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A novel methylation class, "neuroepithelial tumor, with PLAGL1 fusion" (NET-PLAGL1), has recently been described, based on epigenetic features, as a supratentorial pediatric brain tumor with recurrent histopathological features suggesting an ependymal differentiation. Because of the recent identification of this neoplastic entity, few histopathological, radiological and clinical data are available. Herein, we present a detailed series of nine cases of PLAGL1-fused supratentorial tumors, reclassified from a series of supratentorial ependymomas, non-ZFTA/non-YAP1 fusion-positive and subependymomas of the young. This study included extensive clinical, radiological, histopathological, ultrastructural, immunohistochemical, genetic and epigenetic (DNA methylation profiling) data for characterization. An important aim of this work was to evaluate the sensitivity and specificity of a novel fluorescent in situ hybridization (FISH) targeting the PLAGL1 gene. Using histopathology, immunohistochemistry and electron microscopy, we confirmed the ependymal differentiation of this new neoplastic entity. Indeed, the cases histopathologically presented as "mixed subependymomas-ependymomas" with well-circumscribed tumors exhibiting a diffuse immunoreactivity for GFAP, without expression of Olig2 or SOX10. Ultrastructurally, they also harbored features reminiscent of ependymal differentiation, such as cilia. Different gene partners were fused with PLAGL1: FOXO1, EWSR1 and for the first time MAML2. The PLAGL1 FISH presented a 100% sensitivity and specificity according to RNA sequencing and DNA methylation profiling results. This cohort of supratentorial PLAGL1-fused tumors highlights: 1/ the ependymal cell origin of this new neoplastic entity; 2/ benefit of looking for a PLAGL1 fusion in supratentorial cases of non-ZFTA/non-YAP1 ependymomas; and 3/ the usefulness of PLAGL1 FISH., (© 2024. The Author(s).)

Aims: The SOX10 transcription factor is important for the maturation of oligodendrocytes involved in central nervous system (CNS) myelination. Currently, very little information exists about its expression and potential use in CNS tumour diagnoses. The aim of our study was to characterize the expression of SOX10 in a large cohort of CNS tumours and to evaluate its potential use as a biomarker., Methods: We performed immunohistochemistry (IHC) for SOX10 and OLIG2 in a series of 683 cases of adult- and paediatric-type CNS tumours from different subtypes. The nuclear immunostaining results for SOX10 and OLIG2 were scored as positive (≥10% positive tumour cells) or negative., Results: OLIG2 and SOX10 were positive in diffuse midline gliomas (DMG), H3-mutant, and EZHIP-overexpressed. However, in all DMG, EGFR-mutant, SOX10 was constantly negative. In diffuse paediatric-type high-grade gliomas (HGG), all RTK1 cases were positive for both OLIG2 and SOX10. RTK2 cases were all negative for both OLIG2 and SOX10. MYCN cases variably expressed OLIG2 and were all immunonegative for SOX10. In glioblastoma, IDH-wildtype, OLIG2 was mostly positive, but SOX10 was variably expressed, depending on the epigenetic subtype. All circumscribed astrocytic gliomas were positive for both OLIG2 and SOX10 except pleomorphic xanthoastrocytomas, astroblastomas, MN1-altered, and subependymal giant cell astrocytomas. SOX10 was negative in ependymomas, meningiomas, pinealoblastomas, choroid plexus tumours, intracranial Ewing sarcomas, and embryonal tumours except neuroblastoma, FOXR2-activated., Conclusion: To conclude, SOX10 can be incorporated into the IHC panel routinely used by neuropathologists in the diagnostic algorithm of embryonal tumours and for the subtyping of paediatric and adult-type HGG., (© 2024 The Authors. Histopathology published by John Wiley & Sons Ltd.)

