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The differential diagnosis of pleomorphic rhabdomyosarcoma (PRMS) includes:

Other rhabdomyosarcoma subtypes, all of which can have anaplastic features. PRMS is seen in adults, whereas alveolar and embryonal RMS are seen in younger patients. Moreover, thorough sampling will usually reveal more typical areas in cases of alveolar or embryonal RMS.

Pleomorphic sarcoma (MFH): Immunohistochemical analysis is essential in differentiating PRMS from other adult pleomorphic sarcomas. Immunoreactivity for desmin, muscle-specific actin, sarcomeric alpha-actin, MyoD1, and myogenin supports the diagnosis of PRMS.

Pleomorphic leiomyosarcoma: This tumor usually has low-grade areas composed of intersecting fascicles of tumor cells with typical smooth muscle features. Actin and desmin may be positive in both PRMS and pleomorphic leiomyosarcoma; however, MyoD1 and myogenin are expressed only by the former.

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