Malignant ovarian and testicular germ cell tumors: Common characteristics but different prognoses.

Both ovarian and testicular germ cell tumors (GCTs) arise from the primordial germ cell and share many similarities. Both malignancies affect mainly young patients, show remarkable responsiveness to cisplatin-based therapy, and have an excellent prognosis, which also highlights the importance of minimizing long-term side effects. However, certain differences can be noted: The spreading of the disease differs, and the staging system and treatment recommendations are dissimilar. Moreover, the prognosis for ovarian GCTs is significantly inferior to that for testicular cancer, as exemplified in this review comparing the survival in Swedish patients diagnosed with testicular (1995-2022) and ovarian (1990-2018) GCTs. The 5-year overall survival in ovarian GCTs was 85.2%, versus 98.2% for testicular GCTs. How can this be explained? One reason may be the difference in knowledge, experience, and evidence because the incidence rate of testicular cancer is more than 15 times that of ovarian GCTs. Given the rarity of the disease in women and the lack of established guidelines, a comprehensive understanding of the disease and treatment decisions is challenging. The main objective of this review is to derive insights from testicular GCTs (seminoma and non-seminoma) by reviewing etiological, tumor biological, and clinical knowledge, and to thereafter suggest actions for ovarian GCTs based on this. We hypothesize that by adopting specific treatment strategies from testicular GCTs-including de-escalating adjuvant chemotherapy for low-risk patients and implementing more standardized and intensive treatment protocols in cases of relapse-we can improve the prognosis and minimize long-term side effects in ovarian GCT patients.

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 (SCTs) in cryptorchid dogs and germ cell tumors (GCTs) 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.

Diagnosis and Treatment of Early-Stage Testicular Cancer: AUA Guideline Amendment 2023.

PURPOSE: The purpose of this American Urological Association (AUA) guideline amendment is to provide a useful reference on the effective evidence-based treatment strategies for early-stage testicular cancer. METHODOLOGY/METHODS: The original methodology protocol included searches of PubMed®, Embase®, and the Cochrane Central Register of Controlled Trials (CENTRAL) from January 1980 through August 2018. The search strategy used medical subject heading (MeSH) terms and key words relevant to the diagnosis and treatment of early-stage testicular cancer. The searches conducted for the update presented herein utilized the same methodological protocol to capture literature published through March 2023. When sufficient evidence existed, the body of evidence was assigned a strength rating of A (high), B (moderate), or C (low) for support of Strong, Moderate, or Conditional Recommendations. In the absence of sufficient evidence, additional information is provided as Clinical Principles and Expert Opinions. RESULTS: Updates were made to statements on imaging, seminoma management, non-seminoma management, surveillance for stage I testicular cancer, and additional survivorship. Further revisions were made to the methodology and reference sections as appropriate. CONCLUSIONS: This guideline seeks to improve clinicians' ability to evaluate and treat patients with early-stage testicular cancer based on currently available evidence. Future studies will be essential to further support or refine these statements to improve patient care.

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.

Primary retroperitoneal lymph node dissection for metastatic non-seminomatous germ cell tumours: outcomes and adjuvant chemotherapy.

OBJECTIVES: To compare the outcomes and treatment burden of primary retroperitoneal lymph node dissection (pRPLND) alone versus pRPLND + adjuvant chemotherapy (AC) in patients with pathological stage II (PSII) non-seminomatous germ cell tumours (NSGCT). PATIENTS AND METHODS: Retrospective review of the Princess Margaret Cancer Center eTestes cancer database identified patients with PSII NSGCT after pRPLND between 1995 and 2020. The primary outcome was relapse-free survival (RFS). Secondary outcomes included disease-specific survival (DSS), burden of relapse treatment, and factors associated with relapse. RESULTS: A total of 109 PSII patients were included in the study. There were 96 patients treated with pRPLND alone and 13 treated with pRPLND + AC. The median follow-up was 61 months. The 5-year RFS was 72% for the pRPLND-only group vs 92% for the pRPLND + AC group (hazard ratio [HR] 4.372, 95% confidence interval [CI] 0.59-32.36; P = 0.11). Within the pRPLND-only group the 5-year RFS differed by pN stage (pN1 = 94% vs pN2/N3 = 67%, P = 0.03). Despite a higher relapse rate within the pRPLND-only group, the DSS was similar at 5 years (98% pRPLND only vs 100% pRPLND + AC, P = 0.48). Only 24 (25%) of the patients in the pRPLND-only group required any subsequent chemotherapy. Despite achieving similar survival, the cumulative post-RPLND treatment burden was less for the pRPLND-only group than the pRPLND+AC group overall (average 1.23 vs 2.46 cycles of chemotherapy per patient in group). CONCLUSION: The majority of patients with PSII NSGCT treated with pRPLND alone do not experience a recurrence or require chemotherapy. Despite a lower relapse risk when AC is given, no difference in survival was seen but higher chemotherapy burden was entertained. AC may constitute overtreatment for most patients with PSII NSGCT treated with pRPLND.

