WAF1/p21 protein expression is an independent prognostic indicator in superficial and invasive bladder cancer

The inhibitor of cyclin-dependent kinases WAF(1) gene product p21 is able to arrest mammalian cell cycle by mediating p53 and other factors. The prognostic value and interrelationships between p21 expression and various parameters in bladder cancer have not been fully elucidated. We retrospectively investigated the immunohistochemical expression of p21 protein in consecutive paraffin sections from 131 transitional cell carcinomas (TCCs) and related it to p53 protein expression, clinicopathologic parameters, proliferative fraction, and survival. Positivity was displayed in 45% of cases, among which one fourth was accompanied by p53 accumulation. p21 expression was statistically related to advanced T category. No association was shown between p21 and p53 or proliferation rate. Low grade invasive TCCs tended to be more often p21 positive than high grade invasive TCCs. Most superficial tumors displayed neither p21 nor p53 expression, whereas the combined phenotypes p53/p21+ and p53+/p21- predominated among invasive tumors. P21 labeling index emerged by multivariate analysis as the single independent indicator of shortened overall (P = 0.0294) and disease-free (P = 0.0414) survival in superficial TCCs. Conversely, in invasive tumors, loss of p21 expression was a predictor of shortened disease-free survival (P = 0.0234) and was associated with poor outcome when accompanied by p53 accumulation (P = 0.0033). In conclusion, our results indicate that p21 activation occurs early in tumorigenesis, appears associated with invasiveness, and is capable of cell cycle control in TCCs mostly through p53-dependent pathways. Finally, p21 expression, alone or in combination with p53 and irrespective of other clinicopathologic parameters, plays distinct roles in determining clinical outcome in superficial and invasive tumors, suggesting that urothelial bladder cancer represents two different diseases.