Giannini, C.

Abstract Background Intracranial mesenchymal tumors, FET::CREB fusion-positive (ICMT), show fusions involving FET RNA-binding protein family genes (EWSR1 or FUS) and CREB family of transcription factors (ATF1, CREB1, or CREM). The methylation signature(s), gene expression characteristics, and clinical behavior of this important tumor type require further characterization. Methods We study the methylation profiles of 81 ICMT cases (61 newly profiled cases and 20 cases from publicly available sources). Clinicopathologic and genomic data were recorded for each case when available. Results ICMT showed a relatively distinct methylation signature compared to related tumors. Among the 65 cases where fusion types were documented, the identified fusions included EWSR1::ATF1 (25 cases), EWSR1::CREB1 (12 cases), EWSR1::CREM (21 cases), FUS::CREM (3 cases), and SMARCA2::CREM (4 cases). We confirmed the prior description of 2 distinct subgroups of ICMT (subclasses A and B). The majority of the cases belonged to subclass A (n = 69; 85%), which showed a higher median age compared to subclass B patients (26 years vs. 15 years). Subclass B cases (n = 12; 15%) showed shorter progression-free survival (P < 0.01). Gene expression analysis of ICMT showed key overexpressed markers in ICMT, with significant CREM overexpression regardless of fusion type, when compared to either meningioma alone or a larger group of CNS tumors. Conclusions This work provides further characterization of ICMT as an important CNS mesenchymal neoplasm that is prone to tumor recurrence, showing 2 prognostically relevant methylation subclasses and warranting diagnostic distinction from other epigenetically and histologically related tumors. ICMTs show substantial overexpression of the CREM gene, independent of fusion type.

This short review highlights significant changes and recent findings incorporated to varying extent in the WHO 2016 definition of a variety of tumours, including peripheral nerve sheath tumours, meningiomas, mesenchymal nonmeningothelial tumours, melanocytic tumours, lymphomas and histiocytic tumours, germ cell tumours and non‐neuroendocrine pituitary tumours. Most notable classification changes include: adding ‘hybrid nerve sheath tumours’ to the spectrum of benign nerve sheath tumours; an updated definition of atypical meningioma (WHO grade II), including cases with brain invasion; recognizing dural solitary fibrous tumour (SFT) and haemangiopericytoma (HPC) as a single tumour entity characterized by NAB2 and STAT6 gene fusions for which the term SFT/HPC was chosen; recognizing that pituitary granular cell tumour, spindle cell oncocytoma, and pituicytoma all share nuclear expression of TTF‐1, possibly representing a spectrum of a single nosological entity derived from posterior pituitary glial cells. The most significant diagnostic markers which have emerged include: inactivation of NF1, CDKN2A, and PRC2 components, SUZ12 and EED in MPNST, leading to neurofibromin and H3K27me3 expression loss; GNAQ and GNA11 mutations in CNS primary melanocytic tumours; BRAFV600E mutation in histiocytic tumours (Langerhans cell histiocytosis and Erdheim‐Chester disease) and papillary craniopharyngioma, which provides both a diagnostic marker in the appropriate pathological setting and a therapeutic target. The WHO 2016 Classification has balanced cutting‐edge knowledge on the molecular characteristics of the miscellaneous CNS tumours reviewed here with a practical approach for their daily diagnostic work‐up. Much more progress can be expected in the classification of these neoplasms in the near future.