Clinical significance of tumor infiltration length along the bile duct mucosa and submucosa in hilar cholangiocarcinoma

Introduction

Hilar cholangiocarcinoma (HCCA) is the most common subtype of cholangiocarcinoma, with a high degree of malignancy. If untreated, the median overall survival is only 5–10 months (1-3). At present, radical resection is the only way to achieve long-term survival and potential cure (4). The past decade has witnessed unprecedented advances in surgical technology and imaging diagnosis; about 40% of patients with HCCA can undergo radical resection, and the 5-year survival rate has been significantly improved (5-7). Bile duct margin is an important risk factor for recurrence and survival of HCCA patients after resection (8). Computed tomography (CT) and magnetic resonance cholangiopancreatography (MRCP) are the most commonly used imaging method for preoperative evaluation of tumor location and extent to achieve a negative margin (R0) for HCCA. Although modern imaging techniques provide more details to identify the extent of tumors, they are only more sensitive to space-occupying lesions (9,10). However, imaging may seriously underestimate the longitudinal invasion of HCCA, which can be explained by the spread of the tumor along the bile duct wall with microinvasion (10). Although a frozen section of the bile duct margin is commonly performed during surgery to confirm that the margin is negative, overwhelming evidence substantiates that the accuracy of frozen sections is only between 57% and 90% compared with permanent histopathology (11,12).

Over the years, the surgical approach for HCCA has gradually changed from simple cholangiectomy to combined hepatectomy, although the optimal scope of resection remains controversial. An increasing body of evidence suggests that extensive hepatectomy, including more than half of the liver, should be performed for patients with Bismuth types I, II, III and IV (13,14). However, some researchers argue that liver tissue should be removed as little as possible, and partial hepatectomy should be adopted to reduce surgical complications and perioperative mortality (15). In this respect, for patients with Bismuth type I and type II, many surgeons think that visibility of the scope of the tumor is limited on imaging (16,17). For such cases, local or extrahepatic cholangiectomy is recommended by Chinese guidelines and experts consensus (18-21). According to the anatomical characteristics of the bile duct, the average lengths of the left, right and common hepatic ducts are 1.7, 0.9, and 2.5 cm, and the length of the common bile duct is 4–8 cm (22,23). Current evidence suggests that when HCCA infiltrates along the bile duct, it is likely to extend beyond the left and right hepatic ducts to the secondary bile duct in the liver and may also involve the pancreatic segment bile duct distally. A European study on the evaluation of the pathological report of HCCA also pointed out that the distance between the tumor and the resection margin of the bile duct should be described in the pathological report, which is helpful for a comprehensive assessment of the prognosis and selection of adjuvant treatment (24). However, there is a lack of accurate measurement methods during pathological sampling of HCCA domestically and internationally.

Clinically, surgeons place much emphasis on the boundary of HCCA infiltrating along the bile duct and the scope of surgical resection to achieve R0 resection. However, few studies have comprehensively reported the infiltration length of HCCA along the bile duct mucosa and submucosa, and many errors have been reported with previous measurement methods. Herein, we adopted original ink marking and measurement methods to make the results more objective and accurate and discussed the effect of the infiltration length of HCCA along the bile duct mucosa and submucosa on radical surgery. We present this article in accordance with the STROBE reporting checklist (available at https://cco.amegroups.com/article/view/10.21037/cco-24-123/rc).

Methods

Patients

Thirty-one patients with HCCA who underwent en bloc and extended liver resection in the Department of Biliary-Pancreatic Surgery of Sun Yat-sen Memorial Hospital from January 2020 to December 2021 were included in this study. The inclusion criteria were as follows: (I) HCCA was diagnosed by preoperative examination and postoperative pathology, (II) the first operation was performed in the Sun Yat-sen Memorial Hospital, and all patients underwent en bloc and extended liver resection combined with total caudate lobe and extrahepatic bile duct. Patients were excluded for the following reasons: (I) preoperative radiotherapy, chemotherapy and other anti-tumor treatments; (II) the postoperative specimens were not marked and measured in accordance with the indicated methods; (III) missing clinical or pathological data. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of Sun Yat-sen Memorial Hospital, Sun Yat-sen University (No. SYSKY-2022-124-01) and individual consent for this retrospective analysis was waived.

