
==== Front
Int J Surg
Int J Surg
JS9
International Journal of Surgery (London, England)
1743-9191
1743-9159
Lippincott Williams & Wilkins Hagerstown, MD

38788199
IJS-D-24-01067
10.1097/JS9.0000000000001661
00005
3
Original Research
The effectiveness of combined extrahepatic bile duct resection in radically resected cases with intrahepatic cholangiocarcinoma: a SEER-based retrospective cohort study and an external validation
Lv Tian-Run MD ab849211303@qq.com

Wang Jun-Ke PhD ab1353781922@qq.com

Li Fu-Yu MD, PhD ab*lfy_74@hotmail.com

Hu Hai-Jie PhD abhhj1063557621@163.com

a Division of Biliary Tract Surgery, Department of General Surgery, West China Hospital, Sichuan University
b Research Center for Biliary Diseases, West China Hospital, Sichuan University, Chengdu, Sichuan, China
* Corresponding author. Address: Division of Biliary Tract Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China. Tel.: +86 028 8542 2465; fax: +86 028 8542 2465. E-mail: lfy_74 @hotmail.com (F.-Y. Li).
9 2024
24 5 2024
110 9 53425354
22 3 2024
9 5 2024
Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.
2024
https://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms. http://creativecommons.org/licenses/by-nc-sa/4.0/

Objective:

To evaluate the effectiveness of the combined extrahepatic bile duct resection (EHBDR) in cases with intrahepatic cholangiocarcinoma (IHCC) in terms of clinicopathological features and long-term survival.

Methods:

Radically resected cases with IHCC from 2000 to 2020 were identified from Surveillance, Epidemiology, and End Results (SEER) database. Comparative analyses were performed between resected IHCC patients who received EHBDR and those without EHBDR. Moreover, an external validation was further performed based on a single-center cohort.

Results:

A total of 1521 radically resected cases with IHCC (EHBDR: 189) were identified from the SEER database. Comparable age, sex, race, marital status, liver cirrhosis, differentiation status, and adjuvant chemotherapy were acquired between the two groups. EHBDR was associated with a higher incidence of adequate lymphadenectomy (P<0.001). The incidence of cases with T3–4 or N+ disease was significantly higher in EHBDR group (P<0.001). Adjuvant radiotherapy was more frequently performed in cases with EHBDR (P<0.001). EHBDR failed to bring any survival benefit and was associated with a worse prognosis even after matching. Similar findings have also been revealed in the external validation cohort (n=522, EHBDR: 117). EHBDR was associated with more extended resections, more aggressive tumor biological features, and worse prognosis. In the matched validation cohort, EHBDR was still associated with a higher incidence of early recurrence.

Conclusion:

EHBDR was an indicator of the advanced stage and failed to bring any survival benefit. It is the tumor stage that really determines the prognosis. More in-depth analyses focusing on different situations of EHBDR with more detailed clinical data are required.

Keywords:

bile duct resection
extrahepatic bile duct resection
intrahepatic cholangiocarcinoma
prognosis
OPEN-ACCESSTRUE
SDCT
==== Body
pmcIntroduction

Highlights

The current study first explored the effectiveness of combined extrahepatic bile duct resection (EHBDR) in cases with intrahepatic cholangiocarcinoma (IHCC) based on Surveillance, Epidemiology, and End Results (SEER) data.

After data incorporation of cases staged purely via the 7th American Joint Committee on Cancer (AJCC) criteria and cases staged purely via the 8th AJCC criteria, a relatively large sample size was acquired with a powerful conclusion.

Moreover, with our own single-center cohort incorporated, an external validation was performed, which further validated our findings based on the SEER cohort.

Consistent with previous findings, our results indicated that combined EHBDR was not associated with any survival benefit. EHBDR was an indicator of advanced disease. Cases for EHBDR should be high selected and well-prepared.

However, our study only provided a rough and direct analysis of the significance of bile duct resection without conducting specific analyses based on different situations. The effectiveness of combined EHBDR in IHCC cases should be further explored, especially for cases with lymph node metastasis around the hepatoduodenal ligament or many enlarged and undetermined lymph nodes around the hepatoduodenal ligament.

Intrahepatic cholangiocarcinoma (IHCC) is a deadly intrahepatic bile duct-derived primary liver malignancy (PLM), ranking as the second most common PLMs after hepatocellular carcinoma (HCC)1. Compared with cases with extrahepatic cholangiocarcinoma, IHCC cases rarely present with typical symptoms related to biliary obstruction, such as obstructive jaundice, particularly in the early stages of the disease2. Therefore, most cases with IHCC are diagnosed with an advanced disease, sharing a dismal prognosis. Currently, radical resection remains the cornerstone therapy among various therapeutic regimes for IHCC. However, even for cases with early-stage disease who received treatment at experienced high-volume centers, the overall prognosis remained unsatisfactory, with a reported 5-year survival rate ranging from 20% to 30%3,4.

The unfavorable postoperative prognosis of IHCC primarily arises from the early recurrence after surgery and the subsequent uncontrolled progression of the disease4. Therefore, identifying risk factors that predict early recurrence is crucial for achieving long-term survival. According to the latest 8th American Joint Committee on Cancer (AJCC) guidelines, apart from the three most conventional factors (T, N, and M), non-tumorous parenchymal fibrosis, primary sclerosing cholangitis, and serum CA19-9 level greater than 200 U/ml are highlighted as clinically relevant factors. Additionally, surgical margin, tumor size, tumor number (multi-focal tumors), microvascular invasion, lymph node metastasis, and perineural invasion have also been proven to be closely associated with the overall prognosis5–8. Most of these factors mentioned above can only be detected pathologically after surgery and cannot be controlled intraoperatively. On the contrary, there is a need to consider modifiable and adjustable factors that could impact the overall prognosis, such as performing combined extrahepatic bile duct resection (EHBDR).

