Daily increment of residual liver regeneration (DIRER) predicts tumor recurrence and mortality after radical hepatectomy for hepatocellular carcinoma

Introduction

Hepatocellular carcinoma (HCC) is one of the most common and aggressive malignancies globally, ranking as one of the leading causes of cancer-related mortality worldwide (1,2). Even in early-stage HCC, characterized by tumors smaller than 2 cm without vascular invasion or satellite lesions (3), the 5-year recurrence rate remains alarmingly high, reaching up to 70% after curative resection (4,5). This substantial risk of recurrence highlights the urgent need to identify reliable biomarkers and risk factors that can predict tumor recurrence post-hepatectomy, ultimately improving patient survival outcomes.

Postoperative liver regeneration is a complex biological process that involves the upregulation of various key molecules, such as hepatocyte growth factor (HGF), transforming growth factor-β (TGF-β), and tumor necrosis factor-α (TNF-α), as well as signaling pathways, like Wnt/β-catenin, Notch, Hippo/Yap/Taz (5,6). While these factors are critical for liver recovery following resection, emerging evidence suggests that they may also facilitate tumor growth and recurrence (7-10). This dual role of liver regeneration is particularly evident in clinical interventions designed to enhance liver regrowth, such as portal vein embolization (PVE) and associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) (11,12). Although these strategies aim to mitigate the risk of insufficient residual liver volume (RLV), they have been shown to unintentionally promote tumor proliferation and elevate the risk of recurrence (7,13).

Recent studies have attempted to quantify the relationship between liver regeneration and tumor recurrence or prognosis. For instance, Nam et al. used the liver volume regeneration index (LVR-index) to assess regenerative capacity and found it to be predictive of overall survival (OS) in patients (14). Similarly, Liu et al. employed the hepatic regeneration rate (HRR) as a core indicator to explore its association with tumor-free survival (15). However, these studies typically evaluated regenerative capacity at single time points ranging from weeks to months postoperatively, failing to fully capture the dynamic regeneration process in the very early postoperative period. To address this gap, our study introduces the daily increment of residual liver regeneration (DIRER) as a novel metric. By quantifying the regeneration rate within the first postoperative week, we aim to systematically investigate the impact of early liver regeneration on the risk of HCC recurrence following radical hepatectomy. We present this article in accordance with the STROBE reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-aw-841/rc).

Methods

Data source and participant screening

This retrospective cohort included 3,821 patients who underwent hepatectomy at the Eastern Hepatobiliary Surgery Hospital between 2017 and 2019. Patient selection was based on predefined inclusion and exclusion criteria, and comprehensive clinical data were systematically documented for each participant. The inclusion criteria were as follows: (I) histopathologically confirmed HCC; (II) availability of complete preoperative and postoperative (5–7 days after surgery) three-dimensional (3D) imaging data for liver volume reconstruction; (III) age under 65 years; (IV) Barcelona Clinic Liver Cancer (BCLC) stage 0–B without extrahepatic metastases, macrovascular invasion, or invasion into adjacent organs; and (V) Child-Pugh score below 9 (grade A or B).

Exclusion criteria included: (I) presence of other concurrent malignancies; (II) history of prior hepatectomy; (III) history of postoperative anti-cancer therapy; (IV) severe postoperative complications; (V) non-R0 resection; (VI) recurrence within 1 month after hepatectomy; (VII) additional intraoperative procedures beyond the hepatectomy that could influence postoperative outcomes (e.g., biliary-enteric anastomosis); (VIII) incomplete clinical data; and (IX) failure to maintain follow-up within the first month post-hepatectomy.

Patients were followed every 2 months for the first 6 months post-surgery, then every 6 months thereafter, and the median follow-up period for all patients was 60 months. Follow-up evaluations included alpha-fetoprotein (AFP) levels, abdominal ultrasound, and enhanced imaging studies [computed tomography (CT) or magnetic resonance imaging (MRI)]. If recurrence or metastasis was suspected, enhanced CT or MRI was performed, followed by positron emission tomography (PET)/CT or bone scans if further evaluation was needed.

