Should lymphadenectomy be routine procedure for primary intrahepatic cholangiocarcinoma patients undergoing curative hepatectomy? a retrospective cohort study with propensity-score matching analysis

doi:10.21203/rs.3.rs-2245109/v1

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Research Article

Should lymphadenectomy be routine procedure for primary intrahepatic cholangiocarcinoma patients undergoing curative hepatectomy? a retrospective cohort study with propensity-score matching analysis

https://doi.org/10.21203/rs.3.rs-2245109/v1

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Journal Publication

published 30 Nov, 2023

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Background

Whether routine lymphadenectomy (LD) leads to better outcomes in patients with primary intrahepatic cholangiocarcinoma (ICC) undergoing curative hepatectomy is unclear.

Materials and Methods

This study enrolled 269 consecutive patients who underwent liver resection for primary ICC from January 2009 to July 2020 in West China hospital. The association of the nodal status with disease-free survival (DFS) and overall survival (OS) was analyzed using the Cox proportional hazards model and 1:1 propensity score matching (PSM) analysis.

Results

75 (27.9%) patients had undergone curative liver resection combined with LD (LD + group), and 194 (72.1%) patients had only received curative liver resection without LD (LD- group and Nx group). Metastatic nodal disease was observed in 48% of LD + patients (N1 groups, n = 36), and the remaining 39 patients without metastatic nodal disease were classified as N0 group. During the follow-up period, 116 patients (43.1%) have developed tumour recurrence and 101 patients (37.5%) died with recurrence. Multivariate analysis showed that lymph node metastasis (N1, OR 3.682, 95%CI 1.949–6.957, p < 0.001) was associated with worse OS, but LD+ (OR 0.504, 95%CI 0.298–0.853, p = 0.011) was associated with improved OS. And adjuvant therapy was a protective factor for both DFS (OR 0.602, 95%CI, 0.447–0.810, p = 0.001) and OS (OR 0.683, 95%CI 0.484–0.963, p = 0.030). After 1:1 PSM, the LD + patients (n = 74) expressed similar 1-, 3- and 5-year DFS rates (40.0%, 7.9% and 7.9% vs 29.0%, 13.7% and 13.7%, p = 0.741) and OS rates (56.0%, 26.6% and 22.2% vs 58.9%, 25.6%, and 16.4%, p = 0.644) with LD- patients (n = 74). Furthermore, among the 75 LD + patients, 48 patients underwent hepatic hilar lymphadenectomy (HHL), and 27 patients underwent extended hepatic hilar lymphadenectomy (EHL). Both DFS (p = 0.504) and OS (p = 0.215) were similar between the HHL and EHL groups.

Conclusion

Routine LD and adjuvant therapy may contribute to improved OS in crude analysis. LD may contribute to accurate staging without excessive risk, and recommended adjuvant therapy according to tumor stage, which may contribute to better survival. Therefore, LD could be still recommended as a routine procedure during curative hepatectomy for ICC patients.

Hepatectomy

Intrahepatic Cholangiocarcinoma

Lymphadenectomy

Propensity score matching analysis

Intrahepatic cholangiocarcinoma (ICC) arises in the hepatic parenchyma either directly from cholangiocytes or from the transdifferentiation of hepatocytes. In recent decades, the incidence of ICC has dramatically increased, rendering it the second most common primary hepatic cancer [1, 2]. Although hepatic resection remains the first-line curative treatment, the 5-year overall survival (OS) rates of ICC patients ranged from 30–35% after hepatectomy [3]. Recently, several studies have identified that the lymph node status was one of the most important prognostic factors for ICC [4–8]. Clinicians have focused on the lymph node dissection in ICC patients, but its effects in ICC surgical radical treatment remain controversial [3, 4, 7, 9]. Actually, it is unclear whether lymph node clearance is truly beneficial for survival. Thus, we aimed to explore the effect of lymphadenectomy (LD) on ICC patients undergoing heoatectomy.

Study population

Clinical data from all consecutive patients who underwent liver resection for primary ICC lesions in the West China Hospital of Sichuan University, China, from January 2009 to July 2020, were retrieved from a prospective database for this study. The inclusion criteria included: age > 18 years old; underwent initial curative hepatectomy; histologically diagnosed as primary ICC lesions. And the exclusion criteria included: presenting with metastatic disease at the time of diagnosis (American Joint Committee on Cancer [AJCC] stage M1) (n = 13); underwent palliative resection or treated with non-surgical regimens (n = 9); recurrent ICC lesions(n = 7); mixed ICC and hepatocellular carcinoma lesions(n = 17). Eventually, a total of 269 patients with ICC who underwent initial curative hepatectomy were enrolled in this study.

