Clinical history: 76 year old woman with cholelithiasis and gallstone pancreatitis. Sections of gallbladder are shown.
What is the most probable diagnosis?
Gallbladder carcinoma is the most common adenocarcinoma of the extrahepatic biliary tract. It occurs more commonly in females at a mean age of 65. Gallbladder carcinoma is more common in Latin America and in Native Americans. Risk factors for carcinoma include chronic inflammation, cholelithiasis (especially cholesterol stones), porcelain gallbladder, GI polyposis syndromes and long-term Salmonella infection. Only 0.2% of people with gallstones develop carcinoma, however, of those with a porcelain gallbladder, 10% will develop carcinoma. Many carcinomas present with symptoms of cholecystitis and are identified incidentally upon cholecystectomy.
Grossly, many carcinomas are small and difficult to identify, thus sampling of the cystic duct margin is of utmost importance to ensure that incidental tumoral tissue is not left in the patient. The fundus is the most common site for gallbladder adenocarcinoma (60%) followed by the body (30%) and the neck (10%). Most gallbladder carcinomas have a diffuse, infiltrative, fibrous growth pattern which may be difficult to distinguish from features secondary to chronic inflammation. Only 30% have polypoid growth.
Histologically, the carcinomas are composed of well-formed, irregularly shaped glands haphazardly placed within a desmoplastic stroma. The epithelial lining is composed of cuboidal cells with pink, granular or pale cytoplasm and usually containing intracytoplasmic mucin. Frequently the cells show a high nuclear grade, however, one variant is composed of atrophic-looking glands that are lined by cells that at initial examination appear benign but the presence of nuclear grooves indicates their malignant nature. Gallbladder adenocarcinomas are graded by the degree of glandular differentiation with >95% glands being well-differentiated, 40-94% being moderately differentiated and 5-39% being poorly differentiated.
The immunohistochemical profile of adenocarcinomas of the gallbladder shows positivity for CK7, CEA, MUC1, MUC5AC, CA 19-9 and occasionally CK20. Some of these markers may only be focally positive. Overexpression of p53 is found in nearly 50% of cases.
The differential diagnosis includes reactive atypia in the context of inflammation, Rokitansky-Aschoff sinuses and Luschka’s ducts. Inflammation-induced atypia should retain lobular arrangement of glands in the periductal tissue, no infiltrative clusters or single cells and should not show areas of necrosis. Rokitansky-Aschoff sinuses may pose a diagnostic difficulty because they often penetrate deep into the gallbladder wall but they generally have a flask-like shape and have an undulating contour in contrast to a carcinoma which is composed of scattered, small, irregular glandular structures and may show cytological atypia. The Luschka duct’s should be continuous with the gallbladder lumen and, again, should show only reactive atypia.