Paraneoplastic Hyperthyroidism in Advanced Testicular Non-Seminomatous Germ Cell Tumors: Prevalence and Clinical Management.

INTRODUCTION: Paraneoplastic hyperthyroidism (PH) has been reported in patients with testicular germ cell tumors (GCTs), sporadically. This disorder is caused by extremely elevated serum levels of beta-human chorionic gonadotropin (bHCG). To date, little is known about the prevalence of PH, and its clinical features are poorly understood. The aim of the present study was to analyze the relative frequency and clinical features of PH in GCTs and evaluate their effects on therapeutic outcomes. METHODS: A cohort of 438 patients treated for testicular GCT from 2017 to 2023 was retrospectively analyzed for histology, age, clinical stage, and presence of PH. The clinical features of the patients with PH were evaluated descriptively. The relative frequency of PH was compared among the subgroups using descriptive statistical methods. RESULTS: Three patients with PH were identified; all had clinical symptoms of hyperthyroidism, suppressed serum levels of thyroid-stimulating hormone (TSH), and increased levels of tri-iodothyronin (fT3). All the patients had advanced, metastasized, and non-seminomatous GCTs. Serum bHCG levels ranged from 225,00 U/L to 1,520,000 U/L. The prevalence of PH was 0.7% in the entire GCT population and 60% in those with very high bHCG serum levels. All the patients received standard cisplatin-based chemotherapy along with thyrostatic treatment. The clinical symptoms of the hyperthyroidism rapidly disappeared. TSH levels normalized with decreasing bHCG levels. The PH treatment did not affect the therapeutic outcomes of the patients. CONCLUSION: PH may occur in 0.7% of all patients with GCT but may be present in up to 60% of patients with very high levels of bHCG. Measuring serum levels of TSH and fT3 should be performed in addition to routine diagnostic measures in all patients with poor prognosis GCTs. Thyrostatic medication is recommended for patients with the clinical symptoms of hyperthyroidism. Early recognition of hyperthyroidism and prompt intervention will reduce comorbidity and help optimize therapeutic outcomes.

The prognostic impact of treatment centralization in patients with testicular germ cell tumors: analysis of hospital-based cancer registry data in Japan.

BACKGROUND: To identify the prognostic impact of treatment centralization in patients with testicular germ cell tumors (TGCT). METHODS: We used a hospital-based cancer registry data in Japan to extract seminoma and non-seminoma cases that were diagnosed in 2013, histologically confirmed, and received the first course of treatment. To compare the 5-years overall survival (OS) rates of patients stratified by institutional care volume, we performed a Cox proportional hazards regression analysis using inverse probability of treatment weighting (IPTW) method to adjust patient backgrounds. RESULTS: A total of 1767 TGCT patients were identified. The 5-years OS rates for stage II and III TGCT patients treated at low-volume institutions (< 7 cases) were significantly worse than high-volume institutions (≥ 7 cases) (91.2% vs. 83.4%, p = 0.012). Histological stratification revealed that 5-year OS rates for stage II and III seminoma patients in the low-volume group were significantly worse than the high-volume group (93.5% vs. 84.5%, p = 0.041). Multivariate OS analysis using an IPTW-matched cohort showed that institutional care volume was an independent prognostic factor (hazard ratio 2.13 [95% confidence interval: 1.23-3.71], p = 0.0072). CONCLUSION: Our results indicate that stage II and III TGCT patients experience lower survival rates at low-volume institutions and would benefit from treatment centralization.

MicroRNAs in Testicular Germ Cell Tumors: The Teratoma Challenge.