Of the initial cohort of 3,821 patients, 608 met the inclusion criteria after exclusions, which included 1,839 lacking 3D imaging assessments, 893 non-HCC cases, 377 older than 65 years, 92 patients at BCLC stage > B, and 12 with a Child-Pugh grade > B. Additional exclusions encompassed 170 cases with postoperative therapy, 21 with concurrent malignancies, 13 with severe complications, 42 with prior hepatectomies, 23 with non-R0 resections, and 9 with recurrence within 1 month. Ultimately, 330 patients with complete follow-up data were identified. After excluding 6 patients lost to follow-up, 324 remained in the final analysis (Figure 1). Among these 324 patients, 128 (39.5%) had underlying liver cirrhosis.

Figure 1 Flow diagram of the present study. 3D, three-dimensional; BCLC, Barcelona Clinic Liver Cancer; HCC, hepatocellular carcinoma.

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Ethics Review Board of the Eastern Hepatobiliary Surgery Hospital (No. EHBHKY2022-H-P002), and individual consent for this analysis was waived due to the retrospective nature.

Measures

Primary outcomes

Primary outcomes were recurrence-free survival (RFS) and OS. RFS was defined as the time from hepatectomy to the first recurrence or the last follow-up, and OS was defined as the time from hepatectomy to death or last follow-up. Tumor recurrence was classified as early (within 2 years) or late (after 2 years).

Independent variables

Key independent variables included various parameters of liver volume and regeneration. Preoperative and postoperative 3D imaging, using image photogrammetric suite (IPS) software (developed by Xudong, Shenzhen, China), assessed liver volume changes. Intraoperative liver resection volume was measured directly using the water displacement method (drainage method). Briefly, the freshly resected specimen was completely immersed in a graduated cylinder prefilled with sterile normal saline. The volume of displaced fluid, which equals the specimen volume according to Archimedes’ principle, was recorded. Subsequently, the RLV (mL) was calculated by subtracting this measured resection volume from the total preoperative liver volume. The RLV to body weight ratio (RLVw, mL/kg) was calculated as RLV divided by preoperative body weight. Postoperative change in RLV (ΔRLV, mL) was determined by subtracting the preoperative RLV from the total liver volume measured at a single time point within postoperative days 5–7. The DIRER (mL/day) was then defined as the average daily increment over this period, calculated by dividing ΔRLV by the number of days from surgery to the postoperative CT scan (i.e., DIRER = ΔRLV/number of days).

Covariates

Covariates were factors that could influence patient outcomes and were classified into preoperative, intraoperative, and postoperative variables. Preoperative variables included treatment history, liver function [e.g., albumin-bilirubin (ALBI) score >−2.6 indicating liver dysfunction (16)], and tumor characteristics [e.g., serum AFP levels >400 ng/mL to differentiate high and low AFP levels (17), presence of gastroesophageal varices was confirmed via endoscopy, CT, or MRI]. The extent of hepatectomy was categorized as minor (fewer than three segments) or major (three or more segments). Tumor-related parameters, such as tumor diameter, satellite nodules, microvascular invasion (MVI), tumor capsule, and liver cirrhosis, were derived from postoperative pathological reports. Tumor differentiation was graded using the Edmondson-Steiner classification (grades I–II tumors as well-differentiated, grades III–IV tumors as poorly differentiated) (18).

Intraoperative variables included surgical characteristics. Postoperative variables included complications, classified by the International Study Group of Liver Surgery (ISGLS) (19) and Clavien-Dindo grading systems (20). ISGLS grades 0–A indicated no or mild post-hepatectomy liver dysfunction, while grade B indicated postoperative liver dysfunction (no grade C liver dysfunction was observed). In the Clavien-Dindo classification, grades I–II indicated mild postoperative complications, while grades III–IV represented more severe but treatable complications. No grade V complications were reported. Additional information was obtained from clinical assessments and laboratory test results.

Statistical analysis

Continuous variables were first assessed for normality using the Shapiro-Wilk test. Normally distributed data are presented as mean ± standard deviation (SD) and were compared between groups using the Student’s t-test. Non-normally distributed data are presented as median with interquartile range (IQR) and were compared using the Mann-Whitney U test (for comparisons between two groups) or the Kruskal-Wallis H test (for comparisons across more than two groups). Categorical variables are expressed as counts (percentages) and were analyzed using Pearson’s Chi-squared test or Fisher’s exact test, as appropriate. Prognostic factors were identified using univariable and multivariable Cox proportional-hazards regression models. Univariable and multivariable logistic regression analyses were used to calculate odds ratio (OR) or relative risk (RR). Factors with a P value <0.05 in the univariable analysis were included in the multivariable analysis.

