BACKGROUND: Testicular germ cell tumor (TGCT) is the most common type of tumor in young men. Type II germ cell tumors including postpubertal-type teratomas are derived from the germ cell neoplasia in situ (GCNIS), whereas prepubertal-type teratomas arise independently of the GCNIS. The consomic mouse strain 129.MOLF-Chr19 (M19) is a suitable murine model of such tumors, but its characterization remains incomplete.
OBJECTIVE: Here, we interrogated the suitability of testicular tumors in M19 mice as a model of human TGCT by analyzing their histological features and gene expression signature.
METHODS: Testes collected from M19 mice of different ages were categorized by macroscopic appearance based on size and the degree of suspected tumorigenesis. Histological sections from selected tumors were stained with Hematoxylin and Eosin, and expression of genes associated with tumorigenesis was determined in frozen tissue samples from a large range of tumors of different subclasses using RT-qPCR and Fluidigm Dynamic Arrays.
RESULTS: Macroscopically, testicular specimens appeared very heterogeneous concerning size and signs indicating the presence of a tumor. Histological analysis confirmed the development of teratomas with areas of cells corresponding to all three germ cell layers. Gene expression analyses indicated upregulation of markers related to proliferation, vascular invasive potential and pluripotency, and revealed a strong correlation of gene expression with tumor size and a significant intercorrelation of individual genes.
CONCLUSIONS: TGCT in M19 mice is reminiscent of human testicular teratomas presenting with areas of cells derived from all germ layers and showing a typical gene signature. We thus confirm that these mice can serve as a suitable murine model of pure teratomas for preclinical research.

BACKGROUND: Germinal testicular tumors are the most common malignant neoplasm in men around 20 to 34 years. Even though they are unusual, they have increased incidence in the last decade; they have an excellent prognosis and overall survival at five years, approximately 95%. Divergent data exists regarding treatment options in patients with first, second, and third relapses with conventional therapy. Some studies describe the possible benefit of using high-dose chemotherapy associated with a bone marrow transplant with variable results.
METHODS:  The present study describes clinical outcomes, clinical response, mortality, overall survival, and progression-free survival to two years in a group of patients with germinal malignant tumors, seminoma versus non-seminomatous with evidence of progression of the disease at first, second, or third conventional chemotherapy regimens, and who received high dose chemotherapy and bone marrow transplantation at the National Cancer Institute between 2010 and 2021.
RESULTS: A retrospective observational study of case series showed that 57% of patients in third-line therapy received high-dose chemotherapy and bone marrow transplantation, with progression disease median time from diagnosis more than two years. Patients in the post-graft period presented infectious complications (71%). The most common were febrile neutropenia (29%) with a mortality rate of 71% (n=5), progression-free survival of 2.3 months, and overall survival of 7.4 months.
CONCLUSIONS:  These results show that in this group of patients, regimens with high-dose chemotherapy associated with bone marrow transplants, have a worse prognosis compared to other cohorts of patients, and may not be the best candidates for this rescue therapy.

Aberrant male germline development can lead to the formation of seminoma, a testicular germ cell tumor. Seminomas are biologically similar to primordial germ cells (PGCs) and many bear an isochromosome 12p [i(12p)] with two additional copies of the short arm of chromosome 12. By mapping seminoma transcriptomes and open chromatin landscape onto a normal human male germline trajectory, we find that seminoma resembles premigratory/migratory PGCs; however, it exhibits enhanced germline and pluripotency programs and upregulation of genes involved in apoptosis, angiogenesis, and MAPK/ERK pathways. Using pluripotent stem cell-derived PGCs from Pallister-Killian syndrome patients mosaic for i(12p), we model seminoma and identify gene dosage effects that may contribute to transformation. As murine seminoma models do not exist, our analyses provide critical insights into genetic, cellular, and signaling programs driving seminoma transformation, and the in vitro platform developed herein permits evaluation of additional signals required for seminoma tumorigenesis.

BACKGROUND: 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.
CONCLUSIONS: 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.

BACKGROUND: Testicular cancer is the most common solid malignancy among men aged 15-35. Radical orchiectomy and platinum-based chemotherapy (BEP) are curative in the majority of patients, including advanced, metastatic cases. According to current urooncology guidelines all non-seminoma patients harbouring post-chemotherapy residual masses of ≥ 1 cm should undergo salvage retroperitoneal lymph node dissection (RPLND). However, only 10% of residual tumors contain viable disease.
OBJECTIVE: To assess patient outcomes and complications considering different treatment regimens and clinical characteristics.
METHODS: In a retrospective cross-sectional study patients (n=127) who underwent postchemotherapy RPLND between 2007 and 2023 at our referral center were evaluated. The patients received systemic treatment at various oncology centers. The number of BEP cycles received were occasionally different from standard. Only patients with normal postchemotherapy serum tumor markers and primary testicular or extragonadal germ cell neoplasms were included. Treatment groups were established according to the number of BEP cycles received, and the extent of RPLND (bilateral or modified template). Treatment outcomes and complications were assessed.
RESULTS: Standard 3-4 courses of BEP were received by 100 (78,7%) patients, while 11 (8,7%) patients underwent less, and 16 (12,6%) more courses than standard. On histopathologic evaluation viable germ cell tumor, teratoma, and necrosis/fibrosis was present in 26 (20,5%), 67 (52,7%) and 34 (26,8%) of specimen, respectively. In the 5-6 BEP series subgroup high rate of viable disease (37,5%) was found and significantly more nephrectomies were performed, than other chemotherapy subgroups. Extratesticular GCT, viable disease in residual mass or progression after RPLND indicated lower survival. Mild (Clavien-Dindo I-II) or no postoperative complications were reported in 93,7% of cases.
CONCLUSIONS: The study suggests no significant benefit from exceeding 3-4 courses of BEP. Timely salvage RPLND should be performed in high volume centers for optimal treatment outcomes with acceptable complication rates. Adherence to the Heidenreich criteria is advisable where practical.