Based on the latest National Comprehensive Cancer Network (NCCN) guidelines (Version 2.2023 – 10 May 2023), partial hepatectomy combined with a regional lymphadenectomy of the porta hepatis is considered as the standard surgical procedure for cases with resectable IHCC. However, to our knowledge, IHCC shares a high incidence of lymph node metastasis, and lymph nodes around the hepatoduodenal ligament (HDL) are the most common metastatic sites (around 82% of cases with lymph node metastasis were detected with positive lymph nodes around the HDL (Fig. 1A)9. Based on the liver’s congenital lymphatic drainage pathways (Fig. 1B), lymph nodes around the HDL and submucosal lymphatic vessels around the common bile duct (CBD) are potential pathways for lymph node metastasis, especially for tumors located in the right liver, which is similar to the metastatic pattern of gallbladder carcinoma (GBC). A prior study has highlighted the high incidence of micro-venous, lymphatic, or perineural invasion (PNI) around the HDL in GBC patients, especially for cases without an obvious extrahepatic bile duct infiltration10. This underscores the necessity of thorough lymphadenectomy encompassing all fibroadipose and lymphatic tissue surrounding the entire HDL for biliary tract cancers, particularly for IHCC cases6. However, the thorough skeletonization of the HDL often poses risks of bile duct ischemia, stenosis, vascular rupture, and bleeding11. In such circumstances, it is currently unclear whether combined EHBDR could contribute to more thorough tumor clearance, a higher lymph node yield for improved staging, and reduce the occurrences of bile duct stenosis and bleeding.

Figure 1 Images illustrating and depicting the lymph node metastasis around the hepatoduodenal ligament. (A) In the representative case with IHCC combined with lymph node metastasis around the hepatoduodenal ligament, the orange arrow indicated the primary tumor, and the red arrow indicated metastatic lymph nodes around the hepatoduodenal ligament. (B) The image depicts the lymphatic drainage pattern of the intrahepatic and extrahepatic biliary system. IHCC, intrahepatic cholangiocarcinoma.

Therefore, the current study was performed to evaluate the effectiveness of combined EHBDR in cases with IHCC after curative-intent resection.

Materials and methods

Patients of the training cohort

The U.S. Surveillance, Epidemiology, and End Results (SEER) is the largest publicly available cancer database, encompassing almost 28% of the American population12. Patients’ clinicopathological and survival information were extracted from the SEER Program (www.seer. cancer.gov) SEER*Stat database released in April 2023: version 8.4.1.2; SEER 17 Regs Custom Data (with SEER Plus data). The “Primary Site—labeled-liver” variable was used to identify cases with primary sites located in the liver from 2000 to 2020 (from 17 registries). The variable “behavior-malignant” was used to focus on malignant cases. Only cases with pathologically confirmed IHCC were considered eligible. The pathologically diagnosed variables were restricted to “Positive histology”. The pathology-related subtypes were restricted to “Cholangiocarcinoma” and “Combined hepatocellular carcinoma and cholangiocarcinoma”. Considering the similarities between 7th AJCC staging criteria and 8th AJCC staging criteria, cases only staged pathologically by 7th AJCC staging criteria [Derived AJCC TNM, 7th ed (2010–2015), cases only staged by Derived SEER Combined pTNM (2016–2017)], and cases only staged by 8th AJCC staging criteria [Derived EOD 2018 TNM (2018+)] were incorporated together. Therefore, T stages were roughly classified into T1–T2 and T3–T4. Similarly, N stages were also toughly classified into node negative (N−) and node positive (N+). Cases with distant metastasis (M1) would be ruled out. Finally, only M0 cases who received curative surgery with adequate surgery-related information [RX Summ—Surg Prim Site (1998+)—20 to 60, 65 to 75] and survival information (>1 month) were finally included. The detailed process of case selection and identification is summarized in Figure 2.

Figure 2 The specific process of patient selection, identification, and study design. BDR, bile duct resection; IHCC, intrahepatic cholangiocarcinoma.

Variable identification of the training cohort

A total of 12 variables were incorporated for further analyses, including diagnosis age, sex, race, marital status, concurrent liver cirrhosis, the number of resected lymph nodes, T stage, N stage, tumor differentiation status, pathological subtypes, adjuvant radiotherapy, and adjuvant chemotherapy. Based on our previous experience, the continuous data “Age” was classified into categorical variables: ≤60 and >60. The continuous data “Resected lymph nodes” was switched into categorical variables: <6, ≥6, and unknown. This kind of classification criteria is consistent with the 8th edition of the AJCC staging system for IHCC in a minimum number of six resected lymph nodes is recommended, which is also deemed as adequate lymphadenectomy. Minor adjustments were also applied to other categorical variables. For example, Marital status was simplified into three groups: married, single, and unknown. Accumulating evidence has revealed the relationship between marital status and the overall prognosis in cases with various cancers13–15. Therefore, the variable “marital status” has also been incorporated into the current research. Race was simplified into four groups: Asian, White, Black, and Others.

Patients of the external validation cohort

To further validate our findings, we retrospectively reviewed radically resected cases with pathologically confirmed IHCC at our hospital from 1 January 2011, to 1 January 2023. Only M0 cases with adequate survival information (recorded survival period >0 months) and complete clinical data would be deemed eligible. Upon admission, all surgical candidates have received thorough systemic body examinations, including blood tests and radiological imaging such as Computed Tomography (CT), Magnetic Resonance Imaging (MRI), and even Positron Emission Tomography-Computed Tomography (PET-CT), to conduct an initial assessment of tumor staging and to exclude patients who were not suitable for curative-intent surgery. For surgical candidates, a preoperative multidisciplinary discussion in identifying the optimal surgical regime, especially the extent of resection, would always be applied. All cases in the external validation cohort were staged according to the 8th AJCC staging system.

Variables identification of the external validation cohort

As for the external validation cohort, more detailed clinical data were collected, allowing for additional analyses of various valuable variables. These newly provided variables included preoperative obstructive jaundice, preoperative CA19-9 level, major hepatectomy, combined multivisceral resections, surgical margin, PNI, lymph-vascular invasion (LVI), tumor number, satellite nodules, major vascular invasion, microvascular invasion, mortalities within 90 days after surgery, postoperative any complications, recurrence, and recurrence within 6 months after surgery.