Pilocytic astrocytomas (PA) typically exhibit distinct clinical, radiological, histopathological, and genetic features. DNA-methylation profiling distinguishes PA according to their location (infratentorial, midline, hemispheric, or spinal). In the hemispheric location, distinguishing PA from glioneuronal tumors remains a common diagnostic challenge for neuropathologists. Furthermore, the current version of the DKFZ classifier seems to have difficulty separating them from gangliogliomas. In this study, after central radiological review, we identified a histopathologically defined set of PA (histPA, n = 11) and a cohort of DNA-methylation defined PA (mcPA, n = 11). Nine out of the 11 histPA matched the methylation class of hemispheric PA, whereas 2 cases were classified at the end of the study as dysembryoplastic neuroepithelial tumors. Similarly, the mcPA cohort contained tumors mainly classified as PA (7/11), but 4 cases were classified as glioneuronal. The analysis of the 16 tumors with an integrated diagnosis of PA revealed that they affect mainly children with a wide spectrum of radiological, histopathological (i.e. a predominantly diffuse growth pattern), and genetic characteristics (large range of mitogen-activated protein kinase alterations). Based on these results, we consider hemispheric PA to be different from their counterparts in other locations and to overlap with other glioneuronal tumors, reinforcing the necessity of interpreting all data to obtain an accurate diagnosis., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Association of Neuropathologists, Inc. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Erythroblastic sarcoma (ES) (previously called chloroma or granulocytic sarcoma) are rare hematological neoplams characterized by the proliferation of myeloid blasts at extramedullary sites, and primarily involve the skin and soft tissue of middle-aged adults. ES may be concomitant with or secondary to myeloid neoplasms (mostly acute myeloid leukemia (AML)) or in isolated cases (de novo) without infiltration of the bone marrow by blasts. ES share cytogenetic and molecular abnormalities with AML, including RUNX1T1 fusions. Some of these alterations seem to be correlated with particular sites of involvement. Herein, we report an isolated erythroblastic sarcoma with NFIA::RUNX1T1 located in the central nervous system (CNS) of a 3-year-old boy. Recently, two pediatric cases of CNS MS with complete molecular characterization have been documented. Like the current case, they concerned infants (2 and 3 years-old) presenting a brain tumor (pineal involvement) with leptomeningeal dissemination. Both cases also harbored a NFIA::RUNX1T3 fusion. ES constitutes a diagnostic challenge for neuropathologists because it does not express differentiation markers such as CD45, and may express CD99 which could be confused with CNS Ewing sarcoma. CD43 is the earliest pan-hematopoietic marker and CD45 is not expressed by erythroid lineage cells. E-cadherin (also a marker of erythroid precursors) and CD117 (expressed on the surface of erythroid lineage cells) constitute other immunhistochemical hallmarks of ES. The prognosis of patients with ES is similar to that of other patients with AML but de novo forms seem to have a poorer prognosis, like the current case. To conclude, pediatric ES with NFIA::RUNX1T1/3 fusions seem to have a tropism for the CNS and thus constitute a potential pitfall for neuropathologists. Due to the absence of circulating blasts and a DNA-methylation signature, the diagnosis must currently be made by highlighting the translocation and expression of erythroid markers., (© 2023. The Author(s).)

Diffuse midline gliomas (DMG) H3 K27-altered are incurable grade 4 gliomas and represent a major challenge in neuro-oncology. This tumour type is now classified in four subtypes by the 2021 edition of the WHO Classification of the Central Nervous System (CNS) tumours. However, the H3.3-K27M subgroup still appears clinically and molecularly heterogeneous. Recent publications reported that rare patients presenting a co-occurrence of H3.3K27M with BRAF or FGFR1 alterations tended to have a better prognosis. To better study the role of these co-driver alterations, we assembled a large paediatric and adult cohort of 29 tumours H3K27-altered with co-occurring activating mutation in BRAF or FGFR1 as well as 31 previous cases from the literature. We performed a comprehensive histological, radiological, genomic, transcriptomic and DNA methylation analysis. Interestingly, unsupervised t-distributed Stochastic Neighbour Embedding (tSNE) analysis of DNA methylation profiles regrouped BRAF V600E and all but one FGFR1 MUT DMG in a unique methylation cluster, distinct from the other DMG subgroups and also from ganglioglioma (GG) or high-grade astrocytoma with piloid features (HGAP). This new DMG subtype harbours atypical radiological and histopathological profiles with calcification and/or a solid tumour component both for BRAF V600E and FGFR1 MUT cases. The analyses of a H3.3-K27M BRAF V600E tumour at diagnosis and corresponding in vitro cellular model showed that mutation in H3-3A was the first event in the oncogenesis. Contrary to other DMG, these tumours occur more frequently in the thalamus (70% for BRAF V600E and 58% for FGFR1 MUT ) and patients have a longer overall survival with a median above three years. In conclusion, DMG, H3 K27 and BRAF/FGFR1 co-altered represent a new subtype of DMG with distinct genotype/phenotype characteristics, which deserve further attention with respect to trial interpretation and patient management., (© 2023. The Author(s).)

