In the latest version of the World Health Organization Classification (WHO) of Central Nervous System Tumors, the terminology "medulloepithelioma" has disappeared as a distinct tumor type in favor of "embryonal tumor with multilayered rosettes (ETMR)", characterized by frequent alterations of C19MC. However, medulloepithelioma persists in the current WHO classification of eye tumors, where two variants exist (teratoid and non-teratoid), harboring frequent DICER1 mutations. DNA-methylation profiling has demonstrated that ETMR and intraocular medulloepitheliomas represented two distinct methylation classes. Outside the CNS and the eye, exceptional observations of medulloepitheliomas have been reported, most of them before the genetic and epigenetic eras. Herein, we report a pediatric case of a presacral tumor classified as a teratoid medulloepithelioma with genetic and epigenetic charaterizations. Using DNA-methylation profiling analysis, the tumor was classified between ETMR, non C19MC-altered, and intra-ocular medulloepithelioma, arguing for a potential distinct cell origin, not represented in the current epigenetic classifiers.

Diffuse intrinsic pontine glioma (DIPG) is the pediatric tumor with the worst prognosis. BIOMEDE was a randomized phase 2 trial comparing the efficacy in terms of overall survival (OS) (primary endpoint) of epidermal growth factor receptor (EGFR) inhibitor erlotinib, mTOR inhibitor everolimus and multitargeted tyrosine kinase inhibitor dasatinib in combination with radiotherapy in patients with a biopsy-proven DIPG. Tumors were assessed centrally for immunohistochemical biomarkers (EGFR overexpression or PTEN loss) together with whole-exome and RNA sequencing. A cohort of 66 children with the same inclusion criteria and treated previously with temozolomide-based regimen was used to compare outcome. Treatment allocation was performed by randomization in 233 patients, designed so that a drug could not be allocated if the corresponding biomarker was absent: 36 received erlotinib, 102 received dasatinib and 95 received everolimus. The trial was ended for futility of the primary endpoint following the recommendations of the independent data monitoring committee: OS from biopsy was not different from the control cohort (median OS = 10.8 months (95% confidence interval (CI): 9.5-13.0)) in any of the three arms (median OS = 9.7 months (95% CI: 7.8-14.6) for erlotinib; 9.9 months (95% CI: 8.8-11.2) for dasatinib; and 11.9 months (95% CI: 10.7-14.2) for everolimus). Everolimus showed significantly less ocular, renal, skin and gastrointestinal side effects and treatment discontinuation for toxicity (secondary endpoint). TP53 mutations, frequently linked to multiple structural chromosomal aberrations, were the strongest predictor for poor survival in multivariate analysis (hazard ratio = 2.8 (95% CI: 1.9-4.2), P < 0.0001). Both mutations in and activation of the mTOR pathway were associated with a better response to everolimus. Four long-term survivors treated with an mTOR inhibitor were alive free of treatment over 6 years from diagnosis. With comprehensive tumor profiling, BIOMEDE validated prognostic biomarkers as well as informative theranostic biomarkers for future trials. ClinicalTrials.gov: NCT02233049 .

Adamantinomatous craniopharyngioma (ACP) is a benign epithelial tumor classically diagnosed in childhood and only exceptionally during fetal life. We report a case of prenatally diagnosed ACP at 30 weeks of gestation (WG). Routine third-trimester ultrasound (US) revealed a midline suprasellar brain mass with mixed, solid, and cystic components with calcifications. Fetal MRI confirmed the initial findings, suggesting the differential diagnosis of either teratoma or craniopharyngioma. The parents opted for a medical termination of pregnancy, performed under the current French ethics law at 31WG. Fetopathological examination demonstrated an isolated suprasellar tumor. Histopathology was consistent with the diagnosis of adamantinomatous craniopharyngioma. Including the present contribution, fewer than 20 prenatal diagnoses of craniopharyngioma have been reported so far. Notably, all fetal cases correspond to the adamantinomatous subtype and share similar radiological and histological features. This observation enhances the concept that the full morphological phenotype of ACP is already established during fetal life. Despite its benign nature, ACP may lead to severe long-term visual, endocrine, and neurodevelopmental morbidity. This case contributes to the better understanding of fetal ACP and highlights the importance of accurate prenatal diagnosis and fetopathological examination for establishing its diagnosis.

