Dysplasia and carcinoma of the gallbladder: pathological evaluation, sampling, differential diagnosis and clinical implications

Pathological evaluation of gallbladder neoplasia remains a challenge. A significant proportion of cases presents as clinically and grossly inapparent lesions, and grossing protocols are not well established. Among epithelial alterations, pseudo-pyloric gland metaplasia is ubiquitous and of no apparent consequence, whereas goblet cell metaplasia and a foveolar change in surface cells require closer attention. Low-grade dysplasia is difficult to objectively define and appears to be clinically inconsequential by itself; however, extra sampling is required to exclude the possibility of accompanying more significant lesions. For high-grade dysplasia ('high-grade BilIN', also known as 'carcinoma in situ'), a complete sampling is necessary to rule out invasion. Designating in-situ or minimally invasive carcinomas limited to muscularis or above as early gallbladder carcinoma (EGBC) helps to alleviate the major geographical differences (West/East) in the criteria for 'invasiveness' to assign a case to pTis or pT1. Total sampling is crucial in proper diagnosis of such cases. A subset of invasive GBCs (5-10%) arise from the intracholecystic neoplasm (ICN, 'adenoma-carcinoma sequence') category. Approximately two-thirds of ICNs have invasive carcinoma. However, this propensity differs by subtype. True 'pyloric gland adenomas' (> 1 cm) are uncommon and scarcely associated with invasive carcinoma. A distinct subtype of ICN composed of tubular, non-mucinous MUC6⁺ glands [intracholecystic tubular non-mucinous neoplasm (ICTN)] forms a localised pedunculated polyp. Although it is morphologically complex and high-grade, it appears to be invasion-resistant. Some of the invasive carcinoma types in the gallbladder have been better characterised recently with adenosquamous, neuroendocrine, poorly cohesive and mucinous carcinomas often being more advanced and aggressive.