Pleomorphic sarcomas and mimics - A practical algorithmic approach to avoid pitfalls!

Pleomorphic sarcomas represent a heterogenous group of sarcomas characterized by marked nuclear anaplasia and overlapping high-grade morphology, often requiring ancillary studies for accurate subclassification. This category includes undifferentiated pleomorphic sarcoma, myxofibrosarcoma, and pleomorphic variants of rhabdomyosarcoma, leiomyosarcoma, and liposarcoma, as well as dedifferentiated liposarcoma and malignant PEComa, among others. Equally important are several non-sarcoma mimics, including superficial CD34-positive pleomorphic fibroblastic tumor and, perhaps most importantly, non-mesenchymal malignancies, such as undifferentiated / dedifferentiated or transdifferentiated melanoma and sarcomatoid carcinoma, which can closely resemble pleomorphic sarcomas, but require fundamentally different management. In this review, we summarize key diagnostic pearls of these entities and present a practical, algorithmic approach integrating clinical, radiologic, gross, histologic, immunohistochemical, and molecular findings to facilitate accurate classification, minimize diagnostic pitfalls, and reduce clinically significant diagnostic errors.