• biliary tract;
  • intraductal papillary neoplasm;
  • intraepithelial neoplasm;
  • mucinous neoplasm;
  • pancreas;
  • peribiliary glands


  1. Top of page
  2. Abstract

There are peribiliary glands around the biliary tract, and these glands drain into the bile duct lumen. Interestingly, small amounts of pancreatic exocrine acini are intermingled with these glands. Experimental studies using animals suggest that the biliary tract shows some potential for pancreatic differentiation. It is noteworth that the biliary tract and pancreas have similar pathological features. IgG4-related sclerosing cholangitis and autoimmune pancreatitis are representative inflammatory diseases with similar features. Intraductal papillary neoplasms are found in the biliary tract and also in the pancreas: intraductal papillary neoplasm of the bile duct (IPNB) and intraductal papillary mucinous neoplasm of the pancreas (IPMN). IPNB and IPMN share common histologic and phenotypic features and biological behaviors. Interestingly, mucinous cystic neoplasm (MCN) arises in both the pancreas and the heaptobiliary system. Intraductal tubular neoplasia is found in both the biliary tract and pancreas as well. Intraepithelial neoplasm is found in the biliary tract and pancreas: biliary intraepithelial neoplasm (BilIN) and pancreatic intraepithelial neoplasm (PanIN). BilIN and PanIN are followed by conventional invasive adenocarcinoma, while IPNB and IPMN are followed by tubular adenocarcinoma and mucinous carcinoma in both organs. Further study of the biliary tract's pathophysiology based on its similarity to pancreatic counterparts is warranted.


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  2. Abstract

Heterogeneous inflammatory and neoplastic diseases develop in the biliary tract, and their pathogenesis and the etiology of these diseases have been evaluated based on individual diseases categories.1 The biliary tract and pancreas are adjacent to each other, with the common bile duct of the biliary tract and the pancreatic duct uniting at the papilla Vater, and secreting pancreatic juice and bile into the duodenum. Both organs derive from the foregut at almost the same time, and recent studies using animals have revealed that they show plasticity to each other during development.2 Furthermore, studies with genetically altered animals showed that the biliary tract shows pancreatic differentiation,3–5 though this is prevented physiologically in humans. Diseases of the biliary tract and pancreas have a similar pathophysiology.6,7 For example, advanced cholangiocarcinoma and preneoplastic or early intraepithelial neoplasms of the biliary tract show similar morphological or genetical changes to their pancreatic counterparts.8,9 Mucinous cystic neoplasm is also reported to develop in the pancreas and to a lesser frequency along the hepatobiliary system.8,10 These findings suggest that some biliary tract and pancreatic diseases develop via the same process and show similar morphology and phenotypes.

In this review, we propose a novel approach to understanding the biliary tract's pathology based on similarities to pancreatic counterparts. First, the anatomy and development of the biliary tract are reviewed based on the view that the biliary tract is potentially an incomplete pancreas. Then, several inflammatory and neoplastic diseases of the biliary tract are discussed based on similarities to pancreatic counterparts.


  1. Top of page
  2. Abstract

A. Anatomy and development of the biliary tract and peribiliary glands

Anatomy of the biliary tract

The biliary tract is generally divided into the extrahepatic bile duct and gallbladder, and the intrahepatic bile duct.11 The common hepatic and bile ducts including the right and left hepatic bile ducts are included in the extrahepatic bile duct. The ‘extrahepatic biliary system’ consists of a set of extrahepatic bile ducts, together with the gallbladder and the cystic duct connecting the gallbladder to the main duct system (Fig. 1), while the term ‘extrahepatic bile ducts’ is reserved just for those ducts that lie between the cystic duct and the liver and for the common bile duct.5


Figure 1. Anatomy of the extrahepatic biliary duct system cited from ref.5

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The intrahepatic bile duct, proximal to the right or left hepatic bile duct, is composed of the intrahepatic large and small bile ducts.12 The former correspond to the first to third branches of both hepatic ducts, while the latter which are recognizable under a microscope, are composed of septal and interlobular bile ducts. Interestingly, the intrahepatic large bile duct and extrahepatic bile ducts are accompanied by peribiliary glands. The biliary tract is lined by a single layer of cuboidal to high columnar simple epithelium (cholangiocytes) according to the size of the bile duct.

Peribiliary glands

Around the extrahepatic and intrahepatic large bile duct are peribiliary glands.13–15 These glands can be divided into intramural and extramural type. The former are scattered within the bile duct walls, and are simple tubular mucous glands. The latter are located in the periductal connective tissue1 (Fig. 2a,b), and are branched tubuloalveolar seromucous glands (Fig. 3a). Observatons of serial section revealed that the extramural glands drain into the large bile duct lumina via their own conduits, while the intramural glands drain directly into the bile duct lumen.1 These glands are positive for pancreatic exocrine enzymes and also lactoferrin and lysozyme.17


Figure 2. Peribiliary glands. a. Biliary cyst of an adult showing tree-like projections on both sides of the bile duct cited from ref.1 b. Schematic presentation of the peribiliary glands cited from ref.16

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Figure 3. Peribiliary glands of extramural type. a. Branched tubuloalveolar seromucous glands are located in the peribiliary connective tissue. HE. b. Pancreatic exocrine acini are admixed with peribiliary glands. HE.

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In this context, the biliary tract is the drainage system of the liver parenchyma and of the peribiliary glands. The latter drain via their own conduits or directly into the bile duct lumen, while the bile secreted by hepatocytes drains into the biliary tract lumen and eventually into the duodenal lumen (Fig. 4).


Figure 4. Schema of the liver, biliary tract, pancreas and duodenum. The biliary tract drains both exocrine glands. a. The biliary tract representing drainage from the liver parenchyma. b. The biliary tract representing drainage from the peribiliary glands (x). ○ shows peribiliary glands on the biliary cast and also histology.

