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Posterior fossa type A (PF-EPN-A, PFA) ependymoma are aggressive tumors that mainly affect children and have a poor prognosis. Histopathology shows significant intratumoral heterogeneity, ranging from loose tissue to often sharply demarcated, extremely cell-dense tumor areas. To determine molecular differences in morphologically different areas and to understand their clinical significance, we analyzed 113 PF-EPN-A samples, including 40 corresponding relapse samples. Cell-dense areas ranged from 0 to 100% of the tumor area and displayed a higher proportion of proliferating tumor cells (p < 0.01). Clinically, cell density was associated with poor progression-free and overall survival (p PFS  = 0.0026, p OS  < 0.01). Molecularly, tumor areas with low and high cell density showed diverging DNA methylation profiles regarding their similarity to distinct previously discovered PF-EPN-A subtypes in 9/21 cases. Prognostically relevant chromosomal changes at 1q and 6q showed spatial heterogeneity within single tumors and were significantly enriched in cell-dense tumor areas as shown by single-cell RNA (scRNA)-sequencing as well as copy number profiling and fluorescence in situ hybridization (FISH) analyses of different tumor areas. Finally, spatial transcriptomics revealed cell-dense areas of different tumors to be more similar than various different areas of the same tumor. High-density areas distinctly overexpressed genes encoding histone proteins, WNT5A, TGFB1, or IGF2. Relapsing tumors displayed a higher proportion of cell-dense areas (p = 0.036), a change in PF-EPN-A methylation subtypes (13/32 patients), and novel chromosome 1q gains and 6q losses (12/32 cases) compared to corresponding primary tumors. Our data suggest that PF-EPN-A ependymomas habor a previously unrecognized intratumoral heterogeneity with clinical implications, which has to be accounted for when selecting diagnostic material, inter alia, by histological evaluation of the proportion of cell-dense areas., (© 2024. The Author(s).)

Background: Survival in recurrent ependymomas in children and adolescents mainly depends on the extent of resection. Studies on repeated radiotherapy and chemotherapy at relapse have shown conflicting results., Methods: Using data from the German multi-center E-HIT-REZ-2005 study, we examined the role of local therapy and the efficacy of chemotherapy with blockwise temozolomide (TMZ) in children and adolescents with recurrent ependymomas., Results: Fifty-three patients with a median age of 6.9 years (1.25-25.4) at first recurrence and a median follow-up time of 36 months (2-115) were recruited. Gross- and near-total resection (GTR/NTR) were achieved in 34 (64.2%) patients and associated with a markedly improved 5-year overall survival (OS) of 48.7% vs. 5.3% in less than GTR/NTR. Radiotherapy showed no improvement in OS following complete resection (OS: 70 (CI: 19.9-120.1) vs. 95 (CI: 20.7-169.4) months), but an advantage was found in less than GTR/NTR (OS: 22 (CI: 12.7-31.3) vs. 7 (CI: 0-15.8) months). Following the application of TMZ, disease progression was observed in most evaluable cases (18/21). A subsequent change to oral etoposide and trofosfamide showed no improved response. PF-A EPN were most abundant in relapses (n = 27). RELA-positive EPN (n = 5) had a 5-year OS of 0%., Conclusion: The extent of resection is the most important predictor of survival at relapse. Focal re-irradiation is a useful approach if complete resection cannot be achieved, but no additional benefit was seen after GTR/NTR. Longer-term disease stabilization (>6 months) mediated by TMZ occurred in a small number of cases (14.3%)., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Young children with brain tumours are at high risk of developing treatment-related sequelae. We aimed to assess neuropsychological outcomes 5 years after treatment. This cross-sectional study included children under 4 years of age with medulloblastoma (MB) or ependymoma (EP) enrolled in the German brain tumour trials HIT2000 and HIT-REZ2005. Testing was performed using the