Impact of underlying liver etiology on post-hepatectomy survival outcomes in hepatocellular carcinoma patients

Introduction

Background

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and a major contributor to global cancer-related mortality (1-3). In most cases, HCC develops in the context of chronic liver injury caused by various etiologies, such as hepatitis B virus (HBV), hepatitis C virus (HCV), alcohol-related liver disease (ALD), and more recently, metabolic dysfunction-associated steatotic liver disease (MASLD) (4-6).

Rationale and knowledge gap

Surgical resection remains a primary curative strategy for patients with localized HCC and sufficient hepatic functional reserve (1-8). However, prognosis following hepatectomy is influenced by tumor characteristics, such as size, number, or vascular invasion, and by the condition of the background liver (4-6). The etiology of liver disease impacts hepatic architecture, inflammation, fibrosis progression, and regenerative capacity. For example, MASLD is frequently associated with obesity, insulin resistance, and systemic metabolic dysfunction, whereas viral liver disease (VLD) is linked to persistent necroinflammatory activity (9). These differences may influence liver regeneration and long-term oncological outcomes. Despite the central importance of liver function in surgical planning, the prognostic role of underlying etiological factors in post-hepatectomy survival has not been thoroughly evaluated. Clarifying this clinical relationship is crucial for improving individualized treatment strategies and predicting outcomes in patients with HCC.

In recent decades, the global epidemiology of chronic liver disease has undergone a significant shift. While the prevalence of VLD is gradually declining due to widespread vaccination and antiviral therapies, MASLD has rapidly emerged as the leading cause of chronic liver injury in many countries (10). MASLD encompasses a spectrum of hepatic and systemic metabolic disorders linked to obesity, type 2 diabetes, insulin resistance, and dyslipidemia (9,11). Unlike VLD, which follows a relatively predictable course with defined therapeutic targets, MASLD-related hepatocarcinogenesis remains more heterogeneous and poorly understood. The absence of reliable biomarkers or standardized surveillance protocols for MASLD patients has made it difficult to predict which patient will progress to HCC. Moreover, patients with MASLD often present with multiple comorbidities and relatively advanced disease stages at diagnosis (12), which may negatively impact surgical outcomes and long-term survival. Despite these concerns, few studies have rigorously evaluated the oncologic behavior and postoperative prognosis of HCC patients with MASLD undergoing curative hepatectomy, compared to other etiological groups such as HBV, HCV, or ALD (13). Based on this clinical context, we hypothesize that HCC patients with a background of MASLD may experience poorer survival outcomes following hepatectomy than those with viral or alcohol-related etiologies. By examining survival differences according to liver disease cause, with special emphasis on MASLD, our study aims to clarify the prognostic significance of background etiology and provide evidence to guide individualized risk assessment and surgical decision-making.

Objective

Therefore, given the shifting landscape of chronic liver disease and the uncertain prognostic implications of emerging etiologies such as MASLD, it is crucial to investigate the mechanism by which these underlying factors influence outcomes after surgical intervention. Therefore, the aim of this study was to evaluate the impact of different etiological backgrounds on long-term survival in 396 patients consecutively undergoing curative hepatectomy for HCC at two academic institutions, where the principal author served as the responsible surgeon between 1994 and 2023. Special attention was given to patients with MASLD, whose clinical trajectory may differ from that of those with traditional etiologies. We conducted a retrospective, dual-institutional analysis of patients with HCC, classifying them according to underlying liver disease etiology, and compared postoperative survival outcomes across groups. This study seeks to provide insight into the role of etiology in surgical prognosis and support more tailored clinical decision-making in managing HCC. We present this article in accordance with the STROBE reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1809/rc).

Methods

Patients

A total of 396 consecutive cohort patients, or only those treated by the authors, were consecutively examined. This study retrospectively collected data from 243 consecutive patients at the Department of Surgical Oncology, Nagasaki University of Biomedical Sciences, between April 1994 and March 2015. Data were obtained from 153 consecutive patients treated by the principal author at the Department of Surgery, University of Miyazaki Faculty of Medicine, between April 2015 and December 2023. The minimum follow-up period for survivors was 24 months. The principal author primarily managed and coordinated treatment for all patients throughout the study period. In-hospital data of all patients were retrospectively and consecutively collected from patient charts at both institutions. Thus, data collection bias remained. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Review Boards of Nagasaki University (No. 25020605, February 6, 2025) and Miyazaki University (No. O-1613, October 23, 2024). Informed consent was obtained from all the patients before treatment. Patient consent was confirmed via an opt-out procedure, publicly announced at outpatient clinics and on the institutional websites for 1 month, in accordance with institutional ethical policy. Data were retrieved from anesthetic and patient electronic charts, as well as institutional databases, covering the initial hospitalization period following radical operations, and from electronic medical records at both institutions. Using this information, patient outcomes were determined based on data collected by the coauthors.

