Cyclin D1 expression in papillary superficial bladder cancer: Its association with other cell cycle-associated proteins, cell proliferation and clinical outcome

Cyclin D1 contributes to regulate G1 progression by forming a complex with different cyclin-dependent kinases. It has oncogenic properties and is frequently overexpressed in several human tumor types. In our study, expression of cyclin D1 and Ki67, a proliferation marker, was evaluated by Immunohistochemistry in human papillary superficial (pTa-pT1) bladder cancers and was correlated with p27(Kip1), p21(waf1) and c-erbB-2 expression, with p53 gene status and protein expression, ploidy and cancer progression. Cyclin D1 expression was neither associated with tumor stage nor with tumor grade but high cyclin D1 expression (greater than or equal to25% positive nuclei) was significantly associated with p53 gene mutation (p = 0.012), low P21(Waf1) (p = 0.015) and high p27(KiP1) (p = 0.016) protein expression. Ki67 expression was not associated with tumor stage but a high proliferation index (greater than or equal to10% positive nuclei) was significantly associated with high tumor grade (p = 0.001) and with DNA aneuploidy (p = 0.005). There was no significant difference in proliferative activity between high and low cyclin D1 expressor tumors. Patients whose tumors showed high expression of cyclin D1 displayed a significantly longer disease-free survival (p < 0.001 by log-rank test). Increased Ki67 expression was significantly associated with shorter disease-free survival (p = 0.003). Both cyclin D1 (p = 0.027; RR = 1.898) and Ki67 (p = 0.047; RR = 1.932) protein expressions were Independent predictors of reduced disease-free survival on a multivariate analysis that also included p27 Kip 1 expression and tumor stage. The simultaneous presence of low cyclin D1, low p27(Kip1) and high Ki67 expression defined a high-risk group of patients who displayed a significantly increased risk of recurrence (p < 0.0001). These results suggest that evaluation of cell cycle-associated markers can help to identify high-risk patients and may affect the management of patients with papillary superficial bladder cancer.