Beyond conventional biomarkers: the role of alpha-fetoprotein in gastroenteropancreatic neuroendocrine neoplasms

Background Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) represent a diverse group of tumors, ranging from well-differentiated neuroendocrine tumors to poorly differentiated neuroendocrine carcinomas. Current biomarkers for GEP-NENs are weak and lack sufficient sensitivity and specificity, complicating diagnosis and prognosis. Alpha-fetoprotein (AFP), a well-established biomarker in other cancers, has been reported as a potentially useful biomarker also for GEP-NENs, but its clinical relevance remains unclear. This narrative review evaluates AFP’s role in GEP-NENs. Materials and methods We conducted a systematic search of PubMed, Scopus, and Web of Science up to December 1, 2025, using MeSH terms and free-text keywords related to AFP and GEP NENs. Only studies reporting measurable circulating AFP levels in GEP-NENs patients were included. Eligible study designs comprised retrospective or prospective studies and interventional trials. Non-English publications, case reports, small case series, reviews, and editorials were excluded. Results We identified ten studies evaluating circulating AFP in GEP-NENs, comprising nine retrospective cohorts’ studies and one prospective study. 2,132 patients were included, with AFP measurements available for 1,222. AFP elevation was rare in GEP-NENs but consistently associated with advanced disease, high tumor grade, and increased proliferative activity. Elevated AFP levels correlated with poorer survival outcomes and higher treatment response rates in patients undergoing chemotherapy. However, despite these associations, the prognostic value of AFP diminished after adjusting for clinicopathological factors, limiting its role as an independent biomarker. Conclusions Current evidence suggests that AFP identifies biologically aggressive subsets of GEP-NENs, reflecting disease burden in specific contexts. While AFP should not be considered an independent biomarker, it holds potential as a contextual signal of aggressive tumor biology and as an adjunctive tool within integrated clinical and pathological frameworks.