Enhancing Tumor Classification in Testicular Cancer: Segmentation-based Pretraining and Multimodal Prediction

Molecular Genetic Parameters in Pathogenesis and Prognosis of Testicular Germ Cell Tumors

Aim of this review article was to critically analyse the recently described zytogenetic and molecular markers for testicular germ cell tumors with regard to their clinical utility. The isochromosome i(12p) represents the most common and characteristic cytogenetic finding which already appears in testicular carcinoma in situ. A number of proto-oncogenes (Cyclin D and PTHLH) as well as putative tumor suppressor genes are localized on 12p; however, their role in pathogenesis and prognosis of testicular germ cell tumors has not been defined yet. Clinical characteristics of patients with familial testicular germ cell tumors indicate a genetic background for the development of testicular tumors. Although a number of chromsomal loci encoding potential testicular tumor susceptibility genes have been identified, the genetic basis of testicular cancer pathogenesis is still unknown. With regard to molecular prognostic risk factors most of the reported data on proliferation markers, tumor suppressor genes, proteases and adhesion molecules have to be confirmed in prospective randomized trials prior to their widespread clinical use. Based on the available data on prospective studies percentage of embryonal carcinoma and vascular invasion appear to be the most significant prognosticators. Investigation and identification of those factors determining the aggressive biologic behavior of embryonal carcinoma compared to all other histological components appear to be most promising in research for prognosticators of metastatic disease. In conclusion, the increasing knowledge of molecular genetic events involved in pathogenesis and prognosis of testicular germ cell tumors will not only help to better understand development and progression of testicular cancer, but it also will define new approaches to classification and management of germ cell tumors.

Testicular non-seminoma: ESMO Clinical Recommendations for diagnosis, treatment and follow-up

Testicular tumors are incredibly diverse and one of the most challenging areas in surgical pathology. Because of the rarity and overlapping features with numerous entities occurring in the testis and paratestis, these tumors pose a diagnostic challenge even to the most experienced general pathologists. In 2016, the latest "World Health Organization (WHO) classification of testicular tumors" was released, which incorporated several updates to the previous 2004 classification system. These updates involved several entities, including germ cell tumors, sex cord-stromal tumors, tumors containing both germ cells and sex-cord stromal cells, a miscellaneous group of testicular tumors and paratesticular tumors. In addition, significant changes were also introduced in the 2018 AJCC TNM staging (8th edition) regarding testicular tumors. The germ cell tumors are divided into 2 major groups; tumors derived from germ cell neoplasia in situ (GCNIS) and those unrelated to GCNIS. The GCNIS associated tumors include seminomatous and nonseminomatous germ cell tumors, which constitute a heterogeneous group of tumors. Non-GCNIS-associated tumors include prepubertal-type teratoma, prepubertal yolk sac tumor, mixed prepubertal-type teratoma and yolk sac tumor and spermatocytic seminoma. In the sex cord-stromal category, the tumors are classified based on their cells of origin. Most are Leydig cell tumors and Sertoli cell tumors; however, several mixed and diverse entities based on cell types are included in this group. Gonadoblastoma is the only tumor in the mixed germ cell and sex cord-stromal tumor category. Because of recent advances in molecular techniques, abundant new genetic information has emerged which helped classify the tumors based on the molecular alterations and provided insights into the tumor pathogenesis. This review focused on the updates related to testicular germ cell tumors and sex cord-stromal tumors and described the morphologic, immunohistochemical and molecular characteristics with an aim to provide a practical diagnostic approach and an update on relevant recent molecular advances.

Spontaneous regression of testicular tumors known as burnt-out tumor of testis is a rare entity and is seen in about 5% of testicular germ cell tumors. It is described as a spontaneously, completely, or partially regressed testicular tumor with or without metastasis in the absence of any treatment. This entity is now included in the 2016 classification of testicular tumors. This is probably only the second case presented in India. High degree of awareness of this entity by the pathologist, clinician, and radiologist is necessary for proper management and survival of the patient.

