Background: Laparoscopic liver resection has been reported as a safe and effective approach for the management of hepatocellular carcinoma (HCC). However, its perioperative and oncological outcomes have not been evaluated in left hepatectomy patients. The aim of the present study is to compare the outcomes of left hepatectomy through laparoscopic and open approaches in left HCC. Methods: From December 2012 to October 2016, laparoscopic left hepatectomy (LLH) was performed in 40 patients and open left hepatectomy (OLH) was performed in 80 patients. All clinical data were analyzed retrospectively. Propensity score matching of patients in a 1:1 ratio was conducted based on tumor size and presence of microvascular invasion. Results: Tumor size and presence of microvascular invasion were higher in the OLH group than the LLH group (
Hepatocellular carcinoma; Hepatectomy; Laparoscopy; Tumor recurrence; Survival; Minimal invasive surgery
Laparoscopic liver surgery requires additional advanced skills over open surgery. Since the first laparoscopic liver resection in the 1990s, there has been continuous improvement in laparoscopic techniques and devices, and accumulating data have allowed the development of laparoscopic liver resection of hepatocellular carcinoma (HCC) in cirrhotic patients [[
Significant advantages of laparoscopic wedge resection or left lateral sectionectomy versus open procedures have been widely reported [[
Previous published studies reported that the oncological outcomes of laparoscopic hepatectomy were comparable to those of open hepatectomy [[
In this study, we aimed to compare the outcomes of purely laparoscopic left hepatectomy (LLH) and open left hepatectomy (OLH) in patients with left HCC.
This study included patients who underwent surgical resection of solitary HCC based on preoperative radiological images between December 2012 and October 2016. This study was approved by the Samsung Medical Center Institutional Review Board (SMC-2017-05-090). A total of 139 patients underwent left hepatectomy because of HCC. The diagnosis of HCC was proved based on pathology after hepatectomy. Ruptured HCC cases (n = 5); those with a the history of locoregional therapies such as transarterial embolization (TACE) (n = 11), radiofrequency ablation (RFA) (n = 2), or the combination of TACE and RFA (n = 2); and open conversion cases because of uncontrolled bleeding during laparoscopic procedure (n = 1) were excluded. Two clinically comparable groups of patients were studied: those undergoing laparoscopic left hepatectomy (n = 40) and those undergoing open left hepatectomy (n = 80). The study included hepatectomy from four surgeons. Selection criteria for laparoscopic approach were surgeon dependent. One surgeon did not perform any laparoscopic approach, but three surgeons performed both approaches. Open hepatectomy was performed in cases with previous abdominal surgery or large tumor and in patients who did not agree to undergo LLH because of the expense.
Demographic, preoperative laboratory, and pathologic data were prospectively collected in the electrical medical records. None of the patients received postoperative adjuvant therapy before recurrence. The procedures used for surveillance after liver resection have been described previously [[
All liver resections were intended to be totally laparoscopic and were performed according to the described procedures and the surgeon's usual practice. The patient was placed in a supine position with the legs apart. Pneumoperitoneum was created by carbon dioxide insufflation at a pressure of 11–12 mmHg, and a 0-degree flexible laparoscope camera was used. When the tumor was located in segment 4, an intraoperative sonographic examination was performed to confirm the exact tumor location and its relationship to major blood vessels. Parenchymal transection was performed with the different types of energy devices (Sonicison, Medtronics or Harmonic Ace, Ethicone or Ligasure, Medtronics) in accordance with the surgeon's usual practice; devices used were advanced bipolar device, and/or cavitron ultrasonic surgical aspirator (CUSA. EXcel, Valleylab, Boulder, CO). The corresponding Glissonean branch was managed using individual vessel ligation or temporary inflow control of the Glisson (TICGL) method according to the surgeon's preference [[
Open left hepatectomy was performed through a reverse L-incision. After exploration of the abdominal cavity, the anterior approach was applied to dissect and clamp the left Glissonean pedicle below the hilar plate. When the tumor was located in segment 4, intraoperative sonographic examination was performed to confirm the exact tumor location and its relationship to major blood vessels. Parenchymal transection was achieved using a cavitron ultrasound surgical aspirator (CUSA EXcel; Valleylab, Boulder, CO, USA). Individual vessel ligation of hepatic artery and portal vein before parenchymal transection was performed and intermittent inflow control was done when necessary. Hemostasis was achieved by monopolar electrocoagulation, argon beam, clips, or non-absorbable sutures. Systematic routine placement of an abdominal drain was performed during surgery.
