The expression of epithelial markers, particularly cytokeratins, has traditionally been regarded as evidence of epithelial differentiation. However, an increasing number of mesenchymal neoplasms are now recognized to exhibit keratin and other epithelial marker expression, creating significant diagnostic challenges and raising the possibility of misclassification as carcinoma.

This lecture reviews the expanding spectrum of soft tissue tumors with epithelial immunophenotypes and discusses practical strategies for their recognition. Classic entities such as epithelioid sarcoma, synovial sarcoma, and pseudomyogenic hemangioendothelioma will be reviewed alongside newly characterized neoplasms, including keratin-positive giant cell-rich tumor/xanthogranulomatous epithelial tumor, TFCP2-rearranged rhabdomyosarcoma, and nodular necrotizing fibroblastic tumor among a few others. Particular attention will be paid to recently recognized molecular alterations and their correlation with morphology and immunophenotype.

The presentation will emphasize a pattern-based diagnostic approach integrating histopathologic features, immunohistochemistry, and molecular pathology, highlighting common pitfalls and useful discriminating markers. The increasing recognition of these entities underscores the limitations of relying on cytokeratin expression alone and illustrates the growing importance of molecular classification in modern soft tissue pathology.

A practical understanding of these tumors is essential to avoid diagnostic errors that may lead to inappropriate clinical management.