Adenocarcinoma admixed with neuroendocrine carcinoma of the cervix: a clinicopathological diagnostic study and molecular features

Cervical adenocarcinoma admixed with neuroendocrine carcinoma (A-NEC) is a rare and aggressive tumor with limited molecular characterization and no standardized treatment. This study aims to delineate its clinicopathological and molecular features to improve diagnostic accuracy and identify potential therapeutic targets. Fourteen rigorously diagnosed cervical A-NEC cases (2016–2024) were retrospectively analyzed according to the WHO 2020 criteria. Comprehensive evaluation included cytology, histomorphology, HPV genotyping, and immunohistochemical profiling of neuroendocrine markers, Ki-67, p53, PTEN, PI3K, and PD-L1. All patients presented with abnormal bleeding or discharge. While cytology detected abnormalities in all evaluable cases (10/10), it did not identify neuroendocrine components. Histology revealed interdigitated HPV-associated adenocarcinoma and neuroendocrine carcinoma (predominantly small cell type). Molecular analysis showed component-specific heterogeneity: although TP53 and PD-L1 expression were concordant, the neuroendocrine component exhibited PTEN loss in all 8 evaluable cases (8/8) and PI3K overexpression in 5/8 cases-a pattern not observed in adenocarcinoma components. NEC demonstrated high proliferative activity (median Ki-67 80%). Survival events were concentrated within the first 24 months. This clinicopathological analysis of 14 cervical A‑NEC cases highlights the diagnostic limitations of cytology and the need for histopathological confirmation in surgical specimens. The neuroendocrine component exhibits distinct molecular features (PTEN loss, PI3K overexpression), indicating dysregulation of the PI3K‑AKT‑mTOR pathway as a potential research target. Most events occur within 24 months, underscoring the importance of early monitoring. These findings improve the understanding of this rare malignancy and support future multicenter studies.