Data Collection

In addition to baseline demographic data, including age and sex, data regarding the hepatitis B virus surface antigen (HBsAg) status, Child-Pugh classification, aspartate aminotransferase (AST) level, carbohydrate antigen 19 − 9 (CA19-9) level, blood loss volume, intraoperative blood transfusions, perioperative complications, and tumour characteristics were collected for each patient. Specifically, these data included the presence of liver cirrhosis, the tumour size, the number of lesions, the morphological sub-type, the histological grade, and the tumour invasion status (vascular/perineural/biliary). In addition, information regarding the surgical procedure (major or minor hepatectomy), treatment with LD, and adjuvant therapy, such as adjuvant chemotherapy, transcatheter arterial chemoembolization and radiotherapy were collected for each patient. The surgical margin and nodal status were determined from the final post-operative pathological report.

Follow-up

After discharge, the patients were followed every 3 months during the first 2 years after the initial operation and every 6 months thereafter. Recurrence was defined as the appearance of a new lesion that exhibited radiological features intra- or extra-hepatically. The date of the last follow-up and the survival status were collected for all patients. Furthermore, non-tumour-related death occurred in 20 cases during the follow-up period: intracerebral bleeding in 2 cases; multiple organ dysfunction syndrome (MODS) in 2 cases; pulmonary failure in 3 cases; kidney failure in 1 case; gastrointestinal bleeding in 1 case; acute cardiac infarction due to atrial myxoma in 1 case; liver failure in 9 cases; car accident in 1 case.

Clinical Terms

The tumour size was defined as the largest diameter (in centimetres) of the resected specimen. The histological grade was defined as well, moderately or poorly differentiated, and the highest histological grade was used to define the tumour grade in patients with multiple resected specimens. The major liver resection was defined as resection of three or more liver segments [10]. Post-operative complications were stratified according to the Clavien-Dindo classification [11]. Major complications were defined as those of grade IIIa or above. DFS was defined as the interval between the date of the operation and the date of the diagnosis of the first recurrence or the last follow-up. OS was measured from the date of the operation to the date of death or the last follow-up.

Statistical Analyses

Continuous data are expressed as the median and range/interquartile range (IQR). Qualitative variables are expressed as the frequency (percentage). Student’s t test or the Mann-Whitney U test was used for intergroup comparisons of quantitative variables as appropriate, whereas the χ2 test or Fisher’s exact test was used to compare categorical data. A survival analysis was conducted using the Kaplan-Meier method, and the significance of differences between survival curves was determined using the log-rank test. Multivariate regression analysis of the survival distributions were carried out using the Cox proportional hazard model. To eliminate selection bias, patients were matched 1:1 by propensity scores [12] based on their baseline characteristics. All statistical analyses were performed using SPSS 23.0 (SPSS, Inc., Chicago, IL). Two-sided P values < 0.05 were considered statistically significant.

Perioperative clinical characteristics

Patients were followed until the date of death or the final date of the study, December 30, 2020. A total of 269 patients underwent initial hepatectomy for primary ICC. The majority of patients were male (n = 169, 62.8%), and most patients were younger than 65 years (n = 215, 79.9%). Nearly two-thirds (n = 159, 60.2%) of the patients presented with a unifocal lesion. Only one in three patients presented with a tumour size < 5 cm (n = 89, 34.0%). More than half of the patients were positive for HBsAg (n = 148, 55.0%) and presented with cirrhosis (n = 146, 54.3%). The invasion of adjacent structures was not noted in most patients. Specifically, macrovascular invasion, microvascular invasion, periductal invasion, and perineural invasion were only observed in 12.6% (n = 34), 18.4% (n = 49), 5.9% (n = 16) and 7.5% (n = 20) of tumours, respectively. Poorly differentiated lesions were found in one-third (n = 83, 30.9%) of patients, and a positive surgical margin was found in 17 (6.3%) patients. Regarding liver function, as defined by the Child-Pugh classification, of which 254 (94.4%) patients were class A, 15 (5.6%) patients were class B, and none was class C.

