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.

miR-371a-3p Predicting Viable Tumor in Patients Undergoing Retroperitoneal Lymph Node Dissection for Metastatic Testicular Cancer: The SWENOTECA-MIR Study.

PURPOSE: The SWENOTECA-MIR prospective multicenter study aims to assess the clinical value of miR-371a-3p as a novel marker in metastatic germ cell tumor patients undergoing retroperitoneal lymph node dissection (RPLND), to predict the presence of viable residual tumor. MATERIALS AND METHODS: A total of 114 patients (86 nonseminomas, 28 seminomas) who underwent surgery for presumed metastatic disease pre chemotherapy (primary RPLND) and post chemotherapy RPLND were included. The expression of miR-371a-3p was evaluated using reverse transcription-digital droplet polymerase chain reaction before and after RPLND. Pre- and postoperative miR-371a-3p levels were statistically compared, and optimism-corrected performance calculations compared with conventional serum tumor markers. Associations were evaluated by logistic regression. Patients who underwent primary RPLND were categorized into seminoma and nonseminoma groups. RESULTS: Among the seminoma patients (n = 24) undergoing primary RPLND, all had normal conventional markers. Six patients received adjuvant treatment before surgery. miR-371a-3p exhibited a sensitivity of 74%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 21% for viable tumor. The levels of miR-371a-3p significantly decreased after surgery. In the nonseminoma group (n = 18) treated with primary RPLND, 22% had elevated conventional markers and 3 had received prior adjuvant treatment. miR-371a-3p showed a sensitivity of 34%, specificity of 88%, positive predictive value of 67%, and negative predictive value of 62% for the primary nonseminoma patients. No association was observed between stage or prior adjuvant treatment and the outcome of the miR test. In the postchemotherapy group (n = 72), the miR-371a-3p sensitivity was 9%, reducing to 0 when excluding patients with seminoma (n = 4). Teratomas and benign histology were essentially negative. CONCLUSIONS: Our study highlights miR-371a-3p as a fairly sensitive and highly specific marker for prechemotherapy seminomas, outperforming conventional markers. However, in prechemotherapy nonseminomas as well as in postchemotherapy patients, we observed low sensitivity and no significant differences in miR-371a-3p levels before and after surgery, suggesting limited utility for miR-371a-3p in this context.

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.

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.

Maediastinal germ cell tumors: analysis using hospital-based cancer registry data in Japan.

OBJECTIVES: Mediastinal germ cell tumors are rare and few large-scale studies on mediastinal germ cell tumors are reported. We aimed to investigate the clinical characteristics and survival outcomes of patients with mediastinum germ cell tumors in Japan. METHODS: A hospital-based cancer registry data in Japan was used to identify and enroll patients diagnosed with mediastinal germ cell tumors in 2012-2013. The datasets were registered from 80 institutions. RESULTS: The selection criteria were met by 123 patients, the majority of whom were male. The median age at diagnosis was 39 years (range 25-89 years) and the most common age groups at diagnosis was 30-39 years, followed by 40-49 years and ≥ 50 years. The histology of non-seminoma (55.3%) was slightly more frequent than that of seminoma (44.7%). The most common histological subtype in non-seminoma was yolk sac tumor, followed by mixed germ cell tumor. The 5-year survival of seminoma and non-seminoma were 96.4% and 57.3%, respectively (p < 0.001). Non-seminomatous mediastinal germ cell tumors, malignant teratomas, mixed germ cell tumors, and yolk sac tumors had comparable survival rates, while those with choriocarcinoma showed the worst prognosis. CONCLUSIONS: This is the first report showing the clinical characteristics and survival outcomes of mediastinal germ cell tumors in Japan using a real-world large cohort database.

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.

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.

Thirty-Year-Old Male Patient with Non-Seminoma and Coincidental Rectal Cancer.

We present the case of a 31-year-old male patient with non-seminoma (90% embryonal carcinoma, 10% teratoma) pT1b L1 V0 Pn0 R0 cN2 cM0, Clinical Stage IIb and "good prognosis group" according to IGCCCG of the left testis. According to EAU guidelines, he received three cycles of BEP. After the second cycle, he developed recurrent, clinically not significant rectal bleeding, which we associated with deep thrombocytopenia. Following chemotherapy, there was one lymph node in the CT scan left, with a diameter of 0.9 cm at the inferior mesenteric arteria and the rectal bleeding did not stop; so coloscopy and staging revealed rectal cancer (adenocarcinoma) with peritoneal carcinosis. The patient was scheduled for radio-chemotherapy. Next-generation sequencing of the adenocarcinoma showed two mutations in KRAS and TP53 genes. To our knowledge, this is the first case of non-seminoma and coincidental rectal cancer. Furthermore, this case underlines the significance of molecular biological studies for the development of individualized targeted therapies, especially in younger patients and in chemo- and/or platin-resistance.