Initial surveillance in men with marker negative clinical stage IIA non-seminomatous germ cell tumours.

OBJECTIVES: To assess whether extended surveillance with repeated computed tomography (CT) scans for patients with clinical stage IIA (CS IIA; <2 cm abdominal node involvement) and negative markers (Mk-) non-seminomatous germ cell tumours (NSGCTs) can identify those with true CS I. To assess the rate of benign lymph nodes, teratoma, and viable cancer in retroperitoneal lymph node dissection (RPLND) histopathology for patients with CS IIA Mk- NSGCT. PATIENTS AND METHODS: Observational prospective population-based study of patients diagnosed 2008-2019 with CS IIA Mk- NSGCT in the Swedish and Norwegian Testicular Cancer Group (SWENOTECA) registry. Patients were managed with surveillance, with CT scans, and tumour markers every sixth week for a maximum of 18 weeks. Patients with radiological regression were treated as CS I, if progression with chemotherapy, and remaining CS IIA Mk- disease with RPLND. The end-point was the number and percentage of patients down-staged to CS I on surveillance and rate of RPLND histopathology presented as benign, teratoma, or viable cancer. RESULTS: Overall, 126 patients with CS IIA Mk- NSGCT were included but 41 received therapy upfront. After surveillance for a median (range) of 6 (6-18) weeks, 23/85 (27%) patients were in true CS I and four (5%) progressed. Of the remaining 58 patients with lasting CS IIA Mk- NSGCT, 16 received chemotherapy and 42 underwent RPLND. The RPLND histopathology revealed benign lymph nodes in 11 (26%), teratoma in two (6%), and viable cancer in 29 (70%) patients. CONCLUSIONS: Surveillance with repeated CT scans can identify patients in true CS I, thus avoiding overtreatment. The RPLND histopathology in patients with CS IIA Mk- NSGCT had a high rate of cancer and a low rate of teratoma.

Higher expression of SALL4-A isoform is correlated with worse outcomes and progression of the disease in subtype of testicular germ cell tumours.

BACKGROUND: The transcription factor SALL4 is associated with embryonic pluripotency and has proposed as a novel immunohistochemistry (IHC) marker for diagnosing germ cell tumours. SALL4 comprises three isoforms, and SALL4-A being the full-length isoform. Studying its isoforms could revolutionize testicular cancer prognosis and subtype differentiation. METHODS: The expression and clinical significance of isoform 'A' of SALL4 was evaluated in 124 testicular germ cell tumours (TGCTs) subtypes, adjacent 67 normal tissues and 22 benign tumours, using immunohistochemistry on tissue microarrays (TMA). RESULTS: A statistically significant higher expression of nuclear and cytoplasmic SALL4-A was detected in TGCTs histological subtypes and benign tumours compared to the normal tissues. Seminoma and yolk sac tumours had the highest nuclear and cytoplasmic expression of SALL4-A. A significant correlation was detected between the higher nuclear expression of SALL4-A and increased pT stages (P = 0.026) in seminomas. Whereas in embryonal carcinomas, cytoplasmic expression of SALL4-A was associated with the tumour recurrence (P = 0.04) and invasion of the epididymis (P = 0.011). CONCLUSIONS: SALL4-A isoform expression in the cytoplasm and nucleus of TGCTs may be associated with histological differentiation. In the seminoma subtype of TGCTs, higher expression of SALL4-A may be used as a predictive indicator of poorer outcomes and prognosis.