Of the 269 patients, 171 (63.6%) underwent major liver resection, and 98 (36.4%) underwent minor resection. Complications occurred in 18 patients, including MODS in one, acute respiratory and circulatory failure in two, liver failure in three, respiratory failure in four, pleural effusion in 4, intraabdominal bleeding in one, liver abscess in one, pulmonary embolism in one, and pleuro-peritoneal infectious shock in one. Three of these eighteen patients died, and the remaining patients were cured. For histological examination, the mass-forming morphological tumour variance was most common (n = 263, 97.8%), followed by the papillary morphology (n = 4, 1.5%), and mixed mass-forming and periductal-infiltrating variant (n = 2, 0.7%). Of note, 75 patients (27.9%) underwent concomitant LD (LD + group). Metastatic nodal disease was observed in 48% (n = 36) of these patients, who were therefore classified as N1 according to the AJCC TNM staging system. The remaining patients without metastatic nodal disease were classified as N0, and the 194 patients who did not undergo concomitant LD were classified as Nx/LD-. Post-operatively, 70 (26.0%) patients received antiviral therapy, and 97 (36.1%) patients received adjuvant therapy, including adjuvant chemotherapy, transcatheter arterial chemoembolization and radiationtherapy.

Factors Associated With Dfs And Os

During the follow-up period, tumour recurrence developed in 116 patients (43.1%) with a median DFS of 5 months (IQR: 3–13), and 101 patients (37.5%) died with a median OS of 11 months (IQR: 5–24). Specifically, the 1-, 3- and 5-year DFS rates were 35.7%, 18.2% and 12.8%, respectively (Fig. 1a). While OS was 57.5% at 1 year after surgery, a dramatic decrease in survival was observed over time, as only 30.4% and 21.1% of patients survived for 3 and 5 years, respectively (Fig. 1b).

Multivariate analysis showed that AST ≥ 31 IU/L (OR 1.615, 95%CI, 1.192–2.188, p = 0.002), tumour diameter ≥ 5 cm (OR 1.679, 95%CI, 1.211–2.327, p = 0.002), multifocal lesions (OR 1.514, 95%CI, 1.120–2.048, p = 0.007), macrovascular invasion (OR 1.564, 95%CI, 1.034–2.364, p = 0.034), Perineural invasion (OR 1.793, 95%CI, 1.004–3.204, p = 0.048), and Periductal invasion (OR 2.127, 95%CI, 1.041–4.347, p = 0.038) were associated with reduced DFS. Notably, adjuvant therapy (OR 0.602, 95%CI, 0.447–0.810, p = 0.001) was an independent protective factor for DFS (Table 1). Moreover, reduced OS was noted among patients presenting with tumours ≥ 5 cm in diameter (OR 1.849, 95%CI 1.260–2.713, p = 0.002), multifocal lesions (OR 1.500, 95%CI 1.067–2.108, p = 0.02), macrovascular invasion (OR 1.569, 95%CI 1.038–2.370, p = 0.032), periductal invasion (OR 2.899, 95%CI 1.154–7.281, p = 0.024), CA19-9 ≥ 36.2 U/mL (OR 1.571, 95%CI, 1.119–2.207, p = 0.009), a positive margin status (OR 2.142, 95%CI 1.030–4.454, p = 0.042), and lymph node metastasis (OR 3.682, 95%CI 1.949–6.957, p < 0.001). Notably, adjuvant therapy (OR 0.683, 95%CI 0.484–0.963, p = 0.030) and lymphadenectomy (OR 0.504, 95%CI 0.298–0.853, p = 0.011) were protective factors for OS (Table 2).

Table 1

Clinicopathological factors associated with DFS in ICC patients.
Variables	Univariate analysis	Multivariate analysis
Variables	P value	OR (95% CI)	P value
Age ( ≧ 65)	0.645		0.585
Gender (male)	0.007		0.225
HBsAg positive	0.006		0.418
Child-Pugh Class (A/B)	0.910		0.875
AST ≧ 31 IU/L	< 0.001	1.615 (1.192–2.188)	0.002
CA-199 ≧ 36.2 U/mL	0.352		0.324
Tumor diameter ≧ 5 cm	< 0.001	1.679 (1.211–2.327)	0.002
Multifocal lesions	< 0.001	1.514 (1.120–2.048)	0.007
Major hepatectomy	0.175		0.482
Lymphadenectomy	0.304		0.920
Tumor differentiation (Poor)	0.004		0.122
Macrovascular invasion	< 0.001	1.564 (1.034–2.364)	0.034
Microvascular invasion	< 0.001		0.063
Perineural invasion	0.205	1.793 (1.004–3.204)	0.048
Periductal invasion	0.277	2.127 (1.041–4.347)	0.038
Margin positive	0.671		0.663
Lymph node metastasis	0.024		0.143
Pathological cirrhosis	0.010		0.349
Antiviral therapy	0.083		0.631
Adjuvant therapy	< 0.001	0.602 (0.447–0.810)	0.001
AST = alanine aminotransferase; CA19-9 = carbohydrate antigen 19 − 9; DFS = disease-free survival; HBsAg = hepatitis B virus surface antigen; OR, odds ratio; CI = confidence interval; ICC, intrahepatic cholangiocarcinoma.

