Review of a Rare Precancerous Lesion – Intraductal Papillary Neoplasm of the Bile Duct (IPNB)

1. Introduction

According to the WHO classification of tumors of the digestive tract, intraductal papillary neoplasm of the bile duct (IPNB) is a rare tumor of the bile ducts characterized by intraductal papillary or villous neoplasms covered by neoplastic epithelium with fine fibrovascular stalks in the dilated bile duct(1). It is considered a precursor lesion of cholangiocarcinoma (CCA) and can affect any segment of the bile duct, but most commonly the left lobe of the liver(2).

IPNB has been classified into four subtypes: pancreatobiliary, intestinal, gastric and oncocytic, similar to intraductal papillary mucinous neoplasms of the pancreas (IPMN)(3). The pancreaticobiliary subtype is the most common with the highest rate of invasive components(3). Depending on the characteristics of the covering epithelial tissue, IPNBs are categorized as low-grade and high-grade(4).

A Japanese group (Japan Biliary Association and the Korean Association of Hepato-Biliary-Pancreatic Surgery) has established a new classification of IPNBs that is useful from a clinicopathologic point of view: Type 1 (low-grade dysplasia and high-grade dysplasia with regular architecture) and Type 2 (high-grade dysplasia with irregular architecture)(2).

The development of IPNB is related to factors such as chronic biliary tract inflammation and genetic alterations, different pathologies and also primitive sclerosing cholangitis (PSC), choledochal cysts and hepatolithiasis(5). IPNB is mainly reported in the countries of the Far East where clonorchiasis (infection by the parasite Clonorchis sinensis) is endemic(6). The clinical symptoms are abdominal pain, often in the epigastrium and right hypochondrium, jaundice and febrile episodes. The age at which the disease occurs is 50-70 years, with men predominating(7).

Due to the high risk of malignant transformation and the increased rate of locoregional recurrence, surgical intervention is considered the cornerstone of treatment, so that R0 resection is recommended to improve long-term survival(8).

2. Epidemiolgy, etiology and pathogenesis

IPNB is a rare disease with a prevalence of 4 to 15 % among tumors of the biliary tract(9). IPNB has been reported mainly from East Asia and the incidence is thought to be higher in these countries than in others(10). Hepatolithiasis and infections with Clonorchiasis sinensis (CS) or Opisthorchis viverrini (OV) are the main risk factors for IPNB in East Asian countries (11). In addition, patients with IPNB may often have cholecystolithiasis and choledocholithiasis (11). The IPNBs detected in Asian countries were more frequently intrahepatic and less frequently extrahepatic (12). IPNBs also appear to develop in primary sclerosing cholangitis (PSC) and congenital biliary tract diseases (12).

Interestingly, IPNB or IPNB associated with invasive carcinoma has been observed predominantly with dilatation of the intrahepatic and perihilar bile ducts, indicating the presence of sclerosing cholangitis involving the peribiliary glands (2).

The average time from the development of hepatolithiasis to the appearance of IPNB is 6-8 years, and the development of intraductal carcinoma in situ to the appearance of an invasive lesion may take 1-2 years(4).

In a recent paper, Kubo et al. proposed that cholangiocarcinomas may be particularly common in young adults exposed to chemicals such as dichloromethane and 1,2-dichloropropane(13). Premalignant or early cancerous lesions such as biliary intraepithelial neoplasia and intraductal papillary neoplasm of the biliary tract, as well as nonspecific biliary tract lesions such as fibrosis, were found at various sites of the biliary tract in all eight patients for whom surgical specimens were available(13).

3. Pathology

IPNB can occur anywhere along the biliary tree and have been described as single or multiple papillary masses.

Histologically, IPNB are defined as tumors with papillary proliferation of neoplastic biliary epithelial cells with fibrovascular stalks in the bile duct, with microscopic and macroscopic presence of mucin and dilatation upstream of the bile duct(14). Using hematoxylin-eosin staining and based on mucin nuclear protein profiling assays, IPNB is classified into four types(3).