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Development of the biliary tract and peribiliary glands

Together with the liver and ventral pancreas, the extrahepatic biliary system arises from the ventral endoderm of the foregut.2,5 It is continuous at its caudal end with the duodenal epithelium and at the cephalic end with the primitive hepatic sheets. Both hepatic ducts and part of the cystic duct develop from the cephalic end of the diverticulum, while the caudal segment develops into the gallbladder, a part of the cystic duct and the common hepatic duct. The intrahepatic ducts develop from the ductal plate surrounding the intrahepatic branches of the portal vein. At about 9–10 weeks, primitive hepatocytes surrounding portal vein branches near the liver hilum form the so-called ductal plate. The ductal plate is composed of a layer of epithelial cells showing a biliary epithelial phenotype and of those showing a hepatocyte phenotype.15 Along with the remodelling of the plate, an anastomosing network of bile ducts is formed, excess ductal epithelium undergoes resorption and bile ducts appear within the definitive portal tracts.5,18 The entire process of duct development progresses centrifugally from the porta hepatis and also from the larger to the smaller portal tracts in the liver. Interestingly, the peribiliary glands around the intrahepatic large bile ducts also derive from the ductal plate.15

B. Is the biliary tract an incomplete pancreas?

Pancreatic exocrine acini are a component of peribiliary glands

Exocrine acini of pancreas are physiologically intermingled with peribiliary glands, though their distribution is usually patchy and infrequent14,15 (Figs 3b,4b). These acini consist of three cell types: acinar cells with eosinophilic zymogen-like granules, clear cells resembling centriacinar cells, and ductular elements. Langerhans' islets are not found. Immunohistochemically, constituent cells of those acini contained pancreatic α-amylase and trypsin but lacked insulin-, glucagon-, and somatostatin-immunoreactive endocrine cells. The numbers of pancreatic exocrine acini or cells in the peribiliary glands seem to be too small to have a significant physiological role, and furthermore, their numbers vary between individual persons. But their presence could be of great interest from the point of view of developmental biology and pathology. In addition, α-amylase and trypsin are also immunohistochemically observed in the lining epithelia of the intrahepatic large ducts, septal ducts and peribiliary glands.15,19 Some epithelia of peribiliary glands, positive for both α-amylase and trypsin, histologically resemble pancreatic acinar cells, suggesting that the epithelia of intrahepatic large ducts, septal ducts and peribiliary glands contain pancreatic α-amylase and trypsin in addition to exocrine acini in the peribiliary glands.

The biliary tract has bipotential differentiation

Hes1 encodes the basic helix-loop-helix protein, which represses expression of Neurog3, a promoter for pancreatic exocrine and endocrine differentiation.3–5 Expression of Hes1 is controlled by the evolutionarily conserved Notch pathway. Hes1 operates as a general negative regulator of endodermal endocrine differentiation, and defects in Notch signaling lead to accelerated pancreatic endocrine differentiation.3 Hes1 is expressed in the extrahepatic biliary epithelium throughout development. In Hes1 knock-out mice, biliary epithelium ectopically expresses the proendocrine gene Neurog3, differentiates into pancreatic endocrine and exocrine cells and forms acini and islet-like structures in the mutant bile ducts, followed by the conversion of much of the extrahepatic biliary primordium to ectopic pancreas. Thus, biliary epithelium has the potential for pancreatic exocrine and even islet-like cell differentiation, though Hes1 determines biliary organogenesis by preventing the pancreatic differentiation program, probably by directly repressing transcription of Neurog3.3–5 During the development, pancreatic exocrine acini mature from the peribiliary glands and there are exocinre acini intermingled with peribiliary glands around the biliary tract, suggesting that the regulation by Hes1 is not perfect in the biliary tract in human.13,15

It is possible that an occasional random reduction of Hes1 expression in biliary epithelial cells de-represses Neurog3 and consequently activates the exocrine and endocrine program, possibly followed by the development of pancreatic tissue. Sox9 is another transcription factor important in pancreatic development. In the developing pancreas, its expression is restricted to mitotically active, Pdx1 (the pancreatic key master regulator)-positive progenitor cells, and is one of the factors regulating Hes1.20 Thus, fluctuations of Sox9 may also cause de-stability and activation of Neurog3 in a subset of cells.

Taken together, the expression of Hesl, Neurog3, Notch and Pdx1 is strictly controlled in the development and normal anatomy of the biliary tract. A disturbance of gene regulation and expression, however, may lead to the acquisition of potentially pancreatic features or potentiality of pancreatic differentiation in the biliary tract and may be involved in the pathogenesis of several biliary tract pathologies, particularly under neoplastic conditions with genetic and epigenetic alterations.


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  2. Abstract

There are several inflammatory biliary diseases with the pancreatic counterparts showing similar features. IgG4-related sclerosing cholangitis (IgG4-SC) and lymphoplasmaytic sclerosing pancreatitis (LPSP) (also called autoimmune pancreatitis) are representative.6,21 In addition, both primary sclerosing cholangitis (PSC) and idiopathic duct-centric chronic pancreatitis (IDCP) are associated with inflammatory bowel disease (IBD), suggesting a common etiopathogenesis in these two diseases.22,23

A. IgG4 related sclerosing cholangitis and lymphoplasmaytic sclerosing pancreatitis

Lymphoplasmaytic sclerosing pancreatitis is characterized by dense lymphoplasmacytic infiltration, extensive fibrosis with myofibroblastic proliferation, severe atrophy and loss of exocrine acini, diffuse or massive swelling of the pancreatic parenchyma and irregular narrowing of the main pancreatic duct.6,21 About 50–90% of patients with LPSP show biliary lesions presenting with obstructive jaundice or fever, and the biliary lesions resemble LPSP.6 Grossly, the affected bile ducts and portal tracts look whitish, medullary and fleshy, and the border is rather expansive and sharp against surrounding tissue including the liver parenchyma. The lumens of affected bile ducts are stenotic. The extrahepatic bile duct, particularly its intrapancreatic portions, is frequently affected, and the hilar or intrahepatic large bile ducts are also infrequently affected. That is, (i) both mainly affect middle-aged and elderly men, while children and youths are not affected. Characteristically, IgG4-SC and LPSP are not associated with IBD; (ii) dense lymphoplasmacytic infiltration with abundant IgG4+ plasma cells in the affected tissue and notable eosinophilic infiltration in some cases (Fig. 5a). Interestingly, biliary lining epithelial cells of the affected bile ducts and those of the pancreatic duct are spared relatively; (iii) myofibroblasts proliferate in these lesions, and are responsible for fibrosis; (iv) sclerosing inflammation with lymphplasmacytic infitlration extending to parapancreatic and peri-bile duct connective tissue, and perineural infiltration of lymphocytes are seen. Obliterative phlebitis, easily identifiable by EVG staining, is constantly and characteristically seen in the affected parts of LPSP and IgG4-SC, probably reflecting growth of inflammatory lesions into the venous lumen; (v) some cases show a tumorous lesion which is regarded as a nodular expansion of inflammatory lesions appearing as hepato-biliary inflammatory pseudotumor or mass-forming chronic pancreatitis. In exceptional cases, the inflammatory pseudotumor is clinically an overwhelming feature, and cholangitis or pancreatitis belonging to IgG4-SC and LPSP is later demonstrated in surgically resected specimens; and (vi) serologically, ANA and other autoantibodies are not infrequently detected, and γ-globulin and IgG, particularly IgG4, levels are elevated in the serum of IgG4-SC patients, suggesting an abnormality of the humoral immune system. An elevated serum level of IgG4 is associated with disease activity in LPSP and probably in IgG4-SC.IgG4-SC and LPSP respond well to steroid therapy. vii) Immunohistochemically, there are many IgG-positive plasma cells, a great majority of which are positive for IgG4, in the affected bile duct and pancreas of IgG4-SC and LPSP.