Table 2

Clinicopathological factors associated with OS in ICC patients.
Variables	Univariate analysis	Multivariate analysis
Variables	P value	OR (95% CI)	P value
Age ( ≧ 65)	0.304		0.219
Gender (male)	0.441		0.398
HBsAg positive	0.112		0.098
Child-Pugh Class (A/B)	0.821		0.809
AST ≧ 31 IU/L	< 0.001		0.055
CA-199 ≧ 36.2 U/mL	0.001	1.571 (1.119–2.207)	0.009
Tumor diameter ≧ 5 cm	< 0.001	1.849 (1.260–2.713)	0.002
Multifocal lesions	< 0.001	1.500 (1.067–2.108)	0.020
Major hepatectomy	0.389		0.989
Lymphadenectomy	0.432	0.504 (0.298–0.853)	0.011
Tumor differentiation (Poor)	0.003		0.226
Macrovascular invasion	0.002		0.052
Microvascular invasion	< 0.001	1.569 (1.038–2.370)	0.032
Perineural invasion	0.004		0.056
Periductal invasion	0.071	2.899 (1.154–7.281)	0.024
Margin positive	0.202	2.142 (1.030–4.454)	0.042
Lymph node metastasis	< 0.001	3.682 (1.949–6.957)	< 0.001
Pathological cirrhosis	0.06		0.072
Antiviral therapy	0474		0.869
Adjuvant therapy	0.345	0.683 (0.484–0.963)	0.030
AST = alanine aminotransferase; CA19-9 = carbohydrate antigen 19 − 9; OS = overall survival; HBsAg = hepatitis B virus surface antigen; OR, odds ratio; CI = confidence interval; ICC, intrahepatic cholangiocarcinoma.

Survival Analysis After Propensity Score-match (Psm) Analysis

To investigate the association of the nodal status with DFS and OS, a 1:1 PSM analysis was performed between the crude LD- (n = 194) and LD+ (n = 75) groups. There was no significant difference in terms of major complications (p = 0.347), blood loss (p = 0.999) or blood transfusions (p > 0.99) between these two groups after matching (Table 3). Furthermore, these two groups showed no significant differences in the 1-, 3- and 5-year DFS rates (LD- vs. LD+; 29.0%, 13.7% and 13.7% vs. 40.0%, 7.9% and 7.9%, p = 0.741; Fig. 2a) or the 1-, 3- and 5-year OS rates (LD- vs. LD+; 58.9%, 25.6%, and 16.4% vs. 56.0%, 26.6% and 22.2%, p = 0.644; Fig. 2b).