• The pancreaticobiliary type is the most common and consists of columnar cells with eosinophilic cytoplasm and round nuclei that are positive for MUC1 and negative for MUC2(15).
• The intestinal type resembles an intestinal villous neoplasm, and the neoplastic cells constantly express MUC2 and MUC5AC but not MUC1(16).
• The gastric type has columnar cells that resemble the gastric furrow and express MUC5AC but are negative for MUC1 and MUC2(16).
• The oncocytic type consists of cells with intense eosinophilic cytoplasm expressing MUC5AC but with inconstant expression of MUC1 and/or MUC2(17).

Depending on the degree of dysplasia and the depth of invasion, IPNB is divided into four stages: IPNB with low- to moderate-grade dysplasia; IPNB with high-grade dysplasia; intraductal growth-type cholangiocarcinoma, AJCC stage T1; and intraductal growth-type cholangiocarcinoma, AJCC stage T2 or higher(18).

 4. Clinical manifestation and blood tests

The most common symptoms are iintermittent abdominal pain in the right upper quadrant, fever and jaundice, but 15%  of patients have no symptoms at diagnosis (19). Anemia and weight loss are relatively rare. The second most common clinical manifestation of IPNB is acute cholangitis, which does not occur in classic cholangiocarcinoma(20).

The clinical manifestations may be related to the following mechanisms: Detachment of tumor emboli from the origin, leading to acute obstruction of the bile duct; due to the presence of gallstones (much more frequent in IPNB than in typical cholangiocarcinomas); macroscopic mucin hypersecretion in almost one third of IPNB patients (21). The massive mucin secretion in the bile ducts temporarily prevents the outflow of bile, which leads to obstruction and subsequently to jaundice and acute cholangitis. Jaundice is variable in these situations, with bilirubin levels rising and falling depending on the amount of mucus obstructing the bile duct.

Most IPNB are found in the hepatic hilum and left lobe of the liver (5). Elevated levels of alkaline phosphatase, carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) have been reported, although they are unlikely to have high sensitivity or specificity for the diagnosis of IPNB. Serum CA19-9 levels may reflect the degree of tumor invasiveness. Importantly, the clinicopathologic features, prognosis, and surgical methods differ between IPNB of the intrahepatic and extrahepatic bile ducts (22).

5. Imaging and endoscopic techniques

The main morphologic changes are the presence of an intraductal mass and surrounding intraepithelial neoplastic biliary mucosa, diffuse or segmental dilatation of the bile ducts with or without cystic changes (to a maximum of 125 mm), and ductal and periductal invasion, including macroinvasion into the liver (23). The imaging patterns can be specifically categorized into five subtypes (Table 1 and Figure1) (3).

5.1. Ultrasound approach

On ultrasound, IPNB is recognized by the presence of hyperechoic nodules, dilatation of the bile ducts and diffuse dilatation of the bile ducts with intraductal nodules(24). Although in most cases an US examination helps to differentiate a stone from a tumor, the accuracy of the examination depends on the examiner(6).

In addition, the presence of mucin cannot be detected sonographically (6). Endoscopic ultrasonography (EUS) and intraductal ultrasonography (IDUS) are useful to assess tumor size, invasion and lymph node invasion even in the presence of thick mucin, which affects resectability and prognosis (25).

Figure 1. Schematic drawing of intraductal papillary neoplasms of the bile duct showing five imaging patterns (3).

5.2. Computed tomography and magnetic resonance image

Computed tomography (CT) can detect tumors larger than 1 cm and dilated bile ducts with a sensitivity of 50%(18). In a previous report, almost all cases showed bile duct dilatation and an intraductal mass on CT, and the IPNB enhancement pattern was isodense or hyperdense in the late arterial phase and non-hyperdense in the late portal venous phase (26).

Other CT findings include infiltration along the canal wall and marked enlargement of the margin at the base of the lesion(27). A cystic mass can affect more than one lobe of the liver (28). On magnetic resonance imaging (MRI), IPNBs may appear as isointense or as hypointense masses on T1-weighted images and hyperintense masses on T2-weighted images (29). MRI imaging may distinguish IPNB as an associated invasive carcinoma from noninvasive IPNB with intraepithelial neoplasia by the following criteria: a visible intraductal mass, tumor mass size greater than 2.5 cm, tumor multiplication, thickening of the bile duct walls, and invasion into adjacent organs(30). MRI with magnetic resonance cholangiography (MRC) can be helpful in differentiating IPNB with invasive carcinoma associated with non-invasive PNB with intraepithelial neoplasia (30).

