Hepatocellular Carcinoma: Recent Advances in Curative Liver Resection

Abstract

Hepatocellular carcinoma is the third leading cause of cancer mortality and the sixth most common cancer worldwide, posing a serious global health burden. Liver resection (LR) represents the main form of curative treatment, and it is constantly evolving, along with massive progress in the last 20 years in order to improve the safety of hepatectomy and to broaden the indication of LR. This chapter highlights the recent advances in the surgical management of HCC, including (1) the optimization of future liver remnant (FLR) with portal vein embolization, associating liver partition and portal vein ligation for staged hepatectomy and radiological simultaneous portohepatic vein embolization, (2) the advantages of anatomic LR compared to non-anatomic LR, (3) the minimal invasive liver surgery (MILS) approach via laparoscopic and robotic LR, (4) simulation as well as navigation with three-dimensional liver reconstruction and simulated LR, and application of fluorescence imaging, (5) the utilization of new parenchymal transection devices, and (6) liver transplantation (LT) versus LR. With a deeper understanding of segmental liver anatomy, assistance from simulation and navigation system, advances in FLR optimization, MILS, new parenchymal transection devices, and LT, liver surgeons should tailor the surgical plan according to each individual to achieve the best outcome for patients.

1. Introduction

Liver cancer represents one of the leading solid malignancies and the most common cause of cancer-related death. Among them, hepatocellular carcinoma (HCC) constitutes more than 90% of the primary liver tumors, with 840.000 newly diagnosed cases and over 780.000 deaths per year [1]. As the third leading cause of cancer mortality and the sixth most common cancer across the world, HCC poses a serious global health burden and results in a significant matter of disease concern [2]. At present, liver transplantation (LT), local tumor ablation (LTA), and liver resection (LR) represent the three main forms of curative options for HCC. Unfortunately, due to the severe liver graft shortage, the risk of withdrawal from the lengthy waiting list due to tumor progression, and the stringent selection criteria, only a humble fragment of HCC patients can benefit from LT. In the same circumstances, LTA faces restrictions in its application caused by location challenges (subdiaphragmatic or subcapsular tumor), large tumor diameter (more than three cm), and close vicinity to structure (vascular, biliary, and organ). Thus, LR remains the backbone of curative therapy thanks to its flexible indication and its available facilities. The five years overall survival in HCC patients who achieve curative treatment with LR reaches 60–80% which is significant better and more promising as opposed to unresectable HCC [3]. Given its importance, in the last 20 years, LR is extendedly indicated in a more advanced stage and continues to be ameliorated with massive progress in safety and in widened indication.

In this chapter, we highlight the recent advances in the surgical management of HCC including (1) the optimization of the future liver remnant, (2) the advantages of anatomic resection compared to non-anatomic resection, (3) the minimal invasive approach via laparoscopic and robotic LR, (4) simulation and navigation in LR, and (5) the utilization of new parenchymal transection devices.

2. Advances in surgical management of HCC

2.1 Optimization of the predicted insufficient future liver remnant

The post-hepatectomy liver failure (PHLF) due to the insufficient future liver remnant (FLR) remains a critical concern in hepatectomy when the indication of major LR is essential for curative purposes. In general, a minimum FLR of 30% of the total liver volume (TLV) is a safe frontier for patients with normal liver, whereas preservation of 40–50% of TLV is imperative in case of chronic liver disease such as hepatic fibrosis or steatosis and cholestasis [4, 5]. Therefore, various strategies have been proposed to improve the resectability rate by achieving adequate compensatory liver hypertrophy.

