Leiomyosarcoma is a rare type of cancer that affects smooth muscle tissue. Leiomyosarcomas are exceedingly rare in the oral cavity, particularly in the buccal mucosa. The diagnosis is challenging due to non-specific clinical features and significant overlap of morphological findings with several spindle cell tumors. We reported the clinicopathological and immunohistochemical features of a rare recurrent case of leiomyosarcoma in a 73-year-old female presenting clinically as a painful nodule on the posterior right buccal mucosa. Microscopically, the lesion showed atypical spindle cells arranged in a fascicular pattern and frequent mitotic figures. Immunohistochemistry showed strong positivity for vimentin, α-SMA, HHF35, h-caldesmon, and focal positivity for desmin. CD34 highlighted numerous blood vessels distributed throughout all tumor stroma. S-100 protein, myogenin, and pan-cytokeratin (AE1/AE3) were negative. Surgical excision followed by chemotherapy was carried out, and no recurrence was observed after 1 year of follow-up. Careful histopathological and immunohistochemistry analysis of these lesions is essential to ensure a correct diagnosis. Early surgical excision with tumor-free margins and prolonged follow-up is strongly recommended.
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