The New Molecularly Defined CNS Sarcomas: FET::CREB Fusion-Positive Intracranial Mesenchymal Tumour, CIC-Rearranged Sarcoma, and DICER1-Mutant Primary Intracranial Sarcoma

The 2021 WHO Classification of Tumours of the Central Nervous System introduced three molecularly defined mesenchymal entities: intracranial mesenchymal tumour, FET::CREB fusion-positive; CIC-rearranged sarcoma; and primary intracranial sarcoma, DICER1-mutant. Each is genetically defined yet morphologically non-specific, and each mimics a commoner neoplasm: meningioma, Ewing or embryonal tumour, and high-grade glioma respectively. Existing accounts describe these tumours descriptively and in parallel. This review instead reads all three through a single mechanistic lens, tracing each defining lesion to its diagnostic phenotype. We compare the available diagnostic modalities and propose a practical, tiered testing algorithm. Two findings stand out. DNA methylation profiling is the diagnostic backbone for CIC-rearranged and DICER1-mutant sarcoma but has no dedicated class for FET::CREB fusion-positive intracranial mesenchymal tumour, which it actively misassigns to meningioma, making RNA-based fusion testing indispensable. Alone among the three, DICER1-mutant sarcoma may arise on a germline background, so its diagnosis triggers counselling and surveillance for the patient's family. Across all three, molecular characterisation has largely resolved diagnostic ambiguity without yet delivering therapy: mechanistically rational targets remain preclinical, and management rests on resection and borrowed adjuvant regimens. Closing that diagnostic-to-therapeutic gap will require registries, standardised outcome reporting and molecularly stratified trials.