Large-Cell Neuroendocrine Carcinoma of the Ampulla of Vater: A Systematic Literature Review of a Rare and Aggressive Entity.

Neuroendocrine carcinomas of the ampulla of Vater are rare but highly aggressive, poorly differentiated neoplasms associated with poor outcomes. This contrasts with ampullary adenocarcinoma, which is generally associated with more favourable survival following curative resection, and with well-differentiated periampullary neuroendocrine tumours, which typically demonstrate more indolent behaviour and better prognosis. A Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-compliant systematic review was conducted across PubMed/MEDLINE, Embase, Scopus, Web of Science, and Google Scholar (from inception to July 2025) to identify reported cases of large-cell neuroendocrine carcinoma (LCNEC) of the ampulla of Vater. Studies reporting extractable patient-level clinicopathological, treatment, and outcome data were included. Data were standardised and synthesised descriptively due to the rarity and heterogeneity of the condition. A total of 22 patient-level cases of LCNEC of the ampulla of Vater were identified from 14 studies. The median age was 70 years (range: 44-84), with a male predominance. Tumours were generally small at presentation (median size approximately 20 mm); however, lymph node metastasis was present in 16 of 20 evaluable patients (80%). All patients underwent pancreaticoduodenectomy or pylorus-preserving pancreaticoduodenectomy. Adjuvant chemotherapy was administered in 12 of 22 patients (55%), most commonly platinum-based regimens. Tumour recurrence occurred in approximately 55-60% of cases, most frequently involving the liver. Median overall survival was approximately 11 months, with eight patients (36%) alive at the last follow-up. LCNEC of the ampulla of Vater is an aggressive malignancy with poor prognosis despite surgical resection. This review highlights a clinically important "size-biology paradox," whereby relatively small tumours demonstrate early metastatic behaviour and adverse outcomes. Tumour biology appears to outweigh conventional staging parameters, underscoring the need for early recognition, accurate histopathological classification, and consideration of systemic therapy. Further multicentre studies are required to optimise management strategies and improve patient outcomes.