Survival of Testicular Pure Embryonal Carcinoma vs. Mixed Germ Cell Tumor Patients across All Stages.

Background and Objectives: The impact of pure histological subtypes in testicular non-seminoma germ cell tumors on survival, specifically regarding pure embryonal carcinoma, is not well established. Therefore, this study aimed to test for differences between pure embryonal carcinoma and mixed germ cell tumor patients within stages I, II and III in a large population-based database. Materials and Methods: We relied on the Surveillance, Epidemiology and End Results (SEER) database (2004-2019) to identify testicular pure embryonal carcinoma vs. mixed germ cell tumor patients. Cumulative incidence plots depicted cancer-specific mortality that represented the main endpoint of interest. Multivariable competing risks regression models tested for differences between pure embryonal carcinoma and mixed germ cell tumor patients in analyses addressing cancer-specific mortality and adjusted for other-cause mortality. Results: Of 11,223 patients, 2473 (22%) had pure embryonal carcinoma. Pure embryonal carcinoma patients exhibited lower cancer-specific mortality relative to their mixed germ cell tumor counterparts for both stage III (13.9 vs. 19.4%; p < 0.01) and stage II (0.5 vs. 3.4%, p < 0.01), but not in stage I (0.9 vs. 1.6%, p = 0.1). In multivariable competing risks regression models, pure embryonal carcinoma exhibited more favorable cancer-specific mortality than mixed germ cell tumor in stage III (hazard ratio 0.71, p = 0.01) and stage II (hazard ratio 0.11, p < 0.01). Conclusions: Pure embryonal carcinoma exhibits a more favorable cancer-specific mortality profile relative to mixed germ cell tumor in stage II and III testicular cancers. Consequently, the presence of mixed germ cell tumor elements may be interpreted as a risk factor for cancer-specific survival.

Outcomes of men with HIV and germ cell cancer: Results from an international collaborative study.

BACKGROUND: Previous studies have shown that men with HIV and germ cell cancer (HIV-GCC) have inferior overall survival (OS) in comparison with their HIV-negative counterparts. However, little information is available on treatments and outcomes of HIV-GCC in the era of combination antiretroviral therapy (cART). METHODS: This study examined men living with HIV who were 18 years old or older and had a diagnosis of histologically proven germ cell cancer (GCC). The primary outcomes were OS and progression-free survival (PFS). RESULTS: Data for 89 men with a total of 92 HIV-GCCs (2 synchronous GCCs and 1 metachronous bilateral GCC) were analyzed; among them were 64 seminomas (70%) and 28 nonseminomas (30%). The median age was 36 years, the median CD4 T-cell count at GCC diagnosis was 420 cells/µL, and 77% of the patients on cART had an HIV RNA load < 500 copies/mL. Stage I disease was found in 44 of 79 gonadal GCCs (56%). Among 45 cases with primary disseminated GCC, 78%, 18%, and 4% were assigned to the good-, intermediate-, and poor-prognosis groups, respectively, of the International Germ Cell Cancer Collaborative Group. Relapses occurred in 14 patients. Overall, 12 of 89 patients (13%) died. The causes of death were refractory GCC (n = 5), an AIDS-defining illness (n = 3), and other causes (n = 4). After a median follow-up of 6.5 years, the 5- and 10-year PFS rates were 81% and 73%, respectively, and the 5- and 10-year OS rates were 91% and 85%, respectively. CONCLUSIONS: The 5- and 10-year PFS and OS rates of men with HIV-GCC were similar to those reported for men with HIV-negative GCC. Patients with HIV-GCC should be managed identically to HIV-negative patients. LAY SUMMARY: Men living with HIV are at increased risk for germ cell cancer (GCC). Previous studies have shown that the survival of men with HIV-associated germ cell cancer (HIV-GCC) is poorer than the survival of their HIV-negative counterparts. This study examined the characteristics, treatments, and outcomes of 89 men with HIV-GCC in the era of effective combination antiretroviral therapies. The long-term outcomes of men with HIV-GCC were similar to those reported for men with HIV-negative GCC. Patients with HIV-GCC should be managed identically to HIV-negative patients.

