Gallstone disease is common in both Western and Asian countries. Hepatolithiasis is one type of gallstone disease that is rare in Western countries but common in many Asian countries [1,2]. Although hepatolithiasis is benign in nature, its prognosis is generally regarded to be unfavorable because of its association with recurrent cholangitis, biliary stricture, liver abscess, atrophy or cirrhosis of the affected liver, and development of intrahepatic cholangiocarcinoma [3,4]. Thus, surgical resection of the hepatolithiasis-involved liver is often recommended. It is generally accepted that the risk of malignant transformation into a hepatobiliary cancer is much reduced after resection of the hepatolithiasis-involved liver. We herein present a case of a patient with perihilar cholangiocarcinoma arising from the remnant hilar bile duct at 29 years after the initial hepatectomy for left-sided hepatolithiasis and at 16 years after completion left hepatectomy.

A 50-year-old female patient who had suffered from recurrent cholangitis was diagnosed with multiple hepatolithiasis in the remnant medial section and right lobe of the liver. The patient underwent left lateral sectionectomy and bypass choledochoduodenostomy for left-sided hepatolithiasis 13 years before. The remnant medial section parenchyma was markedly atrophied and filled with multiple intrahepatic stones (Fig. 1A–C). The patient underwent completion left hepatectomy to remove the remnant medial section parenchyma (Fig. 1D). The resected specimen showed no evidence of malignancy. Epithelium of the left hepatic duct including the bile duct margin showed a low-grade dysplasia. The patient was followed up every 6–12 months. At 4 years after the left hepatectomy, intrahepatic duct stenosis with stone formation was identified at segment VI. The segmental stenosis at the right posterior hepatic duct was dilated by radiological intervention and intrahepatic duct stones were removed through percutaneous transhepatic cholangioscopy (Fig. 2).

Figure 1. Prerioperative imaging study findings before the completion left hepatectomy. (A) Preoperative computed tomography (CT) shows markedly atrophy of the remnant left medial section filled with multiple intrahepatic stones. (B, C) Preoperative magnetic resonance cholangiography shows multiple intrahepatic stones in the remnant left medial section and right lobe. (D) Post-hepatectomy CT shows complete removal of the hepatolithiasis-involved the remnant left medial section.

Figure 2. Management of recurrent hepatolithiasis at 4 years after completion left hepatectomy. (A) Magnetic resonance cholangiography shows intrahepatic duct stenosis with stone formation at segment VI. (B, C) Segmental stenosis at the right posterior hepatic duct was dilated and intrahepatic duct stones were removed through percutaneous transhepatic cholangioscopy. (D) Follow-up computed tomography shows resolution of intrahepatic duct stenosis and loss of intrahepatic duct stones.

The patient underwent follow-up studies every 6–12 months for the next 10 years. One session of the follow-up study was skipped due to coronavirus-19 pandemic. At 16 years after the completion left hepatectomy, she visited a local general hospital due to fatigability and upper abdominal pain. The laboratory findings showed highly elevated levels of liver enzymes and total bilirubin. The interval of follow-up visit was prolonged to be 15 months after the last follow-up study. The patient was referred to our institution for further evaluation. Follow-up computed tomography (CT) showed a 3-cm-sized intraductal mass at the first-order right hepatic duct and abscesses at the caudate lobe (Fig. 3A). The intraductal mass was rapidly enlarged to be 4 cm in size at the CT scan taken one month later (Fig. 3B, C). There were enlarged aortocaval lymph nodes, in which metastasis could not be excluded. There was no evidence of tumor invasion into the right portal vein and the right hepatic artery (Fig. 3D). Magnetic resonance cholangiography showed an intraductal mass with marked dilatation of the right hepatic duct (Fig. 4A, B). Endoscopic retrograde cholangiography was performed for tissue biopsy and two endoscopic retrograde biliary drainage tubes were inserted (Fig. 4C, D). The endoscopic biopsy finding was poorly differentiated adenocarcinoma. Fluorodeoxyglucose positron emission tomography-CT revealed a mass of hypermetabolic uptake at the hepatic hilum and mild hypermetabolic lymph node enlargement at the aortocaval area (Fig. 5).