Testicular germ cell tumors (TGCTs) are relatively common in young men, making accurate diagnosis and prognosis assessment essential. MicroRNAs (miRNAs), including microRNA-371a-3p (miR-371a-3p), have shown promise as biomarkers for TGCTs. This review discusses the recent advancements in the use of miRNA biomarkers in TGCTs, with a focus on the challenges surrounding the noninvasive detection of teratomas. Circulating miR-371a-3p, which is expressed in undifferentiated TGCTs but not in teratomas, is a promising biomarker for TGCTs. Its detection in serum, plasma, and, potentially, cystic fluid could be useful for TGCT diagnosis, surveillance, and monitoring of therapeutic response. Other miRNAs, such as miR-375-3p and miR-375-5p, have been investigated to differentiate between TGCT subtypes (teratoma, necrosis/fibrosis, and viable tumors), which can aid in treatment decisions. However, a reliable marker for teratoma has yet to be identified. The clinical applications of miRNA biomarkers could spare patients from unnecessary surgeries and allow for more personalized therapeutic approaches. Particularly in patients with residual masses larger than 1 cm following chemotherapy, it is critical to differentiate between viable tumors, teratomas, and necrosis/fibrosis. Teratomas, which mimic somatic tissues, present a challenge in differentiation and require a comprehensive diagnostic approach. The combination of miR-371 and miR-375 shows potential in enhancing diagnostic precision, aiding in distinguishing between teratomas, viable tumors, and necrosis. The implementation of miRNA biomarkers in TGCT care could improve patient outcomes, reduce overtreatment, and facilitate personalized therapeutic strategies. However, a reliable marker for teratoma is still lacking. Future research should focus on the clinical validation and standardization of these biomarkers to fully realize their potential.

Differentially expressed messenger RNA/proteins can distinguish teratoma from necrosis in postchemotherapy retroperitoneal lymph node dissection tissue.

BACKGROUND: Before postchemotherapy retroperitoneal lymph node dissection (pcRPLND), in patients with metastasized germ cell tumors (GCTs), those harboring necrosis (NEC) cannot be distinguished from those who have teratoma (TER), resulting in relevant overtreatment, whereas microRNA-371a-3p may be predictive for viable GCT. The purpose of this study was to explore messenger RNA (mRNA) and proteins to distinguish TER from NEC in pcRPLND tissue. METHODS: The discovery cohort consisted in total of 48 patients, including 16 each with TER, viable GCT, and NEC. Representative areas were microdissected. A NanoString panel and proteomics were used to analyze 770 genes and >5000 proteins. The most significantly and differentially expressed combination of both parameters, mRNA and its associated protein, between TER and NEC was validated using immunohistochemistry (IHC) in an independent validation cohort comprising 66 patients who were not part of the discovery cohort. RESULTS: The authors observed that anterior gradient protein 2 homolog (AGR2) and keratin, type I cytoskeletal 19 (KRT19) were significantly differentially expressed in TER versus NEC in mRNA and protein analyses (proteomics). The technical validation using IHC was successful in the same patients. These proteins were further validated by IHC in the independent patient cohort and exhibited significantly higher levels in TER versus NEC (p < .0001; area under the curve, 1.0; sensitivity and specificity, 100% each). CONCLUSIONS: The current study demonstrated that KRT19 and AGR2 mRNA and protein are overexpressed in TER versus NEC in pcRPLND tissue and might serve as a future diagnostic target to detect TER, for instance, by functional imaging, to avoid overtreatment. PLAIN LANGUAGE SUMMARY: The proteins and the corresponding genes called AGR2 and KRT19 can differentiate between teratoma and necrosis in remaining tumor masses after chemotherapy in patients who have metastasized testicular cancer. This may be a way to improve presurgical diagnostics and to reduce the current overtreatment of patients with necrosis only, who could be treated sufficiently by surveillance.

Post-chemotherapy robot-assisted retroperitoneal lymph node dissection for metastatic germ cell tumors: safety and perioperative outcomes.

