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Simple Summary: Our findings confirm the role of developmental aspects in extracranial germ cell tumors (eGCTs). Strong associations between syndromes or congenital anomalies and eGCTs may hint at the need for research to identify potential causes and mechanisms. Strong effects were observed for Swyer and Currarino syndrome. The strengths of the associations emphasize the need for further elaboration on presently discussed pathophysiological mechanisms. For other suggested risk factors such as Klinefelter, Turner, and Down syndrome, the strength of risk appears to be substantially low and may be missed because of diagnostic bias for the first two or lack of power for the latter. A number of further syndromes were identified in single cases. Most of these pertain to girls. GCTs are developmental tumors and are likely to reflect ontogenetic and teratogenetic determinants. The objective of this study was to identify syndromes with or without congenital anomalies and non-syndromic defects as potential risk factors. Patients with extracranial GCTs (eGCTs) registered in MAKEI 96/MAHO 98 between 1996 and 2017 were included. According to Teilum's holistic concept, malignant and benign teratomas were registered. We used a case–control study design with Orphanet as a reference group for syndromic defects and the Mainz birth registry (EUROCAT) for congenital anomalies at birth. Co-occurring genetic syndromes and/or congenital anomalies were assessed accordingly. Odds ratios and 95% confidence intervals were calculated and p-values for Fisher's exact test with Bonferroni correction if needed. A strong association was confirmed for Swyer (OR 338.6, 95% CI 43.7–2623.6) and Currarino syndrome (OR 34.2, 95% CI 13.2–88.6). We additionally found 16 isolated cases of eGCT with a wide range of syndromes. However, these were not found to be significantly associated following Bonferroni correction. Most of these cases pertained to girls. Regarding non-syndromic defects, no association with eGCTs could be identified. In our study, we confirmed a strong association for Swyer and Currarino syndromes with additional congenital anomalies. [ABSTRACT FROM AUTHOR]

Simple Summary: Pediatric COG stage II and III adrenocortical carcinoma (ACC) is one of the most unpredictable and challenging tumors in terms of prognosis and management. The EXPeRT/PARTNER recommendation suggested inclusion of the five-item microscopic score to guide management in these patients. In this study, we report on 18 pediatric ACC stage II and 37 stage III patients registered with the German MET studies. We explored the five-item microscopic and the pS-GRAS score to predict outcome. Three-year event-free survival estimates were 76.5% in stage II and 49.8% in stage III patients. In COG stage III patients, EFS was impaired for patients with unfavorable histology according to the five-item score. No differences were observed in stage II patients and in the pS-GRAS groups. Further research including molecular studies is needed to identify high-risk features in locally advanced pediatric ACC tumors. Background: Locally advanced tumors account for approximately 50% of children and adolescents with adrenocortical carcinoma (ACC), and of these, up to 50% relapse. We explored the five-item microscopic score and the pS-GRAS score for guiding management. Methods: Data from children and adolescents with COG stage II and III ACC registered in the MET studies were included. The five-item and pS-GRAS score were retrospectively calculated. Results: By December 2021, 55 patients with stage II and III (stage II n = 18, stage III n = 37) had been reported. Median age was 4.3 years [0.1–17.8], median duration of follow-up 6.0 years [0–16.7]. 3-year event-free survival (EFS) rate was 76.5% and 49.8% (p = 0.088), respectively. In stage II tumors, neither the five-item score (p = 0.872) nor pS-GRAS grouping (p = 0.218) had any effect as prognostic factors. In stage III patients, EFS was impaired in tumors with unfavorable histology according to the five-item score (100% vs. 30.8%, p = 0.018). No difference was observed for pS-GRAS groups (p = 0.798). Conclusions: In patients with COG stage III, but not stage II, the five-item score affected EFS. Further studies are needed to identify patients at risk in COG stage II. [ABSTRACT FROM AUTHOR]

