Challenging Scenarios and Debated Indications for Laparoscopic Liver Resections for Hepatocellular Carcinoma

Simple Summary Minimally invasive liver resections are nowadays performed worldwide for both benign and malignant lesions. Good short-term and safe long-term outcomes have been reported. Despite this growing implementation of the technique, challenging scenarios and debated indications still exist. There is currently a lack of high-quality evidence regarding minimally invasive liver resections in portal hypertension, advanced cirrhosis, lesions in the posterosuperior segments and large and recurrent tumors. Abstract Laparoscopic liver resections (LLRs) have been increasingly adopted for the treatment of hepatocellular carcinoma (HCC), with safe short- and long-term outcomes reported worldwide. Despite this, lesions in the posterosuperior segments, large and recurrent tumors, portal hypertension, and advanced cirrhosis currently represent challenging scenarios in which the safety and efficacy of the laparoscopic approach are still controversial. In this systematic review, we pooled the available evidence on the short-term outcomes of LLRs for HCC in challenging clinical scenarios. All randomized and non-randomized studies reporting LLRs for HCC in the above-mentioned settings were included. The literature search was run in the Scopus, WoS, and Pubmed databases. Case reports, reviews, meta-analyses, studies including fewer than 10 patients, non-English language studies, and studies analyzing histology other than HCC were excluded. From 566 articles, 36 studies dated between 2006 and 2022 fulfilled the selection criteria and were included in the analysis. A total of 1859 patients were included, of whom 156 had advanced cirrhosis, 194 had portal hypertension, 436 had large HCCs, 477 had lesions located in the posterosuperior segments, and 596 had recurrent HCCs. Overall, the conversion rate ranged between 4.6% and 15.5%. Mortality and morbidity ranged between 0.0% and 5.1%, and 18.6% and 34.6%, respectively. Full results according to subgroups are described in the study. Advanced cirrhosis and portal hypertension, large and recurrent tumors, and lesions located in the posterosuperior segments are challenging clinical scenarios that should be carefully approached by laparoscopy. Safe short-term outcomes can be achieved provided experienced surgeons and high-volume centers.


Introduction
Hepatocellular carcinoma (HCC) is the most common primary liver tumor and the third leading cause of cancer-related deaths worldwide [1,2]. Whenever feasible, liver resection (LR) is one of the treatments of choice in very early and early-stage disease,

Study Selection
The same two authors independently screened the titles and abstracts of the studies that were identified with the electronic search. Duplicate studies were excluded. The following criteria were set: (1) studies reporting laparoscopic liver resections for the abovementioned indications; (2) studies reporting at least one perioperative outcome. The following exclusion criteria were set: (1) studies reporting non-laparoscopic liver resections, (2) studies not reporting separate outcomes for laparoscopic liver resections and (3) studies in which it was impossible to retrieve or calculate the data of interest. In the case of more than one report from the same center, only the most recent or the highest-quality study was included in the review. Advanced cirrhosis was defined as a Child-Pugh score of B or more [12]. Portal hypertension was defined as the presence of indirect signs of clinically significant portosystemic shunts (radiological or biochemical) or by a portosystemic gradient of more than 10 mmHg [13]. Segments VII, VIII, and IVa were considered posterosuperior [14]. A size of >5 cm was considered a large HCC [15].

Data Extraction
The same two authors extracted the main data as follows: (1) first author, study type, and subgroup; (2) number and characteristics of patients including Child-Pugh and/or MELD score; (3) intraoperative characteristics including the number of major/minor hepatectomies, anatomic or non-anatomic resections, operative time, blood loss, Pringle maneuver, conversion rates, and (4) postoperative outcomes including complications, Clavien-Dindo et al. [16] grade, liver-specific complications (bile leak, ascites, and liver failure) and mortality. Liver failure was defined according to the classification of International Study Group of Liver Surgery (ISGLS) [17] Major complications were defined as Clavien-Dindo > II. Relevant texts, tables, and figures were reviewed for data extraction, and whenever further information was required, the corresponding authors of the papers were contacted by e-mail. Discrepancies between the two reviewers were resolved by consensus discussion. Quality assessment was performed according to the Newcastle-Ottawa Scale (Table 1) [18]. Table 1. Newcastle-Ottawa scale for quality assessment of the included studies.

Results
The literature search yielded 566 articles; after duplicate removal, 401 titles and abstracts were reviewed ( Figure 1). Of these, 226 papers were excluded based on abstract and title; 175 articles were assessed for eligibility and full text screened. Of these, 139 articles were excluded. Finally, a total of 36 articles dated between 2006 and 2022 fulfilled the selection criteria and were included in this systematic review . There was no disagreement between the authors regarding eligibility. The articles consisted of 33 retrospective and three prospective reports, gathering a total of 1859 patients. Characteristics of the included studies are summarized in Table 2.