BACKGROUND AND OBJECTIVES:Subependymal giant cell astrocytomas (SEGA) are low-grade intraventricular tumors generally associated with tuberous sclerosis complex. Although mechanistic target of rapamycin inhibitors are recommended as first-line therapy for progressive SEGA without hydrocephalus, surgery is still relevant because 40% of patients are drug resistant. This study aimed to evaluate surgical outcomes in terms of tumor control, complication rates, and ventriculoperitoneal shunt (VPS) requirement, through a single-center retrospective series and a meta-analysis. METHODS:We retrospectively analyzed 31 pediatric SEGA resections performed over 2 decades at a tertiary care center. Clinical, radiological, and surgical variables were examined to identify predictors of outcome. In addition, a systematic literature review and meta-analysis were conducted to contextualize our findings. RESULTS:Gross total resection was achieved in 64.5% of cases, with a 19.3% rate of transient postoperative complications and a 6.4% incidence of VPS placement. No permanent morbidity or mortality occurred. Favorable outcome was associated with a smaller tumor volume and absence of preoperative hydrocephalus. The meta-analysis confirmed that preoperative hydrocephalus was the main predictor of postoperative complications (odds ratio 2.30) and shunt dependence (odds ratio 3.45). Five-year progression-free survival was 90.9% in the gross total resection subgroup and 100% in patients with unilateral tumors. Bilateral tumor location was an independent predictor of recurrence (hazard ratio = 17.79, P = .02). CONCLUSION:Microsurgical resection of SEGA is a safe and effective therapeutic option, particularly in patients without hydrocephalus. Early surgical intervention may reduce the need for VPS and long-term complications, offering a valid alternative or complement to mechanistic target of rapamycin inhibitor therapy, with durable tumor control especially in unilateral cases.

EGFR gene amplification constitutes a diagnostic hallmark for glioblastoma, IDH-wildtype (GB, IDH-WT). Herein, we demonstrated that EGFR IHC is a highly specific and sensitive biomarker for identifying EGFR amplification and should be part of the neuropathologist's routine panel of antibodies.

BACKGROUND:Astroblastomas are rare brain tumors predominantly affecting children and young adults, for which molecular subtypes and clinical management remain undefined. METHODS:We analyzed tumor samples, molecular profiles, and clinical data from 200 patients, classified as "Astroblastoma, MN1-altered" under WHO criteria, using DNA methylation profiling, DNA/RNA profiling/sequencing, and survival analyses. RESULTS:DNA methylation analyses identified 3 groups: Group A (n = 143, characterized by MN1::BEND2 fusions, predominantly supratentorial location, with striking female predominance and favorable survival); Group B (n = 37, epigenetically and transcriptionally closely related to Group A, but characterized by EWSR1::BEND2 fusions, with spinal and infratentorial locations and poor prognosis); and Group C (n = 20, epigenetically and transcriptionally distinct, characterized by MN1::CXXC5 fusions, exclusively supratentorially located, with favorable survival). Progression-free and overall survival were significantly shorter in Group B (5-year PFS 14%; 10-year OS 54%) compared to A (5-year PFS 47%; 10-year OS 89%) and C (5-year PFS 75%; 10-year OS 89%). Radiotherapy improved PFS in Group B (hazard ratio 0.25), while no clear benefit was identified for Groups A and C. CONCLUSIONS:Astroblastoma, MN1-altered, comprises 3 molecularly and clinically distinct groups, characterized by different fusion genes, including those without MN1. These new insights, including the identification of potential predictive biomarkers like 14q/16q loss, provide a framework for the development of risk-stratified therapeutic approaches. Importantly, we identified a molecularly defined high-risk group that benefits from radiation therapy. Our findings redefine Astroblastoma as a molecularly diverse tumor type, propose a refined classification, support the development of risk-adapted therapeutic strategies and provide a rational standard of care.