Simple Summary: Hepatoblastoma is the most common malignant liver tumor in children. Small cell undifferentiated histology and low alpha-fetoprotein have been previously reported as factors associated with poor prognosis. It is important to exclude rhabdoid tumors (a rare pediatric liver tumor that is difficult to cure) in patients diagnosed with hepatoblastoma with alpha-fetoprotein levels less than 100 ng/mL and in patients with hepatoblastoma with small cell undifferentiated histology since the treatment for these patients is very different. When rhabdoid tumors are correctly diagnosed with testing for loss of SMARCB1, neither hepatoblastoma with small cell undifferentiated component nor alpha-fetoprotein less than 100 ng/mL confer poor prognosis. Small cell undifferentiated (SCU) histology and alpha-fetoprotein (AFP) levels below 100 ng/mL have been reported as poor prognostic factors in hepatoblastoma (HB); subsequent studies reported SMARCB1 mutations in some SCU HBs confirming the diagnosis of rhabdoid tumor. The Children's Hepatic tumors International Collaboration (CHIC) database was queried for patients with HB who had AFP levels less than 100 ng/mL at diagnosis or were historically diagnosed as SCU HBs. Seventy-three of 1605 patients in the CHIC database were originally identified as SCU HB, HB with SCU component, or HB with low AFP levels. Upon retrospective review, they were re-classified as rhabdoid tumors (n = 11), HB with SCU component (n = 41), and HB with low AFP (n = 14). Seven were excluded for erroneously low AFP levels. Overall survival was 0% for patients with rhabdoid tumors, 76% for patients with HB with SCU component, and 64% for patients with HB with AFP less than 100 ng/mL. Patients with HB with SCU component or low AFP should be assessed for SMARCB1 mutations and, if confirmed, treated as rhabdoid tumors. When rhabdoid tumors are excluded, the presence of SCU component and low AFP at diagnosis were not associated with poor prognosis in patients diagnosed with HB. [ABSTRACT FROM AUTHOR]

Simple Summary: Pediatric adrenocortical tumors have a poor prognosis. The EXPeRT consortium recently published recommendations for their management. In this study, we report on 161 pediatric ACT patients registered with the German Malignant Endocrine Tumor studies and explore those recommendations. The median age at the diagnosis was 4.3 years, and the mean follow-up was 4.5 years. The 3-year overall (OS) and event-free survival (EFS) estimates were 65.5% and 50.6%. The clinical presentation and prognosis were defined by age. The OS was impaired for patients aged ≥ 4 years, following the initial biopsy, tumor spillage, and incomplete tumor resection, with unfavorable histology, according to the five-item microscopic score and COG stages III and IV. COG stages III and IV and unfavorable histology were impacted as negative prognostic factors upon the EFS and OS. Background: Adrenocortical tumors (ACTs) encompassing the adrenocortical adenoma (ACA), carcinoma (ACC), and tumors of undetermined malignant potential (ACx) are rare endocrine neoplasms with a poor prognosis. We report on pediatric ACT patients registered with the Malignant Endocrine Tumor studies and explore the EXPeRT recommendations for management. Patients: Data from the ACT patients (<18 years) were analyzed. For the risk prediction, the patients were retrospectively assigned to the COG stages and the five-item score. Results: By December 2021, 161 patients with ACT (ACA n = 51, ACx n = 19, and ACC n = 91) had been reported (the median age at the diagnosis was 4.3 years with a range of 0.1–17.8), with lymph node and distant metastases in 10.7% and 18.9% of the patients with ACC/ACx. The mean follow-up was 4.5 years (with a range of 0–16.7). The three-year overall (OS) and event-free survival (EFS) rates were 65.5% and 50.6%. In the univariate analyses, the OS was impaired for patients aged ≥ 4 years (p = 0.001) with the initial biopsy (p = 0.016), tumor spillage (p = 0.028), incomplete tumor resection (p < 0.001), unfavorable histology (p = 0.047), and COG stages III/IV (p = 0.002). Multivariate analysis revealed COG stages III/IV and an unfavorable five-item score as independent negative prognostic factors for the EFS and OS. Conclusions: Age defines the clinical presentation and prognosis in pediatric ACTs. The outcome is best predicted by the COG stage and five-item score. [ABSTRACT FROM AUTHOR]

