Central Nervous System (CNS) embryonal tumors represent a heterogeneous group of highly aggressive tumors occurring preferentially in children but also described in adolescents and adults. In 2021, the CNS World Health Organization (WHO) classification drastically changed the diagnosis of the other CNS embryonal tumors including new histo-molecular tumor types. Here, we report a pediatric case of a novel tumor type among the other CNS embryonal tumors classified within the methylation class “CNS Embryonal Tumor with BRD4–LEUTX Fusion”. The patient was a 4-year girl with no previous history of disease. For a few weeks, she suffered from headaches, vomiting and mild fever associated with increasing asthenia and loss of weight leading to a global deterioration of health. MRI brain examination revealed a large, grossly well-circumscribed tumoral mass lesion located in the left parietal lobe, contralateral hydrocephalus and midline shift. Microscopic examination showed a highly cellular tumor with a polymorphic aspect. The majority of the tumor harbored neuroectodermal features composed of small cells with scant cytoplasm and hyperchromatic nuclei associated with small “medulloblastoma-like” cells characterized by syncytial arrangement and focally a streaming pattern. Tumor cells were diffusely positive for Synaptophysin, CD56, INI1 and SMARCA4 associated with negativity for GFAP, OLIG-2, EMA, BCOR, LIN28A and MIC-2. Additional IHC features included p53 protein expression in more than 10% of the tumor’s cells and very interestingly, loss of H3K27me3 expression. The Heidelberg DNA-methylation classifier classified this case as “CNS Embryonal Tumor with BRD4:LEUTX Fusion”. RNA-sequencing analyses confirmed the BRD4 (exon 13)–LEUTX (exon 2) fusion with no other molecular alterations found by DNA sequencing. Our case report confirmed that a new subgroup of CNS embryonal tumor with high aggressive potential, loss of H3K27me3 protein expression, BRDA4–LEUTX fusion, named “Embryonal CNS tumor with BRD4–LEUTX fusion”, has to be considered into the new CNS WHO classification.

Purpose of review Primary central nervous system lymphoma (PCNSL) is a rare central nervous system (CNS) malignancy, which represents a heterogenous group of tumors. Among PCNSL, diffuse large B-cell lymphoma of the CNS (CNS-DLBCL) represents the most common tumor type. Multiomics studies have recently revealed the complex genomic landscape of these rare diseases. These findings lead to a potential new molecular and epigenetic classification. Recent findings Our review is focused on CNS-DLBCL in immunocompetent patients. CNS-DLBCL are derived from self-reactive/polyreactive precursor cells. An early molecular event such as MYD88 mutation leads to escape elimination of precursor cells, which, by a dysregulated GC reaction, acquire auto-/polyreactivity of the B-cell tumoral cells for antigens physiologically expressed in the CNS. Most of CNS-DLBCL tumor cells harbor a non-GCB, ABC-like immunophenotype associated with a late GC (exit) B-cells genotype by gene expression profiling. Various mechanisms of genetic alterations are involved in the pathogenesis of PCNSL, including point mutations [nonsomatic hypermutation (SHM), aberrant SHM (aSHM)], SHM/aSHM, chromosome copy gains or losses, and DNA hypermethylation. Constitutive NFκB activation plays a key role in lymphoma cell proliferation and survival by dysregulation of toll-like receptor (mutations of CARD11 and MYD88), BCR (CD79B), JAK-STAT, and NFκB signaling pathways. Summary Multiomics approaches have succeeded to substantially improve the understanding of the pathogenesis, as well as the molecular and epigenetic events in PCNSL. Challenges remain due to the obvious heterogeneity of CNS-DLBCL, and improvement is needed for their classification.