Abstract
Background
Comparative evidence of laparoscopic second hepatectomy using standardized anatomical resection techniques is limited. This study compared laparoscopic versus open second hepatectomy using Takasaki’s Glissonean pedicle approach combined with Honda’s laparoscopic innovations for recurrent hepatocellular carcinoma (HCC).
Methods
A retrospective cohort study was conducted at Tokyo Women’s Medical University Hospital (2010–2024). Of 152 patients who underwent a second hepatectomy for recurrent HCC, 72 were matched (36 per group) using the optimal Mahalanobis distance propensity score matching (PSM) across 25 covariates.
Results
Laparoscopic surgery was associated with lower blood loss (27.5 vs. 366.5 mL; P<0.001), fewer complications (8.3% vs. 25.0%; P=0.048), and shorter postoperative hospital stay (7.0 vs. 11.0 days; P<0.001). No conversions occurred, and 90-day mortality was zero in both groups. R0 resection was universal. Five-year overall survival (OS; 43.7% vs. 44.4%; P=0.77) and recurrence-free survival (PFS; 26.7% vs. 23.6%; P=0.83) were comparable. Residual temporal confounding persisted after matching [standardized mean difference (SMD) for surgery phase =−0.72].
Conclusions
Laparoscopic second hepatectomy using the Glissonean pedicle approach was associated with favorable perioperative outcomes and survival rates comparable to those of open surgery in selected patients. Therefore, a multicenter prospective validation is warranted.
Keywords: Laparoscopic hepatectomy, second hepatectomy, hepatocellular carcinoma (HCC), Glissonean pedicle approach, propensity score matching (PSM)
Highlight box.
Key findings
• In this propensity score-matched analysis (72 patients, 36 in each group), laparoscopic second hepatectomy using Takasaki’s Glissonean pedicle approach with Honda’s laparoscopic innovations was associated with significantly lower intraoperative blood loss (median 27.5 vs. 366.5 mL, P<0.001), a lower complication rate (8.3% vs. 25.0%, P=0.048), and a shorter postoperative stay (median 7.0 vs. 11.0 days, P<0.001; therehwereono conversionsnord 90-day mortality ineitherhgroups.
• Five-year overall survival (43.7% vs. 44.4%, log-rank P=0.77) and recurrence-free survival (26.7% vs. 23.6%, log-rank P=0.83) were comparable between groups.
What is known and what is new?
• Several studies have compared laparoscopic and open second hepatectomy for recurrent hepatocellular carcinoma (HCC); however, these studies are limited by small sample sizes, insufficient control for confounding variables, and a focus limited to the surgical approach without evaluating the specific resection techniques employed, particularly the Glissonean pedicle approach.
• This study is the first to evaluate the combined application of Takasaki’s Glissonean pedicle approach and Honda’s laparoscopic technical innovations in a propensity score-matched comparison of laparoscopic vs. open second hepatectomy for recurrent HCC.
What is the implication, and what should change now?
• Laparoscopic second hepatectomy using the Glissonean pedicle approach may be a feasible and oncologically adequate alternative to open surgery for selected patients with recurrent HCC, when performed by experienced surgeons in high-volume hepatobiliary centers.
• Multicenter prospective studies with longer follow-up periods are warranted to validate these findings, define patient selection criteria, and confirm the long-term oncological equivalence of this approach.
Introduction
Hepatocellular carcinoma (HCC) is a major global health challenge (1,2). Even with improved surveillance and initial curative treatment options, HCC is characterized by a high recurrence rate, with 60–70% of patients experiencing intrahepatic recurrence within 5 years of initial hepatectomy (1,3,4). Among curative treatment options for recurrent HCC, second hepatectomy is the first-line treatment in selected patients, achieving 5-year overall survival (OS) rates of 41–73% (3,5,6). Only 15–30% of patients with recurrent HCC are eligible for a second hepatectomy because of technical challenges, including postoperative adhesions, altered anatomic landmarks, compromised liver function reserve, and limited remnant liver volume after initial resection (5,6). Early second hepatectomy has been shown to improve survival, minimize perioperative morbidity and preserve liver function are important to extend treatment options and improve outcomes in this high-risk population (5,7,8).
Second hepatectomy for recurrent HCC is still predominantly performed via open surgery (9-11). In contrast, laparoscopic liver resection has emerged as an advantageous alternative to conventional open surgery, associated with reduced surgical trauma, lower intraoperative blood loss, less postoperative pain, faster recovery, and shorter hospitalization (12-14). These benefits are particularly relevant in the context of a second hepatectomy, where minimizing morbidity is mandatory to preserve future treatment options and maintain quality of life while achieving oncological adequacy (15,16). However, laparoscopic second hepatectomy in HCC remains technically demanding and has achieved limited clinical adoption worldwide (12,17), largely because extensive intra-abdominal adhesions, reported in over 80% of patients, and structural alterations in hepatic vascular anatomy present technical barriers compared to primary laparoscopic hepatectomy (18). These challenges are increased for tumors in the posterosuperior liver segments or near previous resection sites, where restricted visualization and instrumental maneuverability compromise operative feasibility and safety (19).
Although several studies have compared laparoscopic and open second hepatectomy, notable knowledge gaps persist. Most studies are limited by small sample sizes, inadequate control of confounding variables, short follow-up durations, and insufficient reporting of the surgical technique applied, making it difficult to reproduce results and compare findings across studies. The Glissonean pedicle approach, proposed by Takasaki et al., has emerged as a widely accepted standard technique for anatomical liver resection, including second hepatectomy (20,21). This approach is guided by segmental anatomy and involves isolating and dividing each Glissonean pedicle as a single structure without individual vessel dissection, thereby dividing each hepatic segment into six to eight cone-shaped territories (22,23). This technique enables precise parenchyma-sparing resection with early vascular control, and has been adopted in both open and laparoscopic settings, however, no comparative study of second hepatectomy has standardized this approach across both surgical arms (22,24,25).
Extending Takasaki’s anatomical framework, Honda et al. have further developed a series of laparoscopic technical innovations designed to adapt the Glissonean pedicle approach to minimally invasive surgery (23,26-30). However, the combined application of Honda’s laparoscopic innovations and Takasaki’s Glissonean pedicle approach in second hepatectomy has not been evaluated in comparative studies, limiting the evidence for patient selection and operative strategy.
