Wu Tsung-Teh, Levy Michael, Correa Arlene M, Rosen Charles B, Abraham Susan C
Division of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota, USA.
Cancer. 2009 Oct 1;115(19):4564-75. doi: 10.1002/cncr.24471.
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.
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).
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.
In aggregate, these findings provide morphologic support for the epidemiologic role of alcohol and HCV in the development of CCA.
胆管上皮内瘤变（BilIN）代表肝内大胆管的一系列增殖性和/或细胞学非典型病变。BilIN被认为是通过发育异常-癌序列导致肝内胆管癌（CCA）发生的主要途径。最近，一项针对肝内胆管结石、胆总管囊肿和原发性硬化性胆管炎患者的大型观察者间一致性研究，根据核异型性增加和核极性丧失，提出了3类BilIN的诊断标准：BilIN-1、BilIN-2和BilIN-3。尽管肝内CCA、丙型肝炎病毒（HCV）感染和酒精（EtOH）消费之间存在流行病学关联，但BilIN作为非胆汁性肝病患者潜在的前驱病变尚未得到系统研究。
我们提交了244例移植肝的12个石蜡块，这些移植肝包括乙醇性肝硬化（n = 94）、HCV肝硬化（n = 44）、乙醇+HCV（n = 26）和非肝硬化对照（如因代谢紊乱、大面积肝坏死而切除的肝脏）（n = 80），所有胆管形态分为正常/反应性、化生或BilIN-1、-2或-3（扁平或乳头状）。
与单独HCV感染和非肝硬化患者相比，因乙醇性和乙醇+HCV肝硬化而接受移植的肝脏中BilIN的患病率最高，BilIN累及的胆管数量更多，且BilIN分级有向更高等级转变的趋势。在乙醇性肝硬化患者中，BilIN的最高分级为：BilIN-0 = 3%，BilIN-1 = 35%，BilIN-2 = 57%，BilIN-3 = 4%；在乙醇+HCV患者中：4%，38%，54%，4%；在HCV患者中：18%，55%，20%，7%；在非肝硬化患者中：分别为45%，39%，16%，0%。在单因素和多因素分析中，乙醇（P <.001）、乙醇+HCV（P <.001）和HCV肝硬化（P <.001）均是BilIN分级的显著预测因素。多灶性BilIN（≥10个胆管）在91%的乙醇性肝硬化、92%的乙醇+HCV肝硬化和61%的HCV肝硬化患者中存在，而在非肝硬化患者中仅为34%（单因素和多因素分析中的P值分别为<.0001、<.001和.002）。BilIN的乳头状或微乳头状结构在乙醇性肝硬化患者中（47%）也比在乙醇+HCV肝硬化患者（19%）、HCV肝硬化患者（23%）或非肝硬化患者（17%）中更常见（单因素和多因素分析中的P <.001）。BilIN-3仅出现在肝硬化患者中（164例肝硬化肝脏中有8例，5%），并与肝脏其他部位的CCA（2例）或肝细胞/CCA混合性癌（1例）相关。
总体而言，这些发现为酒精和HCV在CCA发生中的流行病学作用提供了形态学支持。