The fifth edition of the World Health Organization (WHO) Classification of Tumors of the Central Nervous System has identified many new tumor types and has established, for the first time, essential and desirable diagnostic criteria for each of them. Among these, genetic alterations play an important role associated with morphology. For the first time, epigenetic data can also constitute essential and/or desirable criteria. These genetic abnormalities can be fusions, deletions or gains/amplifications and can thus be detected by fluorescence in situ hybridization techniques. The purpose of this article is to present the advantages and limitations of this technique in reference to its specific use within neuro-oncopathology in light of the 2021 WHO classification., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Recent epigenomic analyses have revealed the existence of a new DNA methylation class (MC) of infant-type hemispheric glioma (IHG). Like desmoplastic infantile ganglioglioma/astrocytoma (DIG/DIA), these tumors mainly affect infants and are supratentorial. While DIG/DIA is characterized by BRAF or RAF1 alterations, IHG has been shown to have receptor tyrosine kinase (RTK) gene fusions (ALK, ROS1, NTRK1/2/3, and MET). However, in this rapidly evolving field, a more comprehensive analysis of infantile glial/glioneuronal tumors including clinical, radiological, histopathological, and molecular data is needed. Here, we retrospectively investigated data from 30 infantile glial/glioneuronal tumors, consecutively compiled from our center. They were analyzed by two experienced pediatric neuroradiologists in consensus, without former knowledge of the molecular data. We also performed a comprehensive clinical, and histopathological examination (including molecular evaluation by next-generation sequencing, RNA sequencing, and fluorescence in situ hybridization [FISH] analyses), as well as DNA methylation profiling for the samples having sufficient material available. The integrative histopathological, genetic, and epigenetic analyses, including t-distributed stochastic neighbor embedding (t-SNE) analyses segregated tumors into 10 DIG/DIA (33.3%), six IHG (20.0%), three gangliogliomas (10.0%), two pleomorphic xanthoastrocytomas (6.7%), two pilocytic astrocytomas (6.7%), two supratentorial ependymomas, ZFTA fusion-positive (6.7%), two supratentorial ependymomas, YAP1 fusion-positive (6.7%), two embryonal tumors with PLAGL2-family amplification (6.7%), and one diffuse low-grade glioma, MAPK-pathway altered. This study highlights the significant differential features, in terms of histopathology (leptomeningeal infiltration, intense desmoplasia and ganglion cells in DIG/DIA and necrosis, microvascular proliferation, and siderophages in IHG), and radiology between DIG/DIA and IHG. Moreover, these results are consistent with the literature data concerning the molecular dichotomy (BRAF/RAF1 alterations vs. RTK genes' fusions) between DIG/DIA and IHG. This study characterized histopathologically and radiologically two additional cases of the novel embryonal tumor characterized by PLAGL2 gene amplification., (© 2023 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.)