5.3. Cholangiography

Endoscopic retrograde cholangiography (ERC) and magnetic resonance cholangiography (MRC) are useful to visualize the entire biliary tree to show the location of the IPNB(31).

ERC is useful for detecting mucobilia, which is observed in nearly 1/3 of patients with IPNB, and for demonstrating diffuse dilatation of the bile duct with an irregular or amorphous filling defect (Figure 2) (2). In addition, communication between the cyst and the bile duct is detected in almost half of the patients (9). During ERCP, brush cytology samples and sometimes tissue samples are taken.

MRC is a standard non-invasive method for determining the degree of stenosis or dilatation of the bile duct and the presence of multifocal intraductal tumors, but cannot detect the presence of excess mucin at the level of the bile ducts (32). IPNB usually shows a signal defect against the bile, which is characterized by a high signal intensity(4). The bile duct affected by IPNB need not have an obvious stenosis, but localized dilatation of the bile ducts often occurs due to mucin production by the tumor (27).

However, a large amount of mucin secretion or a completely obstructing tumor prevents opacification of the entire bile duct. Cholangiography cannot detect multiple small tumors or lesions limited to the mucosa. It also cannot distinguish between tumors and lithiasis or benign bile duct strictures (18).

Figure 2. Endoscopic retrograde cholangiography of intraductal papillary neoplasm of the bile duct (IPNB).

(A) Reveals the dilated bile ducts and the amorphous filling defect marked with the red asterisk; (IPNB) in the dilated bile duct at the hilar portion and protective pancreatic stent, for the prevention of acute pancreatitis after ERCP (marked with a yellow asteriks)

(B) Placed plastic biliary stent (marked with a red asterisk) and protective pancreatic stent, for the prevention of acute pancreatitis after ERCP (marked with a yellow asterisk)

5.4. Cholangioscopy

During oral cholangioscopy (POCS) and percutaneous transhepatic cholangioscopy (PTCS), the bile duct is visualized endoscopically or radiologically, the extent of the lesions is assessed and biopsies are taken for histopathological examination(33).

With PTCS, additional lesions can be visualized in a third of IPNB patients after the classic imaging examinations (CT, MRI), which is why a cholangioscopy prior to surgery is considered essential (18). A POCS can be performed during ERCP, which leads to an early and accurate diagnosis of IPNB. In this way, complications caused by PTCS, such as catheter displacement, hemobilia and distant seeding of neoplastic cells, are avoided(34).

5.5. Position-emission tomography

PET-CT is used in patients with renal insufficiency and for the detection of incipient distant metastases if the tumor shows increased absorption of fludeoxyglucose(35). Imaging studies and their value in IPNB are shown in table 2.

Table 2. Imaging techniques and their value in IPNB(18)

EUS- Endoscopic ultrasound ; IDUS- Intraductal ultrasonography; CT- Computed tomography; MRI- Magnetic resonance imaging; PET/CT- Position-emission tomography

6. Diagnosis and diferential diagnosis

The low incidence of IPNB and the absence of clinical symptoms complicate the diagnosis of this pathology, so the use of various imaging and endoscopic procedures helps the physician to make a correct diagnosis(36).

CT and MRI cannot detect tumors < 1 cm or mucin hypersecretion, so cholangiography and cholangioscopy may help (37).

In certain situations, biopsy may underestimate the true stage of disease due to foci at different stages of development (multifocal IPNB) or improperly taken biopsies. Invasive methods such as ERC or cholangioscopy may be necessary for the differential diagnosis of IPNB. Cholangiocarcinoma often appears as a single intrahepatic mass with dilatation of the upstream bile ducts(38).

Differential diagnoses of IPNB include recurrent pyogenic cholangitis with bile duct stones, cholangiocarcinoma, hepatocarcinoma (HCC)  with bile duct invasion, intraductal metastases, localized Caroli disease and biliary cystic tumors such as non-invasive mucinous cystic neoplasms, also known as biliary cystadenomas (BCA), and mucinous cystic neoplasms with associated invasive carcinoma or biliary cystadenocarcinomas (BCAC)(39). The diagnosis and treatment of IPNB is summarized in the flowchart in Figure 3.

