Predictive value of topoisomerase II alpha immunostaining in urothelial bladder carcinoma

Aims-The nuclear enzyme DNA topoisomerase II has been shown to be required for chromatin condensation and chromosomal segregation during mitosis; its isoform topo II alpha is linked with active cell proliferation in mammalian cells. The aim of this study was to examine the relation of the expression of topo II alpha to the biological behaviour of conventional urinary bladd er cancer. Methods-Formalin fixed, paraffin wax embedded tissue from 94 specimens of b ladder urothelial cancer were immunohistochemically stained for topo II alp ha. For each case, a topo II alpha index was determined. A similar index ha d been determined for Ki-67, a known cell proliferation marker. Each case h ad also been graded, staged, and evaluated for DNA ploidy as well as for p5 3 and bcl-2 immunoreactivity. Results-Raised topo II alpha expression tin greater than or equal to 10% of malignant nuclei) correlated with two adverse prognosticators-high grade ( p = 0.027) and invasion of the muscularis propria (p = 0.013), but with no other evaluated parameter. By multivariate survival analysis using Cox's pr oportional hazard model, high expression of topo II alpha was found to be p redictive for worse survival (p = 0.0047). Patients' age, tumour stage, and grade were also retained as independent prognostic factors (p = 0.0349, p = 0.00005, and p = 0.0130, respectively). The negative influence of increas ed topo II alpha immunopositivity on patients' survival was also seen in th e subgroup of patients with non-muscle invasive carcinomas (p = 0.0004), in patients with a bcl-2 negative phenotype (p = 0.0330), and in those with l ow Ki-67 indices (p = 0.0341). Conclusions-Because topo II alpha and Ki-67 failed to demonstrate a signifi cant interrelation, they appear to be different molecules that both functio n at separate phases in the complex process of cellular proliferation. The assessment of increased topo II alpha immunoreactivity in specimens from ur othelial carcinomas might help to select patients (particularly among those with superficial tumours) in the worse prognostic categories for new thera peutic strategies.