Biliary Intralepithelial Neoplasia in Patients Without Chronic Biliary Disease

BACKGROUND: Biliary intraepithelial neoplasia (BillN) represents a spectrum of proliferative and/or cytologically atypical lesions of the large intrahepatic bile ducts. BillN is believed to be a major pathway leading to the development of intrahepatic cholangiocarcinoma (CCA) through a dysplasia-carcinoma sequence. Recently, a large interobserver agreement study in patients with hepatolithiasis, choledochal cysts, and primary sclerosing cholangitis proposed diagnostic criteria for 3 categories of BillN based on increasing grades of nuclear atypia and loss of nuclear polarity: BillN-1, BillN-2, and BillN-3. BillN 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. METHODS: 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 BillN-1, -2, or -3 (flat or papillary). RESULTS: Livers transplanted for EtOH and EtOH + HCV cirrhosis had the highest prevalence of BillN, greater numbers of ducts with BillN, and a shift toward higher grades of BillN as compared with HCV alone and with noncirrhotics. In EtOH, the highest grades of BillN were 0 = 3%, BillN-1 = 35%, BillN-2 = 57%, BillN-3 = 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 (P <.001), EtOH + HCV (P <.001), and HCV cirrhosis (P <.001) were all significant predictors of BillN grade. Multifocal BillN (>= 10 ducts) was present in 91% of EtOH, 92% of EtOH + HCV, and 61% of HCV cirrhosis, as compared with only 34% of noncirrhotics (P values of <.0001, <.001, and .002, respectively, in both univariate and multivariate analysis). Papillary or micropapillary architecture of WIN was also more common in EtOH (47%) than in EtOH + HCV (19%), HCV (23%), or noncirrhotics (17%) (P <.001 in both univariate and multivariate analysis). BillN-3 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. CONCLUSIONS: In aggregate, these findings provide morphologic support for the epidemiologic role of alcohol and HCV in the development of CCA. Cancer 2009;115:4564-75. (C) 2009 American Cancer Society.