Resident Short Reviews
Updates on Precancerous Lesions of the Biliary Tract Biliary Precancerous Lesion Sanaz Ainechi, MD; Hwajeong Lee, MD
Precursor lesions of invasive adenocarcinoma of the bile duct (cholangiocarcinoma) have been increasingly recognized during the past decade because of the results of multiple studies on the carcinogenesis of cholangiocarcinoma, technologic advancements in diagnostic imaging modalities, and an increase in the volume of elective procedures. The two main precursor lesions of cholangiocarcinoma that have evolved are biliary intraepithelial neoplasia and intraductal papillary neoplasm of the bile duct. These lesions demonstrate histomorphologic similarities to pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasm of the pancreas, respectively, whereas mechanisms of carcinogenesis and risk of progressive disease appear distinct. An enhanced understanding of the clinical presentation and pathologic features of precursor lesions of the biliary tract and use of the correct terminology will facilitate efficient communication between surgeons, oncologists, and pathologists and improve quality of patient care. (Arch Pathol Lab Med. 2016;140:1285–1289; doi: 10.5858/arpa.2015-0396-RS)
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ecent advancements in research on neoplasia of the biliary tract have greatly enhanced our understanding of its precursor lesions and contributed to the evolution of new classification systems and terminologies for precancerous lesions of the bile duct. Similar to other alimentary tract neoplasia, most invasive carcinomas of the biliary tree arise from preexisting precursor lesions. Two main precursor lesions of invasive adenocarcinoma of the bile duct (cholangiocarcinoma) are biliary intraepithelial neoplasia (BilIN) and intraductal papillary neoplasm of the bile ducts (IPN-B).1 In addition, mucinous cystic neoplasm was acknowledged as a precancerous lesion by the 2010 World Health Organization (WHO) classification,2 whereas intraductal tubular/tubulopapillary neoplasm (ITN) of the bile duct was subsequently described as an additional distinct subtype.3 We aim to summarize the clinical presentation Accepted for publication January 18, 2016. From the Department of Pathology and Laboratory Medicine, Albany Medical Center, Albany, New York. The authors have no relevant financial interest in the products or companies described in this article. Reprints: Hwajeong Lee, MD, Department of Pathology and Laboratory Medicine, Albany Medical Center, 47 New Scotland Ave, MC81, Albany, NY 12208 (email:
[email protected]). Arch Pathol Lab Med—Vol 140, November 2016
and diagnostic criteria of precursor lesions of the bile duct, mainly BilIN and IPN-B, and to remark on associated practical issues that should be considered in the diagnosis and prognosis of these lesions. NORMAL HISTOLOGY OF THE BILIARY TRACT Biliary mucosa is lined by a single layer of columnar epithelium with basally oriented oval nuclei and lightly eosinophilic cytoplasm. Intrahepatic and extrahepatic biliary mucosa is flat, whereas gallbladder mucosa exhibits villous configuration. Goblet cells are not seen in normal biliary epithelium. Periductal mucous glands are lined by mucinfilled cuboidal cells, and mucin from these glands drains into the lumen via sacculi (recesses; Figure 1). CLINICAL PRESENTATION AND DIAGNOSTIC IMAGING In the West, the major risk factors for neoplasia involving bile ducts are primary sclerosing cholangitis, Thorotrast deposition, abnormal choledochopancreatic junction, and choledochal cyst. In Southeast Asia, intrahepatic cholangiocarcinoma is more frequent than extrahepatic cholangiocarcinoma, for which hepatolithiasis and fluke infestation are common predisposing factors.4 Also, longstanding inflammation, such as chronic hepatitis C and alcoholic cirrhosis, are newly suggested risk factors for small intrahepatic bile duct neoplasia.5 There is a geographic variation in the incidence of cholangiocarcinoma of various sites, with the highest rates of ampullary and intrahepatic bile duct cancer in Asia, and gallbladder cancer in South America, especially Chile. Precursor lesions are more frequent than invasive carcinoma, and they show a parallel distribution.5,6 Because of advances in radiographic imaging, massforming bile duct lesions, including IPN-B, are increasingly diagnosed. Also, an increase in elective cholecystectomies has raised the overall incidence of neoplastic lesions of the gallbladder. Biliary intraepithelial neoplasia does not produce clinical symptoms, nor is it detectable by imaging studies. Its incidence parallels that of invasive carcinoma (approximately 7000 new cases annually), although the actual incidence of BilIN cannot be accurately determined. This precancerous lesion is most commonly identified in specimens with invasive carcinoma, and less frequently in elective cholecystectomy specimens. Primary sclerosing cholangitis patients as well as gallbladder cancer patients are at higher risk of developing BilIN (40%–60%). Approximately 1% to 3.5% Biliary Precancerous Lesion—Ainechi & Lee 1285
Figure 1. Biliary mucosa is lined by cuboidal cells with basally located nuclei and lightly eosinophilic cytoplasm, without goblet cells. Periductal mucous glands (arrows) are lined by cuboidal cells with intracytoplasmic mucin (hematoxylin-eosin, original magnification 3100).