2.1.1 Portal vein embolization (PVE)

PVE was initially introduced by the Japanese Professor Makuuchi in 1990 to minimize the risk of PHLF in patients who underwent major LR due to hilar cholangiocarcinoma [6]. The essential core behind this technique is to stimulate the enlargement of FLR by embolizing the portal vein (PV) of the tumor-bearing hepatic lobe before LR. Administration of embolic agents (such as polyvinyl alcohol particles, microspheres, gel foam, N-butyl cyanoacrylate glue, or sodium tetradecyl sulfate foam with or without combination coils/plugs) will decrease the targeted portal vascular flow by creating PV occlusion and then consequently promote hypertrophy of the non-embolized hepatic lobe via mirror liver regeneration following resection. The ultimate goal of successful PVE consists of distal PV blockage to prevent intrahepatic collaterals as well as proximal PV occlusion to stop the venous inflow in the targeted hepatic segments. This strategy has been recognized as a powerful solution for inadequate FLR modulation. The access of the targeted PV can be achieved via one of the four following approaches: the percutaneous transjugular and the intraoperative transileocolic venous approaches are clinically less preferred due to their invasiveness and the requirement of anesthesia support, whereas the transhepatic contralateral approach (in which embolization is performed from the FLR), and the transhepatic ipsilateral approach (in which embolization is performed from the tumor-bearing lobe) are widely used [7]. After PVE, approximately 80–90% of candidates are qualified to undergo hepatectomy, while the remaining patients do not experience adequate FLR hypertrophy [8, 9]. The mean percent FLR hypertrophy was 30.9% with an interval of time 40.3 ± 26.3 days between PVE and curative hepatectomy [9]. The inadequate liver regeneration volume and the presence of tumor progression or metastasis during the long waiting time increase the risk of drop out from the list of subsequent LR. PVE offers an acceptable rate of major complications (less than 5%) including puncture-related complications (vascular injury, biloma, or infection) and embolization-related complications (embolic material migration, non-targeted vein embolization, proximal venous thrombosis, parenchymal infarction, and portal hypertension) [9, 10, 11]. Contraindications to PVE in clinical practice consist of portal hypertension, PV thrombus, occlusion of the PV in the FLR, biliary obstruction (biliary drainage before the procedure is required), extrahepatic metastasis, uncorrectable coagulopathy, and renal failure.

2.1.2 Sequential transarterial chemoembolization (TACE) and portal vein embolization (PVE)

Sequential TACE and PVE have been proposed to overcome the aforementioned limitations of PVE alone. The insufficient degree of FLR hypertrophy after PVE alone may be explained by the underlying liver disease that impairs the capacity of liver regeneration, the existence of arterioportal shunt in HCC patients, and the reimbursing rise of hepatic artery (HA) blood flow at the embolized lobe. As shown in a recent systematic review and meta-analysis (SRMA), the sequential TACE and PVE had demonstrated superior advantages in oncological outcomes with greater liver resectability rate and percentage increase in FLR, better overall survival, longer disease-free survival (DFS), as well as its safety with comparable overall morbidity, mortality, and PHLF in compared to PVE alone [12]. In fact, the mean increase in percentage FLR volume varies from 7–18%, according to different studies [13, 14, 15]. On the other hand, careful attention must be devoted during glissonean pedicle dissection due to heavy inflammatory adhesion and choledochal varices following the sequential TACE and PVE, which might cause more challenges and difficulties in a subsequent surgery. Another drawback is the risk of severe infarction or necrosis of the residual non-cancerous liver parenchyma, especially in patients with underlying liver disease, due to double occlusion of the arterial and portal venous systems; however, only a mild elevation in liver function test, as well as minimal necrosis in the resected specimen of non-cancerous liver parenchyma were reported in most of the cases [14, 16, 17].

