A snapshot on current approaches to lymphadenectomy in liver resection for intrahepatic cholangiocarcinoma: results from an international survey

This study was performed and reported according to the Checklist for Reporting Results of Internet E-Surveys (CHERRIES) [16]. During February 2023, a closed-survey (i.e. only accessible through invitation) was distributed via email to the members of the International Hepato-Pancreato-Biliary Association (IHPBA) and the members of Associazione Chirurgia Epato-bilio-Pancreatica (AICEP, Italian chapter of the IHPBA). The survey was composed of 29 questions on demographics, annual volume of surgeries for ICC, preoperative evaluation of nodal status, definition of adequate lymphadenectomy, and perioperative management of ICC (Appendix 1). The invitation email provided participants with details regarding the survey’s subject, the research team involved, and its objectives. Additionally, it outlined the estimated duration (approximately 5 min). Participants received no reminders. The survey was closed end of June 2023. The total number of invited participants, the number of participants who opened the email and the response rates were calculated. IP addresses or cookies were used to prevent multiple responses by the same individual and were deleted after the survey was closed. The survey was performed using REDCap electronic data capture tools hosted at the Institutional server of the IRCCS Istituto Nazionale dei Tumori (Milan, Italy) [17], and tested for usability and technical functionality. All submission were nominal. Submissions could be modified until the end of the survey collection period. Institutional Review Board approval was not requested since no patients were involved and informed consent was implied when participants completed the survey.

The dataset was manually reviewed for entry errors. Incomplete submissions were included in the analysis if more than 50% of the survey had been completed and truncated at the last completed subsection.

Categorical variables were expressed as number and percentage, while numerical variables as median and interquartile range (IQR). We performed the following subgroup analyses: (1) East versus West; (2) surgeons from high volume (≥ 10 liver resections for ICC per year) vs low volume (< 10 liver resection for ICC per year) centers; (3) perceived importance of pre-nodal staging (very important/mandatory vs important/slightly important/not important at all). Categorical variables were compared using Fisher’s exact test, while numerical variables with Student’s t test. All analyses were two-sided. All analyses were performed in IBM SPSS Statistics for Microsoft Windows 24.0th Edition (IBM Corp., Armonk, NY, USA).

The survey was sent to 3138 members, and the email was opened by 2087 members. The participants included in the analysis were 234, 11.2% of all surgeons who were administered the survey. The number of complete surveys was 208 (89%), while 26 (11%) participants submitted at least 50% of the survey. Table 1 reports the demographic characteristics of the participants, the volume of their center and the center’s routine assessment of specific mutations for ICC. Participants from high volume centers (> 10 liver resections for ICC per year) were 47%. Supplementary Fig. 1 shows the country of origin of the participants: the majority came from European countries (133, 57%), followed by the United States (36, 15%). Patients from Eastern countries were 27 (11%).

Preoperative evaluation of nodal status was deemed mandatory by 60 (26%), very important by 92 (39%), important by 64 (27%), slightly important by 16 (7%) and not important at all by 2 (1%) participants. Figure 1a shows the diagnostic assessment modalities which participants consider mandatory for the preoperative assessment of nodal status. More than 30% of participants consider contrast-enhanced CT scan the only mandatory imaging modality required for preoperative assessment, while 35 (15%) do not consider CT scan mandatory at all. Figure 1b shows the purely radiological criteria which the participants consider suspicious for nodal metastases. Other radiological characteristics were nodal morphology (regardless of size), necrosis, FDG-PET avidity, location along the nodal drainage of the liver, loss of hilar fat. In case of radiological suspicion 100 (43%) of participants would perform further investigations: 71 (30%) FDG-PET, 55 (23.5%) endoscopic ultrasound (EUS) with biopsy, 4 (2%) EUS alone. Figure 1c shows the grade of suspicion of nodal metastases according to different radiologic findings. Over 90% of participants deemed a positive biopsy from EUS and presence of MRI/CT suspicion with concomitant FDG-PET uptake as highly suspicious for nodal metastases.