RFS and OS were estimated using the Kaplan-Meier method, with group differences assessed by the log-rank test. DIRER and RLVw cutoffs were determined using X tile software (21). Subgroup and interaction analyses were performed using SPSS software, version 26.0 (IBM Corp., Armonk, NY, USA). All statistical tests were two-sided, and a P value <0.05 was considered statistically significant. Figures and graphs were generated using R software, version 4.2.0 (Vienna, Austria).

Results

Characteristics of HCC patients

Table 1 summarizes the characteristics of the 324 HCC patients. Of these, 241 had hepatitis B, with 169 receiving full-course antiviral therapy. The majority (309 patients) were classified as BCLC stage A, and 277 had solitary tumors. Among these, 209 underwent radical resection via minor hepatectomy, while 115 underwent major hepatectomy, with 56 requiring perioperative blood transfusion. Postoperative histology revealed poor tumor differentiation in 308 cases and MVI in 146, indicating a high recurrence risk. Most patients had favorable perioperative recovery, with only 26 patients experiencing ISGLS-defined liver dysfunction and 37 having severe complications according to Clavien-Dindo grade.

The median postoperative RLV was 913.24 (IQR, 802.18–1,070.05) mL, with a RLVw of 14.21 (IQR, 12.29–16.16) mL/kg. Liver regeneration within 7 days post-surgery showed a volume increase of 146.62 (IQR, 88.90–226.48) mL, with a mean increase of 2.33 (IQR, 1.43–3.41) mL/kg of RLVw and a daily increment (DIRER) of 19.09 (IQR, 12.51–31.59) mL.

High DIRER suggests poorer prognosis in HCC patients, with a higher likelihood of early recurrence

Table 2 shows the univariable and multivariable Cox proportional-hazards models identifying independent prognostic factors for RFS and OS. Significant factors included the extent of hepatectomy [hazard ratio (HR) =1.46, P=0.007 for RFS; HR =1.44, P=0.02 for OS], MVI (HR =1.38, P=0.02 for RFS; HR =1.41, P=0.02 for OS), tumor capsule (HR =1.60, P=0.006 for RFS; HR =1.80, P=0.001 for OS), RLV (HR =1.00, P=0.03 for RFS; HR =1.00, P=0.001 for OS), RLVw (HR =0.92, P<0.001 for RFS; HR =0.93, P=0.01 for OS), ΔRLV (HR =1.01, P<0.001 for RFS; HR =1.01, P<0.001 for OS), change in RLVw (ΔRLVw) (HR =1.48, P<0.001 for RFS; HR =1.52, P<0.001 for OS), and DIRER (HR =1.05, P<0.001 for RFS; HR =1.05, P<0.001 for OS) were independent prognostic factors for both RFS and OS. Apart from MVI and tumor capsule, which are well-established risk factors (22,23), other indicators were associated with tumor resection and postoperative liver regeneration (ΔRLV, ΔRLVw, and DIRER).

In multivariable analysis, MVI (HR =1.64, P=0.001 for RFS; HR =1.65, P=0.004 for OS), tumor capsule (HR =1.69, P=0.005 for RFS; HR =1.53, P=0.04 for OS), and DIRER (HR =1.06, P=0.003 for RFS; HR =1.06, P=0.004 for OS) were confirmed as independent prognostic factors for both RFS and OS, while RLVw (HR =0.87, P=0.02) was independently associated with RFS alone. Therefore, DIRER was identified as a statistically significant factor associated with patient prognosis in this study.

Early recurrence was correlated with the malignant properties of the primary tumor, such as residual micrometastases or multinodular lesions, while late recurrence was linked to chronic liver conditions (cirrhosis or chronic hepatitis B/C) and new mutations during liver regeneration (24-26). MVI (HR =1.84, P=0.001), tumor capsule (HR =1.61, P=0.02), and DIRER (HR =1.05, P=0.02) were associated with early recurrence, while the Clavien-Dindo grades III–IV (HR =2.41, P=0.02) and antiviral treatment (HR =0.50, P=0.04) were independent prognostic factors for late recurrence. Notably, RLVw was not significantly associated with either early or late recurrence of HCC (P>0.05) (Table S1). Therefore, DIRER may exacerbate early tumor recurrence.

