Identification and characterization of a novel distinct Pineal Neoplasm with Neuroendocrine and Epithelial...

Pineal region tumors are rare neoplasms that occur in all ages and account for less than 1% of all central nervous system (CNS) tumors in adults but are more frequent in children. Here, we describe a previously unrecognized tumor type of pineal origin characterized by a unique and consistent DNA methylation profile that does not match any known CNS tumor class and is distinct from all currently recognized pineal tumor entities. The presented cohort (n = 27) displayed a balanced sex distribution with a mean patient age of 35 years (range 7-75 years). The histopathological analyses demonstrated a highly cellular tumor showing various degrees of necrosis, mitotic activity, papillary structures, rosettes, epithelioid cytology, or signet-ring cells. The tumors consistently expressed cytokeratin 18, synaptophysin, chromogranin A, and OTX2, whereas CRX expression was absent. Four out of 16 tumors (25%) showed ATRX mutations and/or loss of protein expression as revealed by immunohistochemistry. Single-nucleus RNA sequencing confirmed molecular distinctiveness from other pineal neoplasms but revealed the closest similarities to papillary tumors of the pineal region (PTPR). Projection of the transcriptome data onto the cellular trajectory of the developing murine pineal gland suggests that pinealocyte progenitors are the cellular origins. Taken together, our findings define a novel type of pineal region tumor that we provisionally named 'Pineal Neoplasm with Neuroendocrine and Epithelial Differentiation' (PINNED). Recognition of this tumor type appears to be important for the accurate diagnosis of pineal region tumors and may have implications for future tumor classification and treatment strategies.