Neoplastic precursors (dysplasia, intraepithelial neoplasia) of the gallbladder and biliary tract: Terminology, classification, pathologic diagnosis, and clinical significance

In the past decade, there have been significant developments in the terminology, classification and understanding of the precursor neoplastic lesions of the gallbladder and bile ducts. Many analogies with their pancreatic counterparts have been identified. Multiple cell lineages (biliary, intestinal, foveolar, pyloric, and oncocytic) are recognized, with differential molecular/genetic fingerprints. Two distinct types have been characterized: (1) Non-tumour forming ("flat") type dysplasia, now also recognized under the heading of biliary intraepithelial neoplasia (BilIN). As in other organs, low-grade BilINs seem to be negligible. High-grade BilINs of the bile ducts seldom are encountered outside the setting of adenocarcinoma and thus also typically clinically irrelevant, perhaps except when they involve the margins. In the gallbladder, low-grade dysplasia is believed to be clinically inconsequential. Cases with gallbladder high-grade dysplasia (also known as "carcinoma in situ") also are often cured, although some may have recurrence/metastasis attributable to missed invasion or field-defect/field-effect emphasizing the crucial nature of total sampling. (2) Polypoid/papillary preinvasive neoplasms (tumoural intraepithelial neoplasia; TINs; i.e., adenoma-carcinoma sequence), for which, in the bile ducts, two distinct entities have been characterized, intraductal papillary neoplasms, and intraductal tubular/tubulopapillary neoplasms. In the gallbladder, all TINs have been proposed to be unified under the umbrella of intracholecystic papillary-tubular neoplasms. Non-invasive TINs are often curable if invasion is excluded definitively, although some exhibit recurrence/metastasis (due to missed invasion and/or field phenomenon). Invasive carcinomas arising in TINs appear to have less aggressive behaviour than ordinary invasive carcinomas. It is important to appreciate the clinicopathologic characteristics of these precursor lesions, both for management purposes and as invaluable models of carcinogenesis.