TP53 Alterations Are Associated With Poor Survival in Patients With Primary Mediastinal Nonseminoma Germ Cell Tumors.

BACKGROUND: Primary mediastinal nonseminoma germ cell tumors (PMNSGCT) are a subgroup of nonseminoma germ cell tumors (GCT) with poor prognosis. In this study, PMNSGCT-specific genomic landscape was analyzed and correlated with clinical outcomes. METHODS: DNA was extracted and sequenced from 28 archival tumor tissue of patients with mediastinal GCT (3 seminoma and 25 nonseminoma). Overall survival (OS) and association with gene alterations were estimated using the Kaplan-Meier and univariate Cox regression methods. RESULTS: Three patients (11%) had a karyotype XXY, 17/28 (61%) tumor samples presented chromosome 12p amplification. Somatic mutations were detected in 19/28 (68%) samples. The most frequently mutated genes were: TP53 (13/28; 46%), KIT (5/28; 18%), and KRAS (5/28; 18%). Deleterious TP53 alterations were associated with significantly reduced overall survival (HR: 7.16; P = .012). CONCLUSIONS: TP53 alterations are common in PMNSGCT and are associated with reduced overall survival, potentially underlying the poor sensitivity to chemotherapy observed in these patients.

Prognostic factors in patients with clinical stage I nonseminoma-beyond lymphovascular invasion: a systematic review.

OBJECTIVE: To systematically evaluate evidence on prognostic factors for tumor recurrence in clinical stage I nonseminoma patients other than lymphovascular invasion (LVI). METHODS: We performed a systematic literature search in the biomedical databases Medline (via Ovid) and Cochrane Central Register of Controlled Trials (search period January 2010 to February 2021) for full text publications in English and German language, reporting on retro- or prospectively assessed prognostic factors for tumor recurrence in patients with stage I nonseminomatous germ cell tumors. RESULTS: Our literature search yielded eleven studies reporting on 20 potential prognostic factors. Results are based on cohort studies of mostly moderate to low quality. Five out of eight studies found a significant association of embryonal carcinoma (EC) in the primary tumor with relapse. Among the different risk definitions of embryonal carcinoma (presence, predominance, pure), presence of EC alone seems to be sufficient for prognostification. Interesting results were found for rete testis invasion, predominant yolk sac tumor, T-stage and history of cryptorchidism, but the sparse data situation does not justify their clinical use. CONCLUSIONS: No additional factors that meet the prognostic value of LVI, especially when determined by immunohistochemistry, could be identified through our systematic search. The presence of EC might serve as a second, subordinate prognostic factor for clinical use as the data situation is less abundant than the one of LVI. Further efforts are necessary to optimize the use of these two prognostic factors and to evaluate and validate further potential factors with promising preliminary data.

Clinical characteristics, treatment patterns and relapse in patients with clinical stage IS testicular cancer.

PURPOSE: Clinical stage I (CSI) testicular germ cell tumors (TGCT) represents disease confined to the testis without metastasis and CSIS is defined as persistently elevated tumor markers (TM) after orchiectomy, indicating subclinical metastatic disease. This study aims at assessing clinical characteristics and oncological outcome in CSIS. METHODS: Data from five tertiary referring centers in Germany were screened. We defined correct classification of CSIS according to EAU guidelines. TM levels, treatment and relapse-free survival were assessed and differences between predefined groups (chemotherapy, correct/incorrect CSIS) were analyzed with Fisher's exact and Chi-square test. RESULTS: Out of 2616 TGCT patients, 43 (1.6%) were CSIS. Thereof, 27 were correctly classified (cCSIS, 1.03%) and 16 incorrectly classified (iCSIS). TMs that defined cCSIS were in 12 (44.4%), 10 (37%), 3 (11.1%) and 2 (7.4%) patients AFP, ß-HCG, AFP plus ß-HCG and LDH, respectively. In the cCSIS group, six patients were seminoma and 21 non-seminoma. Treatment consisted of active surveillance, carboplatin-mono AUC7 and BEP (bleomycin, etoposide and cisplatin). No difference between cCSIS and iCSIS with respect to applied chemotherapy was found (p = 0.830). 5-year relapse-free survival was 88.9% and three patients (11%) in the cCSIS group relapsed. All underwent salvage treatment (3xBEP) with no documented death. CONCLUSION: Around 1% of all TGCT were classified as cCSIS patients. Identification of cCSIS is of critical importance to avoid disease progression and relapses by adequate treatment. We report a high heterogeneity of treatment patterns, associated with excellent long-term survival irrespective of the initial treatment approach.