Expression of CD44 is associated with aggressiveness in seminomas.

BACKGROUND: Testicular germ cell tumors (TGCTs) exhibit diverse biological and pathological features and are divided in two main types, seminomas and nonseminomatous germ cell tumors (NSGCTs). CD44 is a cell surface receptor, which is highly expressed in malignancies and is implicated in tumorigenesis affecting cell-matrix interactions and cell signaling. METHODS AND RESULTS: Here, we examined the expression of CD44 in tumor cell lines and in patients' material. We found that CD44 is over-expressed in TGCTs compared to normal tissues. Immunohistochemical staining in 71 tissue specimens demonstrated increased expression of CD44 in some patients, whereas CD44 was absent in normal tissue. In seminomas, a high percentage of tumor and stromal cells showed cytoplasmic and/or cell surface staining for CD44 as well as increased staining for CD44 in the tumor stroma was found in some cases. The increased expression of CD44 either in tumor cells or in stromal components was associated with tumor size, nodal metastasis, vascular/lymphatic invasion, and disease stage only in seminomas. The increased stromal expression of CD44 in TGCTs was positively associated with angiogenesis. CONCLUSIONS: CD44 may exhibit diverse biological functions in seminomas and NSGCTs. The expression of CD44 in tumor cells as well as in tumor stroma fosters an aggressive phenotype in seminomas and should be considered in disease treatment.

A population-based validation of the IGCCCG Update Consortium for survival in metastatic non-seminoma testis cancer.

BACKGROUND: In 2021, the International Germ Cell Cancer Collaborative Group (IGCCCG) Update Consortium reported improved overall survival (OS) rates in a modern cohort of metastatic non-seminoma testis cancer patients within each of the IGCCCG prognosis groups (96% in good vs. 89% in intermediate vs. 67% in poor), compared to the previous IGCCCG publication (92% in good vs. 80% in intermediate vs. 48% in poor). We hypothesized that a similar survival improvement may apply to a contemporary North-American population-based cohort of non-seminoma testis cancer patients. PATIENTS AND METHODS: The Surveillance, Epidemiology, and End Results (SEER) database (2010-2018) was used. Kaplan-Meier plots and multivariable Cox regression models tested the effect of IGCCCG prognosis groups on overall mortality (OM). RESULTS: Of 1672 surgically treated metastatic non-seminoma patients, 778 (47%) exhibited good vs. 251 (15%) intermediate vs. 643 (38%) poor prognosis. In the overall cohort, five-year OS rate was 94% for good prognosis vs. 87% for intermediate prognosis vs. 65% for poor prognosis. In multivariable Cox regression models predicting OM, intermediate (Hazard ratio [HR] 2.4, 95% confidence interval [CI] 1.4-3.9, P < 0.001) and poor prognosis group (HR 6.6, 95% CI 1.0-1.0, P < 0.001) were independent predictors of higher OM, relative to good prognosis group. CONCLUSIONS: The survival improvement reported by the IGCCCG Update Consortium is also operational in non-seminoma testis cancer patients within the most contemporary SEER database. This observation indicates that the survival improvement is not only applicable to centres of excellence, but also applies to other institutions at large.

Survival of stage III non-seminoma testis cancer patients versus simulated controls, according to race/ethnicity.

