Laparoscopic Liver Resection for Intrahepatic Cholangiocarcinoma: A Single-Center Experience

Abstract

Background:

Despite recent advances in the field of laparoscopic liver surgery, intrahepatic cholangiocarcinoma (iCC) as an entity has been nearly exempted from the new approaches because of proposed technical difficulties in achieving lymphadenectomy (LAD) and beneficial oncologic outcomes.

Materials and Methods:

Clinical courses of all consecutive patients (n = 159) undergoing liver resection for iCC at the Department of Surgery, Charité—Universitätsmedizin between January 2015 and October 2019 were studied. Ultimately, after applying selection criteria 27 laparoscopic liver resections were compared with 31 open liver resections.

Results:

Preoperative patient characteristics were similar with regard to general health and tumor characteristics. However, patients in the laparoscopic group tended to have more advanced liver fibrosis. When LAD was performed laparoscopically, a median of eight lymph nodes were resected, complying with current AJCC treatment guidelines. Patients undergoing laparoscopic resection showed lower overall morbidity contributing at least in part to a markedly decreased hospital stay.

Conclusions:

Herein, we report on one of the largest series of laparoscopically resected iCC, with a high proportion of major resections. Our data show laparoscopic resection to achieve noninferior outcomes to open resection despite impaired preoperative liver function.

Introduction

In recent years substantial progress has been made in the establishment of different minimally invasive approaches to address various hepatic lesions.^1–3 Indeed, the perceptible trend has been from minor resections of benign lesions to complex surgical oncology. With hepatocellular carcinoma (HCC) and colorectal liver metastasis (CRLM) constituting the most frequent lesions, the focus has shifted toward extending the indication to include more complex resections.^4,5 Various case series and three randomized controlled trials have shown laparoscopic liver resection (LLR) to be a safe procedure, capable of eliciting favorable oncologic outcomes while achieving shorter hospitalization than laparotomy.^6–12 Even patients with previous abdominal surgeries and extensive malignancies in posterosuperior segments can be suitable for laparoscopic resection.^6,13–15

Several landmark impediments not taken into consideration persist that remain classical indications for open liver resection (OLR). As such, experience with laparoscopic biliary reconstruction and radical hilar lymphadenectomy (LAD) is scarce at best with very few high volume centers reporting small case series for the most part.^16–18 Cholangiocarcinomas (CCAs) continue to be operated by laparotomy almost exclusively, as tumor characteristics entail difficulties for surgical resection such as the need for extended hepatectomy and LAD. Previous reports have shown nodal involvement in CCA to be ∼40% as disease spread usually occurs along the lymphatic vessels to the lymph nodes of the hepatoduodenal ligament and the hepatic artery and its upstream supply.^19,20 Although the role of LAD in case of CCA is not clearly defined in EASL guidelines,²¹ most centers have integrated LAD in their routine management of resections in accordance with ESMO guidelines.²² Nodal involvement is a crucial factor, determining outcomes alongside tumor-free resection margins.²³ Laparotomy has been nearly inevitable for respective procedures. Consequently, CCA are poorly represented in studies of LLR.

The aim of this study was to validate the hypothesis that laparoscopy is feasible in patients with intrahepatic cholangiocarcinoma (iCC) and can elicit noninferior outcomes compared with open surgery.

Materials and Methods

Study population

Clinical courses of all consecutive patients from January 2015 to October 2019 who underwent liver resection owing to iCC at the Department of Surgery, Charité—Universitätsmedizin Berlin, Germany were analyzed in this study. Included were all patients undergoing curative-intent resection for iCC independent of tumor size and number of lesions with disease radiologically confined to the liver and local lymph nodes. Exclusion criteria were vascular and biliary reconstruction, trisectionectomy and multivisceral resections. Major hepatectomy was defined as a resection of at least three segments of the liver.²⁴

Preoperative patient evaluation

Preoperative diagnostic imaging was performed using triphasic, contrast-enhanced computed tomography and/or magnetic resonance imaging with liver-specific contrast agents. Subsequently, each case was discussed in a multidisciplinary weekly hepato-pancreato-biliary (HPB) tumor board consisting of hepatologists, medical oncologists, surgeons, radiologists, and radiotherapists to ascertain that surgery was the best treatment strategy.

Surgical approaches

Minimal invasive surgery was performed in the French position (supine position with legs apart). Dependent on tumor size, location, and adjacency to relevant structures, three different approaches were applied: standard multiport laparoscopic liver surgery (MILL), single-incision laparoscopic liver surgery (SILS), hand-assisted laparoscopic liver surgery (HALS), or a hybrid approach, which have been described elsewhere.^25,26 Indication for the specific surgical approach was given at the operating surgeon's discretion.

