Surgical Treatment of Intraductal Papillary Neoplasm of the Bile Duct: A Report of Two Cases and Review of the Literature

Intraductal papillary neoplasm of the bile duct (IPNB) is a rare bile duct tumor characterized by intraductal papillary or villous neoplasms covered by neoplastic epithelium with fine fibrovascular stalks in the dilated bile ducts (1). Its true etiology remains unknown. Herein, we report two cases of IPNB that underwent surgical resection. The first case was a 66-year-old male who complained of upper abdominal pain for three years. We found obstruction of the common bile duct and dilation of the intrahepatic and extrahepatic bile ducts after MRCP. Laparoscopic hepatic segmentectomy (S2, S3, S4), resection of the common bile duct, cholecystectomy, and hepaticojejunostomy were performed. The second case was a 67-year-old male with asymptomatic dilation of the intrahepatic duct. The patient underwent robot-assisted laparoscopic hepatic segmentectomy (S5, S6, S7, S8), resection of the common bile duct, hepaticojejunostomy and cholecystectomy.


Case 1
A 66-year-old man was referred to our hospital due to abdominal pain. Three years ago, he had presented with right upper quadrant abdominal pain, which worsened after meals, and the pain was more frequent in recent months. He had no noteworthy medical or family history. Physical examination was unremarkable.
Enhanced computed tomography (CT) at our hospital revealed interruption of the intrapancreatic common bile duct ( Figure 1B) and dilatation of the extrahepatic and intrahepatic bile duct, which was especially obvious in the left lobe of the liver ( Figure 1A). To evaluate dilatation of the bile duct, magnetic resonance cholangiopancreatography (MRCP) was performed. MRCP showed dilatation of the extrahepatic and intrahepatic bile ducts, irregular dilatation and thickening of the bile duct in the left lobe of the liver (Figures 1C-H). At the same time, there were localized nodular prominences in the bile duct lumen. Laboratory values on admission were as follows: tumor markers, alpha-fetoprotein (AFP) 2. 6 ng/mL (normal range 0.00-8.78 ng/mL), ferritin (Fer) 153.96 ng/mL (normal range 21.80-274. 66 ng/mL), carcinoembryonic antigen (CEA) 2. 57 ng/mL (normal range 0.00-5. 00 ng/mL), and cancer antigen 19-9 (CA199) 47. 85 U/mL (normal range 0.00-37.0 U/mL). A routine blood examination was not abnormal. The level of g-glutamyltranspeptidase (g-GTP) was elevated, 109 U/L (normal range 7-49 U/L) ( Table 1).
After the relevant preoperative examination was completed, laparoscopic hepatic segmentectomy (S2, S3, S4), resection of the common bile duct, cholecystectomy, and hepaticojejunostomy were performed. On intraoperative cholangioscopy, we found the left hepatic duct filled with mucus and papillary protrusions adhering to the surface of the left hepatic duct ( Figure 1I). No abnormalities were detected in the common bile duct. Laparoscopic hepatic segmentectomy (S2, S3, S4), resection of the common bile duct, cholecystectomy, and hepaticojejunostomy were performed. The bile duct was filled with greenish -yellow mucus -like sludge ( Figures 1J, K). Microscopically, the intrahepatic bile duct, common bile duct and cystic duct were lined by papillary growth neoplasia with high-grade intraepithelial neoplasia ( Figures 1L, M). Gene detection was performed using DNA extracted from paraffinembedded bile ducts. Gene detection revealed KRAS codon 12 (p. G12F) mutation, and the mutation frequency was 62.9% ( Figure 1N).
The postoperative course was uneventful, and the patient was discharged from the hospital on the 7th postoperative day. The patient had no recurrence and no complications for 8 months after surgery.

Case 2
A 67-year-old male with diabetes mellitus was admitted to our hospital due to finding dilatation of extrahepatic and intrahepatic bile ducts by accident during a routine medical examination 15 days ago. The patient was asymptomatic. He did not feel abdominal pain or abdominal distension. The patient did not have a history of viral hepatitis or alcoholic liver disease. There were no remarkable findings during the physical examination.
Intraoperative cholangioscopy was performed to evaluate the common bile duct. The common bile duct wall was rough and full of white flocculus ( Figures 2G, H). Therefore, the patient underwent robot-assisted laparoscopic hepatic segmentectomy (S5, S6, S7, S8), resection of the common bile duct, hepaticojejunostomy and cholecystectomy. Grossly, the intrahepatic bile duct lumen was filled with yellow, gelatinous, sticky mucous masses. The diameter of the largest one was 18 mm. The patient's postoperative course was uneventful. The patient was discharged from our department 13 days after surgery. The patient was followed up for 6 months after the operation, and there were no signs of recurrence. ( Figure 2K).