of cholecystectomies, especially those involving lithiasis, are found to have incidental BilIN.7,8 There is no sex predilection for BilIN. Intraductal papillary neoplasm of the bile ducts is less common compared with BilIN, accounting for 10% to 15% of bile duct tumors. Most patients are between the ages of 50 and 60 years, with a male predominance.9 Although IPN-B is common in the extrahepatic bile duct, hilum, and distal common bile duct according to Western literature, it is more frequently reported in the intrahepatic biliary tree in Southeast Asia, presumably reflecting the differences in predisposing factors and pathogenesis.6,10 Abdominal pain and jaundice are the most common clinical symptoms of individuals with IPN-B. Mucin-producing variant of IPN-B presents with macroscopic mucin hypersecretion, impeding bile flow and resulting in obstructive jaundice and cholangitis. Especially multifocal and extensive IPN-B tends to recur, and is strongly associated with invasive carcinoma. Biliary intraepithelial neoplasia is a microscopic disease of the biliary epithelium; thus, the utility of conventional imaging modalities as a diagnostic tool is limited. On the other hand, advanced techniques, such as diffusion-weighted imaging or magnetic resonance cholangiopancreatography, can detect papillary lesions within the duct, including IPN-B. Mucin-producing variant of IPN-B causes dilatation of duct lumina proximal to the tumor, which can be visualized by magnetic resonance imaging.1 Of note, bile duct stones may mimic or mask intraductal tumors on radiologic studies, warranting a cautious approach. Although cross-sectional imaging studies are helpful in diagnosing early biliary tract neoplasia, at the present time these are not recommended as a screening test in high-risk patients.11 PATHOLOGIC FEATURES Grossly, BilIN may manifest as subtle granularity, thickened velvety texture of the mucosa, or effacement of the underlying tissue layers, but it mostly appears normal by macroscopic examination.7 Biliary intraepithelial neoplasia is commonly noted in the mucosa adjacent to invasive carcinoma, although multicentricity is common.12,13 Intraductal papillary neoplasm of the bile ducts manifests as exophytic papillary lesion and is grossly visible. Overpro1286 Arch Pathol Lab Med—Vol 140, November 2016
duction of mucin or papillary growth may fill and expand the bile duct and lead to dilatation or multilocular cystic changes of the affected duct segment.14 Microscopically, the distinction between BilIN and IPN-B is based on the size of the lesion and the pattern of proliferation. Biliary intraepithelial neoplasia is a flat lesion with adenomatous epithelium, and it may form micropapillary projections into the lumen (Figure 2).9 Further, BilIN is histologically classified as classic type—consisting of columnar/cuboidal cells with eosinophilic cytoplasm and round nuclei—and intestinal type—characterized by columnar cells with elongated and hyperchromatic nuclei, nuclear pseudostratification, and occasional goblet-type cytoplasmic mucin resembling intestinal adenoma.5,15 These two types express different immunoprofiles, suggestive of distinct carcinogenic pathways. For example, the common immunophenotype of the classic type is cytokeratin 7–positive (CK7þ)/CK20, whereas at least one intestinal immunomarker (CK20, caudal-type homeobox protein 2 [CDX2], or mucin core protein 2 [MUC2]) is expressed in the intestinal type of