Table 3

PSM between LD- and LD + Patients Resulting in 74 Pairs of Matched Patients.
Variables	Before PSM				After PSM
Variables	LD(-) group n = 194	LD(+) group n = 75	P value	LD(-) group n = 74	LD(+) group n = 74	P value
Age, median (range)	54 (27–87)	56 (36–77)	0.694	53 (31–73)	56 (36–77)	0.192
Gender (male), n (%)	121 (62.4)	48 (64.0)	0.804	47 (63.5)	48 (64.9)	0.864
HBsAg positive, n (%)	107 (55.2)	41 (54.7)	0.942	44 (59.5)	40 (54.1)	0.507
Child-Pugh Class (B), n (%)	10 (5.2)	5 (6.7)	0.851	5 (6.8)	5 (6.8)	> 0.99
AST, IU/L, median (range)	31 (10–701)	31 (10–451)	0464	30 (14–701)	31 (10–451)	0.681
CA-199 (U/mL), median (range)	35.4 (0-1000)	43.8 (0-5533)	0.102	33.4 (0-1000)	48.1 (0-5533)	0.064
Tumor diameter (cm), median (range)	6 (0.5–18.4)	6.7 (2–17)	0.034	6 (0.5–15)	6.7 (2–17)	0.687
Unifocal lesions, n (%)	121 (62.4)	40 (53.3)	0.175	45 (60.8)	40 (54.1)	0.406
Major hepatectomy, n (%)	116 (59.8)	55 (73.3)	0.039	50 (67.6)	54 (73.0)	0.472
Negative surgical margin, n (%)	182 (93.8)	70 (93.3)	> 0.99	69 (93.2)	69 (93.2)	> 0.99
Blood loss (mL), median (range)	300 (50-4000)	300 (20-1500)	0.064	300 (100–4000)	300 (20-1500)	> 0.99
Transfusion, n (%)	28 (14.4)	20 (26.7)	0.019	16 (21.6)	20 (27.0)	> 0.99
Major complications, n (%)	14 (7.2)	4 (5.3)	0.579	7 (9.5)	4 (5.4)	0.347
Tumor differentiation, poor, n (%)	59 (30.4)	24 (32.0)	0.800	18 (24.3)	23 (31.1)	0.358
Macrovascular invasion, n (%)	21 (10.8)	13 (17.3)	0.150	11 (14.9)	12 (16.2)	0.821
Microvascular invasion, n (%)	34 (17.5)	15 (20.0)	0.637	13 (17.6)	15 (20.3)	0.675
Perineural invasion, n (%)	16 (8.2)	5 (6.7)	0.665	2 (2.7)	5 (6.8)	0.442
Periductal invasion, n (%)	12 (6.2)	4 (5.3)	> 0.99	2 (2.7)	4 (5.4)	0.681
Cirrhosis, n (%)	110 (56.7)	36 (48.0)	0.199	45 (60.8)	36 (48.6)	0.137
Antiviral therapy, n (%)	53 (27.3)	17 (22.7)	0.435	14 (18.9)	17 (23)	0.545
Adjuvant therapy, n (%)	67 (34.5)	30 (40.0)	0.403	35 (47.3)	29 (39.92)	0.319
PSM = propensity score matching; LD = lymphadenectomy; AST = alanine aminotransferase; CA19-9 = carbohydrate antigen 19 − 9; HBsAg = hepatitis B virus surface antigen.

Among the LD + patients, groups N0 patients and N1 patients had no significant differences in the clinical features (Supplemental Table 1). Notably, these two groups showed no significant differences in the 1-, 3- or 5-year DFS rates (N0 vs. N1; 45.4%, 12.1% and 12.1% vs. 33.4%, 0, 0, p = 0.058, Supplemental Fig. 1a) but did show significant differences in the 1-, 3- and 5-year OS rates (N0 vs. N1; 73.5%, 39.7% and 29.8% vs. 34.9%, 12.2% and 12.2%, p < 0.001, Supplemental Fig. 1b). Moreover, groups N0 patients and Nx patients also had no significant differences in the clinical features (Supplemental Table 2). These two groups showed no significant differences in the 1-, 3- or 5-year DFS rates (N0 vs. Nx; 45.4%, 12.1% and 12.1% vs. 34.0%, 20.0, 18.7, p = 0.780, Supplemental Fig. 2a) and in the 1-, 3- and 5-year OS rates (N0 vs. Nx; 73.5%, 39.7% and 29.8% vs. 58.4%, 31.7% and 21.0%, p = 0.142, Supplemental Fig. 2b). Additionally, 32 N1 patients and 32 Nx patients were matched based on propensity scores (Supplemental Table 3). Similarly, there were no significant differences in the 1-, 3- or 5-year DFS rates (N1 vs. Nx; 35.7%, 0 and 0 vs. 34.4%, 9.4% and 9.4%, p = 0.249, Supplemental Fig. 3a) and in the 1-, 3- and 5-year OS rates (N1 vs. Nx; 39.5%, 13.8% and 13.8% vs. 46.9%, 19.5% and 7.8%, p = 0.195, Supplemental Fig. 3b) between these two groups.