DIRER thresholds of 17.95 and 31.58 mL/day were identified as cutoffs for RFS and OS, categorizing patients into high and low regeneration groups. Kaplan-Meier survival analysis revealed prolonged RFS and OS in the low-regeneration group (Figure 2A,2B). In the recurrent HCC patients, no significant association was found between regeneration rate and recurrence type (P=0.89), though higher regeneration was associated with a higher frequency of multiple tumor recurrence (RR =1.83, P=0.02) (Figure 2C).

Figure 2 Comparison of RFS (A) and OS (B) for low and high DIRER groups. (C) RR of different recurrence patterns in HCC for low and high DIRER groups. (D) The impact of major or minor hepatic resection on the prognosis of HCC of different diameters. CI, confidence interval; DIRER, daily increment of residual liver regeneration; HCC, hepatocellular carcinoma; HR, hazard ratio; OS, overall survival; RFS, recurrence-free survival; RR, relative risk.

Major hepatectomy for HCC ≤5 cm may negatively impact patient prognosis

Interaction analysis further demonstrated an interplay between DIRER and satellites (P_interaction=0.048) in influencing RFS, and between DIRER and sex (P_interaction=0.002) in affecting OS. However, no significant interactions were observed for tumor diameter, extent of hepatectomy, or other indicators (all P_interaction>0.05) (Figure S1). To explore the relationship between the extent of hepatectomy and prognosis, subgroup analyses based on tumor size and surgical range were performed. Patients undergoing major hepatectomy had higher recurrences when tumor diameter was ≤5 cm (HR =1.95, P=0.02 for RFS; HR =2.59, P=0.001 for OS) (Figure 2D). These results underscore the importance of attaining adequate surgical margins during hepatectomy to optimize patient outcomes.

RLVw is associated with DIRER and serves as a prognosis indicator in HCC patients

The liver has a remarkable regenerative capacity, restoring its volume and function after partial resection. Patients with higher DIRER had more frequent perioperative transfusion (OR =2.46, P=0.008). However, no significant differences were observed between groups regarding the frequency of minor or major hepatectomy (Table S2).

Furthermore, RLVw (HR =0.86, P<0.001) was an independent predictor of DIRER. Lower RLVw values, indicating larger resections and decreased residual liver-to-body weight ratios, were associated with faster liver regeneration but also with poorer prognosis (Figure S2). This result further reinforces our conviction that the extent of hepatectomy is critical to patient prognosis.

Lower DIRER is associated with an increased incidence of postoperative complications

Postoperative complications graded by Clavien-Dindo were not associated with long-term prognosis (Table 2) but were significantly correlated with DIRER (OR =0.28, P=0.002) (Table S2). Patients with slower liver regeneration experienced higher rates of both mild (P<0.002) and severe complications (P<0.001) (Table 3). These findings indicate that slower liver regeneration (reflected by a lower DIRER) is a significant predictor of a higher incidence of postoperative complications.

Discussion

This study utilized 3D reconstruction technology to accurately assess liver volume changes before and after partial hepatectomy, systematically monitoring liver regeneration. Our findings demonstrate that the DIRER is significantly associated with tumor recurrence, suggesting that early liver regeneration may play a crucial role in the recurrence of HCC following hepatectomy. Furthermore, we identified several key determinants of early liver regeneration, including preoperative liver function, tumor characteristics, and the extent of hepatectomy, all of which were predictive of postoperative outcomes.

Postoperative liver regeneration and HCC recurrence

The biological processes underpinning HCC progression share significant molecular similarities with liver regeneration. Normal liver regeneration represents a tightly regulated physiological process involving orchestrated activation and regulation of various signaling pathways. In response to stress or liver injury, pathways such as HGF/Met, interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3), TNF-α/nuclear factor-κB (NF-κB), and epidermal growth factor (EGF)/EGF receptor (EGFR) work in concert to mediate hepatocyte proliferation (27,28). The plasma in blood is rich in hepatocyte-related growth factors and cells that secrete relevant factors, while the red blood cells in blood ensure sufficient oxygen supply to the body. This may be one of the reasons why our findings suggest that perioperative blood transfusion could promote postoperative liver regeneration. Additionally, precise regulation of cell cycle proteins and cyclin-dependent kinases ensures orderly hepatocyte proliferation and regeneration (29).

However, liver regeneration induced by partial hepatectomy creates a unique microenvironment that may activate micrometastatic foci, promoting tumor cell proliferation and leading to HCC recurrence. This phenomenon underscores the dual role of liver regeneration-associated signaling networks in hepatocarcinogenesis and tumor progression (30). Our findings suggest that while liver regeneration is crucial for post-surgical recovery, it may paradoxically foster conditions that promote recurrence in HCC patients.