Measurement of tumor markers and histological findings

Clinicopathological patient data, including protein induced by vitamin K absence or antagonist-II (PIVKA-II; Sanko Junyaku Co., Tokyo, Japan) and alpha-fetoprotein (AFP) levels, were retrieved from the archives at our institute. In our hospital, the normal values for AFP and PIVKA-II in patients with HCC are <20 ng/mL and <40 mAU/mL, respectively. Elevated levels of AFP and PIVKA-II were defined as values exceeding these normal ranges. Tumor-related factors were compared with histopathological findings from the resected specimens. For assessment, we used the classification rules established by the Liver Cancer Study Group of Japan for primary liver cancer (14). Tumor staging (0–4) for hepatic fibrosis and the histological activity index (HAI) score as defined by Knodell et al. (15), were used for histopathological evaluation. The Milan criteria, a set of guidelines established to select suitable candidates with HCC for liver transplantation, aim to achieve optimal post-transplant survival and low recurrence rates. These criteria were applied for analysis, which are defined as (I) a single HCC tumor ≤5 cm; or (II) up to three tumors, each ≤3 cm, with no macrovascular invasion or distant metastasis (16).

Statistical analysis

Differences in categorical data between groups and prevalence were assessed using the chi-squared test, Fisher’s exact test, or Dunnett’s multiple comparison test. Differences in continuous data between groups were evaluated using the Student’s t-test or the Mann-Whitney test. Recurrence-free survival (RFS) and overall survival (OS) were calculated using the Kaplan-Meier method, and differences between groups were tested for significance using the log-rank test. Multivariate analysis was performed using the Cox proportional hazards regression model. The factors that cause metabolic diseases or habitual issues, such as obesity, diabetes, and dyslipidemias, are tightly associated with MASLD. Therefore, these factors were avoided in the multivariate analysis as the strong confounding factors for MASLD. A two-tailed P value of <0.05 was considered significant. Statistical analyses were performed using SPSS software version 23 (Statistical Package for the Social Science, Inc., Chicago, IL, USA).

Results

Perioperative parameters

Basic patient data are as follows: 323 (82%) males and 73 (18%) females, with a mean age of 67.2±10.5 years (standard deviation; range, 16–87 years) at the time of surgery. Eighty-one patients (20%) presented with normal liver morphology. Chronic VLD was present in 251 patients (63%), including HBV in 113, HCV in 123, and both HBV and HCV in 15. ALD was present in 29 patients (7%), MASLD in 31 patients (8%), and primary biliary cholangitis (PBC) in four patients (2%). Liver cirrhosis was observed in 133 patients (34%).

According to the Child-Pugh classification, 377 patients (95%) were classified as class A, and 19 patients as class B. The mean AFP level was 3,704±31,330 µg/mL, with AFP levels >400 ng/mL observed in 93 patients (23%). The mean PIVKA-II level was 4,026±16,768 ng/mL, and PIVKA-II levels >40 mAU/mL were observed in 142 patients (40%). According to the Liver Cancer Study Group of Japan, the pathological tumor-node-metastasis (TNM) stage of HCC was stage I in 57 patients (14%), stage II in 177 (45%), stage III in 103 (26%), stage IVA in 55 (14%), and stage IVB in four (1%).

Tumor number was solitary in 295 patients (74%), and the maximum of five nodules resected. The mean tumor size was 44.6±36.2 mm, with sizes <20 mm in 86 patients (21%), 20–50 mm in 194 (49%), and >50 mm in 115 (29%). Microvascular tumor involvement was observed in 108 patients (27%), with involvement of the portal vein in 93, hepatic vein in 44, and bile duct in 18. The Milan criteria (a single tumor ≤5 cm, or up to three tumors ≤3 cm, with no macrovascular invasion or distant metastasis) were met in 256 patients (65%) (16). Knodell’s histological fibrosis score of 3 (pre-cirrhotic) or 4 (cirrhotic liver) was observed in 195 patients (49%) (15). Based on macroscopic tumor findings, the simple nodular type was observed in 147 patients (37%), whereas other types (simple nodular with extra-capsular growth, confluent type, and invasive type) were observed in 247 patients (63%) (14).