Perioperative period and surgical procedure

The ratio of residual liver volume to standard liver volume was routinely calculated by CT before operation (25). After the serum total bilirubin concentration was restored to nearly normal levels by biliary drainage, the liver function was evaluated by the indocyanine green clearance test (26). Selective portal vein embolization (PVE) was performed preoperatively in patients without sufficient residual liver volume or liver function for safe resection (27).

All operations were performed by the same experienced surgeon. The basic surgical procedures included en bloc and extended liver resection, including at least half of the liver volume combined with total caudate lobe and extrahepatic bile duct, regional lymph node dissection and Roux-en-Y choledochojejunostomy. Resection and reconstruction of the portal vein and/or hepatic artery were conducted when hilar vessels adhered to the tumor and could not be separated from the tumor (28). If the pancreatic segment of the common bile duct was involved and the peripancreaticoduodenal metastatic lymph nodes invaded the head of the pancreas, combined pancreaticoduodenectomy was indicated (29).

Specimen handling and pathological evaluation

All the resected specimens were treated immediately after removal from the patient. In order to determine the location of the tumor, the main bile duct in the hilar region was dissected longitudinally along the anterior wall (Figure 1A). The branches of intrahepatic bile ducts were named according to the classification system of bile ducts (30). Then, the proximal and distal bile ducts were sampled, including the gross tumor margin and the bile duct resection margin. The ink was absorbed with a 2 mL syringe to mark the gross tumor boundary and bile duct resection margin (Figure 1B). Each segment of the bile duct was fixed on a separate foam plate with a No. 3 insect nail to prevent curling and deformation in the formalin solution. Then, it was placed in a specimen box filled with 10% formalin solution and the box was labeled with the specimen name. The procedure was performed by the surgeon, who took photos and videos of the whole process. After 24 hours of fixation, the pathologist characterized the gross findings of the tumor and measured the length (t1) of the gross tumor boundary from the proximal and distal bile ducts, respectively. The proximal and distal bile duct specimens was embedded in paraffin and serially sectioned longitudinally at intervals of 1–2 mm along the two ink marks. After staining, the length (t2; Figure 1C) between the microscopic margin of the tumor and the margin of the proximal and distal bile duct marked with ink was measured. The length (d = t1 − t2; Figure 1D) of HCCA infiltration along the proximal and distal bile ducts beyond the gross tumor boundary could be calculated by the difference value. The bile duct wall was divided into the mucous and the submucous layers. According to the above method, the infiltration distance of each proximal and distal bile duct wall layer could be obtained (Figure 2A). To assess whether the specimens fixed with insect nails would undergo significant shortening and deformation, we calculated the ratio between the length of the two inks under a microscope. The ratio of the length of the two inks under the naked eye was between 0.9 and 0.98 (Figure 2B). The above measurements were performed by the same two pathologists.

Figure 1 Methods of excised specimen and tumor measurements. (A) The en bloc excised specimen was cut longitudinally from the distal bile duct to the proximal bile duct. (B) Specimen of the common bile duct. B1: distal common bile duct and tumor (including distal common bile duct margin and gross tumor margin); B2: ink-marked distal common bile duct resection margin (left) and gross tumor margin (right). (C) Measurement of tumor infiltration length under the microscope. C1: the margin of bile duct resection marked with ink under the microscope (stained with hematoxylin and eosin and observed under an Olympus BX53 microscope at ×20 magnification, the part circled by the dotted line); C2: to measure the length of the tumor margin marked under the microscope from the bile duct margin. (D) Schematic diagram of calculation of tumor microinfiltration distance along the mucosa and submucosa of the bile duct. d: the length of the tumor microinfiltration distance; t1: the length of the gross tumor boundary from the bile duct margin; t2: the length of the microscopic tumor boundary from the bile duct margin. B1r, caudate bile duct; B5, S5 segment bile duct; B6, S6 segment bile duct; B7, S7 segment bile duct; B8, S8 segment bile duct; CBD, common bile duct; LHD, left hepatic duct; RHD, right hepatic duct.