Figure 5. a. IgG4-related sclerosing cholangitis of the biliary tract. Arrow shows damaged peribiliary glands in the duct wall. HE. b. Peribiliary glands are affected in IgG4-related sclerosing cholangitis. HE.

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The gallbladder is not infrequently affected (chronic sclerosing cholecystitis) in patients with IgG4-SC, and chronic sclerosing cholecystitis shows a similar morphology to LPSP.24 Taken together, IgG4-SC and LPSP including chronic sclerosing cholecystitis belongs to a spectrum of IgG4-related sclerosing diseases. In some cases, the hilar or intrahepatic bile ducts are involved alone, although the pancreatic lesions are minimal or appear to be unaffected radiologically and clinically.

Suspected autoantigens

IgG-SC and LPSP are freguently found in the same patients, suggesting that pathologic agent(s) inherent in the hepatobiliary system and pancreas may be a target.7,25 These organs are connected by a duct system, suggesting some agent(s) in this duct to be responsible for the development of these diseases. Peribiliary glands which are physiologically distributed around the large bile ducts, are severely damaged in IgG4-SC. These glands are known to contain small amounts of exocrine pancreatic acini. In LPSP, exocrine acini are severely damaged and lost (Fig. 5b), raising possibility that some antigen(s) or enzyme(s) located in pancreatic exocrine acini could be a target of immunological attack.7 This may explain pathoanatomically why the extrahepatic and intrahepatic large bile ducts and more severely the exocrine pancreas are affected simultaneously in this disease spectrum.

B. Primary sclerosing cholangitis and idiopathic duct-centric chronic pancreatitis

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by inflammation and periductal fibrosis of the intrahepatic and/or extrahepatic bile ducts, and a prototype of sclerosing cholangitis.26 The luminal side including lining biliary epithelial cells, of the bile ducts is preferentially affected. Progressive obliteration of the biliary tree leads to biliary cirrhosis and needs liver transplantation. Primary sclerosing cholangitis is frequently associated with IBD.27 Primary sclerosing cholangitis responds poorly, if at all, to typical immunosuppressive therapies including steroids. The ages of patient with PSC are more broadly distributed. As for the pancreatic lesions of PSC, there were some reports that the pancreas shows occasionally non-specific inflammatory changes.

Idiopathic duct-centric chronic pancreatitis (IDCP) is characterized by inflammatory infiltrates (including neutrophils) that are denser in the lobules than in interlobular fibrotic areas.22,23 Neutrophils are also prominent in the ducts, and destruction of the duct epithelium is commonly seen. Patient ages were more broadly distributed. Interestingly, IDCP patients are associated with IBD, particularly ulcerative colitis, suggesting a common etiopathogenesis of IDCP and PSC. However, the relationship between IDCP and PSC has not been clarified. These pancreatic pathologic features related to PSC are different from the above-mentioned LPSP.


  1. Top of page
  2. Abstract

Most biliary and pancreatic neoplasia are of ductal lineage, characterized by tubule (gland), cyst, papilla formation, or mucin production and expression of mucin-related glycoproteins. As experienced in routine specimens, some neoplastic diseases of the bile duct closely resemble those of the pancreas, clinicopathologically. That is, not only invasive duct carcinoma but in situ neoplastic spectrum of the ducts characterizing intraepithelial neoplasm, intraductal papillary neoplasms and mucinous cystic neoplasms similarly develop in both organs. Understanding the genetic and molecular mechanisms of ductal carcinogenesis common in the biliary tract and pancreas will help us to explore carcinogenesis and develop more efficient preventions and therapies against these tumors.

A. Conventional cholangiocarcinoma and its intraepithelial precursor lesions with respect to pancreatic counterparts

1. Resemblance of cholangiocarcinoma to invasive duct carcinoma of the pancreas and intraepithelial neoplasia

Cholangiocarcinoma (CC) and invasive duct adenocarcinoma (DA) of the pancreas are the most common and significant malignant neoplasms of the biliary tract and pancreas.28–30 Cholangiocarcinoma and DA are usually well-differentiated tubular adenocarcinomas with or without a micropapillary component and with abundant fibrous stroma. They show frequent lymphatic and perineural invasion, and are characterized by insidious infiltration and rapid dissemination.28–30 Both are an intractable malignant tumor, usually resistant to surgical and chemotherapeutic approaches, and show a poor prognosis in spite of these therapies and regardless of their relatively well-differentiated histologic appearance. These findings suggest that biological behaviors of conventional CC and invasive DA are similar or close to each other, although other factors such as surgical approaches to these organs may cause some differences in the post-operative prognosis of these two malignant tumors.

Cholangiocarcinoma develops through a multi-step carcinogenesis, and pre-malignant or in-situ non-invasive neoplastic lesions of the biliary tract have been known to occur as biliary dysplasia or atypical biliary epithelium. So far, at least two types of precursor lesions have been proposed: a microscopic lesion of flat or low-papillary dysplastic epithelium (biliary intraepithelial neoplasia, BilIN), and a macroscopic lesion of intraductal papillary neoplasm (intraductal papillary neoplasia of the bile duct, IPNB).9,31–34

2. Characterization of BilIN

Biliary intraepithelial neoplasia is now accepted in the World Health Organization (WHO) classification of biliary tumors, in a similar fashion as pre-malignant lesions of other organs such as the pancreas (pancreatic intraepithelial neoplasia [PanIN]) and prostate (prostatic intraepithelial neoplasia [PIN]).32,34,35 BilIN is usually found in the large intrahepatic bile duct and also extrahepatic bile ducts, and is classified into three grades based on the degree of cellular and structural atypia32,36 (Fig. 6a,b). BilIN-1, corresponding to low-grade dysplasia, shows mild cellular/nuclear atypia such as nuclear membrane irregularity or nuclear enlargement with only a minimal disturbance of cellular polarity. BilIN-2, corresponding to high-grade dysplasia, has evident cellular/nuclear atypia, but not enough to suggest overt carcinoma, with a focal disturbance of cellular polarity. BilIN-3, corresponding to carcinoma in situ, shows a diffuse disturbance of cellular polarity with or without distinct cellular/nuclear atypia corresponding to an overt carcinoma. The BilIN system is shown to be applicable to premalignant intraepithelial lesions arising in an apparently normal biliary tract and also to those in chronic biliary diseases such as PSC, choledochal cyst and hepatolithiasis.34 The diagnostic criteria would be also applicable to pre-malignant lesions of the gallbladder and also in the peribiliary glands.


