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Differential Diagnosis: Neoplasms that can have pleomorphic appearance include: lineage-specific sarcomas (pleomorphic variants of leiomyosarcoma, rhabdomyosarcoma, and liposarcoma), dedifferentiated liposarcoma (especially for retroperitoneal tumors), sarcomatoid carcinomas, sarcomatoid mesothelioma, melanoma, and even anaplastic lymphoma.

When faced with a high-grade pleomorphic neoplasm, a panel of immunohistochemical markers is often used, including keratins, p63, p40, S-100 protein, melanocytic markers (HMB45, melan-A), muscle markers (SMA, desmin, MyoD1, myogenin), CD30, and ALK1. The selection of specific markers is guided by tumor morphology. In retroperitoneal tumors, FISH for MDM2 amplification may be required to rule out dedifferentiated liposarcoma.

Undifferentiated pleomorphic sarcoma (UPS) shows no identifiable line of differentiation and it remains a diagnosis of exclusion.. The individual entities in the differential diagnosis of UPS are discussed in the next several images.

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