Figure 2 Microscopic annotations and measurements. (A) Tumor infiltration along bile duct wall (stained with hematoxylin and eosin and observed under an Olympus BX53 microscope at ×20 magnification, the red arrows indicate cancer). A1: normal proximal bile duct; A2: infiltration of proximal bile duct mucosa; A3: infiltration of proximal bile duct submucosa; A4: normal distal common bile duct; A5: infiltration of distal common bile duct mucosa; A6: infiltration of distal common bile duct submucosa. (B) Measurement of the length between two inks under the microscope (stained with hematoxylin and eosin and observed under an Olympus BX53 microscope at ×20 magnification, histological pictures in the upper right corner are ink marks seen under the microscope). B1: ink mark of bile duct margin; B2: ink mark of the gross tumor margin.

Clinical parameters and definitions

The bile duct wall is divided into mucosal epithelium, lamina propria and adventitia layer (Figure 3). The mucosal epithelium is mainly composed of monolayer columnar epithelial cells, and the lamina propria and adventitia are loose connective tissue, including blood vessels, lymphatic vessels, nerves and elastic fibers. Some smooth muscle layers are scattered or continuously distributed between the lamina propria and the adventitia, mostly in the extrahepatic bile duct, especially in the lower segment of the common bile duct, while there is little or no muscle layer in the intrahepatic secondary bile duct (31). We defined the mucous layer in this study as the mucosal epithelium; the submucous layer implied the lamina propria and adventitia beneath the mucosal epithelium, including the smooth muscle layer, if present.

Figure 3 The structure of the bile duct wall (stained with hematoxylin and eosin and observed under an Olympus BX53 microscope at ×20 magnification). A: mucosal epithelium layer; B: lamina propria layer; C: adventitia layer.

Statistical analysis

The data were analyzed and processed by SPSS statistical software (IBM Statistics 25.0). The categorical variables were described as frequency and percentage, and continuous variables as mean, standard deviation, minimum and maximum. A P value <0.05 was statistically significant.

Results

Baseline data

A total of 31 patients with HCCA were included in the study, including 15 males and 16 females, with a mean age of 61.7±11.1 years. Table 1 summarizes the clinicopathological features of the patients, including the extent of hepatectomy, gross type, degree of differentiation and TNM stage, etc.

Tumor infiltrating length along the bile duct

A total of 42 proximal and 31 distal bile ducts were evaluated in 31 surgically resected specimens, with an average of 1.4 proximal bile ducts per patient (range, 1–3 proximal bile ducts). If the bile duct margin was positive, it was calculated according to the maximum length of infiltration that could be observed. If there were two or more proximal bile ducts, the bile duct with the longest tumor invasion length was analyzed.

As shown in Figure 4, in most cases, the infiltration length along the proximal bile duct mucosa and submucosa and distal bile duct mucosa were within the 5–10 mm range. In most cases, the infiltration length of distal bile duct submucosa was within the 10–15 mm range. It was found that the average tumor infiltration length along the mucosa and the submucosa of the proximal bile duct was 8.5±5.2 and 8.6±4.9 mm, respectively, and the maximum length was 20.0 mm in both layers. The average infiltration length of the tumor along the mucous layer of the distal bile duct was 12.8±7.5 mm, with a maximum of 33.0 mm. In contrast, the average infiltration length along the submucosa of the distal bile duct was 11.5±7.2 mm, with a maximum of 32.0 mm. Table 2 summarizes the relationship between different pathological features and infiltration length.