The 8th edition of the American Joint Committee on Cancer (AJCC) manual divides T1 stage testicular cancer into T1a and T1b, but it is only applicable to seminoma. The purpose of this observational study is to discuss further the possibility of extending this classification system to any T1 testicular cancer. Testicular cancer patients from 2000 to 2018 in the Surveillance, Epidemiology, and End Results (SEER) database were included in this analysis. After patient selection, univariate and multivariate Cox regression were used to evaluate the impact of tumor size on survival in patients with T1 testicular cancer. A time-dependent receiver operation curve (ROC) was used to determine the best tumor size cut-off value for further T1 subgroup classification. Restricted cubic splines (RCS) analysis was used to compare different tumor sizes with the best tumor size cut-off value. Propensity score matching (PSM) analysis was conducted to generate baseline balanced data to validate findings. A total of 6,630 patients were included in this study. In the Cox regression model, we found that T1b staged tumor (>34 mm) was an independent risk factor of overall survival [OS, adjusted hazard ratio (HR): 1.57, 95% confidence interval (CI): 1.12-2.21] and cancer-specific survival (CSS, adjusted HR: 5.027, 95% CI: 1.95-12.93). Further PSM analysis consolidated our results. For any T1 testicular cancer, a tumor size of 34 mm could be used as the demarcation point to assess the prognosis. Adopting personalized treatments and follow-up plans may help improve the OS and CSS rate for testicular cancer patients.

Study question Do the clinical stage and histological characteristics of testicular cancer affect sperm quality? Summary answer Sperm concentration, motility and normal morphology significantly decreased in patients with testicular cancer. However, semen parameters were not significantly associated with tumor histology. What is known already Testicular cancer is rare in most countries, with an incidence ranging from ∼1/100,000 to 10/100,000, and represents about 1% of all cancers in men, but about 60% of all cancers in young males aged between 15 and 35 years. Additionally, the incidence of testicular cancer has doubled in the last 20-40 years. While it is clear that chemotherapy treatment can negatively impact infertility, it is increasingly recognized that male-factor infertility may play a significant role in the overall health status of men, and men with infertility may be at higher risk of developing testicular cancer. Study design, size, duration Retrospective data from 284 males, diagnosed with testicular cancer, undergoing to semen cryopreservation before surgery or chemo- or radiotherapy treatments, from January 2016 to June 2022 at Maternal and Child Department, Gynecology and Obstetrics Unit, Couple Sterility Center at Federico II, University of Naples, were included in the study. Participants/materials, setting, methods All patients signed their informed consent to cryopreservation. In order to have an internal control group coming from the same region, results of semen analysis from male partners of couples with certain female factors (bilateral tubal imperviousness or in case of egg donation) were included in the study. After semen collection and liquefaction, the semen specimens were cryopreserved following manufacturer’s protocol with media conteining TEST-yolk buffer. Main results and the role of chance Overall, taking in to consideration the semen cryopreservation, per WHO 2021 criteria, we observed that the majority of semen parameters of patients with testicular cancer resulted between 5°percentile and 25° percentile. The unique parameter over the 50°percentile was the semen volume. Comparing results from male partners of couples with certain female factors and testicular cancer patients several features were significant different. Especially, semen volume resulted significantly increased in cases respect to the control (p = 0,011). Instead, from microscopic evaluation semen concentration, percentage of total sperm motility and % of spermatozoa with normal morphology appeared significantly decreased in patients with testicular cancer (p = 0,000; p = 0,000; p = 0,002). Based on Histopathological Classification of Testicular Tumors the 59% (168/284) were classified as classic seminoma, 14% (41/284) mixed germ cell tumors including seminomatous and nonseminomatous cell tumors, 13% (38/284) nonseminomatous mixed germ cell tumors, 12% (35/284) nonseminomatous germ cell tumors including 4 cases of teratoma and 30 cases of embryonal carcinoma and 2 cases of cariocarcinoma. However, abnormal semen parameters were not significantly associated with tumor histology. Limitations, reasons for caution No information about semen quality after thawing and ICSI outcome could represent the main limitation for a complete information of the preservation program in these patients. Wider implications of the findings We presented our monocentric experience of oncofertility preservation program with especially attention to testicular cancer patients. Presented data emphasizes the importance of semen monitoring in young men and the fertility preservation in management of the patient. Trial registration number not applicable

Therapeutic Potential of SOX2 Inhibition for Embryonal Carcinoma

Performance and Clinical Evaluation of the 92-Gene Real-Time PCR Assay for Tumor Classification