2.1.3 Associated liver partition and portal vein ligation for staged hepatectomy (ALPPS)

The rationale of ALPPS consists of PV ligation on the tumor-bearing lobe and simultaneous severance between the tumor-side liver and the residual liver by liver parenchymal transection during stage one. In stage two, completion of subsequent hepatectomy is achieved by resection of ipsilateral HA, bile duct, and hepatic vein (HV) with a shorter delay of time (usually one or two weeks later). A sufficient FLR volume is ensured by the assessment of computed tomography (CT) or magnetic resonance imaging (MRI)-based liver volumetry measurement. Compared with traditional two-stage hepatectomy (TSH), ALPPS is distinctive with speedy enhancement of adequate FLR hypertrophy following maximal separation of the tumor-bearing lobe to be removed and without risk of dropout due to tumor progression while waiting for liver hypertrophy. As opposed to PVE, data from SRMA have emphasized the advantages of ALPPS with a significant increase in FLR with shorter intervals of time (76% vs. 37%) and a higher rate of stage two completion (100% vs. 77%) [18, 19, 20]. Despite preceding benefits, major concerns have been expressed about the safety of ALPPS due to its high rate of morbidity and mortality. The reported major complications range from 21.4% to 54.1% [21, 22, 23, 24], and the 90-day mortality rate varies from 5% to 11.8% [22, 25]. Although statistical difference was not reached, ALPPS was proved to have a trend toward higher morbidity and mortality compared to TSH [18, 20]. Thus, in an effort to minimize the invasive complications of this approach, numerous variations on the classical ALPPS have been proposed such as partial ALPPS [26], monosegment ALPPS [27], mini ALPPS [28], radiofrequency ALPPS [29], minimally invasive ALPPS (laparoscopic ALPPS [30] and robotic-assisted ALPPS [31]), tourniquet alPPS [32], hybrid ALPPS [33], salvage ALPPS [34], left and right ALPPS [35]. These modified protocols have ameliorated the safety of ALPPS and improved its morbidity and mortality rate [36]. In terms of oncological outcome, ALPPS offers an overall survival (OS) of 86% at 6 months, falling to 59% at 2 years, and DFS of 59% at 1 year, falling to 41% at 2 years [37]. Indeed, there were no statistical differences regarding OS and DFS between patients who underwent ALPPS and TSH [38].

2.1.4 Liver venous deprivation (LVD)

Another possible approach to achieve the desired FLR volume is LVD, which is associated with simultaneous hepatic vein embolization (HVE) and PVE in the tumor-bearing liver. The concomitant occlusion of the PV and one or even two HV (called extended LVD) induces resonant damage to the ipsilateral lobe and thereby redirects the blood supply to the contralateral lobe, which subsequently accelerates hypertrophy of the FLR. Data from recent SRMA emphasized the promising results of LVD with a significantly higher degree of FLR hypertrophy before major hepatectomy than PVE and with a comparable capacity of regeneration to ALPPS [39]. In addition, LVD was safe, with lower major complications and a 90-day mortality rate compared to PVE and ALPPS [39]. The resection rate following LVD was impressive, with approximately 86–100% of patients who successfully underwent hepatectomy [40, 41, 42]. Despite remarkable benefits, the preliminary results of this new technique remain to be carefully explored and validated thoroughly in more studies.

2.2 Anatomic resection (AR) in hepatectomy

2.2.1 The concept of AR

The concept of AR in hepatectomy was initially introduced by the distinguished Japanese professor Makuuchi [43]. AR consists of systematic excision of the tumor-bearing portal tributaries and the corresponding hepatic territory, using PV branches dye-staining method [44] or Glissonean pedicle transection technique [45]. Indeed, the pre-ischemic control of the PV is performed, followed by the complete removal of one or more corresponding Couinaud’s segments supplied by a branch of the PV and HA (including segmentectomy, bisectionectomy, trisectionectomy, or hemihepatectomy). As liver tumor tends to invade the intrahepatic vascular structure, the entire and thorough elimination of tumor-bearing portal territory suppresses the risk of tumor dissemination (tumor thrombus, daughter nodule, or metastasis) in the corresponding segment through the PV blood flow [46, 47]. Conversely, nonanatomic resection (NAR) is a parenchyma-sparing surgery regardless of the anatomical liver segment, in which the tumor resection is performed with a margin of uninvolved tissue. This protocol is preferred in patients with poor liver function or cirrhosis.