Abstract Background Approximately 12,000 adolescents and young adults (ages 15-39, AYAs) are diagnosed with a primary central nervous system (CNS) tumor each year. DNA methylation profiling has transformed CNS tumor classification by refining diagnostic accuracy and identifying biologically distinct subtypes, but its application has not been systematically evaluated in the AYA population. In this study, we examined the spectrum of CNS tumor types across age groups, with a focus on the AYA population. Methods We assembled a large dataset of CNS tumor samples with age annotations and methylation profiles matching with high confidence to a CNS tumor type using the NCI/Bethesda classifier. Prevalence of tumor type, methylation class and DNA copy number aberrations were compared across age strata (pediatric, AYA and adult). Results The cohort of 21,099 CNS tumors included 5139 tumors from AYAs (24%), which showed a mixed pattern, with tumors typical of childhood (e.g. medulloblastoma) as well as those common in older adults (e.g. glioblastoma). Several tumor types were specifically enriched in the AYA, including IDH-mutant astrocytoma, pleomorphic xanthoastrocytoma, posterior fossa group B ependymoma, and diffuse hemispheric glioma, H3 G34-mutant, among others. Distinct methylation subclasses of multiple tumor types were observed in the AYA, and patterns of genomic aberrations showed age-specific distributions. Conclusion Large-scale methylation profiling revealed unique classification patterns of CNS tumors in AYAs, with specific tumor types, subclasses, and genomic alterations enriched in this population. These data may serve as a valuable reference resource for better understanding the spectrum of CNS tumors affecting AYA patients.

Central nervous system (CNS)-type tumors may occur in the ovary, often associated with a mature teratomatous component. Because of their rarity, little is known about the tumor types historically designated within the primitive neuroectodermal tumors (PNET) terminology and whether they share histopathological and molecular features akin to those of their CNS counterparts. Herein, we retrospectively investigated data from 13 ovarian tumors, initially diagnosed as either “PNETs” or CNS-type neoplasms. For each tumor we performed comprehensive histopathologic, genetic and epigenetic analyses and retrieved clinical data when available. Integrated diagnoses were established after a central review of histopathological and molecular data, the following entities were identified: four embryonal tumors with multilayered rosettes (non C19MC-altered), three medulloblastomas, SHH-activated, three ependymomas not elsewhere classified, one Ewing sarcoma, one sarcoma, DICER1-mutant, and one peripheral neuroblastoma. Interestingly, none of the ETMRs harbored a C19MC amplification or DICER1 mutation. The three medulloblastomas, SHH-activated were histopathologically and molecularly similar to their CNS counterparts. Ependymomas did not show any classifying molecular alteration and presented a distinct epigenetic profile when compared with CNS ependymomas. These results indicate that ovarian “PNETs” comprise a heterogeneous spectrum of CNS and extra-CNS embryonal or non-embryonal tumor types, and that brain tumor methylation classifiers may be used to classify these tumors. Moreover, these components are characterized by distinct molecular alterations from primary CNS tumors, without C19MC alterations for ETMRs, with an overrepresented SHH-subgroup for medulloblastomas, and with an epigenetic profile distinct from CNS counterparts in ovarian ependymomas. These data need to be confirmed before they can be incorporated into future patient personalized treatment.

BACKGROUND:Approximately 12 000 adolescents and young adults (ages 15-39, AYAs) are diagnosed with a primary central nervous system (CNS) tumor each year. DNA methylation profiling has transformed CNS tumor classification by refining diagnostic accuracy and identifying biologically distinct subtypes, but its application has not been systematically evaluated in the AYA population. In this study, we examined the spectrum of CNS tumor types across age groups, with a focus on the AYA population. METHODS:We assembled a large dataset of CNS tumor samples with age annotations and methylation profiles matching with high confidence to a CNS tumor type using the NCI/Bethesda classifier. Prevalence of tumor type, methylation class and DNA copy number aberrations were compared across age strata (pediatric, AYA, and adult). RESULTS:The cohort of 21 712 CNS tumors included 5351 tumors from AYAs (25%), which showed a mixed pattern, with tumors typical of childhood (eg, medulloblastoma) as well as those common in older adults (eg, glioblastoma). Several tumor types were specifically enriched in the AYA, including IDH-mutant astrocytoma, pleomorphic xanthoastrocytoma, posterior fossa group B ependymoma, and diffuse hemispheric glioma, H3 G34-mutant, among others. Distinct methylation subclasses of multiple tumor types were observed in the AYA, and patterns of genomic aberrations showed age-specific distributions. CONCLUSION:Large-scale methylation profiling revealed unique classification patterns of CNS tumors in AYAs, with specific tumor types, subclasses, and genomic alterations enriched in this population. These data may serve as a valuable reference resource for better understanding the spectrum of CNS tumors affecting AYA patients.

