Immunohistochemical analysis of the progression of flat and papillary preneoplastic lesions in intrahepatic cholangiocarcinogenesis in hepatolithiasis

Background: Two types of precursor lesions, flat‐type ‘biliary intraepithelial neoplasia (BilIN)’ and papillary‐type ‘intraductal papillary neoplasm of the bile duct (IPNB)’, are proposed in the tumorigenesis of intrahepatic cholangiocarcinoma (ICC) in hepatolithiasis. Methods: In this study, the participation of cancer‐related molecules in the progression of these two precursor lesions was examined, using 64 hepatolithiatic livers with BilIN lesions (45 livers) and IPNB lesions (19 livers) and 10 hepatolithiatic livers without neoplastic lesions as a control. The expression of E‐cadherin, β‐catenin, matrix metalloproteinase‐7 (MMP‐7), membrane type 1‐MMP (MT1‐MMP), cyclin D1 and c‐myc was immunohistochemically examined. Results: The membranous expression of β‐catenin decreased along with the progression in both BilIN and IPNB lineages. Membranous expression of E‐cadherin was significantly decreased in invasive ICC with BilIN and IPNB in comparison with non‐invasive counterparts. MMP‐7 and MT1‐MMP were commonly expressed in invasive ICC with BilIN (100%), while non‐invasive lesions (BilIN‐1, ‐2, ‐3) and the IPNB lineage were only occasionally and weakly positive for these molecules. Cyclin D1 and c‐myc, target molecules of Wnt signalling, were frequently positive in the IPNB lineage (65 and 54% respectively), and interestingly nuclear β‐catenin staining, reflecting activation of Wnt signalling, was observed only in the IPNB lineage (22%) (P