Current status and future perspectives of minimally invasive liver surgery for hepatocellular carcinoma.

INTRODUCTION
Hepatocellular carcinoma (HCC) is one of the most common types of primary liver cancers, and most HCC develop in cirrhotic livers.1,2 Liver transplantation (LT) is theoretically the most effective treatment, because it can cure both HCC and the underlying damaged liver. However, LT is not always possible in patients with HCC due to the scarcity of potential donors.3 Nowadays, hepatectomy is a safer first-line curative treatment for HCC than previously believed, especially in patients with preserved liver function, because of technical advances and improvements in postoperative management.4,5

HISTORY OF LAPAROSCOPIC LIVER RESECTION

Early pioneers and initial cases (early 1990s)
Since the first reported case of laparoscopic liver wedge resection in 1992, an increasing number of studies have described the safety and feasibility of laparoscopic liver resection (LLR).6-9 Shortly thereafter, in 1992, Biertho et al.10 performed laparoscopic partial hepatectomy to treat a liver tumor and demonstrated the technical feasibility of laparoscopic resection of the hepatic tissue.

Growth of minor laparoscopic liver resection (late 1990s)
A major breakthrough occurred in 1996, when teams in Europe and Asia independently reported the first cases of anatomic LLR beyond simple wedge excision. Left lateral sectionectomy (LLS) became the prototype for minor anatomical LLR because the left lateral section is relatively accessible laparoscopically. In the late 1990s, minor liver resections were increasingly performed worldwide by early adopters.11

Transition to major laparoscopic hepatectomy (2000s)
As surgical teams gained experience with minor LLRs, attention shifted to extending this approach to major liver resection.12 Laparoscopic left hepatectomy was the first attempted major hepatectomy. Although progress was initially slow, by the mid-2000s pioneering surgeons in high-volume centers began performing purely laparoscopic right hepatectomy.13

Global adoption and consensus conferences
Over the past three decades, pioneering surgeons have expanded the feasibility of minimally invasive minor hepatectomies from small peripheral resections to complex major hepatectomies.14 Recently, LLR has been commonly performed in patients with HCC and other liver tumors.6
There have been two international consensus meetings on LLR. The first International Consensus Conference on Laparoscopic Liver Resections (ICCLLR) was held in Louisville in 2008. During this conference, many experts in the field of LLR gathered and discussed the feasibility of LLR, particularly focusing on its safety.13 LLR was recommended for small HCCs located in the anterolateral segments of the liver (segments 2-6) and was considered best for laparoscopic LLS. However, it was not recommended for major LLR. Nguyen et al.15 published an extensive review of 127 related articles comprising nearly 3,000 cases of LLR worldwide and concluded that LLR was safe with minimal morbidity and mortality rates.
The second ICCLLR meeting was held in Morioka, Japan, in 2014.16 The attending experts recommended three projects to protect patients: a prospective reporting registry for LLR, a difficulty scoring system to guide LLR, and establishment of an international society for LLR. The second consensus meeting focused on comparisons between LLR and open hepatectomies and showed the benefits of LLR over open surgery. Finally, the International Laparoscopic Liver Society was officially launched during the International Hepato-Pancreato-Biliary Association meeting in São Paulo, Brazil in 2016.17
Since the second ICCLLR meeting, the indications for robotic hepatectomy have expanded and evidence have been provided.18 Recently, many studies have attempted to compare outcomes between LLR and robotic hepatectomy and have shown similar outcomes between the two groups.19
The third ICCLLR will be held in Seoul, Korea in 2025 and a consensus meeting on laparoscopic major hepatectomy will be organized.

INDICATIONS FOR LLR

Tumor location
LLR is not widely accepted because of the technical difficulties, inconvenient bleeding control, fear of possible gas embolism, and limited access to the posterosuperior part of the liver.20 Therefore, LLR has been limited to tumors located in the anterolateral segments or left side of the liver. Currently, indications for LLR have been expanded to the right and posterosuperior segments of the liver because of new laparoscopic instruments and improvements in laparoscopic techniques (Fig. 1).21
Based on the first international position statement on LLR published in 2008, the best indications for LLR were single small tumors located in the peripheral liver. Left lateral sectionectomy should be considered laparoscopically. However, major laparoscopic hepatectomy should be reserved for experienced surgeons because of the difficulty of the procedure.13 Thereafter, the limitation of the location of the tumor has been overcome by improvements in laparoscopic techniques, better visualization of the operative field using a flexible laparoscope, and the introduction of a laparoscopic Cavitron Ultrasonic Surgical Aspirator (Valleylab, Boulder, CO, USA) and laparoscopic ultrasound.22-24 A report describing the safety and feasibility of LLR for HCCs located in the posterosuperior segments have shown oncologic outcomes similar to those of open hepatectomies.25 Many reports have shown that LLR has beneficial effects, including reduced bleeding, lower complication rates, and earlier recovery than open hepatectomy.26