Postoperative histological assessment included maximal tumor size, encapsulation, intrahepatic metastasis, multicentric occurrence, microvascular invasion, serosal involvement, and cirrhosis. The histologic grade of HCC was assigned according to the Edmonson-Steiner system as well differentiated (grade I), moderately differentiated (grade II), or poorly differentiated (grade III, IV).
All statistical analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA). Continuous variables are described as median with range. Categorical variables are expressed as number and percentage of patients. Fisher's exact test was conducted to evaluate differences in the frequencies of categorical variables between the groups. Mann-Whitney U analysis was conducted to evaluate differences in continuous variables between the two groups. The Kaplan-Meier survival method was performed to evaluate differences in patient survival between the two groups. Prognostic factors of patient survival were identified by Cox regression analysis. To overcome possible selection bias, 1:1 propensity score matching between the laparoscopic left hepatectomy and open left hepatectomy cohorts was applied using multiple logistic regression and a 1:1 matching requirement via the nearest-neighbor matching method. Statistical matching was executed using R 3.2.1 (Vienna, Austria;
The LLH group contained 40 patients, and the OLH group contained 80 patients. All patients underwent curative hepatectomy. Patient baseline and preoperative characteristics of the two groups are summarized in Table [
Table 1 Baseline characteristics
Before matching After matching OLH (n = 80) LLH (n = 40) P-value Open (n = 37) Laparoscopic (n = 37) P-value Gender (male) 68 (85.0%) 31 (77.5%) 0.319 31 (83.8%) 30 (81.1%) 0.705 Age 58 (29–80) 59 (34–78) 0.269 55 (29–79) 58 (34–78) 0.203 Etiology 0.253 0.321 NBNC 17 (21.3%) 7 (17.5%) 3 (8.1%) 6 (16.2%) HBV 58 (72.5%) 29 (72.5%) 31 (83.8%) 27 (73.0%) HCV 2 (2.5%) 4 (10.0%) 0 (0%) 4 (10.8%) Alcohol 3 (3.8%) 0 (0%) 3 (8.1%) 0 (0%) WBC (/μL) 5780 (2070–10,840) 5370 (3660–8870) 0.334 5240 (2070–9690) 5480 (3660–8870) 0.912 NLR 0.61 (0.23–1.53) 0.69 (0.17–1.30) 0.054 0.67 (0.26–1.53) 0.72 (0.17–1.30) 0.294 Hemoglobin (g/dL) 14.2 (8.4–17.0) 14.2 (9.6–17.2) 0.743 14.1 (8.4–17.0) 14.3 (9.6–17.2) 0.947 Platelets (/μL) 172,500 (44,000–397,000) 177,500 (83,000–302,000) 0.892 168,000 (44,000–266,000) 180,000 (83,000–259,000) 0.662 Total bilirubin (mg/dL) 0.6 (0.2–1.8) 0.5 (0.2–1.5) 0.993 0.6 (0.2–1.8) 0.5 (0.2–1.5) 0.341 AST (U/L) 31 (14–120) 28 (16–80) 0.041 32 (14–120) 25 (16–69) 0.055 ALT (U/L) 27 (5–254) 24 (11–100) 0.467 34 (5–254) 24 (11–100) 0.018 ALP (U/L) 74 (38–155) 65 (40–177) 0.065 76 (48–132) 64 (41–177) 0.063 INR 1.04 (0.87–1.27) 1.03 (0.87–1.60) 0.495 1.04 (0.96–1.27) 1.03 (0.87–1.60) 0.618 Albumin (g/dL) 4.4 (3.2–5.2) 4.5 (4.0–5.2) 0.196 4.3 (3.4–5.2) 4.5 (4.0–5.2) 0.098 Creatinine (mg/dL) 0.89 (0.50–2.08) 0.91 (0.51–4.21) 0.330 0.88 (0.56–2.08) 0.91 (0.51–4.21) 0.319 CRP (mg/dL) 0.09 (0.03–3.68) 0.07 (0.03–0.42) 0.427 0.11 (0.03–3.68) 0.07 (0.03–0.42) 0.250 AFP (mg/dL) 33.8 (1.3–200,000) 11.8 (1.3–19,481) 0.124 13.8 (1.3–14,841) 13.0 (1.3–19,481) 0.541 PIVKA-II (mAU/mL) 278.5 (12–75,000) 32.5 (13–3695) 0.001 43 (12–1270) 33 (15–2685) 0.569 ICG-R15 (%) 9.8 (4.2–20.7) 9.3 (2.1–37.1) 0.689 8.0 (4.2–18.2) 9.3 (5.1–37.1) 0.173
