Should lymphadenectomy be recommended in radical surgery of intrahepatic cholangiocarcinoma patients? A retrospective study

doi:10.21203/rs.3.rs-4817115/v1

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Research Article

Should lymphadenectomy be recommended in radical surgery of intrahepatic cholangiocarcinoma patients? A retrospective study

https://doi.org/10.21203/rs.3.rs-4817115/v1

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Purpose

Intrahepatic cholangiocarcinoma (ICC) is an extremely deadly cancer with high recurrence incidence, particularly in patients with lymph node metastasis (LNM). The necessity of lymphadenectomy including lymph node biology (LNB) and dissection (LND) during ICC radical surgery remains debate.

Methods

We retrospectively analyzed the patients diagnosed with ICC and underwent radical surgery at the Cancer Hospital of the Chinese Academy of Medical Sciences from 2012 to 2023.

Results

A total of 308 ICC patients were involved in this study. pLNM + group had poorer OS (P < 0.0001) and poorer DFS (P < 0.0001) compared with pLNM- group. Compared to the LN- group, LN + group exhibited worse OS (P = 0.038) and worse DFS (P = 0.003). After PSM and IPTW, compared with LN- group, LNB exhibited longer operation time (all P < 0.05) and longer hospitalization days (all P < 0.05) with no significant differences in complications, DFS, and OS. Compared with LN- group, LND group had no better DFS and OS, only more complications (all P < 0.05), longer operation time (all P < 0.001), higher risk of bleeding (all P < 0.05), transfusion (IPTW: P = 0.027) and longer hospitalization days (IPTW: P = 0.0006). Compared with LNB group, LND had longer operation time (P = 0.0227), higher risk of bleeding (P = 0.032) and transfusion (P = 0.019), and more postoperative complications (P = 0.02), with no difference in DFS and OS.

Conclusion

LND only achieves the effect of LNB while negatively affects postoperative recovery without survival benefit for ICC patients. LND is not recommended while standardizing LNB is recommended as a routine operation during the radical surgery of ICC patients.

intrahepatic cholangiocarcinoma

inverse probability of treatment weighted analysis

hepatology

lymph node biology

lymph node dissection

propensity score matching analysis

Intrahepatic cholangiocarcinoma (ICC) is one of the most fatal malignant tumors around the world, accounting for 5–30% of all primary liver cancers.(A. J. Lee & Chun, 2018) The risks of ICC include infections (eg., HBV, HCV and Epstein-Barr virus), bad lifestyle (eg., alcohol consumption and smoking), metabolic and genetic risk factors.(Massarweh & El-Serag, 2017) The onset of ICC is insidious. Many ICC patients have no special symptoms in the early stage and enter the advanced stage once discovered.(P. Chen et al., 2023) Despite the development of a series of new treatment strategies and progress over the past few decades, the prognosis of ICC remains dismal.

Liver resection (LR) or radical surgery is the mainstay of treatment, but only a minority of patients (15%) are candidates for surgery.(Roy et al., 2021) The tumor recurrence rate in LR is high (50–70%),(Rhee et al., 2023) the current 5-year overall survival (OS) rate after LR is only 25%-40%.(Mazzaferro, Gorgen, Roayaie, Droz Dit Busset, & Sapisochin, 2020) How to increase the survival rate and reduce the recurrence rate of LR needs further study. LNM is strongly associated with high recurrent rate and poor prognosis in ICC.(S. H. Kim, Han, Choi, Choi, & Kim, 2022b) Lymphadenectomy is important method for the precise pathological diagnosis of LNM during the LR in ICC including lymph node biology (LNB) and lymph node dissection (LND).(Yoh et al., 2018) However, the benefits and indications for lymphadenectomy remain unclear. Whether lymphadenectomy can be used as a routine intraoperative resection during LR remains a source of debate.(Zhang et al., 2018) Whether lymphadenectomy has the potential to reduce the risk of locoregional recurrence, and the uncertainty about the survival benefit and postoperative complications have been the focus of controversy.(R. Zhou et al., 2019) In this article, we retrospectively analyzed the patients who were diagnosed with ICC and underwent surgical treatment at the Cancer Hospital of the Chinese Academy of Medical Sciences from 2012 to 2023. The purpose of this article is to explore whether ICC patients benefit from lymphadenectomy and whether lymphadenectomy should be recommended in operable ICC patients.

2.1 Patients and follow-up

This retrospective study collected and analyzed the original clinical data of patients diagnosed with ICC and underwent radical surgery at the Cancer Hospital of the Chinese Academy of Medical Sciences from January 2012 to January 2023. This study was approved by the Ethics Committee of National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (Approval number: 21/315–2986). All research was conducted in accordance with both the Declarations of Helsinki and Istanbul. Patients meet the following conditions are included in the criteria: (1) who were diagnosed with ICC by postoperative pathological diagnosis; (2) who undergoing radical liver tumor resection; (3) who were able to receive regular follow-up visits. Patients meet the following conditions were excluded from this study: (1) who were mixed with hepatocellular carcinoma or other malignant tumors, (2) who were with distant metastasis, (3) who were dead in one month, (4) who were lost to follow-up.

Our last follow-up for all patients were in February 2024, all patients with the minimum follow-up time of 1 year. The definition of the follow-up was: patients were followed up every 3 months in the first 2 years after surgery, and every 6 months thereafter. For cases that cannot return to the hospital for reexamination, follow-up was conducted via phone or WeChat. Patients who were follow-up lost were excluded from this study. The examination items included blood routine, biochemistry, tumor markers (carcinoembryonic antigen (CEA), Alpha fetoprotein (AFP), and Carbohydrate antigen 19 − 9 (CA199)), CT or enhanced MRI examination. If recurrence was suspected, enhanced CT and MRI, puncture biopsy and further treatment were performed.

2.2 Grouping and definition

Lymphadenectomy containing LNB and LND was defined as the LNs were resected during the operation. Therefore, ICC patients without under lymphadenectomy was involved in LN- group. LN + group was defined as the patients whose lymphadenectomy was performed during the operation, the number of resected LNs were collected. LN + group was divided into pLNM + group and pLNM- group according to the postoperative pathology: whether LNM was confirmed in the resected LNs. LN + group was also divided into the LNB group and LND group according to the definition of LNB and LND: (1) LNB was defined as the biopsy of suspiciously swollen LNs during surgery, the number of LNs resected during surgery is less than 6 without systematic dissection of LNs. (2) LND was defined the systematic dissection of LNs, scope to at least the second station and the resection of at least 6 or more LNs,(Lluís et al., 2023) including hepatoduodenal ligament LN, parahepatic artery LN, and LNs based on the location of the primary ICC tumor.(Ke et al., 2021; Lluís et al., 2023)

2.3 Data collections and definitions

We collected the following data of indicators from the medical record writing system: (1) Sex. (2) Age was defined as the initial diagnostic age, patients over 65 years old are defined as elderly patients. (3) Body mass index (BMI): whose BMI over 25 were defined as overweight. (4) Hepatobiliary history, such as gallbladder surgery, percutaneous transhepatic cholangial drainage (PTCD), and interventional surgery for hemangioma. (3) Neoadjuvant treatment, including neoadjuvant chemoradiotherapy, targeted or immunotherapy, interventional or other therapy. (4) HBV infection, determined by the five quantitative hepatitis B tests. (5) Preoperative patient serum tumor marker: CEA, AFP, CA199 levels. Since the data of the “CEA”, “CA199”, and “AFP” were extremely different (range between 1 and 100000), we took the Log2 logarithm of these three to reduce the huge differences between patients to facilitate subsequent PSM and IPTW analysis. (6) Enlarged LNs: preoperative imaging CT or MRI diagnosis that the diameter of LN minor axis around the liver is over 10 mm with or without central necrosis or inhomogeneous enhancement.(Ke et al., 2021)

Besides, we collect the following data through the surgical system: (1) Lymphadenectomy, as the definition in above in section 2.2 Grouping and definition. (2) Operation time, refers to the time between the first incision and the final incision. (3) Bleeding, refers to the amount of blood loss during the operation, estimated by the surgeon referring to the amount of suction. (4) Transfusion, refers to the amount of blood transfused during surgery, which can be precisely calculated in the transfusion record.

