Recent advances in surgical techniques and perioperative management lead to a redefinition of the actual frontiers of Laparoscopic Liver Resection (LLR) by including patients with more advanced disease. Nonetheless, because of both underlying liver conditions and technical difficulty, LLR for Hepatocellular Carcinoma (HCC) is still considered as a challenging procedure. Specific concerns exist about LLR in cirrhotic patients, posterosuperior segments, giant and multiple tumors, as well as repeat resections.
HCC develops in a cirrhotic liver in approximately 80–90% of cases, and the incidence of cirrhosis is expected to increase worldwide due to the prevalence of obesity, fatty liver disease, and alcoholic steato-hepatitis . After an initial phase in which the presence of cirrhosis was considered a contraindication to laparoscopy, several studies investigated the outcomes of LLR in cirrhotic patients. These patients often present a risk of postoperative hepatic decompensation and failure, as well as low platelets and impaired coagulation. A metanalysis of 11 studies comprising 1618 patients indicated a 16–26% reduction in the hazard ratio of death for patients with HCC and cirrhosis who underwent LLR . In addition, LLR was associated with reduced blood loss, reduced major complications, and shorter length of hospital stay.
When considering liver resection in patients with liver cirrhosis, it is important to consider not only the oncological outcomes but also the surgical stress on both the patient and the liver. An important consequent advantage of LLR in cirrhotic patients is the lower incidence of postoperative liver failure and ascites, given the reduced interruption of portosystemic shunts and the avoidance of electrolyte imbalances as a result of the exposure of the abdominal content to the air . Furthermore, the reduced invasiveness of laparoscopy, which minimizes liver manipulation, preserves collateral vessels and the abdominal musculature, and can be a key factor in expanding the classic limitations of liver surgery . In fact, the advantages of LLR have been confirmed even in advanced Child-B cirrhotic patients: a propensity score-matched study involving international high-volume centers showed reduced blood loss, morbidity, and major complications in the LLR group in this setting .
In the first years of the spread of LLR, huge-volume tumors were considered a contraindication due to both technical and oncological issues. The last decades saw an extension of tumor burden-related indications for LR. Currently, the EASL guidelines recommend LR in cases of a resectable lesion regardless of its size, while the AASLD guidelines advocate LR in patients with Child–Pugh A cirrhosis and resectable HCC with a diameter less than 5 cm. Meanwhile, according to APASL, all tumors without extrahepatic metastases are potentially resectable regardless number and size of lesions [10,11,44]. However, expert centers published several experiences involving LLR for giant tumors, and, as the technical challenges become easier to face with widespread minimally invasive experience, the fear for oncological results and PHLF still exists.
Recently, Hong et al. published suitable long-term outcomes from a nationwide cohort of 466 patients with large HCC, suggesting a worse prognosis in subgroups with low platelets and tumors >10 cm . Similarly, suitable long-term outcomes for giant HCC were shown by Thng et al., who found the presence of satellite nodules and blood transfusions as the only negative predictors of worse prognosis . The safety of LLR for large malignant tumors was previously reported by different authors, with a recent international multicenter matched cohort study with regression discontinuity analyses that also concluded that the safety of MILS also for tumors larger than 10 cm, even if technically demanding [60,61]. Accordingly, the size of the tumor is taken into account in the Iwate difficulty score so that tumors larger than 3 cm are considered of increased difficulty .
Giant tumors indeed are extremely demanding to operate on, where limits of what is considered technically feasible can easily be reached. The placement of trocars, the mobilization of a liver lobe, and the accidental tumor perforation by shear forces are examples of possible intraoperative difficulties. Further arguments against the laparoscopic procedure for giant tumors include that conventional recovery bags are too small, and a comparatively long incision is required to retrieve the specimen. In this respect, the question of feasibility depends primarily on whether the resection can be performed safely, and, if technically feasible, well-known advantages of LLR have also been confirmed in the literature for giant tumors .
