Hepatolithiasis is defined as the presence of stones within the intrahepatic bile ducts, proximal to the right and left hepatic ducts. Hepatolithiasis has a poor prognosis due to other associated complications such as recurrent cholangitis, biliary strictures, liver abscess, liver atrophy, or cirrhosis.12 Additionally, hepatolithiasis is an important leading cause of intrahepatic cholangiocarcinoma.34

Hepatolithiasis treatment includes both non-surgical and surgical approaches. Non-surgical procedures, such as percutaneous transhepatic cholangioscopic lithotripsy, show a high clearance rate of intrahepatic stones; however, these treatments are not effective for preventing recurrence of hepatolithiasis and removal of benign biliary strictures.567 Surgical treatment can be divided into minor and major hepatectomies, depending on the resection range. The range of minor hepatectomy is generally limited to atrophic segments and intrahepatic stones. In this context, a residual intrahepatic biliary stricture may remain, which is a risk factor for hepatolithiasis. Unlike minor hepatectomy, the range of major hepatectomy includes all intrahepatic duct stones and a wider segment, including the intrahepatic biliary strictures. Thus, major hepatectomy can be the fundamental treatment for hepatolithiasis by eliminating not only the stones but also the benign biliary stricture, which is a crucial cause of the stones.

Previous studies have reported the rate of unidentified underlying cholangiocarcinoma before hepatectomy in patients with hepatolithiasis.28 In these reports, it is uncertain whether the resection range includes all intrahepatic biliary strictures and their segments. To confirm the incidence of underlying biliary neoplasm in patients with hepatolithiasis, we need to investigate patients who underwent major hepatectomy for both hepatolithiasis and intrahepatic biliary strictures.

Here, we evaluated the incidence of underlying biliary neoplasm in patients who underwent major hepatectomy for benign hepatolithiasis, based on preoperative diagnosis.

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Of the 73 patients with preoperative benign hepatolithiasis, 20 patients (27.4%) were confirmed as pathological biliary neoplasm, and 53 patients as chronic inflammation with bile duct stones. Of the 20 patients, 12 (16.4%) presented with biliary intraepithelial neoplasia (BIN) and 1 (1.4%) with intraductal papillary mucinous neoplasm (IPMN) as the premalignant lesions. Cholangiocarcinoma was pathologically confirmed in 7 patients (9.6%) (Table 1).

The main intrahepatic biliary strictures were categorized according to their location at the confluence of the right hepatic duct and the left hepatic duct, at the first branch of the intrahepatic bile duct, at the second branch of the bile duct, or at the third branch of bile duct. Biliary stricture at the first branch of bile duct was observed in 23 patients (43.4%) of the benign stricture group and 8 patients (40.0%) of the biliary neoplasm group. A biliary stricture was identified at the second branch of the bile duct in 28 patients (52.8%) in the benign stricture group and in 11 patients (55%) in the biliary neoplasm group. One patient each in the benign stricture group and in the biliary neoplasm group had a biliary stricture at the confluence of the right and left hepatic ducts. A stricture at the third branch of bile duct was seen in 1 patient in the biliary stricture group. Postoperative pathological examination confirmed that the location of the intrahepatic strictures was consistent with that of concomitant biliary neoplasms (Table 2).

The variables considered were sex, age, the type of surgical procedure, location of the biliary stricture, preoperative symptoms, preoperative serum CA 19-9, presence of atrophy in preoperative image, and preoperative serum total bilirubin level. The main symptoms of patients with hepatolithiasis were abdominal pain, fever, jaundice, and weight loss. Results from the statistical analysis showed no significant difference when comparing the benign stricture group and the pathologically proven biliary neoplasm group. Although sex appeared to be significant, it was not a definitive factor (Table 3).

According to the Clavien-Dindo classification, postoperative complications above grade IIIa developed in 14 patients (19.1%). Of these, 10 patients (13.7%) were treated by procedures such as pig-tail catheter insertion, for intra-abdominal abscess (9.6%), bile leakage (1.4%), or pleural effusion (2.7%). Three patients (4.1%) were re-operated for wound infection, bile duct injury, and common bile duct primary repair site dehiscence. Only 1 patient (1.4%) expired during the hospital stay as a result of aspiration pneumonia, and not by hepatic failure or surgical complications (Table 4).

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Epidemiological, pathological, and genetic studies demonstrate a relationship between hepatolithiasis and cholangiocarcinoma.121314 The overall incidence of hepatolithiasis-related cholangiocarcinoma has been reported as 5% to 13%.151617 In a cohort study, 65 years or older (hazard ratio, 3.029; p-value, 0.017) and having stone removal only as the initial treatment (hazard ratio, 2.873; p-value, 0.012) were found to be significant risk factors for the development of cholangiocarcinoma.18 The authors reported that hepatectomy could significantly reduce the risk of developing cholangiocarcinoma (hazard ratio, 0.066; p-value, 0.010). In another cohort study, it was reported that hepatectomy significantly reduced the risk of developing cholangiocarcinoma.19 In general, hepatic resection might offer an advantage in eliminating the risk of developing cholangiocarcinoma because of complete removal of both the intrahepatic stones and the bile ducts involved, which are likely to have a hidden malignancy. In this regard, hepatic resection could be considered as a primary treatment in hepatolithiasis.

