Copyright
©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
Clinicopathological significance of histological diversity in gastric adenocarcinoma with primitive enterocyte phenotype: A methylation-driven aggressive entity
Hou-Qiang Li, Lan-Qing Zheng, Wen-Tao Huang, Xun-Bin Yu, Xia Zhang, Lan Lin, Shan-Shan Lv, Xi-Yao Yan, Xiao-Yan Chen
Hou-Qiang Li, Xun-Bin Yu, Xia Zhang, Lan Lin, Shan-Shan Lv, Xi-Yao Yan, Xiao-Yan Chen, Department of Pathology, Fuzhou University Affiliated Provincial Hospital, Fuzhou 350001, Fujian Province, China
Hou-Qiang Li, Department of Pathology, Shengli Clinical Medical College of Fujian Medical University, Fuzhou 350001, Fujian Province, China
Hou-Qiang Li, Department of Pathology, Fujian Provincial Hospital, Fuzhou 350001, Fujian Province, China
Lan-Qing Zheng, Department of Nursing, Fuzhou University Affiliated Provincial Hospital, Fuzhou 350001, Fujian Province, China
Wen-Tao Huang, Department of Hepato-Pancreato-Biliary Surgery, Fuzhou University Affiliated Provincial Hospital, Fuzhou 350005, Fujian Province, China
Author contributions: Li HQ conceptualized, wrote and reviewed the paper, and designed the experiments; Li HQ, Zheng LQ, Zhang X, Yu XB, Lin L, Yan XY, and Lv SS performed the experiments; Li HQ and Zheng LQ analyzed the data; Li HQ, Zheng LQ, Yu XB, Huang WT, and Chen XY provided reagents/materials/analysis tools; and all authors have read and approved the final manuscript.
Supported by the Startup Fund for Scientific Research, Fujian Medical University, No. 2020QH1168; Fujian Provincial Science and Technology Innovation Joint Funds, No. 2024Y9023; and the Fujian Provincial Natural Science Foundation of China, No. 2024J011644.
Institutional review board statement: This study was approved by the Medical Ethics Committee of Fujian Provincial Hospital, approved No. K2021-04-094.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: The data presented in this study are available upon request from the corresponding author on reasonable request.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
https://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Hou-Qiang Li, Researcher, Department of Pathology, Fuzhou University Affiliated Provincial Hospital, No. 134 East Street, Fuzhou 350001, Fujian Province, China.
docli254@163.com
Received: April 28, 2025
Revised: May 22, 2025
Accepted: June 23, 2025
Published online: July 28, 2025
Processing time: 87 Days and 23 Hours
BACKGROUND
Gastric adenocarcinoma with primitive phenotypes has recently attracted increasing attention due to its aggressive nature and challenging diagnosis. Gastric adenocarcinoma with enteroblastic differentiation (GAED) and hepatoid adenocarcinoma (HAC) were previously regarded as gastric adenocarcinoma with primitive enterocyte phenotype (GAPEP). GAPEP is known for its poor prognosis, and the accurate diagnosis of GAPEP directly affects therapeutic decision-making. Despite their poor prognosis and morphological heterogeneity, the molecular drivers of GAPEP, particularly methylation-driven mechanisms, remain poorly explored.
AIM
To investigate the clinicopathological and molecular characteristics of GAPEP and establish an integrative diagnostic strategy to guide therapeutic decision-making.
METHODS
Based on the expression profile and morphology, patients were divided into three groups: GAPEP (including GAED and HAC), conventional gastric cancer (CGC), and CGC expressing primitive phenotypic markers. We analyzed clinicopathological features and overall survival. Data from The Cancer Genome Atlas were also analyzed, and functional enrichment analysis was conducted.
RESULTS
GAPEP showed diverse morphology, and immunohistochemical staining alone was not adequate for accurate diagnosis. Histologically, GAPEP was characterized by large, polygonal tumor cells with supranuclear or subnuclear vacuoles, a “piano keyboard-like” appearance, and clear or eosinophilic cytoplasms. Compared to CGC and CGC expressing primitive phenotypic markers, GAPEP displayed more aggressive clinical features. Molecular analysis showed significant differences in molecular subtypes, TP53 mutation, ERBB2 amplification, ARID1A mutation, MSI status, and CpG island methylator phenotype category. Genomic analysis revealed that TP53 mutations, APC mutations, and ERBB2 amplifications were more frequent in GAPEP. Genes involved in methylation processes were highly upregulated in GAPEP. HAC and GAED shared similar clinicopathological and genetic characteristics. Functional enrichment analysis highlighted the critical role of methylation in the development of GAPEP.
CONCLUSION
The diversity and aggressiveness of GAPEP are driven by deregulated methylation, necessitating the integration of morphological and immunohistochemical diagnosis. Targeting methylation can provide new therapeutic opportunities for treating this aggressive cancer.
Core Tip: Gastric adenocarcinoma with primitive enterocyte phenotype (GAPEP) exhibits aggressive behavior and diverse morphologies, including tubular-papillary and solid types, which necessitate integrated histopathological, immunohistochemical, and molecular experiments for accurate identification. This study highlighted GAPEP’s methylation-driven pathogenesis, with methylation dysregulation (e.g., DNMT3A/B/L, TET1/3 and EZH2 upregulation). Gastric adenocarcinoma with enteroblastic differentiation and hepatoid adenocarcinoma shared similar clinicopathological and genetic features, suggesting a common origin. Targeting methylation pathways (e.g., DNMT inhibitors) offers potential therapeutic avenues for this lethal cancer, emphasizing the critical role of epigenetic mechanisms in the pathogenesis of GAPEP.