Figure 4 Histogram of proximal/distal bile duct mucosa and submucosa infiltration length.

Changes in the Bismuth-Corlette classification

During preoperative imaging examination, according to the Bismuth-Corlette classification, 31 patients were classified as type II (n=1), type IIIa (n=10), type IIIb (n=9) and type IV (n=11). However, postoperative pathological results showed that 1 case of type II, 3 cases of type IIIa and 3 cases of type IIIb lesions were type IV lesions. Overall, the accuracy of preoperative imaging diagnosis for type III lesions was 68.4% (13/19). Figure 5 shows the extent of tumor infiltration during preoperative imaging examination and in resected specimens.

Figure 5 Preoperative imaging and resected gross specimens. (A) The preoperative imaging diagnosis was type IIIa, and the pathological diagnosis was type IV. (B) The preoperative imaging diagnosis was type IIIb, and the pathological diagnosis was type IV. (C) The preoperative imaging diagnosis was type IIIb, and the pathological diagnosis was type IV. The tumor’s location is circled in imaging. The solid blue line marks the extent of the gross tumor, and the red dashed line marks the extent of bile duct mucosa and submucosa infiltration. B23, S2 and 3 segment bile duct; B4, S4 segment bile duct; B5, S5 segment bile duct; B6, S6 segment bile duct; B7, S7 segment bile duct; B8, S8 segment bile duct; CBD, common bile duct; LHD, left hepatic duct; RHD, right hepatic duct.

Margin status

Of the 31 patients in this study, 23 (74.2%) had histological evidence of non-invasive cancer at the incision margins (R0). Of the 17 patients who underwent extensive left hepatectomy [left hemihepatectomy (n=3), enlarged left hemihepatectomy (n=13) and left trisectionectomy (n=1)], 11 (64.7%) underwent R0 resection. Of the 14 patients who underwent extensive right hepatectomy [right hemihepatectomy (n=2), enlarged right hemihepatectomy (n=10) and right trisectionectomy (n=2)], 12 (85.7%) underwent R0 resection. Of the 18 patients with Bismuth IV confirmed by pathology, 12 (66.7%) achieved R0 resection after extensive hepatectomy. Table 3 summarizes the margin status of extensive hepatectomy. The main reason for non-R0 resection was positive margins of bile ducts and/or vessels.

Discussion

Surgical resection represents the main curative approach for HCCA at present. It is well-established that the efficacy of surgical resection is closely related to the status of the bile duct margin. A negative bile duct margin can improve the survival rate of patients and reduce tumor recurrence (8). However, due to the biological characteristics of HCCA infiltration along the bile duct wall, especially the mucosa and submucosa, preoperative imaging and intraoperative frozen section examination cannot accurately judge the extent of the tumor (10,11). Therefore, it is necessary to explore the length of HCCA infiltration along the bile duct to select the surgical approach and the extent of resection.

In prior studies on the infiltration length of HCCA, the sampling or measurement methods were not described in detail, which led to doubts about the robustness of their conclusions (33-35). In this study, the original ink marking and measurement method was adopted; i.e., the surgeon marked the macroscopic tumor boundary and bile duct resection margin with ink before the fresh specimen was sent to the pathology department. Given that the surgeon could more clearly visualize the location of the macroscopic tumor boundary during the operation, he was responsible for the marking task. This marking method has two benefits: first, for short or irregular bile duct tissue, marking is more helpful for pathologists to distinguish the longitudinal axis of the bile duct to achieve full-length sampling and longitudinal section along the bile duct, which is the basis for measuring the length of infiltration. Moreover, it enables accurate recognition of the end of the cutting edge under the microscope to measure the length from the boundary of the microscopic tumor to the cutting edge. Since it is difficult to directly measure the length of tumor infiltration along the mucosa and submucosa of the bile duct beyond the macroscopic boundary under the microscope, we calculated the difference.