Selection of suitable patients in the presence of liver cirrhosis
The most important factor to consider for hepatectomy in cirrhosis is balancing surgical stress on the patient and oncological outcomes, such as the resection margin.6 Because patients with HCC usually have chronic liver disease or cirrhosis, they may be predisposed to liver failure after surgery. Laparoscopic liver resection is also contraindicated in patients with severely damaged livers, including esophageal varices and low platelet count, and is usually considered a contraindication for LLR, similar to open hepatectomy.27,28 Therefore, preoperative selection of the type and extent of LLR is important, and the postoperative remnant functional reserve is always estimated before LLR.
The Child-Turcotte-Pugh (CTP) score, based on five easily measurable variables, is considered the gold standard for selecting candidates for hepatectomy.29,30 However, posthepatectomy liver failure could develop even in patients categorized as CTP class A. To predict the survival of patients undergoing transjugular intrahepatic portosystemic shunt, the model for end-stage liver disease (MELD) score has been developed31 and has been adopted for the selection of patients waiting for LT.32 The MELD score outperformed the CTP classification in terms of determining surgical risk.33
Indocyanine green (ICG) retention rate at 15 minutes (ICGR-15) has been traditionally used to predict liver function.34 However, the cutoff value is unclear, and inter- and intra-observer biases in ICGR-15 testing have been reported.

Oncological outcomes of LLR in patients with liver cirrhosis and its challenges
Many recent reports have shown similar oncological outcomes between LLR and open liver resection. However, LLR is associated with better short-term outcomes, including morbidity and mortality rates.35-37 According to a comprehensive systematic review and meta-analysis prepared at the second ICCLLR, the LLR of HCC in patients with chronic liver disease showed better rates of postoperative liver failure and ascites.38,39
Radiofrequency ablation is a challenging LLR for HCC in patients with cirrhosis, whereas percutaneous ablation carries the risk of tumor seeding in patients with peripherally located lesions.40 Recent matched studies have shown that LLR showed better overall and disease-free survival than percutaneous ablation in selected patients with HCC located in the left lateral section or anterolateral segments of the liver.41-43

Anatomical vs. non-anatomical resection
Anatomical resection offers certain advantages over non-anatomical resection in the treatment of HCC.44,45 Most recurrences in the liver occur as a result of subclinical metastases, which originate from the primary tumor via microscopic vascular invasion, spread peripherally along the intrasegmental branches, and are the most important factors associated with the poor prognosis of HCC.46 Consequently, systematic removal of the hepatic segment fed by tumor-bearing portal tributaries, involving anatomical resection of the entire functional unit, is theoretically more effective in eradicating tumors and metastases.47 However, segmentectomy of isolated segment 6 or 7 is challenging in open or laparoscopic procedures.48 Furthermore, adequate resection margins are difficult to achieve when performing segmentectomy for deep or large tumors located in segment 6 or 7.49 Therefore, laparoscopic right posterior sectionectomy may become the treatment of choice for deep or large tumors located in the upper right posterior section of the liver, especially if resection of segment 6 is not possible.50 Right hepatectomy is usually performed if the tumor is close to, or has invaded, the right hepatic vein. In such cases, extended right posterior sectionectomy may be feasible.51 For tumors located in segment 7 or 8, a hepatic vein-guided or hepatic vein-first approach may be good options.52

TEXTBOOK OUTCOMES AFTER LLR
Textbook outcomes (TOs) and their implications have been studied in various surgical procedures, including laparoscopic hepatectomy. One of the earliest studies was conducted by Hobeika et al.,53 who analyzed the TOs after laparoscopic LLS and right hepatectomy and defined benchmark values for other centers. The following factors were independently associated with failure to achieve TOs after laparoscopic LLS: year of surgery, American Society of Anesthesiologists score, inflow clamping for >40 minutes, and duration of surgery.54
A study of the TOs of HCC in the anterolateral segment of the liver revealed significant differences in the 5-year recurrence-free and overall survival rates in patients who achieved TOs than those who did not among all patients and in a subgroup of patients with cirrhosis.55 Moreover, TOs are important markers for assessing hospital and surgeon performance and predicting overall survival. As the number of surgeons who complete the learning curve increases, the number of patients with TOs will gradually increase with a subsequent improvement in overall survival.56

CONCLUSIONS
Recently, with improvements in laparoscopic techniques and the development of new technologies, the anatomical limitations of LLR are being overcome. Minor liver resection may become the standard-of-care for liver resection. For major LLR and donor hepatectomy, international meetings and registries are important for the propagation of LLR and the education of surgeons.