When Immunophenotype Is Not Identity: A Clinicopathological Review of Neuroendocrine Differentiation in Tumors of the Female Genital Tract

Neuroendocrine differentiation in tumors of the female genital tract is an uncommon but diagnostically consequential finding. Its interpretation is challenging because neuroendocrine marker expression does not necessarily define a neuroendocrine neoplasm. Focal or aberrant staining for synaptophysin, chromogranin A, CD56 or INSM1 may occur in otherwise conventional gynecologic carcinomas, whereas true poorly differentiated neuroendocrine carcinomas represent aggressive tumors with distinct prognostic and therapeutic implications. This narrative review examines neuroendocrine differentiation across the cervix, endometrium, ovary, vagina and vulva from an integrated clinicopathologic perspective. We emphasize that neuroendocrine differentiation should be approached as a diagnostic and biological spectrum, ranging from incidental immunophenotypic expression to carcinoma with neuroendocrine differentiation, mixed neuroendocrine/non-neuroendocrine tumors, well-differentiated neuroendocrine tumors and poorly differentiated neuroendocrine carcinomas. Morphology remains the diagnostic anchor, while immunohistochemistry, molecular context and clinicoradiologic correlation refine classification and help exclude mimics or metastatic disease. Site-specific interpretation is essential: cervical neuroendocrine carcinoma is commonly HPV-associated and clinically aggressive; endometrial tumors require integration with p53, mismatch repair, POLE and SWI/SNF-related contexts; ovarian lesions demand distinction between primary well-differentiated neuroendocrine tumors, poorly differentiated carcinomas and metastases; and vaginal or vulvar tumors require careful exclusion of adjacent extension, cutaneous mimics and extragenital primaries. We propose a practical diagnostic framework that separates incidental marker expression from clinically meaningful neuroendocrine differentiation and links this distinction to reporting, prognosis and treatment. The central diagnostic question is not whether neuroendocrine markers are expressed but whether their expression defines a morphologically, biologically and clinically meaningful tumor category.