*OLH open left hepatectomy, LLH laparoscopic left hepatectomy, NBNC non B non C, HBV hepatitis B virus, HCV hepatitis C virus, WBC white blood cells, NLR neutrophil-lymphocyte ratio, AST aspartate transaminase, ALT alanine transaminase, ALP alkaline phosphatase, CRP C-reactive protein, AFP alpha-fetoprotein, PIVKA-II protein induced by vitamin K absence/antagonism-II, ICG-R15 indocyanine green retention rate at 15 min
The median operation time in the LLH group was longer than that in the OLH group (266 min vs. 239 min; P = 0.005), but no statistically significant difference was found between the two groups after matching (Table [
Table 2 Perioperative and pathologic characteristics
Before matching After matching Open (n = 80) Laparoscopic (n = 40) P-value Open (n = 37) Laparoscopic (n = 37) P-value Perioperative Operative time (min) 239 (99–599) 267 (141–509) 0.005 239 (99–599) 267 (141–509) 0.129 Blood loss (mL) 300 (100–1700) 275 (50–2000) 0.230 300 (100–1700) 250 (50–2000) 0.468 RBC transfusion 2 (2.5%) 3 (7.5%) 0.332 2 (5.4%) 2 (5.4%) 0.337 RBC transfusion (unit) 2.5 (1–4) 2 (1–2) 0.201 2.5 (1–4) 1.5 (1–2) 0.375 Hospitalization (days) 13 (6–71) 9 (5–21) < 0.001 13 (6–45) 9 (5–21) < 0.001 Pathologic Tumor size (cm) 4.2 (0.9–14) 2.6 (0.6–11.5) < 0.001 2.8 (1.1–10) 2.8 (0.9–11.5) 0.225 Free resection margin (mm) 10 (1–60) 15 (1–65) 0.173 13 (1–50) 15 (1–65) 0.476 Tumor necrosis 38 (47.5%) 13 (32.5%) 0.170 15 (40.5%) 12 (32.4%) 0.466 Tumor hemorrhage 46 (57.5%) 18 (45.0%) 0.245 17 (46.0%) 16 (43.2%) 0.808 Encapsulation 0.598 0.292 None 5 (6.3%) 4 (10.3%) 2 (5.4%) 4 (11.1%) Partial 20 (25.3%) 11 (28.2%) 9 (24.3%) 10 (27.8%) Complete 54 (68.4%) 24 (61.5%) 26 (70.3%) 22 (61.1%) Microvascular invasion 64 (81.0%) 24 (61.5%) 0.027 25 (67.6%) 23 (63.9%) 0.730 PVTT 12 (15.2%) 5 (12.8%) 1.000 3 (8.1%) 4 (11.1%) 0.680 BDTT 4 (5.1%) 0 (0%) 0.301 3 (8.1%) 0 (0%) 1.000 Serosal involvement 2 (2.5%) 0 (0%) 1.000 0 (0%) 0 (0%) 1.000 Intrahepatic metastasis 9 (11.4%) 3 (7.7%) 0.749 4 (10.8%) 2 (5.6%) 0.440 Multicentric occurrence 4 (5.1%) 1 (2.6%) 1.000 2 (5.4%) 1 (2.8%) 0.586 Cirrhosis 33 (41.8%) 18 (46.2%) 0.696 20 (54.1%) 15 (41.7%) 0.260
*OLH open left hepatectomy, LLH laparoscopic left hepatectomy, RBC red blood cells, PVTT portal vein tumor thrombosis, BDTT bile duct tumor thrombosis
The overall complication rate was 10.0% (n = 8) in the OLH group and 7.5% (n = 3) in the LLH group (P = 0.468). Atrial fibrillation (n = 1), ascites (n = 1), increased total bilirubin level (n = 1), nausea (n = 2), pleural effusion (n = 1), and pulmonary artery embolization (n = 1) developed in the OLH group and ascites (n = 1), cardiac enzyme elevation (n = 1), and pleural effusion (n = 1) in the LLH group. However, none of the patients had complications greater than Clavien–Dindo classification III. All complications were controlled with pharmacologic treatment or conservative management.
