Similar to the
pancreatic carcinoma sequence model,
cholangiocarcinoma reportedly follows a stepwise
carcinogenesis process via the precursor lesion biliary intraepithelial
neoplasia (
BilIN). Given that autophagy plays an important role in the occurrence and development of
carcinomas, we examined the involvement of autophagy in multistep cholangiocarcinogenesis. Thirty-six patients with hepatolithiasis associated with
BilIN and/or
cholangiocarcinoma, 7 with
intrahepatic cholangiocarcinoma, 8 with intraductal papillary
neoplasm of the bile duct (IPNB), and 6 with control livers were surveyed. Their lesions were categorized as follows: invasive
carcinoma (n = 16), IPNB (n = 8), BIlN-3 (n = 16),
BilIN-1/2 (n = 40), nonneoplastic large bile duct (n = 55), and peribiliary gland (n = 55). We examined the immunohistochemical expression of
autophagy-related proteins,
microtubule-associated proteins light chain 3β (LC3),
beclin-1, and p62/sequestosome-1 (p62), as well as tumor suppressor gene product p53. The extent of expression was semiquantitatively assessed. The status of KRAS mutations at
codons 12 and 13 was examined in selected cases of
BilIN-1/2. The expression of LC3 (cytoplasmic),
beclin-1 (cytoplasmic), and p62 (cytoplasmic and nuclear) was significantly higher in
BilIN-1/2, BilIN-3, IPNB, and invasive
carcinoma than in large bile duct and peribiliary gland (P < .01). KRAS mutation was detected in 6 (40%) of 15
BilIN-1/2 lesions, and there was no correlation between the status of KRAS mutation and the expression of
autophagy-related proteins. In conclusion, this study is the first to disclose that the expression of
autophagy-related proteins, LC3,
beclin-1, and p62, was increased at an early stage of multistep cholangiocarcinogenesis in hepatolithiasis. Autophagy, probably deregulated autophagy, may be related to the occurrence and development of
cholangiocarcinoma.