Therefore, the decision whether to operate laparoscopically or rather conventionally open should be based on the findings and, again, on the own learning curve and personal experiences made. In researchers' experience, the trocars’ positioning is fundamental, and it depends on both the experience of the surgeon of the center, as well as on the segment to be resected. The manipulation of the liver must be performed with caution, using protections under the hepatic retractors so as not to damage the tumor capsule. The mobilization of the liver can also be performed laparoscopically in the case of large tumors, in which case the correct trocar positioning and the experience of both the surgeon and the operator that holds the rotating camera are once again important.
Besides giant tumors, the role of LLR in the case of multiple HCCs is also debated. From an oncological point of view, in Western countries, the best candidates have always been defined as those with a single tumor, and the treatment of multifocal non-metastatic HCC consisted of LT, within Milan criteria, or ablation/chemoembolization for the remaining patients . As early as 2014, Eastern countries did not consider the presence of multiple HCCs as a contraindication, and a recent Japanese national series reported better results in Child A patients than radiofrequency or TACE in terms of OS, albeit at the cost of greater morbidity . A definitive green light came from a randomized trial confirming that LR provided better OS for patients with multiple HCC outside of Milan criteria than TACE , even if the number of tumors was an independent risk factor. Recently a propensity score-matched analysis including multiple HCC within Milan criteria finally confirmed the safety of the laparoscopic approach .
Obviously, published data come from the long experience of high-volume centers for complex LLR. In researchers' experience, an expert ultrasonography-guided parenchymal dissection is indispensable . Three-dimensional laparoscopy should be mentioned as an additional supportive visual tool, as well as the use of ICG that can further help to both detect superficial lesions and guide difficult parenchymal dissection . Further technological research is supposed to help surgeons in this scenario, such as the application of virtual realities, which could also be beneficial in this context .
In conclusion, LLR should be considered in multinodular HCCs, but more robust studies are needed to support clinical practice. A personalized strategy can also be proposed, combining both laparoscopic ablation and resection when technically demanding, and the size and position of the lesions can benefit from it .
The technical difficulty associated with LLR is linked to different aspects, such as parenchymal transection, hemostasis at the transection plane, and limited ability to explore deep and posterior regions of the liver. Therefore, LLR was initially reserved for superficial or left-sided lesions. The successive improvements in laparoscopic techniques and the introduction of new technologies mean that LLR is technically feasible in postero-superior (PS) segments (I, IVa, VII, VIII), too  (Figures 1 and 2). LLR of PS segments are considered major liver resections, according to the most recent international consensus , since they have shown a significantly longer operative time, length of hospital stay, rate of open conversion, and estimated blood loss when compared to antero-lateral resections .
At the same time, improved laparoscopic techniques, better visualization of the operative field using a flexible laparoscope, and routine use of an ultrasonic cavitron for transecting the deeper portion of the liver parenchyma have allowed to reach excellent outcomes for LLR for HCC located in the PS segments, resulting in reduced blood loss, fewer complications, and shorter postoperative hospital stay compared with OLR tor the same segments in retrospective studies [72,73]. An international multicenter randomized trial for LLR in PS segments (orange segments trial) is still ongoing, and it will allow obtaining a definitive confirmation.
Segments 7 and 8 are the more posterior ones, rated as 5 on the Iwate score, because of unfavorable working angles and a poor operating view, especially with the classic trocar positioning, from caudal to cranial. Thus, different approaches have been proposed: Morise proposed a left lateral position for posterior sectionectomy and the semi-prone position S7 segmentectomy, with or without an intercostal placement or a lateral positioning of the trocars . Newer dissection strategies have also been proposed, such as the diamond technique, allowing safe LLR in PS segments, even in cirrhotic patients .
In researchers' experience, it is the surgeon’s ability to master both hepatic anatomy and laparoscopic liver surgery that makes the difference, with the need to know how to deal with any dangerous bleeding from the hepatic veins and probably know when to convert to prevent them happen. The approaches described in the literature can probably all be used indifferently but consistently with the experience of the surgeon and the center. Finally, also for the resections of the PS segments, and perhaps above all, technology can once again come to the aid for the resections of patients with HCC. In fact, the use of the ICG allows obtaining both a positive and a negative counter-staining, facilitating the transection line in the Glissonian approach for anatomical resections, as originally described by Takasaki, useful specifically for HCC treatment [32,76]. At the same time, 3D modeling or virtual reality could help to clarify the difficult relationships of the lesions with the hepatic veins, even if their real role needs to be proved .