PURPOSE: To evaluate the feasibility, safety, and early oncologic outcomes after post-chemotherapy robot-assisted retroperitoneal lymph node dissection (PC-RARPLND) for metastatic germ cell tumors (mGCT). METHODS: We retrospectively analyzed patients from four tertiary centers who underwent PC-RARPLND for mGCT, from 2011 to 2021. Previous treatment of mGCT, intraoperative and postoperative complications, and early oncologic outcomes were assessed. RESULTS: Overall, 66 patients were included. The majority of patients had non-seminoma mTGCT (89%). Median size of retroperitoneal lymph node (RLN) before surgery was 26 mm. Templates of PC-RARPLND were left modified, right modified, and full bilateral in 56%, 27%, and 14%, respectively. Median estimated blood loss and length of stay were 50 mL [50-150] and 2 [1-3] days. Four patients (6.1%) had a vascular injury, only one with significant blood loss and conversion to open surgery (OS). Two other patients had a conversion to OS for difficulty of dissection. No patient had transfusion, most frequent complications were ileus (10.6%) and symptomatic lymphorrea (7.6%) and no complications grade IIIb or more occurred. With a median follow-up of 16 months, two patients had a relapse, all outside of the surgical template (one in the retrocrural space with reascending markers, one in lungs). CONCLUSION: PC-RARPLND is a challenging surgery. In expert centers and for selected patients, it seemed safe and feasible, with a low morbidity. Further prospective evaluation of this procedure and long-term oncologic results are needed.

Habitual physical activity modulates cardiometabolic health in long-term testicular cancer survivors.

PURPOSES: Physical activity (PA) may mitigate late cardiometabolic toxicity of cisplatin-based chemotherapy in testicular germ cell tumor (TGCT) long-term survivors. In this cross-sectional study, we evaluated the effects of habitual PA on metabolic syndrome (MetS) prevalence, and on the markers of cardiometabolic health and chronic inflammation in a population of long-term TGCT survivors. METHODS: MetS prevalence was evaluated, and habitual PA was assessed using Baecke's habitual PA questionnaire in TGCT survivors (n=195, age=41.1±8.1years, 11.7±5.2years post-therapy) and healthy male controls (n=41, age=38.2±8.8years). Participants were stratified into low- and high-PA groups based on median values. Differences were examined between low- and high-PA groups (in the entire sample, TGCT survivor sub-samples differing in disease stage, and healthy controls), and between TGCT survivors and controls. Next, TGCT survivors were stratified into age- and BMI-matched sub-groups based on post-treatment time (5-15/15/30years) and number of chemotherapy cycles (≤3/>3), allowing us to detect age- and BMI-independent effects of habitual PA on cardiometabolic health in the given TGCT survivor sub-populations. A correlation matrix of habitual PA and sport activity with cardiometabolic and pro-inflammatory markers was generated. RESULTS: TGCT survivors had higher MetS prevalence than controls. Patients with high habitual PA had lower waist circumference and Systemic Inflammation Index. Habitual PA scores correlated positively with HDL-cholesterol and negatively with waist circumference and atherogenic risk. Furthermore, cardiometabolic benefits of habitual PA were more pronounced in patients with disease stages 1 and 2. Effects of habitual PA on patients sub-populations stratified by chemotherapy dose and post-treatment time clearly showed that higher levels of habitual PA were associated with lower numbers of MetS components, except for patients who received more than 3 chemotherapy cycles and were examined more than15 years post-therapy. CONCLUSIONS: Higher levels of habitual PA effectively mitigated cardiometabolic toxicity in TGCT survivors. Patients with higher cumulative doses of chemotherapy may need structured exercise interventions involving higher-intensity physical activity to achieve significant improvements in cardiometabolic health.

From Surviving Cancer to Getting on With Life: Adult Testicular Germ Cell Tumor Survivors' Perspectives on Transition From Follow-Up Care to Long-Term Survivorship.

