susceptibility gene, with potential clinical utility. In addition to highlighting DNA-repair deficiency as a potential mechanism driving TGCT susceptibility, this analysis also provides new avenues to explore management strategies and biological investigations for high-risk individuals.