Major hepatectomy was defined as the removal of at least three segments of the liver. Combined multivisceral resections were defined as the removal of organs other than the liver, gallbladder, and extrahepatic bile duct, such as the combined resection of the duodenum or the colon. Postoperative complications encompassed conditions like intra-abdominal infection, bleeding, bile leakage, pulmonary infection, and ascites. These complications were identified by reviewing patients’ electronic medical records, blood tests, and radiological examinations before and after surgery. Postoperative recurrence was determined by the detection of recurrent lesions on radiological examinations, potentially accompanied by an increase in the CA19-9 tumor biomarker levels.

Follow-up of the external validation cohort

All postoperative patients were regularly followed up in the outpatient clinic of our hospital every 2–3 months in the first 2 years and every 6 months thereafter. Follow-up assessments involved enhanced chest and abdominal CT scans, as well as monitoring serum tumor markers. Postoperative survival statuses were routinely updated in our cancer database annually through telephone interviews or by reviewing outpatient medical records. The most recent follow-up was conducted on 1 January 2024.

Inclusion criteria for patients in the external validation cohort

Patients with pathologically confirmed IHCC who underwent radical resection and were categorized as M0.

Patients with sufficient survival data (recorded survival period >0 mo).

Patients with comprehensive clinical data available.

Patients with adequate follow-up information.

Exclusion criteria for patients in the external validation cohort

Patients lacking pathological confirmation of IHCC.

Patients who failed to receive curative-intent surgery.

Patients who received radical resection but did not have detailed surgical information or adequate follow-up data.

Patients without adequate required clinical data for further analysis.

Study design

Firstly, comparative analyses were conducted between patients who received EHBDR and those who did not, focusing on clinicopathological features and long-term survival in both the SEER-derived cohort and the external validation cohort. Subgroup analyses, categorized by different T and N classifications, were subsequently performed between the two groups. A propensity score matching (PSM) was also performed for a more in-depth evaluation of the effectiveness of EHBDR. Details of the study design have been summarized in Figure 2. Current study was approved by the ethical committee of our hospital (ethical number: 20232416) and was registered with the Chinese Clinical Trial Registry (https://www.chictr.org.cn/indexEN.html). Data was reported based on STROCSS 2021 criteria16 (Supplemental Digital Content 1, http://links.lww.com/JS9/C665).

Statistical analysis

R software 4.2.2 was used for statistical analysis. R package tableone was used for baseline comparison and subsequent table output. Categorical data are recorded as numbers (percentages). Categorical variables were evaluated via χ 2 and Fisher’s exact tests. Survival analyses were accomplished via R packages survminer and survival. Kaplan–Meier curves and the corresponding risk table were depicted via R command ggsurvplot. Overall survival (OS) was defined as the living time from the date of receiving radical surgery to the date of death or last follow-up. Cancer-specific survival (CSS) was defined as the living time from the date of radical surgery to the date of death due to cancer progression. Disease-free survival (DFS) was defined as the date of surgery to the date of an obvious detection of recurrence either radiologically or pathologically. R packages survminer, dplyr, survival, and rms were used for the construction of the Cox-proportional hazards model, which was presented with hazard ratio (HR) and its 95% confidence interval (CI). P values lower than 0.05 indicated statistical differences.

To evaluate the effectiveness of EHBDR more independently and avoid the survival impact brought by many other prognostic factors, the PSM analysis was further performed (R package MatchIt, method=“nearest”, caliper=0.05, ratio=2/1). Matching factors mainly included age, sex, and other independent prognostic factors.

Results

SEER cohort

Comparison of clinicopathological features and long-term survival between patients who received EHBDR and those without EHBDR

As is summarized in Table 1, a total of 1521 resected cases with pathologically confirmed IHCC from SEER data were included, and 189 cases received the combined EHBDR. Patients who received EHBDR were comparable to those without EHBDR in the following parameters: age, sex, race, marital status, concurrent liver cirrhosis, differentiation status, and adjuvant radiotherapy. However, the number of cases who achieved adequate lymphadenectomy was significantly higher in the EHBDR group than those without EHBDR (P<0.001). Moreover, patients who received EHBDR were generally in a more advanced stage and the incidence of cases with T3–T4 or N+ disease was significantly higher in the EHBDR group (P<0.001). Additionally, when stratified by OS, adjuvant radiotherapy was more frequently performed in cases with EHBDR (P<0.001). As for postoperative long-term survival, cases who received combined EHBDR shared a much worse OS (median survival time: 31 vs 43 mo, P<0.001) (Fig. 3A) or CSS (median survival time: 18 vs 20 mo, P=0.034) (Fig. 3G). Subgroup analyses were performed based on different T and N categories, and the results were similar in that the long-term survival of cases with EHBDR was inferior to those without EHBDR (Fig. 3B–F, H–L).

Table 1 Comparative analyses between cases with BDR and those without BDR base on OS and CSS before PSM of the SEER cohort.

