8148/2 Biliary intraepithelial neoplasia, grade 3 (BilIN-3)



Definitions

Gallbladder and extrahepatic biliary tract
ICD-O-3 topography code: C23-C24.0

Biliary intraepithelial neoplasia (BilINs) are characterized by atypical epthelial cells with multilayering of nuclei and micropapillary projections into the gallbladder/extrahepatic duct lumen 1
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Zen Y, Adsay NV, Bardadin K, Colombari R, Ferrell L, Haga H, Hong SM, Hytiroglou P, Klöppel G, Lauwers GY, van Leeuwen DJ, Notohara K, Oshima K, Quaglia A, Sasaki M, Sessa F, Suriawinata A, Tsui W, Atomi Y, Nakanuma Y (2007)
Biliary intraepithelial neoplasia: an international interobserver agreement study and proposal for diagnostic criteria.
Mod Pathol 20: 701-9



2
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Zen Y, Aishima S, Ajioka Y, Haratake J, Kage M, Kondo F, Nimura Y, Sakamoto M, Sasaki M, Shimamatsu K, Wakasa K, Park YN, Chen MF, Atomi Y, Nakanuma Y (2005)
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 55: 180-8



. These premalignant lesions also occur in intrahepatic bile ducts. The atypical cells have an increased nucleus-to-cytoplasm ratio, partial loss of nuclear polarity, and nuclear hyperchromasia. BilIN-1 and BilIN-2 correspond to low-grade and intermediate-grade lesions and BilIN-3 corresponds to high grade lesions 3
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Zen Y, Adsay NV, Bardadin K, Colombari R, Ferrell L, Haga H, Hong SM, Hytiroglou P, Klöppel G, Lauwers GY, van Leeuwen DJ, Notohara K, Oshima K, Quaglia A, Sasaki M, Sessa F, Suriawinata A, Tsui W, Atomi Y, Nakanuma Y (2007)
Biliary intraepithelial neoplasia: an international interobserver agreement study and proposal for diagnostic criteria.
Mod Pathol 20: 701-9



.

BilIN of the gallbladder
The incidence of BilIN-3 parallels that of invasive carcinoma and its prevalence is higher in countries in which gallbladder carcinoma is endemic than in countries in which it is sporadic. The incidence of BilIN-3 in gallbladders with lithiasis varies from 0.5% to 3%
4
 
Albores-Saavedra J, Henson DE, and Klimstra DS eds.
Tumors of the Gallbladder, Extrahepatic Bile Ducts, and Ampulla of Vater
Armed Forces Institute of Pathology: Washington, DC 2000



. This variation in the incidence of BilIn-3 is partially attributable to a lack of uniformity in morphological criteria and sampling methods. In addition to cholelithiasis, BilIN-3 occurs in the mucosa adjacent to most invasive carcinomas and can be found in patients with familial adenomatous polyposis (FAP), sclerosing cholangitis and pancreatobiliary reflux 5
 
Albores-Saavedra J, Henson DE, and Klimstra DS eds.
Tumors of the Gallbladder, Extrahepatic Bile Ducts, and Ampulla of Vater
Armed Forces Institute of Pathology: Washington, DC 2000



6
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Bergquist A, Glaumann H, Persson B, Broomé U (1998)
Risk factors and clinical presentation of hepatobiliary carcinoma in patients with primary sclerosing cholangitis: a case-control study.
Hepatology 27: 311-6



7
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Bergquist A, Glaumann H, Stål P, Wang GS, Broomé U (2001)
Biliary dysplasia, cell proliferation and nuclear DNA-fragmentation in primary sclerosing cholangitis with and without cholangiocarcinoma.
J Intern Med 249: 69-75



8
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Boberg KM, Jebsen P, Clausen OP, Foss A, Aabakken L, Schrumpf E (2006)
Diagnostic benefit of biliary brush cytology in cholangiocarcinoma in primary sclerosing cholangitis.
J Hepatol 45: 568-74



9
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Duarte I, Llanos O, Domke H, Harz C, Valdivieso V (1993)
Metaplasia and precursor lesions of gallbladder carcinoma. Frequency, distribution, and probability of detection in routine histologic samples.
Cancer 72: 1878-84



10
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Gilloteaux J, Combetta J (2005)
Carcinoma in situ of the cystic duct.
Ultrastruct Pathol 29: 79-84



11
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Haworth AC, Manley PN, Groll A, Pace R (1989)
Bile duct carcinoma and biliary tract dysplasia in chronic ulcerative colitis.
Arch Pathol Lab Med 113: 434-6



12
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Katabi N, Albores-Saavedra J (2003)
The extrahepatic bile duct lesions in end-stage primary sclerosing cholangitis.
Am J Surg Pathol 27: 349-55



13
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Lal A, Okonkwo A, Schindler S, De Frias D, Nayar R (2004)
Role of biliary brush cytology in primary sclerosing cholangitis.
Acta Cytol 48: 9-12



14
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Ludwig J, Wahlstrom HE, Batts KP, Wiesner RH (1992)
Papillary bile duct dysplasia in primary sclerosing cholangitis.
Gastroenterology 102: 2134-8