BACKGROUND: It is unknown whether 5-year overall survival (OS) differs and to what extent between the American Joint Committee on Cancer stage III non-seminoma testicular germ cell tumor (NS-TGCT) patients and simulated age-matched male population-based controls, according to race/ethnicity groups. METHODS: We identified newly diagnosed (2004-2014) stage III NS-TGCT patients within the Surveillance Epidemiology and End Results database 2004-2019. For each case, we simulated an age-matched male control (Monte Carlo simulation), relying on Social Security Administration (SSA) Life Tables with 5 years of follow-up. We compared OS rates between stage III NS-TGCT patients and simulated age-matched male population-based controls, according to race/ethnicity groups (Caucasian, Hispanic, Asian/Pacific Islander and African American). Both, cancer-specific mortality (CSM) and other-cause mortality (OCM) were computed. RESULTS: Of 2054 stage III NS-TGCT patients, 60% were Caucasians versus 33% Hispanics versus 4% Asians/Pacific Islanders versus 3% African Americans. The 5-year OS difference between stage III NS-TGCT patients versus simulated age-matched male population-based controls was highest in Asians/Pacific Islanders (64 vs. 99%, Δ = 35%), followed by African Americans (66 vs. 97%, Δ = 31%), Hispanics (72 vs. 99%, Δ = 27%), and Caucasians (76 vs. 98%, Δ = 22%). The 5-year CSM rate was highest in Asians/Pacific Islanders (32%), followed by African Americans (26%), Hispanics (25%), and Caucasians (20%). The 5-year OCM rate was highest in African Americans (8%), followed by Caucasians (4%), Asians/Pacific Islanders (4%), and Hispanics (2%). CONCLUSION: Relative to SSA Life Tables, the highest 5-year OS disadvantage applied to stage III NS-TGCT Asian/Pacific Islander race/ethnicity group, followed by African American, Hispanic and Caucasian, in that order.

Primary Retroperitoneal Lymph Node Dissection for Clinical Stage II A/B Seminomas: A Systematic Review and Meta-Analysis.

INTRODUCTION: Chemotherapy and radiation therapy are considered standard treatments for stage II seminoma patients; however, these therapies are associated with long-term toxicities. Recently, retroperitoneal lymph node dissection has emerged as an alternative strategy, and the first three phase II trials were published in 2023 with promising results. The present study conducted a systematic review and meta-analysis to evaluate this surgery as an alternative treatment for stage IIA/B seminoma patients. PURPOSE: Seminomas are the most common testicular tumors, often affecting young adult males. Standard treatments for stage II seminomas include chemotherapy and radiation therapy, but these therapies are associated with long-term toxicities. Thus, identifying alternative strategies is paramount. Herein, we conducted a systematic review and meta-analysis to appraise the efficacy and safety of retroperitoneal lymph node dissection (RPLND) for treating this condition. METHODS: We systematically searched the PubMed, Embase, and Cochrane databases for studies evaluating RPLND as a primary treatment for stage II A/B seminomas. Using a random-effects model, single proportion and means and pooled 2-year recurrence-free survival rates with hazard rates and 95% CI were calculated. RESULTS: Seven studies were included, comprising 331 males with stage II seminomas. In the pooled analysis, the recurrence rate was 17.69% (95% CI 12.31-24.75), and the 2-year RFS rate was 81% (95% CI 0.77-0.86). The complication rate was 9.16% (95% CI 6.16-13.42), the Clavien-Dindo > 2 complication rate was 8.83% (95% CI 5.76-13.31), and the retrograde ejaculation rate was 7.01% (95% CI 3.54-13.40). The median operative time was 174.68 min (95% CI 122.17-249.76 min), median blood loss was 105.91 mL (95% CI 46.89-239.22 mL), and patients with no evidence of lymph node involvement ranged from 0-16%. CONCLUSIONS: Primary RPLNDs for treating stage IIA/B seminomas have favorable RFS rates, with low complication and recurrence rates. These findings provide evidence that this surgery is a viable alternative therapy for these patients.

Overexpression of SerpinB9 in non-seminomatous germ cell tumors.

Serpinb9 is an inhibitor of granzyme B and is potentially involved in the immune escape of tumor cells. In the present study, bioinformatics analysis using open databases suggested that SerpinB9 is overexpressed in testicular embryonal carcinoma. Immunohistological analysis was performed on 28 cases of testicular germ cell tumors to investigate the relationship between SerpinB9 expression in testicular germ cell tumors and the tumor immune environment. SerpinB9 was significantly upregulated in the non-seminoma group and inversely correlated with the number of tumor-infiltrating CD8-positive cells. In addition, yolk sac tumors were characterized by the loss of human leukocyte antigen-class I expression. These findings suggest that SerpinB9 contributes to the immune escape of testicular germ cell tumors. Targeting therapy for SerpinB9 might therefore be useful in immunotherapy for testicular germ cell tumors resistant to immune checkpoint inhibitors.