Simple Summary: It is well known that different cancer predisposition syndromes are associated with characteristic WT-features. The following findings from our retrospective analysis of patients with nephroblastoma treated according to the SIOP/GPOH trials between 1989 and 2017 are relevant: (1) The outcome of patients with a cancer predisposition syndrome is not always favorable despite early diagnosis, small tumors and less metastatic disease. This finding is partly depending on complications related to the underlying syndrome. (2) Predisposition syndromes seem to be underdiagnosed as several clinical and pathological features of Wilms tumor being clearly linked to a cancer predisposition syndrome did not lead to genetic counseling before and after WT diagnosis. As a conclusion, in children with a nephroblastoma and specific clinical and pathological features that are in line with a nephroblastoma cancer predisposition syndrome such a syndrome should always be considered and ruled out if unknown at the time of tumor diagnosis. (1) Background: about 10% of Wilms Tumor (WT) patients have a malformation or cancer predisposition syndrome (CPS) with causative germline genetic or epigenetic variants. Knowledge on CPS is essential for genetic counselling. (2) Methods: this retrospective analysis focused on 2927 consecutive patients with WTs registered between 1989 and 2017 in the SIOP/GPOH studies. (3) Results: Genitourinary malformations (GU, N = 66, 2.3%), Beckwith-Wiedemann spectrum (BWS, N = 32, 1.1%), isolated hemihypertrophy (IHH, N = 29, 1.0%), Denys-Drash syndrome (DDS, N = 24, 0.8%) and WAGR syndrome (N = 20, 0.7%) were reported most frequently. Compared to others, these patients were younger at WT diagnosis (median age 24.5 months vs. 39.0 months), had smaller tumors (349.4 mL vs. 487.5 mL), less often metastasis (8.2% vs. 18%), but more often nephroblastomatosis (12.9% vs. 1.9%). WT with IHH was associated with blastemal WT and DDS with stromal subtype. Bilateral WTs were common in WAGR (30%), DDS (29%) and BWS (31%). Chemotherapy induced reduction in tumor volume was poor in DDS (0.4% increase) and favorable in BWS (86.9% reduction). The event-free survival (EFS) of patients with BWS was significantly (p = 0.002) worse than in others. (4) Conclusions: CPS should be considered in WTs with specific clinical features resulting in referral to a geneticist. Their outcome was not always favorable. [ABSTRACT FROM AUTHOR]

Rhabdomyosarcomas (RMSs) are the most common soft tissue sarcomas in children/adolescents less than 18 years of age with an annual incidence of 1–2/million. Inter/intra-tumour heterogeneity raise challenges in clinical, pathological and biological research studies. Risk stratification in European and North American clinical trials previously relied on clinico-pathological features, but now, incorporates PAX3/7- FOXO1 -fusion gene status in the place of alveolar histology. International working groups propose a coordinated approach through the INternational Soft Tissue SaRcoma ConsorTium to evaluate the specific genetic abnormalities and generate and integrate molecular and clinical data related to patients with RMS across different trial settings. We review relevant data and present a consensus view on what molecular features should be assessed. In particular, we recommend the assessment of the MYOD1-LR122R mutation for risk escalation, as it has been associated with poor outcomes in spindle/sclerosing RMS and rare RMS with classic embryonal histopathology. The prospective analyses of rare fusion genes beyond PAX3/7-FOXO1 will generate new data linked to outcomes and assessment of TP53 mutations and CDK4 amplification may confirm their prognostic value. Pathogenic/likely pathogenic germline variants in TP53 and other cancer predisposition genes should also be assessed. DNA/RNA profiling of tumours at diagnosis/relapse and serial analyses of plasma samples is recommended where possible to validate potential molecular biomarkers, identify new biomarkers and assess how liquid biopsy analyses can have the greatest benefit. Together with the development of new molecularly-derived therapeutic strategies that we review, a synchronised international approach is expected to enhance progress towards improved treatment assignment, management and outcomes for patients with RMS. • Review molecular methods and data for childhood and adolescent rhabdomyosarcoma. • The use of germline and somatic genetic abnormalities plus gene expression signatures. • A consensus view of priorities for analyses within and across rhabdomyosarcoma clinical trials. • Priorities include fusion genes, MYOD1 and TP53 mutations and liquid biopsies. • A coordinated approach may more rapidly lead to better management and treatments. [ABSTRACT FROM AUTHOR]