Median tumor size in the OLH group was larger than that in the LLH group (4.2 cm vs. 2.6 cm; P < 0.001). The incidence of microvascular invasion was higher in the OLH group was higher than in the LLH group (81.0% vs. 61.5%; P = 0.027). However, tumor size and microvascular invasion were not different between the two groups after matching. Free resection margin, tumor necrosis, tumor hemorrhage, encapsulation, portal vein tumor thrombosis (PVTT), bile duct tumor thrombosis (BDTT), serosal involvement, intrahepatic metastasis, multicentric occurrence, and cirrhosis were not different between the two groups before and after matching (Table [
The median follow-up period was 26.0 months (range, 2.5–48.2 months) for the OLH group and 22.8 months (range, 2.8–48.4 months) for the LLH group before matching (P = 0.226). Recurrence of HCC was observed in 13 patients (16.3%) in the OLH group and 8 patients (20.0%) in the LLH group. Initial recurrence sites were liver (n = 12) and synchronous liver and lung (n = 1) in the OLH group. The initial recurrent site in the LLH group was liver in seven patients and peritoneum in one patient. However, no trocar-site deposits were observed in the LLH group. Two patients (2.5%) in the OLH group and two patients (5.0%) in the LLH group died of HCC recurrence. The disease-free survival (DFS) and patient survival (PS) in the LLH group were similar to those in the OLH group before matching (P = 0.570 and P = 0.452, respectively, Fig. 1). The DFS and PS at 3 years were 79.6 and 93.9% in the LLH group and 91.1 and 93.8% in the OLH group, respectively. The DFS in the LLH group was worse than that in the OLH group after matching, but there was no statistically significant difference between the two groups (P = 0.189). The PS in the LLH group was similar to that in the OLH group (P = 0.545; Fig. 2).
No risk factors for predicting HCC recurrence were revealed after propensity score matching (Table [
Table 3 Risk factors for HCC recurrence in left hepatectomy patients after propensity matching in the univariate analysis
Hazard ratio 95% CI P-value Laparoscopic left hepatectomy 2.404 0.683–8.460 0.172 Gender (female) 0.546 0.077–3.885 0.546 Age 0.998 0.958–1.041 0.940 NLR 2.310 0.105–51.005 0.596 Hemoglobin 0.979 0.777–1.235 0.860 Platelets 0.996 0.986–1.006 0.387 AST 1.232 0.610–2.491 0.561 ALT 1.082 0.610–1.920 0.788 ALP 1.715 0.211–13.911 0.614 Albumin 0.358 0.085–1.508 0.161 CRP 0.996 0.690–1.437 0.983 AFP 0.954 0.810–1.123 0.570 PIVKA-II 1.309 0.948–1.806 0.102 ICG-R15 3.038 1.032–8.938 0.044 Tumor size 1.636 0.480–5.579 0.431 Tumor necrosis 1.273 0.351–4.612 0.713 Tumor hemorrhage 0.281 0.060–1.327 0.109 Encapsulation 0.357 0.080–1.590 0.177 Microvascular invasion 1.392 0.423–4.583 0.587 PVTT 3.075 0.538–17.575 0.207 Intrahepatic metastasis 1.646 0.203–13.334 0.641 Multicentric occurrence 2.874 0.496–16.650 0.239 Free resection margin 1.669 0.670–4.160 0.271 Cirrhosis 1.043 0.994–1.008 0.766 Operative time 1.043 0.352–3.088 0.940 RBC transfusion 2.300 0.387–13.673 0.360
*NLR neutrophil-lymphocyte ratio, AST aspartate transaminase, ALT alanine transaminase, ALP alkaline phosphatase, CRP C-reactive protein, AFP alpha-fetoprotein, PIVKA-II protein induced by vitamin K absence/antagonism-II, ICG-R15 indocyanine green retention rate at 15 min, PVTT portal vein tumor thrombosis, RBC red blood cells
Laparoscopic liver resection has become more frequent, and the results of large series have been reported worldwide, confirming the technical feasibility, postoperative benefit, and oncological safety of this technique [[