Glioneuronal tumors are a heterogenous group of CNS neoplasms that can be challenging to accurately diagnose. Molecular methods are highly useful in classifying these tumors-distinguishing precise classes from their histological mimics and identifying previously unrecognized types of tumors. Using an unsupervised visualization approach of DNA methylation data, we identified a novel group of tumors (n = 20) that formed a cluster separate from all established CNS tumor types. Molecular analyses revealed ATRX alterations (in 16/16 cases by DNA sequencing and/or immunohistochemistry) as well as potentially targetable gene fusions involving receptor tyrosine-kinases (RTK; mostly NTRK1-3) in all of these tumors (16/16; 100%). In addition, copy number profiling showed homozygous deletions of CDKN2A/B in 55% of cases. Histological and immunohistochemical investigations revealed glioneuronal tumors with isomorphic, round and often condensed nuclei, perinuclear clearing, high mitotic activity and microvascular proliferation. Tumors were mainly located supratentorially (84%) and occurred in patients with a median age of 19 years. Survival data were limited (n = 18) but point towards a more aggressive biology as compared to other glioneuronal tumors (median progression-free survival 12.5 months). Given their molecular characteristics in addition to anaplastic features, we suggest the term glioneuronal tumor with ATRX alteration, kinase fusion and anaplastic features (GTAKA) to describe these tumors. In summary, our findings highlight a novel type of glioneuronal tumor driven by different RTK fusions accompanied by recurrent alterations in ATRX and homozygous deletions of CDKN2A/B. Targeted approaches such as NTRK inhibition might represent a therapeutic option for patients suffering from these tumors., (© 2023. The Author(s).)

The Central Nervous System (CNS) tumor with BCOR internal tandem duplication (ITD) has recently been added as a novel embryonal histomolecular tumor type to the 2021 World Health Organization (WHO) Classification of CNS Tumors. In addition, other CNS tumors harboring a BCOR/BCORL1 fusion, which are defined by a distinct DNA-methylation profile, have been recently identified in the literature but clinical, radiological and histopathological data remain scarce. Herein, we present two adult cases of CNS tumors with EP300::BCOR fusion. These two cases presented radiological, histopathological, and immunohistochemical homologies with CNS tumors having BCOR ITD in children. To compare these tumors with different BCOR alterations, we performed a literature review with a meta-analysis. CNS tumors with EP300::BCOR fusion seem to be distinct from their BCOR ITD counterparts in terms of age, location, progression-free survival, tumor growth pattern, and immunopositivity for the BCOR protein. CNS tumors from the EP300::BCOR fusion methylation class in adults may be added to the future WHO classification., (© 2023. The Author(s).)

The fifth edition of the World Health Organization Classification of Tumors of the Central Nervous System (CNS) now includes mesenchymal tumors that occur uniquely or frequently in the CNS. Moreover, this version has aligned the terminology of mesenchymal tumors with their soft tissue counterparts. New tumor types have been added, such as the "intracranial mesenchymal tumor, FET-CREB fusion-positive", the "CIC-rearranged sarcoma", and the "Primary intracranial sarcoma, DICER1-mutant". Other entities (such as rhabdomyosarcoma) have remained in the current WHO classification because these tumor types may present specificities in the CNS as compared to their soft tissue counterparts. Based on an extensive literature review, herein, we will discuss these newly recognized entities in terms of clinical observation, radiology, histopathology, genetics and outcome, and consider strategies for an accurate diagnosis. In light of this literature analysis, we will also introduce some potentially novel tumor types., (© 2023. The Author(s).)