Testicular Cancer Treatments and Sexuality: A Narrative Review.

The incidence of testicular cancer (TC) has been rapidly increasing over the past years. Diagnosis and early treatment have shown good oncological control, guaranteeing the patient different treatment approaches according to histology and tumor stage. Currently, physicians usually prioritize oncological outcomes over sexual outcomes and quality of life, considering as a first aim the overall survival of the patients; however, differently from other neoplasms, quality of life is still strongly affected among TC patients, and sexual outcomes are frequently compromised after each TC treatment. Several studies have suggested that each treatment approach may be associated with sexual dysfunctions, including erectile dysfunction, ejaculatory disorders, fertility issues, and hormonal changes. Since testicular cancer patients are more frequently young men, the subject of this work is substantial and should be analyzed in detail to help specialists in the management of this disease. The aim of the current narrative review is to generally describe every treatment for TC, including surgery, chemotherapy, radiotherapy, and retroperitoneal lymph node dissection, and to establish which sexual dysfunction may be specifically associated with each therapy.

Updating germ cell tumour pathogenesis - the ability of seminomas for FOXA2-driven extra-embryonic differentiation.

AIMS: Testicular germ cell tumours are the most common solid malignancies in young men of age 14-44 years. It is generally accepted that both seminomas and non-seminomas arise from a common precursor, the germ cell neoplasia in-situ, which itself is the result of a defective (primordial) germ cell development. The stem cell-like population of the non-seminomas, the embryonal carcinoma, is capable of the differentiation of all three germ layers (teratomas) and extra-embryonic tissues (yolk-sac tumours, choriocarcioma) into cells. In contrast, seminomas are thought to have a limited differentiation potential. Nevertheless, several studies have highlighted their ability to undergo reprogramming to an embryonal carcinoma or differentiation into other non-seminomatous entities. Here, we demonstrate that in approximately 5% of seminomas, the yolk-sac tumour driver gene FOXA2 is detectable at the protein level, indicative of an occult yolk-sac tumour subpopulation that putatively arose from seminoma cells, as the presence of other GCT entities could be excluded. The presence of these subpopulations might render the tumour more aggressive and argue for an adjustment of the therapeutic concept. We used our data to update the model of germ cell tumour pathogenesis, especially regarding the developmental potential of seminomas. Additionally, we suggest to include detection of FOXA2 into standard routine diagnosis of seminomas.

Primary Mediastinal Germ Cell Tumors (PMGCT): A Real-world Analysis From A Tertiary Cancer Care Center in India.

BACKGROUND: Primary mediastinal GCT (PMGCT) is a rare entity and comprises 10-15% of all mediastinal tumors. We present our institutional experience of MGCT treated with multimodality management. MATERIALS AND METHODS: We conducted a retrospective analysis between 2010 to 2020 of all mediastinal germ cell tumors registered at our center. Data on patient demographics, treatments received, treatment toxicities and response were recorded. Overall survival and relapse free survival were estimated using Kaplan-Meier methods. RESULTS: A total of 30 patients were identified. The median age was 25.5 (range, 18-45) years. Common presenting features included cough (70%) and shortness of breath (70%). Histology wise, 60% patients were non seminomatous histology, whereas 33.3% patients were Seminoma. Twenty-seven (90%) patients received chemotherapy as the first-line treatment, of whom five patients (16.6%) underwent surgery and radiation therapy subsequently. Median follow-up was 26.9 months. Thirteen patients (43.3%) had complete response (43.3%) and eight patients had partial response (26.7%), while three patients (5.5%) had progressive disease. Three-year relapse-free survival rate was 69.6% (95% confidence interval [CI], 42.8-85.6%). Overall survival (OS) at 3 years was 73.4% (95% CI, 49.4-87.3%). Patients with seminoma had a 3 year OS of 90.0% (95% CI, 47.3-98.5%) compared to those with non-seminoma (63.53% [95% CI, 32.3-83.3%]). CONCLUSIONS: Multiagent chemotherapy is the backbone of treatment in PMGCT. Seminomatous PMGCT have excellent prognosis, while further improvement is needed in those with nonseminomatous tumor.

