Incidence of Apoptosis, Cell Proliferation and bcl-2 Expression in Transitional Cell Carcinoma of the Bladder: Association with Tumor Progression

Abstract

Purpose Apoptosis is the distinctive form of programmed cell death that complements cell proliferation in maintaining normal tissue homeostasis. The significance of constitutive apoptosis in the development and progression of transitional cell carcinoma of the bladder has yet to be investigated. In the present study, the incidence of baseline apoptosis and the expression of 2 genes regulating this molecular process, bcl-2 and TGF-beta 1, as well as the level of cell proliferation, were examined by an intensive immunohistochemical analysis in normal bladder and bladder cancer specimens. Materials and Methods Apoptosis was detected by in situ end-labeling of fragmented DNA using the terminal deoxynucleotidyl transferase reaction in 45 paraffin-embedded primary transitional cell carcinoma specimens, 9 metastatic lymph nodes and 5 normal bladder specimens. The proliferation status of the tumor cells among the same bladder cancer specimens was evaluated by using a monoclonal antibody that recognizes the proliferation-associated nuclear antigen, Ki-67. Results The apoptotic index of normal transitional epithelium (0.06 percent) was significantly lower than that of all grades of transitional bladder carcinoma (p = 0.006). Although the apoptotic index of transitional carcinomas increased with increasing grade, this difference failed to achieve statistical significance, ranging from 0.54 plus/minus .23 percent in grade I to 1.24 plus/minus .77 percent in grade III. The proliferative index, as determined by Ki-67 positivity, also increased with increasing grades of tumor (12.8 plus/minus 8.4 percent in grade I to 22.6 plus/minus 15.2 percent in grade III) and was significantly greater than in normal urothelium (0.64 plus/minus 0.52 percent, p = 0.003). Bcl-2 expression was significantly lower in the normal transitional epithelium and in the well and moderately differentiated tumors (grades I-II) when compared with poorly differentiated (grade III) tumors (p = 0.004). The incidence of bcl-2 expression in all bladder specimens analyzed was uniformly low (less than 5.3 percent). Transforming growth factor-beta 1 expression was not detected in any of the normal bladder specimens, primary tumors, or metastatic lymph nodes analyzed. Conclusions The present findings revealed that no statistically significant correlation exists between the frequency of apoptosis and the pathological stage of bladder tumors, while they clearly demonstrate a strong direct correlation between an increased rate of cell proliferation and bladder cancer progression.