As mentioned above, 75 (27.9%) patients in this study underwent concomitant LD, 48 (64%) patients underwent hepatic hilar lymphadenectomy (HHL), and 27 (36%) patients underwent extended hepatic hilar lymphadenectomy (EHL). Additionally, metastatic nodal disease was observed in 36 (48%) of patients. As shown in Table 4, the most common metastatic site was the hepatoduodenal ligament (n = 18, 50.0%). Notably, in some patients, the first metastatic lymph node was more distant, skipping local nodes (n = 12, 33.3%). It seemed that more patients in the EHL group (n = 18, 66.7%) was detected with positive lymph node metastasis than those in the HHL group (n = 18, 37.5%, p = 0.015) in crude analysis. However, the difference of positive lymph node metastasis was not significant after PSM analysis between EHL and HHL groups (61.9% vs 38.1%, p = 0.123). Additionally, more patients in the HHL group received transfusion compared with the patients in the EHL group (42.9% vs 12.3%, p = 0.04, Table 5) after matching. There were no significant differences in the 1-, 3- and 5-year DFS rates (HHL vs. EHL; 32.7%, 13.1% and 13.1% vs. 39.9%, 0 and 0, p = 0.504, Fig. 3a) or the 1-, 3- and 5-year OS rates (HHL vs. EHL; 63.8%, 35.8% and 35.8% vs. 48%, 20.6% and 20.6%, p = 0.215, Fig. 3b) between the HHL and EHL groups after matching.

Table 4

Sites of metastatic nodes of 36 patients with metastatic nodal disease.
Sites of metastatic notes	Patients (n = 36)	Percentage (%)
Hepatoduodenal ligament	18	50
Peri-pancreatic	6	16.7
Distant	12	33.3

Table 5

PSM between HHL and EHL Patients Resulting in 21 Pairs of Matched Patients.
Variables	Before PSM				After PSM
Variables	HHL group n = 48	EHL group n = 27	P value	HHL group n = 21	EHL group n = 21	P value
Age, median (range)	54 (36–77)	59 (37–73)	0.282	60 (39–72)	56 (337 − 73)	0.419
Gender (male), n (%)	32 (66.7)	16 (59.3)	0.521	10 (47.6)	12 (57.1)	0.537
HBsAg positive, n (%)	30 (62.5)	11 (40.7)	0.069	8 (38.1)	10 (47.6)	0.533
Child-Pugh Class (B), n (%)	2 (4.2)	3 (11.1)	0.344	1 (4.8)	2 (9.5)	> 0.99
AST, IU/L, median (range)	30.5 (10–449)	33 (18–451)	0.191	28 (17–154)	33 (18–451)	0.150
CA-199 (U/mL), median (range)	36.2 (0.6–5533)	80.8 (0-1000)	0.971	36.2 (0.6–5533)	123.2 (0-1000)	0.595
Tumor diameter (cm), median (range)	6.55 (3–17)	7 (2–13)	0.948	6.5 (3–17)	7 (2–13)	0.854
Unifocal lesions, n (%)	24 (50.0)	16 (59.3)	0.440	11 (52.4)	10 (47.6)	0.758
Major hepatectomy, n (%)	35 (72.9)	20 (74.1)	0.913	14 (66.7)	15 (71.4)	0.739
Negative surgical margin, n (%)	45 (93.8)	25 (92.6)	> 0.99	19 (90.5)	10 (90.5)	> 0.99
Blood loss (mL), median (range)	375 (20 -1500)	300 (50 -1000)	0.067	400 (20 -1500)	300 (50 -1000)	0.190
Transfusion, n (%)	17 (35.4)	3 (11.1)	0.022	9 (42.9)	3 (14.3)	0.040
Major complications, n (%)	3 (6.3)	1 (3.7)	> 0.99	0 (0)	1 (4.8)	> 0.99
Tumor differentiation, poor, n (%)	16 (33.3)	8 (29.6)	0.741	4 (19.0)	7 (33.3)	0.292
Macrovascular invasion, n (%)	10 (20.8)	3 (11.1)	0.453	2 (9.5)	3 (14.3)	> 0.99
Microvascular invasion, n (%)	11 (22.9)	4 (14.8)	0.400	3 (14.3)	4 (19.0)	> 0.99
Perineural invasion, n (%)	3 (6.3)	2 (7.4)	> 0.99	1 (4.8)	2 (9.5)	> 0.99
Periductal invasion, n (%)	2 (4.2)	2 (7.4)	0.616	2 (9.5)	2 (9.5)	> 0.99
Cirrhosis, n (%)	25 (52.1)	11 (40.7)	0.345	7 (33.3)	10 (47.6)	0.346
Lymph node metastasis, n (%)	18 (37.5)	18 (66.7)	0.015	8 (38.1)	13 (61.9)	0.123
Antiviral therapy, n (%)	14 (29.2)	3 (11.1)	0.073	1 (4.8)	3 (14.3)	0.606
Adjuvant therapy, n (%)	22 (45.8)	8 (29.6)	0.169	8 (38.1)	8 (38.1)	> 0.99
PSM = propensity score matching; HHL = hepatic hilar lymphadenectomy; EHL = extended hepatic hilar lymphadenectomy; AST = alanine aminotransferase; CA19-9 = carbohydrate antigen 19 − 9; HBsAg = hepatitis B virus surface antigen.

