Updates in keratin-positive mesenchymal neoplasia

Increased access to and utilization of molecular testing in recent years has resulted in rapid discovery of fusion-driven entities in mesenchymal neoplasia. A subset of these rare tumors are defined by cytokeratin expression, which can lead to diagnostic overlap with more common keratin-positive neoplasms (poorly differentiated carcinomas, mesothelioma, etc). Recent examples include spindle cell rhabdomyosarcomas with TFCP2 fusions, keratin-positive giant-cell rich tumors with HMGA2::NCOR2 fusions, NR1D1- rearranged sarcomas, malignant epithelioid neoplasms with FET::CREB fusions, and the very recently described ossifying spindled and epithelioid tumors (OSET). This review will address the unique clinical, histologic, and immunophenotypic characteristics of these rare neoplasms and provide practical considerations for molecular testing in challenging cases of keratin-positive mesenchymal neoplasia.