Pathologic classification and staging of biliary tract cancer

Abstract

Pathologic classification and theranostic evaluation of biliary tract cancers are rapidly evolving. Intrahepatic peripheral small-duct type cholangiocarcinomas that recapitulate hepatocyte-accociated cholangioles have been recognized as separate, and recently shown to have targetable molecular alterations such as isocitrate dehydrogenase (IDH) and fibroblast growth factor receptor (FGFR), whereas the adenocarcinomas arising from large ducts (including most perihilar cancers) are closer to pancreatic ductal adenocarcinomas both morphologically, behaviorally, and molecularly. Distinct relatives of these two groups (such as cholangioblastic and tubulocytsic cholangiocarcinomas of the former, and sarcomatoid, poorly cohesive cell, mucinous and others of the latter group) are now better characterized. Our understanding of etiopathogenesis of biliary tract cancers (BTC) is also improving: In addition to stones, parasites, sclerosing cholangitis and other inflammatory factors, the role of anatomic variations like pancreatobiliary maljunction (and related choledochal cysts) and low union are being appreciated. The analysis of these risk groups also led to better characterization of preinvasive/precancerous neoplasms. Intraductal and intracholecystic neoplasms are tumoral forms of intraepithelial neoplasia (i.e., represent adenoma carcinoma sequence) which often lead to ordinary invasive cancers but may display different biology and behavior. This broad category is highly heterogenous and several distinct types are now recognized, such as oncocytic, tubulopapillary in bile ducts, and tubular/nonmucinous in gallbladder all with highly different clinicopathologic associations, behavior, and field risk. The preoperative differential of BTC from pseudotumoral cholangitides such as primary sclerosing cholangitis, IgG4-related and idiopathic, remain a major challenge. At the same time, BTCs are not limited to adenocarcinomas and their precursors; biliary system can be afflicted by a wide range of neoplasms from neuroendocrine to secondary tumors to lymphomas and others. It is important to recognize these distinct categories so that proper management protocols can be employed. Staging of BTCs have various shortcomings due to anatomic complexity, histologic variability, evolving staging protocols, relatively limited experience, and intercontinental differences in pathologic criteria, all contributing to vastly different opinions which will need to be addressed in further studies and consensus. Due to their relative rarity, and anatomic complexity of the region (leading to challenges) for radiologists, as well as the fact that they require sophisticated surgery, biliary tract tumors used to come to pathologists’ attention less commonly in the past. Thus, evolution of knowledge on the histopathologic, molecular, and biologic characteristics of biliary tract cancers (BTC) have been more sluggish compared to other organ cancers. In fact, many of the concepts and terminology now used for BTC have been extrapolated from the pancreas (Adsay, 2015; Albores-Saavedra et al., 2015; Adsay et al., 2016; Nakanuma and Sudo, 2017; Adsay and Basturk, 2024; Basturk and Adsay, 2024). Because of their topographical and phylogenetic relationship as well as their histopathologic and behavioral similarities, BTCs are also often regarded under the broad category of “pancreato-biliary cancers” along with the pancreatic ductal adenocarcinomas. While there are indeed many commonalities between the cancers arising from these different sites, at the same time, not surprisingly, there are also substantial differences between them that are being appreciated increasingly (Adsay and Basturk, 2024; Schirmacher et al., 2019; Ethun et al., 2017). As a result, more refined classification and staging are developing for these organs. In the ensuing text, an overview of these is provided.