For patients with larger HCC tumors, major hepatectomy is often required. Previous studies have reported that liver regeneration rates following major hepatectomy are significantly higher throughout the recovery period and within the first postoperative week compared to minor hepatectomy (31). Additionally, tumor burden itself is an independent risk factor for HCC recurrence (32). These factors may introduce potential analytical bias, which we sought to mitigate. In patients stratified by DIRER, there were no significant differences in tumor resection extent or remnant liver volume between groups. Subgroup analyses further demonstrated that regardless of tumor burden, a higher extent of hepatectomy rate is associated with poorer prognosis. This was validated through statistical analysis, which revealed no significant interaction effects between these variables.

While prior research has shown an association between wider resection margins and reduced recurrence risk, these studies often categorized patients using a threshold margin of 1 cm without considering more refined stratifications (33,34). In the stratified analysis of this study, it was observed that when tumor diameters were ≤5 cm, larger resection volumes were associated with poorer outcomes. These findings highlight the importance of careful preoperative planning regarding the extent of hepatectomy, particularly for tumors located at hepatic segmental boundaries. Direct calculations of resected liver volume in this study, along with the incorporation of the standardized RLV (RLVw), revealed a significant negative correlation between RLVw and DIRER, while lower RLVw predicted higher recurrence. These results demonstrate that lower RLVw is associated with higher DIRER rates, suggesting that RLVw may serve as a preoperative predictor of DIRER, but also excessive resection of HCC may increase the risk of recurrence.

Key determinants of liver regeneration

Maintaining sufficient liver volume during surgery is critical for preserving postoperative liver function in HCC patients (35,36). A study has indicated that when the percentage of remnant liver volume falls below 42.7%, the risk of post-hepatectomy liver failure (PHLF) increases significantly (37). Ensuring adequate RLV has been shown to effectively reduce postoperative complications. This principle is particularly important for HCC patients with cirrhosis, whose compensatory liver function is already compromised (38).

However, our findings revealed that preserving larger liver volumes results in higher RLVw and lower DIRER, which are paradoxically associated with increased postoperative complications. This may be attributable to the inhibitory effect of these complications on liver regeneration. Previous studies have demonstrated that postoperative complications significantly impede the recovery of liver function and volume (39). For instance, postoperative infections involve complex interactions among endotoxins, Kupffer cells, and hepatocytes, suppressing the production of cytokines essential for early liver regeneration (40,41). Similarly, bile leaks may result in bile salt loss, impairing fibroblast growth factor activity, thereby inhibiting liver regeneration (42,43). Postoperative complications may act as both a consequence of delayed liver regeneration and a suppressor of the regenerative process. This bidirectional relationship warrants careful consideration in surgical planning and postoperative management strategies.

This study has several limitations. First, as a single-center retrospective analysis, it predominantly involved Asian patients with HBV-related HCC, and the generalizability of our findings to other populations and HCC etiologies requires validation through international multicenter studies. Second, the analysis did not comprehensively assess the impact of preoperative treatments, such as tyrosine kinase inhibitors or immune checkpoint inhibitors, which are increasingly integral to clinical practice and may significantly affect long-term survival outcomes. Lastly, while this study introduces the concepts of RLVw and DIRER, the relatively small sample size limited our ability to establish definitive thresholds for these indicators. Future large-scale prospective studies across diverse patient populations and incorporating modern therapeutic approaches are needed to verify our results and optimize these concepts.

Conclusions

In conclusion, this study highlights that accelerated liver regeneration following partial hepatectomy significantly increases the risk of early tumor recurrence. Careful intraoperative management of RLV is closely associated with improved long-term outcomes in HCC patients. Additionally, the establishment of DIRER thresholds provides valuable reference points for surgical planning and clinical decision-making.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-aw-841/rc

Data Sharing Statement: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-aw-841/dss

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-aw-841/prf

Funding: This work was supported by the National Natural Science Foundation of China (Nos. 82573103, 82302906, and 82270634).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-aw-841/coif). S.Z. is from Xunfei Healthcare Technology Co., Ltd. The other 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 Institutional Ethics Review Board of the Eastern Hepatobiliary Surgery Hospital (No. EHBHKY2022-H-P002), and individual consent for this analysis was waived due to the retrospective nature.

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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