		OS	CSS	
Variables	Groups	Overall (n=1521)	BDR (n=189)	BDNR (n=1332)	P	Overall (n=628)	BDR (n=88)	BNDR (n=540)	P	
Age	>60	1044 (68.6)	121 (64.0)	923 (69.3)	0.154	421 (67.0)	51 (58.0)	370 (68.5)	0.066	
	≤60	477 (31.4)	68 (36.0)	409 (30.7)		207 (33.0)	37 (42.0)	170 (31.5)		
Sex	Female	783 (51.5)	88 (46.6)	695 (52.2)	0.162	306 (48.7)	39 (44.3)	267 (49.4)	0.421	
	Male	738 (48.5)	101 (53.4)	637 (47.8)		322 (51.3)	49 (55.7)	273 (50.6)		
Race	Asian	211 (13.9)	19 (10.1)	192 (14.4)	0.311	89 (14.2)	10 (11.4)	79 (14.6)	0.470	
	White	1193 (78.4)	158 (83.6)	1035 (77.7)		492 (78.3)	73 (83.0)	419 (77.6)		
	Black	108 (7.1)	11 (5.8)	97 (7.3)		43 (6.8)	4 (4.5)	39 (7.2)		
	Others	9 (0.6)	1 (0.5)	8 (0.6)		4 (0.6)	1 (1.1)	3 (0.6)		
Marital	Married	948 (62.3)	116 (61.4)	832 (62.5)	0.478	391 (62.3)	57 (64.8)	334 (61.9)	0.635	
	Single	509 (33.5)	68 (36.0)	441 (33.1)		209 (33.3)	29 (33.0)	180 (33.3)		
	Unknown	64 (4.2)	5 (2.6)	59 (4.4)		28 (4.5)	2 (2.3)	26 (4.8)		
Cirrhosis	Yes	44 (2.9)	2 (1.1)	42 (3.2)	0.272	75 (11.9)	9 (10.2)	66 (12.2)	0.052	
	No	148 (9.7)	17 (9.0)	131 (9.8)		27 (4.3)	0 (0.0)	27 (5.0)		
	Unknown	1329 (87.4)	170 (89.9)	1159 (87.0)		526 (83.8)	79 (89.8)	447 (82.8)		
Number of resected LNs	<6	1197 (78.7)	126 (66.7)	1071 (80.4)	<0.001	496 (79.0)	53 (60.2)	443 (82.0)	<0.001	
	≥6	301 (19.8)	57 (30.2)	244 (18.3)		126 (20.1)	32 (36.4)	94 (17.4)		
	Unknown	23 (1.5)	6 (3.2)	17 (1.3)		6 (1.0)	3 (3.4)	3 (0.6)		
T stage	T1–T2	1215 (79.9)	128 (67.7)	1087 (81.6)	<0.001	448 (71.3)	51 (58.0)	397 (73.5)	0.005	
	T3–T4	306 (20.1)	61 (32.3)	245 (18.4)		180 (28.7)	37 (42.0)	143 (26.5)		
N stage	N−	1162 (76.4)	117 (61.9)	1045 (78.5)	<0.001	408 (65.0)	38 (43.2)	370 (68.5)	<0.001	
	N+	359 (23.6)	72 (38.1)	287 (21.5)		220 (35.0)	50 (56.8)	170 (31.5)		
Differentiation grade	Well to moderate	862 (56.7)	109 (57.7)	753 (56.5)	0.952	348 (55.4)	45 (51.1)	303 (56.1)	0.443	
	Poorly to undifferentiated	417 (27.4)	50 (26.5)	367 (27.6)		197 (31.4)	28 (31.8)	169 (31.3)		
	Unknown	242 (15.9)	30 (15.9)	212 (15.9)		83 (13.2)	15 (17.0)	68 (12.6)		
Pathology	IHCC	1494 (98.2)	187 (98.9)	1307 (98.1)	0.566	617 (98.2)	87 (98.9)	530 (98.1)	1.000	
	CHCC-CC	27 (1.8)	2 (1.1)	25 (1.9)		11 (1.8)	1 (1.1)	10 (1.9)		
Adjuvant radiotherapy	Performed	218 (14.3)	45 (23.8)	173 (13.0)	<0.001	98 (15.6)	17 (19.3)	81 (15.0)	0.341	
	Not performed	1303 (85.7)	144 (76.2)	1159 (87.0)		530 (84.4)	71 (80.7)	459 (85.0)		
Adjuvant chemotherapy	Performed	786 (51.7)	104 (55.0)	682 (51.2)	0.351	315 (50.2)	49 (55.7)	266 (49.3)	0.301	
	Not performed	735 (48.3)	85 (45.0)	650 (48.8)		313 (49.8)	39 (44.3)	274 (50.7)		
BDNR, bile duct non-resected; BDR, bile duct resected; CHCC-CC, combined hepatocellular carcinoma and cholangiocarcinoma; CSS, cancer-specific survival; IHCC, intrahepatic cholangiocarcinoma; LN, lymph node; OS, overall survival; PSM, propensity score matching.

Figure 3 Kaplan–Meier curves presenting the survival difference between patients who received BDR and those without BDR in the SEER (Surveillance, Epidemiology, and End Results) cohort before propensity score matching. (A) OS of the entire cohort; (B) OS among cases with T1–T2 disease; (C) OS among cases with T3–T4 disease; (D) OS among cases with N− disease; (E) OS among cases with N+ disease; (F) OS among cases with T3–T4 and N+ disease; (G) CSS among the entire cohort; (H) CSS among cases with T1–T2 disease; (I) CSS among cases with T3–T4 disease; (J) CSS among cases with N− disease; (K) CSS among cases with N+ disease; (L) CSS among cases with T3–T4 and N+ disease. BDR, bile duct resection; CSS, cancer-specific survival; N−, lymph node negative; N+, lymph node positive; OS, overall survival.

Univariate and multivariate Cox regression of prognostic factors for OS and CSS

As is summarized in Table 2, sex (male vs. female), liver cirrhosis (no vs. yes vs. unknown), EHBDR (not performed vs. performed), T stage (T1–T2 vs. T3–T4), N stage (N− vs. N+), and tumor differentiation grade (well to moderate vs. poorly to undifferentiated vs. unknown) were prognostic factors for OS. Sex (male vs. female), liver cirrhosis (no vs. yes vs. unknown), T stage (T1–T2 vs. T3–T4), N stage (N− vs. N+), and differentiation grade (well to moderate vs. poorly to undifferentiated vs. unknown) were independent prognostic factors for OS.

Table 2 Univariate and multivariate Cox regression for prognostic factors for OS and CSS of the SEER cohort.

