Reduced p21(WAF1/CIP1) expression is an early event in gallbladder carcinogenesis and is of prognostic significance for patients with carcinomas of the gallbladder

The molecular basis underlying the development and progression of gallbladd er carcinoma (GBC) remains poorly understood. To evaluate the roles of p21( WAF1/CIP1) and p53 in gallbladder carcinogenesis and to assess their progno stic significance for patients with GBC, we used immunohistochemistry to ex amine the expression of p21(WAF1/CIP1) and p53 protein in a series of surgi cally resected specimens, including normal epithelia, precancerous lesions adenoma, and dysplasia, and carcinomas of the gallbladder. Reduced p21(WAF1 /CIP1) expression was frequently observed in carcinomas (18 of 37 lesions; 49%), and even in precancerous lesions adenomas (3 of 7; 43%) and dysplasia s (5 of 5; 100%). p53 overexpression was detected in 43% of the adenomas, 6 0% of the dysplasias and 57% of the carcinomas. There was an inverse relati onship between p21(WAF1/CIP1) and p53 expression in GBCs (P =.01). Survival analysis indicated that reduced p21(WAF1/CIP1) expression was significantl y associated with shortened disease-free and overall survival (P=.04 and .0 3, respectively) for patients with stages II to IV GBCs. These observations suggest that reduced p21(WAF1/CIP1) expression and p53 overexpression cont ribute to GBC from an early stage and that determination of p21(WAF1/CIP1) expression in surgically resected specimens would add prognostic informatio n to conventional pathologic examinations for patients with advanced-stage GBC. HUM PATHOL 32: 771-777. (C) 2001 by W.B. Saunders Company.