validated Wuerzburg Intelligence Diagnostics (WUEP-D), which includes Kaufman-Assessment-Battery, Coloured Progressive Matrices, Visual-Motor Integration, finger tapping "Speed", and the Continuous Performance Test. Of 104 patients in 47 centres, 72 were eligible for analyses. We assessed whether IQ was impacted by disease extent, disease location, patient age, gender, age at surgery, and treatment (chemotherapy with our without craniospinal irradiation [CSI] or local radiotherapy [LRT]). Median age at surgery was 2.3 years. Testing was performed at a median of 4.9 years after surgery. Patients with infratentorial EPs (treated with LRT) scored highest in fluid intelligence (CPM 100.9±16.9, mean±SD); second best scores were achieved by patients with MB without metastasis treated with chemotherapy alone (CPM 93.9±13.2), followed by patients with supratentorial EPs treated with LRT. In contrast, lowest scores were achieved by patients that received chemotherapy and CSI, which included children with metastasised MB and those with relapsed MB M0 (CPM 71.7±8.0 and 73.2±21.8, respectively). Fine motor skills were reduced in all groups. Multivariable analysis revealed that type of treatment had an impact on IQ, but essentially not age at surgery, time since surgery or gender. Our results confirm previous reports on the detrimental effects of CSI in a larger cohort of children. Comparable IQ scores in children with MB treated only with chemotherapy and in children with EP suggest that this treatment strategy represents an attractive option for children who have a high chance to avoid application of CSI. Longitudinal follow-up examinations are warranted to assess long-term neuropsychological outcomes., Competing Interests: J.E.W. is currently a employee of AbbVie, but during the trial and data analysis he served as a clinical neurooncologist in several hospitals, lastly Cleveland Clinic, Ohio. His employment has no impact on the results of this trial. Furthermore, this does not alter our adherence to PLOS ONE policies on sharing data and materials. No other author has any competing interest to declare.

Purpose: Epigenetic profiling has recently identified clinically and molecularly distinct subgroups of ependymoma. The 2016 World Health Organization (WHO) classification recognized supratentorial ependymomas (ST-EPN) with REL-associated protein/p65 (RELA) fusion as a clinicopathological entity. These tumors represent 70% of pediatric ST-EPN characterized by recurrent C11orf95-RELA fusion transcripts, which lead to pathological activation of the nuclear factor 'kappa-light-chain-enhancer' of activated B-cells (NF-κB) signaling pathway. Cyclin-dependent kinase inhibitor 2A (CDKN2A) inactivation has also been reported to correlate with poor prognosis. Here, we systematically describe magnetic resonance imaging (MRI) characteristics of RELA-fused ST-EPN, with respect to CDKN2A deletion status., Methods: Our cohort of patients with ST-EPN (n = 57) was obtained from the database of the German Brain Tumor Reference Center of the German Society for Neuropathology and Neuroanatomy (DGNN), and tumors were diagnosed according to the 2016 WHO classification. Molecular characterization identified 47 RELA-fused tumors. We analyzed the preoperative MRI according to standardized criteria, and comparison was performed between CDKN2A altered (n = 21) and CDKN2A wild type (n = 26) tumors., Results: The RELA-fused ST-EPN showed a spectrum of predominantly hemispheric tumors with cysts and necrosis. Statistical analysis on CDKN2A status revealed significant differences in terms of younger manifestation age (p =0.002) and more intratumoral hemorrhage in T2-weighted imaging (T2WI) (p =0.010) in wild type tumors; however, the location was not a parameter for differentiation., Conclusion: This study first provides comprehensive MRI data for RELA-fused ST-EPN as a distinct entity, with further interest on CDKN2A genomic status. Patient stratification by morphological MRI alone seems difficult at present. The results may support ongoing research in ST-EPN within the framework of the radiogenomics concept.