		OS	CSS	
		Univariate analysis	Multivariate analysis	Univariate analysis	Multivariate analysis	
Variables	Groups	HR (95% CI)	P	HR (95% CI)	P	HR (95% CI)	P	HR (95% CI)	P	
Age	≤60	Reference			Reference			
	>60	1.148 (0.984–1.339)	0.079			1.104 (0.935–1.304)	0.245			
Sex	Male	Reference	Reference	Reference			
	Female	0.808 (0.701–0.932)	0.003	0.835 (0.723–0.965)	0.014	0.881 (0.753–1.031)	0.113			
Race	Asian	Reference			Reference			
	White	0.988 (0.799–1.223)	0.914			0.855 (0.682–1.072)	0.175			
	Black	1.053 (0.754–1.470)	0.764			0.965 (0.670–1.389)	0.847			
	Others	1.005 (0.370–2.731)	0.993			0.777 (0.285–2.119)	0.623			
Marital status	Married	Reference			Reference			
	Single	1.001 (0.859–1.166)	0.987			1.071 (0.904–1.269)	0.426			
	Unknown	1.071 (0.749–1.533)	0.706			1.233 (0.840–1.811)	0.284			
Cirrhosis	No	Reference	Reference	Reference	Reference	
	Yes	1.216 (0.798–1.852)	0.363	1.308 (0.857–1.996)	0.214	1.129 (0.727–1.754)	0.588	1.269 (0.815–1.975)	0.292	
	Unknown	1.397 (1.114–1.752)	0.004	1.388 (1.106–1.743)	0.005	1.430 (1.122–1.823)	0.004	1.406 (1.101–1.796)	0.006	
BDR	Not performed	Reference	Reference	Reference	Reference	
	Performed	1.435 (1.174–1.754)	<0.001	1.168 (0.952–1.434)	0.136	1.276 (1.017–1.600)	0.035	1.151 (0.913–1.449)	0.234	
N stage	N−	Reference	Reference	Reference	Reference	
	N+	2.564 (2.192–2.999)	<0.001	2.340 (1.990–2.752)	<0.001	1.494 (1.265–1.763)	<0.001	1.424 (1.201–1.687)	<0.001	
Number of harvested LNs	<6	Reference			Reference			
	≥6	1.093 (0.912–1.310)	0.334			1.174 (0.965–1.429)	0.109			
	Unknown	0.770 (0.383–1.548)	0.463			1.016 (0.454–2.274)	0.970			
Grade	Well to moderate	Reference	Reference	Reference	Reference	
	Poorly to undifferentiated	1.334 (1.136–1.566)	<0.001	1.351 (1.151–1.587)	<0.001	1.440 (1.206–1.720)	<0.001	1.480 (1.239–1.770)	<0.001	
	Unknown	1.038 (0.835–1.291)	0.736	0.989 (0.794–1.231)	0.921	1.019 (0.802–1.296)	0.875	0.973 (0.765–1.238)	0.827	
Pathological subtype	HCC-HCC	Reference			Reference			
	IHCC	1.248 (0.721–2.161)	0.429			0.730 (0.402–1.327)	0.303			
T stage	T1–T2	Reference	Reference	Reference	Reference	
	T3–T4	1.956 (1.665–2.299)	<0.001	1.663 (1.410–1.961)	<0.001	1.539 (1.291–1.834)	<0.001	1.484 (1.242–1.774)	<0.001	
Adjuvant chemotherapy	Not performed	Reference			Reference			
	Performed	1.001 (0.867–1.156)	0.985			0.942 (0.805–1.102)	0.452			
Adjuvant radiotherapy	Not performed	Reference			Reference			
	Performed	1.093 (0.896–1.333)	0.380			0.881 (0.710–1.093)	0.250			
BDNR, bile duct non-resected; BDR, bile duct resected; CHCC-CC, combined hepatocellular carcinoma and cholangiocarcinoma; CSS, cancer-specific survival; IHCC, intrahepatic cholangiocarcinoma; LN, lymph node; OS: overall survival.

Liver cirrhosis (no vs. yes vs. unknown), EHBDR (not performed vs. performed), T stage (T1–T2 vs. T3–T4), N stage (N− vs. N+), and differentiation grade (well to moderate vs. poorly to undifferentiated vs unknown) were prognostic for CSS. Liver cirrhosis (no vs. yes vs. unknown), T stage (T1–T2 vs. T3–T4), N stage (N− vs. N+), and differentiation grade (well to moderate vs. poorly to undifferentiated vs. unknown) were independent prognostic factors for CSS.

PSM analyses

In order to evaluate the significance of EHBDR independently in resected cases with IHCC in terms of OS and CSS, PSM analyses were performed via controlling age, sex, and their corresponding independent prognostic factors (OS: cirrhosis, T stage, N stage, and tumor differentiation grade; CSS: cirrhosis, T stage, N stage, and tumor differentiation grade). After a ratio of 1:2 matching, as is summarized in Table 3, all analyzed clinical parameters were comparable between two groups, either for the entire cohort or cases that died due to cancer. However, the long-term survival of cases with EHBDR was still inferior to those without EHBDR, even when focused on different T and N categories (Fig. 4A–L).

Table 3 Comparative analyses between cases with BDR and those without BDR base on OS and CSS after PSM of the SEER cohort.

