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2026 , Vol. 58 >Issue 2: 257 - 265

DOI: https://doi.org/10.19723/j.issn.1671-167X.2026.02.006

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

  • Bixian LUO ,
  • Hongming LIU ,
  • Weixun XIE ,
  • Weihua GONG , *
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  • Department of Gastrointestinal Surgery, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310058, China
GONG Weihua, e-mail,

Received date: 2025-11-30

  Online published: 2026-02-05

Supported by

the Key Research and Development Program of Zhejiang Province(2025C02054)

the National Natural Science Foundation of China(82470416)

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All rights reserved. Unauthorized reproduction is prohibited.
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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

Cite this article

Bixian LUO , Hongming LIU , Weixun XIE , Weihua GONG . Novel clinical insights and frontier issues in alpha- fetoprotein-producing gastric cancer[J]. Journal of Peking University(Health Sciences), 2026 , 58(2) : 257 -265 . DOI: 10.19723/j.issn.1671-167X.2026.02.006

产甲胎蛋白胃癌(alpha-fetoprotein-producing gastric cancer, AFPGC)作为一种特殊类型的胃癌，具有独特的生物学特征和较高的侵袭转移潜力，近年来受到学界越来越多的关注。甲胎蛋白(alpha-fetoprotein, AFP)不仅是胃癌的一个血清标志物，还是AFPGC患者特有的生物学特征之一。尽管AFP水平在部分患者的血清中无明显升高，但其在胃癌组织中却表达增高，这一特性使得AFPGC在临床诊断和治疗中面临较大挑战，尤其是在免疫逃逸机制和肿瘤微环境的塑造方面。关于AFPGC分子机制、基因突变及免疫逃逸的具体作用仍需深入探讨。随着对其生物学特性研究的不断推进，临床上癌胚抗原(carcinoembryonic antigen，CEA)、人绒毛膜促性腺素(human chorionic gonadotropin，HCG)、维生素K缺乏或拮抗剂-Ⅱ诱导的蛋白质(protein induced by vitamin K absence or antagonist-Ⅱ，PIVKA-Ⅱ，又称异常凝血酶原)等标志物的联合升高提示AFPGC高恶性潜能，为AFPGC的早期诊断、预后评估和个体化治疗提供了临床诊疗思路。

1 AFPGC的分型和新临床特征

1.1 AFPGC的基因型

2014年，国际上把胃癌分为4种不同基因型，包括爱泼斯坦-巴尔病毒阳性型(Epstein-Barr virus positive, EBV+)、微卫星不稳定型(microsatellite instability, MSI)、基因组稳定型(genomically stable, GS)、染色体不稳定型(chromosomal instability, CIN)[1]。绝大多数AFPGC被分类为CIN，等位基因丢失的中位数指数为72%，这比正常胃腺癌高50%[2]，AFPGC患者可能因其独特的遗传特征而对免疫疗法产生不同反应。此外，其他研究表明，CIN是转移进展的驱动因素，这可能部分导致AFPGC的侵袭性表型[3]。

1.2 AFPGC并不等同于胃肝样腺癌

AFPGC是指患者外周血AFP水平升高或者胃癌组织免疫组化染色AFP呈阳性，而胃肝样腺癌(hepatoid adenocarcinoma of the stomach, HAS)更关注病理形态学，通常是指发生在肝脏以外、具有异常肝细胞分化的胃肿瘤，两者之间存在部分重叠人群，患者均预后不良[4]。AFPGC起源于胃腺体，少部分肝细胞样分化局部存在，而HAS则是一种具有胃腺癌和肝细胞癌双重特征的特殊胃癌亚型。HAS的肿瘤成分是单克隆来源，且分子特征和基因突变谱更接近肝癌。HAS与肝细胞癌(hepatocellular carcinoma, HCC)在分子特征和代谢通路上更为相似，尤其在肝细胞样分化、AFP和磷脂酰肌醇蛋白聚糖3(glypican-3，GPC3)等肝癌标记物的表达上有显著重叠。HAS的基因突变谱与肝癌高度重合，尤其在MET/HGF通路和蛋氨酸循环等代谢相关通路的异常上[5]。因此，HAS的治疗策略可能需要结合胃癌和肝癌的治疗方法，而AFPGC则主要依赖传统的胃癌治疗。AFPGC与HAS和HCC的具体区别详见表 1。1993年，日本新潟大学医学院的学者通过AFPGC的形态学、组织化学和生化分析，提出了4种亚型(表 2)[6]。
表1 AFPGC与HAS和HCC的区别

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

AFPGC, alpha-fetoprotein-producing gastric cancer; HAS, hepatoid adenocarcinoma of the stomach; HCC, hepatocellular carcinoma; AFP, alpha-fetoprotein; IHC, immunohistochemistry.

