Laparoscopic hepatic resection for intrahepatic cholangiocarcinoma: a narrative review of the current literature

Introduction

Cholangiocarcinoma (CCA) is the second most common primary malignant liver tumor, and it is classified according with the anatomical location in intrahepatic (ICC) and extrahepatic (ECC). The ICC which arises proximal to the second order bile ducts, represent approximately 10% of the CCA (1,2).

Even though liver resection remains the only potential curative treatment for patients with ICC, it has been estimated that less than 30% of ICC patients are resectable for advanced disease at the time of diagnosis. ICC patients without negative prognostic factors (vascular invasion, multifocal disease, nodal metastases) who underwent surgical resection with curative intent have a 3- and 5-year survival rates of 60–70% and 30–40% respectively (3-5).

In recent years, laparoscopic liver resection (LLR) gained a key role in the surgical treatment of malignant and benign liver tumors. The recent Southampton guidelines strongly supported the LLR for the management of HCC, benign, and metastatic disease with robust evidence, LLR is associated with less intraoperative blood loss, early oral feeding, fewer complications, shorter postoperative hospital stay, and similar oncological outcomes compared to open liver resections (OLR) (6-8).

Even though the laparoscopic approach has showed similar oncologic outcomes of patients with HCC and colorectal liver metastases, few data are available regarding the application of LLR for ICC patients (9,10).

Surgery with curative intent for ICC frequently require major hepatectomies and vascular/biliary reconstructions, as well as regional lymphadenectomy. The paucity of studies regarding the feasibility and safety of LLR for ICC, controversies about lymphadenectomy and the high technical skills required for perform this type of surgery are some of the limiting factors which could justify the limited diffusion of LLR for ICC (9,11-14).

The aim of this study is to review the current literature regarding the role of the laparoscopy in the treatment of ICC focusing on short-term and long term-outcome.

Specifically, due to the controversy of different aspects of LLR for ICC we aimed to analyze in our review the technical feasibility and safety of LLR, the oncological results in terms of radical resection rate and the adequacy of laparoscopic lymphadenectomy compared to OLR. Furthermore, we would like to investigate long-term outcomes in terms of disease-free survival (DFS) and overall survival (OS). We present the following article in accordance with the Narrative Review reporting checklist (available at https://ls.amegroups.com/article/view/10.21037/ls-22-17/rc).

Methods

We therefore designed and conducted this review with the aim to provide the actual evidence regarding the role of LLR of ICC.

Identification of eligible studies was performed by searching PubMed (Medline) Embase and Cochrane library. The following combination of text words were used “intrahepatic cholangiocarcinoma”, “laparoscopic surgery”, “laparoscopic liver resection” “laparoscopic hepatectomy” “laparoscopy” “minimally invasive surgery”.

Inclusion criteria were: (I) English language studies; (II) study reporting the use of a LLR of ICC; (III) studies reporting on at least one intraoperative, postoperative, and long-term oncological outcomes after laparoscopic resection for ICC.

After search, 1,645 manuscripts were selected for initial screening. Among them, 10 papers have been deemed eligible for the study.

The extracted data included authors, year of publication, number of patients, time of enrollment, time of follow-up, tumor characteristics (tumor size and number), type of surgical resection (e.g., major or minor hepatectomy, bile duct resection), oncological safety (rate of LND and number of harvested lymph nodes, rate of R0), perioperative and short-term outcome as well as long term outcome. If the data on long term outcome were not provided in the literature, Engauge Digitizer 11.1 software was used to extract the survival rate at the corresponding time point from the survival curves (http://plotdigitizer.sourceforge.net).

Characteristic of studies included in the analysis

All studies have been published since 2015. The studies included in our analysis were all retrospective studies and predominantly coming from Eastern centers (7/10; 70%). Moreover, 80% of studies on LLR have small patients’ sample (<30 patients). 8 studies were monocentric, one study involved two referral centers and finally one study included data from a multicentric American database.

Here it the search strategy summary (Table 1).

Results

Role of staging laparoscopy in ICC

A subgroup of ICC patients (approximately 25%) are deemed unresectable at laparotomy because of metastases (liver, nodal, or peritoneal) or locally advanced disease with extensive vascular or biliary involvement (15).

The optimization of preoperative planning, and the improving in quality imaging such as the magnetic resonance imaging with cholangiopancreatography (MRI/MRCP) have improved the preoperative detection of liver metastases, reducing the number of unnecessary laparotomies (16).

Data on the role of a staging laparoscopy in ICC patients are scarce. Weber et al., in a study including 53 patients with ICC performed a staging laparoscopy in 22 patients with potentially resectable disease of whom 6 (27%) were deemed unresectable for peritoneal metastases (n=4) and intrahepatic metastases (n=2) (17). Likewise, Goere et al., in a small series on 11 ICC patients described a 36% yield and 67% accuracy of staging laparoscopy in detecting peritoneal carcinomatosis and liver metastases (18).

Given the recent improvement of quality of preoperative imaging, the utility of a diagnostic laparoscopy to assess the tumor resectability, remains unclear (15,18,19).

