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Meningioangiomatosis (MAM) remains a poorly understood lesion responsible for epileptic disease. In the past, MAM was primarily described in the context of neurofibromatosis type 2 before being mainly reported sporadically. Moreover, the malformative or tumoral nature is still debated. Because a subset of MAM are associated with meningiomas, some authors argue that MAM corresponds to an infiltration pattern of these tumors. For these reasons, MAM has not been added to the World Health Organization (WHO) Classification of Central Nervous System Tumors as a specific entity. In the present study, we characterized a series of pure MAM (n = 7) and MAM associated with meningiomas (n = 4) using histopathology, immunohistochemistry, genetic (fluorescent in situ and DNA sequencing analyses), and epigenetic (DNA‐methylation profiling) data. We evidenced two distinct morphological patterns: MAM with a fibroblastic‐like pattern having few lesional cells, and MAM with a more cellular pattern. A subset was associated with the genetic alterations previously reported in meningiomas (such as a KMT2C mutation and a hemizygous deletion of chromosome 22q including the NF2 gene). The DNA‐methylation profile, using a t‐distributed stochastic neighbor embedding analysis, evidenced that MAM (pure or associated with meningiomas) clustered in a separate group from pediatric meningiomas. The present results seem to suggest that MAM represents a neoplastic lesion and encourage the further study of similar additional series so that it may be included in a future WHO classification. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

This article discusses a case study of a rare brain tumor called diffuse midline glioma (DMG) with ependymal features. DMG is a type of brain tumor that primarily affects children and is characterized by alterations in a specific gene called H3K27. The case study focuses on a specific subtype of DMG called EGFR-subtype, which is associated with mutations in the EGFR gene. The study highlights the challenges in diagnosing this subtype and emphasizes the importance of integrating radiological, histopathological, genetic, and epigenetic data for an accurate diagnosis. The authors suggest that DMG with ependymal features may be misdiagnosed as another type of brain tumor called posterior fossa ependymoma, and further research is needed to better understand the characteristics and prognosis of this subtype. [Extracted from the article]

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. [ABSTRACT FROM AUTHOR]

Aims: NTRK gene fusions have been described in a wide variety of central nervous system (CNS) and soft tissue tumours, including the provisional tumour type 'spindle cell neoplasm, NTRK‐rearranged' (SCN–NTRK), added to the 2020 World Health Organisation Classification of Soft Tissue Tumours. Because of histopathological and molecular overlaps with other soft tissue entities, controversy remains concerning the lineage and terminology of SCN–NTRK. Methods and results: This study included 16 mesenchymal tumours displaying kinase gene fusions (NTRK fusions and one MET fusion) initially diagnosed as infantile fibrosarcomas (IFS), SCN–NTRK and adult‐type fibrosarcomas from the soft tissue, viscera and CNS. We used immunohistochemistry, DNA methylation profiling, whole RNA‐sequencing and ultrastructural analysis to characterise them. Unsupervised t‐distributed stochastic neighbour embedding analysis showed that 11 cases (two CNS tumours and nine extra‐CNS) formed a unique and new methylation cluster, while all tumours but one, initially diagnosed as IFS, clustered in a distinct methylation class. All the tumours except one formed a single cluster within the hierarchical clustering of whole RNA‐sequencing data. Tumours from the novel methylation class co‐expressed CD34 and S100, had variable histopathological grades and frequently displayed a CDKN2A deletion. Ultrastructural analyses evidenced a myofibroblastic differentiation. Conclusions: Our findings confirm that SCN‐NTRK share similar features in adults and children and in all locations combine an infiltrative pattern, distinct epigenetic and transcriptomic profiles, and ultrastructural evidence of a myofibroblastic lineage. Further studies may support the use of new terminology to better describe their myofibroblastic nature. [ABSTRACT FROM AUTHOR]

The I CIC- i rearranged sarcoma was introduced into the 2021 World Health Organization (WHO) Classification of Tumours of the Central Nervous System (CNS), by homology of its soft-tissue counterpart.1 In the CNS, I CIC i fusions mainly implicate I DUX4 i or I NUTM1 i genes but non- I CIC i fusions (such as I ATXN1::DUX4 i and I ATXN1::NUTM1 i ) have been recently described.1-3 However, DNA-methylation profiling of all I CIC- i and non- I CIC- i fused CNS mesenchymal tumours showed that all cases clustered together.2 In soft tissue, it has been evidenced that whatever the fusion partner, the I CIC i translocation induces an oncogenic activation of the PEA3 family transcription factors, including ETV4.1 Consequently, ETV4 immunohistochemistry (IHC) may represent a specific biomarker for all I CIC- i rearranged sarcomas, whereas NUT immunoexpression is only observed in I CIC::NUTM1 i -fused sarcomas.1 In the CNS, the diagnosis of I CIC- i rearranged sarcoma may be challenging for neuropathologists, and a common diagnostic biomarker of all fusions may help to identify this rare tumour type. Our work is the first to evaluate the sensitivity and specificity of ETV4 in a large cohort of molecularly defined CNS tumours. ETV4 immunohistostaining is a sensitive and specific diagnostic biomarker for CIC-rearranged sarcoma of the central nervous system. [Extracted from the article]