Figure 6. Biliary intraepithelial neoplasm (BilIN). a. BilIN2, HE. b. BilIN3. HE.

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In the pancreas, PanIN is the precursor of DA and microscopic intraepithelial proliferative changes.32,35,37 PanINs are classified morphologically into three grades as in BilINs. PanIN-1 ((flat lesion, PanIN-1A) or (papillary, PanIN-1B)), PanIN-2 and PanIN-3. Molecular studies revealed that PanIN-2 and PanIN-3 represent a distinct step towards invasive carcinoma. PanINs, and particularly higher grade PanINs (PanIN-3), are more common in pancreas with an invasive cancer than they are in pancreas with chronic pancreatitis.

Similarities between BilIN and PanIN.

BilIN and PanIN are both intraepithelial neoplasia, and show similar histologies. However, BilINs are usually found in the intrahepatic large bile duct and extraheaptic bile ducts, while PanINs are usually found in smaller ducts or ductules. PanINs arise in the smaller pancreatic ducts, measuring less than 0.5 cm.34,35,37 Similar phenotypic or genetic events may occur in the development of both BilIN and PanIN. In our previous studies, BilIN and PanIN showed similar expression patterns of mucin core proteins (MUC1 and MUC2) and cytokeratins (CK7 and CK20), suggesting that similar phenotypic changes might occur in both BilIN and PanIN.9,38 It is possible to think that BilIN is a biliary counterpart of PanIN. PanINs and BilINs were also found to be multifocal, supporting the above mentioned suggestion.

Kras activation in mature acinar cells induces PanIN lesions, and Notch promotes both initiation and dysplastic progression of these acinar-derived PanINs.35,37 At the cellular level, Notch/Kras co-activation promotes rapid reprogramming of acinar cells to a duct-like phenotype, providing an explanation for how a characteristically ductal tumor can arise from non-ductal acinar cells. A growing number of observations have highlighted acinar to ductal metaplasia in association with PanIN lesions. The acini in the lobules of lobulocentric atrophy described earlier are often characterized by prominent acinar-ductal metaplasia. As will be discussed in greater detail later, the association of acinar-ductal metaplasia with PanIN lesions has led investigators working with genetically engineered mouse models of pancreatic cancer to suggest that PanINs develop from acinar cells that undergo acinar-ductal metaplasia.35,37 BilINs are usually found in the intrahepatic large bile ducts. While the histogenesis of BilIN remains only speculative, pancreatic exocrine acini and ductular cells are identifiable in the peribiliary glands and also the presence of pancreatic enzymes is detectable in the intrahepatic large bile ducts and extrahepatic large bile ducts, suggesting that these exocrine acini in the peribiliary glands and biliary epithelia expressing pancreatic enzymes may be a source for the development of BiIIN as speculated in PanINs.

B. Intraductal papillary neoplasm of the biliary tract with respect to pancreatic counterpart

Recently, great attention is being drawn to intraductal papillary neoplasm of the pancreatobiliary systems.9,12,38–42 In the extrahepatic and intrahepatic large bile ducts, papillary tumors with benign features and also different malignant potentials are known to occur. Among them, biliary papilloma is a rare neoplasm composed of papillary proliferation of biliary epithelium with delicate fibrovascular stalks, and multiple occurring biliary papillomas are known as biliary papillomatosis.43,44 Billiary papilloma and biliary papillomatosis (BPs) are known to progress to invasive carcinoma. Some CCs also show mainly papillary proliferation in the bile duct lumen and also shows invasive lesions, and those cases are classified as the papillary type of bile duct carcinoma or intraductal growth-type of ICC (papillary CC). Our studies showed that BPs and the intraductal component of papillary CC share several pathological and phenotypic characteristics, which are different from those of non-papillary-CC. In addition, patients with BPs or papillary-CC show more favorable prognoses compared to patients with non-papillary-CC. These data strongly suggest that papillary ICC and BPs may be of the same category and the former might have derived from malignant changes of BP with variable invasion.

As described below, clinicopathological features of BPs and papillary-CC resemble those of intraductal papillary mucinous neoplasm of the pancreas (IPMN-P).40–42 So, we propose to call BPs and papillary-CC collectively as intraductal papillary neoplasm of the biliary tract (IPNB).31,39 IPNBs develop in apparently normal bile ducts and also are associated with preceding pathologic biliary diseases such as PSC, hepatolithiasis, congenital biliary diseases and liver fluke infection.31 Clinicopathological characteristics will be described with reference to IPMN-P.