Figure 3. Flow chart for diagnosis and treatment of intraductal papillary neoplasms of the bile

7. Treatment

A treatment plan must be established for all patients with IPNB, as high-grade dysplasia with invasion is common and recurrent cholangitis and obstructive jaundice occur in papillary tumors with mucin hypersecretion, even if the dysplasia has a low-grade (40).

7.1. Surgical treatment

In contrast to conventional cholangiocarcinoma, where there is a well-defined pathological classification helping with the diagnostic, the staging and the treatment, the detailed classification of IPNB is not yet well established. Therefore, many factors are considered when deciding on the extent of resection, including the location of the tumor, the number, the presence of intrahepatic stones, the degree of bile duct dilatation around the tumor and the patient’s condition(41).

Patients without distant metastases are evaluated for surgical resection. IDUS or EUS are used to assess the extrahepatic bile ducts and visualize the nearby lymph nodes (42). Patients with IPNBs located on the intrahepatic bile duct are treated with hepatectomy. If the tumor invades one of the two hepatic ducts, both the affected hemificum and the common bile duct are resected (43).

For IPNBs localized in the extrapancreatic part of the bile duct, a complete resection of the bile duct from its confluence with the intrapancreatic part with extended lymphadenectomy is recommended (44). For IPNB located at the level of the common bile duct or at the level of the hepatic hilum, a lymphadenectomy at the hilum is essential, and resection of the caudal segment and the portal vein can be added as required (45).

Extrahepatic IPNBs are usually removed by biliary resection or pancreatoduodenectomy, whereas intrahepatic and perihilar biliary IPNBs are removed by hepatobiliary resection (2). Duodenopancreatectomy and bile duct resection are used for IPNBs with extrahepatic localization, while hepatectomy is the chosen approach for intrahepatic IPNBs(19). The subclassification of IPNB type 1 and 2 also plays an important role in the choice of surgical procedure.

Type 1 usually develops in the intrahepatic bile duct and shows less aggressive behavior than type 2. The types of surgical intervention for type 2 may include hepatectomy, duodenopancreatectomy, and resection of the bile ducts (46).

Chang et al. analyzed the patterns of tumor spread in patients with papillary extrahepatic bile duct carcinoma and recommended an optimal resection margin of 16 mm (47). Due to the limited length of the bile duct, it is quite difficult to achieve a proper resection, so a margin of at least 1-2 cm from the tumor is recommended (47). Patients with IPNB can achieve a better long-term prognosis through effective surgical resection (48). Therefore, it is important to accurately localise the lesion and surrounding intraepithelial neoplastic zone and determine an appropriate resection based on radiologic imaging, preoperative endoscopic techniques, and histopathologic results (48).

If major surgery is not possible, various treatments are available, such as percutaneous transhepatic biliary drainage, cholangioscopic electrocoagulation, intraluminal iridium-192 therapy, argon plasma coagulation and adjuvant therapies (chemotherapy), but for palliative purposes, not curative (49).

Partial hepatectomy followed by adjuvant chemotherapy can also be performed (50). Recently, the treatment of IPNB using argon plasma coagulation with a follow-up period of more than two years was reported (50).

7.2. Palliative treatment

In situations where surgery is contraindicated, palliative treatment is the recommended method. Endoscopically inserted biliary stents (plastic or metal) and radiologically guided transhepatic biliary drainage reduce jaundice and treat angiocolitis, improving the quality of life and short-term survival (51).

8. Discussion

IPNB is a neoplasm of the bile ducts with malignant potential as it may be followed by full blown cholangiocarcinoma (9). The bile ducts invaded by the neoplasm appear dilated due to intraductal tumor growth and mucus hypersecretion and can be detected by imaging and endoscopy (2). IPBN was originally described in 1894 by Chappet as biliary papillomatosis, and in 1976 by Neumann et al. as multicentric biliary papillomatosis associated with invasive adenocarcinoma (7). The term IPNB was used by Zen et al. in 2006 and included in the World Health Organization classification of biliary tract tumors in 2010(52).