Aims: Dysembryoplastic neuroepithelial tumour (DNT) is a glioneuronal tumour that is challenging to diagnose, with a wide spectrum of histological features. Three histopathological patterns have been described: specific DNTs (both the simple form and the complex form) comprising the specific glioneuronal element, and also the non‐specific/diffuse form which lacks it, and has unclear phenotype–genotype correlations with numerous differential diagnoses. Methods: We used targeted methods (immunohistochemistry, fluorescence in situ hybridisation and targeted sequencing) and large‐scale genomic methodologies including DNA methylation profiling to perform an integrative analysis to better characterise a large retrospective cohort of 82 DNTs, enriched for tumours that showed progression on imaging. Results: We confirmed that specific DNTs are characterised by a single driver event with a high frequency of FGFR1 variants. However, a subset of DNA methylation‐confirmed DNTs harbour alternative genomic alterations to FGFR1 duplication/mutation. We also demonstrated that a subset of DNTs sharing the same FGFR1 alterations can show in situ progression. In contrast to the specific forms, "non‐specific/diffuse DNTs" corresponded to a heterogeneous molecular group encompassing diverse, newly‐described, molecularly distinct entities. Conclusions: Specific DNT is a homogeneous group of tumours sharing characteristics of paediatric low‐grade gliomas: a quiet genome with a recurrent genomic alteration in the RAS‐MAPK signalling pathway, a distinct DNA methylation profile and a good prognosis but showing progression in some cases. The "non‐specific/diffuse DNTs" subgroup encompasses various recently described histomolecular entities, such as PLNTY and diffuse astrocytoma, MYB or MYBL1 altered. [ABSTRACT FROM AUTHOR]

Aims: We searched for recurrent pathological features and molecular alterations in a retrospective series of 72 low‐grade epilepsy‐associated neuroepithelial tumours (LEATs) with a prominent oligodendroglioma‐like component, in order to classify them according to the 2021 World Health Organization (WHO) classification of central nervous system (CNS) tumours. Methods: Centralised pathological examination was performed as well as targeted molecular analysis of v‐Raf murine sarcoma viral oncogene homologue B (BRAF) and fibroblast growth factor receptor 1 (FGFR1) by multiplexed digital polymerase chain reaction (mdPCR). DNA methylation profiling was performed in cases with sufficient DNA. In cases with no genetic alteration by mdPCR and sufficient material, RNA sequencing was done. Results: We first reclassified our cohort into three groups: ganglioglioma (GG, n = 14), dysembryoplastic neuroepithelial tumours (DNTs, n = 19) and glioneuronal tumours/paediatric‐type low‐grade glioma (LGG) not otherwise specified (GNT/PLGG NOS, n = 39). mdPCR found an alteration in 38/72 cases. Subsequent RNA sequencing revealed a fusion transcript involving BRAF, FGFR1/2/3 or neurotrophic tyrosine kinase receptor type 2 [NTRK2] in 9/25 cases. DNA methylation profiling found 12/46 cases with a calibrated score ≥0.9. Unsupervised hierarchical clustering revealed two clusters: Cluster 1 was enriched with cases classified as DNT at histology, belonging to the LGG–DNT methylation class (MC), with haematopoietic progenitor cell antigen (CD34) negativity and FGRF1 alterations; Cluster 2 was enriched with cases classified at histology as GG, belonging to the LGG–GG MC MC, with BRAF V600E mutation and CD34 positivity. The tumours reclassified as GNT/PLGG NOS were equally distributed across both clusters. Interestingly, all polymorphous low‐grade neuroepithelial tumour of the young belonged to Cluster 2, whereas diffuse LGG mitogen‐activated protein kinase (MAPK) pathway‐altered were equally distributed among the two clusters. This led us to build an algorithm to classify LEATs with a prominent oligodendroglioma‐like component. Conclusions: Integrated histomolecular diagnosis of LEATs with a prominent oligodendroglioma‐like component remains challenging. Because these tumours can be split into two major clusters of biological significance, the clinicopathological relevance of the four types recognised by the WHO CNS5 within this spectrum of tumours is questionable. [ABSTRACT FROM AUTHOR]