Undifferentiated Round Cell Sarcomas: Retrospective Morphological, Immunohistochemical, and Molecular Re-Evaluation...

Undifferentiated round cell sarcomas (URCSs) are aggressive neoplasms with overlapping histology but distinct molecular profiles. Accurate subclassification is crucial for prognosis and therapy, particularly in tumors lacking classic Ewing sarcoma alterations. In this retrospective study, 59 URCSs were re-evaluated morphologically, immunohistochemically, and molecularly. Fifty-three were classified as Ewing sarcoma, and six as non-Ewing sarcoma: three BCOR::CCNB3, two CIC::DUX4, and one ZC3H7B::BCOR. Ewing sarcomas showed uniform round cells with thin fibrovascular stroma. BCOR-altered sarcomas often contained spindle cells and myxoid stroma, whereas CIC::DUX4 tumors displayed epithelioid cells with eosinophilic cytoplasm, nucleoli, and myxoid stroma. Stromal features and cellular morphology differed significantly between Ewing and non-Ewing groups. Immunohistochemically, Ewing sarcomas had higher NKX2.2 and CD99 expression while BCOR-altered tumors showed strong nuclear BCOR positivity. WT1 staining revealed distinct paranuclear positivity in both CIC::DUX4 cases. Our unique ZC3H7B::BCOR case involved a young adult with spindle cell morphology, myxoid stroma, and negative BCOR staining, underscoring diagnostic challenges and contributing novel clinicopathologic data on this exceedingly rare subtype. These findings highlight key morphologic and immunophenotypic clues to differentiate URCS subgroups and reinforce the importance of integrated histopathological and molecular evaluation to achieve accurate diagnosis and subclassification.