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A novel histomolecular tumor, the "intracranial mesenchymal tumor (IMT), FET::CREB fusion-positive", has recently been identified and added to the 2021 World Health Organization Classification of Tumors of the Central Nervous System. One of the essential diagnostic criteria defined in this classification is the intracranial location of the tumor. Herein, we report a spinal case of IMT with a classical EWSR1::CREM fusion. We compare its clinical, histopathological, immunophenotypical, genetic and epigenetic features with those previously described in IMT, FET::CREB fusion-positive. The current case presented histopathological (epithelioid morphology with mucin-rich stroma, and expression of EMA and desmin), radiological (an extraparenchymal lobulated mass without dural tail), genetic (fusion implicating the EWSR1 and CREM genes), and epigenetic (DNA-methylation profiling) similarities to previously reported cases. This case constitutes the third "extracranial" observation of an IMT. Our results added data suggesting that the terminology "IMT, FET::CREB fusion-positive" is provisional and that further series of cases are needed to better characterize them.

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.

A novel histomolecular tumor of the central nervous system, the “intracranial mesenchymal tumor (IMT), FET-CREB fusion-positive” has recently been identified in the literature and will be added to the 2021 World Health Organization Classification of Tumors of the Central Nervous System. However, our latest study using DNA-methylation analyses has revealed that intracranial FET-CREB fused tumors do not represent a single molecular tumor entity. Among them, the main subgroup presented classical features of angiomatoid fibrous histiocytoma, having ultrastructural features of arachnoidal cells, for. Another tumor type with clear cell component and histopathological signs of aggressivity clustered in close vicinity with clear cell sarcoma of soft tissue. Herein, we report one case of IMT with a novel SMARCA2-CREM fusion which has until now never been described in soft tissue or the central nervous system. We compare its clinical, histopathological, immunophenotypic, genetic and epigenetic features with those previously described in IMT, FET-CREB fusion-positive. Interestingly, the current case did not cluster with IMT, FET-CREB fusion-positive but rather presented histopathological (clear cell morphology with signs of malignancy), clinical (with a dismal course with several recurrences, metastases and finally the patient’s death), genetic (fusion implicating the CREM gene), and epigenetic (DNA-methylation profiling) similarities with our previously reported clear cell sarcoma-like tumor of the central nervous system. Our results added data suggesting that different clinical and histomolecular tumor subtypes or grades seem to be included within the terminology “IMT, FET-CREB fusion-positive”, and that further series of cases are needed to better characterize them.

Posterior fossa group A ependymomas (EPN_PFA) are characterized by a loss of H3 K27 trimethylation due to either EZHIP overexpression or H3 p.K27M mutation, similar to H3 K27-altered diffuse midline gliomas (DMG), but in reverse proportions. Very little data is available in the literature concerning H3 K27M-mutant EPN_PFA. Here, we retrospectively studied a series of nine pediatric tumors initially diagnosed as H3 K27M-mutant EPN_PFA to compare them to EZHIP-overexpressing EPN_PFA in terms of radiology, follow-up, histopathology, and molecular biology (including DNA-methylation profiling). Seven tumors clustered within EPN_PFA by DNA-methylation analysis and t-distributed stochastic neighbor embedding. Among the two remaining cases, one was reclassified as a DMG and the last was unclassified. H3 K27M-mutant EPN_PFA cases were significantly older than their counterparts with an EZHIP overexpression. Radiological and histopathological central review of our seven H3 K27M-mutant EPN_PFA cases found them to be similar to their counterparts with an EZHIP overexpression. Sequencing analyses revealed HIST1H3B (n = 2), HIST1H3C (n = 2), H3F3A (n = 1), and HIST1H3D (n = 1) K27M mutations (no sequencing analysis available for the last case which was immunopositive for H3K27M). Consequently, HIST1H3C/D mutations are more frequently observed in EPN_PFA than in classic pontine DMG, H3K27-mutant. Overall survival and event-free survival of EZHIP-overexpressing and H3 K27M-mutant EPN_PFA were similar. After surgery and radiation therapy, 5/7 patients were alive at the end of the follow-up. In summary, the diagnosis of EPN_PFA must include tumor location, growth pattern, Olig2 expression, and DNA-methylation profiling before it can be differentiated from DMG, H3 K27-altered.