Figure 3. Preoperative computed tomography (CT) findings taken at 16 years after the completion left hepatectomy. (A) A 3-cm-sized intraductal mass (arrow) is identified at the first-order right hepatic duct and abscess is formed at the caudate lobe. (B, C) Follow-up CT taken 1 month later shows marked growth of the intraductal tumor (arrows). (D) The right hepatic artery is not encased with the tumor.

Figure 4. Preoperative cholangiography findings taken at 16 years after the completion left hepatectomy. (A, B) Magnetic resonance cholangiography shows intraductal mass (arrow) with marked dilatation of the right hepatic duct. (C, D) Endoscopic retrograde cholangiography is performed for tissue biopsy and two endoscopic retrograde biliary drainage tubes are inserted.

Figure 5. Preoperative fluorodeoxyglucose positron emission tomography finding. A mass of hypermetabolic uptake is visible at the hepatic hilum with mild hypermetabolic lymph node enlargement at the aortocaval area.

At an age of 66 years, the third liver operation was performed for the patient at 16 years after the completion left hepatectomy and at 29 years after the initial left lateral sectionectomy. A right subcostal incision was made along the previous operation scar. After meticulous dissection of adhesions, the hepatoduodenal ligament was exposed. The choledochoduodenostomy was transected and the opening at the first portion of the duodenum was repaired (Fig. 6A). The common bile duct, the right hepatic artery, and the main portal vein were sequentially isolated. The distal bile duct was transected and securely repaired after confirmation of tumor negativity at the distal bile duct resection margin (Fig. 6B). The enlarged first-order right hepatic duct was meticulously dissected from the right portal vein and the right hepatic artery (Fig. 6C). It was then transected after meticulous palpation of the intraductal mass (Fig. 6D). The right anterior and posterior intrahepatic bile duct openings were exposed as a figure of 8 (Fig. 6E, F). Frozen section biopsies were performed at 3, 6, 9, and 12 o’clock directions of the bile duct openings, from which all margins were tumor-negative. The bulk of the tumor-containing bile duct and the caudate lobe were meticulously transected from the retrohepatic vena cava after ligation of the left portal vein stump. Extensive lymph node dissection was performed at the hepatoduodenal ligament and the aortocaval area.

Figure 6. Intraoperative photographs showing resection of the tumor. (A) The choledochoduodenostomy (arrow) was transected to make the operative field wide. (B) The common bile duct, the right hepatic artery and the main portal vein are isolated with transection of the distal bile duct. Arrow indicated the site of choledochoduodenostomy. (C) The enlarged first-order right hepatic duct is dissected from the right portal vein and the right hepatic artery. (D) The first-order right hepatic duct (arrow) is transected after palpation of the intraductal mass. (E, F) The right anterior and posterior intrahepatic bile duct openings (arrows) are exposed as a figure of 8.

After resection of the tumor and lymph nodes, cluster hepaticojejunostomy was performed (Fig. 7). The transverse diameter of the figure of 8-shaped intrahepatic bile duct openings was approximately 4 cm. Edges of these opening were partially repaired to facilitate anastomosis. The anterior wall of the bile duct openings was anchored with multiple 5-0 Prolene sutures. Thereafter, the posterior wall of the bile duct openings was continuously sutured with 5-0 Prolene sutures after dividing it into 4 segments with 3 internal intervening sutures. The anterior wall was finally closed using interrupted sutures that were previously anchored.

Figure 7. Intraoperative photographs showing the procedures of cluster hepaticojejunostomy. (A) The anterior wall of the bile duct openings is anchored with multiple 5-0 Prolene sutures. (B, C) The posterior wall of the bile duct openings is continuously sutured with 5-0 Prolene sutures after dividing it into four segments with three internal intervening sutures. (D) The anterior wall is closed by using interrupted sutures that are previously anchored.