Tumor size and location are two important factors determining the indications for laparoscopic liver resection in patients with HCC. We have used the Glissonean approach of left hepatic artery and left portal vein for inflow control in patients with hepatocellular carcinoma [[
Our study included solitary HCC patients who were diagnosed in the preoperative radiologic images. In our study, intrahepatic metastasis in 12 patients (10%) and multicentric occurrence in 5 patients (4.2%) were reported in the pathology. There was a slight difference between preoperative imaging and pathologic report. Intrahepatic metastasis or multicentric occurrence were not detected in the preoperative images because of small size.
The present study found that the duration of operation, blood loss, transfusion rate, and operative complication rates were not significantly different between the laparoscopic and open hepatectomy groups after matching. However, the hospitalization stay was shorter in the LLH group than in the OLH group. The open conversion rate in the patients who underwent laparoscopic hepatectomy was 2.3–4.1% in published studies [[
Previous studies are summarized in Table [
Table 4 Review of published literature on HCC patients
Authors Study Group Operation Blood loss (mL) Transfusion (n) Operative time (min) Hospital stay (days) Morbidity (≥Grade III) Aldrighetti et al. [2] Retrospective LR (n = 16) Alla 258 4 150 6.3 4 (25%) / 1 OR (n = 16) 617 (P = 0.008) 6 (P=NS) 240 (P = 0.044) 9.0 (P = 0.039) 7 (43.7%) / 0 (P=NS) Tranchart et al. [1] Retrospective LR (n = 42) Alla 364 4 (9.5%) 233 6.7 10 / 4 Matching OR (n = 42) 723 (P < 0.001) 7 (16.7%) (P = 0.51) 221 (P = 0.90) 9.6 (P < 0.001) 18 / 5 Cheung et al. [3] Retrospective LR (n = 32) Alla 150 0 232.5 4 12 (18.8%) / 12 Matching OR (n = 64) 300 (P = 0.001) 3 (P = 0.534) 204.5 (P = 0.938) 7 (P < 0.001) 2 (6.3%) / 1 Komatsu et al. [13] Retrospective LR (n = 38) Right/Left Hepatectomy 100 2 365 7.5 12 (31.6%) / 5 Matching OR (n = 38) 80 (P = 0.094) 1 (P = 0.556) 300 (P < 0.001) 10.0 (P = 0.079) 23 (60.5%) / 7 (P = 0.011) Zhang et al. [20] Retrospective LR (n = 20) Left hepatectomy 180 0 143 7 0 (0%) OR (n = 25) 350 (P < 0.05) 0 137 (P > 0.05) 12 (P < 0.05) 10 (40%) / 2 (P < 0.05) Xiang et al. [17] Prospective LR (n = 128) Alla 456 23 (18.0%) 234 11.4 26 (20.3%) / 12 Tumor size: 5–10 cm OR (n = 207) 481 (P = 0.589) 42 (20.3%) (P = 0.602) 236 (P = 0.886) 15.8 (P < 0.001) 74 (35.7%) / 37 (P = 0.003) Yoon et al. [7] Retrospective LR (n = 33) Right hepatectomy 126 0 297 10.0 1 Matching OR (n = 33) 132 (P = 0.613) 0 176 (P < 0.001) 13.9 (P < 0.001) 7 (P = 0.054)
All
Two studies that included only left hepatectomy reported that operative time for the laparoscopic approach was significantly longer than that for open hepatectomy [[
The mortality and morbidity rates of patients who underwent laparoscopic left hepatectomy were 0 and 7.5%, respectively. Our results are better than those of several other reports [[
Despite an exponential growth in cases of laparoscopic liver resection, the outcomes in HCC patients are yet to be fully elucidated. To overcome selection bias as much as possible, propensity score matching was employed in this study. The propensity score model reduces the different distribution of covariates among individuals allocated to specific intervention [[
In the present study, tumor size was larger and presence of microvascular invasion was higher in the OLH group that in the LLH group before matching. Large tumor size as a contraindication to laparoscopic hepatectomy remains controversial. Therefore, we performed propensity score matching using these two variables to compare the oncological outcomes between LLH and OLH.
