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Severe hepatic steatosis as a protective prognostic factor in combined hepatocellular-cholangiocarcinoma: A multicenter pathological study
Han Wang, Zhen-Ying Cao, Chun-Yan Xia, Xia Sheng, Yun Zhao, Hong-Zhen Chen, Wen-Ming Cong, Miao-Xia He, Hui Dong
Han Wang, Zhen-Ying Cao, Wen-Ming Cong, Hui Dong, Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai 200438, China
Han Wang, Miao-Xia He, Department of Pathology, Changhai Hospital, Naval Medical University, Shanghai 200433, China
Chun-Yan Xia, Department of Pathology, Changzheng Hospital, Naval Medical University, Shanghai 200003, China
Xia Sheng, Department of Pathology, Minhang Hospital, Fudan University, Shanghai 201199, China
Yun Zhao, Department of Pathology, Huadong Hospital, Fudan University, Shanghai 200040, China
Hong-Zhen Chen, Department of Pathology, Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou 310015, Zhejiang Province, China
Co-first authors: Han Wang and Zhen-Ying Cao.
Co-corresponding authors: Miao-Xia He and Hui Dong.
Author contributions: Wang H and Cao ZY wrote the manuscript, were involved in the acquisition, analysis, and interpretation of data, and substantially participated in the writing of this paper, they contributed equally to this article, they are the co-first authors of this manuscript; Wang H, Cao ZY, Xia CY, Sheng X, Zhao Y, Chen HZ, Cong WM, He MX, and Dong H accessed and verified the study data; Cong WM, He MX, and Dong H participated in the conception and design of the study; He MX and Dong H jointly supervised the research project, provided critical guidance throughout study design and data interpretation, they contributed equally to this article, they are the co-corresponding authors of this manuscript; and all authors thoroughly reviewed and endorsed the final manuscript.
Supported by the Noncommunicable Chronic Diseases-National Science and Technology Major Project, No. 2023ZD0500100; Shanghai Leading Talent Program of Eastern Talent Plan, No. BJWS2024084; Municipal Hospital Clinical Technology Promotion and Management Optimization Project by Shanghai Shenkang Hospital Development Center, No. SHDC22023208; Shanghai Science and Technology Innovation Action Plan-Medical Innovation Research Project, No. 22Y11909100; Naval Medical University Basic Medical Research Project, No. 2023NQ095; and Take-off Project Talent Program of EHBH, No. TF2024XSJJ02.
Institutional review board statement: This study was approved by the Medical Ethics Committee of Eastern Hepatobiliary Surgery Hospital, approval No. EHBHKY2022-H010-P001.
Informed consent statement: The need for patient consent was waived due to the retrospective nature of the study.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: Dataset available from the corresponding authors at
huidongwh@126.com or
hmm26@163.com. Consent was not obtained but the presented data are anonymized and risk of identification is low.
Corresponding author: Hui Dong, PhD, Associate Faculty, Associate Professor, Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, No. 225 Changhai Road, Yangpu District, Shanghai 200438, China.
huidongwh@126.com
Received: November 20, 2025
Revised: December 18, 2025
Accepted: February 5, 2026
Published online: May 15, 2026
Processing time: 175 Days and 12.3 Hours
BACKGROUND
Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare and aggressive primary liver cancer characterized by the presence of both hepatocellular and cholangiocellular differentiation within the same tumor. Its diagnostic complexity and low incidence have resulted in a scarcity of well-established prognostic pathological parameters to guide clinical management. Given the rising global prevalence of metabolic dysfunction-associated steatotic liver disease and alcohol-related liver disease, and their close association with the occurrence of primary liver cancer, it is plausible that hepatic steatosis influences the prognosis of cHCC-CCA.
AIM
To investigate the specific clinicopathological role of background hepatic steatosis in patients with cHCC-CCA who underwent curative-intent liver resection.
METHODS
This multicenter study analyzed 310 patients with cHCC-CCA who underwent curative-intent hepatectomy between 2013 and 2017. Hepatic steatosis in liver tissue was graded pathologically: Grade 0-1 (< 33% hepatocytes) was defined as negligible hepatic steatosis (n = 283, 91.3%), and grade 2-3 (≥ 33% hepatocytes) as severe hepatic steatosis (n = 27, 8.7%). Primary endpoints were recurrence-free survival (RFS), overall survival, early (≤ 2 years) and late (> 2 years) RFS.
RESULTS
Patients with severe hepatic steatosis had a significantly prolonged RFS compared to those with negligible steatosis (P = 0.035), with 5-year RFS rates of 28.8% vs 15.7%. This benefit was primarily observed in early RFS (P = 0.024) and was more pronounced in non-cirrhotic patients. In contrast, no statistically significant difference was found in overall survival (P = 0.586) or late RFS (P = 0.931) between the two groups. Multivariate logistic regression analysis showed higher body mass index and lymphocyte count, and lower lactate dehydrogenase were independent predictors for the presence of severe steatosis. Furthermore, multivariate Cox regression analysis confirmed severe hepatic steatosis as an independent protective factor for RFS (hazard ratio = 0.614) and early RFS (hazard ratio = 0.577).
CONCLUSION
Severe hepatic steatosis is a protective factor associated with RFS and early RFS in patients with cHCC-CCA who underwent hepatectomy, which is especially significant in the absence of liver cirrhosis.
Core Tip: This retrospective multicenter study investigated the prognostic influence of hepatic steatosis in patients with combined hepatocellular-cholangiocarcinoma (cHCC-CCA). Severe hepatic steatosis was associated with a favorable prognosis in cHCC-CCA patients. This protective effect was particularly significant in preventing early recurrence and was more pronounced among non-cirrhotic patients. We propose that the evaluation of hepatic steatosis be incorporated into the routine pathological diagnosis of cHCC-CCA to optimize postoperative management for this tumor entity.