Preoperative transarterial embolization (TAE) was performed in 78 patients (20%). Operative procedures included hemihepatectomy or more extensive hepatectomy in 48 patients (12%), central bisectionectomy in seven (2%), segmentectomy or sectionectomy in 161 (41%), and limited resection in 180 (45%). Since 2010, laparoscopic hepatectomy has been performed in 61 patients (15%). Radical hepatectomy was performed in all patients, and hepatic tumors were completely resected without macroscopic exposure of the amputated sections to the remaining liver tissue. The mean blood loss was 847±910 mL, and blood loss >1,500 mL was observed in 67 patients (17%). Allogeneic blood transfusions were administered to 116 patients (29%). After the hepatectomy, hepatic failure occurred in 10 patients (3%), and long-term ascites was observed in 60 (15%) patients. Cancer-related death occurred in 120 patients (30%), non-cancer-related death in 40 patients (10%), and survival was observed in 236 patients (60%). Cancer recurrence occurred in 228 patients (57%). Reoperation for cancer recurrence was performed in 42 patients (11%), including living-related liver transplantation in one patient. The minimum follow-up period of the non-censored case was 24 months.

Relationship between clinicopathological findings and background liver injuries (Table 1)

Among the 396 patients who underwent hepatectomy for HCC, background liver diseases were classified into five categories: chronic VLD (n=251), MASLD (n=31), ALD (n=29), PBC (n=4), and unknown etiology (n=81). The prevalence of vascular involvement tended to be lower in patients with MASLD than in the other categories; however, this difference was not statistically significant (P=0.056). Comparative analysis showed that patients with chronic VLD and ALD exhibited a significantly higher prevalence of advanced liver fibrosis (P<0.001). No significant differences were observed among etiological groups in the incidence of tumor-related stage or HCC-related tumor markers. In patients with chronic VLD, poorer liver function classified as Child-Pugh B tended to be more frequent than in the other groups, including MASLD; however, this difference was not statistically significant (P=0.08). In patients with chronic VLD, intraoperative blood transfusion tended to be used more frequently than in other patient groups, although this difference was not statistically significant (P=0.07). No significant differences were observed across etiological groups in the incidence of postoperative complications such as hepatic failure or ascites. However, tumor recurrence was significantly more common in patients with chronic VLD and ALD (P<0.001). Deaths attributable to HCC were more frequently noted in the chronic VLD and unknown etiology groups, whereas MASLD and PBC patients exhibited no HCC-related mortality, although the sample size for these groups was small.

Relationship between patient survivals and background liver injuries

Survival outcomes, including RFS and OS, were stratified by liver disease etiology (Figure 1, respectively). MASLD demonstrated the most favorable prognosis, with a 5-year RFS of 54% and a 10-year OS of 100%. In contrast, the chronic VLD group showed markedly lower rates, with a 5-year RFS of 31% and a 10-year OS of 49%. Statistically significant differences were observed between MASLD and chronic VLD for both RFS (P<0.001) and OS (P<0.001). Similarly, patients with unknown etiology showed better RFS than those with chronic VLD (P<0.001). While MASLD tended to have better RFS and OS than ALD, these differences did not reach statistical significance (0.050<P<0.100).

Figure 1 Tumor-recurrence free survival (A) and overall patient survival (B) were analyzed using the Kaplan-Meier method with log-rank tests. MASLD, metabolically-associated steatotic liver disease; mRFS, mean RFS; mOS, mean OS; OS, overall survival; PBC, primary biliary cholangitis; RFS, recurrence-free survival; VLD, viral liver disease.

In univariate Cox regression analysis (Table 2), several clinical variables were significantly associated with worse tumor-free survival and OS, including multiple tumor presentation, larger tumor size (≥5 cm), presence of vascular invasion, nonadherence to Milan criteria, advanced fibrosis, non-simple nodular tumor morphology, R1 surgical margin, elevated tumor markers, and prolonged postoperative ascites. The presence of MASLD was not significantly associated with tumor recurrence risk. Subsequent multivariate analysis confirmed that chronic VLD, multiple tumors, vascular tumor involvement, poorer liver function, as indicated by Child-Pugh classification, R1 surgical margin, and postoperative ascites were independent predictors of HCC tumor recurrence after hepatectomy (P<0.05). Poorer liver function, postoperative ascites, and R1 surgical margin showed a higher risk ratios (RR) for tumor recurrence (RR >1.5). For OS, chronic VLD and R1 surgical margins remained significant prognostic factors of poor OS (P<0.01), while MASLD was independently associated with significantly better survival compared to chronic VLD patients (P<0.05).

