Undifferentiated Small Round Cell Sarcomas of Bone and Soft Tissue With EWSR1/FUS :: NFATC2 Fusions

Context.— The latest WHO (World Health Organization) Classification of Bone and Soft Tissue Tumours (5th edition) has recently defined undifferentiated round cell sarcomas (URCSs) with EWSR1/FUS::NFATC2 (EWS RNA binding protein 1 or FUS RNA binding protein fused with nuclear factor of activated T cells 2) fusions. Given the rarity of this fusion, cytologic findings remain unreported, and information regarding clinical presentation, biological behavior, diagnostic markers, and molecular characteristics is scarce. Objective.— To provide a review of the clinicopathologic, molecular, and prognostic features of URCSs with EWSR1/FUS::NFATC2 fusions. Classic histopathologic findings, uncommon variations, and diagnostic pitfalls are addressed, along with the utility of recently developed immunohistochemical and molecular markers. Data Sources.— Bringing together our institutional expertise and a thorough evaluation of the literature, this review captures key findings and trends through an extensive PubMed search. By integrating our own practical insights with evidence-based data, we offer a well-rounded perspective that sheds light on both foundational concepts and new advancements in the field. Conclusions.— This review underscores the importance of integrating clinicopathologic features and immunohistochemical results with EWSR1/FUS testing to effectively identify sarcomas with rare gene fusions via next-generation sequencing, which carry prognostic significance. Additionally, URCS-harboring EWSR/FUS::NFATC2 fusions exhibit notable differences from Ewing sarcoma and other URCSs, including a limited response to neoadjuvant chemotherapy; unique morphologic characteristics; and distinct genomic, transcriptomic, and epigenetic (methylation) profiles. Given the potential differences in biological behavior, accurate subclassification of EWSR1/FUS fusion variants is essential.