WAF(1)/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 t o arrest mammalian cell cycle by mediating p53 and other factors. The progn ostic value and interrelationships between p21 expression and various param eters in bladder cancer have not been fully elucidated. We retrospectively investigated the immunohistochemical expression of p21 protein in consecuti ve paraffin sections from 131 transitional cell carcinomas (TCCs) and relat ed it to p53 protein expression, clinicopathologic parameters, proliferativ e fraction, and survival. Positivity was displayed in 45% of cases, among w hich one fourth was accompanied by p53 accumulation. p21 expression was sta tistically related to advanced T category. No association was shown between p21 and p53 or proliferation rate. Low grade invasive TCCs tended to be mo re often p21 positive than high grade invasive TCCs. Most superficial tumor s displayed neither p21 nor p53 expression, whereas the combined phenotypes p53/p21+ and p53+/p21- predominated among invasive tumors. P21 labeling in dex emerged by multivariate analysis as the single independent indicator of shortened overall (P = 0.0294) and disease-free (P = 0.0414) survival in s uperficial TCCs. Conversely, in invasive tumors, loss of p21 expression was a predictor of shortened disease-free survival (P = 0.0234) and was associ ated with poor outcome when accompanied by p53 accumulation (P = 0.0033). I n conclusion, our results indicate that p21 activation occurs early in tumo rigenesis, appears associated with invasiveness, and is capable of cell cyc le control in TCCs mostly through p53-dependent pathways. Finally, p21 expr ession, alone or in combination with p53 and irrespective of other clinicop athologic parameters, plays distinct roles in determining clinical outcome in superficial and invasive tumors, suggesting that urothelial bladder canc er represents two different diseases.