2.2.2 AR versus NAR

Although several retrospective studies did not reveal long-term outcomes advantages of AR vs. NAR [48, 49, 50, 51], recently published SRMA have demonstrated the superiority of AR over NAR in terms of OS and DFS [52, 53, 54]. However, AR was proven to be associated with longer operation time, significant blood loss, and wider surgical margins [52]. Besides, there was no statistical difference regarding the rate of blood transfusion or postoperative complications between these two techniques [52, 54]. Despite the positive results of the aforementioned SRMA, the divergence benefits of AR vs. NAR might be due to the bias in research design, including diversification in tumor size, tumor location, background of liver function, operation technique, and presence of microvascular invasion (MVI). Therefore, it is currently impossible to reach a final conclusion about the advantages of AR in hepatectomy. Further prospective randomized studies with larger sample size and multicenter design might help to define the true effect of AR.

2.2.3 AR and resection margin (RM) status in the context of MVI

Despite being a matter of controversy, the current data and the clinical practices support the application of AR with curative purposes in reducing the risk of tumor dissemination and metastasis [55, 56]. Previous comprehensive report have focused attention on RM status since micrometastases could expand via invasion of PV branches, which is also known as MVI, even at an early stage with solitary and small tumor [57]. A multi-institutional data with 801 patients revealed the negative impact of RM status and MVI, in which patients with concomitant narrow RM and MVI suffered for postoperative death and recurrence by about two-fold [58]. Given that the incidence of MVI was correspondingly associated with the distance from the primary tumor, a proximal RM and a distal RM of 1 cm are recommended for HCC with a diameter of less than 3 cm, whereas a 1 cm proximal RM and a 2 cm distal RM should be achieved for HCC with diameter higher than 3 cm [57]. Other reports have revealed that the occurrence of PV invasion and intrahepatic micrometastasis was found within 1 cm of the primary tumor, and this phenomenon was rarely broadened to more than 2 cm [57, 59]. An optimal cut-off value of RM higher than 1 cm was then mostly accepted [58, 60, 61]. Given that, it is crucial to apply AR with wide RM, if technically feasible and safe, when the presence of MVI is determined before hepatectomy [58, 61, 62]. A large multicenter propensity score-matched study of 1965 patients highlighted the significance of AR and RM status, in which patients with AR and wide RM group (≥1 cm) had better median OS (78.9 vs. 51.5 vs. 48.0 vs. 36.7 months, p < 0.001) and better median recurrence-free survival (RFS) (23.6 vs. 14.8 vs. 17.8 vs. 9.0 months, P < 0.001) than those with AR and narrow RM, NAR and wide RM, and NAR and narrow RM groups, respectively [63]. Additionally, regardless of AR or NAR technique, patients with wide RM significantly gained lower operative margin recurrence rates than those with narrow RM [63]. On the other hand, non-tumor-bearing liver parenchyma preservation, also known as parenchyma-sparing LR or NAR, represents a matter of consideration, especially in cirrhotic patients and in patients with insufficient FLR volume. In such a situation when AR and wide RM were unfeasibly obtained at the same time, priority selection should be reserved for AR or for NAR with wide RM? The recent report from 906 HCC patients has emphasized the critical role of wide RM, and this vital feature must be primarily ensured, especially in case of MVI, to improve long-term outcomes [61].

2.3 The minimally invasive liver surgery (MILS)

In 1991, the first case of laparoscopic liver resection (LLR) was incidentally reported in women with benign liver tumor during laparoscopic surgery for gynecologic purposes [64]. Since then, the hepato-biliary-pancreatic (HBP) surgery society has experienced the giant advances of MILS in curative treatment of liver tumors. During the last three decades, the unstoppable developments of the two excellent representatives of MILS, which are LLR and, later, robotic liver resection (RLR), have drastically proved themselves as an alternative approach to traditional open LR. Progress in operational devices, along with accumulated experiences, have promoted the expansion of LLR and RLR indications in clinical practice. The first international consensus conference in Louisville (United States) in 2008 [65], the second meeting in Morioka (Japan) in 2014 [66], and then the recent reunion in Southampton (United Kingdom) in 2017 [67] have witnessed the worldwide adoption of MILS in HBP surgery. Today, LLR should be considered as a standard approach for wedge resection and left lateral or anterior sectionectomy, whereas major hepatectomy, living donor hepatectomy, and ALPPS should be performed at high-volume centers with comprehensive experiences.

