Neuroendocrine Differentiation in Primary Head and Neck Mucosal Melanomas: Diagnostic Challenges and Clinical Implications in the United States

Primary head and neck mucosal melanoma is a rare and aggressive malignancy distinct from cutaneous melanoma, with no known association with UV exposure and a poorly understood pathogenesis. Diagnosis is often challenging due to its morphologic diversity and potential overlap with other malignancies. A subset of mucosal melanomas has been reported to express neuroendocrine markers, but data remain limited. We analyzed 19 specimens of head and neck mucosal melanoma, assessing morphology and immunoprofile with melanocytic markers, including SOX10, S100, HMB-45, Melan-A, and the neuroendocrine markers synaptophysin, chromogranin, and INSM1. While 4 specimens exhibited synaptophysin positivity, none were positive for all 3 neuroendocrine markers, and only 1 specimen stained for INSM1. The absence of chromogranin suggests that synaptophysin expression may be aberrant rather than indicative of true neuroendocrine differentiation. As a result, the use of synaptophysin alone should be discouraged, and more specific markers such as chromogranin and INSM1 should be used in conjunction. A broad immunohistochemical panel and a high index of suspicion are essential to avoid misclassification of head and neck mucosal melanomas.