Testicular germ cell tumour arising 15 years after radiotherapy with 18 Gy for germ cell neoplasia in situ.

PURPOSE: Germ cell neoplasia in situ (GCNis), the precursor of adult testicular germ cell tumours (GCTs), is found in 5-6% of contralateral testicles in patients with testicular GCT and in the tumour-surrounding tissue of > 90% of testes undergoing testis-sparing surgery (TSS) for GCT. Local radiotherapy to the testis with 18-20 Gy eradicates GCNis while preserving Leydig cells. The frequency of treatment failures is so far unknown. METHODS: A 22-year-old patient with right-sided seminoma clinical stage I and contralateral GCNis received radiotherapy with 18 Gy to his left testicle. Fifteen years later he underwent orchiectomy of the irradiated testis for seminoma with adjacent GCNis. The patient is well 1 year postoperatively while on testosterone-replacement therapy. The literature was searched for further cases with GCTs arising despite local radiotherapy. RESULTS: Six failures of radiotherapy have been reported previously. An estimated total number of 200 and 100 radiotherapeutic regimens with 18-20 Gy applied to cases with contralateral GCNis and with TSS, respectively, are documented in the literature. CONCLUSION: Cumulative experience suggests that radiotherapy with 18-20 Gy to the testis may fail with an estimated frequency of around 1%. Reasons for failure are elusive. A primary radioresistant subfraction of GCNis is hypothesized as well as technical failures regarding application of the radiotherapeutic dose volume in small and mobile testes. Caregivers of patients with TSS and contralateral GCNis should be aware of local relapses occurring after intervals of > 10 years.

Analysis of connexin 43, connexin 45 and N-cadherin in the human sertoli cell line FS1 and the human seminoma-like cell line TCam-2 in comparison with human testicular biopsies.

BACKGROUND: Germ cell tumors are relatively common in young men. They derive from a non-invasive precursor, called germ cell neoplasia in situ, but the exact pathogenesis is still unknown. Thus, further understanding provides the basis for diagnostics, prognostics and therapy and is therefore paramount. A recently developed cell culture model consisting of human FS1 Sertoli cells and human TCam-2 seminoma-like cells offers new opportunities for research on seminoma. Since junctional proteins within the seminiferous epithelium are involved in cell organization, differentiation and proliferation, they represent interesting candidates for investigations on intercellular adhesion and communication in context with neoplastic progression. METHODS: FS1 and TCam-2 cells were characterized regarding gap-junction-related connexin 43 (Cx43) and connexin 45 (Cx45), and adherens-junction-related N-cadherin using microarray, PCR, Western blot, immunocytochemistry and immunofluorescence. Results were compared to human testicular biopsies at different stages of seminoma development via immunohistochemistry to confirm the cell lines' representativeness. Furthermore, dye-transfer measurements were performed to investigate functional cell coupling. RESULTS: Cx43, Cx45 and N-cadherin mRNA and protein were generally detectable in both cell lines via qualitative RT-PCR and Western blot. Immunocytochemistry and immunofluorescence revealed a mainly membrane-associated expression of N-cadherin in both cell lines, but gene expression values were higher in FS1 cells. Cx43 expression was also membrane-associated in FS1 cells but barely detectable in TCam-2 cells. Accordingly, a high gene expression value of Cx43 was measured for FS1 and a low value for TCam-2 cells. Cx45 was primary located in the cytoplasm of FS1 and TCam-2 cells and revealed similar low to medium gene expression values in both cell lines. Overall, results were comparable with corresponding biopsies. Additionally, both FS1 and TCam-2 cells showed dye diffusion into neighboring cells. CONCLUSION: The junctional proteins Cx43, Cx45 and N-cadherin are expressed in FS1 and TCam-2 cells at mRNA and/or protein level in different amounts and localizations, and cells of both lines are functionally coupled among each other. Concerning the expression of these junctional proteins, FS1 and TCam-2 cells are largely representative for Sertoli and seminoma cells, respectively. Thus, these results provide the basis for further coculture experiments evaluating the role of junctional proteins in context with seminoma progression.

Guideline of guidelines: follow-up after orchidectomy for clinical stage 1 testicular cancer.