Discussion

In this retrospective study of 396 patients who underwent hepatectomy for HCC, we investigated the clinical significance of the underlying liver disease etiology on perioperative outcomes, tumor recurrence, and long-term survival. Our findings highlight that the type of underlying liver injury, particularly MASLD (which has increased worldwide in recent years) (9-13), influences the degree of liver fibrosis, functional reserve, biological behavior of HCC, and post-hepatectomy patient prognosis. Notably, MASLD-associated HCC may represent a clinically and biologically distinct subgroup with unique therapeutic and prognostic implications (12). This study demonstrates that the etiology of underlying liver disease substantially impacts the biological behavior of HCC and the long-term prognosis following hepatectomy. In particular, patients with MASLD exhibited notably favorable outcomes compared to those with chronic VLD or ALD. HCC patients with VLD have gradually decreased in many countries, including Japan, due to the development of anti-viral drug therapies, preventive management, and lifelong follow-up (17). Compared to the era when most cases were VLD, the prognosis of HCC patients is expected to be significantly improved with recent treatment modalities (18). Therefore, in this study, we focused on MASLD and reevaluated the changes in clinicopathological characteristics and prognostic factors, based on the principal author’s consistent treatment approach during this period.

Despite MASLD patients presenting with advanced liver fibrosis in more than half of the cases, similar to those with chronic VLD or ALD, their postoperative clinical course was significantly more favorable in our results. Advanced liver fibrosis was significantly more common in chronic VLD and ALD, and was associated with poorer survival and recurrence outcomes. However, fibrosis alone did not fully explain differences in prognosis, as patients with MASLD with advanced fibrosis still demonstrated excellent survival outcomes. This underscores the importance of fibrosis staging and functional liver reserve, as indicated by postoperative ascites, Child-Pugh status, and blood transfusion rates. These factors may be more critical predictors of outcome than etiology alone, supporting the need for comprehensive preoperative liver function assessment beyond imaging and fibrosis scoring. From an oncologic perspective, HCC in MASLD patients exhibited fewer prognostic factors of HCC, such as tumor size, vascular involvement, and tumor-related stage. Despite a higher non-tumorous fibrotic degree, preoperative liver function remained good. According to surgical records, blood transfusion and complication rates tended to be lower in MASLD patients than in those with chronic VLD, which likely contributes to their better prognosis. In other reports, patients with HCC arising from MASLD demonstrated significantly better outcomes following hepatectomy than those with chronic VLD. These differences suggest that HCC in MASLD patients may follow a more indolent clinical course than that in chronic VLD. Additionally, MASLD was independently associated with improved OS in multivariate analysis, whereas chronic VLD remained a significant risk factor for recurrence and mortality. Despite comparable rates of advanced fibrosis between the two groups, liver functional reserve and postoperative complication rates (e.g., ascites, R1 margin) were generally more favorable in patients with MASLD, possibly contributing to their superior outcomes (18). MASLD-related HCC may possess a less aggressive oncologic phenotype, or these patients may undergo surgical resection at a relatively earlier stage of disease progression due to more frequent metabolic surveillance than expected (17).

In contrast, HCC patients with chronic VLD exhibited the poorest liver function or fibrotic staging, more frequent adverse oncological prognostic factors, and worse surgical outcomes compared to other etiological groups. This may be due to varying degrees of liver parenchymal injury and the longer duration of exposure to the disease. Regarding ALD, this etiology may not decrease (19), and cases with moderate habitual drinking might be included in MASLD or cryptogenic etiology HCC patients. Severe ALD cases were not included in these series; although their fibrotic staging was advanced, the surgical outcomes tended to be better than those of chronic VLD. Despite the limited number of PBC patients, they exhibited better liver function, T2 stage, and good surgical outcomes, which indicate a favorable prognosis for hepatectomy.

Interestingly, although advanced fibrosis was prevalent in both MASLD and chronic VLD groups, only chronic VLD showed significantly higher tumor recurrence and poorer OS. Furthermore, postoperative ascites and R1 resection margins, both strong predictors of poor outcomes, were more frequent in chronic VLD cases. In contrast, hepatectomy-related complications, such as prolonged ascites, were less common in MASLD. This suggests that liver functional reserve may be relatively preserved in MASLD, despite histological fibrosis, possibly due to distinct pathophysiological mechanisms compared to chronic VLD (9-13). The survival analysis based on background liver etiology demonstrated that patients with MASLD exhibited notably favorable OS, despite the observation of tumor relapses. This result may be attributed to better liver functional reserve and less aggressive HCC behavior, even in cases of recurrence. Multivariate Cox regression revealed that MASLD was independently associated with improved OS, although it was not a significant risk factor for tumor recurrence.