In addition, we reviewed the pathology reports following the standard postoperative pathology procedures: (1) LNM, refers to whether tumor cell infiltration was found in the resected LNs. (2) T stage, according to the latest AJCC surgical pathological staging.(Meng, Pan, Hong, Chen, & Chen, 2017) (3) Microvascular invasion, refers to the invasion of the portal vein, portal artery, hepatic vein, or capsule blood vessels of liver tissue adjacent to the tumor margin.(N. R. Kim et al., 2024) (4) Liver capsule invasion, refers to the tumor tissue cells were detected in Glisson capsule. (5) Differentiation, refers to the degree of differentiation of tumor tissue, divided into highly differentiated, moderately differentiated, and poorly differentiated groups. (6) Lymphocyte invasion: refers to the abnormal proliferation and aggregation of lymphocytes in tissues and organs, forming invasive lesions. (7) Tumor number, more than 3 tumors are called multiple tumors. (8) Tumor size, we took a cut-off of 4 cm, and masses larger than 4 cm were called large tumors.

Meanwhile, we collected the postoperative and outcome data: (1) Postoperative hospitalization day. (2) Total postoperative hospitalization day. (3) Postoperative complication, refers to the complications during hospitalization after surgery, including biliary fistula, infection, liver failure, liver hemorrhage, renal failure, hepatic encephalopathy, atelectasis. (4) Post treatment, including the chemotherapy, radiotherapy, transcatheter arterial chemoembolization treatment (TACE), targeted therapy, and immunotherapy. (5) Recurrence, refers to either a new lesion with ICC radiological features, or with distant metastasis radiological features. The site and time of recurrence or metastasis were collected. Disease-free survival (DFS) was defined as the duration from the date of surgery to tumor recurrence or metastasis. (6) Survival: the final outcome of the patients, refers to whether the patients were currently in a state of survival or death to the last follow-up time. OS was calculated from the date of surgery to the date of death or the last follow-up.

2.4 Statistical analysis

We used R software (version: R4.4.0, https://www.R- proje ct. org/, Vienna, Austria), and IBM SPSS Statistics software (version: IBM SPSS Statistics 26, https://www.ibm.com/support/pages/downloading-ibm-spss-statistics-26) for data analysis and graphing. We used the "survival" and "survminer" packages to perform univariate and multivariate COX analysis and drawing KM curves. We used SPSS to perform 1:1 paired PSM with the matching tolerance set to 0.02. Univariate cox analysis was performed to screen out variable factors with P values less than 0.05, and then these factors were included in multivariate cox analysis. Continuous variables are reported as mean ± SD, or median and IQR, depending on whether they conform to normal distribution. For continuous variables that conform to the normal distribution, we used the independent sample t test. For continuous variables that do not conform to the normal distribution, The Kruskal-Wallis or Mann-Whitney U test were used. The chi-square or Fisher's exact test were used to test categorical variables, and the ANOVA test were used to test the three groups of continuous variables. Statistical significance was defined as a two-sided P value < 0.05.

3.1 Clinical characteristics of ICC patients included in the study

The flow chat of this study was described in Figure 1. 370 patients who were diagnosed ICC and under radical surgery, and we excluded the following total 62 patients: 31 patients who had HCC (mixed carcinoma), 4 patients who were death within 1 month, 11 patients who had distant metastasis, and 16 patients who were follow-up lost. Finally, a total of 308 patients were included (Table 1). Our loss to follow-up rate was controlled within 5%. Among them, 225 (73.1%) patients underwent lymphadenectomy, of which 110 patients underwent LND and 115 underwent LNB, and postoperative pathology proved that 78 patients had LNM. 52 (16.9%) patients experienced postoperative complications. The risk of postoperative complications was relatively high, mainly concentrated in biliary fistula (38.5%), infection (42.3%), liver failure (23.1%), liver hemorrhage (9.6%), and others (renal failure, hepatic encephalopathy, atelectasis, etc.,19.2%). In addition, 133 (43.1%) patients received adjuvant treatment after surgery, mainly chemotherapy (63.2%), radiotherapy (24.6%), and TACE treatment (9.8%). 200 patients experienced postoperative recurrence, the ICC tumor recurrence rate reached 64.9%. The 1-year DFS rate was 52.9%, the 3-year DFS rate was 20.5%, and the 5-year DFS rate was 13.6%. The main site of recurrence were primary tumors site and liver metastasis (72.5%), retroperitoneal metastasis (13%), lung metastasis (7.5%), bone metastasis (3.5%). The survival rate is extremely poor, with 1-year survival rate of 75.3%, 3-year survival rate of 34.7%, and 5-year survival rate of 22.4%.

3.2 Patients underwent lymphadenectomy had worse postoperative outcomes and poorer prognosis

According to the group definition, 83 patients were in the LN- group, 110 patients were in the LNB group, and 115 patients were in the LND group. The comparison of the baseline of the three groups was shown in Table 1. The comparison of the baseline of the LN- and LN+ groups was shown in Supplementary Table 1. Patients with HBV rate (LN- vs. LN+: 61.45% vs. 48.0%, χ²=4.389, P=0.036) in the LN+ group were significantly lower compared with the LN- group. LN+ group had a higher T stage (χ²=16.86, P=0.0008) and more lymphocyte infiltration (χ²=7.078, P=0.008), which were associated with worse prognosis. The operation time of LN+ group was significantly longer than that of LN- group (259.406 ± 92.950min vs. 220.711 ± 90.423min, P<0.0001), the difficulty of operation was significantly increased. At the same time, the patient's bleeding risk (LN- vs. LN+(rank mean):119.7 vs. 167.35, P<0.0001) and blood transfusion risk (LN- vs. LN+(rank mean):141 vs. 159.5, P=0.022) in the LN+ groups were significantly higher than those in the LN- group. The postoperative hospitalization days (7.819 ± 3.073 day vs. 10.778 ± 5.746 day, P<0.0001) and total hospitalization days (14.012 ±5.230 day vs.17.316 ± 7.637 day, P=0.0003) in the LN+ groups were significantly longer than those in the LN- group. The risk of postoperative complications (LN- vs. LN+: 7.23% vs. 20.44%, χ²=7.546, P=0.006) in the LN+ groups were significantly higher than that in the LN- group. In addition, the prognostic survival rate (5-year OS rate: LN- vs. LN+: 25.3% vs. 21.3%, χ²= 4.288, P=0.038) and DFS rate (5-year DFS rate: LN- vs. LN+: 19.3% vs. 11.6%, χ²=9.903, P=0.003) of the LN+ group were significantly lower than that of the LN- group (Figure 2A and 2B), LN+ patients had a worse prognosis, contrary to the conclusions of many previous studies. In addition, the LN- group has the best outcome compared with LNB and LND group (Figure 2C and 2D), especially in the DFS rate (χ²= 11.333, P=0.003). Since the baselines of those groups were not uniform, we used PSM and IPTW to adjust confounding factors may affect the prognosis.