According with the Expert Consensus Statement from the American Hepato-Pancreato-Biliary Association the use of laparoscopic ultrasonography may further increase the utility of staging laparoscopy especially for detection of small intrahepatic metastases (20).

Russolillo et al. investigated the additional value of laparoscopic ultrasonography in patients with proximal biliary cancers, including 44 ICC patients. The authors reported a 11.4% yield of staging laparoscopy without the use of ultrasound that increased to 19% when intraoperative ultrasound was used (21).

In conclusion, the role of a staging laparoscopy in ICC is still debated. Despite the risk of unexpected liver metastases has been reduced with improvements of the preoperative imaging assessment, staging laparoscopy with ultrasonography may be useful in high-risk patients (high levels of CA19-9, suspected vascular invasion and peritoneal disease).

LLR of ICC

The primary target of surgery for ICC should be to achieve a microscopically (R0) negative margins, incomplete resection (R1/R2) have been proved to be one of the most relevant factors associated with worse survival (22). To achieve a curative resection for ICC, extensive surgery is frequently necessary including major hepatectomies with vascular/biliary reconstructions and regional lymphadenectomy.

Although a growing number of studies have demonstrated safety of LLR for in major hepatectomies for large liver lesions, the available data regarding LLR for ICC are prevalently focused on small solitary tumors and minor hepatectomies.

Among the 10 studies included in this analysis, 573 patients underwent LLR for ICC with a rate of major hepatectomies for ICC ranging between 33% and 75% (10,12,23-30). for lesions with a median size ranging from 3.5 to 6 cm, a detailed description of the data is reported in Table 2.

Of note, laparoscopic biliary reconstruction has been described only in the study conducted by Martin et al., based on the National Cancer Database (NCDB), who reported 21 cases of laparoscopic bile duct resection among 312 LLR for ICC, on the contrary laparoscopic vascular reconstruction for ICC patients was not reported in literature (25).

According to the European Association for the Study of the Liver (EASL) guidelines for the treatment of ICC, a regional LND is recommended to achieve adequate staging information and reduce the incidence of locoregional recurrence (31). Although several single-institution series have demonstrated the feasibility of laparoscopic lymphadenectomy, the safety and adequacy of laparoscopic LND for ICC is still a matter of debate (9).

Haber et al., in a study regarding 27 LLR and 31 OLR for ICC, described an equal rate of LND between two groups (85% for LLR and 94% for OLR group, P=n.s) (29). Likewise, Kinoshita et al., in a study on 15 LLR and 21 OLR for ICC showed no difference in LND between the LLR and OLR group (40% vs. 30% respectively, P=n.s.) (26). Conversely, a lower rate of LND in the LLR was reported in the studies by Kang et al. (LLR 30% vs. 75.4% OLR; P<0.001) and Ratti et al. (LLR 83% vs. OLR 88.5%; P=0.005) (27,30).

Data regarding the adequacy of LND, assessed with number of harvested lymph node, of single-high specialized centers showed similar results for LLR and OLR, with a median of 8 lymph node retrieved in the laparoscopic group (29,30). Conversely, a recent study of Martin et al. including data from the NCDB (National Cancer Database) of 2,309 resected ICC patients (1,997 OLR, 312 LLR) showed that patients who underwent a LLR were less likely undergo an LND compared to OLR group (LLR: 39%, n=120 vs. OLR: 61%, n=1,210, P<0.001), moreover an adequate lymph node evaluation (≥6 nodes) was less frequent in (LLR 9%, n=27 vs. OLR 15%, n=305, P<0.001) (25). These results should be evaluated in light of some limitations of this study, firstly, this is a national cancer database study, moreover in more than 40% of patients definitive diagnosis of ICC was accomplished only after surgical resection, accounting for the low rate of overall LND (the rate of dissection of one or more lymph node was only 58%, n=1,330).

Regarding the oncological safety of LLR, the reported R0 resection can be achieve in more than 80% (range, 81–100%) of patients who underwent LLR for ICC, with values comparable with OLR (10,24-26,29,30).

In a recent metanalysis on 6 retrospective studies, including 384 LLR and 2,147 OLR for ICC, Wei et al. reported that patients who underwent LLR had more commonly an R0 resection (81.6% for LLR vs. 73.8% for OLR, P=0.008), however, similarly to other reports, major hepatectomy rate and tumor size were significantly lower for LLR (32).

In conclusion, LLR for ICC is still prevalently reserved for smaller tumor which required a minor hepatectomy, Safety and feasibility of laparoscopic LND is still debated although, accordingly to recent single high volume centers data laparoscopic LND can be performed with similar results compared to OLR, allowing the retrieve of adequate number of lymph node without an increase of procedural complications (29,30,33).

Perioperative and short-term outcomes

Several studies have described the advantages of the LLR for other primary and secondary liver tumors in terms of reduction of intraoperative blood loss, transfusion rate and shorter hospital stay, however data on perioperative morbidity and mortality of LLR for ICC are more limited (34-36).