15
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Nakanishi Y, Zen Y, Kawakami H, Kubota K, Itoh T, Hirano S, Tanaka E, Nakanuma Y, Kondo S (2008)
Extrahepatic bile duct carcinoma with extensive intraepithelial spread: a clinicopathological study of 21 cases.
Mod Pathol 21: 807-16



16
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Narayanan Menon KV (2006)
Primary sclerosing cholangitis, chronic ulcerative colitis, and bile duct dysplasia--Case presentation.
Liver Transpl 12: S14



17
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Suster S, Huszar M, Herczeg E, Bubis JJ (1987)
Adenosquamous carcinoma of the gallbladder with spindle cell features. A light microscopic and immunocytochemical study of a case.
Histopathology 11: 209-14



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BilIN of the extrahepatic bile ducts
BilINs of the extrahepatic and intrahepatic biliary tree share clinical, morphological, and immunophenotypical features
18
 
Bosman FT, Carneiro F, Hruban RH, Theise ND (Eds.)
WHO Classification of Tumours of the Digestive System.
4th Edition
International Agency for Research on Cancer: Lyon 2010



.





Liver and intrahepatic bile ducts
ICD-O-3 topography code: C22

Biliary intraepithelial neoplasia (BilIN) is a premalignant flat lesion arising from the intrahepatic large bile ducts. BilIN is not infrequently encountered in the intrahepatic large bile ducts in chronic biliary diseases such as hepatolithiasis
19
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Zen Y, Aishima S, Ajioka Y, Haratake J, Kage M, Kondo F, Nimura Y, Sakamoto M, Sasaki M, Shimamatsu K, Wakasa K, Park YN, Chen MF, Atomi Y, Nakanuma Y (2005)
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 55: 180-8



. BilINs are characterized by atypical epithelial cells with multilayering of nuclei and micropapillary projections into the duct lumen 20
Click to access Pubmed
Zen Y, Adsay NV, Bardadin K, Colombari R, Ferrell L, Haga H, Hong SM, Hytiroglou P, Klöppel G, Lauwers GY, van Leeuwen DJ, Notohara K, Oshima K, Quaglia A, Sasaki M, Sessa F, Suriawinata A, Tsui W, Atomi Y, Nakanuma Y (2007)
Biliary intraepithelial neoplasia: an international interobserver agreement study and proposal for diagnostic criteria.
Mod Pathol 20: 701-9



21
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Zen Y, Aishima S, Ajioka Y, Haratake J, Kage M, Kondo F, Nimura Y, Sakamoto M, Sasaki M, Shimamatsu K, Wakasa K, Park YN, Chen MF, Atomi Y, Nakanuma Y (2005)
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 55: 180-8



. The atypical cells have an increased nucleus-tocytoplasm ratio, partial loss of nuclear polarity, and nuclear hyperchromasia. They are divisible into BilIN-1, BilIN-2 and BilIN- 3 according to degree of atypia: BilIN-1 and BilIN-2 correspond to low- and intermediate- grade lesions (ICD-O code, 8148/0), and BilIN-3 to high-grade lesions (ICD-O code, 8148/2)22
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Zen Y, Adsay NV, Bardadin K, Colombari R, Ferrell L, Haga H, Hong SM, Hytiroglou P, Klöppel G, Lauwers GY, van Leeuwen DJ, Notohara K, Oshima K, Quaglia A, Sasaki M, Sessa F, Suriawinata A, Tsui W, Atomi Y, Nakanuma Y (2007)
Biliary intraepithelial neoplasia: an international interobserver agreement study and proposal for diagnostic criteria.
Mod Pathol 20: 701-9



. Some peribiliary glands in chronic hepatobiliary diseases may show BilIN lesions. BilINs are also seen in the hilar and extrahepatic bile ducts. Interestingly, similar intraepithelial biliary lesions are also encountered in the small intrahepatic bile ducts in livers with chronic hepatis C, alcoholic cirrhosis, thorotrast deposition, and PSC, suggesting that they may be precursor and early lesions of ICC arising from small bile ducts and ductules 23
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Fleming KA, Boberg KM, Glaumann H, Bergquist A, Smith D, Clausen OP (2001)
Biliary dysplasia as a marker of cholangiocarcinoma in primary sclerosing cholangitis.
J Hepatol 34: 360-5



24
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Torbenson M, Yeh MM, Abraham SC (2007)
Bile duct dysplasia in the setting of chronic hepatitis C and alcohol cirrhosis.
Am J Surg Pathol 31: 1410-3



. Extensive intraductal spread of BilINs along the intrahepatic bile ducts without grossly visible tumour lesions has been reported 25
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Aishima S, Nishihara Y, Tsujita E, Taguchi K, Soejima Y, Taketomi A, Ikeda Y, Maehara Y, Tsuneyoshi M (2008)
Biliary neoplasia with extensive intraductal spread associated with liver cirrhosis: a hitherto unreported variant of biliary intraepithelial neoplasia.
Hum Pathol 39: 939-47



26
 
Bosman FT, Carneiro F, Hruban RH, Theise ND (Eds.)
WHO Classification of Tumours of the Digestive System.
4th Edition
International Agency for Research on Cancer: Lyon 2010



.