Recent SRMA focusing on 13 randomized controlled trials (RCTs) studies in minor LR have emphasized the superiority of LLR over open LR regarding short-term benefits such as lower postoperative complications, lesser blood loss, shorter hospital stay, and faster functional recovery [68]. In terms of long-term oncological outcomes, current evidence encourages LLR with comparable OS and RFS rates compared to open LR [69, 70] or even with better long-term prognosis in cirrhotic HCC patients [71]. On the other hand, the application of RLR in HCC patients seems to overcome LLR in some features such as improvement of surgical manipulations with articulated instruments, better surgical view with three-dimensional (3D) magnified field of vision, greater dexterity and precision with tremor control [72, 73]. As a consequence, RLR approach might be recommended to confer benefits in complex and difficult contexts such as vascular or biliary dissection, suture hemostasis during liver parenchymal dissection, posterosuperior segmentectomy, and biliary-enteric anastomosis [74, 75, 76]. Since the implementation of RLR in the field of HBP was recently introduced within 10 years, long-term reports of RLR are scarce. Despite significantly longer surgical time and higher cost, recent SRMA has proved the equivalent benefits of RLR with no statistical difference in length of hospital stay, blood loss, and the incidence of conversion compared to LLR [77]. As there is a lack of robust data, further investigations are required to evaluate and standardize this technique.

2.4 The simulation and navigation in LR

2.4.1 Preoperative simulation using three-dimensional (3D) visualization

Preoperative simulation using 3D imaging software refers to a modality used to virtually reconstruct the liver anatomy by displaying and exploring the intrahepatic structures such as the tumors and the adjacent components. Currently, there are several software which are specified for 3D liver simulation including Synapse Vincent (Fujifilm Medical, Japan), HepaVision (Mevis, Germany) VirtualPlace (AZE, Japan), Ziostation (Ziosoft, Japan), OVA (Hitachi Medical Corporation, Japan), and VR-Render (IRCAD, France) [78]. These tools permit the preoperative design and analysis of the surgical resection plan by investigating the FLR volume and the area perfused by targeted hepatic blood vessels or drained by a specific HV. At initial, CT or MRI imaging data were obtained, stored, and then transferred to the simulation software. Afterward, comprehensive information on the whole liver including hepatic blood vessels (inferior vena cava, HV, HA, and PV), bile duct, liver parenchymal as well as liver tumors were extracted and displayed with marked colors for anatomical identification. According to the patient’s status and liver tumor characteristics, different resection planes could be designed to determine the most appropriate approach. The total liver volume and the estimated percent of FLR volume will be automatically analyzed and calculated to avoid the PHLF. In fact, reported data have confirmed the reliability and accuracy of preoperative 3D virtual planning software with a high correlation between the planned and the actual FLR [79, 80].