Contemporary options and future perspectives: three examples highlighting the challenges in testicular cancer imaging.

PURPOSE: One of the main issues in testicular germ cell tumors (TGCTs) management is to reduce the necessary amount of treatment to achieve cure. Excess treatment burden may arise from late diagnosis of the primary as well as from false positive or negative staging results. Correct imaging is of paramount importance for successful management of TGCT. The aim of this review is to point out the current state of the art as well as innovative developments in TGCT imaging on the basis of three common challenging clinical situations. METHODS: A selective literature search was performed in PubMed, Medline as well as in recent conference proceedings. RESULTS: Regarding small testicular lesions, recent studies using elastography, contrast-enhanced ultrasound or magnetic resonance imaging (MRI) showed promising data for differentiation between benign and malignant histology. For borderline enlarged lymph nodes FDG-PET-CT performance is unsatisfactory, promising new techniques as lymphotropic nanoparticle-enhanced MRI is the subject of research in this field. Regarding the assessment of postchemotherapeutic residual masses, the use of conventional computerized tomography (CT) together with serum tumor markers is still the standard of care. To avoid overtreatment in this setting, new imaging modalities like diffusion-weighted MRI and radiomics are currently under investigation. For follow-up of clinical stage I TGCTs, the use of MRI is non-inferior to CT while omitting radiation exposure. CONCLUSION: Further efforts should be made to refine imaging for TGCT patients, which is of high relevance for the guidance of treatment decisions as well as the associated treatment burdens and oncological outcomes.

Associations of serum levels of microRNA-371a-3p (M371) with risk factors for progression in nonseminomatous testicular germ cell tumours clinical stage 1.

PURPOSE: Lymphovascular invasion (LV1) and presence of > 50% embryonal carcinoma (> 50% EC) represent risk factors for progression in patients with clinical stage 1 (CS1) nonseminomatous (NS) testicular germ cell tumours. As serum levels of microRNA-371a-3p (M371) are capable of detecting small amounts of GCT, we evaluated if LV1 and > 50% EC are associated with M371 levels. METHODS: M371 serum levels were measured postoperatively in 153 NS CS1 patients and both pre- and postoperatively in 131 patients. We registered the following factors: age, tumour size, LV status, > 50% EC, teratoma in primary, preoperative elevation of classical tumour markers. M371 expression was compared among subgroups. The ability of M371 to predict LV1 was calculated by receiver operating characteristics (ROC) curves. Multiple regression analysis was used to look for associations of M371 levels with other factors. RESULTS: Postoperatively elevated M371 levels were found in 29.4% of the patients, but were neither associated with LV status nor with > 50% EC. Likewise, relative decrease of M371 was not associated. ROC analysis of postoperative M371 levels revealed an AUC of 0.5 for the ability to predict LV1 while preoperative M371 had an AUC of 0.732. Multiple regression analysis revealed significant associations of preoperative M371 levels with LV status (p = 0.003), tumour size (p = 0.001), > 50% EC (p = 0.004), and teratoma component (p = 0.045). CONCLUSION: Postoperatively elevated M371 levels are not associated with risk factors for progression in NS CS1 patients. However, the significant association of preoperative M371 expression with LV1 deserves further evaluation.

How to classify, diagnose, treat and follow-up extragonadal germ cell tumors? A systematic review of available evidence.

