330 The Korean Journal of Hepatology Vol. 17. No. 4, December 2011 about progression of BilIN to invasive cholangiocarcinoma epithelium and to evaluation of patients with hepatolithiasis, in which immunohistochemical staining of p21, p53 and choledocal cyst and primary sclerosing cholangitis patients. cyclin-D1 antibodies revealed up-regulation of these proteins So, it is hoped that understanding of BilIN could be able to with histological progression from BilIN to invasive help us better understand of biliary tract neoplasia. cholangiocarcinoma.6 A molecular study also revealed This case shows variable degree of BilINs at cystically stepwise increase of promoter CpG island methylation and dilated intrahepatic bile duct proximal to benign stricture of decrease of repetitive element methylation in BilIN-cholan- extrahepatic bile duct. These findings suggest that chronic giocarcinoma sequence.7 stimuli at bile duct epithelium could promote dysplastic BilIN is usually not recognized on macroscopic examination. change and these stimuli may be the cause of development On macroscopic examination, mucosa shows only discolored, of cholangiocarcinoma. granular or plaque-like appearance. Microscopically, BilIN shows enlargem ent of cells, pseudostratification and micropapillae formation.1-3 According to the degree of cytological and architectural atypia, BilINs are divided into BilIN-1, BilIN-2 and BilIN-3. BilIN-1 correspond to low grade lesion (ICD-O code, 8148/0), BilIN-2 to intermediate lesion (ICD-O code, 8148/0) and BilIN-3 to high grade lesion (ICD-O code, 8148/2).1 Some of hyperplastic or regenerative change could show cytological and structural features resembling BilINs, but these lesions lack sufficient atypia to be regarded as neoplastic. Precursor lesions of intra- and extrahepatic biliary tract are not easily accessible due to the anatomic location, so it is difficult to get biopsy samples through endoscopic or needle biopsy. Furthermore, BilIN is mostly flat or micropapillary lesion that neither form mass lesion nor cause bile duct obstruction. Early detection or regular follow up of BilIN is very difficult. This is why the natural course or prognosis of BilIN is not well understood. Till now, the knowledge and clinical utilization of BilIN is limited. But it can provide the information about carcinogenesis of cholangiocarcinoma and this classification of precursor lesion of malignancy could be applicable to clinical or pathologic studies of biliary REFERENCES 1. Bosman FT, Carneiro F, Hruban RH, Theise ND. WHO classification of tumours of the digestive system. 4th ed. Lyon: International Agency for Research on Cancer, 2010:222-223,270-271. 2. Zen Y, Aishima S, Ajioka Y, Haratake J, Kage M, Kondo F, et al. 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 2005;55:180-188. 3. Zen Y, Adsay NV, Bardadin K, Colombari R, Ferrell L, Haga H, et al. Biliary intraepithelial neoplasia: an international interobserver agreement study and proposal for diagnostic criteria. Mod Pathol 2007;20:701-709. 4. Wu TT, Levy M, Correa AM, Rosen CB, Abraham SC. Biliary intraepithelial neoplasia in patients without chronic biliary disease: analysis of liver explants with alcoholic cirrhosis, hepatitis C infection, and noncirrhotic liver diseases. Cancer 2009;115:4564-4575. 5. Lewis JT, Talwalkar JA, Rosen CB, Smyrk TC, Abraham SC. Precancerous bile duct pathology in end-stage primary sclerosing cholangitis, with and without cholangiocarcinoma. Am J Surg Pathol 2010;34:27-34. 6. Nakanuma Y, Sasaki M, Sato Y, Ren X, Ikeda H, Harada K. Multistep carcinogenesis of perihilar cholangiocarcinoma arising in the intrahepatic large bile ducts. World J Hepatol 2009;1:35-42. 7. Kim BH, Cho NY, Shin SH, Kwon HJ, Jang JJ, Kang GH. CpG island hypermethylation and repetitive DNA hypomethylation in premalignant lesion of extrahepatic cholangiocarcinoma. Virchows Arch 2009;455: 343-351.