Intraductal papillary neoplasm of bile duct (IPNB), a rare variant of bile duct tumor, is characterized by papillary or villous growth within bile duct lumen often presenting with mucin hypersecretion and dilatation of the bile duct [1-4]. In 2010 and 2019, the World Health Organization classified IPNB as a distinct clinical and pathological entity, being the biliary counterpart of intraductal papillary mucinous neoplasm (IPMN) of the pancreas [5-8]. IPNB is regarded as a precursor lesion of cholangiocarcinoma. Histologically, IPNB can range widely. It has been classified as low- or high-grade dysplasia and IPNB with invasive carcinoma [7]. Pathological features of IPNBs also differ markedly, including various types of intrahepatic and extrahepatic lesions. A high-grade IPNB can be regarded as a malignant lesion because of the potential of tumor recurrence after curative resection [8]. We herein report a case of IPNB recurrence at seven years after curative resection of IPNB with high-grade dysplasia.

A 59-year-old male patient visited a local general hospital for epigastric pain. Initial imaging studies showed intrahepatic duct dilatation with hyperbilirubinemia. After performing percutaneous transhepatic biliary drainage, his jaundice was rapidly resolved. Initial bile cytology at an outside hospital was suspected of malignancy. However, endoscopic biopsy through endoscopic retrograde cholangiopancreatography (ERCP) showed no evidence of malignancy. The patient was referred to our center for further evaluation. Pathology slide review favored nonspecific inflammation. By contrast, magnetic resonance cholangiography (MRC) and biliary dynamic computed tomography (CT) scan showed mild diffuse biliary dilatation, focal dilatation of a segment VIII bile duct (B8) branch, mural enhancement in the far distal common bile duct (CBD), and clonorchiasis with or without neoplasm (Fig. 1A–C). ERCP was performed for repetitive brush cytology. ERCP showed mild dilatation of the common hepatic duct and intrahepatic duct without noticeable stricture (Fig. 1D). Endoscopic biopsy of the distal CBD was negative for malignant cells. Cholangiohepatitis with Clonorchis sinensis infestation was clinically suspected. After recovery of his general condition, the patient was discharged and regularly followed up in the outpatient clinic.

Figure 1. Radiologic findings at initial symptom presentation. Biliary dynamic computed tomography (A) and magnetic resonance imaging with cholangiography (B, C) showed mild diffuse biliary dilatation and focal dilatation of a segment VIII branch (arrow). Endoscopic retrograde cholangiopancreatography (D) showed mild dilatation of the common hepatic duct and intrahepatic ducts without noticeable stricture.

Four years later, the patient presented fever with chilling sense and visited the emergency room of our institution. Liver dynamic CT showed slight worsening of B8 dilatation with suspicious intraductal soft tissue lesions and a separate 3 cm-sized mass in the right hepatic dome (Fig. 2A, B). MRC showed intraductal papillary neoplasm along with enlarging hepatic abscess in the right liver dome (Fig. 2C, D). These findings indicated that liver abscess was formed due to bile duct obstruction caused by papillary neoplasm. Thus, after controlling infection, surgical resection of the intraductal mass and abscess was planned.

Figure 2. Follow-up radiologic findings after four years. Liver dynamic computed tomography (A, B) showed slight worsening of the segment VIII duct dilatation with suspicious intraductal soft tissue lesions (arrow) and a separate 3 cm-sized mass in the right hepatic dome (arrowhead). Magnetic resonance imaging with cholangiography (C, D) showed significantly increased extent of the intraductal papillary lesion (arrow).

The patient underwent R0 resection with right anterior segmentectomy. Gross examination of the specimen revealed a well-defined papillary soft mass size of 2.5 cm×0.8 cm×0.8 cm confined to the bile duct. Firm lesion adjacent to the bile duct mass was an abscess, well-defined fibrotic mass of 3 cm×2.6 cm×2.6 cm in size with extensive necrosis (Fig. 3). Papillary mass was diagnosed as IPNB with a high-grade dysplasia, intestinal type having clear resection margins. Additional immunohistochemical stain showed that the tumor was MUC1 negative but focally positive (<10%) for MUC2 (Fig. 4). The patient recovered uneventfully. He was regularly followed with laboratory tests and abdomen CT every four months for four years and then every six months for next two years. Until six years after the operation, follow-up abdomen CT scans showed mild intrahepatic duct dilatation without worsening (Fig. 5A). Thus, annual checkup thereafter until postoperative ten years was planned for the patient.

Figure 3. Microphotographs of the resected specimen. Intraductal papillary mass was diagnosed as intraductal papillary neoplasm (A: H&E stain, ×50), showing high-grade dysplasia (B: H&E stain, ×200). Immunohistochemical stain showed focal positivity for MUC2 (C: ×400).

Figure 4. Gross photographs of the resected specimen after right anterior sectionectomy showing intraductal papillary lesions (arrow) and liver abscess (arrowhead).

Figure 5. Follow-up liver dynamic computed tomography. Images taken at one month after hepatectomy (A) showed only mild intrahepatic duct dilatation, which was worsened after seven years (B).

At postoperative seven years and eight months, CT scan revealed more prominent intrahepatic duct dilatation (Fig. 5B) although he had no subjective symptoms. A 2 cm-sized highly attenuating mass in the distal CBD was identified on CT and MRC (Fig. 6A–C), which suggested extrahepatic recurrence of IPNB. Fluorodeoxyglucose-positron emission tomography showed focal hypermetabolic uptake of the intraductal mass (Fig. 6D). Serum cancer antigen 19-9 (CA19-9) was not elevated. This recurrent tumor was eligible for repeated resection.

