Cell cycle proteins and apoptosis in urothelial tumors of urinary bladder and relationship with prognosis

SUMMARYIn the present study, the expression paterns of cell cycle regulation proteins and apoptosis related proteins were investigated in urothelial carcinoma and the prognostic value of these markers for tumor progression was evaluated.Eighty patients with urothelial neoplasm of the urinary bladder were included in the study. Histologic grading and staging were assessed according to 1998 WHO-ISUP and 2004 TNM classification. Fourteen (% 17,5) cases were classified as Ta, 46 (%57,5) as T1 and 20 (%25) as T2. Tumors were classified as papillary neoplasm of low malignant potential (PUNLMP) in 14 (%17,5), low-grade papillary carcinoma in 38 (% 47,5) and high-grade papillary carcinoma in 28 (%35).We examined cyclin D1, cyclin E, p21, p27 and survivin expressions immunohistochemically in transurethral resection of 80 cases with urothelial neoplasms. The expressions of the markers were correlated with tumor stage, grade and clinical outcome.Low cyclin D1 expression was significantly associated with advanced pathological stage (p=0,01). p21 expression was significantly lower in T2 tumors compared with T1 tumors (p=0,01). Low cyclin D1 expression was significantly associated with low expression p21 in T2 tumors (p=0,004). However no significant correlation was found between cyclin D1, p21 and other parameters. Our findings suggest that in urothelial carcinoma, loss of both cyclin D1 and p21 expressions are related to tumor progression and furthermore evaluation of cyclin D1 and p21 may help to idendify high-risk patients with urothelial carcinoma. Patients with tumors displaying high p27 expression had fewer recurrence (p=0,001). There was no significant correlation between p27 and tumor grade, stage. These findings support that p27 may represent an independent prognostic factor in urothelial carcinoma. Cyclin E immunoreactivity was not associated with any pathologic characteristics and clinical outcomes. Advancing tumor grade (p=0,01) and stage (p=0,01) were accompained by an increase in survivin expression. These findings support a role of survivin in urothelial carcinoma progression.In conclusion, our findings support a role for cyclin D1, p21 and survivin as strong markers for predicting the biological potential of bladder tumors and identifying those tumors most likely to progress to muscle invasive disease. Furthermore, the expression of p27 protein may be a useful prognostic marker to evaluate the recurrences of urothelial carcinoma.