3.3 LNM is an extremely poor prognosis risk factor in ICC patients.

According to the pathology reports, we divided the ICC patients into pLNM+ group, pLNM- group and LN- group (the patients without performing the lymphadenectomy). After KM analysis, we found that pLNM+ group had extremely poor prognosis compared with pLNM- and LN- group (Figure 3). In pLNM+ group, the 5-year OS rate was only 7.7%, no patients survived longer than 6 years, the median OS time was only 17 months, extremely lower than other groups (median OS time: pLNM+ vs. pLNM- vs. LN-: 17 months vs. 57 months vs. 54 months, P<0.0001). In addition, almost all the pLNM+ patients recurred within 5 years. The median DFS time was only 7 months, extremely lower than other groups (median DFS time: pLNM+ vs. pLNM- vs. LN-: 7 months vs. 20 months vs. 42 months, P<0.0001).

3.4 Univariate and multivariate COX analysis were performed to find the covariates of the PSM and IPTW.

By using R 4.3.3, we performed the univariate and multivariate COX analysis of OS and survive (Table 2). After Univariate COX analysis, the P value of the “hepatobiliary history (P=0.034)”, “CEA(log2) (P<0.0001)”, “CA199(log2) (P<0.0001)”, “HBV infection (P=0.068)”, “Imaging (P=0.052)”, “Surgical approach (P=0.018)”, “T (P<0.0001)”, “liver capsule invasion (P=0.022)”, “lymphocyte invasion (P=0.007)” were all less than 0.1, thus we used those baseline characteristics to perform the multivariate COX analysis. After multivariate COX analysis, we found that the P value of “hepatobiliary history (P=0.0194)”, “CEA(Log2) (P<0.0001)”, “CA199(Log2) (P=0.0081)”, “T stage (P<0.0001)”, “lymphocyte invasion (P=0.0459)” were less than 0.05, thus we involved those confounding factors as well as the “liver capsule invasion (P=0.0552)”, “surgery approach (P=0.0675)” as the covariates of the PSM and IPTW.

3.5 LNB only increased the difficulty of the operation and had no effect on the prognosis.

During PSM analysis, we used a matching tolerance of 0.02, and finally successfully matched 53 pairs of patients on a 1:1 basis. After PSM and IPTW, those previously unbalanced baselines have been unified. After PSM and IPTW, the operation time of LNB is still significantly longer than that of the LN- group (LN- vs. LNB: PSM: 222.000±83.320 min vs.259.849±89.398 min, P=0.0262; IPTW: 219.693±81.953 min vs. 261.900±80.597 min, P=0.0026), with longer post hospitalization days (LN- vs. LNB: PSM: 8.396±3.387 day vs.10.453±6.874 day, P=0.0534; IPTW: 8.274±3.557 day vs. 10.290 ±6.139 day, P=0.018) and total hospitalization days (LN- vs. LNB: PSM: 14.453±5.666 day vs.17.453±8.794 day, P=0.0393; IPTW: 14.623±5.326 day vs. 17.024 ±8.438 day, P=0.0476). At the same time, we found that there was no significant difference in the risk of bleeding (PSM: P=0.8581, IPTW: P=0. 1754) and blood transfusion (PSM: P=0.5873, IPTW: P=0.838), and there was no significant difference in postoperative complications (PSM: P=0.4341, IPTW: P=0.2352). By using KM analysis, we found that LNB had no effect on the prognosis (Figure 4), no matter on OS (PSM: P=0.82, IPTW: P=0. 76) or DFS (PSM: P= 0.63, IPTW: P=0. 25).

3.6 LND group showed worse outcomes compared with LN- group

After using PSM, 40 pairs of patients were successfully matched 1:1 basis, and there was no statistical difference in the above baseline factors. Compared with LN- group, LND group had no better DFS (Figure 5, PSM: P=0.78, IPTW: P=0.09) and OS (PSM: P=0.91; IPTW: P=0.77), only more complications (PSM: P=0.0153; IPTW: P=0.0119), longer operation time (LN- vs. LND: PSM: 214.300±76.706 min vs. 287.050±95.606 min, P=0.0003; IPTW: 210.949±76.871 min vs. 276.612± 87.432min, P=0.0001), higher risk of bleeding (PSM: P=0.0152; IPTW: P=0.001) and transfusion (PSM: P=0.0919; IPTW: P=0.027), longer postoperative hospitalization days (before: P<0.0001; PSM: P=0.2545; IPTW: P=0.0006) and longer total hospitalization days (before: P=0.0002; PSM: P=0.9672; IPTW: P=0.0036).

3.7 LND causes worse postoperative outcomes and does not bring any survival benefit to patients.

115 patients were included in the LNB group and 110 patients were in the LND group. The comparison of the baseline characteristics of the LNB group and LND group can be seen in Table 5. There was no significant difference in preoperative and intraoperative characteristics between the two groups at baseline, thus it is no need for PSM or IPTW to adjust the baseline levels between the two groups. The operation time of LND was significantly longer than that of the LNB group (LNB vs. LND: 256.226±78.678min vs. 291.927±97.419min, P=0.0027), the difficulty of the operation was significantly increased. At the same time, the bleeding risk (P=0.017) and blood transfusion risk (P=0.0321) of patients in the LND group were significantly higher than those in the LNB group. Although the postoperative hospitalization days (LNB vs. LND: 10.409±6.205 day vs.11.164 ± 5.223 day, P=0.3256) and total hospitalization days (LNB vs. LND: 17.113±8.184 day vs. 17.527±7.051 day, P=0.6852) of the LND group were not significantly different from those of the LNB group, the incidence of postoperative complications in the LND group was significantly higher than LNB group (LNB vs. LND: 13.91% vs. 27.27, P=0.0204). There was no significant statistical difference in the prognostic OS rate (P=0.28) and postoperative DFS rate (P=0.14) of the LND group (Figure 6).

ICC is a highly malignant tumor with poor prognosis, only a small number of ICC patients (10%-15%) are suitable for surgical treatment.(Roy et al., 2021) Even with surgical treatment, ICC is still associated with high recurrence and poor survival outcomes. In our study, the ICC tumor recurrence rate reached an astonishing 64.9%, and the 5-year DFS rate was only 13.6%. The survival rate was extremely poor, 5-year survival rate was only 22.4%. Consistent with previous studies, Jeong, J. et al. demonstrated that more than 50% of ICC patients developed disease progression within 20 months after radical surgery, and the 5-year OS rate was between 30% and 35%.(Jeong, Tanaka, & Iwakiri, 2022) Mazzaferro, V. et al. reported that 50–70% of the patients developed recurrence after a median of 26 months. The median OS after radical surgery was 40 months, and the 5-year OS rate was 25–40%.(Mazzaferro et al., 2020) LNM is an independent risk factor for poor prognosis after surgical resection as the result 3.3 described. Consistent with previous study, up to 45–65% of ICC patients found LNM at the time of clinical diagnosis.(Sposito et al., 2022) The 5-year OS of pN0 patients was 35–50%, while that of pN1 patients was only 0–20%.(Navarro et al., 2020) Once LNM was confirmed, the median survival time after radical surgery decreased to 15–20 months, and the 5-year OS rate decreased to 15%.(Hyder et al., 2014) ICC does have a poor prognosis, especially the patients with LNM.

