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.