{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T10:31:46Z","timestamp":1792146706720,"version":"4.4.0"},"reference-count":28,"publisher":"Wiley","issue":"19","license":[{"start":{"date-parts":[[2009,8,10]],"date-time":"2009-08-10T00:00:00Z","timestamp":1249862400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancer"],"published-print":{"date-parts":[[2009,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>BACKGROUND:<\/jats:title><jats:p>Biliary intraepithelial neoplasia (BilIN) represents a spectrum of proliferative and\/or cytologically atypical lesions of the large intrahepatic bile ducts. BilIN is believed to be a major pathway leading to the development of intrahepatic cholangiocarcinoma (CCA) through a dysplasia\u2010carcinoma sequence. Recently, a large interobserver agreement study in patients with hepatolithiasis, choledochal cysts, and primary sclerosing cholangitis proposed diagnostic criteria for 3 categories of BilIN based on increasing grades of nuclear atypia and loss of nuclear polarity: BilIN\u20101, BilIN\u20102, and BilIN\u20103. BilIN has not been systematically studied as a potential precursor lesion in patients with nonbiliary liver disease, despite the epidemiologic association between intrahepatic CCA, hepatitis C infection (HCV), and alcohol (EtOH) consumption.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS:<\/jats:title><jats:p>We submitted 12 paraffin blocks targeted to the large intrahepatic and hilar ducts in each of 244 explanted livers with EtOH cirrhosis (n = 94), HCV cirrhosis (n = 44), EtOH + HCV (n = 26), and noncirrhotic controls (eg, livers removed for metabolic disorders, massive hepatic necrosis) (n = 80), and classified all bile duct profiles as normal\/reactive, metaplastic, or BilIN\u20101, \u20102, or \u20103 (flat or papillary).<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS:<\/jats:title><jats:p>Livers transplanted for EtOH and EtOH + HCV cirrhosis had the highest prevalence of BilIN, greater numbers of ducts with BilIN, and a shift toward higher grades of BilIN as compared with HCV alone and with noncirrhotics. In EtOH, the highest grades of BilIN were 0 = 3%, BilIN\u20101 = 35%, BilIN\u20102 = 57%, BilIN\u20103 = 4%; in EtOH + HCV: 4%, 38%, 54%, 4%; in HCV: 18%, 55%, 20%, 7%; and in noncirrhotics: 45%, 39%, 16%, 0%, respectively. In both univariate and multivariate analysis, EtOH (<jats:italic>P<\/jats:italic> &lt; .001), EtOH + HCV (<jats:italic>P<\/jats:italic> &lt; .001), and HCV cirrhosis (<jats:italic>P<\/jats:italic> &lt; .001) were all significant predictors of BilIN grade. Multifocal BilIN (\u226510 ducts) was present in 91% of EtOH, 92% of EtOH + HCV, and 61% of HCV cirrhosis, as compared with only 34% of noncirrhotics (<jats:italic>P<\/jats:italic> values of &lt;.0001, &lt;.001, and .002, respectively, in both univariate and multivariate analysis). Papillary or micropapillary architecture of BilIN was also more common in EtOH (47%) than in EtOH + HCV (19%), HCV (23%), or noncirrhotics (17%) (<jats:italic>P<\/jats:italic> &lt; .001 in both univariate and multivariate analysis). BilIN\u20103 occurred only in the setting of cirrhosis (8 of 164 cirrhotic livers, 5%) and was associated with CCA (2 cases) or mixed hepatocellular\/CCA (1 case) elsewhere in the liver.<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSIONS:<\/jats:title><jats:p>In aggregate, these findings provide morphologic support for the epidemiologic role of alcohol and HCV in the development of CCA. Cancer 2009. \u00a9 2009 American Cancer Society.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cncr.24471","type":"journal-article","created":{"date-parts":[[2009,8,11]],"date-time":"2009-08-11T01:07:13Z","timestamp":1249952833000},"page":"4564-4575","source":"Crossref","is-referenced-by-count":70,"title":["Biliary intraepithelial neoplasia in patients without chronic biliary disease"],"prefix":"10.1002","volume":"115","author":[{"given":"Tsung\u2010Teh","family":"Wu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Levy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arlene M.","family":"Correa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles B.","family":"Rosen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan 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