The MASLD background itself was an independent positive prognostic factor beyond traditional tumor- and liver function-related variables. These findings challenge the conventional assumption that steatotic or fibrotic livers universally predict poor prognosis, supporting the notion that the clinical course of HCC arising in MASLD fundamentally differs from that of other etiologies. From a clinical perspective, these observations carry essential implications. With the global increase in MASLD prevalence (12), especially among aging and metabolically burdened populations, recognizing MASLD as a distinct and potentially less aggressive background becomes crucial for guiding surgical decision-making, risk stratification, and postoperative surveillance. In contrast to chronic VLD, where careful margin planning and vigilant follow-up are necessary due to a high recurrence risk associated with factors such as obesity, hypercholesterolemia, fatty liver, or diabetes mellitus (20), MASLD patients may represent more suitable candidates for curative resection, even in the presence of fibrosis, provided that liver function is preserved. However, despite these promising findings, they must be interpreted cautiously due to the relatively small number of MASLD cases. Further prospective studies are needed to validate the oncological behavior of MASLD-related HCC and to better elucidate the interaction between metabolic risk profiles, tumor biology, and liver function over time.

The strengths of our study include comprehensive data analysis, a relatively large sample size, and the consistent experiences of the same surgeon over approximately 30 years. Various univariate and multivariate analyses were used to identify independent risk factors. All hepatectomies were performed using the same strategy, operative indication, and standardized procedures. Our present results showed the crucial issue of a few institutional cohorts in the era of increased metabolic disease patients worldwide. These findings may influence surgical decision-making, surveillance strategies, or the refinement of prognostic models. At the same time, given the very limited size of the MASLD subgroup, any clinical conclusions should be framed as preliminary and hypothesis-generating rather than definitive, pending validation in larger, multi-center cohorts. However, the study has several limitations. First, it was a single-center retrospective analysis, which may introduce selection bias and limit the generalizability of the findings. Second, although patients were categorized by liver disease etiology, the sample sizes of specific subgroups, particularly those with MASLD and PBC, were relatively and markedly smaller than the viral cohort. Particularly, patient survival of MASLD and PBC was quite different in comparison with other groups, although the follow-up periods were shorter and the number was smaller. Due to this limitation, the observation of 100% survival at 10 years in MASLD must be interpreted cautiously. The constraints imposed by these subgroup sizes should be more explicitly careful to avoid misleading the main results. This limited our ability to draw robust conclusions for these groups, despite observed trends in survival. Third, histological confirmation of MASLD was not consistently available, and diagnostic classification relied on clinical records and imaging. This could have led to misclassification or underestimation of disease overlap (e.g., coexisting viral or alcoholic injury). Additionally, metabolic factors such as body mass index, diabetes status, or lipid profiles were not fully incorporated into the analysis, which might have provided further insight into the pathophysiological mechanisms linking MASLD to HCC.

Conclusions

This study demonstrated that the etiology of background liver disease significantly impacts postoperative outcomes and long-term prognosis in 396 patients undergoing hepatectomy for HCC, all operated on by the same investigator over approximately 30 years. Among the various etiologies, patients with MASLD exhibited a notably favorable prognosis, with lower recurrence rates and superior OS compared to those with chronic VLD or ALD. These findings suggest that MASLD-related HCC may represent a distinct clinical entity with relatively indolent tumor behavior and better-preserved liver function, even in the presence of fibrosis of non-tumorous liver parenchyma. As the global prevalence of MASLD continues to rise, recognizing its prognostic implications is essential for optimizing surgical indications, tailoring postoperative surveillance, and developing etiology-specific treatment strategies. Further prospective, multi-institutional studies are warranted to validate these findings and clarify the biological mechanisms underlying the observed differences in HCC behavior across etiologies.

Acknowledgments

We would like to thank Elsevier, a scientific and medical English editing company (reference number: ASLESTD 1111381), on August 15th, 2025, for editing English grammar.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1809/rc

Data Sharing Statement: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1809/dss

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1809/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1809/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Review Board of Nagasaki University (No. 25020605, February 6, 2025) and Miyazaki University (No. O-1613, October 23, 2024). Informed consent was obtained from all the patients before treatment.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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