Ratti et al., showed for LLR of ICC a reduction of overall postoperative morbidity (14.4% in LLR vs. 24% in OLR, P=0.002). In detail, patients who underwent LLR showed lower wound infection rate (1% in LLR vs. 3.8% in OLR group, P=0.05), lower biliary fistula rate (3.8% in LLR vs. 7.7% in OLR, P=0.03), lower rate of postoperative ascites (6.7% in LLR vs. 10.6% in OLR, P=0.04), and lower rate of lymphatic fistula (1.9% LLR vs. 6.7% in OLR, P=0.03) (30).

Regmi et al. in a recent meta-analysis on 8 papers showed no significant differences for the surgical time between LLR and OLR, a lower overall morbidity in LLR group while the rate of major complication rate was comparable between two group. However, OLR group shower higher rate of major hepatectomies and larger tumors (37).

Likewise, Wu et al., in a study on 43 patients who underwent curative LLR (n=18) or OLR (n=25) for ICC, showed equal operative time, postoperative hospital stays, morbidity (including wound infection, bile leakage, liver failure and pneumonia) and mortality within 30 days, with similar rate of major resection between the two group (28).

In conclusion, the LLR for ICC has been demonstrated to be safe and feasible for ICC patients with similar operative time and a tendency to a lower rate of postoperative complications.

Long-term outcomes

Unfortunately, data on long-term outcomes for LLR in ICC are scarce and clinical studies are recent with a limited number of patients.

Single-center studies have showed comparable long-term outcome, in both 3- and 5-year DFS and 3- and 5-year OS between OLR and LLR resection for ICC (10,12,23,24,30).

A detailed description of DFS and OS data of available studies in literature is reported in Table 3.

Conversely from data reported by single-center studies, Regmi et al., in a metanalysis on 8 papers containing 552 LLR and 2320 OLR demonstrated similar 3-, 5-year DFS and 3 years OS but lowed 5-year OS for the LLR group compared to OLR group (HR: 3.01; 95% CI: 2.16 to 4.19; P<0.001). However, in this study, the 5-year OS analysis was conducted evaluating data of only two studies (37).

Despite the results regarding the long-term outcome of LLR are encouraging, the experience and the follow up of LLR are too preliminary to give conclusive indications and further studies are required to confirm the role of LLR for long term outcomes of ICC.

Discussion

In recent years impressive improvements have been made in LLR for malignant liver disease (6-8) and the benefit of minimally invasive surgery without compromising oncological outcome has been demonstrated for primary and secondary liver tumors. Conversely, laparoscopic treatment of ICC is still a matter of debate and data regarding the safety and feasibility of the LLR in these patients are recent and limited to small clinical series.

The limited use of the laparoscopic approach for ICC is related to different reasons. Firstly, ICC is a relative rare disease when compared to other liver tumors. Secondly, ICC has frequently an advanced stage at diagnosis, for these reasons radical surgery often requires major hepatectomies and associated complex surgical procedures (e.g., vascular resections, removal of adjacent organs and lymph node dissection). The complexity and the required technical skills performing these surgical procedures are the main reasons for the limited application of LLR in ICC (13,14).

However, the interest in LLR for ICC increased in recent years with most of the studies published in the last 5 years. Initially LLR was reserved at small and single tumors while recent reports described the safety of LLR in more complex procedures and the feasibility was demonstrated also in large and multiple ICC.

Similarly, to other liver malignances, the available data on LLR for ICC showed the safety of the procedure providing benefits in terms of intraoperative blood loss, functional recovery with similar overall morbidity and mortality (29,30).

The safety and feasibility of laparoscopic LND is still debated with discordant results for the overall rate of LND and the number of retrieved lymph nodes. More recent literature data seem to demonstrate the adequacy and safety of laparoscopic LND although confirming the complexity of this procedure.

The LLR has been related to good oncologic efficacy with R0 resections rate, OS and DFS similar to those reported for OLR (10,23,26,27). However, considering the relatively short follow up of the laparoscopic approach for ICC, data regarding the long-term oncological outcome should be considered with caution and should be confirmed in larger studies.

There are several limitations of this study. First, all the studies included in this review are retrospective studies and most of them are single center study. Moreover, due of the relatively recent introduction of the laparoscopic technique for ICC, and the rarity of this tumor, the long-term results are still limited.

The available results should be considered preliminary. Further large multicentric well balance prospective studies with adequate oncological approach as well as a longer follow-up would be needed to confirm these data. Moreover, there has no randomized clinical trials involving LLR for ICC and this is needed to reduce the possible selection bias and clarify the risks vs. benefits and improve standardize the approach.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (Roberto Santambrogio and Marco Antonio Zappa) for the series “Laparoscopic Hepato-Biliary Surgery” published in Laparoscopic Surgery. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://ls.amegroups.com/article/view/10.21037/ls-22-17/rc

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://ls.amegroups.com/article/view/10.21037/ls-22-17/coif). The series “Laparoscopic Hepato-Biliary Surgery” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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