Molecular testing is essential for classifying central nervous system (CNS) tumors, with methylation profiling providing the highest diagnostic granularity. However, this requires more resources and time than conventional hematoxylin and eosin (H&E) histopathology, which is widely available globally. Here we propose Hetairos, an artificial intelligence algorithm that predicts 102 methylation-based CNS tumor subtypes from digital H&E slides. Built and validated on 9,606 patients and over 11,000 slides from 11 centers across four continents, Hetairos identified 50-70% of cases with high confidence, achieving an accuracy of 0.87 for its highest-rated predictions. Hetairos outperformed five board-certified neuropathologists in a direct histology-only comparison (0.68 versus 0.30). Prospective evaluation in routine diagnostics confirmed its performance, reducing turnaround time from 12 days (molecular testing) to 12 min. Hetairos supports diagnostic decision-making across the full spectrum of pediatric and adult CNS tumors by narrowing differential diagnoses and guiding efficient testing.

PDGFRA gene amplification is now recognized as a diagnostically and prognostically relevant molecular alteration in central nervous system tumors. Herein, we demonstrated that PDGFRA immunohistochemistry is a highly specific and sensitive biomarker for identifying PDGFRA amplification and should be part of the neuropathologist's routine panel of antibodies.

Tumours historically classified as extraventricular neurocytoma (EVN), initially in comparison with central neurocytoma, are defined by location and morphology; however, emerging molecular data demonstrate that this term is outdated. We report 14 previously unpublished tumours with a robust EVN DNA methylation profile, independent of original histopathologic diagnosis or anatomic location. Integrated molecular analyses identified FGFR1 alterations, particularly FGFR1::TACC1 fusions, as the predominant molecular driver of this tumour class. A smaller number of tumours harboured FGFR1 hotspot mutations (p.N546K and p.K656E). Among these, two cases additionally showed NF1 variants, and one tumour carried a PIK3CA mutation (p.H1047L). In addition, a single case exhibited an NTRK2 fusion. Histologically, tumours exhibited neurocytic differentiation with neuropil islands and a minor glial component, while immunohistochemistry showed frequent OLIG2 expression, contrasting with the typical immunophenotype of central neurocytoma. Notably, tumours with an EVN DNA methylation profile were identified in both extraventricular and intraventricular locations, demonstrating that anatomy-based definitions are inadequate for this tumour type. Clinical follow-up (median 33.2 months) showed predominantly lower grade behaviour, with occasional recurrence. Collectively, these findings support the view that tumours previously labelled as EVN do not represent a direct counterpart of central neurocytoma but instead constitute a molecularly and epigenetically distinct glioneuronal tumour type. We propose the designation glioneuronal tumour with neurocytic differentiation (GNTN) to reflect its biological identity and to align the terminology with contemporary molecular neuropathology, and recommend DNA methylation profiling as an essential diagnostic criterion.

Over the past decade, advances in brainstem biopsies and the discovery of the histone H3 mutation have revealed a new spectrum of brainstem tumors. In the brainstem, diffuse midline gliomas (DMGs) are most common in the pediatric population, followed by less aggressive tumors like pilocytic astrocytomas. The 2016 WHO central nervous system (CNS) classification introduced diagnostic criteria for DMGs, which have since evolved into five subtypes. These new subtypes present challenges for histomolecular diagnosis in biopsies. Recent data suggest these subtypes differ in clinical outcomes and prognosis, and most likely will require different therapies highlighting the need for tissue for diagnostic purposes for brainstem lesions. This chapter will first cover an overview of different brainstem pathologies, followed by a discussion on imaging, treatment standards, and the evolving role of biopsies in DMG including diffuse intrinsic pontine gliomas.