5083 Background: High PAI-1 expression by tumor has been associated with poor prognosis in different cancer types, while high systemic PAI-1 levels may increase the risk of vascular thrombosis. We investigated whether the 4G/5G del/ins polymorphism in the PAI-1 promoter (rs1799889; 4G might lead to higher transcription), is associated with differences in survival and prevalence of cardiovascular events in TC. METHODS: Data were collected on survival and cardiovascular events (venous thromboembolism [VTE] and coronary heart disease [CHD]) of TC patients treated with standard platinum based chemotherapy from 1977-2004. PAI-1 genotype was determined from non-tumor genomic DNA by a Taqman SNP assay. Genotypes were compared for survival (Kaplan-Meier curves + log-rank and Cox-regression analysis), disease outcome (logistic regression) and prevalence of VTE and CHD (χ(2)-test). RESULTS: Data are available for 324 patients with median follow-up of 10 yrs (range 0-28). The 3 genotypes 4G/4G (n = 84), 4G/5G (n = 164), and 5G/5G (n = 76) do not differ in age and initial chemotherapy regime. However, the 4G/4G variant shows a higher prevalence of International Germ Cell Cancer Classification (IGCCC) poor prognosis compared to 4G/5G + 5G/5G (24% vs 10%; p = 0.003), as well as a decreased TC related survival compared to 4G/5G + 5G/5G (83% vs 94%; p = 0.001) with a hazard ratio of 2.68 for TC related death (95%CI 1.26-5.72; adjusted for IGCCC p = 0.011). In addition, the 4G/4G variant shows an odds ratio of 3.35 for refractory TC and early relapses (<2 yrs) (95% CI 1.48-7.58; p = 0.004). The 3 genotypes do not differ significantly in prevalence of VTE (4G/4G 11.9%, 4G/5G 8.5%, 5G/5G 7.9%; p = 0.616) and CHD during/after chemotherapy (4G/4G 6.0%; 4G/5G 4.9%; 5G/5G 2.6%; p = 0.594). CONCLUSIONS: The 4G/4G variant of the PAI-1 4G/5G gene polymorphism is associated with IGCCC poor prognosis, reduced survival and higher prevalence of refractory disease and early relapses. No effect on vascular toxicity was found. The 4G/4G variant of the PAI-1 gene may be an unfavorable prognostic factor as well as an unfavorable predictive factor for response to chemotherapy in patients with TC. No significant financial relationships to disclose.

Dendritic Cell Infiltration In A Patient With Seminomatous Germ Cell Tumor Of The Testis: Is There A Relationship With Infertility And Tumor Stage?

The fifth edition of the World Health Organization (WHO) classification of urogenital tumours (WHO “Blue Book”), published in 2022, contains significant revisions. This review summarises the most relevant changes for renal, penile, and testicular tumours. In keeping with other volumes in the fifth edition series, the WHO classification of urogenital tumours follows a hierarchical classification and lists tumours by site, category, family, and type. The section “essential and desirable diagnostic criteria” included in the WHO fifth edition represents morphologic diagnostic criteria, combined with immunohistochemistry and relevant molecular tests. The global introduction of massive parallel sequencing will result in a diagnostic shift from morphology to molecular analyses. Therefore, a molecular-driven renal tumour classification has been introduced, taking recent discoveries in renal tumour genomics into account. Such novel molecularly defined epithelial renal tumours include SMARCB1-deficient medullary renal cell carcinoma (RCC), TFEB-altered RCC, Alk-rearranged RCC, and ELOC-mutated RCC. Eosinophilic solid and cystic RCC is a novel morphologically defined RCC entity. The diverse morphologic patterns of penile squamous cell carcinomas are grouped as human papillomavirus (HPV) associated and HPV independent, and there is an attempt to simplify the morphologic classification. A new chapter with tumours of the scrotum has been introduced. The main nomenclature of testicular tumours is retained, including the use of the term “germ cell neoplasia in situ” (GCNIS) for the preneoplastic lesion of most germ cell tumours and division from those not derived from GCNIS. Nomenclature changes include replacement of the term “primitive neuroectodermal tumour” by “embryonic neuroectodermal tumour” to separate these tumours clearly from Ewing sarcoma. The term “carcinoid” has been changed to “neuroendocrine tumour”, with most examples in the testis now classified as “prepubertal type testicular neuroendocrine tumour”.

