This study was designed to test the hypothesis that
cyclin D1 overexpression is involved in the multistep process of gallbladder
carcinogenesis and can be used to predict poor prognosis for patients with gallbladder
carcinoma (GBC).
Cyclin D1 expression was examined immunohistochemically in a series of specimens, including 8 normal epithelia, 8 benign
adenomyoma lesions, 6 precancerous
adenomas, and 37
carcinomas of the gallbladder. Four of the 6 (67%)
adenomas and 15 of the 37 (41%)
adenocarcinomas demonstrated
cyclin D1 overexpression (>5% nuclear staining), whereas all normal epithelia and
adenomyoma lesions were negative for
cyclin D1. Kaplan-Meier curves showed that
cyclin D1 overexpression was significantly related to decreased overall survival (P < 0.05) in patients with GBCs. The Cox proportional hazards model identified
cyclin D1 overexpression as an independent prognostic marker for death (P = 0.024; risk ratio, 4.2; 95% confidence interval, 1.2-14.7). To test whether
cyclin D1 overexpression is a critical event in
gallbladder neoplasms,
cyclin-dependent kinase inhibitor p27Kip1 was introduced to ascertain how
cyclin D1 affects clinical outcomes. Subsequently,
neoplasms were divided into three groups on the basis of the combination of
cyclin D1 expression and p27Kip1 status, which had been determined previously. Group 1 showed no abnormality in either
cyclin D1 or p27Kip1 expression. Group 2 showed aberrant expression of one of the two
proteins, whereas group 3 showed concurrent abnormalities in both
proteins. Results indicated that overall survival was greatest in group 1, followed by a significant decrease in group 2 and a more precipitous decrease in group 3. In conclusion,
cyclin D1 overexpression is an early event in gallbladder
carcinogenesis and independently predicts decreased survival for patients with GBC.