Supplementary Fig. 2a shows the different definitions of adequate lymphadenectomy. The majority of participants (76, 33%) considered retrieval of lymph-nodes of the hepatoduodenal ligament to be adequate, while 65 (28%) answered retrieval at specific nodal stations and 64 (28%) retrieval of more than 5 lymph nodes. Only ten (4%) considered sampling of suspicious lymph nodes as adequate. Supplementary Fig. 2b shows the nodal stations that participants retrieve when performing a nodal sampling, with the most common being the stations 12a, 12b, 12p, 8a, 8p, and 5.

The final section of the survey was dedicated to questions regarding perioperative management, including indications to neoadjuvant chemotherapy and lymphadenectomy.

Conditions that warrant neoadjuvant chemotherapy according to the participants (n = 211) are reported in Fig. 2a. The only condition on which the vast majority of participants (78%) agreed was borderline resectable disease, followed by bilobar disease (52%), nodal positivity at preoperative investigations (51%), and portal or hepatic vein invasion (48%). For the 31% who answered “number of nodules”, the median number of nodules after which they would consider neoadjuvant chemotherapy was 2 (IQR 2–3). For the 17% who answered “high CA19-9”, the median CA19-9 level after which they would consider neoadjuvant chemotherapy was 400 (IQR 200–500). For the 10% who answered “size of nodules”, the median size of nodules after which they would consider neoadjuvant chemotherapy was 5 cm (IQR 5–7).

Figure 2b illustrates preoperative variables that influence decision-making regarding lymphadenectomy. More than a third of participants (n = 209) considered presence of severe comorbidites (48%), presence of cirrhosis/chronic liver disease (38%) and multifocal disease/satellitosis (32%) as preoperative variables. For the 14% who answered “patient’s age”, the median age that would influence their decision-making regarding lymphadenectomy was 80 (IQR 75–80). For the 11% who answered “size of nodules”, the median size that would influence their decision-making regarding lymphadenectomy was 5 cm (IQR 3–5). For the 9% who answered “Ca19-9”, the median Ca19-9 level that would influence their decision-making regarding lymphadenectomy was 200 (IQR 100–400).

The majority of participants (81%) stated that they would somehow modify their perioperative management in case of either positive or highly suspicious preoperative investigations for nodal metastases (Fig. 2c). Half of the participants would indicate neoadjuvant treatment, with surgery in case of response, while 3% considered surgery not indicated in this case. Of the 9% who answered “other”, the majority answered that their decision-making would depend on the location of the positive/suspicious nodes.

Figure 2d illustrates which conditions would influence the decision to adopt a minimally invasive approach. Technical feasibility was the most reported factor (71%), while 21.5% of participants reported they always use an open approach.

Figure 2e shows the difference intraoperative strategies regarding lymphadenectomy according to preoperative investigations. The percentage of participants that always perform adequate lymphadenectomy was 64% in case of clinically node positive (cN +) and 62% in clinically node negative (cN0) patients, while 6% reported they perform no lymphadenectomy in case of cN0.

The participants’ opinions on the role of adequate lymphadenectomy in case of no preoperative evidence of nodal metastases are shown in Fig. 2f. The majority of participants (88%) reported adequate staging as a role of adequate lymphadenectomy: this was considered the only role in 41% cases, in conjunction with survival benefit in 30% cases, in conjunction with eligibility to clinical trials in 7% cases, and in conjunction with both survival benefit and eligibility to clinical trials in 10% cases. In Table 2, we report the extent of adequate lymphadenectomy stratified according to the perceived role of lymphadenectomy.