2.4.2 Intraoperative navigation

The concept of navigation in LR began in 1985 when Professor Makuuchi performed the AR using PV branches dye-staining method; however, this method did not always establish a clear recognition of the segmental boundaries for LR [44, 81]. Since then, various techniques and numerous surgical innovations have been proposed to enhance the safety and precision of LR. In the conventional approach, the adjacent segment was intraoperatively differentiated from each other based on the identification of HV via ultrasonography. In reality, due to the 3D irregular form of each liver segment, the three major HV (left, middle, and right HV) are not sufficient to allow precise AR [82, 83]. In this regard, fluorescent navigation with indocyanine green (ICG), a minimal toxic, cost-effective, and water-soluble fluorescent dye that is rapidly absorbed by the liver and secreted into the bile ducts within minutes after intravenous injection [84], has been comprehensively developed to ameliorate the accuracy in AR, especially in the context of real-time surgery for the last few years. With ICG dying, the shape of the segmental borders including the demarcation line on the liver surface and the subsurface borderline in the liver parenchyma could be clearly identified during liver transection. In the laparoscopic approach, the latest findings in SRMA have supported the application of ICG fluorescent navigation with significantly shorter operation time, intraoperative blood loss, hospital stay, and postoperative complications [85]. It seems that this innovation induced better short-term outcomes, however, its impact on long-term prognosis requires more evidence for the final conclusion.

Another aspect of surgical navigation to take into account is the reflection of the preoperative simulation in the intraoperative field. In reality, the intraoperative demand for real-time visualization of precise liver anatomy is vital to identify the exact segmental landmark in AR and also to assure an R0 resection margin for oncological purposes. To overcome the limitation during the exploration of intraparenchymal structure, the Medical Imaging Projection System (MIPS) was introduced to determine the anatomical landmark during AR, thanks to the combination of ICG emission signal and active projection mapping [86]. This system proved to be more convenient than the conventional fluorescent imaging system in which surgeons, with no requirement of specific goggles, can directly focus on the surgical field without having to move their vision to the displayed screen [86]. In addition, instead of using a handheld camera to operate in the area of interest, the MIPS allows users to perform surgery without physiological tremors and to accommodate liver deformities during surgical manipulation thanks to real-time projection [86]. Besides, the introduction of augmented reality (AR), mixed reality (MR), and 3D navigation technology, an advanced fusion imaging technology that superimposes the 3D virtual images from CT or MRI data onto the liver of a patient, had made an evolution in establishing the exact boundary of LR in real-time with a ratio 1:1 [87]. Its clinical integration into intraoperative procedures has been performed, both in open [88, 89, 90] and MILS [91, 92]. The 3D navigation system allows the determination of the exact position of the intraparenchymal targeted lesion [93, 94]. Although current data has revealed some advantages of the aforementioned innovations including increased R0 rate, the elevated number of potential treatable liver lesions, precise AR, improved operation time, and minimized blood loss [95], these technologies require additional evidence for official recognition in the future.

2.5 The utilization of new parenchymal transection devices

In order to complete a successful LR, serious cautions have been reserved for intraoperative hemostatic and biliary control. A meticulous parenchymal dissection are critically required, in which the blood and bile duct system have to be clearly identified. Indeed, the LR procedure consists of two fundamental steps: (1) parenchymal dissection and (2) intrahepatic structures dissection and ligation. Advances in technology with the introduction of new parenchymal transection devices, both in open and MILS approach, have significantly contributed to enhancing this protocol by selectively exposing these structures without damaging them. Since the beginning of hepatectomy with the finger crush technique [96] and then the clamp crushing (CC) technique [97], numerous instruments have been invented and widely used including ultrasonic dissection (such as cavitron ultrasonic surgical aspirator (CUSA) and the harmonic scalpel (HS)), sealing devices (Ligasure), water jet scalpel and vascular stapler.

2.5.1 Ultrasonic dissection

Ultrasonic devices remain one of the most widely used devices in parenchymal transection during LR, especially in donor hepatectomy [98, 99]. The CUSA, the first generation of ultrasonic device, utilizes mechanical wave energy combined with aspiration to fragment and aspirate the liver parenchyma tissue, and then expose biliary ducts over 2 mm and small liver vascular [100]. On the basis of mechanical resistance reflected by the tissue, CUSA induces the fragmentation of hepatocytes without affecting vascular or biliary components since the hepatic parenchyma possesses significantly higher water content and lesser fibrous tissue [101]. This device was helpful and flexible in its use, thanks to its ability to adjust the intensity of dissection according to the degree of liver fibrosis in each patient. Besides individually isolating intrahepatic structures, CUSA offers a well-defined cutting plane as well as precise liver pedicle detection, especially in case of lesions closely located next to the major blood vessels [102]. In the laparoscopic approach, CUSA was useful for the identification of deep-seated intrahepatic vessels [103], especially in the context of challenging parenchyma such as cirrhotic liver [104, 105]. However, as lacking of coagulation function, CUSA’s usage requires additional steps with ties, clips, or staplers to complete hemostasis or biliostasis [106].

