The effect of p21^waf1/iip1 expression and tumor progression in bladder cancer john p. stein, david a. ginsberg

Introduction: We have shown that p53 alterations, as assessed by nuclear accumulation of p53 (p53-altered) is an important predictor of bladder cancer progression. The action of p53 on cell cycle regulation is mediated through the expression of p21^WAF1/CIP1. Wildtype p53 induces p21 expression and cell cycle arrest; p53 alterations result in loss of p21 expression, leading to uncontrolled cell growth. The purpose of this study was to determine the relationship between p21^WAAH/CIP1 expression and tumor progression in bladder cancer. Methods: Tumor specimens were obtained from 242 patients who underwent radical cystectomy for invasive transitional cell carcinoma of the bladder. All cases had been previously evaluated for p53 alterations. Nuclear p21 status was determined in these specimens by immunohistochemical (IHC) techniques using a monoclonal antibody specific to p21. The p21 status was then analyzed in relation to the probability of recurrence, overall survival, and to the p53 status. Results: p21 nuclear reactivity was detected in 156 of 242 (64%) of these bladder tumors. Tumors that maintained p21-expression (p21-positive) demonstrated a significantly decreased probability of recurrence (p=0.0001), and increased overall survival (p=0.0001) compared to bladder tumors that lost p21 expression (p21-negative). The 5-year recurrence for p21-positive bladder tumors compared to p21-negative tumors was 30% verse 76% respectively (p=0.001). Similar results were obtained when p21 status was evaluated in relation to the probability of overall survival. In a multivariable analysis stratified according to grade, stage, lymph node status, and p53 status, p21 expression was an independent predictor of recurrence and survival in these bladder tumors (p=0.0017, p=0.006). When Combining the p53 and p21 status of these bladder tumors, patients with p53aliered/p21 -negative tumors demonstrated a significantly higher rate of recurrence and worse overall survival compared to p53-wildlype/p21-posilive tumors (p=0.001). Patients with either a p53-wjldlype/p21-negalive or p53-altered/p21-positive bladder tumor demonstrated an intermediate rate of recurrence and survival. Conclusion: In patients with transitional cell carcinoma of the bladder, loss of p21-expression as detected by IHC methods predicts a significantly increased risk of tumor recurrence and death, independent of tumor grade and stage. Patients with bladder tumors that lost p21-expression are at highest risk of disease progression and should be considered for adjuvant therapy.