In our retrospective study, compared with LN- group, the OS (P = 0.038) and DFS (P = 0.0027) of the LN + group were significantly lower before PSM and IPTW. The LND group has a worse prognosis, which is contrary to various previous studies that LND could promote the long-term survival.(C. Chen et al., 2022; Ke et al., 2021; S. H. Kim, Han, Choi, Choi, & Kim, 2019) After the baseline comparison, we found that those confounding factors affected the prognosis. Firstly, the LN + group had a higher T stage (P = 0.0008). The higher the T stage, the worse the prognosis.(Huang, Yan, Chen, & Zhang, 2021; Sun, Lv, & Dong, 2021) The higher T stage means the larger tumor diameter, more multiple tumors, or higher probability of vascular invasion,(Zhang et al., 2021) which could be roughly judged by the doctor from a macro perspective during the operation. Thus, the higher the tumor stage, the more likely doctors will choose to perform LNB for accurate staging or LND to prevent metastasis, making it easier for patients with higher T stages to undergo lymphadenectomy, leading higher T stage in LN + group. In addition, the LN + group had higher CEA level (LN- vs. LN+: 1.070 [0.585, 1.963] vs.1.433 [0.766, 2.170], P = 0.0414) and CA199 level (LN- vs. LN+: 4.285 [3.096, 6.794] vs.6.064 [4.070, 9.089], P = 0.0005), which indicate the overloading tumor cells, greater risk of LNM, greater risk of distant metastasis, and poor prognosis.(Q. Li et al., 2022) In postoperative pathology, the tumor tissue of the LN + group had higher lymphocyte infiltration (P = 0.008), also indicates a worse prognosis.(Galun et al., 2018) 69.88% LN- patients received the postoperative adjuvant therapy, higher than the LN + group (52.0%, P = 0.0073). The postoperative adjuvant therapy may improve the prognosis that was another confounding factor contributing to the better survival rate of LN- group. These confounding factors together led to better OS and DFS in the LN- group than in the LN + group.

Therefore, we urgently needed to adjust these confounding factors. In our study, we used PSM and IPTW to unify the baseline characteristics affecting prognosis. PSM is a classical method to reduce the confounding effect in the retrospective study.(S. J. Lee et al., 2022) PSM showed robust matching effect, greatly eliminate the influence of endogenous factors as indicated in the observational study.(Benedetto, Head, Angelini, & Blackstone, 2018) However, there is sample size loss caused by non-pairing in the process of “finding paired samples”. In our study, we included 7 covariates that needed to be adjusted during PSM, resulting in a drastically reduction of patients included, although it further eliminated the influence of irrelevant variables. Only 53 pairs of patients were involved after PSM between LN- and LNB group, the data loss ratio reached 46.5%. Only 40 pairs of patients were involved after PSM between LN- and LND group with the data loss radio of 58.5%. At the same time, IPTW is a rising statistical method without causing data loss.(Austin & Stuart, 2015) IPTW has been used by various ICC research fields to adjust the confounding factors on the basis of maintaining the sample size.(Ke et al., 2023; Sposito et al., 2023)

After univariate and multivariate COX analysis, we involved those seven confounding factors (“hepatobiliary history”, “CEA(Log2)”, “CA199(Log2)”, “T stage”, “lymphocyte invasion”, “liver capsule invasion”, “surgery approach”) as the covariates of PSM and IPTW. Although the there was no significant difference of “hepatobiliary history” between those three groups, ICC patients with a history of hepatobiliary may have a worse prognosis since the certain damage has caused to bile duct cells,(Lurje et al., 2023) thus it is necessary to be involved into adjusted factor. In addition, we found that the “liver capsule invasion (P = 0.0552)”, “surgery approach (P = 0.0675)” had no significant effect on prognosis. However, their P values were close to 0.05 and may have an uncertain impact on prognosis, and previous research has shown the invasion of liver capsule caused worse survival rate,(B. Zhou, Wang, Gao, Xie, & Chen, 2020) and the laparoscopic surgery leads to better short-term outcomes in ICC patients,(Zhao et al., 2023) so we still include these two factors as confounding factors as the covariates of PSM and IPTW. These seven confounding factors have been well adjusted after PSM and IPTW (Supplementary Fig. 1).

As described in results 3.4, Compared with LN- group, LNB group only increased the operation time and postoperative or total hospitalization time after PSM and IPTW, without increasing the complication or risk of bleeding or risk of transfusion. Due to the inaccuracy of preoperative imaging in predicting LNM, LNM staging was inaccurate in up to 40% of ICC patients,(Tsilimigras et al., 2021) LNB is of great significance in the diagnosis of LNM. LNB as the gold standard for pathological diagnosis of LNM, provides accurate nodal staging and enables precise pathological staging for ICC patients.(Sposito et al., 2023) In our study, the NO.8 LN (the common hepatic artery LN) and NO.12 LN (the hepatoduodenal ligament LN) were firstly dissected to achieve the accurate staging during LNB. Previous researches showed that 4 or more LNs are sufficient to obtain accurate staging,(X. Chen et al., 2021) and the No.12 LN and No.8 LN must be included during the LNB for accurate staging since those two are the highest risk areas for LNM (Kang et al., 2021; S. H. Kim, Han, Choi, Choi, & Kim, 2022a). Accurate nodal staging could predict and guide the postoperative adjuvant treatment to achieve better prognosis.(Ke et al., 2021) The benefits of LNB to patients far outweigh the disadvantages of increased surgical difficulty and postoperative hospitalization days compared without LNB. In addition, as described in results 3.6, LNB shortens surgery time with minimal impact on operative duration and avoid the increased risk of bleeding, blood transfusion, and postoperative complications compared with LND. LNB is of great benefit to ICC patients, standardizing LNB is recommended for all patients with ICC for accurate staging but it still needs further research.

LND is still under debated due to it increases the difficulty of surgery, adverse effects on postoperative recovery, and uncertainty about prognosis.(W. Lee et al., 2020; R. Zhou et al., 2019) Although some centers indicated that LND could promote the long-term outcomes and prognosis of ICC patients,(C. Chen et al., 2022; Ke et al., 2021; S. H. Kim et al., 2019; Yoh et al., 2019) many centers including our center did not find the benefit of LND to the therapeutic effect, the OS or DFS was not significant improved after LND.(Hu et al., 2021; D. Y. Li, Zhang, Yang, Quan, & Yang, 2013; R. Zhou et al., 2019; Zhu et al., 2023) In our center, we strictly followed the standard of LND steps and resection range defined by AJCC,(S. H. Kim et al., 2019) at least 6 LNs including the NO.12 LN and NO.8 LN were dissected. However, review of LND showed that the implementation rate of LND in major hepatobiliary surgery centers in the world ranges from 26.9 to 100%, only 10% of ICC patients receive the adequate LND.(Lluís et al., 2023) In addition, many centers do not strictly follow the AJCC guidelines for LND, the mode and steps of LND vary from center to center, depending on the experience of the surgeon. Those contributes to the different or even completely opposite conclusions eventually lead to the debate of LND.

