ABSTRACT
Current histological classification of low-grade glioneuronal tumours does not adequately represent their underlying biology. The neural lineage(s) and differentiation stage(s) involved and the cell state(s) affected by the recurrent genomic alterations are unclear. Here, we describe dysregulated oligodendrocyte lineage developmental programmes in three low-grade glioneuronal tumour subtypes. Ten dysembryoplastic neuroepithelial tumours, four myxoid glioneuronal tumours and five rosette-forming glioneuronal tumours were collected. Besides a comprehensive characterization of clinical features, known diagnostic markers and genomic alterations, we used comprehensive immunohistochemical stainings to characterize activation of rat sarcoma/mitogen-activated protein kinase pathway, involvement of neuronal component, resemblance to glial lineages and differentiation blockage along the stages of oligodendrocyte lineage. The findings were further complemented by gene set enrichment analysis with transcriptome data of dysembryoplastic neuroepithelial tumours from the literature. Dysembryoplastic neuroepithelial tumours, myxoid glioneuronal tumours and rosette-forming glioneuronal tumours occur at different ages, with symptoms closely related to tumour location. Dysembryoplastic neuroepithelial tumours and myxoid glioneuronal tumours contain oligodendrocyte-like cells and neuronal component. Rosette-forming glioneuronal tumours contained regions of rosette-forming neurocytic and astrocytic features. Scattered neurons, identified by neuronal nuclei antigen and microtubule-associated protein-2 staining, were consistently observed in all dysembryoplastic neuroepithelial tumours and myxoid glioneuronal tumours examined, but only in one rosette-forming glioneuronal tumour. Pervasive neurofilament-positive axons were observed only in dysembryoplastic neuroepithelial tumour and myxoid glioneuronal tumour samples. Alterations in B-Raf proto-oncogene, serine/threonine kinase, fibroblast growth factor receptor 1, fibroblast growth factor receptor 3 and platelet-derived growth factor receptor alpha occurred in a mutually exclusive manner, coinciding with strong staining of phospho-p44/42 mitogen-activated protein kinase and low apoptotic signal. All dysembryoplastic neuroepithelial tumours, myxoid glioneuronal tumours and the neurocytic regions of rosette-forming glioneuronal tumours showed strong expression of neuron-glia antigen 2, platelet-derived growth factor receptor alpha (markers of oligodendrocyte precursor cells) and neurite outgrowth inhibitor-A (a marker of developing oligodendrocytes), but lacked the expression of oligodendrocyte markers ectonucleotide pyrophosphatase/phosphodiesterase family member 6 and myelin basic protein. Notably, transcriptomes of dysembryoplastic neuroepithelial tumours were enriched in oligodendrocyte precursor cell signature, but not in signatures of neural stem cells, myelinating oligodendrocytes and astrocytes. Dysembryoplastic neuroepithelial tumour, myxoid glioneuronal tumour and rosette-forming glioneuronal tumour resemble oligodendrocyte precursor cells, and their enrichment of oligodendrocyte precursor cell phenotypes is closely associated with the recurrent mutations in rat sarcoma/mitogen-activated protein kinase pathway.
ABSTRACT
BACKGROUND: "Primary papillary epithelial tumor of the sella (PPETS)" is a recently described rare tumor entity of the central nervous system (CNS) with stereotypic location in the sella. Comprehensive molecular investigations and epigenetic profiles of PPETS have not been performed to date. METHODS: We report a comprehensive clinical, histopathologic, and molecular assessment of 5 PPETS cases in comparison with a cohort composed of 7 choroid plexus papilloma (CPP), 7 central neurocytoma (CN), 15 posterior pituitary tumor (PPT) including 4 pituicytoma, 6 granular cell tumors of the sellar region (GCT), and 5 spindle cell oncocytoma. RESULTS: All PPETS had good outcomes. Immunohistochemically, PPETS tumors showed positive staining with TTF1, EMA, AE1/AE3, MAP2, and Vimentin, but were negatively stained with Syn, GFAP, CgA, and S100, and sporadically stained with Ki-67. In unsupervised hierarchical clustering and t-distributed stochastic neighbor embedding analyses of DNA-methylation data, PPETS and PPT tumors formed a distinct cluster irrespective of their histologic types. However, PPETS tumors did not cluster together with CPP and CN samples. Similar findings were obtained when our samples were projected into the reference cohort of the brain tumor classifier. Substantial fractions of the PPETS and PPT tumors shared broadly similar chromosomal copy number alterations. No mutations were detected using targeted next-generation sequencing. CONCLUSIONS: Though more cases are needed to further elucidate the molecular pathogenesis of these tumors, our findings indicate that PPETS and PPT tumors may constitute a single neurooncological entity.