Pediatric spinal low-grade glioma (LGG) and glioneuronal tumours are rare, accounting for less 2.8-5.2% of pediatric LGG. New tumour types frequently found in spinal location such as diffuse leptomeningeal glioneuronal tumours (DLGNT) have been added to the World Health Organization (WHO) classification of tumours of the central nervous system since 2016, but their distinction from others gliomas and particularly from pilocytic astrocytoma (PA) are poorly defined. Most large studies on this subject were published before the era of the molecular diagnosis and did not address the differential diagnosis between PAs and DLGNTs in this peculiar location. Our study retrospectively examined a cohort of 28 children with LGGs and glioneuronal intramedullary tumours using detailed radiological, clinico-pathological and molecular analysis. 25% of spinal PAs were reclassified as DLGNTs. PA and DLGNT are nearly indistinguishable in histopathology or neuroradiology. 83% of spinal DLGNTs presented first without leptomeningeal contrast enhancement. Unsupervised t-distributed stochastic neighbor embedding (t-SNE) analysis of DNA methylation profiles showed that spinal PAs formed a unique methylation cluster distinct from reference midline and posterior fossa PAs, whereas spinal DLGNTs clustered with reference DLGNT cohort. FGFR1 alterations were found in 36% of spinal tumours and were restricted to PAs. Spinal PAs affected significantly younger patients (median age 2 years old) than DLGNTs (median age 8.2 years old). Progression-free survival was similar among the two groups. In this location, histopathology and radiology are of limited interest, but molecular data (methyloma, 1p and FGFR1 status) represent important tools differentiating these two mitogen-activated protein kinase (MAPK) altered tumour types, PA and DLGNT. Thus, these molecular alterations should systematically be explored in this type of tumour in a spinal location., (© 2022. The Author(s).)

Rapid technical advances in molecular biology allowed for the identification of key genetic alterations in central nervous system (CNS) tumors. Our ever-expanding knowledge of brain tumor genetics and the development of new technologies, such as DNA-methylation profiling, required an update of the 2016 fourth edition of the WHO classification of CNS tumors. Updates were regularly published by the Consortium to Inform Molecular Practical Approaches to CNS Tumor Taxonomy-Not Official WHO (c-IMPACT-NOW) until the publication of the fifth edition of the WHO classification of CNS tumors in 2021. In that edition, new types and subtypes are introduced and criteria for histo-molecular diagnostic and grading are refined, especially for diffuse gliomas. The definition of a broad category "diffuse glioma, pediatric subtype" (low or high grade) is a major improvement of the classification. Moreover, the nomenclature was simplified and aligned with that of other blue books. The 2021 edition truly advances the role of molecular diagnostics in CNS tumor classification. Methyloma profiling may become a cornerstone of CNS tumor diagnostic. The new WHO classification will lead to better management of brain tumor patients., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Aim: Rosette-forming glioneuronal tumour (RGNT) is a rare central nervous system (CNS) World Health Organization (WHO) grade 1 brain neoplasm. According to the WHO 2021, essential diagnostic criteria are a 'biphasic histomorphology with neurocytic and a glial component, and uniform neurocytes forming rosettes and/or perivascular pseudorosettes associated with synaptophysin expression' and/or DNA methylation profile of RGNT whereas 'FGFR1 mutation with co-occurring PIK3CA and/or NF1 mutation' are desirable criteria., Material and Methods: We report a series of 46 cases fulfilling the essential pathological diagnostic criteria for RGNT. FGFR1 and PIK3CA hotspot mutations were searched for by multiplexed digital PCR in all cases, whereas DNA methylation profiling and/or PIK3R1 and NF1 alterations were analysed in a subset of cases., Results: Three groups were observed. The first one included 21 intracranial midline tumours demonstrating FGFR1 mutation associated with PIK3CA or PIK3R1 (n = 19) or NF1 (n = 1) or PIK3CA and NF1 (n = 1) mutation. By DNA methylation profiling, eight cases were classified as RGNT (they demonstrated FGFR1 and PIK3CA or PIK3R1 mutations). Group 2 comprised 11 cases associated with one single FGFR1 mutation. Group 3 included six cases classified as low-grade glioma (LGG) other than RGNT (one-sixth showed FGFR1 mutation and one a FGFR1 and NF1 mutation) and eight cases without FGFR1 mutation. Groups 2 and 3 were enriched in lateral and spinal cases., Conclusions: We suggest adding FGFR1 mutation and intracranial midline location as essential diagnostic criteria. When DNA methylation profiling is not available, a RGNT diagnosis remains certain in cases demonstrating characteristic pathological features and FGFR1 mutation associated with either PIK3CA or PIK3R1 mutation., (© 2022 British Neuropathological Society.)