Therefore, we conducted a retrospective cohort study comparing second hepatectomy using the Glissonean pedicle approach (Takasaki’s technique with Honda’s laparoscopic innovations) vs. open second hepatectomy in patients with recurrent HCC. The primary objective was to evaluate perioperative outcomes, oncological adequacy, and long-term survival to determine whether laparoscopic second hepatectomy with anatomical resection techniques is a safe and oncologically effective alternative to open surgery in this high-risk population. We present this article in accordance with the STROBE reporting checklist (available at https://tgh.amegroups.com/article/view/10.21037/tgh-2026-0043/rc).
Methods
We conducted a single-center, retrospective cohort study comparing laparoscopy vs. open surgery for second hepatectomy in all patients with recurrent HCC between January 2010 and December 2024 at Tokyo Women’s Medical University Hospital. This 14-year study period was divided into two surgical leadership phases reflecting institutional technical evolution: the phase 1 (2010–2019) under the supervision of Masakazu Yamamoto who was directly trained by Ken Takasaki, during which open Glissonean pedicle approach had already been standardized, whereas laparoscopic liver resection was still in a developmental stage, and the phase 2 (2020–2024) under the leadership of Goro Honda, characterized by systematic integration of Takasaki’s Glissonean approach into laparoscopic anatomical resection.
Inclusion criteria were: (I) histologically confirmed HCC recurrence after initial hepatectomy; (II) Child-Pugh class A or B; (III) technically resectable disease (liver damage A or B, with adequate future liver remnant, according to the Liver Cancer Study Group of Japan); and (IV) complete clinical and radiological data. Exclusion criteria were: (I) extrahepatic metastases at the time of second hepatectomy; (II) concurrent malignancies; (III) severe comorbidities precluding surgery; (IV) liver transplantation; or (V) incomplete follow-up data. Of 152 eligible patients, 116 underwent open surgery, and 36 underwent laparoscopic surgery. Propensity score matching (PSM) was performed to create balanced treatment cohorts (Figure 1).
Figure 1.
Patient selection and PSM flowchart for comparative analysis of laparoscopic vs. open second hepatectomy in recurrent hepatocellular carcinoma. HCC, hepatocellular carcinoma; PSM, propensity score matching.
Ethics
The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Board of Tokyo Women’s Medical University (No. 2024-0133). Written informed consent was obtained from all patients in accordance with institutional policies.
PSM
Twenty-five covariates were selected for PSM modeling. Covariates were included if they (I) influenced both surgical approach selection and clinical outcomes according to prior literature; (II) were strong predictors of perioperative outcomes; or (III) were baseline characteristics that could affect treatment decisions. The variables were classified into patient-related [age, sex, body mass index (BMI), American Society of Anesthesiologists (ASA) anesthesiology status, and preoperative Eastern Cooperative Oncology Group (ECOG) performance status] (31,32), disease-related (viral etiology, Child-Pugh class (32,33), HCC type, liver background, histological differentiation grade, tumor number, pathological satellite nodules, tumor size, macrovascular invasion, microvascular invasion, bile duct invasion, and surgical margin status) (34-36), preoperative laboratory [indocyanine green retention at 15 minutes (ICG-R15) (37), alpha-fetoprotein (AFP), protein-induced vitamin K absence or antagonist-II (PIVKA-II), serum albumin, prothrombin time, serum creatinine, platelet count, and total bilirubin] (32,35,38). To account for temporal change in surgical technique and institutional experience, the surgical phase (2010–2019 vs. 2020–2024) was included as a covariate.
A PSM was estimated using multivariable logistic regression, with surgical approach (laparoscopic vs. open) as the dependent variable and the 25 covariates as independent variables. Optimal Mahalanobis distance matching with PSM caliper was performed at a 1:1 ratio, without replacement, using the MatchIt package in R version 4.3.0 (R Foundation for Statistical Computing, Vienna, Austria). The caliper was set at 0.2 standard deviations of the logit of the PSM to ensure adequate matching quality. Covariate balance was assessed using standardized mean differences (SMDs), with SMD ≤0.10 considered excellent balance and SMD ≤0.20 considered acceptable balance. Balance was evaluated before and after matching using the Love plot (Figure 2).
Figure 2.
Covariate balance assessment before and after optimal mahalanobis distance matching. Love plot displaying SMDs for 25 baseline covariates comparing laparoscopic vs. open second hepatectomy. Unadjusted (triangles) and adjusted estimates after optimal Mahalanobis distance matching (circles) are shown relative to the standardized mean difference (laparoscopic surgery − open surgery). Vertical dashed lines demarcate thresholds for excellent (|SMD| <0.10) and acceptable (|SMD| <0.20) covariate balance. AFP, alpha-fetoprotein; ASA, American Society of Anesthesiologists; BMI, body mass index; ECOG, Eastern Cooperative Oncology Group; ICG, indocyanine green retention; PIVKA, protein-induced vitamin K absence or antagonist; PT, prothrombin time; SMD, standardized mean difference.
Outcome
Primary outcomes were (I) perioperative outcomes (operative time, intraoperative blood loss (gravimetric method and visual method), conversion rate, Clavien-Dindo complications within 30 days, and hospital stay) and (II) OS (time from second hepatectomy to death from any cause, censored at the date of last contact).
Secondary outcomes included: (I) recurrence-free survival (RFS), defined as the time from the date of surgery from second hepatectomy to the first documented radiological or clinical evidence of tumor recurrence; and (II) liver function recovery, assessed using the albumin-bilirubin (ALBI) grade at 1 and 3 months postoperatively.
Surgical technique
We performed second hepatectomy laparoscopically or via open surgery. In the laparoscopic approach, patients were routinely positioned based on the tumor location, usually supine for the left-lobe tumor, and the left semi-lateral decubitus position with the right side elevated approximately 30° for right-lobe tumors. Pneumoperitoneum was established via the open technique with a 12-mm umbilical camera port at 12–14 mmHg CO2 insufflation. Working ports (5–12 mm) were placed depending on patient habitus, commonly along the right subcostal, epigastric, and anterior axillary positions, and, if needed, an intercostal trocar was added for segment 8 or the posterosuperior segment. For open cases, a subcostal incision with midline extension (J-shaped) was used, with the incision planned considering previous surgical scars.