Introduction: Risk stratification of children with ependymomas of the posterior fossa in current therapeutic protocols is mainly based on clinical criteria. We aimed to identify independent outcome predictors for this disease entity by a systematic integrated analysis of clinical, histological and genetic information in a defined cohort of patients treated according to the German HIT protocols., Methods: Tumor samples of 134 patients aged 0.2-15.9 years treated between 1999 and 2010 according to HIT protocols were analyzed for histological features including mitotic activity, necrosis and vascular proliferation and genomic alterations by SNP and molecular inversion probe analysis. Survival analysis was performed by Kaplan-Meier method with log rank test and multivariate Cox regression analysis., Results: Residual tumor after surgery, chromosome 1q gain and structural genomic alterations were identified as predictors of significantly shorter event-free (EFS) and overall survival (OS). Furthermore, specific histological features including vascular proliferation, necrosis and high mitotic activity were predictive for shorter OS. Multivariate Cox regression revealed residual tumor, chromosome 1q gain and mitotic activity as independent predictors of both EFS and OS. Using these independent predictors of outcome, we were able to build a 3-tiered risk stratification model that separates patients with standard, intermediate and high risk, and which outperforms current stratification procedures., Conclusion: The integration of defined clinical, histological and genetic parameters led to an improved risk-stratification model for posterior fossa ependymoma of childhood. After validation in independent cohorts this model may provide the basis for risk-adapted treatment of children with ependymomas of the posterior fossa.

Background: Data on frequency, clinical presentation, and outcome of primary metastatic intracranial ependymoma in children are scarce., Patients and Methods: Prospective data on patients younger than 21 years with metastatic intracranial ependymoma at first diagnosis, registered from 2001 to 2014 in the HIT-2000 trial and the HIT-2000 Interim Registry, were analyzed., Results: Of 453 registered patients with intracranial ependymoma and central neuropathology review, initial staging included spinal magnetic resonance imaging in all patients and lumbar cerebrospinal fluid (CSF) analysis in 402 patients. Ten patients (2.2%) had metastatic disease, including three with microscopic CSF positivity only (M1 metastasis stage, 0.7% of patients with CSF staging). Location of the primary tumor was supratentorial in four patients (all supratentorial RELA -fused ependymoma [ST-EPN-RELA]) and within the posterior fossa in five patients (posterior fossa ependymoma type A [PF-EPN-A], n  = 4; posterior fossa ependymoma not further classifiable, n  = 1), and multifocal in one patient.All four patients with ST-EPN-RELA were alive in first or second complete remission (CR) 7.5-12.3 years after diagnosis. All four patients with macroscopic metastases of posterior fossa or multifocal ependymoma died. Three patients with initial M1 stage (ST-EPN-RELA, n  = 1; PF-EPN-A, n  = 2) received chemotherapy and local irradiation and were alive in second or third CR 3.0-9.7 years after diagnosis. Progression-free and overall survival of the entire cohort at 5 years was 13% (±6%), and 58% (±16%), respectively., Conclusion: Primary metastatic disease is rare in children with intracranial ependymoma. Prognosis may depend on molecular subgroup and extent of dissemination, and relevance of CSF analysis for initial staging remains to be clarified., Implications for Practice: Childhood ependymoma presenting with metastasis at first diagnosis is very rare with a frequency of 2.4% in this population-based, well-characterized cohort. Detection of microscopic metastases in the cerebrospinal fluid was extremely rare, and impact on prognosis and respective treatment decision on irradiation field remains unclear. Initial metastatic presentation occurs in both supratentorial RELA -fused ependymoma and posterior fossa ependymoma. Prognosis may differ according to extent of metastasis and biological subgroup, with poor prognosis in diffusely spread metastatic posterior fossa ependymoma even after combination therapy with both intensive chemotherapy and craniospinal irradiation, which may help to guide individual therapeutic decisions for future patients., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2019.)