Several medical organisations have developed evidence-based guidelines for the diagnosis, management, and follow-up of testicular cancer. This article aimed to review, compare, and summarise the most updated international guidelines and surveillance protocols for clinical stage 1 (CS1) testicular cancer. We reviewed a total of 46 articles on proposed follow-up strategies for testicular cancer, and six clinical practice guidelines including four guidelines published by urological scientific associations and two guidelines published by medical oncology associations. Most of these guidelines have been developed by panels of experts with different backgrounds in clinical training, and geographic practise patterns, which explains the considerable variability between published schedules, and recommended follow-up intensity. We present you with a comprehensive review of the most important clinical practice guidelines and propose unifying recommendations based on the most up to date evidence to help standardise follow-up schedules based on patterns and risk of disease relapse.

Advances in radiation therapy for testicular seminoma.

PURPOSE: Novel techniques and advances in radiation therapy (RT) have been explored to treat testicular seminoma, a highly radiosensitive and curable histology. We evaluated the historical and current indications for radiation therapy (RT) in testicular seminoma. METHODS: A narrative literature review was performed. Studies of RT for testicular seminoma were included. Additionally, recent trials testing the use of combination or surgical therapies for clinical stage (CS) II were included. Search parameters included radiation therapy, testicular seminoma, surgery, and chemoradiation. Parameters and outcomes assessed were progression-free survival (PFS), overall survival (OS), acute toxicities, long-term sequelae, and rates of secondary malignancies. RESULTS: Practice defining and changing studies in the use or omission of radiation therapy for testicular seminoma were identified along with resultant changes in National Comprehensive Cancer Network (NCCN) and European guidelines. Recent trials in combined chemoradiation and upfront surgical approaches to CS II disease were reviewed. CONCLUSION: RT has historically been used as adjuvant treatment for CS I disease and is highly effective at treating CS II (A/B) testicular seminoma. The drive to maintain therapeutic efficacy and reduce acute and long-term side effects, namely secondary malignancies, is being tested using new radiation technologies, combined modality therapy in the form of chemoradiation and with upfront surgical approaches. Also, as guidelines now "strongly prefer" surveillance instead of adjuvant RT for CS I disease, the current CS II population comprises patients presenting with CS II disease ("de novo") and those who present with CSII after relapsing post orchiectomy for CS I ("relapsed"). Emerging evidence suggests that these two groups have different outcomes with respect to RT and chemoradiation. Consequently, future trials may need to sub-stratify according to these groups.

Outcomes of surveillance versus adjuvant treatment for patients with stage-I seminoma: a single-center experience.

INTRODUCTION: Testicular germ cell tumors (seminoma/non-seminoma) are the most common carcinomas in young males, comprising approximately 1% of all carcinomas. In stage-I disease, orchiectomy can cure approximately 85% of patients. Post-surgical options are adjuvant therapy and active surveillance. Our study examined the effects of management options on stage-I seminoma patients followed in our center. METHODS: We evaluated the patients with stage-I testicular seminoma who underwent radical orchiectomy and followed up in the oncology center between 2001 and 2022. The outcomes of management options, survivals were retrospectively analyzed. The prognostic significance of risk factors for relapse on survival was evaluated. RESULTS: Of the 140 patients with stage-I seminoma, 49 (35%) were treated with adjuvant therapy, and 91 (65%) underwent surveillance. The median follow-up duration was 37 months. During the follow-up period, nine patients in the active surveillance group and four in the adjuvant therapy group had a recurrence. There was no statistically significant difference between the two groups (p = 0.67). In the surveillance group, the univariate and multivariate analyzes identified the presence of lymphovascular invasion (p = 0.005, HR: 0.13) as significant prognostic factor for disease-free survival (DFS). In the surveillance cohort, the 5-year DFS rate was 60% for patients with lymphovascular invasion and 93% for those without. There was statistical significance between the two groups (p = 0.003). CONCLUSION: Our study shows that adjuvant therapy does not significantly improve DFS compared to surveillance in patients. In addition, it has been shown that lymphovascular invasion is an important prognostic indicator for DFS in determining the treatment strategy.