Decoding Cervical Neuroendocrine Carcinoma: A Practical Review of Diagnostic Pitfalls, Differential Diagnosis and Molecular Insights

Cervical neuroendocrine carcinoma (NECC) is a rare but highly aggressive cervical malignancy, accounting for approximately 1% of invasive cervical cancers. Diagnosis is challenging because NECC overlaps morphologically with other poorly differentiated cervical and metastatic tumors, may show crush artifact in small biopsies, and can display variable expression of conventional neuroendocrine markers. This narrative review provides a practical synthesis of the histopathological, immunohistochemical, molecular, and clinical features of NECC, with emphasis on diagnostic pitfalls and differential diagnosis. Recent English-language literature on cervical neuroendocrine carcinoma was reviewed and qualitatively integrated, focusing on morphology, immunohistochemistry, HPV association, molecular alterations, prognosis, and management-relevant diagnostic issues. Accurate diagnosis requires integration of morphology, epithelial differentiation, neuroendocrine marker expression, HPV-related context, and clinic-radiological correlation. Useful markers include broad-spectrum cytokeratins, synaptophysin, chromogranin A, CD56, INSM1, p16, and Ki-67, with additional markers selected according to the differential diagnosis. Diffuse block-type p16 expression and high-risk HPV detection support a cervical HPV-associated origin but are not specific for neuroendocrine differentiation. Molecular studies show frequent association with HPV18 and recurrent alterations involving PI3K/AKT, RAS/MAPK, and TP53-related pathways, although these findings remain insufficiently validated for routine prognostic or therapeutic stratification. NECC requires early recognition and a multimodal diagnostic approach because of its aggressive behavior and poor prognosis. A practical, stepwise integration of morphology, immunohistochemistry, molecular findings, and clinical–radiological data may improve diagnostic consistency and support multidisciplinary management.