BilIN.15 An abrupt transition from normal epithelium to dysplastic epithelium is a characteristic feature. Peribiliary glands (PBGs) may be involved by BilIN, either in the form of direct extension or pagetoid spread of dysplastic cells into the PBGs or Rokitansky-Aschoff sinuses in the gallbladder. A 3-tiered grading system has been proposed for BilIN based on the degree of cellular and nuclear atypia. Although the initial grading system was devised in dysplastic lesions related to hepatolithiasis, the same system is currently applicable to premalignant lesions of other risk factors.16 The progression of dysplasia in BilIN resembles that of pancreatic intraepithelial neoplasia. An international interobserver agreement study of BilIN revealed overall moderate agreement (j value of .45), with lower level of agreement for BilIN-2 (j value of .16).16 The Table summarizes the diagnostic criteria of BilIN.16 Biliary intraepithelial neoplasia is associated with conventional infiltrating tubular cholangiocarcinoma, which usually has a poorer prognosis compared with colloid (mucinous) adenocarcinoma.6 Intraductal papillary neoplasm of the bile ducts is characterized by intraductal, predominantly papillary proliferation with a distinct fibrovascular stalk (Figure 3). The lining cells usually show intracellular mucin production.14 There are no standardized criteria for grading of IPN-B, but it is believed that IPN-B should be graded differently from BilIN, because of a different sequence of dysplasiacarcinoma.4 The WHO classification applies the similar grading scheme of pancreatic intraductal papillary mucinous neoplasms (IPMN) to IPN-B and divides it into 2 groups on the basis of architectural and cellular atypia: IPN-B with low or intermediate dysplasia, and IPN-B with high-grade dysplasia.2 About half of IPN-B is associated with an invasive component at the time of diagnosis.9,10,17 Many authors have considered IPN-B to represent the biliary counterpart of IPMN. Also similarly to IPMN, 4 histologic subtypes of IPN-B have been recognized per epithelial type: pancreatobiliary, intestinal, gastric, and oncocytic.9 The pancreatobiliary type is more frequent in the West and shows poorer outcome when associated with invasive component. On the other hand, the intestinal and gastric types are more common in Asia and show a relatively better survival when associated with invasive components.10 Although the Biliary Precancerous Lesion—Ainechi & Lee
Figure 2. A, Biliary intraepithelial neoplasia (BilIN-2) with patchy micropapillary growth and occasional full-thickness nuclear pseudostratification. Cellular polarity is preserved overall. B, Biliary intraepithelial neoplasia (BilIN-3) displaying micropapillary growth pattern and loss of cellular polarity. Clusters of epithelial cells are budding off of the surface epithelium (hematoxylin-eosin, original magnification 3200). Figure 3. A, Intraductal papillary neoplasm of the common bile duct with prominent papillary growth pattern and well-formed fibrovascular stalks, without invasive component. B, Intraductal papillary neoplasm of the extrahepatic bile duct with marked nuclear pseudostratification and goblet cells, resembling tubular adenoma of the colon. The epithelial cells demonstrated positive staining for cytokeratin 20 and caudal type homeobox protein 2 (CDX2), consistent with intestinal-type immunoprofile (hematoxylin-eosin, original magnifications 325 [A] and 3200 [B]).