PURPOSE: To present the current evidence and the development of studies in recent years on the management of extragonadal germ cell tumors (EGCT). METHODS: A systematic literature search was conducted in Medline and the Cochrane Library. Studies within the search period (January 2010 to February 2021) that addressed the classification, diagnosis, prognosis, treatment, and follow-up of extragonadal tumors were included. Risk of bias was assessed and relevant data were extracted in evidence tables. RESULTS: The systematic search identified nine studies. Germ cell tumors (GCT) arise predominantly from within the testis, but about 5% of the tumors are primarily located extragonadal. EGCT are localized primarily mediastinal or retroperitoneal in the midline of the body. EGCT patients are classified according to the IGCCCG classification. Consecutively, all mediastinal non-seminomatous EGCT patients belong to the "poor prognosis" group. In contrast mediastinal seminoma and both retroperitoneal seminoma and non-seminoma patients seem to have a similar prognosis as patients with gonadal GCTs and metastasis at theses respective sites. The standard chemotherapy regimen for patients with a EGCT consists of 3-4 cycles (good vs intermediate prognosis) of bleomycin, etoposid, cisplatin (BEP); however, due to their very poor prognosis patients with non-seminomatous mediastinal GCT should receive a dose-intensified or high-dose chemotherapy approach upfront on an individual basis and should thus be referred to expert centers Ifosfamide may be exchanged for bleomycin in cases of additional pulmonary metastasis due to subsequently planned resections. In general patients with non-seminomatous EGCT, residual tumor resection (RTR) should be performed after chemotherapy. CONCLUSION: In general, non-seminomatous EGCT have a poorer prognosis compared to testicular GCT, while seminomatous EGGCT seem to have a similar prognosis to patients with metastatic testicular seminoma. The current insights on EGCT are limited, since all data are mainly based on case series and studies with small patient numbers and non-comparative studies. In general, systemic treatment should be performed like in testicular metastatic GCTs but upfront dose intensification of chemotherapy should be considered for mediastinal non-seminoma patients. Thus, EGCT should be referred to interdisciplinary centers with utmost experience in the treatment of germ cell tumors.

Distinct telomere length and molecular signatures in seminoma and non-seminoma of testicular germ cell tumor.

Testicular germ cell tumors (TGCTs) are classified into two main subtypes, seminoma (SE) and non-seminoma (NSE), but their molecular distinctions remain largely unexplored. Here, we used expression data for mRNAs and microRNAs (miRNAs) from The Cancer Genome Atlas (TCGA) to perform a systematic investigation to explain the different telomere length (TL) features between NSE (n = 48) and SE (n = 55). We found that TL elongation was dominant in NSE, whereas TL shortening prevailed in SE. We further showed that both mRNA and miRNA expression profiles could clearly distinguish these two subtypes. Notably, four telomere-related genes (TelGenes) showed significantly higher expression and positively correlated with telomere elongation in NSE than SE: three telomerase activity-related genes (TERT, WRAP53 and MYC) and an independent telomerase activity gene (ZSCAN4). We also found that the expression of genes encoding Yamanaka factors was positively correlated with telomere lengthening in NSE. Among them, SOX2 and MYC were highly expressed in NSE versus SE, while POU5F1 and KLF4 had the opposite patterns. These results suggested that enhanced expression of both TelGenes (TERT, WRAP53, MYC and ZSCAN4) and Yamanaka factors might induce telomere elongation in NSE. Conversely, the relative lack of telomerase activation and low expression of independent telomerase activity pathway during cell division may be contributed to telomere shortening in SE. Taken together, our results revealed the potential molecular profiles and regulatory roles involving the TL difference between NSE and SE, and provided a better molecular understanding of this complex disease.

Management of Germ Cell Tumours of the Testes in Adult Patients: German Clinical Practice Guideline, PART II - Recommendations for the Treatment of Advanced, Recurrent, and Refractory Disease and Extragonadal and Sex Cord/Stromal Tumours and for the Management of Follow-Up, Toxicity, Quality of Life, Palliative Care, and Supportive Therapy.

OBJECTIVES: We developed the first German evidence- and consensus-based clinical guideline on diagnosis, treatment, and follow-up of germ cell tumours (GCT) of the testes in adult patients. We present the guideline content in 2 separate publications. The present second part summarizes therecommendations for the treatment of advanced disease stages and for the management of follow-up and late effects. MATERIALS AND METHODS: An interdisciplinary panel of 42 experts including 1 patient representative developed the guideline content. Clinical recommendations and statements were based on scientific evidence and expert consensus. For this purpose, evidence tables for several review questions, which were based on systematic literature searches (last search in March 2018), were provided. Thirty-one experts, who were entitled to vote, rated the final clinical recommendations and statements. RESULTS: Here we present the treatment recommendations separately for patients with metastatic seminoma and non-seminomatous GCT (stages IIA/B and IIC/III), for restaging and treatment of residual masses, and for relapsed and refractory disease stages. The recommendations also cover extragonadal and sex cord/stromal tumours, the management of follow-up and toxicity, quality-of-life aspects, palliative care, and supportive therapy. CONCLUSION: Physicians and other medical service providers who are involved in the diagnostics, treatment, and follow-up of GCT (all stages, outpatient and inpatient care as well as rehabilitation) are the users of the present guideline. The guideline also comprises quality indicators for measuring the implementation of the guideline recommendations in routine clinical care; these data will be presented in a future publication.