With an increasing incidence and a high cure rate, a growing number of testicular germ cell tumor (TGCT) survivors require specialized follow-up care. However, knowledge of these patients' needs is lacking, leaving TGCT survivors with unmet care needs at risk of symptom burden when transitioning to long-term survivorship. This grounded theory study aimed to understand the perspectives of TGCT survivors' transition from follow-up care to long-term survivorship. A total of 12 adult TGCT survivors in follow-up care or completion less than a year were in-depth semi-structured interviewed. Interviews were audiotaped and transcribed verbatim. Transcripts were analyzed by constant comparison, and the core category "Dealing with back-and-forth forces" emerged in the integrated concepts. Two comparative processes in dealing with those forces were identified: the process of Living beyond the sword of Damocles involved the transition from feeling threatened by cancer to overcoming those threats; the process of Getting on with one's life can be described as transitioning from a period where cancer overruled their lives to carrying on with everyday life. The processes toward long-term survivorship follow general characteristics; the transition itself is an individual journey that depends on (life) experiences. The constructed model can guide healthcare professionals and researchers involved in TGCT survivorship to understand TGCT survivors' individual and ensuing needs. When TGCT survivors receive individualized and tailored follow-up care, it can assist in preventing and reducing long-term and late effects on long-term survivorship.

Kelch-like protein 11 antibody-associated paraneoplastic neurological syndrome: A state-of-the-art review.

The Kelch-like protein 11 antibody-associated paraneoplastic neurological syndrome (KLHL 11-PNS) was first identified in 2019. This novel antibody, targeting the intracellular KLHL 11 antigen, can be detected in serum and cerebrospinal fluid using tissue-based and cell-based assays. It is thought to be a biomarker for a T-cell autoimmunity response. The most likely immunopathogenesis of KLHL 11-PNS appears to be linked to cytotoxic T-cell-mediated neuronal injury and loss. Patients have adult-male predilection, rhombencephalitis (brainstem and / or cerebellar involvement), and a robust oncological correlation with testicular germ cell tumors (predominately seminoma). Brain magnetic resonance imaging demonstrated T2 / fluid-attenuated inversion recovery hyperintensities and atrophy of the temporal lobe, cerebellum, and brainstem. Most patients responded poorly to immunotherapy and oncotherapy and thus had a poor long-term prognosis. We review the literature and provide an update of current knowledge regarding KLHL 11-PNS, including epidemiology, underlying mechanism, clinical presentations, paraclinical and oncological findings, diagnostic workup, and treatment approaches.

The Role of microRNAs in the Gonocyte Theory as Target of Malignancy: Looking for Potential Diagnostic Biomarkers.

Some pediatric patients with cryptorchidism preserve cells with gonocyte characteristics beyond their differentiation period, which could support the theory of the gonocyte as a target for malignancy in the development of testicular neoplasia. One of the key molecules in gonocyte malignancy is represented by microRNAs (miRNAs). The goal of this review is to give an overview of miRNAs, a class of small non-coding RNAs that participate in the regulation of gene expression. We also aim to review the crucial role of several miRNAs that have been further described in the regulation of gonocyte differentiation to spermatogonia, which, when transformed, could give rise to germ cell neoplasia in situ, a precursor lesion to testicular germ cell tumors. Finally, the potential use of miRNAs as diagnostic and prognostic biomarkers in testicular neoplasia is addressed, due to their specificity and sensitivity compared to conventional markers, as well as their applications in therapeutics.

Outcomes of adolescent males with extracranial metastatic germ cell tumors: A report from the Malignant Germ Cell Tumor International Consortium.