Multiple independent genomic profiling efforts have recently identified clinically and molecularly distinct subgroups of ependymoma arising from all three anatomic compartments of the central nervous system (supratentorial brain, posterior fossa, and spinal cord). These advances motivated a consensus meeting to discuss: (1) the utility of current histologic grading criteria, (2) the integration of molecular-based stratification schemes in future clinical trials for patients with ependymoma and (3) current therapy in the context of molecular subgroups. Discussion at the meeting generated a series of consensus statements and recommendations from the attendees, which comment on the prognostic evaluation and treatment decisions of patients with intracranial ependymoma (WHO Grade II/III) based on the knowledge of its molecular subgroups. The major consensus among attendees was reached that treatment decisions for ependymoma (outside of clinical trials) should not be based on grading (II vs III). Supratentorial and posterior fossa ependymomas are distinct diseases, although the impact on therapy is still evolving. Molecular subgrouping should be part of all clinical trials henceforth.

Purpose: Posterior fossa ependymoma comprises two distinct molecular variants termed EPN&#95;PFA and EPN&#95;PFB that have a distinct biology and natural history. The therapeutic value of cytoreductive surgery and radiation therapy for posterior fossa ependymoma after accounting for molecular subgroup is not known., Methods: Four independent nonoverlapping retrospective cohorts of posterior fossa ependymomas (n = 820) were profiled using genome-wide methylation arrays. Risk stratification models were designed based on known clinical and newly described molecular biomarkers identified by multivariable Cox proportional hazards analyses., Results: Molecular subgroup is a powerful independent predictor of outcome even when accounting for age or treatment regimen. Incompletely resected EPN&#95;PFA ependymomas have a dismal prognosis, with a 5-year progression-free survival ranging from 26.1% to 56.8% across all four cohorts. Although first-line (adjuvant) radiation is clearly beneficial for completely resected EPN&#95;PFA, a substantial proportion of patients with EPN&#95;PFB can be cured with surgery alone, and patients with relapsed EPN&#95;PFB can often be treated successfully with delayed external-beam irradiation., Conclusion: The most impactful biomarker for posterior fossa ependymoma is molecular subgroup affiliation, independent of other demographic or treatment variables. However, both EPN&#95;PFA and EPN&#95;PFB still benefit from increased extent of resection, with the survival rates being particularly poor for subtotally resected EPN&#95;PFA, even with adjuvant radiation therapy. Patients with EPN&#95;PFB who undergo gross total resection are at lower risk for relapse and should be considered for inclusion in a randomized clinical trial of observation alone with radiation reserved for those who experience recurrence., (© 2016 by American Society of Clinical Oncology.)

Background: Ependymoblastoma (EBL), ependymoma (EP), and primitive neuroectodermal tumors of the central nervous system not otherwise specified (CNS-PNET NOS) are pediatric brain tumors that can be differentiated by histopathology in the clinical setting. Recently, we described specific MRI features of EBL. In this study, we compare standardized MRI characteristics of EBL with EP and CNS-PNET NOS in a series comprising 22 patients in each group., Methods: All 66 centrally reviewed cases were obtained from the database of the German multicenter HIT trials. We systematically analyzed the initial MRI scans at diagnosis according to standardized criteria, and paired comparison was performed for EBL and EP, as well as for EBL and CNS-PNET NOS., Results: We found differences between EBL and EP regarding age at diagnosis, MR signal intensity, tumor margin and surrounding edema, presence and size of cysts, and contrast enhancement pattern. Although MRI appearance of EBL shares many features with CNS-PNET NOS, we revealed significant differences in terms of age at diagnosis, tumor volume and localization, tumor margins, edema, and contrast enhancement., Conclusion: This is the first study that systematically compares multiple parameters of MRI in pediatric EBL with findings in EP and CNS-PNET NOS. Although a definite differentiation by means of MRI alone might not be feasible in the