5083 Background: High PAI-1 expression by tumor has been associated with poor prognosis in different cancer types, while high systemic PAI-1 levels may increase the risk of vascular thrombosis. We investigated whether the 4G/5G del/ins polymorphism in the PAI-1 promoter (rs1799889; 4G might lead to higher transcription), is associated with differences in survival and prevalence of cardiovascular events in TC. Methods: Data were collected on survival and cardiovascular events (venous thromboembolism [VTE] and coronary heart disease [CHD]) of TC patients treated with standard platinum based chemotherapy from 1977–2004. PAI-1 genotype was determined from non-tumor genomic DNA by a Taqman SNP assay. Genotypes were compared for survival (Kaplan-Meier curves + log-rank and Cox-regression analysis), disease outcome (logistic regression) and prevalence of VTE and CHD (χ2-test). Results: Data are available for 324 patients with median follow-up of 10 yrs (range 0–28). The 3 genotypes 4G/4G (n = 84), 4G/5G (n = 164), and 5G/5G (n = 76) do not differ in age and initial chemotherapy regime. However, the 4G/4G variant shows a higher prevalence of International Germ Cell Cancer Classification (IGCCC) poor prognosis compared to 4G/5G + 5G/5G (24% vs 10%; p = 0.003), as well as a decreased TC related survival compared to 4G/5G + 5G/5G (83% vs 94%; p = 0.001) with a hazard ratio of 2.68 for TC related death (95%CI 1.26–5.72; adjusted for IGCCC p = 0.011). In addition, the 4G/4G variant shows an odds ratio of 3.35 for refractory TC and early relapses (<2 yrs) (95% CI 1.48–7.58; p = 0.004). The 3 genotypes do not differ significantly in prevalence of VTE (4G/4G 11.9%, 4G/5G 8.5%, 5G/5G 7.9%; p = 0.616) and CHD during/after chemotherapy (4G/4G 6.0%; 4G/5G 4.9%; 5G/5G 2.6%; p = 0.594). Conclusions: The 4G/4G variant of the PAI-1 4G/5G gene polymorphism is associated with IGCCC poor prognosis, reduced survival and higher prevalence of refractory disease and early relapses. No effect on vascular toxicity was found. The 4G/4G variant of the PAI-1 gene may be an unfavorable prognostic factor as well as an unfavorable predictive factor for response to chemotherapy in patients with TC. No significant financial relationships to disclose.

Testicular seminoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Testicular tumors constitute a rare type of cancer affecting adolescents and young adults with recent reports confirming an increase in incidence worldwide. The purpose of this study was to estimate the epidemiological characteristics and histological subtypes of testicular tumors in the Lebanese population according to the WHO classification of testicular and paratesticular tumors. In this single institutional retrospective study, all patients diagnosed with a testicular tumor in Hotel-Dieu de France Hospital University in Beirut between 1992 and 2014 were enrolled. The age, subtype based on the 2004 WHO classification and body side of tumor were analyzed. A total of two hundred and forty-four (244) patients diagnosed with a testicular tumor in our institution were included in the study. Two hundred and one patients (82.4% of all testicular tumors) had germ cell tumors (TGCT). Among TGCT, 50% were seminomatous tumors, 48% non-seminomatous tumors (NST) and 2% were spermatocytic seminomas. The NST were further divided into mixed germ cell tumors (63.9%), embryonic carcinomas (18.6%), teratomas (15.4%) and yolk sac tumors (2.1%). The mean age for testicular tumors was 32 years. The mean age for germ cell tumors was 31 years and further subtypes such as seminomatous tumors had a mean age of 34 years, 28 years in non-seminomatous tumors and 56 years in spermatocytic seminoma. Patients with right testicular tumor were the predominant group with 55% of patients. Three patients (1.2%) presented with bilateral tumors. The distribution of different subgroups and the mean age for testicular tumors proved comparable to most countries of the world except for some Asian countries. Germ cell tumors are the most common subtype of testicular tumors with seminomatous tumors being slightly more prevalent than non-seminomatous tumors in Lebanese patients.