表2 AFPGC的临床分型及其AFP、VEGF、CEA表达情况[16]

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%)

AFPGC, alpha-fetoprotein-producing gastric cancer; AFP, alpha-fetoprotein; VEGF, vascular endothelial growth factor; CEA, carcinoembryonic antigen.

我们通过文献复习总结了AFPGC的AFP、血管内皮生长因子(vascular endothelial growth factor, VEGF)、CEA的表达情况，为后续临床应用VEGF受体抑制剂(如阿帕替尼、呋喹替尼等)提供了分子生物学依据，也有利于理解AFP和CEA双阳性胃癌的临床独特性。

1.3 AFPGC患者的AFP蛋白可以不出现在外周血，仅在胃癌组织中表达

临床中我们发现，外周血AFP水平和胃癌组织的AFP表达水平可以呈现不一致的现象，部分AFPGC患者外周血的AFP水平正常，但是其胃癌组织的免疫组化染色可以呈现强阳性。事实上，AFP作为一种血清糖基化蛋白，它的N端含有一个1~19个氨基酸的信号肽序列，此序列在合成过程中会帮助AFP通过内质网来折叠和糖基化修饰[17-18]。AFPGC中的AFP蛋白可以在癌细胞质中蓄积，也可以分泌到细胞外影响肿瘤细胞和免疫细胞的功能(图 1)[16]，这种分泌机制的调控以及AFP胞内和胞外的具体功能目前尚待进一步研究。
图1 AFPGC中AFP表达蛋白情况

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.

1.4 AFPGC具有独特的生物学特性及基因突变和染色体异常特征

与普通胃癌相比，AFPGC具有更高的恶性度和侵袭性，这是因为其具备一些独特的生物学特征。我们通过分析癌症基因组图谱(The Cancer Genome Atlas, TCGA)公共数据库发现，AFP在胃癌组织中高表达(图 2A)，并且其与T分期相关(图 2B、C)，推断AFP能促进胃癌细胞的迁移和侵袭。生存分析发现，AFP高表达的胃癌患者预后更差(图 2D)，多因素分析得出，AFP高表达是独立的预后不良因子(图 2E)，为组织层面的AFP水平可以指导临床诊疗提供了一定的理论依据。因此，对于AFPGC而言，AFP本身可能是促进肿瘤发生、发展的一种因素。
图2 AFP在胃癌预后中的作用

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.

有研究认为，最常见的分子事件是AFPGC中的TP53突变，此突变往往发生于DNA结合结构域，引起p53功能丧失，进而导致肿瘤细胞的恶性表型和高侵袭性，AFPGC最常见的扩增突变为CCNE1、ERBB2和EGFR [12]。另一项研究表明，AFPGC存在ERBB2 (17q12)、CCND1 (11q13.3)、CCNE1 (19q12)、MUC4 (3q29)、MCL1 (1q21.3)、MYC(8q24.21)的扩增，以及ARID1A (1p36.11)、CDKN2A (9p21.3)、CREBBP(16p13.3)、SMAD4 (18q21.2)的缺失，该研究进一步分析表明，具有19q12处CCNE1扩增和/或17q12处ERBB2扩增的AFPGC表现出较差的生存率和更具侵袭性[19]。值得一提的是，ERBB2蛋白扩增在HAS中也更为常见(25%)[20]。因此，针对ERBB2、CCNE等的单靶向、双靶向、抗体药物偶联物(antibody-drug conjugate，ADC)可能是未来治疗AFPGC和HAS的创新药物。
通过分析TCGA公共数据库发现，在AFP胃癌组织中，最常见的基因突变为TTN (52%)、TP53 (46%)和MUC16 (31%)，见图 3A。TP53的高频突变特征与既往报道一致，需要指出的是，尽管TTN突变最常见，但考虑到其作为人类基因组最长基因的特性，这些突变多属于非驱动性的乘客突变，其致癌意义相对有限。相比之下，MUC16可通过参与癌细胞与周围基质的相互作用，改变细胞黏附性，增强肿瘤细胞的侵袭和转移能力，值得深入探讨。进一步的突变特征分析发现，AFP高表达的胃癌组织中最常发生错义突变，在单核苷酸变异(single nucleotide variant，SNV)分类中，C>T转换是最主要的变异类型(图 3B~D)。
图3 AFP高表达的胃癌中基因突变情况

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.