BACKGROUND: Adolescents with extracranial metastatic germ cell tumors (GCTs) are often treated with regimens developed for children, but their clinical characteristics more closely resemble those of young adult patients. This study was designed to determine event-free survival (EFS) for adolescents with GCTs and compared them with children and young adults. METHODS: An individual patient database of 11 GCT trials was assembled: 8 conducted by pediatric cooperative groups and 3 conducted by an adult group. Male patients aged 0 to 30 years with metastatic, nonseminomatous, malignant GCTs of the testis, retroperitoneum, or mediastinum who were treated with platinum-based chemotherapy were included. The age groups were categorized as children (0 to <11 years), adolescents (11 to <18 years), and young adults (18 to ≤30 years). The study compared EFS and adjusted for risk group by using Cox proportional hazards analysis. RESULTS: From a total of 2024 individual records, 593 patients met the inclusion criteria: 90 were children, 109 were adolescents, and 394 were young adults. The 5-year EFS rate was lower for adolescents (72%; 95% confidence interval [CI], 62%-79%) than children (90%; 95% CI, 81%-95%; P = .003) or young adults (88%; 95% CI, 84%-91%; P = .0002). The International Germ Cell Cancer Collaborative Group risk group was associated with EFS in the adolescent age group (P = .0020). After adjustments for risk group, the difference in EFS between adolescents and children remained significant (hazard ratio, 0.30; P = .001). CONCLUSIONS: EFS for adolescent patients with metastatic GCTs was similar to that for young adults but significantly worse than for that children. This finding highlights the importance of coordinating initiatives across clinical trial organizations to improve outcomes for adolescents and young adults. LAY SUMMARY: Adolescent males with metastatic germ cell tumors (GCTs) are frequently treated with regimens developed for children. In this study, a large data set of male patients with metastatic GCTs across different age groups has been built to understand the outcomes of adolescent patients in comparison with children and young adults. The results suggest that adolescent males with metastatic GCTs have worse results than children and are more similar to young adults with GCTs. Therefore, the treatment of adolescents with GCTs should resemble therapeutic approaches for young adults.

Analysis of Genetic Alterations Related to DNA Methylation in Testicular Germ Cell Tumors Based on Data Mining.

Embryonal carcinoma (EC) and seminoma (SE) are both derived from germ cell neoplasia in situ but show big differences in growth patterns and clinical prognosis. Epigenetic regulation may play an important role in the development of EC and SE. This study investigated the DNA methylation-based genetic alterations between EC and SE by analyzing the datasets of mRNA expression and DNA methylation profiling. The datasets were downloaded from the Gene Expression Omnibus database. The differentially expressed genes (DEGs) were identified between EC and SE by limma package in R environment. Gene function enrichment analysis of the DEGs was performed on the DAVID tool, the results of which suggested differences in capability of pluripotency and genomic stability between EC and SE. The minfi package and wANNOVAR tool were used to identify differentially methylated genes. A total of 37 genes were discovered with both mRNA expression and the accordant DNA methylation changes. The findings were verified by the sequencing data from The Cancer Genome Atlas database, and Kaplan-Meier survival analysis was performed. Finally, 5 genes (PRDM1, LMO2, FAM53B, HCN4, and FAM124B) were found that showed both low expression and high methylation in EC, and were significantly associated with relapse-free survival. The findings of methylation-based genetic features between EC and SE might be helpful in studying the role of DNA methylation in cancer development.

Effects of noninherited ancestral genotypes on offspring phenotypes†.

It is well established that environmental exposures can modify the profile of heritable factors in an individual's germ cells, ultimately affecting the inheritance of phenotypes in descendants. Similar to exposures, an ancestor's genotype can also affect the inheritance of phenotypes across generations, sometimes in offspring who do not inherit the genetic aberration. This can occur via a variety of prenatal, in utero, or postnatal mechanisms. In this review, we discuss the evidence for this process in mammals, with a focus on examples that are potentially mediated through the germline, while also considering alternate routes of inheritance. Noninherited ancestral genotypes may influence descendant's disease risk to a much greater extent than currently appreciated, and focused evaluation of this phenomenon may reveal novel mechanisms of inheritance.

Additional surgical procedures and perioperative morbidity in post-chemotherapy retroperitoneal lymph node dissection for metastatic testicular cancer in two intermediate volume hospitals.