Despite preoperative evaluations, it is still difficult to detect underlying biliary neoplasms or chlangiocarcinoma in hepatolithiasis. Catena et al.20 reported that the rate of unrecognized cholangiocarcinoma was quite high at 11.7%, and that it might be underestimated. Although serum CA 19-9 is known as a tumor biomarker for cholangiocarcinoma, its levels could be normal or increased in benign diseases, such as in bacterial cholangitis or choledocholithiasis.2122 In preoperative images or even during the surgery, a diagnosis of cholangiocarcinoma associated with hepatolithiasis is difficult, because the affected liver segment is often fibrotic and scarred.2 Chen et al.2 reported 2 patients (2.0%) having the tumor diagnosed during the operation, and 4 patients (3.9%) having cholangiocarcinoma diagnosed only after pathological examination. They also reported that in 1 patient (1.0%), a cholangiocarcinoma was diagnosed 7 months after the hepatic resection for hepatolithiasis, and the tumor was likely present during the surgery, but was unidentified, and the undetected cholangiocarcinoma was present in the remnant liver even after hepatectomy.

Hepatic resection is regarded as an established treatment, recommended for its ability to resolve not only the stones but also the strictures.2324 Biliary strictures, found in 42% to 96% of patients with hepatolithiasis,252627 may be related to biliary carcinogenesis as an aspect of recurrent cholangitis, bile stasis, and bacterial infections. Biliary stricture is associated with recurrent and chronic inflammations causing prolonged inflammation of the bile duct epithelium, leading to the subsequent development of cholangiocarcinoma.2829 Up to 50% of patients with malignant biliary strictures may have coexistent hepatolithiasis.30 To prevent the development of cholangiocarcinogenesis, hepatic resection, including the biliary stricture, would be considered in cases of hepatolithiasis.

Minor hepatectomy, which involves segmentectomy of 1 or 2 segments and non-anatomical wedge resection, does not include either the first branch or the second branch of the bile duct in the range of resection. In left lateral sectionectomy, where hepatic resection including segments II and III, the resection range includes only the third branch of the bile duct in segments II and III, and does not include the confluence of the segments II duct and III duct, or the second branch of the bile duct. In our study, biliary strictures in hepatolithiasis were mostly located in the first and second branches of the intrahepatic bile duct, and the location of the concomitant biliary neoplasms was consistent with the location of the biliary strictures. Among all the patients who underwent major hepatectomy in benign hepatolithiasis, 31 patients (42.5%) had a biliary stricture at the first branch of bile duct, and 39 patients (53.4%) had a biliary stricture at the second branch of bile duct. Only 1 patient (1.4%) had a biliary stricture at the third branch of the bile duct. In order to completely remove biliary strictures and thus eliminate the hidden biliary neoplasms, major hepatectomy, including the first and second branches of bile duct, would be an appropriate approach in the treatment of hepatolithiasis.

Immunohistochemical studies have identified 2 types of neoplastic lesions preceding invasive intrahepatic cholangiocarcinoma in hepatolithiasis: BIN and IPNM.3132 Ohta et al.33 observed hyperplasia in the epithelium of the bile ducts associated with chronic cholangitis related to hepatolithiasis, and suggested that mucosal dysplasia may be a precursor to the cholangiocarcinoma. It seems that elimination of BIN and IPNM, potential precursors of cholangiocarcinoma, may be required to prevent the development of cholangiocarcinoma in hepatolithiasis.

There also exist concerns regarding surgical complications after major hepatectomy. The surgical techniques of hepatectomy and the perioperative management of patients have sufficiently developed in the past decade, resulting in a marked decrease in the morbidity and mortality following liver surgery.343536 In one study, the cumulative survival rates, excluding unrelated deaths, did not differ significantly between the hepatic resection group and the cholangioscopic lithotomy group.25 In another study evaluating the outcome of hepatectomy for hepatolithiasis, 7 patients (6.8%) underwent re-operation and 2 patients (1.9%) died during hospital stay.2 In our study, 3 patients (4.1%) underwent re-operation and only 1 patient (1.4%) died during hospital stay. The rate of postoperative complication in our study was not significantly different compared to that of other studies.

Our study presents some limitations, including its retrospective nature and the relatively small number of patients involved. Also, there was no comparison of the postoperative complications in major hepatectomy and minor hepatectomy in patients with hepatolithiasis. Finally, no long-term follow-up was performed to confirm that there would be a significant difference in the development of cholangiocarcinoma between major hepatectomy and minor hepatectomy in benign hepatolithiasis.

In our study, the incidence of biliary neoplasm (including cholangiocarcinoma) not detected before hepatectomy was 27.4% in benign hepatolithiasis. Although preoperative evaluations were performed in patients with hepatolithiasis, in order to exclude underlying biliary neoplasm, the incidence of biliary neoplasm was not negligible. Major hepatectomy as the definite treatment was safely performed for these patients. The presence of cholangiocarcinoma was a significant factor influencing the long-term survival in hepatolithiasis patients, as demonstrated by multivariate analysis.214 Major hepatectomy, including not only hepatolithiasis but also concomitant strictures of intrahepatic bile duct, would be one of the appropriate treatment options for preoperative benign hepatolithiasis. However, further research is required to compare major hepatectomy with other treatments, for a prolonged period.

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