Rare intracranial mesenchymal tumors with FET::CREB fusions: clinicopathologic spectrum of four cases with integrated molecular analysis and review of the literature.

Primary intracranial mesenchymal tumors harboring FET::CREB gene fusions were recognized in the 2021 World Health Organization (WHO) Classification of Central Nervous System (CNS) tumors as a provisional entity within mesenchymal, non-meningothelial tumors. Most reported cases to date have arisen in the supratentorial region and abut the meninges. Herein, four cases of intracranial mesenchymal tumors with confirmed FET::CREB fusions are reported. Their clinical histories and neuroimaging findings were reviewed, and the histopathological, immunohistochemical, and molecular genetic features were further described. Three of the four cases showed lipoblastoid cells, and one showed irregular giant cells, which have not been described previously. Among the four cases, three were infratentorial with the same molecular profile EWSR1::CREM fusions and one was supratentorial with EWSR1::ATF1 fusion. Notably, the three infratentorial EWSR1::CREM fusion-positive tumors exhibited different morphologic characteristics from each other. DNA methylation profiling showed that the four tumors formed a unique cluster, besides, none of them clustered with established CNS tumors or extracranial sarcomas reference classes. All patients underwent gross total resection without adjuvant radiotherapy or chemotherapy, and no recurrences were observed during follow-up. Collectively, these tumors display a broad histological spectrum and appear to behave indolently or as low-grade malignancies. However, given the limited number of cases, larger cohorts are required to futher elucidate their biology and refine diagnostic stratification.