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Journal of Peking University (Health Sciences) ›› 2026, Vol. 58 ›› Issue (2): 257-265. doi: 10.19723/j.issn.1671-167X.2026.02.006

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Novel clinical insights and frontier issues in alpha- fetoprotein-producing gastric cancer

Bixian LUO, Hongming LIU, Weixun XIE, Weihua GONG*()   

  1. Department of Gastrointestinal Surgery, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310058, China
  • Received:2025-11-30 Online:2026-04-18 Published:2026-02-05
  • Contact: Weihua GONG
  • Supported by:
    the Key Research and Development Program of Zhejiang Province(2025C02054); the National Natural Science Foundation of China(82470416)

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Abstract:

Alpha-fetoprotein-producing gastric cancer (AFPGC) represents a distinct clinical entity within the landscape of gastric malignancies, characterized by its aggressive biological behavior and unique clinicopathological profile. Most cases are classified under the chromosomal instability (CIN) subtype, featuring a molecular signature often marked by TP53 and MUC16 mutations, as well as significant amplifications of genes like ERBB2 and the cell cycle regulator CCNE1. As a serum tumor marker, alpha-fetoprotein (AFP) is typically highly elevated in AFPGC and correlates closely with tumor T-stage and patient prognosis. However, discordant expression is observed in some cases, characterized by positive intra-tumoral AFP expression in the presence of normal serum AFP levels. Moreover, intra-tumoral AFP plays an important role in both tumor invasiveness and immune evasion. It may promote tumor pro-liferation and metastasis by modulating immune cell activity. The high malignant potential of AFPGC may be attributable to its capacity to actively remodel the tumor milieu toward an immunosuppressive phenotype. Clinical studies have shown that the co-elevation of AFP with other markers, such as carcinoembryonic antigen (CEA), human chorionic gonadotropin (HCG), and protein induced by vitamin K absence or antagonist-Ⅱ (PIVKA-Ⅱ) often indicates a high malignant potential and a poor prognosis in gastric cancer, particularly in patients with advanced disease. Such concurrent detection of two or more biomar-kers facilitates the assessment of tumor aggressiveness as well as provides a clinical basis for early diagnosis and prognostic evaluation. Currently, there are no standardized guidelines for AFPGC treatment, and strategies often rely on individual pathological profile, tumor staging, and biomarker levels. In addition, immune checkpoint inhibitors (ICIs) have shown preliminary efficacy in some cases. Immunotherapy has demonstrated potential in AFPGC treatment, but the overall therapeutic outcomes and underlying mechanisms of resistance warrant further clinical validation and investigation. Individualized and multimodal therapeutic approaches are fundamental to improving clinical outcomes due to the high degree of heterogeneity in AFPGC. Therefore, a comprehensive evaluation of serum AFP levels, radiological findings, and pathological characteristics is essential for the development of personalized treatment regimens.

Key words: Alpha-fetoprotein-producing gastric cancer, Mutation, Tumor escape, Tumor biomarkers

CLC Number: 

  • R735.2

Table 1

Differential characteristics of AFPGC, HAS and HCC"

Features AFPGC HAS HCC
Cellular origin Gastric glandular epithelium Stomach (with hepatoid differentiation) Hepatic parenchyma
AFP levels[7] Elevated (≥7 μg/L) Elevated Significantly elevated (pathognomonic)
Pathological features[8-9] Gastric adenocarcinoma, focal hepatoid changes Dual features of gastric adenocarcinoma and HCC Liver malignancy, hepatoid differentiation
Molecular profile[10-11] Gastric-like, TP53 (55%), CDH1 HCC-like, TP53 (66%) TP53, CTNNB1, TERT promoter mutations
ERBB2 amplification[11] Highest (25.8%) Intermediate (21.05%) Lowest (0.6%)
Molecular/IHC markers[12-13] AFP (+), GPC3 (64.84%) AFP (+), GPC3 (78.1%) AFP (+), GPC3 (+), HCC hallmarks
Therapeutic strategies[14] Resection, chemo, and immunothe-rapy Refractory to gastric cancer regimens, HCC-oriented therapy Transplant, targeted therapy, and immunotherapy
Prognosis[15] Poor, AFP elevation correlated with stage and invasiveness Poor, especially in AFP-high cases, low 5-year survival, frequent liver metastasis Poor, particularly in advanced stages or patients with cirrhosis

Table 2

Clinical subtypes and expression of AFP, VEGF, and CEA in AFPGC[16]"

Subtype n AFP (+) VEGF (+) CEA (+)
Hepatoid 19 7 (36.8%) 9 (47.4%) 7 (36.8%)
Yolk sac tumor-like 32 7 (21.9%) 9 (28.1%) 24 (75.0%)
Fetal gastrointestinal 5 0 (0) 1 (20.0%) 4 (80.0%)
Mixed 8 1 (12.5%) 2 (25.0%) 7 (87.5%)

Figure 1

AFP expression patterns in AFPGC A, diffuse cytoplasmic AFP expression within the malignant glandular epithelium; B, extracellular AFP secretion into the interstitial stroma. AFPGC, alpha-fetoprotein-producing gastric cancer; AFP, alpha-fetoprotein."

Figure 2

Prognostic role of AFP expression in gastric cancer A, comparison of AFP mRNA levels between normal and tumor tissues; B, heatmap correlating AFP expression (high vs. low) with key clinicopatho-logical features; C, correlation between AFP expression and pathologic T stage; D, Kaplan-Meier curves for progress-free survival (PFS) and overall survival (OS); E, integrated forest plot of univariate and multivariate Cox regression analyses. AFP, alpha-fetoprotein."

Figure 3

Genomic mutation landscape in gastric cancer with high AFP expression A, oncoplot of mutated genes; B, summary of variant classifications; C, distribution of variant types; D, profiling of SNV classes. AFP, alpha-fetoprotein; SNV, single nucleotide variant; SNP, single nucleotide polymorphism; INS, insertion; DEL, deletion."

Figure 4

Correlation between AFP expression and immune infiltration in gastric cancer A, tSNE visualization of AFP expression; B, relative expression levels of immune-related markers; C, infiltration levels of CD8+ T cells and activated NK cells stratified by AFP expression status. NK, natural killer cell; AFP, alpha-fetoprotein; FPKM, fragments per kilobase of exon model per million mapped fragments; tSNE, t-distributed stochastic neighbor embedding."

Figure 5

Prognostic value of multi-biomarker models in AFPGC A-E, Kaplan-Meier survival curves illustrating risk-stratified overall survival outcomes based on various biomarker combinations; F, forest plot summarizing the hazard ratio (HR) and 95% confidence interval (CI) for five multivariate Cox regression analysis. All Cox regression models were adjusted for age, gender, tumor grade, and pathologic stage. AFPGC, alpha-fetoprotein-producing gastric cancer; AFP, alpha-fetoprotein; CEA, carcinoembryonic antigen; HCG, human chorionic gonadotropin; PIVKA-Ⅱ, protein induced by vitamin K absence or antagonist-Ⅱ."

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