Figure 6. Preoperative imaging studies taken at seven years and eight months after hepatectomy. A 2 cm-sized highly attenuating mass in the distal common bile duct (arrows) was identified on computed tomography (A) and magnetic resonance imaging with cholangiography (B, C). Fluorodeoxyglucose-positron emission tomography showed focal hypermetabolic uptake (arrow) of the intraductal mass (D).

Routine surgical procedures of pylorus-preserving pancreaticoduodenectomy were performed. Gross examination of the resected surgical specimen showed a well demarcated papillary, intraluminal mass size of 1.3 cm×1 cm×0.2 cm confined in the distal CBD (Fig. 7). It was diagnosed as recurrent IPNB of low grade dysplasia with clear resection margins without lymph node involvement. Immunohistochemical staining was negative for MUC1 but focally positive (<10%) for MUC2.

Figure 7. Gross photographs of the resected specimen after pylorus-preserving pancreaticoduodenectomy. Intraductal papillary mass was identified (arrows) at the distal common bile duct (A) with preservation of the proximal resection margin (B).

The patient recovered uneventfully without specific complications. He has been followed up every three months at the outpatient clinic without any evidence of recurrence at one year after pancreaticoduodenectomy (Fig. 8). After the second operation, follow-up with six-month intervals for ten years was planned for the patient.

Figure 8. Follow-up liver computed tomography taken at one year after pancreaticoduodenectomy. There was no interval change of mild intrahepatic duct dilatation (A). There was no abnormal finding at the pancreaticoduodenectomy site (B).

IPNB was proposed as a new disease entity in 2010 WHO classification [5]. It has been reported sporadically around the world. It is a precursor of invasive carcinoma [1,9,10]. The incidence of IPNB is higher in Far East Asian countries than in Western countries [11,12]. IPNB accounts for 9.9% to 30% of bile duct tumors in Asian countries [13,14] and 7% to 11% in Western countries [6,15]. Analysis of our institutional database found that intrahepatic IPNB accounted for approximately 13% of intrahepatic bile duct tumors undergone hepatic resection.

IPNB is considered a biliary counterpart of pancreatic IPMN. Histologically, IPNB shows papillary proliferation with or without mucin-secreting columnar epithelium with varying degrees of atypia, often causing dilation of the proximal or remote bile duct. Based on histomorphology and immunophenotypical profile, it can be classified into four subtypes: pancreatobiliary, intestinal, gastric, and oncocytic. While oncocytic and gastric types are rare, the pancreaticobiliary type is the most common. It is usually associated with invasive lesions. It shows the lowest survival among the four types, more often showing tumor invasion beyond bile duct and lymph node involvement [16].

The most common clinical manifestation of IPNB is right hypochondralgia (35%–88.5%). Unlike conventional cholangiocarcinoma, in which acute cholangitis is uncommon, repeated episodes of acute cholangitis (5%–59%) is the second most common manifestation, followed by obstructive jaundice (20%–36%). Radiologic findings commonly show bile duct dilatation and intraductal masses. Although ultrasonography, CT, and MRI can detect intraductal masses, their sensitivity of detection ranges from 41.2% to 97%. ERCP can be used to identify mucobilia. Cholangioscopy such as percutaneous transhepatic cholangioscopy can also be used to assess the extent of tumor and confirm histologically [6,17,18].

Surgical resection is the first choice of treatment to achieve curative resection of IPNB. In our previous study with 146 cases of intrahepatic IPNB, 1-, 3-, 5-, and 10-year tumor recurrence rates were 2.0%, 4.2%, 8.4%, and 16.8%, respectively. Their 1-, 3-, 5-, and 10-year patient survival rates were 96.0%, 93.9%, 93.9%, and 82.8%, respectively [8]. Considering that the majority of recurrent lesions were non-surgically treated, pancreaticoduodenectomy after hepatectomy in the present case is an unusual treatment modality.

The recurrent IPNB in the present patient was pathologically proven to have low-grade dysplasia, which was slightly different from the initial IPNB. However, their immunohistochemical status of MUC1/MUC2 stain was identical. Thus, the IPNB at the distal CBD was believed to be a recurrent lesion of the initial intrahepatic IPNB. We have also reported the prognosis of intrahepatic IPNB with low-grade dysplasia, showing 1-, 3-, 5-, and 10-year patient survival rates of 100%, 100%, 100%, and 88.9%, respectively [8]. Thus, we planned the follow-up protocol after considering such a favourable prognosis.

We have previously reported that high serum concentration of CA19-9 and R1 resection are independent risk factors for both tumor recurrence and reduced patient survival in patients with intrahepatic IPNB. Surgical R0 resection is highly recommended as the first-choice treatment for patients with intrahepatic IPNB without distant metastasis [8]. By contrast, the design of treatment for recurrent IPNB is often more limited than that of primary treatment because postoperative recurrence pattern should be objectively analyzed.

The present case indicates that long-term follow-up is necessary for patients who have undergone curative resection for IPNB of low- or high-grade dysplasia, although the risk of tumor recurrence is not high. Aggressive surgical treatment for recurrent IPNB lesion is a viable option to achieve long-term survival after prudent consideration of postoperative recurrence pattern.

There was no funding related to this study.

All authors have no conflicts of interest to declare.

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