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

## TL;DR

This paper reviews the role of alpha-fetoprotein (AFP) in gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs), finding that elevated AFP is linked to aggressive tumors and poor outcomes but is not a standalone biomarker.

## Contribution

The study systematically evaluates AFP's clinical relevance in GEP-NENs, revealing its potential as an adjunctive biomarker for aggressive tumor biology.

## Key findings

- Elevated AFP levels are associated with advanced disease, high tumor grade, and poor survival in GEP-NENs.
- AFP correlates with increased treatment response to chemotherapy but loses prognostic value after adjusting for clinicopathological factors.
- AFP identifies biologically aggressive subsets of GEP-NENs but is not an independent biomarker.

## Abstract

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.

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.

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.

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.

Our review of circulating AFP in GEP-NENs highlights its association with tumor aggressiveness and potential role as an adjunctive biomarker.Infographic summarizing the role of AFP in GEP-NENs includes visuals of the digestive organs, a blood vial labeled AFP, tumor illustrations, graphs, and icons. Highlights include AFP being elevated in aggressive, high-grade tumors, associated with poor prognosis and reduced survival, but showing response to chemotherapy. Methods noted systematic literature review including 2,132 patients. Conclusion states AFP is a marker of aggressive GEP-NENs but not an independent biomarker.

Our review of circulating AFP in GEP-NENs highlights its association with tumor aggressiveness and potential role as an adjunctive biomarker.