This study aimed to explore perspectives and concerns regarding sexuality among adolescents and young adults (AYAs) possibly experiencing late effects after testicular germ cell tumor (TGCT) treatment. A qualitative study was performed in which semi-structured interviews were held with thirteen AYAs from a center of expertise for TGCT in the Netherlands. Data were analyzed using Braun and Clark\'s thematic analysis method. Seven interacting and interconnected themes were found: desire to have children, rediscovering sexuality, insecurity about sexual performance, acceptance of physical change, loss of masculinity, burden on relationship, and openness in discussing sexuality. Concerns about the desire to have children seem to play a significant role. In conclusion, TGCT patients face multiple changes (physical, emotional, relational, and sexual), followed by a difficult period of acceptance, after which a new phase of rediscovering sexuality appeared. These findings can help to make healthcare professionals aware of the underlying mechanisms and concerns about sexuality. Furthermore, insights can help to develop sexuality-themed items for a broader monitoring tool to structurally assess the late effects to support discussing sexuality.

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.

Testicular germ cell tumors (TGCT) are the most frequent cancer in young men in developed countries. Parental occupational exposures during early-life periods are suspected to increase TGCT risk. The objective was to estimate the association between parental occupations at birth and adult TGCT.
A case-control study was conducted, including 454 TGCT cases aged 18-45 from 20 French university hospitals, matched to 670 controls based on region and year of birth. Data collected from participants included parental jobs at birth coded according to the International Standard Classification of Occupation-1968 and the French nomenclature of activities-1999. Odds ratios (OR) for TGCT and 95% confidence intervals (CI) were estimated using conditional logistic regression, adjusting for TGCT risk factors.
Paternal jobs at birth as service workers (OR = 1.98, CI 1.18-3.30), protective service workers (OR = 2.40, CI 1.20-4.81), transport equipment operators (OR = 1.96, CI 1.14-3.37), specialized farmers (OR = 2.66, CI 1.03-6.90), and maternal jobs as secondary education teachers (OR = 2.27, CI 1.09-4.76) or in secondary education (OR = 2.35, CI 1.13-4.88) were significantly associated with adult TGCT. The risk of seminoma was increased for the above-mentioned paternal jobs and that of non-seminomas for public administration and defence; compulsory social security (OR = 1.99, CI 1.09-3.65); general, economic, and social administration (OR = 3.21, CI 1.23-8.39) for fathers; and secondary education teacher (OR = 4.67, CI 1.87-11.67) and secondary education (OR = 3.50, CI 1.36-9.01) for mothers.
Some paternal jobs, such as service workers, transport equipment operators, or specialized farmers, and maternal jobs in secondary education seem to be associated with an increased risk of TGCT with specific features depending on the histological type. These data allow hypotheses to be put forward for further studies as to the involvement of occupational exposures in the risk of developing TGCT, such as exposure to pesticides, solvents, or heavy metals.

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).
CONCLUSIONS: Our results indicate that stage II and III TGCT patients experience lower survival rates at low-volume institutions and would benefit from treatment centralization.

Somatic-type malignancy (STM) can occur infrequently within a primary or metastatic testicular germ cell tumor (TGCT) and is associated with dismal prognosis and survival. STM with chondrosarcomatous features is exceedingly rare and head and neck involvement has not been previously documented. A 39-year-old white man presented with nasal obstruction and epistaxis. Imaging disclosed a 6.9-cm expansile tumor involving the nasal cavity and skull base with intraorbital and intracranial extension. The histopathologic properties of the tumor were compatible with chondrosarcoma, grade II-III. Immunohistochemically, malignant cells were strongly and diffusely positive for S100 and epithelial markers, and showed loss of SMARCB1 expression. IDH1/2 mutations were not detected. Following whole-body PET scan, a 7.0-cm left testicular mass was discovered and diagnosed as seminoma with syncytiotrophoblastic cells, stage pT3NXM1b. Extensive retroperitoneal, mediastinal, and supraclavicular lymphadenopathy was also noticed. Histopathologic examination of the left supraclavicular lymph node revealed metastatic seminoma. By FISH, most metastatic nodal seminoma cells harbored 1 to 4 copies of isochromosome 12p, while the chondrosarcoma featured duplication of 12p. Presence of a malignant TGCT with disseminated supradiaphragmatic lymphadenopathy, the unique immunophenotypic properties of the skull-based chondrosarcoma and lack of IDH1/2 aberrations with gain of 12p strongly support the diagnosis of STM chondrosarcoma arising from metastatic TGCT. The patient did not respond to chemotherapy and succumbed three months after diagnosis. Although exceedingly uncommon, metastasis to the head and neck may occur in patients with TGCT. This case of STM chondrosarcoma demonstrated divergent immunophenotypic and molecular characteristics compared to \"typical\" examples of head and neck chondrosarcoma. High index of suspicion is advised regarding the diagnosis of lesions that present with otherwise typical histomorphology but unexpected immunohistochemical or molecular features.