prognostic relevance of different subtypes is well established in IPMN, it is less clear in IPN-B because of small number of cases and conflicting study results.18 Two pathways of carcinogenesis have been postulated based on immunophenotype of IPN-B. In brief, pancreatobiliary-type IPN-B is most commonly associated with conventional tubular adenocarcinoma, whereas a subset of IPN-B with intestinal phenotype progress into colloid
adenocarcinoma (mucinous adenocarcinoma), with a better survival.10,13 INTRADUCTAL TUBULAR NEOPLASM AND MUCINOUS CYSTIC NEOPLASM Rare case reports of intraductal tumor with predominant tubular growth pattern were followed by a series study of ITN of the bile duct.3 Intraductal tubular neoplasm is a novel
Grading Scheme of Biliary Intraepithelial Neoplasia (BilIN) BilIN-1 Cellular features
Nuclear features
Architecture
Nuclei within the lower two-thirds of the epithelium, focal nuclear pseudostratification, increased nuclear to cytoplasmic ratio Mild irregularities of nuclear membrane, nuclear elongation Flat or micropapillary
Additional features Rare mitosis
BilIN-2
BilIN-3
Loss of cellular polarity, nuclear pseudostratification reaching the luminal surface
Marked loss of cellular polarity, nuclei reaching and piling on the luminal surface, cribriforming
Enlargement, hyperchromasia, and irregular nuclear membrane; variations in nuclear sizes and shapes Flat, pseudopapillary, or patchy micropapillary Rare mitosis, may involve peribiliary glands
Severe nuclear membrane irregularity, hyperchromasia, abnormally large nuclei Rarely flat, pseudopapillary, or micropapillary Mitosis may be seen, may involve peribiliary glands
Reprinted with permission from Macmillan Publishers Ltd. 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(6):701–709. Copyright 2007.16 Arch Pathol Lab Med—Vol 140, November 2016
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noninvasive neoplasm within the bile duct, with a histologic resemblance to intraductal tubulopapillary neoplasm of the pancreas. Intraductal tubular/tubulopapillary neoplasm demonstrates a markedly complex tubular or solid architecture, microscopic necrosis, and stromal desmoplasia within the intraductal component.3 A recent multicenter study of ITN showed that 14 of 20 cases (70%) were intrahepatic, and 16 (80%) were associated with invasive component, with an indolent behavior.19 Distinctive from IPN-B, ITN lacks unequivocal papilla formation and mucin production. However, both IPN-B and ITN share overlapping features, such as intraductal growth, cyst formation, dysplasia, and an association with invasive carcinoma.3,19 Mucinous cystic neoplasm is another rare precursor lesion that can give rise to invasive adenocarcinoma. This tumor occurs predominantly in perimenopausal women. Intrahepatic bile duct is commonly involved, and the size of the cysts tends to be larger compared with IPN-B. Similar to its pancreatic counterpart, biliary mucinous cystic neoplasm is characterized by ovarian-like stroma of the cyst wall and columnar, mucin-containing biliary epithelium.6 Mucinous cystic neoplasm is different from mucin-producing IPN-B. Unlike mucinous cystic neoplasm, IPN-B lacks ovarian-like stroma. Furthermore, IPN-B is grossly connected to the bile duct system, whereas mucinous cystic neoplasm is not. IMMUNOPHENOTYPE Several epithelial markers and mucin markers have been used to characterize preneoplastic lesions. These markers are not used to distinguish IPN-B and BilIN. Rather, the markers are sometimes helpful in determining histologic subtypes of the lesion when morphologic features are not typical of a certain subtype, or when the features are mixed. MUC1 is a sensitive marker of pancreatobiliary differentiation. Expression of MUC1 in cholangiocarcinoma is associated with a poorer outcome.20 Tubular adenocarcinoma with a biliary immunophenotype (MUC1-positive pathway) shows a worse prognosis than colloid adenocarcinoma (MUC2-positive pathway) with intestinal phenotype.15 Colloid adenocarcinoma is usually negative for MUC1. Also, increasing levels