Rosina Paterra

Primary meningeal melanocytic tumors (PMMTs) are rare neoplasms currently stratified by the World Health Organization (WHO) into three grades of malignancy based exclusively on histopathological criteria, while the prognostic significance of molecular alterations remains poorly defined. This study aimed to investigate the prognostic relevance of histopathological and molecular features in PMMTs and to assess the diagnostic utility of immunohistochemical and molecular markers for distinguishing PMMTs from malignant melanotic nerve sheath tumors (MMNSTs). Thirty‐six primary central nervous system (CNS) melanocytic tumors, including 24 PMMTs (10 grade 1, 12 grade 2, and 2 grade 3) and 12 MMNSTs, were analyzed through integrated histopathological, immunohistochemical, genetic, and epigenetic characterization. Among grade 2 PMMTs, descriptively defined CNS‐invasive otherwise benign melanocytomas defined a clinically favorable subgroup, whereas SF3B1 mutations and chromosome 8q gains were associated with higher recurrence rates and shorter recurrence‐free survival. Losses of chromosome 17 or 21q were observed exclusively in MMNSTs, supporting their potential diagnostic utility in distinguishing MMNSTs from PMMTs. These findings demonstrate biological heterogeneity among intermediate‐grade PMMTs and identify molecular markers associated with adverse clinical outcomes. Integrated histopathological and molecular characterization may enhance prognostic stratification and diagnostic accuracy in primary CNS melanocytic tumors.

We report a case of astrocytoma IDH-mutant grade 2, which progressed to an IDH-mutant sarcomatous neoplasia after multiple treatments, including radiotherapy. The last recurrence histologically exhibited sarcomatous morphology, characterized by spindle cells, necrosis, and brisk mitotic activity. The neoplastic cells were negative for GFAP and OLIG2, positive for IDH1p.R132H and P53, with loss of ATRX expression and focal loss of H3 K27me3. Focal immunoreactivity for smooth muscle actin, desmin, and YAP1 was also observed. DNA methylation profiling yielded subthreshold scores suggestive of oligosarcoma, IDH-mutant, using the Heidelberg classifier and undifferentiated sarcoma using the sarcoma classifier. The Bethesda classifier did not provide a confident match. Nevertheless, UMAP analysis showed proximity of the recurrent tumor to the oligosarcoma methylation cluster. Overall, the sarcomatous recurrent neoplasia retained immunophenotypic and molecular features of astrocytomas IDH-mutant, while exhibiting an epigenetic divergent profile. This case expands the spectrum of sarcomatous progression in IDH-mutant diffuse gliomas and raises the possibility that astrocytomas, similar to oligodendrogliomas, may rarely undergo sarcomatous transformation. Additional cases and integrated molecular studies will be required to determine whether such tumors represent a distinct biological subgroup.

Objectives: Polymorphous low‐grade neuroepithelial tumor of the young (PLNTY) was recognized as a new histologic entity in the 2021 World Health Organization (WHO) classification of central nervous system tumors. It represents a distinct epileptogenic tumor, with about 80 cases reported to date across all age groups. The aim of this study is to describe the features of a cohort of PLNTY patients with a multimodal approach. Methods: Patients diagnosed with PLNTY from 2014 to 2023 at our Institute were retrospectively reviewed to collect clinical, EEG, neuroimaging, histopathological, and molecular data. Results: We identified 14 surgically treated patients (median age 21.5 years, range 12–46), with drug‐resistant seizures in 78.6%. Seizure onset preceded surgery by a median period of 4 years (range .5–27). Bilateral interictal epileptiform EEG discharges and/or mislateralizing/mislocalizing ictal EEG discharge and/or semiological signs were found in 85.7% of patients, compared to 19.2% in a group of 26 non‐PLNTY low‐grade epilepsy‐associated tumors (LEATs) ( p < .001). All PLNTYs were supratentorial solid or solid‐cystic cortical mass, involving the temporal ( n = 8), temporo‐occipital ( n = 4), frontal ( n = 1), or parietal lobe ( n = 1). They featured an infiltrative growth pattern, oligodendroglioma‐like cells, strong and often diffuse CD34 immunostaining, and frequent calcifications. Focal cortical dysplasia was associated in 14.3% of cases. Proliferation activity (MIB‐1 labeling index) was very low (1%), except for one case (3%). BRAFV600E was found in 50% ( n = 6/12) of cases, fibroblast growth factor receptor 3 (FGFR3) protein expression in 7 cases, 30.7% ( n = 4/13) carried FGFR3 fusion. No fibroblast growth factor receptor 2 (FGFR2) fusion ( n = 0/6) was identified. Postsurgical seizure outcome was excellent (Engel class I) in all cases. Significance: This study confirms that, despite its name, PLNTY is not limited to pediatric patients. Findings underscore the highly epileptogenic nature of PLNTY and its recognizable electroclinical features, potentially related to its distinctive neuropathology. Most PLNTYs show mitogen‐activated protein kinase (MAPK) pathway activating alterations, demonstrated by BRAFV600E mutation and FGFR3 fusion.

The Kelch domain of LZTR1 and carboxyl tail of EGFR are required for their interaction

EGFR and AXL protein expression in the brain and immunohistochemical characterization of tumors of Lztr1fl/fl;Cdkn2afl/fl;GFAP-Cre+ mice

Vulnerability of LZTR1 inactive cells to combination treatment of EGFR and AXL inhibitors

LZTR1 regulates EGFR and AXL protein stability

LZTR1 co-localized with EGFR and AXL at the cellular membrane upon ligand stimulation

Table S1. List of ubiquitylated peptides from DiGly proteomics assay. Table S2. List of proteins differentially abundant in LZTR1-/- compared toLZTR1+/+ cells quantified by TMT.Table S3. List of top scoring LZTR1 interacting proteins from immunoprecipitation/mass spectrometry.

Mechanism of LZTR1-mediated degradation of RIT1 and the effect of LZTR1 mutations