Adhesiolysis was performed using blunt and sharp dissections. The Pringle maneuver was applied using an external tourniquet system (100-cm polyester tape and 20-cm silicone tube) for intermittent vascular occlusion in laparoscopic cases or during hilar dissection in open approaches, with 15-min clamping and 5-min reperfusion cycles as needed. Intraoperative ultrasonography (IOU) was used to localize tumors, confirm the Glissonean pedicle, determine resection margins, and delineate vascular anatomy.
In the laparoscopic setting, real-time coordination with anesthesiologists maintained central venous pressure (CVP) below the pneumoperitoneum pressure (PPP) by adjusting airway pressure (AWP) to reduce backflow bleeding and gas embolism risk.
Parenchymal transection was performed following Takasaki’s cone unit theory, using intersegmental plane dissection to preserve the hepatic veins while identifying the Glissonean pedicles. A cavitron ultrasonic surgical aspirator (CUSA) with the back-scoring technique and soft coagulation was used for parenchymal excavation and hemostasis. Vascular structures >3 mm were secured with titanium clips. When oncologically feasible, we resected along a demarcation line based on the targeted Glissonean pedicle or with a 10-mm tumor-free margin. Specimens were retrieved via extraction bags through the enlarged umbilical port (laparoscopic) or directly (open). Closed-suction drainage was selectively placed.
All resections classified as ‘partial’ in this cohort were anatomical subsegmentectomies performed through tertiary Glissonean pedicle isolation with IOU confirmed ischemic demarcation, consistent with Takasaki’s cone unit theory at the third-branch level. The Glissonean approach was applied uniformly across both laparoscopic and open surgery, with resection extent differing only in the hierarchical level of pedicle ligation-secondary versus tertiary-not in adherence to anatomical principles.
Pathological assessment and follow-up
All surgical specimens underwent histopathological evaluation, including tumor size, number, differentiation grade, vascular invasion (micro- and macrovascular), architectural pattern, bile duct invasion, and surgical margin status. Patients underwent surveillance with ultrasound and serum tumor markers (AFP and PIVKA-II) every 3–4 months postoperatively, with dynamic computed tomography or magnetic resonance imaging performed as clinically indicated, following the Japan Society of Hepatology guidelines for extremely high-risk HCC patients after curative treatment.
Statistical analysis
All analyses were performed using R version 4.3.0 and SPSS version 27.0 (IBM Corp., Armonk, NY). Continuous variables were presented as medians (interquartile ranges) or means (standard deviations), as appropriate; categorical variables were presented as frequencies and percentages. The chi-square test or Fisher’s exact test was used for categorical variables; the t-test or Mann-Whitney U test was used for continuous variables. Survival curves were estimated using the Kaplan-Meier method, and group comparisons were assessed using the log-rank test. Multivariable survival analysis employed Cox proportional hazards regression, with hazard ratios (HRs) and 95% confidence intervals (CIs) reported. The proportional hazards assumption was tested using Schoenfeld residuals. Statistical significance was defined as P<0.05 (two-tailed).
Results
Patient cohort and PSM
Of 152 consecutive patients who underwent second hepatectomy for recurrent HCC, 36 underwent laparoscopic, and 116 underwent open surgery. After 1:1 PSM using the optimal Mahalanobis distance matching, 72 patients were matched (36 per group). The matching algorithm demonstrated good discrimination (c-statistic =0.78) and excellent overlap in PSM distributions between groups.
Following matching, 19 of 25 variables (76%) achieved excellent balance (SMD ≤0.1). The mean absolute SMD improved from 0.31 pre-matching to 0.13 post-matching, representing a 58% reduction (Figure 2). Notable improvements were observed in demographic characteristics, laboratory values, and tumor-related factors, including macrovascular invasion status, tumor number, and liver function. However, residual imbalances persisted in tumor differentiation (SMD =0.50), albumin (SMD =0.45), prothrombin time (SMD =0.30), bilirubin (SMD =−0.30), and surgery date (SMD =−0.72). The surgery date imbalance reflected a temporal trend in laparoscopic surgery adoption, with most laparoscopic procedures performed during phase 2 (2020–2024), while open surgery patients were concentrated in phase 1 (2010–2019), despite matching.
Baseline characteristics
After PSM, demographic, clinical, and surgical history variables were well balanced (Table 1), including age, BMI, ECOG, ASA, Child-Pugh class, etiology, prior resection type, and preoperative treatment. In addition, tumor pathology was similarly balanced (Table 2): median size of all tumors ≤5 cm, solitary tumors, absence of satellite nodules, R0 margins, absence of macrovascular invasion, and comparable tumor differentiation. However, three characteristics remained imbalanced: ICG-R15 (within the resectable range), surgical era, and previous laparoscopic surgery approach. The latter two reflect that most laparoscopic cases were performed during phase 2 (2020–2024), consistent with progressive institutional adoption and innovation in laparoscopic surgery.
Table 1. Baseline characteristics of patients before and after propensity match score.