The International Society for the Study of Vascular Anomalies (ISSVA) has defined four vascular lesions in the central nervous system (CNS): arteriovenous malformations, cavernous angiomas (also known as cerebral cavernous malformations), venous malformations, and telangiectasias. From a retrospective central radiological and histopathological review of 202 CNS vascular lesions, we identified three cases of unclassified vascular lesions. Interestingly, they shared the same radiological and histopathological features evoking the cavernous subtype of angioleiomyomas described in the soft tissue. We grouped them together with four additional similar cases from our clinicopathological network and performed combined molecular analyses. In addition, cases were compared with a cohort of 5 soft tissue angioleiomyomas. Three out 6 CNS lesions presented the same p.Gly41Cys GJA4 mutation recently reported in hepatic hemangiomas and cutaneous venous malformations and found in 4/5 soft tissue angioleiomyomas of our cohort with available data. Most DNA methylation profiles were not classifiable using the CNS brain tumor (version 12.5), and sarcoma (version 12.2) classifiers. However, using unsupervised t-SNE analysis and hierarchical clustering analysis, 5 of the 6 lesions grouped together and formed a distinct epigenetic group, separated from the clusters of soft tissue angioleiomyomas, other vascular tumors, inflammatory myofibroblastic tumors and meningiomas. Our extensive literature review identified several cases similar to these lesions, with a wide variety of denominations. Based on radiological and histomolecular findings, we suggest the new terminology of “dural angioleiomyomas” (DALM) to designate these lesions characterized by a distinct DNA methylation pattern and frequent GJA4 mutations.

Pediatric bithalamic gliomas encompass several histomolecular tumoral types from benign to malignant and underlines the central role of a comprehensive neuropathological review, including immunohistochemistry, genetic, and epigenetic analyses, to achieve an accurate diagnosis.

The cIMPACT-NOW Update 7 has replaced the WHO nosology of “ependymoma, RELA fusion positive” by “Supratentorial-ependymoma, C11orf95-fusion positive”. This modification reinforces the idea that supratentorial-ependymomas exhibiting fusion that implicates the C11orf95 (now called ZFTA) gene with or without the RELA gene, represent the same histomolecular entity. A hot off the press molecular study has identified distinct clusters of the DNA methylation class of ZFTA fusion-positive tumors. Interestingly, clusters 2 and 4 comprised tumors of different morphologies, with various ZFTA fusions without involvement of RELA. In this paper, we present a detailed series of thirteen cases of non-RELA ZFTA-fused supratentorial tumors with extensive clinical, radiological, histopathological, immunohistochemical, genetic and epigenetic (DNA methylation profiling) characterization. Contrary to the age of onset and MRI aspects similar to RELA fusion-positive EPN, we noted significant histopathological heterogeneity (pleomorphic xanthoastrocytoma-like, astroblastoma-like, ependymoma-like, and even sarcoma-like patterns) in this cohort. Immunophenotypically, these NFκB immunonegative tumors expressed GFAP variably, but EMA constantly and L1CAM frequently. Different gene partners were fused with ZFTA: NCOA1/2, MAML2 and for the first time MN1. These tumors had epigenetic homologies within the DNA methylation class of ependymomas-RELA and were classified as satellite clusters 2 and 4. Cluster 2 (n = 9) corresponded to tumors with classic ependymal histological features (n = 4) but also had astroblastic features (n = 5). Various types of ZFTA fusions were associated with cluster 2, but as in the original report, ZFTA:MAML2 fusion was frequent. Cluster 4 was enriched with sarcoma-like tumors. Moreover, we reported a novel anatomy of three ZFTA:NCOA1/2 fusions with only 1 ZFTA zinc finger domain in the putative fusion protein, whereas all previously reported non-RELA ZFTA fusions have 4 ZFTA zinc fingers. All three cases presented a sarcoma-like morphology. This genotype/phenotype association requires further studies for confirmation. Our series is the first to extensively characterize this new subset of supratentorial ZFTA-fused ependymomas and highlights the usefulness of ZFTA FISH analysis to confirm the existence of a rearrangement without RELA abnormality.

Medulloblastoma (MB), the most frequent embryonic tumor of the cerebellum is classified into four molecular subgroups (WNT group, SHH group, group 3 and group 4). Although the vast majority of MB are sporadic, predisposing genetic diseases have been described in rare WNT MB and more frequently in the SHH group. In a recent pediatric series of SHH-MB, germline alterations of the ELP1 gene have been described in 14% of cases, making this gene the most frequent genetic predisposition in MB. We have investigated the potential interest of ELP1 immunostaining on a large cohort of 132 MB. A complete loss of ELP1 staining was observed in 12 SHH MB (among 57 total SHH MB: 21%). The loss of ELP1 immunostaining was well correlated with the presence of a bi-allelic alteration of the gene except for one case for which the MB had a loss of ELP1 protein expression demonstrated by immunohistochemistry (IHC) and confirmed by whole proteome analysis, although no obvious genetic alteration in the coding sequence of ELP1 could be found. Molecular analysis of a large “molecular” cohort of 266 MB from French centers for which somatic ELP1 was sequenced allows to identify 12 additional MB with bi-allelic ELP1 genetic alterations. Our results demonstrate the benefit of the ELP1 IHC as an accurate and reliable tool to screen ELP1-deficient MB. This new immunohistochemical tool will now be advantageously used to screen SHH MB upfront for genetic alteration in ELP1, and will subsequently help orientating these patients towards genetic counseling.