p27(Kip1) expression in normal epithelia, precancerous lesions, and carcinomas of the gallbladder : association with cancer progression and prognosis

p27(Kip1) is a cyclin-dependent kinase inhibitor that negatively regulates cell proliferation. This study was designed to evaluate the roles of p27(Kip1) in gallbladder carcinogenesis and the prognostic value of p27(Kip1) in patients with gallbladder carcinoma. p27(Kip1) expression was examined immunohistochemically in surgically resected specimens of 8 normal epithelia, 8 adenomyomatosis lesions, 6 precancerous adenomas, and 37 carcinomas of the gallbladder. Decreased p27(Kip1) expression (< 50% nuclear staining) was observed in 16 of the 37 (43%) gallbladder carcinomas, but not in any specimen of normal epithelium, adenomyomatosis, or adenoma. The fact that all of the adenomas showed normal p27(Kip1) expression suggests that decreased p27(Kip1) expression is probably not an early event in gallbladder carcinogenesis. Decreased p27(Kip1) expression was significantly associated with less marked tumor cell differentiation (P = .017), lymphatic invasion (P = .046), lymph node metastasis (P = .007), and advanced TNM stage (stage IV vs. stage I, P = .026; stage IV vs. stage II, P = .005). This suggests that down-regulation of p27(Kip1) expression is a late event in gallbladder carcinogenesis, possibly promoting tumor progression and metastasis. Kaplan- Meier curves showed that decreased p27(Kip1) expression was significantly associated with shorter overall survival (P = .001) in patients with gallbladder carcinomas who had undergone radical surgery. Cox's proportional hazards model revealed decreased p27(Kip1) expression to be an independent predictor for death (P = .034; risk ratio, 3.9; 95% confidence interval, 1.1- 13.7). In conclusion, decreased p27(Kip1) expression significantly correlates with tumor progression and predicts poor prognosis in gallbladder carcinomas.