The original purpose of LND is to accurately stage and prevent suspicious LNM to reduce the risk of recurrence and achieve a better prognosis. However, due to the high complexity and variability of lymphatic system around the liver,(Morine & Shimada, 2015) it is impossible for us to comprehensively dissect all the LNs around the liver. Although we dissected the most suspicious LNs that may develop LNM such as NO.12 and NO.8 LNs,(Kang et al., 2021) the other LNs still have the probability of developing LNM. In addition, LNM is a systemic disease.(D. Y. Li et al., 2013) Researches have proved that LNM in ICC can directly spread to distant regional LNs through the multidirectional lymphatic pathways connected to the systemic lymphatic system.(D. Y. Li et al., 2013) LND performed on ICC patients who are confirmed to have LNM may still only be LN sampling in a broad sense and cannot achieve the dissection effect only the LNB effect. Therefore, it is not surprising that LND does not achieve the original expected prognosis. Furthermore, LND is associated with increased post-operative morbidity.(R. Zhou et al., 2019) As described in Results 3.5, after adjusting the confounding factors by using PSM and IPTW, compared with LN- group, LND significantly increased the operation time, the risk of postoperative complications bleeding, transfusion, prolong the total and postoperative hospitalization days, which were consistent with previous studies.(Yoh et al., 2019) Previous studies indicated that the incidence of complications increases significantly after LND in patients with cirrhosis.(Bagante et al., 2018) ICC patients with cirrhosis need to be more careful to perform LND. LNB can provide almost the same information about staging as LND, but significantly reduces post-operative morbidity.(Choi et al., 2009) As described in Results 3.6, Compared with LNB group, LND still significantly prolong the operation time, increase the risk of postoperative complications bleeding, transfusion without extending the OS or DFS time in ICC patients. Therefore, we do not recommend LND but recommend LNB as a routine resection surgery during ICC radical surgery.

In our study, we collected all the eligible ICC patients in this center over the past ten years. As the top cancer hospital in China, the surgical procedures were strictly carried out in accordance with standard procedures, many operation variables were controlled. By using both PSM and IPTW methods, the confounding factors were also well controlled. At the same time, this study was one of the few retrospective studies on LND, and we have reached a conclusion different from enormous previous literatures, providing a solid theoretical basis for opposing the removal of LND. There are still some limitations in our study. This is a single-center retrospective study with geographical limitations in China and relatively small sample size. The control of variables in retrospective study is far inferior to that in prospective studies, and the loss to follow-up bias is still exist. In the process of PSM and IPTW, the SMD values of some factors exceeds 0.2, which may cause uncertainty although COX analysis showed that those factors did not affect prognosis. This article proposes and highlights the LNB, while standardized LNB needs to be further developed in the future.

LNM is an extremely poor prognosis risk factor for ICC patients. LND can only achieve the effect of LNB while negatively affects postoperative recovery with no survival benefit for ICC patients. LNB enables precise pathological staging, with minimal impact on operative duration and postoperative recovery, avoiding increased risk of bleeding, blood transfusion, and postoperative complications. Thus, LND is not recommended while LNB is recommended as a routine operation during the radical surgery of ICC patients although standardizing LNB still needs further clinical research.

AFP: Alpha fetoprotein; AJCC: American joint committee on cancer; BMI: Body mass index; CA199: Carbohydrate antigen 19-9; CEA: carcinoembryonic antigen; DFS: disease-free survival; ICC: Intrahepatic cholangiocarcinoma; IPTW: inverse probability of treatment weighted analysis; MRI: magnetic resonance imaging; LN: lymph node; LNB: lymph node biology; LNM: lymph node metastasis; LND: lymph node dissection; LR: liver resection; OS: overall survival; PSM: propensity score matching analysis; PTCD: percutaneous transhepatic cholangial drainage; TACE: transcatheter arterial chemoembolization.

Authors' contributions:

Ruoyu Zhang: data collection, data analysis, the original draft preparation, tables, and figures production, with the help of Min Yang, Bo Chen, Feng Ye, Ning Huang, and Liu Mei; Liming Wang: conceptualization, review and critical revision; all authors: literature search, review, commentary, and final approval of the manuscript.

Competing Interests:

The authors declare that they have no conflict of interest.

Fundings:

Liming Wang is supported by the CAMS Innovation Fund for Medical Sciences (CIFMS), 2022-I2M-C&T-B-062.

Supplementary Materials:

See the supplementary materials attached in the attachment.

Acknowledgements:

Fundings:Liming Wang is supported by the CAMS Innovation Fund for Medical Sciences (CIFMS), 2022-I2M-C&T-B-062.

Data availability：

The datasets used in this study are available from the corresponding author upon reasonable request.

Ethics approval:

This study was approved by the Ethics Committee of National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (Approval number: 21/315-2986). All research was conducted in accordance with both the Declarations of Helsinki and Istanbul.

Clinical trial registration:

Not applicable.

Consent to participate:

Informed consent was obtained from all individual participants included in the study.

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Table 1. The baseline characteristics of the LN-, LNB and LND groups.