The pathology of the resected surgical specimen showed poorly differentiated cholangiocarcinoma of 4.9 cm in size (Fig. 8). The tumor showed extension beyond the bile duct with involvement of the liver. The depth of invasion was 12 mm from the surface epithelia. There was lymphovascular invasion, but perineural invasion was not identified. There was no involvement of the distal common bile duct margin and right hepatic duct hepatic parenchyma resection margins. Tumor metastasis was present in 1 (lymph node #12) of 7 lymph nodes.

Figure 8. Gross photograph of the resected specimen showing an intraductal mass.

The patient recovered uneventfully from the surgery. Initial postoperative CT scan showed no abnormal findings (Fig. 9). However, hepatobiliary scintigraphy taken at postoperative 10 days showed abnormal bile collection, indicating minor bile leak from the hepaticojejunostomy site. The upper end of the operative wound was disrupted due to wound infection. Thus, a pigtail catheter was inserted into the suspected bile leak site during a procedure of wound repair. A percutaneous transhepatic biliary drainage tube was also inserted to control the bile leak at the hepaticojejunostomy site. The pigtail catheter was successfully removed at 14 days after wound repair. The patient was discharged from the hospital at 26 days after operation.

Figure 9. Postoperative computed tomography findings taken at 3 days after the second operation. (A, B) Cross-sectional images show the extent of resection. (C, D) The reconstructed second-order right hepatic duct shows good patency.

Adjuvant chemoradiation therapy was performed for local tumor control. The patient has been doing well for 12 months after scheduled adjuvant chemotherapy (Fig. 10).

Figure 10. Fig. 10 . Postoperative computed tomography findings taken 9 months after the third second hepatectomy with bile duct resection. The cross-sectional image (A) and reconstructed image (B) show no abnormal postoperative findings.

Ethical Statements

This study was approved by the Institutional Review Board (IRB) of Asan Medical Center (IRB No: 2021-0527), and informed consent was obtained from the patient.

Hepatolithiasis is an established risk factor for intrahepatic cholangiocarcinoma in Asian countries [4,5]. Patient cases of hepatolithiasis-associated cholangiocarcinoma are not rare, especially in areas with a high prevalence of hepatolithiasis. The overall incidence of hepatolithiasis-associated cholangiocarcinoma has been reported to be 5%–13% [6-8]. This malignant transformation can be detected at any stage, during evaluation, treatment, or follow-up of hepatolithiasis. Detection of hepatolithiasis-associated cholangiocarcinoma during treatment of hepatolithiasis was reported in 12% of patients in Japan, 5% in Taiwan, 9% in Korea, and 10% in Hong Kong [6-12].

The main morphologic features of stone-containing bile ducts in patients with hepatolithiasis are chronic proliferative cholangitis and peribiliary glands proliferation, in which the epithelial lining becomes hyperplastic [13]. Chronic inflammation can cause epithelial cell proliferation, which may increase the rate of cellular DNA synthesis and subsequent production of mutagens coupled with a compromised cellular repair function. If these processes are sustained for a long period of time, they might cause multiple molecular changes necessary to trigger the development of cholangiocarcinoma. During histologic examination with percutaneous choledochoscopy, atypical epithelial hyperplasia and dysplasia are frequently identified [14]. Chen et al. [15] have reported that intraductal papillary neoplasia was found in 30% of patients with hepatolithiasis and presented a histologic spectrum from papillary growth with dysplasia to carcinoma. Biliary carcinogenesis associated with hepatolithiasis is thought to be present as precancerous lesions. It is reported that intraductal papillary neoplasm of the bile duct (IPNB) and biliary intraepithelial neoplasia (BilIN) are the precancerous lesions of biliary tract carcinomas [16].

Similar to hepatolithiasis, IPNB has been frequently reported in Far Eastern Asian countries. IPNB is known to transform from low-grade dysplasia to invasive carcinoma. BilIN is a flat or micropapillary dysplastic epithelium in the bile duct, and can be classified as BilIN-1, BilIN-2, and BilIN-3 [17]. It is frequently found in the surgical margin of resection specimens of cholangiocarcinoma. Both BilIN and IPNB can be seen at the same time in patients with hepatolithiasis [17]. A study of BilIN has presented that metaplastic changes are more frequently observed in BilIN-2/3 than BilIN-1, with gastric-type foveolar metaplasia being the most frequently observed change [17].