Sakamoto et al. found that the average infiltration lengths of proximal bile duct along the mucosa and submucosa were 11.5 and 6 mm, respectively (33), which is different from our findings. This discrepancy may be due to the different definitions used for the level and length of bile duct infiltration. In their study, the bile duct was divided into mucosal, submucosal-intramural, or submucosal-extramural layers. The latter two layers were equivalent to the submucosa referred to in our study. In addition, they defined the submucosal infiltration length as a cancerous extension of the submucosa without mucosal extension, and the average length measured was shorter than ours because the mucosal extension length was not taken into account. In a study by Ebata et al., the average infiltration lengths along the superficial and intramural proximal bile duct were 14 and 4.6 mm; the corresponding values for the distal bile duct were 13.4 and 4.4 mm, respectively (34). However, all types of cholangiocarcinoma, including HCCA, were analyzed in that study. Yamaguchi et al. reported that the average length between macroscopic and microscopic tumor boundaries was 6.1±6.1 mm for the proximal bile duct and 6.2±9.1 mm for the distal bile duct (36). However, they estimated the length by cholangiography without pathological evaluation, which is relatively less accurate. Hayashi et al. also pointed out that the average length of extramucosal infiltration of proximal and distal bile ducts was 12.8 and 6.1 mm, respectively (35). They measured the length of extramucosal infiltration beyond the extent of intramucosal carcinogenesis, and 5 mm-thick sections were obtained perpendicular to the longitudinal axis of the bile duct, which led to significant errors. This approach was significantly different from our method, involving the starting point of measurement and sectioning method. In this study, the length of infiltration was further compared between different sides of liver resection, gross types, TNM stages, and degrees of differentiation. However, more data are needed to verify the conclusion. Herein, we preliminarily substantiated the correlation between infiltration length and pathological features.

It was found that the maximum infiltration length of the proximal bile duct was 2 cm, the maximum infiltration length of the distal bile duct was 3.3 cm, and the average length of the left and right hepatic ducts were 1.7 and 0.9 cm, respectively. Since the common hepatic duct length was about 2.5 cm, and the common bile duct was about 4–8 cm, the tumor may invade the bile duct proximal to the secondary bile duct or distal to the pancreatic segment bile duct. From a surgical point of view, a study measured the length of resectable hepatic ducts in four types of hepatectomy (37). The average length of the resected hepatic duct was 14.1±5.7, 14.9±5.7, 21.3±6.4, and 25.1±6.4 mm during left hemihepatectomy, right hemihepatectomy, left trilobar hepatectomy and right trilobar hepatectomy, respectively. It can be seen that the length of hepatic duct resected by left and right hepatectomy was comparable, while the length of the hepatic duct was significantly shorter during hemihepatectomy than in trisectionectomy. Interestingly, right trisectionectomy was associated with the longest proximal hepatic duct margin. It was suggested that when the liver function is good and the remaining liver volume is estimated to be sufficient, right trisectionectomy should be the first choice for Bismuth IV, followed by left trisectionectomy (37). In our study, the maximum infiltration length of the mucosa and submucosa of the proximal bile duct was 20.0 mm. Accordingly, only trisectionectomy could ensure negative margins. In addition, combination with pancreaticoduodenectomy is indicated if the tumor infiltrates distal to the pancreatic segmental common bile duct.