	level	Overall	LN-	LNB	LND	P value
n		308	83	115	110
sex (%)	male	185 (60.06)	53 (63.86)	67 (58.26)	65 (59.09)	0.7059
	famale	123 (39.94)	30 (36.14)	48 (41.74)	45 (40.91)
Age (%)	≤65 years	234 (75.97)	60 (72.29)	88 (76.52)	86 (78.18)	0.6281
	>65 years	74 (24.03)	23 (27.71)	27 (23.48)	24 (21.82)
BMI (%)	≤25	178 (57.79)	39 (46.99)	69 (60.00)	70 (63.64)	0.0566
	>25	130 (42.21)	44 (53.01)	46 (40.00)	40 (36.36)
Hepatobiliary history (%)	No	288 (93.51)	77 (92.77)	106 (92.17)	105 (95.45)	0.5776
	Yes	20 (6.49)	6 (7.23)	9 (7.83)	5 (4.55)
Neoadjuvant treatment (%)	No	282 (91.56)	80 (96.39)	103 (89.57)	99 (90.00)	0.1792
	Yes	26 (8.44)	3 (3.61)	12 (10.43)	11 (10.00)
HBV infection (%)	Yes	159 (51.62)	51 (61.45)	54 (46.96)	54 (49.09)	0.1058
	No	149 (48.38)	32 (38.55)	61 (53.04)	56 (50.91)
Enlarged LNs(%)	Yes	163 (52.92)	38 (45.78)	57 (49.57)	68 (61.82)	0.0575
	No	145 (47.08)	45 (54.22)	58 (50.43)	42 (38.18)
CEA (median [IQR])		1.379 [0.678, 2.104]	1.070 [0.585, 1.963]	1.433 [0.766, 2.137]	1.433 [0.867, 2.177]	0.119
AFP (median [IQR])		1.678 [1.138, 2.385]	1.632 [1.292, 2.419]	1.722 [1.070, 2.336]	1.700 [1.138, 2.425]	0.7997
CA199 (median [IQR])		5.579 [3.763, 8.747]	4.285 [3.096, 6.794]	6.040 [3.892, 9.069]	6.094 [4.198, 9.068]	0.0022
T stage (%)	T1	153 (49.68)	58 (69.88)	56 (48.70)	39 (35.45)	<0.0001
	T2	108 (35.06)	25 (30.12)	40 (34.78)	43 (39.09)
	T3	30 (9.74)	0 (0.00)	12 (10.43)	18 (16.36)
	T4	17 (5.52)	0 (0.00)	7 (6.09)	10 (9.09)
Liver capsule invasion (%)	Yes	205 (66.56)	53 (63.86)	71 (61.74)	81 (73.64)	0.1389
	No	103 (33.44)	30 (36.14)	44 (38.26)	29 (26.36)
Microvascular invasion (%)	Yes	108 (35.06)	24 (28.92)	39 (33.91)	45 (40.91)	0.2127
	No	200 (64.94)	59 (71.08)	76 (66.09)	65 (59.09)
Differentiation (%)	Low	175 (56.82)	47 (56.63)	65 (56.52)	63 (57.27)	0.8075
	Middle	126 (40.91)	35 (42.17)	48 (41.74)	43 (39.09)
	High	7 (2.27)	1 (1.20)	2 (1.74)	4 (3.64)
Lymphocyte invasion (%)	Yes	146 (47.40)	29 (34.94)	55 (47.83)	62 (56.36)	0.0128
	No	162 (52.60)	54 (65.06)	60 (52.17)	48 (43.64)
Tumor number group (%)	≤3	302 (98.05)	83 (100.00)	112 (97.39)	107 (97.27)	0.3228
	>3	6 (1.95)	0 (0.00)	3 (2.61)	3 (2.73)
Size group (%)	≤4cm	119 (38.64)	37 (44.58)	48 (41.74)	34 (30.91)	0.1068
	>4cm	189 (61.36)	46 (55.42)	67 (58.26)	76 (69.09)
Post treatment (%)	No	175 (56.82)	58 (69.88)	59 (51.30)	58 (52.73)	0.0188
	Yes	133 (43.18)	25 (30.12)	56 (48.70)	52 (47.27)
Operation time (mean (SD))		259.406 (92.950)	220.711 (90.423)	256.226 (78.678)	291.927 (97.419)	<0.0001
bleeding (median [IQR])		200.000 [100.000, 462.500]	100.000 [50.000, 200.000]	200.000 [100.000, 475.000]	300.000 [100.000, 600.000]	<0.0001
transfusion (median [IQR])		0.000 [0.000, 0.000]	0.000 [0.000, 0.000]	0.000 [0.000, 0.000]	0.000 [0.000, 675.000]	0.006
Postoperative hospitalization day (mean (SD))		9.981 (5.323)	7.819 (3.073)	10.409 (6.205)	11.164 (5.223)	<0.0001
Total hospitalization day (mean (SD))		16.425 (7.212)	14.012 (5.230)	17.113 (8.184)	17.527 (7.051)	0.0014
complications (%)	No	256 (83.12)	77 (92.77)	99 (86.09)	80 (72.73)	0.0006
	Yes	52 (16.88)	6 (7.23)	16 (13.91)	30 (27.27)

Table 2. The results of the univariate and multivariate COX analysis about OS and survival.

	Univariate COX			Multivariate COX
Characteristics	HR	CI	P value	HR	CI	P value
Age (>65 years)	0.79	0.54 - 1.15	0.212
sex	0.82	0.6 - 1.11	0.2
BMI (>25)	1.18	0.87 - 1.6	0.291
Hepatobiliary history	1.75	1.04 - 2.93	0.034 *	1.88	1.11-3.18	0.01944 *
Neoadjuvant treatment	1.18	0.71 - 1.98	0.527
CEA (Log2)	1.36	1.24 - 1.5	1.00E-04***	1.26	1.13-1.41	4e-05 ***
AFP (Log2)	1.05	0.95 - 1.16	0.303
CA199 (Log2)	1.16	1.1 - 1.21	1.00E-04***	1.07	1.02-1.13	0.00812 **
HBV infection	1.33	0.98 - 1.8	0.068	1.08	0.79-1.48	0.6157
HCV infection	1.32	0.49 - 3.56	0.585
Imaging	0.74	0.54 - 1	0.052	0.97	0.70-1.35	0.87175
fatty	0.94	0.65 - 1.36	0.75
Open surgery	0.58	0.36 - 0.91	0.018	0.64	0.40-1.03	0.06746
Tumor number	1.34	0.43 - 4.21	0.615
T stage	1.48	1.27 -1.72	<0.0001***	1.33	1.13-1.57	7e-04 ***
Size max (>4cm)	1.1	0.8 - 1.5	0.561
Liver capsule invasion	0.67	0.48 - 0.94	0.022*	0.714	0.50-1.01	0.055
Microvascular invasion	0.84	0.61 - 1.15	0.273
differentiation	0.82	0.62 - 1.08	0.163
Lymphocyte invasion	0.66	0.48 - 0.89	0.007**	0.73	0.53-0.99	0.04593 *
Post treatment	0.86	0.64 - 1.17	0.345

Table 3. The comparison of LN- and LNB before and after PSM or IPTW.