		OS	CSS	
Variables	Groups	Overall (n=546)	BDR (n=182)	BDNR (n=364)	P	Overall (n=254)	BDR (n=83)	BDNR (n=171)	P	
Age	>60	185 (33.9)	62 (34.1)	123 (33.8)	0.949	94 (37.0)	33 (39.8)	61 (35.7)	0.527	
	≤60	361 (66.1)	120 (65.9)	241 (66.2)		160 (63.0)	50 (60.2)	110 (64.3)		
Sex	Female	267 (48.9)	88 (48.4)	179 (49.2)	0.856	115 (45.3)	39 (47.0)	76 (44.4)	0.702	
	Male	279 (51.1)	94 (51.6)	185 (50.8)		139 (54.7)	44 (53.0)	95 (55.6)		
Race	Asian	73 (13.4)	18 (9.9)	55 (15.1)	0.187	43 (16.9)	10 (12.0)	33 (19.3)	0.127	
	White	428 (78.4)	152 (83.5)	276 (75.8)		191 (75.2)	68 (81.9)	123 (71.9)		
	Black	43 (7.9)	11 (6.0)	32 (8.8)		19 (7.5)	4 (4.8)	15 (8.8)		
	Others	2 (0.4)	1 (0.5)	1 (0.3)		1 (0.4)	1 (1.2)	0 (0.0)		
Marital	Married	340 (62.3)	112 (61.5)	228 (62.6)	0.300	156 (61.4)	53 (63.9)	103 (60.2)	0.731	
	Single	185 (33.9)	66 (36.3)	119 (32.7)		89 (35.0)	28 (33.7)	61 (35.7)		
	Unknown	21 (3.8)	4 (2.2)	17 (4.7)		9 (3.5)	2 (2.4)	7 (4.1)		
Cirrhosis	Yes	5 (0.9)	2 (1.1)	3 (0.8)	0.945	3 (1.2)	0 (0.0)	3 (1.8)	0.471	
	No	50 (9.2)	17 (9.3)	33 (9.1)		26 (10.2)	9 (10.8)	17 (9.9)		
	Unknown	491 (89.9)	163 (89.6)	328 (90.1)		225 (88.6)	74 (89.2)	151 (88.3)		
Number of resected LNs	<6	397 (72.7)	123 (67.6)	274 (75.3)	0.126	185 (72.8)	51 (61.4)	134 (78.4)	0.017	
	≥6	139 (25.5)	54 (29.7)	85 (23.4)		65 (25.6)	30 (36.1)	35 (20.5)		
	Unknown	10 (1.8)	5 (2.7)	5 (1.4)		4 (1.6)	2 (2.4)	2 (1.2)		
T stage	T1–T2	387 (70.9)	128 (70.3)	259 (71.2)	0.842	167 (65.7)	51 (61.4)	116 (67.8)	0.314	
	T3–T4	159 (29.1)	54 (29.7)	105 (28.8)		87 (34.3)	32 (38.6)	55 (32.2)		
N stage	N−	349 (63.9)	117 (64.3)	232 (63.7)	0.900	129 (50.8)	38 (45.8)	91 (53.2)	0.266	
	N+	197 (36.1)	65 (35.7)	132 (36.3)		125 (49.2)	45 (54.2)	80 (46.8)		
Differentiation grade	Well to moderate	318 (58.2)	109 (59.9)	209 (57.4)	0.737	141 (55.5)	45 (54.2)	96 (56.1)	0.930	
	Poorly to undifferentiated	144 (26.4)	48 (26.4)	96 (26.4)		79 (31.1)	26 (31.3)	53 (31.0)		
	Unknown	84 (15.4)	25 (13.7)	59 (16.2)		34 (13.4)	12 (14.5)	22 (12.9)		
Pathology	IHCC	540 (98.9)	180 (98.9)	360 (98.9)	1.000	250 (98.4)	82 (98.8)	168 (98.2)	0.741	
	CHCC-CC	6 (1.1)	2 (1.1)	4 (1.1)		4 (1.6)	1 (1.2)	3 (1.8)		
Adjuvant radiotherapy	Performed	107 (19.6)	42 (23.1)	65 (17.9)	0.147	53 (20.9)	15 (18.1)	38 (22.2)	0.445	
	Not performed	439 (80.4)	140 (76.9)	299 (82.1)		201 (79.1)	68 (81.9)	133 (77.8)		
Adjuvant chemotherapy	Performed	312 (57.1)	98 (53.8)	214 (58.8)	0.271	144 (56.7)	45 (54.2)	99 (57.9)	0.579	
	Not performed	234 (42.9)	84 (46.2)	150 (41.2)		110 (43.3)	38 (45.8)	72 (42.1)		
BDNR, bile duct non-resected; BDR, bile duct resected; HCC-CC, combined hepatocellular carcinoma and cholangiocarcinoma; IHCC, intrahepatic cholangiocarcinoma; LN, lymph node; OS, overall survival; PSM, propensity score matching.

Figure 4 Kaplan–Meier curves presenting the survival difference between patients who received BDR and those without BDR in the SEER (Surveillance, Epidemiology, and End Results) cohort after propensity score matching. (A) OS of the entire cohort; (B) OS among cases with T1–T2 disease; (C) OS among cases with T3–T4 disease; (D) OS among cases with N− disease; (E) OS among cases with N+ disease; (F) OS among cases with T3–T4 and N+ disease; (G) CSS among the entire cohort; (H) CSS among cases with T1–T2 disease; (I) CSS among cases with T3–T4 disease; (J) CSS among cases with N− disease; (K) CSS among cases with N+ disease; (L) CSS among cases with T3–T4 and N+ disease. BDR, bile duct resection; CSS, cancer-specific survival; N−, lymph node negative; N+, lymph node positive; OS, overall survival.

External validation cohort

Comparison of clinicopathological features and long-term survival between patients who received EHBDR and those without EHBDR

Initially, a total of 965 radically resected cases with pathologically confirmed IHCC were identified in our own cancer database. Among these, 627 patients had complete follow-up information. Among the 627 patients, 105 cases were excluded from the analysis due to missing vital pathological information or surgical details, resulting in 522 patients being included in the final analysis, with 117 cases having received EHBDR. For continuous variables, such as preoperative CA19-9, only a small number of cases were missing this critical parameter. To address these missing values, multiple imputation methods were employed, specifically utilizing the R package mice for imputation. The overall rate of loss to follow-up was 35.0%. The median follow-up time was 47.5 months, with an interquartile range (IQR) from 36.25 to 65 months. As is summarized in Supplementary Table S1 (Supplemental Digital Content 2, http://links.lww.com/JS9/C666), similar comparative analyses in terms of clinicopathological features and long-term survival were performed in the validation cohort and the results indicated that EHBDR was associated with a higher incidence of preoperative jaundice (P<0.001), more extended range of resections, more aggressive tumor-related pathological features, and worse prognosis. Cases who received EHBDR shared a higher preoperative CA19-9 level (P<0.001). Moreover, major hepatectomy (P<0.001), combined multivisceral resections (P<0.001), positive surgical margins (P<0.001), lymph node metastasis (P<0.001), PNI (P<0.001), LVI (P<0.001), multiple tumors (P<0.001), satellite nodules (P<0.001), poorly differentiated tumor (P=0.001), major vascular invasion (P<0.001), and advanced T3–T4 stage (P<0.001) were more frequently detected in cases with EHBDR. EHBDR was related to a higher incidence of postoperative complications (P<0.001). The overall recurrence rate (P<0.001) and the recurrence rate within 6 months after surgery (P<0.001) were significantly higher in cases who received EHBDR. Survival analyses indicated that EHBDR was associated with worse OS and DFS, and it failed to bring any survival benefit for resected cases with IHCC, even when focused on different T or N categories (Supplementary Figure S1A–L, Supplemental Digital Content 3, http://links.lww.com/JS9/C667).