We showed that DFS was lower in the LLH than in the OLH group after matching, but there were no statistically significant differences in DFS and PS between LLH and OLH. Previous studies reported that DFS and PS in laparoscopic approaches were comparable to those in open approaches (Table [
Table 5 Survival of HCC patients after laparoscopic or open resection in published studies
Authors Disease-free survival Patient survival Tranchart et al. [1] 1-yr, 3-yr, 5-yr in LR: 81.6, 60.9, 45.6% 1-yr, 3-yr, 5-yr in LR: 93.1, 74.4, 59.5% 1-yr, 3-yr, 5-yr in OR: 70.2, 54.3, 37.2% (P = 0.29) 1-yr, 3-yr, 5-yr in OR: 81.8, 73.0, 47.4% (P = 0.25) Cheung et al. [3] – 1-yr, 3-yr, 5-yr in LR: 96.6, 87.5, 76.6% 1-yr, 3-yr, 5-yr in OR: 95.2, 72.9, 57.0% (P = 0.142) Komatsu et al. [13] 3-yr in LR:29.7% 3-yr in LR:73.4 3-yr in OR: 50.3% (P = 0.219) 3-yr in OR: 69.2% (P = 0.951) Xiang et al. [17] 1-yr, 3-yr in LR: 89.4, 67.3% 1-yr, 3-yr in LR: 94.4, 81.4% 1-yr, 3-yr in OR: 88.7, 66.7% (P = 0.902) 1-yr, 3-yr in OR: 93.6, 82.2% (P = 0.802) Yoon et al. [7] 2-yr in LR:85.1% 2-yr in LR:100% 2-yr in OR:83.9% (P = 0.645) 2-yr in OR: 88.8% (P = 0.090)
* yr year, LR laparoscopic resection, OR open resection, DFS
The present study has limitations that include the relatively small sample size, short follow-up duration, and retrospective design. However, our study has the strength of including only left hepatectomy in HCC patients, thus excluding the selection bias of various surgical hepatectomy procedures.
Present study confirmed the recognized advantage of LLH regarding reduced hospitalization and showed a similar complication rate to OLH. Although the LLH group appears to have a lower DFS than the OLH group, there is no statistical difference in the oncological outcome between the two groups. The present study reveals that pure LLH is safe and feasible in selected patients with solitary and small HCC.
JMK design, literature search, data acquisition, analysis, interpretation, and writing, CHDK and JWJ: design and data interpretation, HY and KK: data analysis, KSK, JL, and GSC: acquisition and analysis of data. All authors read and approved the final manuscript.
This study was approved by the Samsung Medical Center Institutional Review Board (IRB) (SMC-2017-05-090). The consent of the participant was exempted through IRB.
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The datasets generated and/or analyzed during the current study are not publicly available because the hospital was not allowed to take the datasets out but are available from the corresponding author on reasonable request.
By Jong Man Kim; Choon Hyuck David Kwon; Heejin Yoo; Kyeung-Sik Kim; Jisoo Lee; Kyunga Kim; Gyu-Seong Choi and Jae-Won Joh