Undifferentiated Round Cell Sarcomas: A Comprehensive Review and Practical Diagnostic Guide with an Emphasis on Superficial Body Sites

Abstract

Undifferentiated round cell sarcomas are rare malignant tumors that can be especially difficult to recognize when arising in the skin or subcutis, where sarcomas are often not suspected and biopsies may be limited. Their round cell morphology and overlapping immunophenotypic profiles can mimic lymphoma, melanoma, Merkel cell carcinoma, and poorly differentiated carcinoma. Recent advances in molecular diagnostics have clarified this heterogeneous group, with the World Health Organization currently recognizing several distinct entities, including Ewing sarcoma, CIC-rearranged sarcoma, BCOR-altered sarcomas, and EWSR1-non-ETS fusion sarcomas. Despite these refinements, superficial presentations remain prone to misclassification. This review provides an overview of undifferentiated round cell sarcomas, emphasizing their clinical, histologic, immunohistochemical, and molecular features, while outlining important mimics at superficial sites. We highlight an integrated diagnostic framework that combines morphology, broad immunohistochemical panels, and molecular testing. Accurate recognition of these tumors is essential, as correct classification directly informs prognosis and therapeutic decision-making.