Abstract
BACKGROUND: The fifth edition of the WHO Classification of Tumors of the Central Nervous System (WHO CNS5) recognized CIC-rearranged sarcoma as a distinct mesenchymal, non-meningothelial tumors, designated as CNS WHO grade 4. This entity is characterized by CIC fusion with various partners, notably NUMT1 or DUX4, serving as its key molecular feature and essential diagnostic criterion. However, due to their rarity, the genetic background, etiology and clinical implications of CIC-fused CNS tumors still remains elusive. In a recent study by Philipp Sievers et al., a set of CIC-fused pediatric high-grade neuroepithelial tumors exhibit a distinct DNA methylation profile (CIC-HGNET), differing from CIC-rearranged sarcomas and suggesting an intermediate malignancy grade.Does all the central nervous system CIC tumors are CIC sarcomas or CIC-HGNETs? In this multi-center study, we assembled a series of CIC-rearranged CNS tumors, specifically those with rare fusion partners. Our aim is to broaden the understanding and diversity of CIC-fused CNS tumors, and to discuss whether CNS tumors with CIC fusions merit classification as a unified entity. MATERIAL AND METHODS: Using histological evaluation, immunohistochemistry, next generation sequencing and DNA methylation cluster analysis. RESULTS: The final cohort included 13 CNS CIC-cases and 6 peripheral CIC sarcoma cases. We find that not all intracranial CIC tumors are CIC sarcomas. Unlike peripheral CIC sarcomas (common features are WT1 positive and GFAP/Olig2 negative with relatively abundant reticular fibers), pure intracranial CIC-LEUTX fusion tumors with some GFAP/Olig2/Syn expression, WT1 negative, and no reticular fibers are still neuroepithelial tumor, not sarcoma. CIC-HGNET does exist. However, CIC-HGNETs can’t include all the intracranial CIC tumors. There were still some cases that methylation failed to cluster, indicating new subtypes in CIC tumors (One case of PXA morphology clustered in GG and one case of embryonal tumor morphology clustered in independent group with near LGG-MYB and ependymoma-ZFTA). Although they are not CIC-HGNET, they also belong to CIC-NET, not sarcoma. This point requires special attention, because the two types of tumors have different treatments and different prognosis. The prognosis of neuroepithelial tumors with CIC-LEUTX fusion are much better than CIC sarcomas! CONCLUSION: Pediatric central nervous system tumor with CIC fusion have heterogeneity. It manifests varied methylation signature and clinical characteristics. Whatever, there are two types in CNS tumor with CIC fusion. One is CIC sarcoma and the other is CIC-NET (including new type of CIC-HGNET).