| Variables | Ovarall (N=152) |
Before propensity score matching | After propensity score matching | ||||
|---|---|---|---|---|---|---|---|
| Laparoscopic surgery (n=36) | Open surgery (n=116) | P value | Laparoscopic surgery (n=36) | Open surgery (n=36) | P value | ||
| Sex | 0.78 | 0.67 | |||||
| Female | 20 (13.2) | 4 (11.1) | 16 (13.8) | 4 (11.1) | 2 (5.6) | ||
| Male | 132 (86.8) | 32 (88.9) | 100 (86.2) | 32 (88.9) | 34 (94.4) | ||
| Age at operation, years | 71.0 [33–87] | 74.0 [46–84] | 71.0 [33–87] | 0.15 | 74.0 [46–84] | 71.0 [54–82] | 0.48 |
| ≤70 years | 69 (45.4) | 13 (36.1) | 56 (48.3) | 0.20 | 13 (36.1) | 15 (41.7) | 0.63 |
| >70 years | 83 (54.6) | 23 (63.9) | 60 (51.7) | 23 (63.9) | 21 (58.3) | ||
| Body mass index, kg/m2 | 22.8±3.3 | 23.2±3.4 | 22.7±3.3 | 0.43 | 23.2±3.4 | 23.2±2.6 | 0.93 |
| Underweight | 15 (9.9) | 4 (11.1) | 11 (9.5) | 0.70 | 4 (11.1) | 1 (2.8) | 0.37 |
| Normal | 64 (42.1) | 13 (36.1) | 51 (44.0) | 13 (36.1) | 15 (41.7) | ||
| Overweight/obese | 73 (48.0) | 19 (52.8) | 54 (46.6) | 19 (52.8) | 20 (55.6) | ||
| ECOG performance status | 0.03 | 0.32 | |||||
| 0 | 95 (62.5) | 17 (47.2) | 78 (67.2) | 17 (47.2) | 21 (58.3) | ||
| 1 | 50 (32.9) | 15 (41.7) | 35 (30.2) | 15 (41.7) | 14 (38.9) | ||
| 2 | 7 (4.6) | 4 (11.1) | 3 (2.6) | 4 (11.1) | 1 (2.8) | ||
| ASA score | 0.56 | 0.79 | |||||
| I | 2 (1.3) | 0 (0) | 2 (1.7) | 0 (0) | 0 (0) | ||
| II | 115 (75.7) | 26 (72.2) | 89 (76.7) | 26 (72.2) | 27 (75.0) | ||
| III | 35 (23.0) | 10 (27.8) | 25 (21.6) | 10 (27.8) | 9 (25.0) | ||
| Etiology | 0.10 | 0.62 | |||||
| HBV | 41 (27.0) | 8 (22.2) | 33 (28.4) | 8 (22.2) | 10 (27.8) | ||
| HCV | 65 (42.8) | 12 (33.3) | 53 (45.7) | 12 (33.3) | 14 (38.9) | ||
| Non-viral | 46 (30.3) | 16 (44.4) | 30 (25.9) | 16 (44.4) | 12 (33.3) | ||
| Liver background | 0.51 | 0.80 | |||||
| NL, NASH, CH | 108 (71.1) | 24 (66.7) | 84 (72.4) | 24 (66.7) | 25 (69.4) | ||
| LC | 44 (28.9) | 12 (33.3) | 32 (27.6) | 12 (33.3) | 11 (30.6) | ||
| Child-Pugh class | 0.57 | 0.49 | |||||
| A | 146 (96.1) | 34 (94.4) | 112 (96.6) | 34 (94.4) | 36 (100) | ||
| B | 6 (3.9) | 2 (5.6) | 4 (3.4) | 2 (5.6) | 0 (0) | ||
| ICG-R15, % | 12.0 [0.0–46.0] | 15.0 [7.9–23.0] | 12.0 [0.0–46.0] | 0.003 | 15.0 [7.9–23.0] | 12.0 [5.0–38.0] | 0.01 |
| <10 | 39 (25.7) | 3 (8.3) | 36 (31.0) | 0.02 | 3 (8.3) | ||
| 10–19 | 88 (57.9) | 25 (69.4) | 63 (54.3) | 33 (91.7) | |||
| ≥20 | 25 (16.4) | 8 (22.2) | 17 (14.7) | ||||
| Alpha-fetoprotein, ng/mL | 6 [1–40,539] | 5 [1–2,941] | 6 [1–40,539] | 0.14 | 5 [1–2,941] | 5 [1–658] | 0.84 |
| ≤200 | 128 (84.2) | 33 (91.7) | 95 (81.9) | 0.16 | 33 (91.7) | 32 (88.9) | >0.99 |
| >200 | 24 (15.8) | 3 (8.3) | 21 (18.1) | 3 (8.3) | 4 (11.1) | ||
| PIVKA-II, mAU/mL | 39.0 [4–102,660] | 32.0 [4–3,426] | 41.5 [8–102,660] | 0.55 | 32.0 [4–3,426] | 25.0 [8–583] | 0.051 |
| <40 | 77 (50.7) | 20 (55.6) | 57 (49.1) | 0.50 | 20 (55.6) | 26 (72.2) | 0.14 |
| ≥40 | 75 (49.3) | 16 (44.4) | 59 (50.9) | 16 (44.4) | 10 (27.8) | ||
| Creatinine, mg/dL | 0.87 [0.45–12.24] | 0.94 [0.63–3.90] | 0.86 [0.45–12.24] | 0.13 | 0.94 [0.63–3.90] | 0.83 [0.45–4.60] | 0.18 |
| ≤1.4 | 139 (91.4) | 34 (94.4%) | 105 (90.5) | 0.73 | 34 (94.4%) | 33 (91.7) | >0.99 |
| >1.4 | 13 (8.6) | 2 (5.6) | 11 (9.5) | 2 (5.6) | 3 (8.3) | ||
| Prothrombin time, % | 90 [41.0–100] | 91.1 [57.3–100] | 90.0 [40.7–100] | 0.73 | 91.1 [57.3–100] | 92.1 [73.9–100] | 0.28 |
| >70 | 140 (92.1) | 33 (91.7) | 107 (92.9) | >0.99 | 33 (91.7) | 36 (100) | 0.24 |
| ≤70 | 12 (7.9) | 3 (8.3) | 9 (7.8) | 3 (8.3) | 0 (0) | ||
| Surgery date, period year | |||||||
| 2010–2019 | 116 (76.3) | 12 | 112 | <0.0001 | 12 | 35 | <0.001 |
| 2020–2024 | 36 (23.7) | 24 | 4 | 24 | 1 | ||
| Previous surgery | <0.001 | 0.006 | |||||
| Laparoscopy | 10 (6.6) | 9 (25.0) | 1 (0.9) | 9 (25.0) | 1 (2.8) | ||
| Open | 142 (93.4) | 27 (75.0) | 115 (99.1) | 27 (75.0) | 35 (97.2) | ||
| Type of previous surgery | 0.51 | 0.80 | |||||
