Neuroendocrine neoplasms of the oral cavity: a narrative review of clinicopathological features and management

Neuroendocrine neoplasms (NENs) of the oral cavity are extremely rare, accounting for less than 1% of all head and neck malignancies. Their diagnosis is challenging due to nonspecific clinical features and significant histopathologic overlap with other intraoral tumors. This narrative review summarizes current evidence on the epidemiology, pathogenesis, diagnosis, and management of head and neck NENs in general, with particular attention on the oral cavity side, encompassing both well- and poorly differentiated forms. Reported cases indicate the gingiva and buccal mucosa as the most frequent primary sites. Clinically, lesions usually present as painless nodules or ulcerated masses. Definitive diagnosis requires integration of morphologic and immunohistochemical findings, typically demonstrating positivity for synaptophysin, chromogranin A, and CD56. In the absence of specific international guidelines for the oral cavity, given the limited availability of data in the literature, the most appropriate approach currently follows the guidelines for managing head and neck NENs, which consists of surgical excision, which remains the treatment of choice for localized disease and is often followed by adjuvant chemoradiotherapy. In advanced or metastatic stages, platinum-based chemotherapy may provide transient disease control but offers limited survival benefit. Novel therapeutic modalities, including immune checkpoint inhibitors and peptide receptor radionuclide therapy, show preliminary promise but lack robust clinical validation. Given the rarity and heterogeneity of these tumors, multidisciplinary management and the establishment of multicenter registries are crucial for improving diagnostic accuracy, standardizing treatment strategies, and enhancing clinical outcomes.