DISCUSSION
Intraductal papillary neoplasm of the bile duct (IPNB) is a rare bile duct tumor characterized by intraductal papillary or villous neoplasms covered by neoplastic epithelium with fine fibrovascular stalks in the dilated bile ducts (1). IPNB is mainly found in patients in Eastern countries, such as Japan, and Korea, where hepatolithiasis and clonorchiasis, which are known to be major risk factors for IPNB, are endemic (4). IPNB shows a slight male predominance, and most patients are between 50 and 70 years of age is reported (4,5).
However, the pathogenesis and nature of IPNB are still unclear. It is likely caused by cholestasis, biliary tract infection, and biliary tract cancer. Studies have found a mechanism for biliary tract cancer due to the progression of chronic inflammation to multistage carcinogenesis and eventually hyperplasia-dysplasia-carcinoma (6). Furthermore, chronic inflammation induces the production of reactive oxygen species and reactive nitrogen species, resulting in DNA damage, which plays an important role in carcinogenesis (7). IPNB symptoms include recurrent and intermittent abdominal pain, cholangitis, and jaundice. However, some patients are asymptomatic (3,8). Histological types of IPNB have been classified into the following four types: gastric, intestinal, pancreaticobiliary, oncocytic, and IPMN, depending on morphologic appearance and mucin staining properties (9). GNAS and KRAS mutations detected in 50% and 46.2% of IPNBs are common in IPNBs. KRAS plays an important role in regulating cell growth and differentiation (10), A recent study has shown that KRAS mutation was detected in one third of intrahepatic cholangiocarcinoma (ICC) and also one third of biliary intraepithelialneoplasia (BilINs) associated with hepatolithiasis (11). Moreover, the KRAS mutation rate in highgrade IPNBs, and invasive IPNBs is significantly higher than lowand intermediate-grade IPNBs. So KRAS mutation may contribute to the pathogenesis of IPNBs (12,13). Research shows that the 5-year survival rate of patients undergoing R0 resection is 59.7%. However, it is still lower than that for patients with benign diseases and better than intrahepatic cholangiocarcinoma (14,15). Surgical resection is the first line treatment for patients with IPNB without distant metastasis because of recurrent cholangitis and obstructive jaundice (1,16). Liver transplantation and pancreaticoduodenectomy can be theoretically regarded as the only curative treatment. However, liver transplantation is unsuitable for patients with advanced tumor invasion or positive lymph nodes (4). Recently, new approaches, such as RFA and APC, have been helpful for patients who are not candidates for surgery due to age or physical condition (17,18).
To further investigate the clinical features and prognosis of IPNB, we gathered case reports of IPNB in PubMed . We searched PubMed for "Intraductal papillary neoplasm of the bile duct" and "case report" during 2002 to 2021. Case reports were included if they reported any aspect of the clinicopathological or surgical characteristics of patients with IPNB confirmed by pathology. Most patients were more than 45 years of age, with a median age of 69 years. Only two patients were younger than 45 years of age. Males slightly predominated the case reports. The geographic distribution of patients was not different from other reviews, with IPNB mainly in Asia. There was only one patient found in Africa. However, the patients was Japanese. The tumor size ranged from 10.6-130. 0 mm, with a median size of 52. 9 mm. IPNB can develop anywhere along the biliary tree, with 25.0% in the right lobe of the liver, 32.5% in the left lobe of the liver, 12.5% in the CBD, 17.5% in the extrahepatic duct and liver and 12.5% in other locations, including the whole liver or gallbladder. The common radiologic findings for IPNB are bile duct dilatation, intraductal mass and cystic lesion. Among all cases, 28 included information on tumor markers, the CA 19-9 of 10 cases was elevated, and 18 were not elevated. The type of surgery depended on various anatomical locations of the tumor and the physical qualifications of the patients. Hepatectomy, which accounted for 40%, was the main surgical approach. Twenty-five percent of patients underwent hepatectomy, extrahepatic bile duct resection, and hepaticojejunostomy. Five percent of patients underwent hepatectomy and segmental pancreatectomy. A total of 7.5% of patients underwent pancreatoduodenectomy. As a palliative treatment, endoscopic treatment is necessary for patients with poor physical conditions. It is worth mentioning that RFA and APC accounted for 7.5% of promising therapeutic strategies and are expected to bring new approaches for IPNB ( Table 2). IPNB lesions frequently contain invasive components. Twenty-three cases (57.5%) contained evidence of high-grade cholangiocarcinoma, while 17 cases (42.5%) ranged from no invasion to medium-grade cholangiocarcinoma. Immunohistochemical data were available for 26 cases, from which we found that CK7 (42.3%), MUC5AC (53.8%) and MUC6 (53.8%) expression was common in the IPNB. Based on the recurrence-free survival (RFS) reported in 23 cases, we found that the range of RFS was 4.0-39.0 months, with a median of 14.0 months ( Table 3).  On further review of the literature, we could conclude that IPNB mainly behaves as in imaging solid mass, cystic lesion and dilation of the bile duct in imaging. Surgical resection is the major treatment for patients in fine condition, and interventional therapies such as RFA and APC are good choices for palliative treatments. Although most IPNB cases are high-grade intraepithelial neoplasia or invasive carcinoma in microscopically, surgical resection could make patients get satisfactory prognosis.

CONCLUSION
In summary, we report two cases of IPNB, a rare tumor of the hepatobiliary system, and analyze published case reports about IPNB. Since IPNB has a high potential for transforming into an invasive lesion, R0 surgical resection is preferred. At the same time, RFA and APC may be new palliative approaches for treating IPNB.

DATA AVAILABILITY STATEMENT
The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/supplementary material.

AUTHOR CONTRIBUTIONS
BL designed the case report. ZL, QL, and WT participated in the operation and management of the patients. BL, ZM, and ML prepared radiological and histology figures. BL, ZL reviewed the literature and drafted the article. All authors contributed to the article and approved the submitted version.