AFP不仅是推动癌变的动力源泉，还是多维度塑造肿瘤微环境的关键因子之一。有研究表明，AFP在肝癌中可以直接削弱免疫细胞的免疫效应，阻断抗原提呈功能，降低CD8+ T细胞毒性与自然杀伤细胞的杀伤力，另外，AFP还能增强免疫抑制细胞的扩增，使得其在宿主与肿瘤细胞之间建立起一种免疫耐受的保护伞，让癌细胞得以逃脱免疫系统的监视和清除[21]。然而，目前关于阐明AFP在胃癌免疫微环境中扮演角色的研究较少。我们使用TCGA公共数据库对AFP与免疫细胞进行分析，通过t-分布随机邻域嵌入(t-distributed stochastic neighbor embedding, tSNE)降维发现有2例异常转录水平高表达AFP的患者(图 4A)，同时，这两例患者的CD8和自然杀伤细胞标志物CD8b和NCAM1相对表达量处于垫底水平(图 4B)，并且AFP的表达水平与CD8+ T细胞和自然杀伤细胞呈负相关(图 4C)。因此，AFPGC的高恶性度可能与其塑造免疫抑制性微环境相关。
图4 胃癌中AFP表达与免疫浸润的关系

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.

2 一些值得临床关注的AFPGC特殊亚型

在AFPGC患者中，如果合并出现CEA、HCG、PIVKA-Ⅱ、CA19-9/CA125等异常升高时，AFPGC会表现出不一样的临床特征和预后。我们先前的临床研究表明，CEA可以作为AFPGC预后不良的重要预测因子，98.25%的CEA和AFP双阳性胃癌患者都会处于TNM临床Ⅲ或者Ⅳ期，预后比AFPGC更差，更容易发生免疫失调、全身性炎症、肝和淋巴结转移、癌相关性血栓[22]。
经过文献检索，我们发现超20篇研究论文是关于AFP和PIVKA-Ⅱ双阳性胃癌，此类胃癌被认为有很高的恶性潜能，多数为低分化腺癌，易出现肝样腺癌，恶性度极高，进展迅速且预后非常差，存活超过1年以上的患者较少，易发生且死于肝衰竭，甚至发生自发性肝破裂[23-24]。1987年，日本金泽大学的一项研究发现，HCG可用作胃癌骨转移的标志物，在发生骨转移的胃癌患者中，组织中的HCG阳性率高达77.8%，且血清HCG水平随化疗或肿瘤切除而下降[25]。在AFPGC患者中，合并HCG升高往往意味着更具侵袭性的生物学行为。有临床病例研究显示，AFP和HCG双阳性的胃癌患者在根治术后短期内就发生了脑转移[26]。此外，在伴有肝和卵巢转移的病例中也观察到AFP、HCG的同时升高[27]。有病理学研究指出，AFP和HCG可能分别由胃肿瘤中的肝样腺癌和绒毛膜癌成分独立分泌，并且在经过有效的手术和/或化疗后，HCG和AFP水平均会出现显著降低[28]。在AFPGC患者中，最严重的情况是AFP、CEA、CA19-9/CA125三阳性胃腺癌，会发生弥散性血管内凝血、脊柱转移瘤、腹膜广泛转移灶，患者往往生存期很短，死于多脏器功能衰竭[29-30]。
上述这些临床现象提示，不同标志物共表达可能反映了AFPGC独特的分子机制。为进一步从基因表达层面探究这些特殊亚型的预后价值，我们利用TCGA数据库，构建了基于不同标志物组合的基因表达风险评分模型。预后分析结果显示(图 5A~E)，无论是AFP合并CEA、CA19-9、CA125、PIVKA-Ⅱ还是HCG的亚型，其高风险评分与患者总生存期缩短显著相关(P值均＜0.05)。我们进一步构建了多变量Cox回归模型(图 5F)，在校正了年龄、性别及TNM分期等临床协变量后，发现所有亚型的高风险评分仍然是预测不良预后的独立危险因素(P值均＜0.05)。这些结果表明，上述标志物的共表达并非临床特征的随机组合，而是与内在的、具有独立预后价值的基因表达密切相关，为临床风险分层和个体化治疗决策提供了新的分子依据。上述特殊类型AFPGC的存在，为将来研究AFPGC的生物学行为和临床特征提供了不一样的视角，也值得学界更多思考和关注。
图5 AFPGC特殊亚型的预后分析

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.