As already mentioned, HCC has a high risk of recurrence after both LT and liver resection. Thus, repeat laparoscopic liver resection (RLLR) has increased thanks to the progressive wide adoption of LLR. Furthermore, LLR reduces the risk of further adhesions. Kanazawa et al. showed that the operation time for RLLR after previous LLR was significantly shorter than after OLR . Belli et al. reported fewer postoperative complications, lower bleedings, and shorter hospital stay after RLLR than repeat OLR . Recently, the feasibility of a laparoscopic approach for repeat resection after LT was also reported, pushing the limits of MILS even further .
Finally, Morise et al. recently published an international multi-institutional propensity score-based study of RLLR for HCC, showing less blood loss and hospital stay for the laparoscopic group, even if the LLR was preferred for patients with favorable tumor characteristics .
Since the first series of robotic liver resections (RLR) reported by Giulianotti et al. in 2003, different advantages of this approach have been proposed: from the ability to articulate the instruments and the magnified three-dimensional vision to ergonomic advantages for the surgeon [82,83]. Several studies have investigated the safety and effectiveness of RLR in different situations, leading to the first international consensus statement on RLR in 2018 [84,85].
Safe and effective RLR for tumors located in the PS segment has been reported by several authors . Similarly, robotic hemi-hepatectomies were associated with less intraoperative blood loss and a shorter operation time than LLR. Hu et al. published a meta-analysis including 487 RLR and 902 LLR showing fewer bleedings for RLR, with longer operation time than LLR . There was no significant difference in hospital stay, conversion rate, R0 resection rate, and total complication rate between the two groups.
The high cost of treatment, as well as logistic and organizational aspects, may be the biggest shortcomings in the development of robotic surgery.
Since the first laparoscopic hepatectomy (LDH) for a living donor LT (LDLT) was performed for a pediatric recipient by Cherqui in 2002, many transplant centers worldwide have adopted this approach, even if some concerns about donor safety still exist . Hong et al. in 2021 published results from a Korean multicenter study on more than 500 LDH, showing similar outcomes to the open approach in terms of safety, with a decreasing operation time . Recently, two meta-analyses involving more than 1000 patients concluded the safety of LDH while showing some advantages in terms of lower blood loss and shorter hospital stay [90,91].
Similarly, the first robotic donor hepatectomy was a right hepatectomy reported by Giulianotti et al. in 2012, with the aim of applying the supposed advantages of the robotic approach also in the field of LT . The first series published by Chen et al. showed comparable results for complication rates, blood loss, and recovery of donor liver function when compared to open hepatectomy, with a shorter length of stay and less postoperative pain, without open conversions; the robotic group had longer operation time . Recent systematic reviews support the safety of the robotic approach, suggesting technical advantages regarding hilar dissection, with no major difference in terms of ischemic time or cosmesis . Therefore, robotic donor hepatectomy has been proposed as a viable option for experienced surgeons in the latest recommendations on robotic liver surgery .
Finally, what seemed to be the major limitation for laparoscopic liver surgery, namely the implantation of the liver graft in the recipient, was also overcome in 2021, a historic event for LT. The operation carried out by Suh et coll. lasted 960 min, including pure laparoscopic total hepatectomy and pure laparoscopic implantation, through a suprapubic incision, and was shown to be safe, without postoperative complications . Further prospective studies on larger sample sizes will have the task of clarifying the benefits of such an incredible procedure.
In conclusion, with the advances in surgical techniques and perioperative management experienced in the recent two decades, indications for LLR in HCC patients have tremendously improved and become technically practicable for the biggest part of lesions. Current advances in both surgical and medical treatment for HCC will probably redefine the actual frontiers of LLR by including patients with more advanced disease. With the exponential growth of LLRs performed around the world, it is important to know the specific limits of this approach in HCC patients in order to put into practice all the pre-, intra-, and postoperative precautions to overcome them, making this technique the standard of care within high-volume hepatobiliary centers. Expertise and learning curve should remain the mainstay, and the selection of appropriate candidates with meticulous preparation are the key points to ensure the success of the approach.