| Minor | 112 (73.7) | 25 (69.4) | 87 (75.0) | 25 (69.4) | 24 (66.7) | ||
| Major | 40 (26.3) | 11 (30.6) | 29 (25.0) | 11 (30.6) | 12 (33.3) | ||
| Recurrence site after first hepatectomy | 0.002 | >0.99 | |||||
| Single | 114 (75.0) | 34 (94.4) | 80 (69.0) | 34 (94.4) | 35 (97.2) | ||
| Multiple | 38 (25.0) | 2 (5.6) | 36 (31.0) | 2 (5.6) | 1 (2.8) | ||
| Preoperative treatment before second hepatectomy | 0.40 | 0.55 | |||||
| Upfront surgery | 79 (52.0) | 22 (61.1) | 57 (49.1) | 22 (61.1) | 19 (52.8) | ||
| Non-ablation | 32 (21.1) | 7 (19.4) | 25 (21.6) | 7 (19.4) | 6 (16.7) | ||
| Ablation | 41 (27.0) | 7 (19.4) | 34 (29.3) | 7 (19.4) | 11 (30.6) | ||
| Preoperative treatment within 6 months prior to second hepatectomy | 0.48 | 0.48 | |||||
| No | 47 (64.8) | 8 (57.1) | 39 (67.2) | 8 (57.1) | 12 (70.6) | ||
| Yes | 25 (35.2) | 6 (42.9) | 19 (32.8) | 6 (42.9) | 5 (29.4) | ||
| Time to recurrence after 1st hepatectomy, months | 44.0 [4.0–282.0] | 38.9 [7.7–144.3] | 46.2 [4.7–282.9] | 0.47 | 38.9 [7.7–144.3] | 52.9 [9.3–282.9] | 0.07 |
| ≤1 year | 9 (9.2) | 2 (5.6) | 7 (6.0) | >0.99 | 34 (94.4) | 35 (97.2) | >0.99 |
| >1 year | 143 (90.8) | 34 (94.4) | 109 (94.0) | 2 (5.6) | 1 (2.8) | ||
Data are presented as median (range), mean ± standard deviation or number (percentage). ASA, American Society of Anesthesiologists; CH, chronic hepatitis; ECOG, Eastern Cooperative Oncology Group; HBV, hepatitis B virus; HCV, hepatitis C virus; ICG-R15, indocyanine green retention rate at 15 min; LC, liver cirrhosis; NASH, non-alcoholic steatohepatitis; NL, normal liver; PIVKA-II, protein induced by vitamin K absence or antagonist-II.
Table 2. Tumor pathology and oncologic characteristics after second hepatectomy.
| Variables | Overall survival (N=152) | Before propensity score matching | After propensity score matching | ||||
|---|---|---|---|---|---|---|---|
| Laparoscopic surgery (n=36) | Open surgery (n=116) | P value | Laparoscopic surgery (n=36) | Open surgery (n=36) | P value | ||
| Tumor size, cm | 2.3 (0.50–9.50) | 1.90 (0.50–3.00) | 2.50 (1.00–9.50) | <0.001 | 1.90 (0.50–3.00) | 2.00 (1.00–4.00) | 0.07 |
| ≤5 | 142 (93.4) | 36 (100.0) | 106 (91.4) | 0.12 | 36 (100.0) | 36 (100.0) | N/A |
| >5 | 10 (6.6) | 0 | 10 (8.6) | 0 | 0 | ||
| Tumor number | <0.001 | 0.67 | |||||
| Solitary | 91 (59.9) | 32 (88.9) | 59 (50.9) | 34 (94.4) | 32 (88.9) | ||
| Multiple | 61 (40.1) | 4 (11.1) | 57 (49.1) | 2 (5.6) | 4 (11.1) | ||
| Satellite nodule | 0.007 | >0.99 | |||||
| No | 125 (82.2) | 35 (97.2) | 90 (77.6) | 35 (97.2) | 35 (97.2) | ||
| Yes | 27 (17.8) | 1 (2.8) | 26 (22.4) | 1 (2.8) | 1 (2.8) | ||
| Differentiation type | 0.055 | 0.34 | |||||
| Well | 15 (9.9) | 7 (19.4) | 8 (6.9) | 7 (19.4) | 6 (16.7) | ||
| Moderate | 109 (71.7) | 25 (69.4) | 84 (72.4) | 25 (69.4) | 29 (80.6) | ||
| Poor | 28 (18.4) | 4 (11.1) | 24 (20.7) | 4 (11.1) | 1 (2.8) | ||
| HCC type | 0.84 | 0.21 | |||||
| Non-trabecular | 32 (21.1) | 8 (22.2) | 24 (20.7) | 8 (22.2) | 4 (11.1) | ||
| Trabecular | 120 (78.9) | 28 (77.8) | 92 (79.3) | 28 (77.8) | 32 (88.9) | ||
| Surgical margin | 0.12 | N/A | |||||
| Negative | 142 (93.4) | 36 (100) | 106 (91.4) | 36 (100) | 36 (100) | ||
| Positive | 10 (6.6) | 0 (0) | 10 (8.6) | 0 (0) | 0 (0) | ||
| Macrovascular invasion | 0.008 | >0.99 | |||||
| No | 114 (75.0) | 33 (91.7) | 81 (69.8) | 33 (91.7) | 33 (91.7) | ||
| Yes | 38 (25.0) | 3 (8.3) | 35 (30.2) | 3 (8.3) | 3 (8.3) | ||
| Microvascular invasion | >0.99 | N/A | |||||
| No | 150 (98.7) | 36 (100.0) | 114 (98.3) | 36 (100.0) | 36 (100.0) | ||
| Yes | 2 (1.3) | 0 | 2 (1.7) | 0 | 0 | ||
| Bile duct invasion | 0.59 | N/A | |||||
| No | 147 (96.7) | 36 (100.0) | 111 (95.7) | 36 (100.0) | 36 (100.0) | ||
| Yes | 5 (3.3) | 0 | 5 (4.3) | 0 | 0 | ||
Data are presented as median (range) or number (percentage). HCC, hepatocellular carcinoma; N/A, not applicable.