individual case, we identify significant differences between these tumor entities., (© The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Ependymal tumors across age groups are currently classified and graded solely by histopathology. It is, however, commonly accepted that this classification scheme has limited clinical utility based on its lack of reproducibility in predicting patients' outcome. We aimed at establishing a uniform molecular classification using DNA methylation profiling. Nine molecular subgroups were identified in a large cohort of 500 tumors, 3 in each anatomical compartment of the CNS, spine, posterior fossa, supratentorial. Two supratentorial subgroups are characterized by prototypic fusion genes involving RELA and YAP1, respectively. Regarding clinical associations, the molecular classification proposed herein outperforms the current histopathological classification and thus might serve as a basis for the next World Health Organization classification of CNS tumors., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Object: Reports on spinal cord ependymoma in children are rare. The aim of this study was to evaluate the clinical spectrum, treatment, and outcome of children with primary ependymoma of the spinal cord who were registered in the database of the pediatric German brain tumor studies Hirntumor (HIT) '91 and HIT 2000., Methods: Between 1991 and 2007, 29 patients (12 male and 17 female, median age at diagnosis 13.6 years) with primary spinal cord ependymoma (myxopapillary ependymoma WHO Grade I, II, and III tumors in 6, 17, and 6 patients, respectively) were identified. Four patients had neurofibromatosis Type 2., Results: With a median follow-up of 4.2 years (range 0.48-15 years), 28 patients (96.6%) were alive. Seven patients (24.1%) developed progressive disease or relapse, 2 after gross-total resection (GTR) and 5 after incomplete resection or biopsy. One patient with anaplastic ependymoma (WHO Grade III) died 65 months after diagnosis of disease progression. Primary adjuvant treatment (radiotherapy, chemotherapy, or both) was used in 8 (50%) of 16 patients following GTR and in 9 (82%) of 11 patients who underwent less than a GTR. Three additional patients were treated adjuvantly following progression. Estimated progression-free survival and overall survival rates at 5 years were 72.3% (95% CI 50%-86%) and 100%, respectively. Progression-free survival at 5 years is 84.4% (95% CI 50%-96%) for patients following GTR compared with 57.1% (95% CI 25%-69%) for patients who achieved a less than GTR (p = 0.088, log-rank test). A high relapse incidence (4 of 6) was observed among patients with myxopapillary ependymoma., Conclusions: Gross-total resection is the mainstay of treatment for patients with primary spinal cord ependymoma and may be achieved in about 50% of the patients using modern surgical techniques. Primary adjuvant treatment was commonly used in children with spinal cord ependymoma irrespective of the extent of resection or tumor grade. The impact of adjuvant treatment on progression-free and overall survival has to be investigated in a prospective trial.

Background: To investigate the neuropsychological outcome of children treated with surgery and posterior fossa irradiation for localized infratentorial ependymoma., Methods: 23 patients (age 0.3 - 14 years at diagnosis) who were treated with local posterior fossa irradiation (54 Gy) underwent one (4 patients) or sequential (19 patients) neuropsychologic evaluation. The last evaluation was performed at a median of 4.5 (1 to 15.5) years after RT., Results: Mean last full scale IQ (FSIQ), verbal IQ (VIQ) and PIQ were 89.1, 94.0, and 86.2 respectively. All patients had difficulties with reading, and individual patients showed deficits in visuospatial, memory and attentional tasks. There was no trend for deterioration of intellectual outcome over time. All 5 children with IQ scores < or = 75 were under the age of four at diagnosis. There was a significant association between the presence of cerebellar deficits and impaired IQ (72.0 vs 95.2, p < 0,001). The absence of hydrocephalus was an indicator of better neuropsychologic outcome (mean FSIQ of 102.6 vs 83.9, p = 0.025)., Conclusion: Within the evaluated cohort, intellectual functions were moderately impaired. Markedly reduced IQ scores were only seen with early disease manifestation and treatment, and postoperative neurological deficits had a strong impact on intellectual outcome.