Results
The literature search yielded 566 articles; after duplicate removal, 401 titles and abstracts were reviewed ( Figure 1). Of these, 226 papers were excluded based on abstract and title; 175 articles were assessed for eligibility and full text screened. Of these, 139 articles were excluded. Finally, a total of 36 articles dated between 2006 and 2022 fulfilled the selection criteria and were included in this systematic review . There was no disagreement between the authors regarding eligibility. The articles consisted of 33 retrospective and three prospective reports, gathering a total of 1859 patients. Characteristics of the included studies are summarized in Table 2.

Comparative Results between Open vs. Minimally Invasive Surgery in Large HCC
Four studies compared the postoperative results of open vs. laparoscopic surgery [30,31,33,35] [30,31]. No differences were found in terms of postoperative mortality.

Comparative Results between Open vs. Minimally Invasive Surgery for Lesions Located in Posterosuperior Segments
Three studies compare the results of laparoscopic and open surgery for HCC located in posterosuperior segments [39,40,42]. All of the studies showed a lower morbidity rate and shorter hospital stay in the laparoscopic group. Only Tagaytay et al. found lower blood loss (218.11 vs. 358.92 mL, p = 0.046) and shorter operative time (7.03 vs. 11.78 days, p = 0.001) in the laparoscopic group. No differences were found in terms of 90-day mortality.

Comparative Results between Open vs. Minimally Invasive Surgery for Recurrent HCC
Eight studies compared the results of laparoscopic vs. open surgery for recurrent HCCs [45,47,[49][50][51][52][53][54]. All of them showed a shorter hospital stay in the laparoscopic group. The majority found lower blood loss [45,[49][50][51]53] and only three studies reported lower postoperative morbidity rate in the laparoscopic group [45,52,54].  [47,50,51]. Gon et al. showed shorter operative time in the laparoscopic group only if the recurrent HCC was located in the controlateral parenhcyma from the previous resection [49]. No statistically significant differences in 90-day mortality was observed.