Perioperative outcomes
Resection extent was comparable (minor: 97.2% vs. 100%, P>0.99; partial: 63.9% vs. 69.4%, P=0.62) (Table 3). Median operative time was 226.5 vs. 177.0 minutes (P=0.11). Blood loss was significantly lower after laparoscopic surgery (median 27.5 vs. 366.5 mL; P<0.001), with no laparoscopic surgery patient exceeding 1,000 mL versus 13.9% in matched open surgery group (P=0.054). No conversion occurred (0/36). According to the Iwate score, 83.3% of laparoscopic cases were of low-to-intermediate difficulty; anterolateral single-segment resections predominated (94.4%), although the posterolateral segments were also represented (S7: 8.3%, S6+7: 5.6%, S8: 16.7%). The data is presented in Table S1.
Table 3. Perioperative outcome.
| Variables | Overall (N=152) | Before propensity score matching | After propensity score matching | ||||
|---|---|---|---|---|---|---|---|
| Laparoscopic surgery (n=36) | Open surgery (n=116) | P value | Laparoscopic surgery (n=36) | Open surgery (n=36) | P value | ||
| Type of surgery | 0.12 | >0.99 | |||||
| Minor | 137 (90.1) | 35 (97.2) | 102 (87.9) | 35 (97.2) | 36 (100) | ||
| Major | 15 (9.9) | 1 (2.8) | 14 (12.1) | 1 (2.8) | 0 (0) | ||
| Resection type | 0.99 | 0.62 | |||||
| Anatomical | 55 (36.2) | 13 (36.1) | 42 (36.2) | 13 (36.1) | 11 (30.6) | ||
| Partial | 97 (63.8) | 23 (63.9) | 74 (63.8) | 23 (63.9) | 25 (69.4) | ||
| Intraoperative blood loss, mL | 350 [1–4,200] | 27.5 [10–732] | 469 [10–4,200] | <0.001 | 27.5 [10–732] | 366.5 [30–2,200] | <0.001 |
| ≤1,000 | 127 (83.6) | 36 (100) | 91 (78.4) | 0.001 | 36 (100.0) | 31 (86.1) | 0.054 |
| >1,000 | 25 (16.4) | 0 | 25 (21.6) | 0 | 5 (13.9) | ||
| Duration of surgery, min | 212 [5–629] | 226.5 [5–451] | 203.0 [6–629] | 0.27 | 226.5 [5–451] | 177.0 [55–629] | 0.11 |
| ≤210 | 76 (50.0) | 15 (41.7) | 61 (52.6) | 0.25 | 15 (41.7) | 23 (63.9) | 0.059 |
| >210 | 76 (50.0) | 21 (58.3) | 55 (47.4) | 21 (58.3) | 13 (36.1) | ||
| Clavien Dindo classification | 0.25 | >0.99 | |||||
| I–II | 8 (33.3) | 2 (66.7) | 6 (28.6) | 2 (66.7) | 4 (44.4) | ||
| IIIa–IIIb | 16 (66.7) | 1 (33.3) | 15 (71.4) | 1 (33.3) | 5 (55.6) | ||
| Complication | 0.16 | 0.048 | |||||
| No | 128 (84.2) | 33 (91.7) | 95 (81.9) | 33 (91.7) | 27 (75.0) | ||
| Yes | 24 (15.8) | 3 (8.3) | 21 (18.1) | 3 (8.3) | 9 (25.0) | ||
| 90-day postoperative mortality | >0.99 | >0.99 | |||||
| No | 152 (100.0) | 36 (100.0) | 116 (100.0) | 36 (100.0) | 36 (100.0) | ||
| Yes | 0 | 0 | 0 | 0 | 0 | ||
| Recurrence site after second hepatectomy | 0.26 | >0.99 | |||||
| Single | 70 (69.3) | 10 (84.6) | 60 (67.4) | 10 (84.6) | 19 (76.0) | ||
| Multiple | 31 (30.7) | 2 (15.4) | 29 (32.6) | 2 (15.4) | 6 (24.0) | ||
| Recurrence type after second hepatectomy | 0.83 | 0.59 | |||||
| Intrahepatic | 85 (84.2) | 11 (83.3) | 74 (84.1) | 11 (83.3) | 22 (91.7) | ||
| Extrahepatic | 10 (9.9) | 2 (16.7) | 8 (9.1) | 2 (16.7) | 2 (8.3) | ||
| Multicentric | 6 (5.9) | 0 | 6 (6.8) | 0 | 0 | ||
| Length of stay, days | 10 [4.0–180.0] | 7.0 [4.0–60.0] | 11.0 [5.0–180.0] | <0.001 | 7.0 [4.0–60.0] | 11.0 [6.0–30.0] | <0.001 |
Data are presented as median [range] or number (percentage).
Complications were less frequent after laparoscopic surgery (8.3% vs. 25.0%; P=0.048); among those with complications, Clavien-Dindo grade I–II predominated in laparoscopic surgery (66.7%) compared with grade IIIa–IIIb in open surgery (55.6%) (P>0.99). In a matched cohort, bile leakage was the most frequent event in both groups, with full complication profiles for the entire cohort (n=152) detailed in Table S2. The 90-day mortality rate was 0% in both groups. The postoperative hospital stay was shorter after laparoscopic surgery (median 7.0 vs. 11.0 days; P=0.001).
Liver function evaluation
Preoperative albumin, bilirubin, platelet, and ALBI scores were comparable (Table 4, Table S3). At one month postoperatively, albumin (3.95 vs. 3.85 g/dL, P=0.14) and bilirubin (0.80 vs. 0.60 mg/dL, P=0.008) showed minor differences within normal ranges. By three months, all parameters normalized without intergroup differences.
