Differential expression of bcl-2 family proteins in bladder carcinomas. Relationship with apoptotic rate and survival

OBJECTIVE: To elucidate the role of various bcl-2 family molecules in the regulation of apoptosis and the progression of urothelial cancer, in relation to standard prognosticators. METHODS: Paraffin-embedded archival tissue from 103 N0M0 consecutive patients with invasive bladder cancer (28 T1, 57 T2, 13 T3 and 5 T4) was immunostained for bcl-2, bax, bcl-XL, bcl-Xs, p53, Ki-67 and with an anti-single stranded DNA monoclonal antibody recognizing the apoptotic cells. Survival analysis was restricted to T2-T4 tumours. Patients were followed-up until death (n = 27) or for a mean (+/- S.D.) follow-up of 37.6 (+/- 17.4) months. Within this period, 39 patients relapsed after a mean (+/- S.D.) period of 13.6 (+/- 12.3) months. RESULTS: Most tumours were immunoreactive for bax (73.1%) and bcl-XL (80.9%) whereas bcl-2 and bcl-XS expression was comparatively less common (44.4 and 28.9%, respectively). The bcl-XL and bcl-XS positivity was related to high grade (P = 0.007) and advanced stage (P = 0.010), respectively. On the contrary, bax and bcl-2 positivity was unrelated to stage or grade. Apoptotic rate was independently influenced only by p53, bcl-2 and proliferation rate. In multivariate analysis of T2-T4 urothelial carcinomas (UC)s, only bax along with T-category and age were the significant predictors of disease-free survival. Increased apoptosis and T-category were also independently related to the overall survival in T2-T4 UCs. CONCLUSIONS: The expression of bcl-2 family members appears to be differentially regulated in association with UC evolution. Most importantly, bax immunostaining offers additional information to that provided by traditional prognosticators, with regard to disease-free survival of T2-T4 UCs.