of MUC1 expression in preneoplastic lesions may be associated with the development of tubular adenocarcinoma.21 MUC2 is an intestinal marker. Variable expression of this apomucin has been observed in both BilIN and IPN-B. In IPN-B, intestinal metaplasia with MUC2 expression is frequently observed. Overexpression of MUC2 in BilIN is considered to be associated with hepatolithiasis, either reflecting a preceding condition or involvement in the formation of stones.21 CK7 is expressed in normal biliary epithelium, as well as most BilIN and IPN-B lesions, regardless of the degree of atypia.21 MUC6 is a component of mucin that is found in gastric pyloric glands. Occasional normal biliary epithelium and PBGs are immunoreactive for MUC6. MUC5AC is normally found in the gastric foveolar epithelium. Both MUC5AC and MUC6 are expressed in biliary epithelium in inflammatory conditions, such as primary sclerosing cholangitis.6,15 The most common immunophenotype of BilIN is negativity for both MUC1 and MUC2, although an increased expression of MUC1 along with the progression of histologic grade of BilIN has been observed.21 Likewise, tubular adenocarcinoma, which is commonly associated 1288 Arch Pathol Lab Med—Vol 140, November 2016
with BilIN, is characterized by the pancreatobiliary immunophenotype with positivity for CK7 and MUC1. Rarely, intestinal phenotype represented by positivity for MUC2, CK20, and CDX2 is found in this BilIN-tubular adenocarcinoma pathway.15 According to the reports from Asia, IPN-B frequently expresses intestinal phenotype (MUC2 and CK20). On the other hand, pancreatobiliary phenotype with MUC1 expression appears to be more common in the West.15 Also, the expression of MUC1 increases in association with tubular adenocarcinoma.6,21 Because IPN-B has been predominantly reported in Asia, an intestinal phenotype IPN-B to colloid carcinoma pathway has been relatively well established. During this carcinogenesis, tumor cells retain both biliary immunophenotype (CK7) and intestinal immunophenotype (MUC2 and CK20). Loss of membranous expression of b-catenin and Ecadherin may be early events in the tumorigenesis of both BilIN and IPN-B. Also, the expression of matrix metalloproteinase-7 (MMP-7) and membrane type 1-MMP (MT1-MMP) was reported to be closely associated with invasive growth of BilIN. The Wnt signaling pathway may play an important role in the tumorigenesis of IPN-B.22 DIFFERENTIAL DIAGNOSES The diagnostic challenge arises when the potential precursor lesion is associated with acute inflammation. Hyperplasia or regenerative changes in the setting of hepatolithiasis or choledochal cyst should be differentiated from BilIN, especially when they exhibit flat, low papillary, or micropapillary architecture. Bile duct stents prior to surgery or biopsy may lead to reactive inflammatory changes, causing diagnostic difficulty. In reactive conditions, the biliary epithelial cells demonstrate round to oval and slightly enlarged nuclei, smooth nuclear membrane, and fine chromatin. Intraepithelial neutrophilic infiltrate is common, which favors a reactive process. The terminology of ‘‘indefinite for dysplasia’’ is recommended when in doubt.16 Rarely, tumor cells of cholangiocarcinoma or metastatic adenocarcinoma may show pagetoid spread along the biliary system, mimicking in situ neoplasia of the bile ducts.23 Recent studies suggested that IPN-B is a biliary counterpart of IPMN of pancreas. Both develop from ventral endoderm of the foregut and show fundamental histopathologic similarities, although macroscopic mucin production is less frequent in IPN-B compared with IPMN.17 HYPERPLASIA-METAPLASIA-NEOPLASIA THEORY A sequence of genetic alterations from hyperplasia, metaplasia, and BilIN to invasive carcinoma is documented. For example, telomere shortening is one of the earliest molecular events occurring in response to inflammation, and varied length of the telomere correlates well with neoplastic progression.24 Gradual increase in the expression of p53 and Ki-67 was observed along the disease progression from metaplasia to precursor, and to invasive carcinoma.25 Moreover, the fact that metaplasia is often noted in the background of BilIN or carcinoma, and that BilIN has been reported in association with 10% to 45% of bile duct carcinomas, supports this sequential evolutionary pathway. Biliary Precancerous Lesion—Ainechi & Lee