  • 1
    IPNB is usually associated with prominent intraductal papillary lesions with delicate fibrovascular cores and also local dilatation of the affected bile ducts (Fig. 7a,b). IPNBs are usually found in the extrahepatic bile duct, hilar bile ducts, or intrahepatic large bile ducts. As seen in IPMN-P, a majority of IPNBs show cellular and structural dysplasia and some are histologically borderline and some adenocarcinoma in situ without any invasive growth corresponding to carcinoma in situ.
  • 2
    IPNB shows four types of tumor cells: (i) the pancreaticobiliary type; (ii) the intestinal type; (iii) the gastric type; and (iv) the oncocytic type. The oncocytic type is usually thought to be a variant of the pancreaticobiliary type (Fig. 7b). Tumor-cell types of IPMN-P also showed these four phenotypes. In IPNB, the gastric type is rare. In IPMN-P, adenoma is more common in the gastric type, whereas the pancreaticobiliary and intestinal types are mostly associated with adenocarcinoma, as seen in IPNB.
  • 3
    Immunohistochemically, IPNBs are characterized by the acquisition of gastro-intestinal phenotypes such as MUC2, MUC5AC, CDX and CK 20. MUC2 is more commonly expressed in the intestinal type than the pancreaticobiliary and gastric types, and double immunostaining of MUC2 and CDX2 reveals double-positive tumor cells. MUC5AC is rather commonly expressed in IPNB and IPMN-P. MUC1 expression is more commonly observed in the pancreaticobiliary type than the intestinal or gastric type.
  • 4
    IPNBs are associated with macroscopic mucin-hypersecretion in one-third of cases. Shibahara et al. reported 30 cases of mucin-hypersecreting bile duct tumor as biliary counterparts of IPMN-P, characterized pathologically by intraductal papillary proliferation of the dysplastic biliary epithelium, suggesting that these cases correspond to IPNB with much mucin secretion.
  • 5
    IPNB is known to be associated with invasive lesions (invasive IPNB), and invasive parts could show tubular adenocarcinoma or mucinous carcinoma. Some cases showed both types of invasive features. These invasion patterns are also seen in IPMN-P. Tubular adenocarcinoma with IPNB is associated with nodular infiltrative growth and showed ill-defined invasive growth with abundant fibrous stroma, and was commonly associated with vascular invasion, lymphatic invasion, and perineural invasion. Mucinous carcinoma with IPNB shows a muconodular growth pattern and consists of extravasated abundant mucin and floating tumor cells. Mucinous carcinoma showed compressive growth. MUC2 expression was commonly observed in IPNB, including non-invasive tumors, whereas MUC1 expression was commonly expressed in tubular adenocarcinoma cases, and rarely in non-invasive IPNB and mucinous carcinoma.9,31 That is, MUC1 expression is associated with tumor progression to tubular adenocarcinoma, while mucinous carcinoma is characterized as MUC1+/MUC2+ and MUC1−/MUC2+, respectively. Lymph node metastasis was more common in IPNB with tubular adenocarcinoma than mucinous carcinoma. These pathological characteristics of IPNB closely resemble those of IPMN-P: two types of tumor progression could occur in IPMN-P, and MUC1-positive pathway to tubular adenocarcinoma and MUC2-positive pathway to mucinous carcinoma.44,45
  • 6
    IPNB shows a favorable post-operative prognosis in comparison with conventional, non-papillary CC. The five-year survival rates of patients with non-invasive IPNB, invasive IPNB, non-papillary-CC and IPMN-P were 100%, 53%, 0% and 58%, respectively.39 In addition, there is increasing evidence that IPNBs with invasive CC, particularly those with mucnous carcinoma, show a rather favorable prognosis, in comparison with non-papilary CC. These findings are known in IPMN-P.

Figure 7. Intraductal papillary neoplasm of bile duct (IPNB). a. Enhanced CT shows a papillary lesion (arrow) in the dilated intrahepatic large bile duct. b. Histologically, an intraductal papillary neoplasm is seen. HE.

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BilIN and IPNB

The discrimination of BilIN and IPNB is usually based on the size of the lesion and the proliferation patterns. BilIN microscopically manifests as flat, pseudopapillary (loss of cellular polarity and pseudostratification) or micropapillary lesions. In contrast, IPNB is grossly visible, and is characterized by prominent papillary proliferation with distinct fibrovascular cores. The clinicopathological features are different between BilIN and IPNB; therefore, the discrimination seems important. Similarly, microscopical PanINs need to be distinguished from the larger IPMNs, and IPMNs tend to have longer and more mucinous papillae than PanINs.

IPNB corresponds to IPMN of the main pancreatic duct type

IPMN-P consists of the main pancreatic duct type and also the branch pancreatic duct type.40–42 There are several pathological differences between IPNB and IPMN-P. The important difference is mucin hypersecretion (macroscopic mucin): Mucin is macroscopically identifiable on the tumor surface in about one third of IPNB cases, whereas abundant mucin-production is usually observed in most cases of IPMN-P. IPMN-P showed lower frequencies of CK20 expression, while a majority of IPNB express CK20. These differences might reflect the difference of subtypes of IPMN-P and IPNB. Among IPMN-P, the gastric type is more common in the branch-duct type and all of those cases are negative for CK20 expression, whereas the pancreaticobiliary or intestinal type frequently occurs in the main-duct type. A majority of IPNB are of the pancreaticobiliary or intestinal type. The intestinal-type IPNB commonly expresses CK20, whereas no cases of the gastric type show CK20 expression. These findings strongly suggest that IPNB corresponds to the main duct type of IPMN-P.39

Which biliary lesion or disease then corresponds to the IPMN of the pancreatic branch type, if present? Possible candidates of IPNB corresponding to the branch type of IPMN-P may be some type of peribiliary cysts. Peribiliary cysts are usually multiple cystic lesions around the hilar bile ducts and also intrahepatic large bile ducts.46 They are also found around the extrahepatic bile ducts. Generally, multiple peribiliary cysts are thought to be heterogeneous in their pathogenesis,47 and interestingly, some present dilated ducts showing papillary epithelial cell proliferation embedded in proliferated peribiliary glands.48 It seems possible that some of these peribiliary cysts might have derived from the epithelial proliferation of conduits of peribiliary glands and then correspond to IPNB corresponding to branch type IPMN-P.

C. IPNB showing cystic dilatation (cystic IPNB) and its relation to biliary MCN

Biliary cystic tumors which are composed of flat, micropapillary, or papillary proliferation of dysplastic or neoplastic biliary epithelial cells, are an infrequent neoplasm occurring in the liver and are rare along the extrahepatic biliary system. In the pancreas, two types of cystic neoplasms are distinguishable.10 The first is mucinous cystic neoplasm (MCN) and the other is IPMN-P with cystic change. The former is pathologically defined as having ovarian-like stroma, it preferentially occurs in females, and does not have a luminal communication with bile ducts. In contrast, IPMN-P with cystic change, which does not have ovarian-like stroma, occurs in both genders and has communication to the pancreatic ductal system. That is, most cases previously reported as pancreatic mucinous cystadenoma and cystadenocarcinoma with a luminal communication to the pancreatic duct or occurring in male patients are now thought to be IPMN-P with cystic change.

Biliary cystic neoplasms usually called biliary cystadenoma and cystadenocarcinoma are thought to be a heterogeneous disease entity with respect to tumor cell types (mucinous or serous), and luminal communication with the bile duct lumen or tumor stroma (presence or absence of ovarian-like stroma).8,49,50 Our recent studies showed that these tumors were mainly classified into two categories: biliary mucinous cystic neoplasm (MCN) and IPNB with cystic changes as described above in pancreatic cystic tumors.

Biliary MCN

The prototype is mucinous cystadenoma with ovarian-like stroma occurring in females (Fig. 8a,b). The lining epithelium is a single layered columnar and mucin-positive biliary epithelium.8,12,50,51 Such patients are relatively young and predominantly female and such cystic tumors are larger in comparison to cystic tumors without ovarian-like stroma. Most reported cases had no luminal communication between the cystic tumor and the bile duct, although recent advances in imaging modalities have revealed direct luminal communication to the bile duct in some cases. Stromal cells with nuclear expression of ER or PgR were consistently observed in such biliary MCN. Most biliary MCNs with ovarian-like stroma are biliary mucinous cystadenoma. This is a rare neoplasm, and occasionally malignant changes are reported in mucinous cystadenoma (mucinous cystadenocarcinoma).


