Sellar region neurocytomas exhibit a CIMP and neuroendocrine-like epigenetic signature distinct from other intra-axial neurocytomas

Abstract

Sellar region neurocytoma (SELN) is a rare neoplasm whose relationship to other neurocytomas within the central nervous system (CNS) has remained unclear. Prior reports have variably classified SELN as a variant of extraventricular neurocytoma (EVN), while immunohistochemical and ultrastructural studies have suggested a hypothalamic origin. Here, we performed unsupervised clustering of DNA methylation data across a large pan-cancer reference set and identified SELN (n = 20) as distinct from other neurocytomas and regional mimics, as well as clustering with neuroendocrine tumors from other organ sites. SELN exhibited a CIMP-like phenotype, TTF1 negativity (0/8), and AVP (vasopressin) promoter hypomethylation, implicating a magnocellular hypothalamic cell of origin. In evaluable cases, a neuronal/neuroendocrine immunophenotype was observed (synaptophysin 8/8, chromogranin A 5/5) with absent pituitary transcription factor expression (PIT1 and TPIT negative 0/4). DNA sequencing (n = 5) and RNA-based fusion profiling (n = 4) did not detect recurrent mutations or gene fusions, respectively. Patients often presented with visual disturbances or headaches and spanned pediatric and older age groups (median 42 years, range 12.5–75), with no sex predilection. Despite locally aggressive imaging features in some cases (cavernous sinus invasion, carotid encasement, hydrocephalus), disease-free survival (n = 13) was comparable to central neurocytoma, with no disease-related deaths during the limited follow-up. Together, these findings support SELN as a molecularly distinct hypermethylated neuroendocrine-like epitype and clinicopathologic entity.