The role of the PBG in tumorigenesis has been recently proposed. The PBGs harbor multipotent stem/progenitor cells. In response to injuries, the progenitor cells may undergo hyperplastic changes and may eventually evolve into mucin-producing carcinoma.26,27 PRACTICAL CONSIDERATIONS Biliary intraepithelial neoplasia usually is associated with conventional tubular cholangiocarcinoma, and hence it harbors a poor prognosis. Because BilIN is found incidentally, the remainder of the specimen should be thoroughly examined and extensively sampled to rule out multifocal BilIN or occult invasive carcinoma.12 In contrast, sometimes IPN-B may be detected without associated invasive carcinoma. Generally, IPN-B shows a better outcome because the tumor tends to be detected at an earlier stage because of symptoms associated with bile duct obstruction. Moreover, colloid adenocarcinoma, which is frequently associated with IPN-B, especially in East Asia, tends to demonstrate a better outcome. According to the 2010 American Joint Committee on Cancer TNM staging system, carcinoma in situ is classified as pTis, whereas BilIN-3 is considered pT0. This may be problematic when dysplastic epithelium involves the resection margin.12 Also, there is no consensus regarding whether the presence of BilIN-3 at a frozen section margin should lead to additional resection.13 Given the high interobserver variability, fluorescent in situ hybridization has been incorporated to refine diagnostic criteria of the precursor lesions. The degree of cytogenetic abnormalities (homozygous 9p21 loss and polysomy) observed in fluorescent in situ hybridization generally correlated with the degree of dysplasia in various lesions.28 Although cytogenetic abnormalities and immunophenotype of these precursor lesions are important from a pathogenetic perspective, the diagnosis of the lesions is purely based on morphologic features. Therefore, in a practical sense, ancillary studies are neither required nor considered confirmatory for diagnosis. SUMMARY Precancerous lesions of cholangiocarcinoma of the biliary tract are increasingly recognized. Biliary intraepithelial neoplasia and IPN-B exhibit distinct histomorphology and immunophenotype, and they eventually evolve into different types of invasive carcinoma depending on their epithelial subtypes. Cognizance of these precancerous lesions combined with the use of common terminology will facilitate efficient and effective communication between disciplines, streamline future collaborative research and knowledge sharing in this rapidly evolving field, and improve the quality of patient care. The authors would like to thank Christine E. Sheehan, MS (administrative director of research, Department of Pathology, Albany Medical Center), for her editorial assistance with the manuscript. References 1. Joo I, Lee JM. Imaging bile duct tumors: pathologic concepts, classification, and early tumor detection. Abdom Imaging. 2013;38(6):1334–1350. 2. Adsay NV, Kloppel G, Fukushima N, et al. Intraductal neoplasms of the pancreas. In: Bosman FT, ed. World Health Organization Classification of Tumours of the Digestive System. Lyon, France: IARC; 2010:304–313.
