Intraductal neoplasms of the bile duct. A new challenge to biliary tract tumor pathology.

Invasive biliary tract carcinomas are usually tubular adenocaricnomas with abundant desmoplastic reactions and frequent ductal and periductal invasion at the time of the diagnosis. Recently, several intraductal neoplasms of the bile duct, particularly at a pre-invasive stage, have been recognized. They include intraductal papillary neoplasm of the bile duct (IPNB), biliary intraepithelial neoplasm (BilIN), and others, such as intraductal tubulopapillary neoplasm (ITPN) of the bile duct. IPNBs are grossly visible predominantly intraductal-growing papillary neoplasms covered by well-differentiated neoplastic epithelium with fine fibrovascular cores in the dilated bile ducts. Regarding their similarities to intraductal papillary mucinous neoplasm of the pancreas (IPMN) of main pancreatic duct type, some IPNBs resemble IPMN ("pancreatic type"), while others are only somewhat similar or variably different from IPMN ("non-pancreatic type"). Some IPNBs develop via a common oncogenic signaling pathway, and others, particularly those of intestinal type, frequently show GNAS mutations, as in IPMN. BilINs are a microscopically recognizable flat or micropapillary pre-invasive neoplasm and are presumed to precede conventional nodular-sclerosing cholangiocarcinomas. ITPN of the bile duct is a rare neoplasm composed of densely packed tubular glands. These three types of neoplasms are not infrequently associated with invasive adenocarcinoma. Pre-invasive intraglandular neoplasms of the peribiliary glands, another epithelial system in the biliary tree, have been also reported. Further characterization of these intraductal and intraglandular neoplasms of the bile duct is needed to overcome devastating invasive biliary tract carcinoma.