Univariate and multivariate Cox regression of prognostic factors for OS and DFS

The results of both univariate and multivariate Cox regression indicated that EHBDR was a risk factor, but it was not an independent prognostic factor for OS (Supplementary Table S2, Supplemental Digital Content 4, http://links.lww.com/JS9/C668) or DFS (Supplementary Table S3, Supplemental Digital Content 5, http://links.lww.com/JS9/C669). Additionally, several other unvalidated prognostic factors, along with independent prognostic factors beyond those identified in the SEER cohort, were identified, including elevated preoperative CA19-9 levels, positive surgical margins, multiple tumors, satellite nodules, and postoperative adjuvant chemotherapy (Supplementary Table S2, Supplemental Digital Content 4, http://links.lww.com/JS9/C668; Supplementary Table S3, Supplemental Digital Content 5, http://links.lww.com/JS9/C669).

PSM analyses

The PSM analyses in the external validation cohort were performed via controlling age, sex, and other independent prognostic factors for OS (preoperative CA19-9 level, combined multivisceral resections, surgical margin status, T stage, N stage, tumor differentiation grade, pathological subtypes, macrovascular invasion, microvascular invasion, tumor number, satellite nodules, and postoperative adjuvant chemotherapy). Owing to the limited number of cases who received EHBDR and numerous factors required to be controlled in the validation cohort, the previous matching ratio of 1:2 utilized in the SEER data-based analyses was abandoned in favor of a 1:1 ratio to include more EHBDR cases in the validation cohort. After matching, as is summarized in Supplementary Table S4, Supplemental Digital Content 6, http://links.lww.com/JS9/C670, a total of 152 cases (76 cases received EHBDR) were identified. Almost all variables were comparable except for preoperative jaundice (P<0.001), PNI (P<0.001), and postoperative complications (P=0.003). Moreover, cases in the EHBDR group still shared a higher early recurrence rate with a borderline P value than those without EHBDR (36.8% vs. 22.4%, P=0.051). Survival analyses in the matched cohort revealed that EHBDR was also associated with a worse prognosis in terms of OS (Supplementary Figure S2A–F, Supplemental Digital Content 7, http://links.lww.com/JS9/C671) or DFS (Supplementary Figure S2G–L, Supplemental Digital Content 7, http://links.lww.com/JS9/C671).

Discussion

Our research represents the first exploration of the significance of combined EHBDR in resected cases with IHCC. Previous studies have systematically evaluated the significance of EHBDR in resected cases with GBC17,18. Their findings consistently indicated that combined EHBDR was not associated with improved long-term survival, and it was even harmful in cases with early-stage disease. The results were similar for resected cases with IHCC in that combined EHBDR was associated with a worse prognosis even though various independent prognostic factors have been matched. The HR of EHBDR was higher than 1, suggesting that EHBDR was a risk factor rather than a protective factor. More importantly, the effectiveness of EHBDR in resected cases with IHCC was further validated in our single-center cohort, with more clinical and pathological variables included.

The reasonability and superiority of EHBDR in IHCC mainly lies in its contribution to tumor clearance. As previously described, tumor cells can disseminate secretly via various methods, especially lymphatic vessel-mediated occult metastasis and hematogenous spreading. The whole extrahepatic bile duct is surrounded by an abundant lymphatic network as well as loose adipose and fibrous connective tissue. As such, tumor clearance can be rather technically challenging and unattainable. By contrast, a thoroughgoing lymphadenectomy, along with the extrahepatic bile duct, often faces various fatal complications due to extensive lymphadenectomy. Owing to the intraoperative electronic or ultrasonic knife-mediated physical burning as well as the loss of protection of loose connective tissue, skeletonized bile duct often faces the risk of ischemia, stricture, and subsequently bile leakage11,19. Skeletonized vascular, such as portal veins or hepatic arteries, are often at risk of spontaneous rupture and hemorrhage11,19. Therefore, considering the unfeasibility of intraoperative confirmation of tumor clearance via direct visual observation as well as the surgical procedure-related deadly complications, en-bloc resection of extrahepatic bile duct might be the optimal choice for cases with IHCC. Additionally, combined EHBDR has been demonstrated to have a greater lymph yield20, which would contribute to a more comprehensive tumor staging and consequently guide clinicians to adopt more appropriate therapeutic regimes.

The only drawback of EHBDR is the morbidity associated with biliary-enteric anastomosis (BEA), with a reported incidence of 3–43%21–24. The loss of duodenal papilla function and the retrograde movement of luminal flora could lead to unbearable symptoms, negatively impacting long-term quality of life21–24. Cholangitis, a common infectious complication following BEA, can lead to urgent hospitalizations and life-threatening events, such as portal vein hypertension, biliary stricture, or cirrhosis25,26. Previous studies have suggested that interrupted sutures were linked to a reduced incidence of anastomotic strictures, a factor closely correlated with cholangitis27. A completed randomized controlled trial in evaluating the effectiveness of running suturing versus interrupted suturing for BEA (ClinicalTrials.gov: NCT02658643) has reported that continuous suturing of BEA was associated with a greatly shortened suturing time versus interrupted suturing28. Moreover, the overall incidence of bile leakage was relatively low among all participates and no anastomotic stenosis was detected28. Additionally, various factors, including the length of the Roux-en-Y limb, the location of the biliary anastomosis, and the presence of preoperative biliary drainage, might also play a role in triggering cholangitis29. Nevertheless, no conclusive evidence has been found to address this issue. One previous systematic review and meta-analysis focusing on the impact of cholangitis following BEA suggested that with modern oncological therapies, complications related to BEA rarely influence the overall quality of life29. Other studies have similarly indicated that these complications typically result in only a transient fever and would not influence the patient’s overall prognosis, except in elderly patients with advanced and deteriorating disease30.

