Human epidermal growth factor receptor 2 in combined hepatocellular-cholangiocarcinoma: Prognostic and predictive guide for adjuvant chemotherapy

doi:10.3748/wjg.v32.i22.117417

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World Journal of Gastroenterology

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1007-9327

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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

Retrospective Study

Copyright: ©Author(s) 2026. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution-NonCommercial (CC BY-NC 4.0) license. No commercial re-use. See permissions. Published by Baishideng Publishing Group Inc.

World J Gastroenterol. Jun 14, 2026; 32(22): 117417
Published online Jun 14, 2026. doi: 10.3748/wjg.v32.i22.117417

Human epidermal growth factor receptor 2 in combined hepatocellular-cholangiocarcinoma: Prognostic and predictive guide for adjuvant chemotherapy

Ru-Yu Han, Yu-Kun Wei, Wei-Na Liu, Yi-Meng Wang, Tian-Qiang Song, Xiang-Dong Tian, Yu-Ren Xia, Lu Chen, Wen-Chen Gong

Ru-Yu Han, Yu-Kun Wei, Wei-Na Liu, Yi-Meng Wang, Tian-Qiang Song, Lu Chen, Department of Hepatobiliary Cancer, Liver Cancer Research Center, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer, Tianjin 300060, China

Xiang-Dong Tian, Department of Endoscopy, Tianjin Medical University Cancer Institute & Hospital, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin 300060, China

Yu-Ren Xia, Department of Pediatric Oncology, Tianjin Medical University Cancer Institute & Hospital, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin 300060, China

Wen-Chen Gong, Department of Pathology, Tianjin Medical University Cancer Institute & Hospital, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin 300060, China

Co-first authors: Ru-Yu Han and Yu-Kun Wei.

Co-corresponding authors: Lu Chen and Wen-Chen Gong.

Author contributions: Chen L, Gong WC, Han RY, and Wei YK designed research; Xia YR, Chen L, Gong WC, Han RY, Wei YK, Song TQ, Tian XD, Liu WN, and Wang YM performed research; Xia YR, Chen L, Gong WC, Han RY, Wei YK, Song TQ, Tian XD, Liu WN, and Wang YM analyzed data; Chen L, Gong WC, Han RY, and Wei YK wrote the paper; Gong WC, Chen L, Tian XD, and Xia YR obtained funding. All authors read and approved the final manuscript. Han RY and Wei YK contributed equally to this work as co-first authors. Both Gong WC and Chen L have played important and indispensable roles in the experimental design and manuscript preparation as co-corresponding authors. Jointly, Gong WC and Chen L applied for and secured the funding for this research project. Gong WC conceptualized, designed, and supervised the overall progression of the study. Chen L provided critical oversight for data re-analysis, interpretation, and the generation of scientific figures. This collaboration between Gong WC and Chen L is crucial for the publication of this manuscript and other manuscripts still in preparation.

AI contribution statement: The entirety of the main text, including the Abstract, Introduction, Materials and Methods, Results, Discussion, and Conclusion, was written solely by the authors in their own words. A professional human language editing service assisted with grammar and readability, but the substance, structure, and scientific arguments of the manuscript remain the authors’ original work. No AI tool participated in the study design, data analysis, or interpretation of results. All elements of research design and scientific interpretation were carried out entirely by the authors.

Supported by National Natural Science Foundation of China, No. 82203423, No. 82373365, No. 82403771, and No. 82472991; Joint Funds of the Natural Science Foundation of Tianjin, No. 25JCLMJC00720; Beijing-Tianjin-Hebei Collaborative Innovation Special Project, No. 25242602D; Tianjin Natural Science Foundation, No. 23JCYBJC00600; and the Tianjin Key Medical Discipline Construction Project, No. TJYXZDXK-3-003A and No. TJYXZDXK-3-016C.

Institutional review board statement: The ethical clearance of the study was obtained from the Institutional Review Board of Tianjin Medical University Cancer Institute & Hospital, No. bc20240058.

Informed consent statement: The retrospective study was reviewed by the ethics committee, and informed consent was waived.

Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.

Data sharing statement: The dataset is available from the corresponding author upon request at gongwenchen@tmu.edu.cn.

Corresponding author: Wen-Chen Gong, Department of Pathology, Tianjin Medical University Cancer Institute & Hospital, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, West Huanhu Road, Ti Yuan Bei, Tianjin 300060, China. gongwenchen@tmu.edu.cn

Received: December 8, 2025
Revised: February 6, 2026
Accepted: March 2, 2026
Published online: June 14, 2026
Processing time: 173 Days and 22.4 Hours

Abstract

BACKGROUND

Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare primary liver cancer with poor prognosis and a lack of reliable markers for prognostic assessment or tailored postoperative therapy. The expression of human epidermal growth factor receptor 2 (HER2) in cHCC-CCA and its potential role in predicting prognosis remain unclear. Therefore, investigating the clinical significance of HER2 and its underlying mechanisms may provide valuable insights to optimize diagnosis and treatment strategies in this disease.

AIM

To investigate the prognostic significance of HER2 and related pathological features in surgically treated patients with cHCC-CCA.

METHODS

This retrospective study included 101 patients with cHCC-CCA who underwent surgical resection at Tianjin Medical University Cancer Institute & Hospital between January 2009 and December 2020. Univariate and multivariate Cox regression analyses were performed to identify independent prognostic risk factors. Kaplan-Meier analysis was used to compare survival across different subgroups, and propensity score matching (PSM) was applied to reduce bias. HER2 expression was assessed using immunohistochemistry, and tertiary lymphoid structures (TLS) were characterized using multiplex immunofluorescence.

RESULTS

A total of 87 patients with pathologically confirmed cHCC-CCA were enrolled. Multivariate Cox regression analysis showed that HER2 positivity was an independent protective factor for postoperative overall survival (hazard ratio = 0.551; P = 0.033). HER2 positivity was also significantly correlated with high TLS abundance. Further survival analysis revealed a key interaction between HER2 status and the efficacy of adjuvant chemotherapy: HER2-negative patients experienced a significant survival benefit (P = 0.0082), whereas HER2-positive patients did not (P = 0.61). This differential treatment effect remained consistent after PSM validation.

CONCLUSION

HER2 is an independent prognostic marker for cHCC-CCA post-surgery, correlates with TLS enrichment, and may predict response to adjuvant chemotherapy, supporting precise postoperative treatment stratification.

Keywords: Combined hepatocellular-cholangiocarcinoma; Human epidermal growth factor receptor 2; Tertiary lymphoid structures; Adjuvant chemotherapy; Prognosis; Surgical resection

Core Tip: Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare liver malignancy with poor prognosis and limited prognostic markers. This study shows that human epidermal growth factor receptor 2 (HER2) expression is an independent prognostic factor and is positively correlated with tertiary lymphoid structures. HER2 status also predicts differential response to adjuvant chemotherapy, with HER2-negative patients benefiting significantly while HER2-positive patients do not. These findings provide a rationale for using HER2 as a biomarker to guide postoperative treatment decisions and support precision stratification of adjuvant therapy in cHCC-CCA, offering practical implications for individualized patient management.