PURPOSE: To evaluate the perioperative morbidity of PC-RPLND in two intermediate volume centers and to identify predictors of high morbidity. METHODS: Retrospective analysis of 124 patients treated with open PC-RPLND at two tertiary referral centers between 2001 and 2018. Perioperative morbidity was determined by analyzing additional surgical procedures, intra-operative blood loss, and postoperative complications. RESULTS: An additional procedure was necessary for 33 patients (26.6%). The risk was higher in patients with IGCCCG intermediate/poor prognosis (OR 3.56; 95% CI 1.33-9.52) and residual tumor size > 5 cm (OR 3.53; 95% CI 1.39-8.93). Blood loss was higher in patients with IGCCCG intermediate/poor prognosis (ß = 0.177; p = 0.029), large residual tumor (ß = 0.570; p < 0.001), an additional intervention (ß = 0.342; p < 0.001) and teratoma on retroperitoneal histology (ß = - 0.19; p = 0.014). Thirty-one patients had a postoperative complication Clavien-Dindo Grade ≥ 2 (25.0%). Complication risk was highest in patients undergoing an additional intervention (OR 3.46; 95% CI 1.03-11.60; p = 0.044). CONCLUSIONS: The rate of additional interventions in our series is comparable to what has been reported in high-volume centers. IGCCCG intermediate/poor prognosis patients with high-volume disease and patients undergoing an additional surgical procedure can be classified as high-risk patients.

Clinical outcome of robot-assisted residual mass resection in metastatic nonseminomatous germ cell tumor.

PURPOSE: To evaluate the outcome of robot-assisted residual mass resection (RA-RMR) in nonseminomatous germ cell tumor (NSGCT) patients with residual tumor following chemotherapy. PATIENTS AND METHODS: Retrospective medical chart analysis of all patients with NSGCT undergoing RA-RMR at two tertiary referral centers between January 2007 and April 2019. Patients were considered for RA-RMR in case of a residual tumor between 10 and 50 mm at cross-sectional computed tomography (CT) imaging located ventrally or laterally from the aorta or vena cava, with normalized tumor markers following completion of chemotherapy, and no history of retroperitoneal surgery. RESULTS: A total of 45 patients were included in the analysis. The Royal Marsden stage before chemotherapy was IIA in 13 (28.9%), IIB in 16 (35.6%), IIC in 3 (6.7%) and IV in 13 patients (28.9%). The median residual tumor size was 1.9 cm (interquartile range [IQR] 1.4-2.8; range 1.0-5.0). Five procedures (11.1%) were converted to an open procedure due to a vascular injury (n = 2), technical difficulty (n = 2) or tumor debris leakage (n = 1). A postoperative adverse event occurred in two patients (4.4%). Histopathology showed teratoma, necrosis and viable cancer in 29 (64.4%), 14 (31.1%), and two patients (4.4%), respectively. After a median follow-up of 41 months (IQR 22-70), one patient (2.2%) relapsed in the retroperitoneum. The one- and 2-year recurrence-free survival rate was 98%. CONCLUSION: RA-RMR is an appropriate treatment option in selected patients, potentially providing excellent cure rates with minimal morbidity. Long-term outcome data are needed to further support this strategy and determine inclusion and exclusion criteria.

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

BACKGROUND: Testicular 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. METHODS: We 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. RESULTS: Prevalence 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. CONCLUSIONS: Although 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.

Genomic characteristics revealed by targeted exon sequencing of testicular germ cell tumors in Japanese men.