	Before PSM and IPTW					After PSM				After IPTW
	level	overall	LN-	LNB	P value	overall	LN-	LNB	P value	overall	LN-	LN+	P value
n		198	83	115		106	53	53		403.87	201.67	202.2
Hepatobiliary history (%)	No	183 (92.42)	77 (92.77)	106 (92.17)	1	97 (91.51)	49 (92.45)	48 (90.57)	1	368.20 (91.17)	182.47 (90.48)	185.73 (91.85)	0.7804
	Yes	15 (7.58)	6 (7.23)	9 (7.83)		9 (8.49)	4 (7.55)	5 (9.43)		35.68 (8.83)	19.20 (9.52)	16.48 (8.15)
Imaging group (%)	Yes	95 (47.98)	38 (45.78)	57 (49.57)	0.7029	53 (50.00)	27 (50.94)	26 (49.06)	1	208.02 (51.51)	103.46 (51.30)	104.56 0.963 (51.71)
	No	103 (52.02)	45 (54.22)	58 (50.43)		53 (50.00)	26 (49.06)	27 (50.94)		195.86 (48.49)	98.21 (48.70)	97.65 (48.29)
CEA (median [IQR])		1.292 [0.678, 2.096]	1.070 [0.585, 1.963]	1.433 [0.766, 2.137]	0.0986	1.170 [0.700, 2.018]	1.070 [0.585, 1.926]	1.433 [0.766, 2.036]	0.3577	1.202 [0.678, 2.003]	1.124 [0.688, 2.101]	1.202 [0.678, 1.930]	0.8612
CA199 (median [IQR])		5.172 [3.576, 8.230]	4.285 [3.096, 6.794]	6.040 [3.892, 9.069]	0.0039	5.102 [3.302, 7.891]	4.591 [3.053, 7.128]	5.343 [3.755, 8.192]	0.306	5.257 [3.509, 8.627]	5.172 [3.309, 9.202]	5.276 [3.611, 8.177]	0.7525
surgery approach (%)	Laparotomy	138 (69.70)	41 (49.40)	97 (84.35)	<0.0001	72 (67.92)	37 (69.81)	35 (66.04)	0.8352	279.42 (69.18)	142.11 (70.47)	137.31 (67.90)	0.75
	Laparoscopy	60 (30.30)	42 (50.60)	18 (15.65)		34 (32.08)	16 (30.19)	18 (33.96)		124.46 (30.82)	59.56 (29.53)	64.90 (32.10)
T stage (%)	T1	110 (55.56)	54 (65.06)	56 (48.70)	0.0376	62 (58.49)	31 (58.49)	31 (58.49)	0.5484	223.77 (55.41)	106.81 (52.96)	116.96 (57.84)	0.9296
	T2	65 (32.83)	25 (30.12)	40 (34.78)		34 (32.08)	18 (33.96)	16 (30.19)		125.11 (30.98)	63.32 (31.40)	61.79 (30.56)
	T3	15 (7.58)	3 (3.61)	12 (10.43)		9 (8.49)	3 (5.66)	6 (11.32)		35.85 (8.88)	20.46 (10.15)	15.39 (7.61)
	T4	8 (4.04)	1 (1.20)	7 (6.09)		1 (0.94)	1 (1.89)	0 (0.00)		19.15 (4.74)	11.08 (5.50)	8.07 (3.99)
Liver capsule invasion (%)	Yes	124 (62.63)	53 (63.86)	71 (61.74)	0.8769	68 (64.15)	32 (60.38)	36 (67.92)	0.5434	256.38 (63.48)	126.91 (62.93)	129.48 (64.03)	0.8939
	No	74 (37.37)	30 (36.14)	44 (38.26)		38 (35.85)	21 (39.62)	17 (32.08)		147.49 (36.52)	74.76 (37.07)	72.73 (35.97)
Lymphocyte invasion (%)	Yes	84 (42.42)	29 (34.94)	55 (47.83)	0.096	42 (39.62)	19 (35.85)	23 (43.40)	0.5513	169.21 (41.90)	86.12 (42.70)	83.10 (41.10)	0.8547
	No	114 (57.58)	54 (65.06)	60 (52.17)		64 (60.38)	34 (64.15)	30 (56.60)		234.66 (58.10)	115.55 (57.30)	119.11 (58.90)
Post treatment (%)	No	117 (59.09)	58 (69.88)	59 (51.30)	0.0133	66 (62.26)	36 (67.92)	30 (56.60)	0.3164	248.48 (61.52)	139.25 (69.05)	109.22 (54.02)	0.0929
	Yes	81 (40.91)	25 (30.12)	56 (48.70)		40 (37.74)	17 (32.08)	23 (43.40)		155.40 (38.48)	62.42 (30.95)	92.98 (45.98)
Operation time (mean (SD))		241.338 (85.405)	220.711 (90.423)	256.226 (78.678)	0.0036	240.925 (88.077)	222.000 (83.320)	259.849 (89.398)	0.0262	240.824 (83.774)	219.693 (81.953)	261.900 (80.597)	0.0026
bleeding (median [IQR])		150.000 [85.000, 400.000]	100.000 [50.000, 200.000]	200.000 [100.000, 475.000]	0.0057	100.000 [50.000, 300.000]	100.000 [50.000, 300.000]	100.000 [50.000, 300.000]	0.8581	100.000 [50.000, 300.000]	100.000 [50.000, 223.062]	200.000 [100.000, 300.000]	0.1754
transfusion (median [IQR])		0.000 [0.000, 0.000]	0.000 [0.000, 0.000]	0.000 [0.000, 0.000]	0.2269	0.000 [0.000, 0.000]	0.000 [0.000, 0.000]	0.000 [0.000, 0.000]	0.5873	0.000 [0.000, 0.000]	0.000 [0.000, 0.000]	0.000 [0.000, 0.000]	0.838
Post days (mean (SD))		9.323 (5.278)	7.819 (3.073)	10.409 (6.205)	0.0006	9.425 (5.491)	8.396 (3.387)	10.453 (6.874)	0.0534	9.284 (5.109)	8.274 (3.557)	10.290 (6.139)	0.018
All days (mean (SD))		15.813 (7.246)	14.012 (5.230)	17.113 (8.184)	0.0028	15.953 (7.514)	14.453 (5.666)	17.453 (8.794)	0.0393	15.825 (7.143)	14.623 (5.326)	17.024 (8.438)	0.0476
complication (%)	No	176 (88.89)	77 (92.77)	99 (86.09)	0.2122	99 (93.40)	51 (96.23)	48 (90.57)	0.4341	367.28 (90.94)	188.65 (93.54)	178.63 (88.34)	0.2352
	Yes	22 (11.11)	6 (7.23)	16 (13.91)		7 (6.60)	2 (3.77)	5 (9.43)		36.60 (9.06)	13.02 (6.46)	23.57 (11.66)

Table 4. The comparison of LN- and LND before and after PSM and IPTW.