If preoperative imaging was deemed suspicious for iCC, LAD was performed along the hepatoduodenal ligament to the superior margin of the pancreas, down the common hepatic artery to the celiac trunk. In case of minimal invasive approaches, LAD was conducted either strictly laparoscopically or alternatively in HALS/hybrid technique.

Both for open and laparoscopic liver resection, routine intraoperative ultrasound was performed repeatedly to ensure sufficient tumor-free resection margins and rule out further intrahepatic lesions. Dissection of the parenchyma was performed in LLR using either energy devices (Thunderbeat^®, Olympus or Harmonic Ace^®; Ethicon, Somerville, NJ), CUSA^® (Integra LifeSciences, Plainsboro Township, NJ) or Waterjet (ERBEJET^®; manufacturer: ERBE Tübingen, Germany), and/or vascular staplers (ECHELON FLEX™ ENDOPATH^®; Ethicon) and in OLR using CUSA (Integra LifeSciences). Inflow control was performed intermittently to decrease intraoperative hemorrhage, as needed.

Postoperative follow-up

Depending on preoperative condition and intraoperative course, patients were transferred to a specialized surgical intensive care unit or directly to a general surgical ward after surgery. Patients were closely monitored for postoperative complications like bleeding, intraabdominal and wound infection, pneumonia, and liver failure. Abdominal drains were removed swiftly if secretion was inconspicuous. Daily routine biochemistry laboratory test was performed to evaluate liver function and inflammatory status.

Staging was performed applying the AJCC criteria.²⁷ Each case was presented postoperatively in the multidisciplinary HPB tumor board to obtain recommendations for the further course in accordance with the guidelines for diagnosis and treatment of CCA.²¹

Postoperative morbidity and mortality were defined as any complication or death occurring within 90 days after the procedure. Postoperative complications were graded in accordance with the Clavien–Dindo classification system.²⁸ Major complications were defined as ≥grade IIIa.

Histological analysis

Resected specimens were postoperatively examined by an expert pathologist to determine diagnosis and tumor extend and resection margins. R0 resections were defined as microscopically free surgical margins. The surrounding liver tissue was further examined with regard to the presence of liver cirrhosis or fibrosis. Both cirrhosis and fibrosis were defined through the Desmet scoring system.²⁹

Statistical analysis

Analysis was performed using SPSS V22.0^® (IBM, Armonk, NY). Categorical variables were compared using χ² test, whereas continuous variables were compared applying the Mann–Whitney U test. A two-sided P < .05 was considered to indicate statistical significance. Values are expressed as medians with range unless otherwise stated.

Results

Between January 2015 and October 2019 a total of 159 liver resections for iCC were performed at our center, 37 of which underwent LLR and 122 OLR. A total of 101 patients met at least one exclusion criteria and were eliminated from further analysis. The remaining 58 patients undergoing either open (n = 31) or laparoscopic resection (n = 27) for iCC were included in the study.

Patients baseline characteristics and operative course

Patient characteristics are summarized in Table 1. No significant differences were observed with respect to preoperative characteristics such as age sex, BMI, and American Society of Anesthesiologists (ASA) score. Patients in the laparoscopic group displayed further progression of liver disease as advanced fibrosis was significantly more prevalent in this group (OLR: >grade II: 4%, LLR: 38%, P = .026). A summary of the operative course and the distinct tumor characteristics are given in Table 2. No significant difference was noted with regard to tumor diameter and resection extent between the two groups. Likewise, operative time was comparable as well.

Table 1.

Patient Characteristics

	Open group (n = 31)	LAP group (n = 27)	P
Age	63 (33–82)	69 (44–83)	.271
Male sex	18 (58%)	13 (48%)	.598
BMI (mean)	24.6 (19–36.2)	24.6 (17.7–31)	.674
ASA score
1	1 (3%)	0 (0%)	.315
2	21 (68%)	15 (56%)
3	8 (26%)	12 (44%)
4	1 (3%)	0 (0%)
Alcohol	3 (10%)	4 (15%)	.694
Smoking	8 (26%)	7 (26%)	1
Diabetes	8 (26%)	5 (19%)	.753
Previous abdominal surgery	15 (45%)	11 (41%)	.795
Liver fibrosis
0	14 (52%)	7 (27%)	.026
1	10 (37%)	6 (23%)
2	2 (7%)	3 (12%)
3	0 (0%)	4 (15%)
4	1 (4%)	6 (23%)

P values in bold indicate statistical significance with a two-sided P < .05.

ASA, American Society of Anesthesiologists; BMI, body mass index.

Table 2.