The harmonic scalpel (HS), an ultrasonic vessel-sealing dissection, mitigated the drawback of the aforementioned device with the capacity of sealing and isolating intrahepatic components up to 3 mm in diameter [107]. This process is achieved using high-frequency ultrasonic energy transmitted between the instrument blades (55,000 Hz) to disrupt the hydrogen bonds and then denature the proteins [108]. Indeed, the hemostasis as well as the biliostasis are completed at low temperature (80°C) with lesser tissue damage as compared to the thermal effect in monopolar electrocautery method [108]. In recipient hepatectomy, HS transection of small HV (lesser than 2 mm) was safer than conventional knot tying without difference in both total procedure and per vessel time [109]. Regarding deep layer parenchymal dissection in LLR, HS was proved to be superior to CUSA in terms of intraoperative blood loss, operation time, and hospital cost, whereas no difference in rate of conversion to laparotomy, length of hospital stay, and postoperative complications was revealed [110]. Findings from recent SRMA have approved the safety of HS in elective parenchymal liver transection with significantly lower overall and major complications [111].

2.5.2 Sealing devices

Sealing devices complete parenchymal transection by sealing small vessels before dissection using a combination of electrothermal energy and pressure to fuse the collagen matrix in the vessel wall [112]. Ligasure, a representative of a sealing device with a bipolar vessel-ligating system, is able to crush the liver parenchyma and simultaneously seal vascular structure up to 7 mm in diameter [112]. In addition, this instrument was designed with a built-in knife that helps to quickly cut the sealed vessel after vascular hemostasis, thereby leading to reduced LR times [113]. In recipient LR during liver transplantation, ligasure was proved to be significantly associated with a shorter hospital stay due to low re-operation rates, postoperative bleeding, and secondary infection related to bleeding in comparison to the conventional monopolar cautery technique [114]. However, despite its safety, findings from RCT revealed no statistical difference in terms of liver transection time, liver transection speed, or the amount of blood loss compared to the CC technique [112]. Further investigations are needed to reach a final conclusion.

2.5.3 Water jet scalpel

The water jet (WJ) technique leverages the high pressure of the fine water flow to cause fragmentation of liver parenchyma, while the exposed elastic intrahepatic structures are individually isolated with spared injury and subsequently ligated [115, 116]. As employed the water flow for breaking liver tissue, the WJ avoids any thermal damage to the remnant liver with significantly lower denaturation thickness in the post LR detached section compared to the conventional CUSA [117]. However, findings from the SRMA of the two RCTs have revealed no statistical difference regarding blood loss, mortality, morbidity, postoperative liver function test, transection time or speed, and median hospital stay between WJ and CUSA [118, 119, 120]. The application of the CC technique has even been proven to be quicker than WJ, with a lower rate of blood loss and similar mortality, morbidity, liver dysfunction, and length of hospital stay [118].

2.5.4 Vascular stapler

The technique of vascular stapler (VS) has been described as below: the liver capsule was initially split with diathermy along the transectional landmark, the subsequent transection of liver parenchyma was then crushed stepwise using a vascular clamp and finally dissected with VS [121]. VS has expressed its effectiveness with the capacity to be continually fired in a quick and ready-to-use fashion [113]. An RCT of VS versus CC technique in elective LR has revealed no difference in terms of intraoperative blood loss as well as postoperative morbidity and mortality [122]. Instead, another RCT emphasized the superiority of VS over ligasure with significantly lesser blood loss and shorter operation time, whereas the surgical morbidity and the grade of complication were comparable [123].

