Biliary intraepithelial neoplasia in patients without chronic biliary disease: analysis of liver explants with alcoholic cirrhosis, hepatitis C infection, and noncirrhotic liver diseases.
BACKGROUND
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-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 BilIN based on increasing grades of nuclear atypia and loss of nuclear polarity: BilIN-1, BilIN-2, and BilIN-3. 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.


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 BilIN-1, -2, or -3 (flat or papillary).


RESULTS
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-1 = 35%, BilIN-2 = 57%, BilIN-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 BilIN grade. Multifocal BilIN (>/=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 BilIN 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). BilIN-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.
Wu
Tsung-Teh
TT
Division of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota, USA.
Levy
Michael
M
Correa
Arlene M
AM
Rosen
Charles B
CB
Abraham
Susan C
SC
D000293:Adolescent; D000328:Adult; D000368:Aged; D001661:Biliary Tract Neoplasms / Q000209:etiology* / Q000473:pathology*; D002675:Child, Preschool; D018281:Cholangiocarcinoma / Q000150:complications / Q000473:pathology; D005260:Female; D006498:Hepatectomy; D006526:Hepatitis C / Q000150:complications*; D006801:Humans; D007223:Infant; D008103:Liver Cirrhosis / Q000150:complications* / Q000473:pathology*; D008104:Liver Cirrhosis, Alcoholic / Q000150:complications / Q000473:pathology; D008107:Liver Diseases / Q000150:complications* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D015995:Prevalence