		Before PSM and IPTW				After PSM				After IPTW
Group	Level	overall	LN-	LND	P value	overall	LN-	LND	P value	overall	LN-	LND	P value
n		193	83	110		80	40	40		382.13	190.35	191.78
Hepatobiliary history (%)	No	182 (94.30)	77 (92.77)	105 (95.45)	0.6294	73 (91.25)	37 (92.50)	36 (90.00)	1	360.68 (94.39)	175.52 (92.21)	185.16 (96.55)	0.179
	Yes	11 (5.70)	6 (7.23)	5 (4.55)		7 (8.75)	3 (7.50)	4 (10.00)		21.45 (5.61)	14.82 (7.79)	6.63 (3.45)
cirrhosis (%)	Yes	77 (39.90)	42 (50.60)	35 (31.82)	0.0128	33 (41.25)	21 (52.50)	12 (30.00)	0.0692	164.36 (43.01)	88.78 (46.64)	75.58 (39.41)	0.4159
	No	116 (60.10)	41 (49.40)	75 (68.18)		47 (58.75)	19 (47.50)	28 (70.00)		217.77 (56.99)	101.57 (53.36)	116.21 (60.59)
Imaging group (%)	Yes	106 (54.92)	38 (45.78)	68 (61.82)	0.0384	43 (53.75)	20 (50.00)	23 (57.50)	0.6538	216.00 (56.52)	109.45 (57.50)	106.54 (55.55)	0.8176
	No	87 (45.08)	45 (54.22)	42 (38.18)		37 (46.25)	20 (50.00)	17 (42.50)		166.14 (43.48)	80.90 (42.50)	85.24 (44.45)
CEA (median [IQR])		1.322 [0.678, 2.104]	1.070 [0.585, 1.963]	1.433 [0.867, 2.177]	0.0487	1.292 [0.585, 2.329]	1.232 [0.744, 2.336]	1.322 [0.560, 2.239]	0.9195	1.322 [0.678, 2.104]	1.263 [0.737, 2.181]	1.322 [0.585, 1.927]	0.986
CA199 (median [IQR])		5.259 [3.644, 8.628]	4.285 [3.096, 6.794]	6.094 [4.198, 9.068]	0.001	5.498 [3.443, 8.929]	5.521 [3.108, 8.769]	5.498 [3.805, 8.929]	0.3481	5.432 [3.799, 9.089]	5.485 [3.613, 9.556]	5.330 [3.807, 8.761]	0.812
T stage (%)	T1	93 (48.19)	54 (65.06)	39 (35.45)	0.0001	45 (56.25)	22 (55.00)	23 (57.50)	0.6081	187.78 (49.14)	95.02 (49.92)	92.75 (48.36)	0.9824
	T2	68 (35.23)	25 (30.12)	43 (39.09)		24 (30.00)	14 (35.00)	10 (25.00)		133.06 (34.82)	65.61 (34.47)	67.44 (35.17)
	T3	21 (10.88)	3 (3.61)	18 (16.36)		7 (8.75)	3 (7.50)	4 (10.00)		37.37 (9.78)	16.84 (8.85)	20.54 (10.71)
	T4	11 (5.70)	1 (1.20)	10 (9.09)		4 (5.00)	1 (2.50)	3 (7.50)		23.92 (6.26)	12.88 (6.76)	11.05 (5.76)
Liver capsule invasion (%)	Yes	134 (69.43)	53 (63.86)	81 (73.64)	0.1928	61 (76.25)	30 (75.00)	31 (77.50)	1	271.43 (71.03)	132.10 (69.40)	139.33 (72.65)	0.6657
	No	59 (30.57)	30 (36.14)	29 (26.36)		19 (23.75)	10 (25.00)	9 (22.50)		110.70 (28.97)	58.25 (30.60)	52.45 (27.35)
Lymphocyte invasion (%)	Yes	91 (47.15)	29 (34.94)	62 (56.36)	0.005	27 (33.75)	14 (35.00)	13 (32.50)	1	175.40 (45.90)	82.79 (43.49)	92.61 (48.29)	0.5848
	No	102 (52.85)	54 (65.06)	48 (43.64)		53 (66.25)	26 (65.00)	27 (67.50)		206.73 (54.10)	107.56 (56.51)	99.17 (51.71)
Post treatment (%)	No	116 (60.10)	58 (69.88)	58 (52.73)	0.0238	47 (58.75)	27 (67.50)	20 (50.00)	0.173	233.70 (61.16)	117.44 (61.70)	116.26 (60.62)	0.9018
	Yes	77 (39.90)	25 (30.12)	52 (47.27)		33 (41.25)	13 (32.50)	20 (50.00)		148.43 (38.84)	72.90 (38.30)	75.52 (39.38)
Operation time (mean (SD))		261.301 (100.645)	220.711 (90.423)	291.927 (97.419)	<0.0001	250.675 (93.579)	214.300 (76.706)	287.050 (95.606)	0.0003	249.636 (91.209)	219.533 (81.816)	279.513 (90.602)	<0.0001
bleeding (median [IQR])		200.000 [100.000, 400.000]	100.000 [50.000, 200.000]	300.000 [100.000, 600.000]	<0.0001	200.000 [100.000, 400.000]	100.000 [87.500, 325.000]	300.000 [100.000, 600.000]	0.0152	169.050 [50.000, 400.000]	100.000 [50.000, 200.000]	200.000 [100.000, 500.000]	0.001
transfusion (median [IQR])		0.000 [0.000, 0.000]	0.000 [0.000, 0.000]	0.000 [0.000, 675.000]	0.0032	0.000 [0.000, 0.000]	0.000 [0.000, 0.000]	0.000 [0.000, 700.000]	0.0919	0.000 [0.000, 0.000]	0.000 [0.000, 0.000]	0.000 [0.000, 0.000]	0.023
Post days (mean (SD))		9.725 (4.719)	7.819 (3.073)	11.164 (5.223)	<0.0001	9.238 (3.806)	8.750 (3.657)	9.725 (3.935)	0.2545	9.402 (4.363)	7.854 (3.073)	10.937 (4.895)	<0.0001
All days (mean (SD))		16.016 (6.554)	14.012 (5.230)	17.527 (7.051)	0.0002	15.150 (5.380)	15.125 (5.827)	15.175 (4.966)	0.9672	15.721 (6.124)	14.233 (5.028)	17.199 (6.751)	0.0009
complication (%)	No	157 (81.35)	77 (92.77)	80 (72.73)	0.0008	67 (83.75)	38 (95.00)	29 (72.50)	0.0153	327.67 (85.75)	177.64 (93.33)	150.02 (78.22)	0.0063
	Yes	36 (18.65)	6 (7.23)	30 (27.27)		13 (16.25)	2 (5.00)	11 (27.50)		54.46 (14.25)	12.70 (6.67)	41.76 (21.78)

Table 5. The baseline characteristics of the LNB group and LND group.

	level	Overall	LNB	LND	P value
n		225	115	110
Hepatobiliary history (%)	No	211 (93.78)	106 (92.17)	105 (95.45)	0.4579
	Yes	14 (6.22)	9 (7.83)	5 (4.55)
Imaging group (%)	Yes	125 (55.56)	57 (49.57)	68 (61.82)	0.0864
	No	100 (44.44)	58 (50.43)	42 (38.18)
CEA (median [IQR])		1.433 [0.766, 2.170]	1.433 [0.766, 2.137]	1.433 [0.867, 2.177]	0.7695
CA199 (median [IQR])		6.064 [4.070, 9.089]	6.040 [3.892, 9.069]	6.094 [4.198, 9.068]	0.7047
surgery approach (%)	Laparotomy	198 (88.00)	97 (84.35)	101 (91.82)	0.1289
	Laparoscopy	27 (12.00)	18 (15.65)	9 (8.18)
T stage (%)	T1	95 (42.22)	56 (48.70)	39 (35.45)	0.1893
	T2	83 (36.89)	40 (34.78)	43 (39.09)
	T3	30 (13.33)	12 (10.43)	18 (16.36)
	T4	17 (7.56)	7 (6.09)	10 (9.09)
Liver capsule invasion (%)	Yes	152 (67.56)	71 (61.74)	81 (73.64)	0.0779
	No	73 (32.44)	44 (38.26)	29 (26.36)
Lymphocyte invasion (%)	Yes	117 (52.00)	55 (47.83)	62 (56.36)	0.251
	No	108 (48.00)	60 (52.17)	48 (43.64)
Post treatment (%)	No	117 (52.00)	59 (51.30)	58 (52.73)	0.9362
	Yes	108 (48.00)	56 (48.70)	52 (47.27)
Operation time (mean (SD))		273.680 (89.936)	256.226 (78.678)	291.927 (97.419)	0.0027
bleeding (median [IQR])		200.000[100.000, 500.000]	200.000[100.000, 475.000]	300.000[100.000, 600.000]	0.017
transfusion (median [IQR])		0.000[0.000, 0.000]	0.000[0.000, 0.000]	0.000[0.000, 675.000]	0.0321
Post days (mean (SD))		10.778 (5.746)	10.409 (6.205)	11.164 (5.223)	0.3256
All days (mean (SD))		17.316 (7.637)	17.113 (8.184)	17.527 (7.051)	0.6852
complication (%)	No	179 (79.56)	99 (86.09)	80 (72.73)	0.0204
	Yes	46 (20.44)	16 (13.91)	30 (27.27)

No competing interests reported.

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Should lymphadenectomy be recommended in radical surgery of intrahepatic cholangiocarcinoma patients? A retrospective study

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1. Introduction

2. Methods

2.1 Patients and follow-up

2.2 Grouping and definition

2.3 Data collections and definitions

2.4 Statistical analysis

3. Results

4. Discussion

5. Concluding remarks

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