Twenty-seven surgeons from Eastern countries were compared to 198 surgeons from Western countries. The two groups had similar percentages of surgeons from high volume centers. Regarding preoperative staging, the Eastern group more frequently reported that FDG-PET was mandatory (48% vs 31%, p = 0.08) and would perform further investigations in case of radiological suspicion of N + (63% vs 40%, p = 0.037). The Eastern group more frequently defined adequate lymphadenectomy as sampling of suspicious nodes (19% vs 3%) and retrieval of LNs of the hepatoduodenal ligaments (42% vs 32%), than as > 5 LNs (19% vs 30%) or from more stations (19% vs 28%), p = 0.002. The Western group was more likely to include in AD-LND station 5 (58% vs 35%, p = 0.034), while the Eastern group station 7 (35% vs 16%, p = 0.030) and station 13 (54% vs 35%, p = 0.082). More participants in the Eastern group reported that LND should be performed according to tumor location (77% vs 48%, p = 0.007). Regarding perioperative treatment, the Western group more frequently would perform neoadjuvant therapy in case of bilobar disease (54% vs 28%, p = 0.018) and high CA19-9 (18% vs 4%, p = 0.087). More participants in the Eastern group reported that presence of cirrhosis/chronic liver disease influences their decision to perform a lymphadenectomy (40% vs 10%, p = 0.0004) and that their decision to perform surgery with a minimally invasive approach is influenced by the suspicion of nodal metastases (32% vs 13%, p = 0.032) and tumor stage (32% vs 16%, p = 0.093).

One-hundred and ten (47%) participants from high volume centers (HV group) were compared with 124 (53%) surgeons from low-volume centers (LV group). Regarding preoperative staging, the HV group more frequently reported that ceCT was mandatory (90% vs 81%, p = 0.06), while EUS + biopsy was more frequently mandatory for the LV group (30% vs 17%, p = 0.031). Regarding perioperative treatment, the HV group more frequently would perform neoadjuvant therapy in case of multifocal ICC (37% vs 26%, p = 0.076), according to size of the largest nodule (15% vs 5.5%, p = 0.037) and in case of bilobar disease (60% vs 44%, p = 0.027). More participants in the LV group thought that neoadjuvant chemotherapy is never warranted (9% vs 1%, p = 0.01). More participants in the HV group reported that presence of cirrhosis/chronic liver disease influences their decision to perform a lymphadenectomy (47% vs 30%, p = 0.015) and that their decision to perform surgery with a minimally invasive approach is influenced by technical feasibility (80% vs 63%, p = 0.009). More surgeons in the LV group reported they always adopt a minimally-invasive approach (28% vs 15%, p = 0.019).

Surgeons who gave high importance to nodal staging (HI group, n = 152, 65%) were compared with surgeons who gave intermediate/low important to nodal staging (ILI group, n = 82, 35%). Regarding preoperative staging, the HI group more frequently reported that ceMRI (49% vs 30%, p = 0.008) and FDG-PET (39% vs 22%, p = 0.009), and EUS + biopsy (28% vs 16%, p = 0.032) were mandatory, and would more frequently perform further investigations in case of radiological suspicion of N + (50% vs 29%, p = 0.002). The HI group was more likely to include station 13 (43% vs 28%, p = 0.029) in adequate LND. Regarding perioperative treatment, the HI group more frequently would perform neoadjuvant therapy in case of nodal positivity at preoperative investigations (62% vs 31%, p < 0.001), portal or hepatic vein invasion (52.5% vs 39%, p = 0.081). More participants in the ILI group thought that neoadjuvant chemotherapy is never warranted (10% vs 3%, p = 0.048). More participants in the HI group reported that patient’s age influences their decision to perform a lymphadenectomy (19% vs 11%, p = 0.097) and that they would recommend neoadjuvant treatment followed by surgery in case of response if preoperative investigations are highly suspicious for nodal disease (72% vs 28%, p = 0.003). Participants in the HI group more frequently reported that their decision to perform surgery with a minimally invasive approach is influenced by the suspicion of nodal metastases (19% vs 8%, p = 0.044). In case of preoperative investigations not suspicious for N +, more surgeons in the HI group reported they always perform adequate lymphadenectomy (76% vs 61%, p = 0.053).