Intraoperative Course and Tumor Characteristics

	Open group (n = 31)	LAP group (n = 27)	P
Tumor diameter (median in mm)	65 (13–153)	60 (14–132)	.404
(extended) Hemihepatectomy	24 (78%)	19 (70%)	.564
Bisegmentectomy	5 (16%)	5 (19%)	1
Monosegmentectomy	1 (3%)	1 (4%)	1
Subsegmentectomy	1 (3%)	2 (7%)	.593
Operative time (minutes)	282 (112–947)	314 (125–439)	.236
Lymphadenectomy	29 (94%)	23 (85%)	.402
Conversion		2 (7%)
Histological grade
G1	0 (0%)	0 (0%)	.549
G2	21 (78%)	17 (74%)
G3	5 (19%)	6 (26%)
G4	1 (4%)	0 (0%)
T stage
1	12 (39%)	10 (40%)	.917
2	11 (36%)	9 (36%)
3	4 (13%)	4 (16%)
4	3 (10%)	2 (8%)
Nodal status
Positive	13 (54%)	6 (32%)	.217
Negative	11 (46%)	13 (68%)
L
0	19 (66%)	16 (67%)	1
1	10 (34%)	8 (33%)
V
0	16 (67%)	24 (86%)	.186
1	8 (33%)	4 (14%)
Harvested lymph nodes	8 (1–40)	8 (1–21)	.440
R0 status	23 (74%)	24 (89%)	.193
MILL		18 (67%)
HALS		8 (30%)
SILS		1 (4%)

HALS, hand-assisted laparoscopic liver surgery; MILL, multiport laparoscopic liver surgery; SILS, single-incision laparoscopic liver surgery.

Of note, LAD was performed in 85% of patients in the LLR group and 94% of patients in the OLR group. In 2 patients in the OLR group and 4 patients in the LLR group, LAD was not performed as the lesions were suspected to be HCC, in which case LAD is not recommended. However, when the tumor was deemed suspicious for iCC and LAD was performed, the number of resected lymph nodes was similar between the two groups (OLR: median 8 versus LLR 8; P = .440).

Postoperative pathology workup revealed no significant differences concerning local tumor extent and grading (Table 2). R0 resection was achieved in 89% of patients undergoing LLR and 74% of patients undergoing OLR. Final diagnosis was consistent with iCC in 25 of 27 patients in the LLR group and 30 of 31 patients in the OLR group; the remaining tumors were diagnosed as mixed HCC/iCC.

Postoperative course

Although ICU stay was similar between the two groups, hospital stay was markedly decreased after laparoscopic surgery (OLR: 12 days versus LLR 10 days, P = .028) (Table 3).

Table 3.

Postoperative Course

	Open group (n = 31)	LAP group (n = 27)	P
ICU stay (days)	1 (0–6)	1 (0–81)	.326
Hospital stay (days)	12 (5–33)	10 (3–94)	.028
Complications
Hematoma	2	0
Pneumonia	0	1
Renal failure	1	0
Urinary tract infection	0	1
Wound infection	5	3
Pleural effusion	2	0
Ascites	0	1
Cholangitis	3	0
Bile leakage	1	2
Intraabdominal abscess	2	0
Postoperative delirium	1	0
Acute coronary syndrome	1	1
Ileus	1	0
Postoperative liver failure
All morbidity	18 (58%)	8 (30%)	.037
Morbidity >grade III	10 (32%)	5 (19%)	.368
Mortality	0 (0%)	2 (7%)	.111

P values in bold indicate statistical significance with a two-sided P < .05.

In analyzing the occurred complications between the two groups, we noted a significant decrease with regard to the overall complication rates hinting at a favorable outcome for laparoscopy (OLR: 58% versus LLR: 30%, P = .037). When only major complications were taken into consideration, however, no significant differences were observed (OLR: 32% versus LLR 19%, P = .368). Two patients in the laparoscopic group died (Clavien–Dindo grade V): One because of postoperative acute coronary syndrome, leading to mesenterial ischemia in the setting of limited inflow owing to massive atherosclerosis of the superior mesenteric artery. The other patient succumbed to posthepatectomy liver failure. A detailed description of the complications is given in Table 3.

Discussion

We report in this study our experience with laparoscopic resections for patients with iCC and compare patients and their respective courses to those of patients who underwent laparotomy. Of note, few reports entail a rate of major resections that measure up to the one we report in this cohort.^17,30

In our cohort, patients undergoing minimal invasive liver surgery feature similar preoperative characteristics compared with patients undergoing laparotomy. This is true of general health, as accounted for by the similar ASA score, and tumor characteristics. Indeed, tumor diameter was not significantly different between the two groups. In keeping with this, neither tumor extent nor grading were markedly different. Ultimately, patients in the two groups underwent a similar distribution of procedures with no marked increase of major resections in the open group, which has been a pivotal point of criticism toward previous studies.