Table 4. ALBI, albumin, bilirubin, and platelet levels prior to second hepatectomy, 1 month, and 3 months after second hepatectomy.
| Variables | Overall (N=72) | Laparoscopic surgery (n=36) | Open surgery (n=36) | P value |
|---|---|---|---|---|
| Prior to second hepatectomy | ||||
| Albumin, g/dL | 4.15 (3.10–4.70) | 4.10 (3.10–4.70) | 4.20 (3.30–4.70) | 0.19 |
| Total bilirubin, mg/dL | 0.80 (0.40–1.60) | 0.80 (0.40–1.60) | 0.70 (0.40–1.50) | 0.03 |
| Platelet counts, /mcL | 135,000 (39,000–331,000) | 127,000 (75,000–331,000) | 144,000 (39,000–263,000) | 0.13 |
| ALBI | −2.79 (−3.34 to −1.83) | −2.74 (−3.13 to −1.83) | −2.85 (−3.34 to −1.88) | 0.09 |
| 1 month after second hepatectomy | ||||
| Albumin, g/dL | 3.90 (2.60–4.70) | 3.95 (2.80–4.79) | 3.85 (2.60–4.60) | 0.14 |
| Total bilirubin, mg/dL | 0.70 (0.10–1.90) | 0.80 (0.10–1.90) | 0.60 (0.10–1.70) | 0.002 |
| Platelet counts, /mcL | 151,500 (18,300–313,000) | 151,500 (40,900–313,000) | 150,500 (18,300–283,000) | 0.93 |
| ALBI | −2.66 (−3.68 to −1.47) | −2.68 (−3.68 to −1.56) | −2.63 (−3.68 to −1.47) | 0.87 |
| 3 months after second hepatectomy | ||||
| Albumin, g/dL | 4.10 (2.70–4.90) | 4.10 (2.70–4.70) | 4.15 (3.10–4.90) | 0.99 |
| Total bilirubin, mg/dL | 0.80 (0.10–2.00) | 0.75 (0.10–1.70) | 0.80 (0.10–2.00) | 0.97 |
| Platelet counts, /mcL | 150,000 (54,000–254,000) | 144,000 (54,000–254,000) | 163,000 (61,000–228,000) | 0.46 |
| ALBI | −2.79 (−3.77 to −1.37) | −2.76 (−3.77 to −1.37) | −2.81 (−3.60 to −1.88) | 0.77 |
Data are presented as median (range). ALBI, albumin-bilirubin.
OS
Before PSM, Kaplan-Meier OS curve is presented in Figure 3A (laparoscopic surgery, n=36; open surgery, n=116). After PSM, OS did not differ between the groups (log-rank P=0.77; Figure 3B). The 1-, 3-, and 5-year OS rates were 86.7%, 71.4%, and 43.7% for laparoscopic surgery versus 100%, 89.5%, and 44.4% for open surgery, respectively. Mean OS was 48.6 months (95% CI, 42.2–54.9) for laparoscopic surgery versus 50.3 months (95% CI, 45.5–55.1) for open surgery. Long-term survival comparison was limited by differential follow-up: median 29.0 months (range, 10.5–47.6 months) for laparoscopic surgery versus 54.5 months (range, 23.8–85.3 months) for open surgery (P<0.001). Cumulative 1-, 3-, and 5-year mortality rates for the entire group (N=152) are presented in Table S4.
Figure 3.
Kaplan-Meier survival analysis comparing laparoscopic and open surgery for a second hepatectomy in recurrent HCC. (A) OS before PSM; (B) OS after PSM; (C) RFS before PSM; (D) RFS after PSM. Shaded areas represent 95% confidence intervals. Vertical tick marks indicate censored observations. Numbers at risk are displayed below each panel. P values were calculated using the log-rank test. HCC, hepatocellular carcinoma; OS, overall survival; PSM, propensity score matching; RFS, recurrence-free survival.
PFS
PSM PFS is presented in Figure 3C. After PSM, median RFS was 25.3 months (95% CI, 16.9–33.7) for laparoscopic surgery versus 21.8 months (95% CI, 7.0–36.6) for open surgery (log-rank P=0.83; Figure 3D). The 1-, 3-, and 5-year RFS rates were 88.9%, 47.4%, and 26.7% versus 67.0%, 38.5%, and 23.6%, respectively. Recurrence was predominantly intrahepatic (83.3% vs. 91.7%; P=0.59) and single-site (84.6% vs. 76.0%; P>0.99). Cumulative 1-, 3-, and 5-year PFS rates for the entire group (N=152) are presented in Table S5.
Discussion
Key findings
In this PSM analysis, laparoscopic second hepatectomy using the Glissonean pedicle approach was associated with significantly lower intraoperative blood loss, a lower complication rate, and a shorter postoperative hospital stay than open surgery, whereas 5-year OS and PFS were comparable between the two groups. These findings suggest that laparoscopic second hepatectomy may be a feasible and safe approach for selected patients when performed by experienced surgeons in high-volume hepatobiliary centers.
Perioperative and oncological outcome
The median intraoperative blood loss in the laparoscopic surgery group (27.5 mL) was lower than the 100–300 mL range reported in recent meta-analyses (21,39-43). The 8.3% complication rate compares favorably with outcomes in high-volume centers, falling below the reported 15–25% range for second hepatectomy (40,44-47). The 36% reduction in postoperative hospital stay is consistent with 30–50% reductions described in comparative laparoscopic series (40,41,43,44,46). Ninety-day mortality was zero in both groups, which is consistent with the 0–5% perioperative mortality reported at experienced high-volume centers (48). All liver function parameters normalized by 3 months, with no differences between the groups, aligning with previous studies that demonstrated comparable postoperative functional outcomes (15). Regarding long-term outcomes, 5-year OS aligned with recent studies reporting 40–50% (3,16,48). Additionally, surgical free-margin resection (R0) was achieved in both matched groups, confirming oncological adequacy in both groups.
The favorable perioperative and oncologic findings are consistent with the systematic application of the tertiary Glissonean pedicle approach, which enables precise anatomical or near-anatomical resection planes through meticulous subsegmental vascular control, even during complex reoperative procedures (22,24,25,49). For HCC, this approach optimizes tumor clearance by respecting anatomical boundaries (portal territories demarcated by hepatic veins) while maintaining oncologic adequacy by systematically eliminating tumor-bearing porta-tributaries (20,23,25). This technical emphasis distinguishes this analysis from prior comparative studies, which have primarily focused on the surgical approach rather than the principles of operative technique. The integration of Takasaki’s Glissonean pedicle approach with Honda’s laparoscopic technique underscores the importance of adhering to rigorous anatomical principles to achieve favorable outcomes in laparoscopic second hepatectomy (22,24,25,48).