Stratification of hepatoblastoma (HB) patients is based on clinical and imaging characteristics obtained at the time of diagnosis. We aim to integrate biomarkers into a tool that accurately predicts survival of HB patients. We retrospectively analysed 174 HB patients for the presence of four biomarkers and explored their prognostic potential by correlating with overall survival (OS) and event-free survival (EFS). Mutations of CTNNB1 , NFE2L2 and TERT were found in 135 (78%), 10 (6%) and 10 (6%) patients, respectively, and the adverse C2 subtype of the 16-gene signature in 63 (36%) patients. C2-patients had more frequent metastatic disease, higher alpha-fetoprotein levels, non-fetal histology and significantly worse 3-year OS (68% versus 95%) and EFS (63% versus 87%) than C1-patients. Patients carrying a NFE2L2 mutation had a significantly worse 3-year OS (57% versus 88%) than NFE2L2 wild-type patients and were more likely to have vessel invasive growth and non-fetal histology. TERT mutations were almost exclusively found in older patients, whereas CTNNB1 mutations showed no association with any clinical feature or outcome. In a multivariable analysis, the C2 subtype remained a significant predictor of poor outcome with hazard ratios of 6.202 and 3.611 for OS and EFS, respectively. When added to the Children's Hepatic tumors International Collaboration risk stratification, the presence of the C2 subtype identified a group of high-risk patients with a very poor outcome. We propose a new stratification system based on the combination of clinical factors and the 16-gene signature, which may facilitate a risk-adapted management of HB patients. • Oncogenic CTNNB1 is the key driver in the genesis of hepatoblastoma. • NFE2L2 mutations predict poor outcome and may indicate resistance to chemotherapy. • TERT mutations are typical for transitional liver cell tumours in older patients. • 16-gene signature enables risk-adapted stratification of hepatoblastoma patients. • Biomarkers need to be validated complementary to clinical risk factors in a prospective trial. [ABSTRACT FROM AUTHOR]

• Completely resected bronchial carcinoids have a favorable outcome. • Lung tissue sparing surgery is safe and feasible. • Atypical bronchial carcinoids occur more frequently compared to adults. • Outcome of children with atypical bronchial carcinoids may be better than in adults. • Molecular studies are needed to improve our understanding of bronchial carcinoids. Bronchial carcinoid tumors (BC) are exceptionally rare in childhood, with an incidence of <0.2/1,000,000 per year. Typical low-grade BCs are distinguished from atypical, intermediate-grade BCs. Little is known about BCs in pediatric patients and management guidelines are missing. In this study, we explored characteristics and outcome of pediatric patients with BC prospectively registered with the Malignant Endocrine Tumor studies. We performed a retrospective multicenter study in children, adolescents, and young adults (aged 0–20 years) with BC reported to the German MET registry between January 1997 and December 2022. Data were last updated on 28 of February 2023. Thirty-two patients were diagnosed at a median age of 15.0 years (range, 9.8–19.2). Atypical BCs (23.3%) were less frequent than typical, but more common than in adulthood. Lymph node metastases were present in 14.3% of cases (atypical BC: 28.6%, typical BC: 10.5%), distant metastases in one (3.1%) patient with atypical BC. 92.6% of patients were in complete remission after surgical resection (median follow-up: 2.7 years). The patient with metastatic spread and one patient with atypical BC and multiple recurrences were on treatment at last follow-up. 5-year event-free survival of typical BC was 100% and 83.3% in atypical BC. Completely resected localized BCs in pediatric patients have a favorable outcome also with lung tissue sparing surgery. Atypical BC with risk of metastatic spread and recurrence occurred more frequently compared to adults. Interdisciplinary management and collaborative efforts are needed to improve our understanding and the management of pediatric BC. [ABSTRACT FROM AUTHOR]