Of interest, patients in the laparoscopy group had a noteworthy impairment in liver function, as advanced liver fibrosis was significantly more prevalent in the laparoscopy group. This did however not translate to higher morbidity in the laparoscopy group. To the contrary, we observed fewer complications in the laparoscopy group with regard to overall morbidity. When only major complications as accounted by a Clavien–Dindo grade of >II were taken into consideration, rates between the two groups were similar. The reported morbidity numbers are in line with those from previous reports evaluating laparoscopy versus open resection for different entities where more data are available.^31,32

For patients with iCC, minimal invasive surgery is able to elicit shorter hospitalization in our cohort, likely conveyed through the well-defined advantages of reducing the operative trauma and the resulting reduced postoperative pain and rapid functional recovery. In contrast to other studies, we can show in our cohort that this can be achieved without excessively prolonging operative times as no noteworthy difference between the two groups is shown.

Initial reports of laparoscopic liver resection were met with wary, as the perceived limited maneuverability were thought to jeopardize intraoperative safety and the oncologic outcome. In our cohort, similar rates of R0 resections between the two groups were achieved. The values in Table 2 are similar to those reported by several large multicenter analysis.^33,34

Recently, a report was published that focused exclusively on laparoscopic LAD independent of whether the indication was gall bladder cancer or iCC.³⁵ The reported R0 resection margins of >95% for both laparoscopic resections and open resections are numbers that are unheard of in this field. Likewise, they report remarkable complication rates of <5% Clavien–Dindo ≥grade III. We cannot find an explanation for the discrepancy besides selection of patients as the proportion of minor procedures markedly outweighed that of major procedures. Of note, our results are in line with other reports on this subject both for laparoscopy¹⁷ and laparotomy.^36,37

LAD is incorporated into our routine management of iCC. However, in a total of 6 patients in the study LAD was not performed, as preoperative imaging was deemed suspicious for HCC, where LAD is not recommended. After pathology workup revealed the diagnosis of iCC, the respective cases were discussed in an interdisciplinary HPB tumor board where consensus was obtained against two-stage LAD. In contrast to a recently published report,³⁸ our study shows that radical LAD is feasible in experienced hands. Of note, in patients in the LLR group undergoing LAD, a median of 8 lymph nodes was retrieved, complying with the recently published AJCC staging manual, which requires the resection of at least six lymph nodes. Because this has been described as the major impediment toward minimizing the operative trauma for patients with iCC, we believe patients should be increasingly considered for laparoscopic resections. In our cohort, patients in the laparoscopic group underwent MILL, SILS, or HALS. Although we most frequently apply MILL to treat any type of lesions in general and iCC specifically, it comes with the trade-off between superior maneuverability and more limited tactile feedback. Conversely, HALS provides the operating surgeon generally with superior tactile ability and a better understanding of tissue properties, especially in the learning curve. In case of severe intraoperative hemorrhage, both HALS and SILS also provide the advantage that the technique can be readily converted to a hybrid approach to relieve the pneumoperitoneum and perform manual compression. These features can further be leveraged in case of iCC where LAD can be performed through a hybrid approach if need be. In case a resection is started as an MILL and conversion is required, it is worth considering to convert to HALS if the lesion is in a beneficial location to do so.

Limitations of this study are certainly its retrospective design and the lack of oncologic long-term data. As too many of the resections were performed in 2019, we are not able yet to provide long-term survival data. Moreover, despite being one of the largest studies with a high percentage of major resections, the sample size is still relatively small and the decision whether surgery was performed open or laparoscopically was given at the operating surgeons' discretion and might therefore entail a selection bias. Of note, 101 patients have been excluded owing to the need for vascular/biliary reconstruction, trisectionectomy, and multivisceral resections/other simultaneous procedures, respectively, which clearly demonstrates that a considerably high proportion of iCC patients remain good candidates for open surgery.

Footnotes

Disclosure Statement

Philipp K Haber, Simon Wabitsch, Anika Kästner, Andreas Andreou and Felix Krenzien have no conflicts of interest or financial ties to disclose. W. Schöning reports personal fees from Merck, personal fees from Bayer, other from Ethicon, outside the submitted work. M. Schmelzle reports personal fees from Merck, personal fees from Bayer, personal fees and other from ERBE, other from Ethicon, other from Takeda, other from Olympus, other from Medtronic, other from Intuitive, outside the submitted work. J. Pratschke reports personal fees from Verb Surgical, other from Medtronic, other from Intuitive, other from Merck, outside the submitted work.

Funding Information

No funding was received for this article.

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