2.6 Liver transplantation (LT) versus LR

In cirrhotic HCC patients with worse liver function, LT represents an ideal alternative for curative purposes to LR, in which both the existing tumor and the preneoplastic underlying liver parenchyma are treated. Given the shortage of donor organs along with the huge number of patients on the waiting list, LT becomes less eligible for a certain amount of patients. In addition, such challenges impede the wide adoption of LT including the heavy financial requirement owing to the high cost of transplant operation and long-term use of immunosuppressant (IS), the availability of a specialized and skilled surgical team as well as the adherence to the side effects arising from lifelong IS use. Thus, the selection between these two curative surgical approaches remains a topic of passionate debate. LR seems to be a preferred therapy for HCC patients with reserved liver function, whereas LT is an appropriate option in case of impaired liver function. Besides, concerns about the long-term outcomes of HCC for LR versus LT have recently gained much attention. Despite longer hospital stay, LT has provided greater overall and event-free survival rates with comparable morbidity and mortality rates than LR [124]. The surveillance, epidemiology, and end results program (SEER) database, which generally represents the entire US population, has also revealed that patients with LT offered a lower risk of overall mortality and cancer-free mortality than those with LR [125]. Likewise, the latest findings from SRMA and from meta-analysis of meta-analyses have again emphasized the superiority of LT over LR with regard to long-term outcomes [111, 126]. Indeed, data from 63 studies involving 8178 cases of LT and 11,626 cases of LR have concluded that LT provided better 5 years OS and RFS compared to LR but not in short-term intervals [111, 126]. As regards to recurrence, current evidence supports the superior role of salvage LT, in which initial LR with curative purpose was performed and followed by LT due to tumor recurrence, then repeat LR with better disease-specific and RFS for treating transplantation-eligible patients with intrahepatic HCC recurrence, even in Child-Pugh class A cirrhotic patients [127].

3. Conclusion

LR remains the cornerstone of HCC treatment in terms of safety, feasibility, and effectiveness. LT represents an optimal alternative to LR in case of severely impaired liver function. Recent inventions and innovations have significantly contributed to the preoperative, intraoperative, and postoperative management of HCC patients. Such attempts have been made to reduce blood loss and improve oncological outcomes. With a deeper understanding of segmental liver anatomy, assistance from simulation and navigation systems, advances in FLR optimization, MILS, new parenchymal transection devices, and LT, liver surgeons should tailor the surgical plan according to each individual to achieve the best outcome for patients.

Conflict of interest

The authors declare no conflict of interest.

Nomenclature

3D	three-dimensional
ALPPS	associated liver partition and portal vein ligation for staged hepatectomy
AR	augmented reality
AR	anatomic resection
CC	clamp crushing
CT	computed tomography
CUSA	cavitron ultrasonic surgical aspirator
DFS	disease-free survival
HA	hepatic artery
HBP	hepato-biliary-pancreatic
HCC	hepatocellular carcinoma
HS	harmonic scalpel
HV	hepatic vein
HVE	hepatic vein embolization
FLR	future liver remnant
ICG	indocyanine green
IS	immunosuppressant
LLR	laparoscopic liver resection
LR	liver resection
LVD	liver venous deprivation
LT	liver transplantation
LTA	local tumor ablation
MILS	minimally invasive liver surgery
MIPS	medical imaging projection system
MR	mixed reality
MRI	magnetic resonance imaging
MVI	microvascular invasion
NAR	nonanatomic resection
PHLF	post-hepatectomy liver failure
PV	portal vein
PVE	portal vein embolization
RCT	randomized controlled trial
RFS	recurrence-free survival
RLR	robotic liver resection
RM	resection margin
SRMA	systematic review and meta-analysis
TACE	transarterial chemoembolization
TSH	two-stage hepatectomy
TLV	total liver volume
VS	vascular stapler
WJ	water jet