OBJECTIVE: To investigate the somatic mutation profiles of testicular germ cell tumors in Japanese men. METHODS: We analyzed the somatic missense mutation profile of testicular germ cell tumors among 21 Japanese men with seminoma (n = 14), pure embryonic carcinoma (n = 3) and mixed testicular germ cell tumor (n = 4) by targeted next-generation sequencing of 409 cancer-related genes covering 1.23 Mb of the genome. RESULTS: We identified a total of 22 missense mutations in 21 primary testicular germ cell tumor samples (0.89 mutations/Mb), of which seven mutations were confirmed to be absent from the germline. KIT:p.Asn822Tyr, KIT:p.Leu576Pro, PIK3CA:p.Glu542Lys and FBXW7:p.Arg505His were statistically and functionally potential. A total of 18 missense mutations were previously unknown in testicular germ cell tumors. PDGFRA amplification from one patient with seminoma was detected. KIT, BCR,PIK3CG, PIK3CA and PDGFRA mutations involved in aberrant signaling of the KIT-PI3K-AKT pathway was detected in 27.3% of detected mutations. CONCLUSIONS: The present investigation identified a low mutation rate in testicular germ cell tumors among Asian patients, 18 novel mutations and PDGFRA amplification. Limitations of the present study are the small sample and missing normal DNA for some testicular germ cell tumors.

Recent malignant testicular tumor trend in Japan, a country with an aging population: a large-scale study of 2012-2015 hospital-based cancer registry data.

OBJECTIVE: Japan's national database of hospital-based cancer registries is estimated to cover ~67% of all new cancer cases. Using this database, we analyzed the characteristics of the recently diagnosed testicular malignancy. METHODS: We obtained data for 6510 adult testicular malignancy patients diagnosed in 2012-2015. The distributions of patient ages, histological diagnoses and testicular germ cell tumor hospital care volumes were determined. RESULTS: The most common histology was seminoma (60.3% of all testicular malignancies), followed by non-seminoma (24.1%) and diffuse large B-cell lymphoma (13.1%). The median and mean ages of the testicular germ cell tumor patients were high at 38 and 39.8 years, respectively. The age distribution peaked at 30-40 years, followed by 40-50 years. Approximately 18% of testicular germ cell tumor patients were ≥50 years. The ages of the diffuse large B-cell lymphoma patients peaked at 70-80 years (mean 67.7 years). When the analysis was limited to the testicular germ cell tumor patients who received first-course cancer treatment at the participating hospitals, the number of high-volume hospitals with ≥20 testicular germ cell tumor care volume was limited to 61 (10.0% of the 605 hospitals that treated ≥1 testicular germ cell tumor patient). However, when the patients who changed hospitals during treatment or relapsed after treatment completion were analyzed together, the number of high-volume hospitals increased to 104 (17.0% of 612 hospitals). CONCLUSION: The testicular germ cell tumor patients' mean age was nearly 40 years. The proportions of older testicular germ cell tumor patients and diffuse large B-cell lymphoma patients were higher than previously thought. The reasons for this trend are unknown, but it is important to address the trend identified herein in a country with a super-aging population.

Effects of testicular dysgenesis syndrome components on testicular germ cell tumor prognosis and oncological outcomes.

PURPOSE: To evaluate whether components of Testicular Dysgenesis Syndrome (TDS) affect testicular germ cell tumor (TGCT) prognosis and oncological outcomes. According to the hypothesis called TDS; undescended testis, hypospadias, testicular cancer and spermatogenic disorders share the same risk factors and have a combined fetal origin. MATERIALS AND METHODS: We retrospectively evaluated the stages and oncological outcomes of 69 patients who underwent radical orchiectomy between January 2010 and December 2014 due to TGCT in our department. The presence of undescended testis, hypospadias and semen parameters disorders were recorded according to anamnesis of patients. RESULTS: Among 69 patients with TGCT, only 16 (23.1%) had TDS. Significantly higher rate of TDS (36.1% vs. 9.1%) was observed at the advanced stages of TGCT(p=0.008). In the TDS group, the rates of local recurrence (50% vs. 11.3%, p< 0.001), distant metastasis (93.6% vs. 3.8%, p< 0.001) and cancer-spesific mortality (87.5% vs. 3.8%, p< 0.001) were found significantly higher than those without TDS. The predicted time for recurrence-free survival (13.70±5.13 vs. 100.96±2.83 months, p< 0.001) metastasis-free survival (13.12±4.21 vs. 102.79±2.21 months, p< 0.001) and cancer-specific survival (13.68±5.38 vs. 102.80±2.19 months, p< 0.001) were also statistically lower in this group. CONCLUSIONS: According to our preliminary results, there is an apparent relationship between TDS and tumor prognosis. Even if the components of TDS alone did not contain poor prognostic features for TGCT, the presence of TDS was found as the most important independent predictive factor for oncological outcomes in both seminomas and nonseminomas as well as all patients with TGCT.