Discussion
Despite the recent advances in surgical techniques and the widespread adoption of minimally invasive approaches for liver resections, patients with advanced cirrhosis, portal hypertension, large and recurrent lesions, and tumors located in the posterosuperior segments still represent a challenge even in the most experienced hands. Indeed, perioperative complications in the above-mentioned settings are potentially high, and long-term outcomes are still under investigation [15]. Careful preoperative evaluation and assessment of potential risk factors is key to guide a thorough discussion of potential risks and benefits, thereby selecting patients and minimizing unexpected events.
Patients with advanced cirrhosis and portal hypertension represent one of the most difficult clinical scenarios in the management of HCC [3]. Indeed, these patients may present with impaired performance status, sarcopenia, encephalopathy, ascites, and severe portosystemic shunts. Therapeutic alternatives such as liver transplantation and locoregional options might come into play, but many patients still undergo resection. The decision of whether to operate on patients with such advanced conditions represents a dilemma. Perioperative risks are high, with increased rates of postoperative morbidity, especially liver failure and ascites [17,55,56]. In this setting, minimally invasive approaches could be beneficial to improve postoperative outcomes [7,9,21]. Indeed, the abdominal cavity is respected as compared to a large open incision, avoiding the interruption of portosystemic shunts, manipulation of the liver is reduced, and the abdominal cavity is not exposed to the air, thus avoiding electrolyte imbalances [57]. However, the LLRs in such patients are technically more challenging. Adhesions are well vascularized, there is an increased bleeding during the transection, and the parenchyma is stiff, thus limiting exposure. According to our review, only four papers have been reported describing LLRs on AC, thus limiting the evidence in this setting. Furthermore, most patients with advanced cirrhosis were scored as Child-Pugh B, while only six patients were scored as C. The literature on liver resection in Child-Pugh C patients is limited both in open and laparoscopic surgery because of the questionable postoperative outcomes [15]. In our opinion, therapeutic alternatives should be well discussed in such patients, as no sufficient data are available so far to support resection, especially in laparoscopy. Although minor and non-anatomical resections were more frequent in these subgroups, intraoperative blood loss was high, the Pringle maneuver was frequently applied (40.4% in AC and 60.6% in PH), and conversion rates were high (8.3% in AC and 9.0% in PH), confirming the technical complexity of these procedures. Despite the potential advantages of the minimally invasive approach, according to our review, AC and PH had the highest rates of morbidity, especially postoperative liver failure (up to 6.7% in PH), ascites production (up to 18.6% in AC) and the highest chance of dying after surgery (5.1% mortality in AC). This confirms that the presence of clinically significant portal hypertension and advanced cirrhosis are important prognostic factors for worse postoperative outcomes, especially in terms of liver decompensation surrogates. For this reason, these very high-risk patients, when considered for surgery, should be managed by experienced surgeons in high volume centers and should be well selected to improve the outcomes.
Large HCCs represent another common surgical dilemma to approach by laparoscopy. These lesions frequently require major hepatectomies and/or anatomic resections. The dissection of the hilar structures, the large parenchymal transection, the major vasculobiliary structures encountered and the extensive mobilizations require specific learning curve, as each of these steps have specific technical challenges [8,58,59]. This is enhanced when dealing with large lesions, since exposure and mobilization are further limited [60]. Notwithstanding, perioperative outcomes were good with no major blood loss or high rates of conversions to open, and only 20% of patients were developing postoperative morbidity, mostly minor in severity. A cutoff of 5 cm was applied by most of the included studies to define large lesions [29][30][31][32][33][34][35]. Together with the dimensions of the tumor that should be further categorized, we also believe that localization of the lesion should be considered in future studies, as perioperative outcomes could be very different between a lesion located close to the hilum or at the periphery. Dimensions and localization would therefore allow for a more precise selection of patients, thereby improving outcomes.
Posterosuperior segments were initially considered as a contraindication to the laparoscopic approach, being defined as the non-laparoscopic segments [61]. Thanks to the widespread adoption of minimally invasive approaches and to the learning curves, nowadays, lesions in the PS segments are frequently approached by laparoscopy, with good short and long-term outcomes for both benign and malignant lesions [62,63]. However, few reports on HCCs in the PS segments exist, as this still represents a challenging indication, especially in cirrhotic patients. According to our review, intraoperative and postoperative outcomes were good, with a morbidity rate as high as 18.6%, thereby disclosing the safety and efficacy of such approach. However, conversion to open was high (15.5%) as was the need for Pringle maneuver (36%), again stressing the technical complexity and thereby confirming the need for advanced technical skills.
Despite the good long-term outcomes of liver resections for HCC, as much as 70% of patients will experience recurrence of their tumor [3,64]. Salvage liver transplantation, for those eligible, represents a valid treatment. However, repeat liver resection could also be used in selected patients, as outcomes are good both in the short and long-term. According to our review, most resections were minor, reflecting the fact that a parenchymal sparing policy is very important in these patients that have already undergone a previous resection. Unnecessary sacrifice of healthy parenchyma should be minimized. We found that repeat resections for recurrent HCCs require long operative time. This is reasonable considering adhesions from previous surgery that can often be vascularized in cirrhotic patients, thereby prolonging the dissection and exposure as well as preparation of the Pringle maneuver. Indeed, the Pringle maneuver was rarely applied (only 0.2% of cases), reflecting the fact that during repeat resections, the pedicle is difficult to sling given previous maneuvers in the area. This makes the liver transection phase potentially riskier, as bleeding cannot be controlled by hilar clamping.
This systematic review has some limitations; first, it is mainly based on retrospective studies, including mostly small and single-center studies. While the evidence is limited for advanced cirrhosis and portal hypertension, more patients have been reported in the setting of large and recurrent lesions and in posterosuperior segments. The wide inclusion period of the studies might also limit the conclusions, since technical evolutions have happened and are still happening in the field of LLRs. Therefore, we need more data to compare minimally invasive surgery and open surgery in the mentioned situations. In this setting, robotics has been increasingly used in the most recent years: from initial skepticism due to the lack of substantial literature to a worldwide adoption of this technique with similar outcomes as compared to laparoscopy [65]. This review was limited to patients operated on by laparoscopy, and conclusions should therefore not be generalized to robotics. Future studies investigating the role of robotic liver resections in challenging scenarios such as the ones depicted in this review are warranted. Long-term outcomes also have been rarely disclosed in these settings [66][67][68]. Further studies should clarify the oncological safety. To our knowledge, this is the first review that includes all the challenging indications for LLRs for HCC. Only Yin et al. explored the role of LLRs in posterosuperior segments, but no pooled evidence exists concerning AC, PH, large lesions, tumors in the PS segments and repeat LLRs [69].

Conclusions
Laparoscopic liver resections for HCC have good short-and long-term outcomes. Advanced cirrhosis and portal hypertension, large and recurrent tumors and lesions located in the posterosuperior segments are challenging clinical scenarios that should be carefully approached by laparoscopy. Safe short-term outcomes can be achieved provided experienced surgeons and high-volume centers. Advanced cirrhosis and portal hypertension are the riskiest scenarios. The selection of patients is key in these settings.