Curative hepatectomy is the most effective treatment for ICC; however, the prognosis after surgical resection remains poor because ICC exhibits aggressive local invasion and frequent metastasis, tending to spread through the lymphatic system [5, 13–15]. Similar with previous reports [4–8], the current study found that lymph node metastasis was a significant risk factor for patients with ICC. Although the importance of lymph node sampling during curative cancer resection has been well established for some gastrointestinal malignancies, the role of routine LD during surgery for hepatobiliary tumours is less defined [16, 17]. While LD is performed for gallbladder cancer and fibrolamellar hepatocellular carcinoma (HCC), LD is not typically performed for HCC, and its role in ICC remains largely undetermined [18]. As a result, wide variation in the utilization of LD in ICC has been noted globally. For example, in the current study, only 27.9% (n = 75) of patients underwent concomitant LD, and among these patients, 48% had lymph node metastasis. The utilization of LD has been reported from approximately 50% in Western centres to more than 75–80% in Eastern centres, noting a lymph node metastasis incidence of approximately 30% in most studies[3, 4, 7, 19]. Collectively, these data not only suggestted that the incidence of lymph node metastasis was approximately 30–50% among patients undergoing LD but also highlight the need for more standardized, evidence-based guidelines for the use of lymph node assessments in patients with ICC [19]. However, the necessity of routine LD remains a matter of debate. Some researchers have suggested routine LD for decreasing locoregional recurrence and optimizing pathological staging [3, 8], while others have recommended routine LD but doubted its value for benefiting patient survival [15, 20]. Although several national guidelines recommend the removal of suspicious lymph nodes, wide variations exist in practice regarding routine LD among patients without suspicious lymph nodes [6, 9, 19, 21]. Thus, the current study investigated whether routine LD is beneficial or essential, as well as which procedure may be better for ICC patients.

While routine LD would contribute to accurate cancer staging. Theoretically, a good prognosis could be achieved by removing tumour lesions and reducing the risk of recurrence according to the recommendations based on cancer staging. Accurate cancer staging remains fundamental for determining the therapeutic decision, informing the prognosis, and making adjuvant treatment plan in patients with malignancy. For a long time, ICC and HCC were staged in the same manner [22]. Given that ICC and HCC were different diseases with varying epidemiologies, risk factors, genetic factors, and natural histories, the 7th edition of the AJCC staging manual established the first specific TNM staging system for ICC, based on clinical data of 598 patients undergoing cancer-directed surgery [23]. Several factors in the staging system were associated with prognosis, including the tumor size, number of tumours and vascular invasion status, which were similarly proven to be predictive factors of prognosis in this study. Notoriously with subsequently reporting several shortcomings for AJCC 7th edition, the newly updated 8th edition of the AJCC staging manual for ICC incorporated several modifications of re-classifications, which not only involves an assessment of the nodal status but also strongly recommends routine LD [24]. And several studies have suggested that patients with advanced locoregional ICC (Any TxN1M0) may benefit from adjuvant therapy [24].

The present study showed there were no significant differences in OS rates between the LD- patients and LD + patients after 1:1 PSM. We have explored the role of LD using extensive statistical analyses to compare patient outcomes based on the lymph node status. Specifically, perhaps of most interest, these data demonstrate that OS was either similar between Nx and N1 patients or between Nx and N0 patients. However, OS was worse among N1 patients than that in N0 patients. Otherwise, multivariate analysis showed that LD was associated with improved OS. Thus, we could infer that the ratio of N0:N1 was nearly to 1 in Nx patients. Additionally, data from the current study served to quantitate and define the heterogeneous outcome of Nx patients, suggesting that Nx patients were in fact a combination of N0 and understaged N1 patients, consistent with a study reported by Bagante et al. [25]. Furthermore, these data emphasized the theory that failure to perform routine LD has contributed to under-staging a subset of patients. Generally, we performed LD in patients who were suspected to have lymph node metastasis according to preoperative image findings or intraoperative macroscopic findings [26]. Notably, the ratio of N1 patients was higher in the LD + group than in the LD- group; therefore, this may explain why the DFS and OS rates were not significant different between the LD- and LD + groups. Furthermore, this study suggested that routine LD would not increase the blood loss volume, number of transfusions, post-operative complication rate, and may in fact improve survival. A previous study has also reported similar findings [20]. However, more studies are needed to confirm this hypothesis. Of note, these data demonstrate key prognostic information in that LD allows accurate staging and long-term outcome prediction in patients with ICC.