[Ultrasonographic and clinical features of common testicular germ cell tumors in children].

OBJECTIVE: To study the ultrasonographic manifestations and clinical features of common pediatric testicular germ cell tumors (TGCT) in children. METHODS: We retrospectively analyzed the laboratory, ultrasonographic and clinical data on 92 children with TGCT diagnosed in Shanghai Children's Hospital from March 2013 to January 2019, and investigated the values of the serum alpha-fetoprotein (AFP) level and maximum diameter of tumors in the diagnosis of benign and malignant tumors using the ROC curve. RESULTS: Of the 92 cases of pediatric TGCT, 64 (69.6%) were pathologically confirmed as benign tumors, including 40 cases of teratoma (62.5%), 18 cases of epidermoid cyst (28.1%) and 6 cases of dermoid cyst (9.4%), and the other 28 (30.4%) as malignant neoplasms, including 26 cases of yolk sac tumor (YST, 92.9%) and 2 cases of mixed germ cell tumor (MGCT, 7.1%). Ultrasonography showed that 62.5% of the teratomas were cystic-solid mixed (25/40) and 32.5% solid masses (12/40), that 33.3% of the epidermoid cysts exhibited a typical sign of "onion ring" (6/18) and 22.2% that of capsular calcification (4/18), and that 42.3% of the YSTs displayed isoechoic (11/26), 30.9% hypoechoic (8/26) solid masses without calcium and 26.9% cystic anechoic lesions (7/26). Color Doppler blood flow imaging manifested abundant blood flow signals in most of the YSTs (25/26, 96.2%) but none in either the epidermoid or the dermoid cysts. The area under the ROC curve (AUC) of the serum AFP value was 0.985, with an optimal cutoff value of 124.2 ng/ml, and the sensitivity and specificity of AFP in the diagnosis of benign and malignant tumors were 92.9% and 93.7%, respectively. The AUC of the maximum diameter of the tumors was 0.796, with an optimal cutoff value of 2.7 cm, and the sensitivity and specificity of the maximum diameter of the tumors in the diagnosis of benign and malignant neoplasms were 57.1% and 93.7%, respectively. CONCLUSIONS: Ultrasonographic images have different characteristic manifestations for different pathological types of pediatric TGCT. Pediatric TGCT has a good prognosis and radical orchiectomy should be considered for the treatment of the tumors with serum AFP ≥ 124.2 ng/ml and a diameter ≥ 2.7 cm.

cd44 deletion suppresses atypia in the precancerous mouse testis.

Loss-of-function of RHAMM causes hypofertility and testicular atrophy in young mice, followed by germ cell neoplasia in situ (GCNIS) of the testis, cellular atypia, and development of the testicular germ cell tumor (TGCT) seminoma. These pathologies reflect the risk factors and phenotypes that precede seminoma development in humans and-given the high prevalence of RHAMM downregulation in human seminoma-link RHAMM dysfunction with the aetiology of male hypofertility and GCNIS-related TGCTs. The initiating event underlying these pathologies, in RHAMM mutant testis, is premature displacement of undifferentiated progenitors from the basal compartment. We hypothesized that cd44 (both cancer initiating cell- and oncogenic progression marker) will drive GCNIS development, induced by RHAMM-loss-of-function in the mouse. We report that cd44 is expressed in a specific subset of GCNIS testes. Its genetic deletion has no effect on GCNIS onset, but it ameliorates oncogenic progression. We conclude that cd44 expression, combined with RHAMM dysfunction, promotes oncogenic progression in the testis.