However, our ultimate results failed to demonstrate any survival benefit brought by EHBDR, which can be explained by various reasons. Firstly, cases who received a combined EHBDR were often found to have an obvious bile duct infiltration. For such cases, the disease itself has evolved into a systemic rather than a localized and regional status, which greatly diminishes the effect of radical resection. Secondly, numerous unrecorded factors such as preoperative comorbidities, postoperative nutritional status, and inconsistencies in postoperative chemotherapy agents might also greatly influence the overall prognosis. However, the absence of related clinical data hindered us from further exploration. Thirdly, owing to the retrospective nature, the evolvement in perioperative management, surgical techniques, and postoperative adjuvant therapies would also impact the overall prognosis to some extent. Fourth, as is indicated in the 8th AJCC guidelines, IHCC exhibits a unique lymphatic drainage pattern, where tumors located in the right liver share a similar drainage pattern with GBC, primarily derived from the hepatic hilar lymph nodes, along with the common bile duct and toward the portal vein lymph nodes. Further evaluation of EHBDR in resected IHCC cases with right liver localization would be more valuable. However, since only two cases with tumors located in the right liver received the combined EHBDR and the inadequate original data of our own cohort, further analysis would not be feasible. Additionally, although the relevant analyses in the external validation cohort evaluated more clinical parameters, such as the overall recurrence rate and the recurrence rate within 6 months after surgery. However, the effectiveness of EHBDR in resected IHCC cases remains to be explored in many other clinical parameters. For example, the period from the date of surgery to the date of an obvious obstructive jaundice. The early occurrence of obstructive jaundice indicated the early recurrence as well as a worsened quality of life. Hepatocyte toxicity caused by high bilirubin levels could also impair liver function chronically and would further shorten the survival period of cancer cases, especially for IHCC cases after partial or more extended hepatectomy. However, such vital clinical information was not specifically recorded in our own cancer database, not even to be recorded in the SEER database. Therefore, the role of EHBDR in resected IHCC cases still requires more in-depth research. Based on the evidence acquired in our research, the combined EHBDR is not associated with any survival benefits and is more likely to be an indicator of advanced disease. Nevertheless, for cases with more advanced disease, such as T3–T4 and N+ cases, the combined EHBDR not only achieved equivalent postoperative survival period between the two groups but also achieved a greater lymph node yield, which would be of clinical benefit for better tumor staging and the application of postoperative adjuvant therapies.

The current study should be interpreted with several limitations. Firstly, the absence of various vital data, such as the time from the date of surgery to the date of the occurrence of obstructive jaundice, has hindered us from further exploration of the effectiveness of EHBDR. More detailed information is required. Secondly, owing to the retrospective nature and the aged cohort (spanned nearly 20 years), various uncontrolled confounding factors might also significantly influence the overall prognosis. Thirdly, although the external validation was performed, the limited sample size, as well as the single-center nature, further undermined its powerfulness. Fourth, in clinical practice, the decision to perform EHBDR is typically based on comprehensive considerations across various aspects. For instance, EHBDR is commonly carried out in IHCC cases with hilar invasion or with an obvious extrahepatic bile duct invasion. However, it could also be applied in cases with lymph node metastasis around the HDL or many enlarged and undetermined lymph nodes around the HDL. In such a circumstance, a simple lymphadenectomy might fail to ensure the tumor clearance, while overly aggressive lymphadenectomy around the HDL poses a significant risk of bile duct injury. Hence, en-bloc resection of the liver, together with the extrahepatic bile duct might contribute to unforeseen or more favorable outcomes. Subgroup analyses are necessary to understand how different scenarios influence the decision to perform EHBDR. Unfortunately, a lack of comprehensive original data has hindered our ability to explore this further. Fifth, despite significant advancements in surgical techniques, varying levels of active engagement in clinical, translational, and basic research, coupled with disparities in perioperative care and differing surgical volumes, lead to considerable differences in short-term and long-term outcomes among cancer patients across regions and countries. These uncontrollable variations could introduce inherent biases into our research. Therefore, the proposal to concentrate cases of malignant diseases in high-volume centers, as suggested by Marano et al.31, holds significant clinical importance. The concentration of medical resources and patients could better mitigate the varying healthcare outcomes resulting from differences in medical expertise and experience among different centers or regions. This is highly relevant to our exploration of the effectiveness of EHBDR in IHCC and could offer valuable insights.

Conclusion

The combined EHBDR failed to bring any survival benefit for resected cases with IHCC. On the contrary, EHBDR indicated a more advanced tumor stage, more aggressive tumor biological features, and a worse prognosis. What truly determines the prognosis is the tumor stage rather than the combined EHBDR. In the future, more in-depth analyses focusing on different situations of EHBDR, especially for cases with lymph node metastasis around the HDL or many enlarged and undetermined lymph nodes around the HDL, are critically required.

Ethical approval

The current study was performed based on a public cancer database (SEER) and was approved by the ethical committee of West China Hospital [2023 (2416)].

Consent

The current study was approved by the ethical committee of West China Hospital (ethics number: 20232416).

Sources of funding

This study was supported by Sichuan Natural Science Foundation Youth Foundation Project (2024NSFSC1949); 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University (ZYJC21046); 1.3.5 project for disciplines of excellence clinical Research Incubation Project, West China Hospital, Sichuan University (2021HXFH001); National Natural Science Foundation of China for Young Scientists Fund (82203782); Sichuan University-Sui Ning School-local Cooperation project (2022CDSN-18); China Telecom Sichuan Company Biliary Tract Tumor Big Data Platform and Application Phase I R&D Project (312230752); the Postdoctor Research Fund of West China Hospital, Sichuan University (2024HXBH134).

Role of the funding source: The funding source has no role in the design and preparation of the manuscript.

Author contribution

T.-R.L.: data acquisition, formal analysis, and drafted the manuscript; J.-K.W.: literature review, manuscript editing, and subsequent revisions; H.-J.H. and F.-Y.L. editing the manuscript; F.-Y.L.: study design and revision of the manuscript.

Conflicts of interest disclosure

All authors declare that they have no conflicts of interest to disclose.

Research registration unique identifying number (UIN)

The current study was performed based on the public SEER data and was registered in the Chinese Clinical Trial Registry (https://www.chictr.org.cn/indexEN.html) (ChiCTR2400079858).

Guarantor

Tian-Run Lv and Fu-Yu Li.

Data availability statement

All data were extracted from the cancer database of SEER database, and they can be provided if required.

Provenance and peer review

Not commissioned, externally peer-reviewed.

Supplementary Material

Tian-Run Lv, Jun-Ke Wang, and Hai-Jie Hu contributed equally to this work and were listed as co-first authors.

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Supplemental Digital Content is available for this article. Direct URL citations are provided in the HTML and PDF versions of this article on the journal’s website, www.lww.com/international-journal-of-surgery.

Published online 24 May 2024
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