Flat-type "biliary intraepithelial
neoplasia (
BilIN)" and papillary-type "intraductal papillary
neoplasm of the bile duct (IPN-B)" are proposed as precursors of invasive, perihilar
intrahepatic cholangiocarcinoma (ICC). Three carcinogenetic pathways are proposed:
BilIN progressing to
tubular adenocarcinoma, and IPN-B progressing to
tubular adenocarcinoma or to
colloid carcinoma.
Carcinogenesis via
BilIN was characterized by
mucin core
protein 2-/
cytokeratin 20-(MUC2-/CK20-) with MUC1 expression, while
carcinogenesis via IPN-B leading to
tubular adenocarcinoma was associated with MUC1 expression or that to
colloid carcinoma with MUC1-negativity. In both the
BilIN and IPNB series, the expression of p21, p53, and
cyclin D1 was upregulated with histological progression. Interestingly, p53 expression was upregulated at the invasive stage of
BilIN, but was low in noninvasive
BilIN, while p53 expression was upregulated in IPN-B1 and reached a plateau in IPN-B2 and invasive ICC. Expression of
p16(INK4a), which was frequent in BilIN1, was decreased in
BilIN-2/3 and invasive
carcinoma. EZH2 expression showed a stepwise increase from
BilIN to invasive
carcinoma. Membranous expression of β-
catenin and
E-cadherin was more markedly decreased in ICC with
BilIN than in ICC with IPNB. Interestingly, disruption of the membranous distribution of β-
catenin and
E-cadherin seems to result in the invasion and
metastasis of
carcinoma cells of
BilIN and IPN-B expressing MMP-7 and
MT1-MMP. Increased expression of
cyclin D1 and c-myc was more frequent in the IPNB lineage than
BilIN lineage, possibly related to the Wnt signaling pathway associated with the nuclear accumulation of β-
catenin. In conclusion,
BilIN and IPN-B progress to invasive ICC through characteristic multistep processes.