Hepatectomy for treatment of hepatolithiasis has theoretical advantages for eliminating the risk of developing hepatolithiasis-associated cholangiocarcinoma and complete removal of stones. In general, hepatectomy seems to reduce the risk of developing cholangiocarcinoma. A cohort study in Japan has reported that hepatectomy can significantly reduce the risk of developing cholangiocarcinoma [18]. However, it is currently unclear whether hepatic resection can reduce the occurrence of hepatolithiasis-associated cholangiocarcinoma. During the follow-up period, the incidence of hepatolithiasis-associated cholangiocarcinoma revealed no significant difference between patients with hepatolithiasis with or without previous hepatic resection [8]. Thus, it is difficult to conclude that hepatic resection can completely prevent the development of cholangiocarcinoma in patients with hepatolithiasis.

Meanwhile, incomplete resection of the hepatolithiasis-associated liver is a matter of concern. Favorable survival outcomes are obtained only for cases with safe surgical margins, even in incidental hepatolithiasis-associated cholangiocarcinoma found in the postoperative pathology [7]. In addition, hepatolithiasis-associated cholangiocarcinoma could develop in the remnant liver adjacent to the resection margin. It is also possible that the undetected cholangiocarcinoma is present in the remnant liver [7,8]. Therefore, aggressive surgical resection, including the neighboring segments, is crucial to achieve sufficient hepatic resection.

In our present case, the hepatolithiasis-associated left lateral section was initially resected and bypass choledochoduodenostomy was performed to facilitate biliary drainage. Thirteen years later, completion left hepatectomy was performed to remove the intrahepatic stone-filled remnant left medial section. The pathology of the hilar bile duct margin showed dysplasia of the epithelium. The patient had been regarded as having a low-risk for de novo cholangiocarcinoma. The patient has been regularly followed up with imaging studies and blood tests every 6–12 months for 16 years after the second completion hepatectomy and endoscopic intervention. Only one session of regular follow-up study was skipped due to the coronavirus-19 pandemic. Unexpectedly, an intraductal mass was identified at the hilar bile duct. We presume that the intraductal cholangiocarcinoma was associated with the dysplasia of the hilar bile duct, which was first identified 16 years before. Such de novo occurrence of perihilar cholangiocarcinoma appears to be very rare because we have not experienced a similar case during long-term follow-up of hundreds of patients who have undergone hepatic resection for hepatolithiasis in our institution.

Because the intraductal mass was located deep at the first-order right hepatic duct, its secure resection required accurate preoperative assessment of the tumor extent and meticulous surgical techniques for bile duct resection and biliary reconstruction. The tumor was located within the right hepatic duct at the initial imaging studies. The intraductal growth pattern revealed its confined location within the bile duct. Considering that the tumor was very closely located to the right hepatic artery, it would be unresectable if the tumor had shown an infiltrative growth pattern. The first-order right hepatic duct was completely resected, thus deeply located the second-order right hepatic duct branches were exposed within the right liver parenchyma. We adopted our customized cluster hepaticojejunostomy technique for reconstruction of such deeply located large-sized bile duct openings [19]. We have rarely experienced surgical complications after application of this technique for biliary reconstruction. However, this patient revealed significant anastomotic bile leak requiring percutaneous drainage over two weeks.

The experience of our present case suggests that there is a risk of de novo hepatobiliary malignancy after hepatic resection for hepatolithiasis. Thus, it is necessary to perform life-long follow-up studies for patients who have undergone hepatic resection for hepatolithiasis. Such follow-up studies should be performed more frequently than the public routine health screening every other year.

There was no funding related to this study.

All authors have no conflicts of interest to declare.

Conceptualization: SH. Data curation: SH. Methodology: SMK, YK, EKJ. Visualization: SH. Writing - original draft: SH, SMK. Writing - review & editing: All.