Figure 8. Biliary mucinous neoplasm. a. Cyst wall shows secondary cyst formation. HE. b. Columnar neoplastic epithelium with clear cytoplasm with ovarian-like stroma. HE.

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IPNB with cystic changes

IPNB could manifest as cystic tumors after cystic ductal dilatation with prominent intraductal mucin accumulation.8,12,50,51 Such cystic neolasms are called cystic IPNBs, and are unilocular or multilocular (Fig. 9a). The left hepatic lobe was more commonly affected. Papillary mural nodules, ranging from 0.5 to 3.2 cm, are usually observed. Cystography and pathological study reveal usually direct luminal communication between intracystic spaces and the bile duct.8 Histologically, dysplastic mucinous epithelium proliferates in a flat, micropapillary, and papillary fashion within intracystic spaces (Fig. 9b). Some cases were associated with invasive mucinous carcinoma as seen in IPNB itself. The cyst wall was composed of fibrous connective tissue with focal lymphocytic infiltration or edematous change. Densely cellular connective tissue resembling ovarian stroma (ovarian-like stroma) was not observed in any cases of IPNB with cystic changes. No stromal cell with nuclear expression of ER or PgR was observed in any cases of IPNB with or without multicystic changes.8 Characteristically, similar neoplastic biliary epithelial cells are also observed in the bile ducts around cystic tumors, which suggests luminal communication between cystic tumors and surrounding bile ducts and a continuous spread of neoplastic cells from cystic spaces to the surrounding bile ducts through this communication.8,12,51 IPNB of cystic type are found in both genders, and are rather small in comparison with biliary MCN8. Mucinous discharge from Vater's ampulla is only occasionally evident on endoscopic examination during endoscopic retrograde cholangiography (ERC).52,53


Figure 9. Intraductal papillary neoplasm with multicystic changes. a. Cut surface. An asterik shows solid neoplasm. b. Histologically, an intraductal papillary neoplasm is seen in the cystic lesion. HE.

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Four phenotypes seen in IPNB are found.8,12,49–51 There is a focal borderline component, while others are adenocarcinomas with or witout invasion. Most cases of biliary cystic tumor without ovarian-like stroma which have been reported as biliary cystadenocarcinoma, are now regarded as IPNB with cystic change.8

D. Intraductal tubular neoplasm

Intraductal tubular neoplasm (ITN) is an uncommon intraluminal polypoid lesion that occurs in the main pancreatic duct in the region of the head or body. It obstructs dilated pancreatic ducts and does not contain any visible mucin.54,55 ITN is composed of tightly packed tubular structures with focal cystic dilation and papillary areas lined by gastric/pyloric epithelium showing minimal to mild to high grade cytological atypia. Malignant transformation is present in a few areas. The tumor cells form tubulopapillae and contain little cytoplasmic mucin. The ITNs are immunohistochemically positive for CK 7 and/or CK 19 and negative for trypsin, MUC2, and MUC5AC. Intraductal tubular carcinomas showing several features that are similar to those of ITN, except for the tubulopapillary growth pattern, are also seen, suggesting that ITNs can be considered to represent a new disease entity encompassing intraductal tubular carcinoma as a morphologic variant.54,55

A similar intraductal tubular neoplasm is also occasionally experienced in the biliary tract (unpublished observation). Histology of the lesion revealed a tubular neoplasm, composed of an admixture of tubular glands resembling pyloric glands with minimal cytologic atypia, and those with dysplastic epithelium with occasional goblet cells resembling tubular adenoma of the intestine. Small foci of carcinoma in situ of intestinal type are also observed. There was no significant formation of papillae and oncocytic cytoplasm. On immunostaining, tubular glands of pyloric gland type were positive for MUC5AC, and negative for MUC2 and CK 20. Although more case studies of ITN in the biliary tracts are required to clarify the tumorigenesis and pathologic features of this rare tumor, the lesion may be the biliary counterpart of the pancreatic ITN.

Among other neoplasms of the biliary tract, bile ductular carcinoma resembling cholangiolocytes or bile ductules around the portal tracts are reported to arise from hepatic stem cells located at periportal areas of hepatic lobules.16,56,57 Bile ductular carcinoma may be therefore different from biliary epithelial neoplasm including cholangiocarcinoma arising from the intrahepatic large bile duct and extrahepatic bile ducts and peribiliary glands, a possible counterpart of conventional DA, IPMN and intraductal tubular neoplasm of pancreas.

In conclusion, embryological and anatomical studies have shown that the biliary tract represent an incomplete pancreas. In fact, exocrine acini are intermingled with peribiliary glands and biliary epithelium of the biliary tract expresses pancreatic enzymes, explaining why some biliary diseases share the pathological features of pancreatic diseases. IPNB and IPMN-P share common histologic and phenotypic features and biological behaviors. Interestingly, MCN with the same features arises both in the pancreas and in the heaptobiliary system. Intraductal tubular neoplasia is also found in both the biliary tract and pancreas. Intraepithelial neoplasm of the biliary tract and pancreas, called BilIN and PanIN, respectively, also show similar sequences and histologies, and are followed by conventional invasive adenocarcinoma or mucinous carcinoma. The similarities of these neoplasms raise the possibility that similar epigenetic and genetic changes occur in the biliary tract and pancreas and are responsible for the development of these neoplastic lesions.

Taken together, a majority of clinical trials and basic researches on the biliary and pancreatic diseases have been done separately, so far. If more comprehensive analysis and approach to these biliary and pancreatic diseases based on their similarities could be challenged and if the clinical data accumulated in the pancreatic diseases could be applied to the analysis of the biliary tract diseases, the patients with biliary tract diseases could receive efficient therapeutic approaches which are already beneficial to pancreatic diseases and have not been applied to biliary tract diseases. In this context, this novel approach proposed here may be beneficial to the patients with biliary tract diseases.