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3. Katabi N, Torres J, Klimstra DS. Intraductal tubular neoplasms of the bile ducts. Am J Surg Pathol. 2012;36(11):1647–1655. 4. 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(4):180–188. 5. Kloppel G, Kosmahl M. Is the intraductal papillary mucinous neoplasia of the biliary tract a counterpart of pancreatic papillary mucinous neoplasm? J Hepatol. 2006;44(2):249–250. 6. Serra S. Precursor neoplastic lesions of the biliary tract. J Clin Pathol. 2014; 67(10):875–882. 7. Adsay NV, Klimstra DS. Benign and malignant tumors of the gallbladder and extrahepatic biliary tract. In: Odze RD, Goldblum JR, eds. Surgical Pathology of the GI Tract, Liver, Biliary Tract, and Pancreas. 2nd ed. Philadelphia, PA: Saunders Elsevier; 2009:853–854. 8. Bergquist A, Glaumann H, Stal P, Wang GS, Broome U. Biliary dysplasia, cell proliferation and nuclear DNA-fragmentation in primary sclerosing cholangitis with and without cholangiocarcinoma. J Intern Med. 2001;249(1): 69–75. 9. Kloppel G, Adsay V, Konukiewitz B, Kleeff J, Schlitter AM, Esposito I. Precancerous lesions of the biliary tree. Best Pract Res Clin Gastroenterol. 2013; 27(2):285–297. 10. Kim KM, Lee JK, Shin JU, et al. Clinicopathologic features of intraductal papillary neoplasm of the bile duct according to histologic subtype. Am J Gastroenterol. 2012;107(1):118–125. 11. Chapman R, Fevery J, Kalloo A, et al. Diagnosis and management of primary sclerosing cholangitis. Hepatology. 2010;51(2):660–678. 12. Katabi N. Neoplasia of gallbladder and biliary epithelium. Arch Pathol Lab Med. 2010;134(11):1621–1627. 13. Matthaei H, Lingohr P, Strasser A, et al. Biliary intraepithelial neoplasia (BilIN) is frequently found in surgical margins of biliary tract cancer resection specimens but has no clinical implications. Virchows Arch. 2015;466(2):133– 141. 14. Goto N, Yoshioka M, Hayashi M, Itani T, Mimura J, Hashimoto K. Intraductal papillary-mucinous neoplasm of the pancreas penetrating to the stomach and the common bile duct. JOP. 2012;13(1):61–65. 15. Zen Y, Quaglia A, Heaton N, Rela M, Portmann B. Two distinct pathways of carcinogenesis in primary sclerosing cholangitis. Histopathology. 2011;59(6): 1100–1110. 16. 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(6):701–709. 17. Rocha FG, Lee H, Katabi N, et al. Intraductal papillary neoplasm of the bile duct: a biliary equivalent to intraductal papillary mucinous neoplasm of the pancreas? Hepatology. 2012;56(4):1352–1360. 18. Schlitter AM, Born D, Bettstetter M, et al. Intraductal papillary neoplasms of the bile duct: stepwise progression to carcinoma involves common molecular pathways. Mod Pathol. 2014;27(1):73–86. 19. Schlitter AM, Jang KT, Kloppel G, et al. Intraductal tubulopapillary neoplasms of the bile ducts: clinicopathologic, immunohistochemical, and molecular analysis of 20 cases. Mod Pathol. 2015;28(9):1249–1264. 20. Park SY, Roh SJ, Kim YN, et al. Expression of MUC1, MUC2, MUC5AC and MUC6 in cholangiocarcinoma: prognostic impact. Oncol Rep. 2009;22(3):649– 657. 21. 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(2):350–358. 22. Itatsu K, Zen Y, Ohira S, et al. Immunohistochemical analysis of the progression of flat and papillary preneoplastic lesions in intrahepatic cholangiocarcinogenesis in hepatolithiasis. Liver Int. 2007;27(9):1174–1184. 23. Ferrell LD. Benign and malignant tumors of the liver. In: Odze RD, Goldblum JR, eds. Surgical Pathology of the GI tract, Liver, Biliary Tract, and Pancreas. 2nd ed. Philadelphia, PA: Saunders Elsevier; 2009:1311–1313. 24. Hansel DE, Meeker AK, Hicks J, et al. Telomere length variation in biliary tract metaplasia, dysplasia, and carcinoma. Mod Pathol. 2006;19(6):772–779. 25. Katabi N, Pillarisetty VG, DeMatteo R, Klimstra DS. Choledochal cysts: a clinicopathologic study of 36 cases with emphasis on the morphologic and the immunohistochemical features of premalignant and malignant alterations. Hum Pathol. 2014;45(10):2107–2014. 26. Cardinale V, Wang Y, Carpino G, Reid LM, Gaudio E, Alvaro D. Mucinproducing cholangiocarcinoma might derive from biliary tree stem/progenitor cells located in peribiliary glands. Hepatology. 2012;55(6):2041–2042. 27. Sato Y, Harada K, Sasaki M, Nakanuma Y. Cystic and micropapillary epithelial changes of peribiliary glands might represent a precursor lesion of biliary epithelial neoplasms. Virchows Arch. 2014;464(2):157–163. 28. Kerr SE, Barr Fritcher EG, Campion MB, et al. Biliary dysplasia in primary sclerosing cholangitis harbors cytogenetic abnormalities similar to cholangiocarcinoma. Hum Pathol. 2014;45(9):1797–1804.
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