This study shows that lymph nodes in the hepatoduodenal ligament were the most common site of nodal metastasis, consistent with the findings reported by Li et al. [27]. Therefore, the routine sampling of 12 lymph nodes is useful for detecting the presence of lymph node metastasis. Notably, we found that early metastasis to distant lymph nodes in approximately one-third of our patients. Previous studies have reported similar results that lymph node metastasis is rarely limited to regional lymph nodes [15, 28]. Moreover, it seems that positive lymph node metastasis was almost detected in two-thirds of patients who underwent EHL, compared with almost two-fifths in HHL group. This may result from that EHL was performed while distal node lymph metastasis was suspected according to surgeon’s assessment. This study expressed no significant difference in blood loss or major complications between HHL and EHL. Nevertheless, transfusion was more common in HHL patients than that in EHL patients, which may result from improvements in surgical technologies. Furthermore, EHL patients showed similar DFS and OS with HHL patients. Thus, both HHL and EHL are safe and useful procedures that could be used for accurate cancer staging. EHL would just be recommend while distal lymph node metastasis is suspected perioperatively.

This study has several limitations, and the main limitation is its retrospective design. Selection bias undoubtedly influenced the choice of treatment. Specifically, patients with suspicious lymph nodes may have been more likely to undergo LD. However, the preferential use of LD in patients with suspicious nodes would have, if anything, further underestimated the prevalence of lymph node metastasis in the Nx group. In turn, this would have biased the results towards the null hypothesis.

In conclusion, survival remains poor among patients undergoing liver resection for ICC. Lymph node metastasis is one of the strongest predictors of survival, thereby guiding the prognosis and the administration of adjuvant therapy. Additionally, routine LD in the form of EHL would not risk reducing short- or long-term survival, and survival can be further enhanced by adjuvant therapy. Thus, LD may contribute to prolonged survival, and could be recommended as routine procedure for patients undergoing resection for ICC in order to achieve accurate staging and provide evidence for providing appropriate adjuvant therapy.

ICC

intrahepatic cholangiocarcinoma

overall survival

DFS

disease free survival

lymphadenectomy

AJCC

American Joint Committee on Cancer

AST

aspartate aminotransferase

HBsAg

hepatitis B virus surface antigen

MODS

multiple organ dysfunction syndrome

IQR

interquartile range

PSM

propensity score-match

HHL

hepatic hilar lymphadenectomy

EHL

extended hepatic hilar lymphadenectomy

HCC

hepatocellular carcinoma.

Ethics approval and consent to participate: This study was approved by Institutional Review Board of the West China Hospital of Sichuan University, and was performed in accordance with the ethical principles of the Declaration of Helsinki. And written informed consents were obtained from all of the patients.

Consent for publication: Not applicable.

Availability of data and materials: All data generated or analysed during this study are included in this published article [and its supplementary information files].

Competing interests: The authors declare that they have no competing interests.

Funding: This study was supported by Sichuan Province Key Research and Development Project (2021YFS0098).

Authors' contributions: Jian Yang conceived of and designed the study; Shan Huang and Jiu-Lin Song analyzed the data and drafted the manuscript; Bo Li and Peng-Sheng Yi provided technical support and revised the manuscript. All of the authors have approved the final version to be published.

Acknowledgements: Not applicable.

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No competing interests reported.

SupplementalTable1.docx
SupplementalTable2.docx
SupplementalTable3.docx
Supplementalfig.1.ppt
Supplemental Fig. 1: DFS rate (a) and OS rate (b) of in 75 ICC Patients after surgery between N0 and N1 patients.
Supplementalfig.2.ppt
Supplemental Fig. 2: DFS rate (a) and OS rate (b) of in 233 ICC Patients after surgery between N0 and Nx patients.
Supplementalfig.3.ppt
Supplemental Fig. 2: DFS rate (a) and OS rate (b) of in 233 ICC Patients after surgery between N0 and Nx patients.

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Should lymphadenectomy be routine procedure for primary intrahepatic cholangiocarcinoma patients undergoing curative hepatectomy? a retrospective cohort study with propensity-score matching analysis

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