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  • 1
    Portman BC, Nakanuma Y. Diseases of bile ducts. In: BurtAD, PortmanBC, FerrellLD, eds. MacSween's Pathology of the Liver, 5th edn. London: Churchill Livingstone, 2006; 51781.
  • 2
    Roskams T, Desmet VJ, Verslype C. Development, structure and function of the liver. In: BurtAD, PortmanBC, FerrellLD, eds. MacSween's Pathology of the Liver, 5th edn. London: Churchill Livingstone, 2006; 75118.
  • 3
    Sumazaki R, Shiojiri N, Isoyama S et al. Conversion of biliary system to pancreatic tissue in Hes1-deficient mice. Nat Genet 2004; 36: 8387.
  • 4
    Fukuda A, Kawaguchi Y, Furuyama K et al. Ectopic pancreas formation in Hes1 -knockout mice reveals plasticity of endodermal progenitors of the gut, bile duct, and pancreas. J Clin Invest 2006; 11: 148493.
  • 5
    Eberhard D, Tosh D, Slack JM. Origin of pancreatic endocrine cells from biliary duct epithelium. Cell Mol Life Sci 2008; 65: 346780.
  • 6
    Zen Y, Harada K, Sasaki M et al. IgG4-related sclerosing cholangitis with and without hepatic inflammatory pseudotumor, and sclerosing pancreatitis-associated sclerosing cholangitis: Do they belong to a spectrum of sclerosing pancreatitis? Am J Surg Pathol 2004; 28: 1193203.
  • 7
    Nakanuma Y, Zen Y. Pathology and immunopathology of immunoglobulin G4-related sclerosing cholangitis: The latest addition to the sclerosing cholangitis family. Hepatol Res 2007; 37 (Suppl. 3): S47886.
  • 8
    Zen Y, Fujii T, Itatsu K et al. Biliary cystic tumors with bile duct communication: A cystic variant of intraductal papillary neoplasm of the bile duct. Mod Pathol 2006; 19: 124354.
  • 9
    Zen Y, Sasaki M, Fujii T et al. Different expression patterns of mucin core proteins and cytokeratins during intrahepatic cholangiocarcinogenesis from biliary intraepithelial neoplasia and intraductal papillary neoplasm of the bile duct—An immunohistochemical study of 110 cases of hepatolithiasis. J Hepatol 2006; 44: 35058.
  • 10
    Zamboni G, Longnecker DS, Kloppel G, Adler G, Hruban RH. Mucinous cystic neoplasm of the pancreas. In: HamiltonSR, AaltonenLA, eds. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Digestive System. Lyon: IARC Press, 2000; 23436.
  • 11
    Nakanuma Y, Hoso M, Sanzen T, Sasaki M. Microstructure and development of the normal and pathologic biliary tract in humans, including blood supply. Microsc Res Tech 1997; 38: 55270.
  • 12
    Nakanuma Y, Zen Y, Harada K et al. Tumorigenesis and phenotypic characteristics of mucin-producing bile duct tumors: An immunohistochemical approach. J Hepatobiliary Pancreat Surg 2009; (in press).
  • 13
    Terada T, Nakanuma Y, Ohta G. Glandular elements around the intrahepatic bile ducts in man; their morphology and distribution in normal livers. Liver 1987; 7: 18.
  • 14
    Terada T, Nakanuma Y, Kakita A. Pathologic observations of intrahepatic peribiliary glands in 1000 consecutive autopsy livers. Heterotopic pancreas in the liver. Gastroenterology 1990; 98: 133337.
  • 15
    Terada T, Nakanuma Y. Development of human intrahepatic peribiliary glands. Histological, keratin immunohistochemical, and mucus histochemical analyses. Lab Invest 1993; 68: 26169.
  • 16
    Nakanuma Y, Sasaki M, Ikeda H et al. Pathology of peripheral intrahepatic cholangiocarcinoma with reference to tumorigenesis. Hepatol Res 2008; 38: 32534.
  • 17
    Saito K, Nakanuma Y. Lactoferrin and lysozyme in the intrahepatic bile duct of normal livers and hepatolithiasis. An immunohistochemical study. J Hepatol 1992; 15: 14753.
  • 18
    Terada T, Kitamura Y, Nakanuma Y. Normal and abnormal development of the human intrahepatic biliary system: A review. Tohoku J Exp Med 1997; 181: 1932.
  • 19
    Terada T, Kato M, Horie S, Endo K, Kitamura Y. Expression of pancreatic alpha-amylase protein and messenger RNA in hilar primitive bile ducts and hepatocytes during human fetal liver organogenesis: An immunohistochemical and in situ hybridization study. Liver 1998; 18: 31319.
  • 20
    McDonald E, Krishnamurthy M, Goodyer CG, Wang R. The emerging role of SOX transcription factors in pancreatic endocrine cell development and function. Stem Cells Dev 2009; 18: 137988.
  • 21
    Kawaguchi K, Koike M, Tsuruta K, Okamoto A, Tabata I, Fujita N. Lymphoplasmacytic sclerosing pancreatitis with cholangitis: A variant of primary sclerosing cholangitis extensively involving pancreas. Hum Pathol 1991; 22: 38795.
  • 22
    Notohara K, Burgart LJ, Yadav D, Chari S, Smyrk TC. Idiopathic chronic pancreatitis with periductal lymphoplasmacytic infiltration: Clinicopathologic features of 35 cases. Am J Surg Pathol 2003; 27: 111927.
  • 23
    Zamboni G, Lüttges J, Capelli P et al. Histopathological features of diagnostic and clinical relevance in autoimmune pancreatitis: A study on 53 resection specimens and 9 biopsy specimens. Virchows Arch 2004; 445: 55263.
  • 24
    Wang WL, Farris AB, Lauwers GY, Deshpande V. Autoimmune pancreatitis-related cholecystitis: A morphologically and immunologically distinctive form of lymphoplasmacytic sclerosing cholecystitis. Histopathology 2009; 54: 82936.
  • 25
    Asada M, Nishio A, Uchida K et al. Identification of a novel autoantibody against pancreatic secretory trypsin inhibitor in patients with autoimmune pancreatitis. Pancreas 2006; 33: 2026.
  • 26
    Nakanuma Y, Harada K, Katayanagi K, Tsuneyama K, Sasaki M. Definition and pathology of primary sclerosing cholangitis. J Hepatobiliary Pancreat Surg 1999; 6: 33342.
  • 27
    Takikawa H, Takamori Y, Tanaka A, Kurihara H, Nakanuma Y. Analysis of 388 cases of primary sclerosing cholangitis in Japan; presence of a subgroup without pancreatic involvement in older patients. Hepatol Res 2004; 29: 15359.
  • 28
    Kloppel G, Adler G, Hruban RH, Kern SE, Longnecker DS, Partanen TJ. Ductal adenocarcinoma of the pancreas. In: HamiltonSR, AaltonenLA, eds. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Digestive System. Lyon: IARC Press, 2000; 22130.