Experts from Japan and Korea have developed a classification system with two subtypes, intrahepatic and extrahepatic, based on the location, characteristics, and prognosis of the disease (2). The intrahepatic type is similar to pancreatic IPMN, whereas the extrahepatic type has a more complex histologic architecture and is associated with invasive cancer and a poorer prognosis (53). Papillary tumors and associated mucus often lead to recurrent attacks of cholangitis and obstructive jaundice, even when these lesions are benign (53).

The usual presentation is pain in the upper right abdomen and obstructive jaundice. Repeated acute cholangitis occurs in up to 50% of patients, and 5% of patients are diagnosed in an asymptomatic state(21). Biliary obstruction with repeated episodes of cholangitis can eventually lead to secondary biliary cirrhosis (SBC) (54). Most symptoms of IPNB are related to mucus-producing activity, which can intermittently obstruct bile flow, leading to obstructive jaundice and cholangitis, and the friable nature of the lesion, which can easily detach, leading to acute biliary obstruction (41).

The time course of bile duct cancer described in the literature involves progression from local chronic inflammation to multistage carcinogenesis (hyperplasia-dysplasia-carcinoma) (55). Chronic inflammation also induces the production of reactive oxygen and nitrogen species, which lead to DNA alterations and play an important role in carcinogenesis (56). The overall prognosis of IPNB is thought to be better than that of conventional cholangiocarcinoma. IPNB without mucin hypersecretion shows a tubulopapillary growth pattern and a uniform degree of cellular atypia, without IPNB with mucin hypersecretion, which shows mixed pathological changes (20).

Postoperative immunohistochemical studies show that almost all IPNBs express CK7, CK20 and mucin (MUC) 5AC, classical markers of biliary, intestinal and gastric epithelium (57).

Nakanuma et al. demonstrated that peribiliary glands (PBGs) contain cells that are responsible for the development of IPNB (16,58). One of the first studies to analyze IPBNs using whole-exome sequencing showed that they are genetically distinct from cholangiocarcinomas and frequently harbor APC and CTNNB1 mutations (59). They have a high malignant potential, with invasive components found in 40 to 80 % of patients(18).

The overall survival of IPNB is higher than that of a cholangiocarcinoma. Lee et al. reported a survival rate of 80% at 5 years after curative resection (6). Also, Rocha et al. showed a median survival of 82 months after R0 resection compared to 36 months with R1 resection and Jung et al. have shown that R1 resection was the only prognostic factor for tumor recurrence and overall survival (41). Long-term survival depends on three important factors, such as the depth and percentage of the invasive component, the cell type of the IPNB and the presence of not of cancer at the resection margins (5).

9. Conclusion

In summary, intraductal papillary neoplasm of the bile duct is a rare biliary tumor that sometimes develops into cholangiocarcinoma. The pathogenesis is not fully understood and its natural history shows similarities with IPMN. The curative treatment is still surgical, with a higher long-term survival rate if IPNB is diagnosed before transformation into a cholangiocarcinoma.

Abbreviations

AJCC – American Joint Committee on Cancer

CA 19-9 – Cancer antigen 19-9

CBD – Common bile duct

CEA –  Carcinoembryonic antigen

CCA – Cholangiocarcinoma

CHD – Common hepatic duct

CS – Clonorchiasis sinensis

CT – Computed tomography

EUS – Endoscopic ultrasound

ERCP – Endoscopic retrograde cholangiopancreatography

HCC – Hepatocarcinoma

IHD – intrahepatic duct

IPNB – Intraductal papillary neoplasms of the bile duct

IPMN – Intraductal Papillary Mucinous Neoplasm

MRC – Magnetic resonance cholangiography

MRI – Magnetic resonance imaging

OV – Opisthorchis viverrine

PBG – Peribiliary glands

PET-CT – Position-emission tomography

POCS – Oral cholangioscopy

PSC – Primitive sclerosing cholangitis

WHO – World Health Organization

Statements

Authors’ contributions: CSG and LMN wrote the manuscript, MM revised the text.

Consent for publication: As the corresponding author, I confirm that the manuscript has been read and approved for submission.

Conflict of interest: All authors declare having no competing interests associated with this publication.

Funding Sources: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sector.

Ethical Approval: This study was not subject to ethical review and approval due to its article format.

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