Intraductal tubulopapillary neoplasms of the bile ducts: identity, clinicopathologic characteristics, and differential diagnosis of a distinct entity among intraductal tumors

Abstract

Among the mass-forming preinvasive (tumoral intraepithelial) neoplasms of the biliary tract, intraductal tubulopapillary neoplasms (ITPN-Bs) are increasingly being recognized as a separate cate-gory. By being intramucosal polypoid proliferations of dysplastic/neoplastic cells, they are highly similar to other members of the "intraductal neoplasms (IDNs)" category (namely, intraductal papillary neoplasms [IPNBs], and intraductal oncocytic papillary neoplasms [IOPNs]); however, they are distin-guished by MUC6-expressing nonmucinous cells that lack intestinal differentiation and form striking tubular configuration. Their molecular/genetic profile is also proving to be different with frequent al-terations in cell cycle and chromatin remodeling genes, which are quite uncommon in other IDNs and cholangiocarcinomas. Despite the conceptual overlaps, they are also very different from intracholecys-tic nonmucinous tubular neoplasms (ICTN) of the gallbladder with the latter being associated with Wnt/beta-catenin pathway alterations, and almost never invasive. In contrast, ITPN-Bs are invasive in an estimated 80% of the cases, although even invasive examples often exhibit a protracted course. Invasive carcinomas arising from ITPN-Bs are overall similar to cholangiocarcinomas (including small duct and large duct patterns) but also often have peculiar characteristics such as more nodular-compact (blunt invasion) pattern. Like other IDNs, the ITPN-Bs have also been classified in the past as intraductal-spreading type of cholangiocarcinomas (and they are still regarded as such in some publi-cations). In small biopsies, they are prone to be mistaken as ordinary adenocarcinomas because of their tubular pattern and pancreatobiliary cytology although their relatively monotonous cytology and zones of back-to-back tubule formation can help in their correct identification. Clinical presentation of ITPN-Bs is generally similar to other intraductal neoplasms; however, in the intrahepatic component, they tend to be more nodular than cystic, and their snake-like intraductal growth pattern is often more strik-ing. In the management (diagnosis and treatment) of these tumors that are in essence adenoma-carcinoma sequence, the invasive and noninvasive components ought to be evaluated separately. Mini-mally invasive examples are commonly curable, and even those more extensively invasive may have a surprisingly good prognosis. In summary, biliary ITPNs form a distinct category not only clinicopath-ologically, immunophenotypically, and molecular-wise but regarding their biological behavior as well.