3 外周血AFP水平可以指导临床诊疗

对于AFPGC的临床治疗，方案较多且尚未形成明确的指南，处于不同阶段的AFPGC患者应用的治疗方案和用药强度也不尽一致，从已发表的研究文献看，早期、进展期、晚期(伴肝和其他脏器远处转移)患者的处理方式呈现多样性：早期AFPGC患者接受内镜下黏膜切除术(endoscopic mucosal resection, EMR)治疗加胃癌根治术，可达治愈[31]；进展期胃癌患者接受胃癌根治术，术后采用替吉奥单药口服，可达治愈[32]，也有患者采用替吉奥联合顺铂新辅助化疗后再接受手术治疗[33]；晚期AFPGC伴肝转移灶的患者，采用化疗和肝动脉内插管化疗[34]。
事实上，AFPGC患者的AFP血清水平越高，生存期会越缩短。有研究发现，血清AFP水平＜100 μg/L的患者通常缺乏典型的组织学特征，而血清AFP水平≥100 μg/L的患者预后明显更差[35]。2014年发表的研究数据显示，血清AFP水平超过300 μg/L者，其1年、3年、5年的生存率显著低于AFP水平低于300 μg/L的患者[36]。Wang等[37]的研究发现，外周血AFP≥160 μg/L的胃癌患者的客观反应率(objective response rate，ORR)明显低于AFP＜160 μg/L的患者(30.4% vs. 68.3%，P＜0.001)，并且建议AFP≥160 μg/L的胃癌患者接受三联化疗方案，而非二联化疗方案。

4 AFPGC研究面临的前沿科学问题

对于AFPGC，目前尚未形成统一、规范的治疗方案。AFPGC在生物学机制上尚未阐明，从上述有别于普通胃癌的特征上看，AFPGC具有独特的复杂性，国内外虽有不少成功治疗的个案报道，但仍然需要后续的循证医学证据来提升AFPGC的诊疗，特别是形成统一、规范的治疗方案，来改善患者的长期存活。
日本学者曾在2016年报道，早期胃癌复发患者中有42.86%的患者血清AFP升高[38]，而我们的研究发现，AFPGC患者中也存在部分高分化腺癌[39]，早期的AFPGC小病灶(≤3 mm)也会分泌大量、高水平的AFP蛋白[40]。因此，在采用内镜黏膜下剥离术(endoscopic submucosal dissection，ESD)治疗早期高分化腺癌特别是AFPGC时，建议追加外科手术治疗，尤其是病理组织学提示存在脉管阳性时。
当普通胃癌患者出现癌性腹膜炎时，血清CA125阳性率可达42.9%[41]，但是，AFPGC较少发生腹膜转移[42]，其血清CA125水平也较少发生变化。这有待今后的研究揭示其中潜在的生物学机制，可能会对阐明普通胃癌的腹膜转移机制提供新的视角或帮助。
AFPGC免疫治疗的疗效有待全面合理评价。肿瘤的免疫疗法为晚期AFPGC患者提供了一种很好的选择，临床已有成功应用免疫检查点抑制剂治疗AFPGC患者的报道，并且发现从PD-1抑制剂切换到PD-L1抑制剂治疗可以克服前者潜在的耐药性[3]。还有文献报道显示，PD-L1阴性的AFPGC患者在接受PD-1抑制剂后，也取得了临床显著获益[43]。我们先前的研究发现，微卫星稳定的普通胃癌在幽门螺杆菌感染情况下，免疫检查点抑制剂的有效率会得到显著提高[44]，但是，目前幽门螺杆菌对微卫星稳定型AFPGC的免疫疗效影响尚未确定，针对Claudin18.2靶点的药物治疗效果也有待将来深入研究。
综上所述，AFPGC是胃癌中的特殊类型，在诊断上需要特别关注外周血AFP水平异常性，在胃癌组织病理学上需要添加AFP的免疫组化染色，而在临床治疗中，需要给予足够强度且合理的化疗和免疫治疗，并需要动态检测和监测肿瘤标志物变化，外加结合影像学的动态评价，甚至在新辅助治疗中，还需要加胃镜组织病理学的额外评估，另外，考虑到AFPGC患者个体差异性较大，建议可采取原日本胃癌协会主席Takeshi Sano教授等推荐的多模式治疗[45-46]，这些综合手段的应用能更全面、更有效地提高患者的诊疗效果和生存时间。

利益冲突  所有作者均声明不存在利益冲突。

作者贡献声明  龚渭华：提出研究思路，总体设计，把关审定论文；罗必显、刘洪铭：设计具体研究方案，全面文献检索，撰写论文初稿；罗必显、刘洪铭、谢伟勋：收集、分析、整理相关数据(包括TCGA数据库及临床数据)，制作可视化图表。所有作者均参与论文修改，并对最终文稿进行审读和确认。

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