Technical advantages
Building on Takasaki’s Glissonean pedicle approach principles, several technical adaptations have been developed at our institution to account for favorable perioperative outcomes in laparoscopic second hepatectomy. First, comprehensive perioperative imaging workups and detailed operative record documentation enabled precise mapping of the Glissonean pedicles targeted for ligation, accurate assessment of operative complexity, and systematic postoperative evaluation. The imaging protocol is more commonly used in Japanese centers (97–100%) than internationally (50). This preoperative planning may partly explain why we observed zero 90-day mortality in our laparoscopic surgery group, comparing favorably to the 0.3–0.5% rate reported in international series of laparoscopic second hepatectomy (16,41). Second, intercostal port placement facilitated resection of posterosuperior segments (S7 and S8) (19). This approach provides a direct working angle to these segments while minimizing the need for extensive ligamentous mobilization and collateral venous bleeding. Using this technique, 11 posterosuperior cases were completed laparoscopically with a zero-conversion rate. This approach was feasible across all Iwate difficulty levels, with 15 intermediate, 4 advanced, and 2 expert-level procedures completed successfully (51). Third, the “back-scoring” technique, in which a CUSA tip is moved in a counter-directional motion from the proximal to distal side of the vessel, selectively dissecting along the intersegmental planes free of Glissonean branches. Maintaining a dry operative field in reoperative cases is important for precise parenchymal transection (26,27). Fourth, the lower blood loss in the laparoscopic group is attributable to the hemodynamic advantage inherent to the pneumoperitoneum environment. Our prior experimental data demonstrated that low airway pressure reduces CVP, which in turn diminishes hepatic vein back-bleeding—the primary source of hemorrhage during parenchymal transection. This physiological mechanism is absent during open surgery and accounts for a substantial portion of the difference in blood loss between groups. This advantage was achieved without raising PPP above CVP, thereby avoiding the risk of gas embolism (29). Fifth, the equivalent oncological outcomes despite a minimally invasive approach are attributable to IOU, which identified tertiary Glissonean branches and mapped their spatial relationships to the tumor in real time. This IOU enabled precise intrahepatic pedicle isolation and defined resection boundaries based on vascular anatomy, consistent with Takasaki’s cone unit concept. Furthermore, this IOU bypasses hilar plate dissection entirely, mitigating the risk of bile duct injury from adhesions formed after the initial hepatectomy (22,52,53). Sixth, craniocaudal one-way dissection from the hepatic vein roots, proceeding from the root toward the periphery, simplified plane identification and minimized split-vein injury by avoiding the fork between branches from the peripheral side (23,26,28,30). Collectively, this standardized technique achieved a zero-conversion rate and reduced postoperative hospital stays, while maintaining liver functional recovery comparable to that of open surgery.
Patient selection
In our study, laparoscopic second hepatectomy was performed in patients with preserved liver function (Child-Pugh A, ICG-R15 ≤15%, ECOG 0–1), favorable tumor characteristics (predominantly solitary lesion ≤5 cm, median disease-free interval >12 months), and no macrovascular invasion. Notably, 30.6% of the laparoscopic cases involved the posterosuperior segments, with zero conversion, showing feasibility beyond traditional anterolateral indications when intercostal trocar placement is implemented. Previous laparoscopic surgery for initial hepatectomy was associated with the selection of a second laparoscopic procedure, reflecting a favorable reoperative field. These patient and technical factors, combined with surgeon experience (40–50 prior laparoscopic hepatectomies), define the applicability criteria supported by this study and aligned with the comparative studies (10,16,21,44,45,48,54,55).
Residual confounding
After PSM, surgery date remained the most imbalanced covariate (SMD =−0.72), with 66.7% of laparoscopic procedures performed in 2020–2024 (phase 2) versus 97.2% of open procedures concentrated in 2010–2019 (phase 1) (P<0.0001). Prior laparoscopic first hepatectomy was also more frequent in the laparoscopic surgery group (25.0% vs. 2.8%; P=0.006), potentially reflecting a more favorable re-operative field and selection toward minimally invasive re-intervention. Accordingly, the perioperative advantages observed with laparoscopy (blood loss 27.5 vs. 366.5 mL; complications 8.3% vs. 25.0%; length of stay 7.0 vs. 11.0 days) may partly reflect residual confounding from institutional learning-curve maturation, evolving perioperative pathways, and baseline differences in prior operative approach, rather than the surgical approach alone. These data nonetheless align with recent propensity-matched evidence from our institution supporting the feasibility and safety of laparoscopic hepatectomy in HCC, including in patients with impaired liver function (56).
Limitations
Our study had several limitations. First, the retrospective single-center design introduces potential selection bias and limits generalizability, despite PSM. Second, the surgical approach performed in the initial hepatectomy may influence the technical difficulties of the second hepatectomy; however, this was not quantified because of the complexity of retrospective standardization. Third, the significant difference in the median follow-up duration between the laparoscopic and open groups (29.0 vs. 54.5 months, P<0.001) represents an important limitation that may affect long-term survival comparisons. This disparity reflects the institution’s adoption of laparoscopic techniques and emphasizes the need for extended follow-up to confirm the durability of these outcomes.
Conclusions
Laparoscopic second hepatectomy using the Glissonean pedicle approach was associated with favorable perioperative outcome, including markedly reduced blood loss, fewer complications, zero conversions, and shorter postoperativestays, with comparable long-term survival to open surgery. These results suggest the feasibility of this approach in experienced hepatobiliary centers for selected patients with recurrent HCC.
Supplementary
The article’s supplementary files as
Acknowledgments
The authors gratefully acknowledge Dr. Yusri Dwi Heryanto and Dr. Afid Brilliana Putra for their valuable advice and support.
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 Review Board of Tokyo Women’s Medical University (No. 2024-0133). Written informed consent was obtained from all patients in accordance with institutional policies.
Footnotes
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tgh.amegroups.com/article/view/10.21037/tgh-2026-0043/rc
Funding: None.
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-2026-0043/coif). The authors have no conflicts of interest to declare.
Data Sharing Statement
Available at https://tgh.amegroups.com/article/view/10.21037/tgh-2026-0043/dss
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