The Bismuth-Corlette classification based on preoperative imaging is important for the selection of HCCA surgery (38). Among the 31 patients in this study, 7 initially classified as type II and III by preoperative imaging were classified as type IV by postoperative pathology. The accuracy of preoperative imaging diagnosis of type III was only 68.4% (13/19). It is conceivable that some patients diagnosed with type I or II on imaging may progress to type III or even type IV. Accordingly, extensive hepatectomy combined with hemihepatectomy is necessary, even for type I and II HCCA. It is widely thought that right hemihepatectomy combined with caudate lobectomy or extended right hemihepatectomy is indicated for patients with Bismuth type I, II and IIIa, left hemihepatectomy with caudate lobectomy for Bismuth IIIb, and extended hemihepatectomy with caudate lobectomy or trisectionectomy for Bismuth IV (13,14,39). Overwhelming evidence substantiates that patients with Bismuth type I and type II who undergo limited resection have a high local recurrence rate and a poor prognosis even after R0 resection (2,5). van Gulik et al. showed that the prognosis of patients with extended resection was significantly better than patients with local resection with similar tumor infiltration (40). While extended liver resection significantly improves survival rates, it also carries a higher risk of postoperative complications. Postoperative liver failure is one of the most common and fatal complications, particularly in patients with underlying liver diseases (25). Additionally, bile leakage is another important complication that may require drainage or reoperation (39). The incidence of postoperative infections is also high, especially in the context of liver failure, where the weakened immune function makes infection control more challenging (25). Studies have shown that preoperative PVE combined with biliary drainage can significantly reduce the incidence of liver failure, thus decreasing the risk of postoperative mortality (39,41,42). Therefore, balancing surgical outcomes with the risk of postoperative complications is crucial, requiring thorough preoperative evaluation and the implementation of preventive measures.

A series of studies have shown that the R0 resection rate of HCCA increases significantly with combined hepatectomy (43,44). Tsao et al. reported that 89% of patients undergoing hepatectomy at Nagoya University had an R0 resection rate of 79%, whereas only 16% of patients undergoing hepatectomy at Lahey Clinical Center had an R0 resection rate of 28% (45). Of the 386 cases of HCCA surgically resected at Nagoya University from 2001 to 2010, nearly 95% underwent extensive hepatectomy, and the R0 resection rate was about 77.5% (46). In our study, 31 patients underwent extensive hepatectomy, and the R0 resection rate was 74.2%, comparable to Nagoya University’s findings. For HCCA with positive margins, the significance of further resection remains subject to debate. Ribero et al. and Ma et al. reported a significant survival benefit with further resection (47,48). However, Endo et al. and Shingu et al. pointed out that further resection did not improve survival (49,50). Considering that the prognosis of re-resection is not optimistic, it is difficult to re-resect the proximal bile duct over 5 mm from an anatomical and technical point of view (34). Therefore, in patients with a good liver function reserve, direct extensive hepatectomy is indicated to minimize the risks of positive resection margins.

There are some limitations in this study. First, this was a single-center study, and there may be confounding factors that were not considered. Moreover, the number of patients in this study was limited. However, because HCCA is relatively rare, a small sample size is common in most studies of HCCA. Finally, our study focused on the proximal and distal margins of the bile duct and did not evaluate the radial margin of HCCA (the margin of the circumferential tumor adjacent to the liver, hilar plate, and blood vessels).

Conclusions

This study revealed the infiltration characteristics of HCCA along the bile duct mucosa and submucosa, and the infiltration length was measured. Indeed, preoperative imaging examination often underestimates the extent of HCCA. With extensive hepatectomy, longer bile ducts can be removed, and the R0 resection rate can be improved.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://cco.amegroups.com/article/view/10.21037/cco-24-123/rc

Data Sharing Statement: Available at https://cco.amegroups.com/article/view/10.21037/cco-24-123/dss

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-24-123/prf

Funding: This work was supported by grants from the National Natural Science Foundation of China (Nos. 82202981, 82173195, and 82173229), the Guang Dong Basic and Applied Basic Research Foundation (No. 2024A1515012993), the Sun Yat-sen University Clinical Research 5010 Program (No. 2018008), and the Science and Technology Program of Guangzhou (Nos. 2024A03J1054, 2023A03J0700, 2023B03J1385, and 2024A04J4776).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-24-123/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of Sun Yat-sen Memorial Hospital, Sun Yat-sen University (No. SYSKY-2022-124-01) and individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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