  • 29
    Shimonishi T, Sasaki M, Nakanuma Y. Precancerous lesions of intrahepatic cholangiocarcinoma. J Hepatobiliary Pancreat Surg 2000; 7: 54250.
  • 30
    Nakanuma Y, Leong ASY, Sripa B, Ponchon T, Vatanasapt V, Ishak KG. Intrahepatic cholangiocarcinoma. In: HamiltonSR, AaltonenLA, eds. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Digestive System. Lyon: IARC Press, 2000; 17380.
  • 31
    Chen TC, Nakanuma Y, Zen Y et al. Intraductal papillary neoplasia of the liver associated with hepatolithiasis. Hepatology 2001; 34: 65158.
  • 32
    Zen Y, Adsay NV, Bardadin K et al. Biliary intraepithelial neoplasia: An international interobserver agreement study and proposal for diagnostic criteria. Mod Pathol 2007; 20: 7019.
  • 33
    Terada T, Nakanuma Y, Ohta T, Nagakawa T. Histological features and interphase nucleolar organizer regions in hyperplastic, dysplastic and neoplastic epithelium of intrahepatic bile ducts in hepatolithiasis. Histopathology 1992; 21: 23340.
  • 34
    Takaori K, Hruban RH, Maitra A, Tanigawa N. Pancreatic intraepithelial neoplasia. Pancreas 2004; 28: 25762.
  • 35
    Zhu L, Shi G, Schmidt CM, Hruban RH, Konieczny SF. Acinar cells contribute to the molecular heterogeneity of pancreatic intraepithelial neoplasia. Am J Pathol 2007; 171: 26373.
  • 36
    Zen Y, Aishima S, Ajioka Y et al. Proposal of histological criteria for intraepithelial atypical/proliferative biliary epithelial lesions of the bile duct in hepatolithiasis with respect to cholangiocarcinoma: Preliminary report based on interobserver agreement. Pathol Int 2005; 55: 18088.
  • 37
    Brune K, Abe T, Canto M et al. Multifocal neoplastic precursor lesions associated with lobular atrophy of the pancreas in patients having a strong family history of pancreatic cancer. Am J Surg Pathol 2006; 30: 106776.
  • 38
    Klöppel G, Kosmahl M. Is the intraductal papillary mucinous neoplasia of the biliary tract a counterpart of pancreatic papillary mucinous neoplasm? J Hepatol 2006; 44: 24950.
  • 39
    Zen Y, Fujii T, Itatsu K et al. Biliary papillary tumors share pathological features with intraductal papillary mucinous neoplasm of the pancreas. Hepatology 2006; 44: 133343.
  • 40
    Ishida M, Egawa S, Aoki T et al. Characteristic clinicopathological features of the types of intraductal papillary-mucinous neoplasms of the pancreas. Pancreas 2007; 35: 34852.
  • 41
    Kim SC, Park KT, Lee YJ et al. Intraductal papillary mucinous neoplasm of the pancreas: Clinical characteristics and treatment outcomes of 118 consecutive patients from a single center. J Hepatobiliary Pancreat Surg 2008; 15: 18388.
  • 42
    Woo SM, Ryu JK, Lee SH, Yoon WJ, Kim YT, Yoon YB. Branch duct intraductal papillary mucinous neoplasms in a retrospective series of 190 patients. Br J Surg 2009; 96: 40511.
  • 43
    Amaya S, Sasaki M, Watanabe Y et al. Expression of MUC1 and MUC2 and carbohydrate antigen Tn change during malignant transformation of biliary papillomatosis. Histopathology 2001; 38: 55060.
  • 44
    Lee SS, Kim MH, Lee SK et al. Clinicopathologic review of 58 patients with biliary papillomatosis. Cancer 2004; 100: 78393.
  • 45
    Adsay NV, Conlon KC, Zee SY, Brennan MF, Klimstra DS. Intraductal papillary-mucinous neoplasms of the pancreas: An analysis of in situ and invasive carcinomas in 28 patients. Cancer 2002; 94: 6277.
  • 46
    Nakanuma Y, Kurumaya H, Ohta G. Multiple cysts in the hepatic hilum and their pathogenesis. A suggestion of periductal gland origin. Virchows Arch A Pathol Anat Histopathol 1984; 404: 34150.
  • 47
    Kida T, Nakanuma Y, Terada T. Cystic dilatation of peribiliary glands in livers with adult polycystic disease and livers with solitary nonparasitic cysts: An autopsy study. Hepatology 1992; 16: 33440.
  • 48
    Terada T, Nakanuma Y. Pathologic observations of intrahepatic peribiliary glands in 1000 consecutive autopsy livers: IV. Hyperplasia of intramural and extramural glands. Hum Pathol 1992; 23: 48390.
  • 49
    Ishak KG, Willis GW, Cummins SD, Bullock AA. Biliary cystadenoma and cystadenocarcinoma: Report of 14 cases and review of the literature. Cancer 1977; 39: 32238.
  • 50
    Devaney K, Goodman ZD, Ishak KG. Hepatobiliary cystadenoma and cystadenocarcinoma. A light microscopic and immunohistochemical study of 70 patients. Am J Surg Pathol 1994; 18: 107891.
  • 51
    Sudo Y, Harada K, Tsuneyama K, Katayanagi K, Zen Y, Nakanuma Y. Oncocytic biliary cystadenocarcinoma is a form of intraductal oncocytic papillary neoplasm of the liver. Mod Pathol 2001; 14: 13049.
  • 52
    Shibahara H, Tamada S, Goto M et al. Pathologic features of mucin-producing bile duct tumors: Two histopathologic categories as counterparts of pancreatic intraductal papillary-mucinous neoplasms. Am J Surg Pathol 2004; 28: 32738.
  • 53
    Goto M, Shibahara H, Tamada S et al. Aberrant expression of pyloric gland-type mucin in mucin-producing bile duct carcinomas: A clear difference between the core peptide and the carbohydrate moiety. Pathol Int 2005; 55: 46470.
  • 54
    Aldores-Saavedra J, Sheahan K, O’Riain C, Shukla D. Intraductal tubular adenoma, pyloric type, of the pancreas: Additional observations on a new type of pancreatic neoplasm. Am J Surg Pathol 2004; 28: 23338.
  • 55
    Nakayama Y, Inoue H, Hamada Y et al. Intraductal tubular adenoma of the pancreas, pyloric gland type: A clinicopathologic and immunohistochemical study of 6 cases. Am J Surg Pathol 2005; 29: 60716.
  • 56
    Kozaka K, Sasaki M, Fujii T et al. A subgroup of intrahepatic cholangiocarcinoma with an infiltrating replacement growth pattern and a resemblance to reactive proliferating bile ductules: ‘bile ductular carcinoma. Histopathology 2007; 51: 390400.
  • 57
    Komuta M, Spee B, Vander Borght S et al. Clinicopathological study on cholangiolocellular carcinoma suggesting hepatic progenitor cell origin. Hepatology 2008; 47: 154456.