Medulloblastoma, the most common malignant brain tumor of childhood, exhibits significant biological complexity that demands deeper exploration. Here, we present a large multiomics dataset integrating data from 384 primary medulloblastoma patient samples across five omic layers: CpG methylome, transcriptome, proteome, phosphoproteome, and metabolome, paired with associated clinical metadata. Data integration revealed intertumoral heterogeneity of lipid metabolism across proteomic subtypes. Notably, while the MYC-FASN-SCD axis drives lipid biosynthesis, pathway inhibition elicits a compensatory escape mechanism in vivo through exogenous fatty acid uptake. Unexpectedly, we demonstrated that MYC triggers lipid storage, creating a unique dependency on lipid droplet-mitochondria communications to sustain tumor maintenance in vivo. Together, this comprehensive analysis reveals a targetable vulnerability downstream of MYC that constitutes a promising therapeutic approach to treat currently untreatable medulloblastoma subtypes.

Meningiomas in pediatric and adolescent/young adult patients are poorly characterized biologically and clinically, and risk stratification is largely extrapolated from adult tumors. We analyze 293 tumors from patients aged 0-39 years using integrated histopathological and molecular profiling. Youth-onset meningiomas are enriched for NF2 and SMARCE1 alterations and exhibit a gain-dominated copy-number landscape, including recurrent chr17q gain, whereas canonical adult high-risk features, such as chr1p loss, lack prognostic significance. Adult-derived prognostic frameworks, including WHO grade, methylation-based stratification and integrated risk scores, fail to predict progression in patients ≤21 years of age. Tumors segregate into age-enriched epigenetic clusters defined by SMARCE1, NF2 and BAP1 alterations. Among NF2-altered tumors, patterns of Merlin inactivation, shaped by germline status and co-occurring copy-number variations, delineate biologically divergent subsets. In patients ≤21 years, extent of resection is the dominant predictor of outcome, while molecular features further refine risk assessment. These findings define pediatric and young adult meningiomas as a distinct molecular entity and support age-adapted risk refinement that integrates molecular features with strong clinical determinants.

Two new cases of low-grade diffusely infiltrative tumour (LGDIT), SMARCB1 mutant, are described in an 18-year-old and a 50-year-old male, both with supratentorial lesions, characteristic rhabdoid histology on a myxoid-collagenous background, and complete INI1 loss. Both tumours showed homozygous SMARCB1 deletion and clustered with previously reported LGDIT on t-SNE analysis, in proximity to ATRT-MYC. These observations reinforce the distinct clinicopathological profile of LGDIT and support its consideration as a provisional CNS tumour type.

BACKGROUND:Central nervous system (CNS) tumors are the second most common type of cancer in children. Their apparent rise in incidence represents a potential public health concern, as it could reflect increased exposure to environmental risk factors unless the trend is primarily driven by changes in classification systems or diagnostic practices. METHODS:This study included 10,074 children aged 0-14 years diagnosed with a primary CNS tumor between 2000 and 2020 in the French National Childhood Cancer Registry. CNS tumors were reclassified according to the fifth edition of the World Health Organization Classification. Joinpoint regression analysis was used to estimate annual changes in incidence. RESULTS:The annual age-standardized incidence rate (ASR) of CNS tumors was 42.1 per million. From 2000-2020, the incidence increased by an average of 0.93% per year [95%CI: + 0.50;+ 1.38], rising from 38.3 to 46.2 cases per million. This upward trend affected both sexes and was particularly evident among children aged 10-14 years. The most marked increases were observed for optic pathway gliomas (+2.15% annually), atypical teratoid/rhabdoid tumors (ATRT, +2.32%), pituitary adenomas (+1.28%), and malignant mesenchymal tumors (+6.53%). The fluctuating incidence of gangliogliomas and glioblastomas largely reflected reclassification within the glial tumor categories. CONCLUSIONS:Most of the observed variations appear to result from improved diagnostic practices in at-risk children (optic pathway gliomas), more accurate tumor categorization (mesenchymal tumors), or enhanced case registration (pituitary adenomas). Only ATRTs show evidence of a true increase in incidence, as diagnostic criteria have remained relatively stable over the past 20 years.''.