Undifferentiated Small Round Cell Sarcomas of Bone and Soft Tissue With EWSR1/FUS::NFATC2 Fusions: A Review of Clinicopathologic Characteristics, Differential Diagnoses, and Patient Management

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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.

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