Evaluation of DNA topoisomerase II alpha expression provides independent prognostic information in non-Hodgkin's lymphomas

Aims: In view of the dual role that DNA topoisomerase IIa (TopoIIa) plays a s a cell proliferation marker and as a possible indicator of chemosensitivi ty, we investigated its expression in non-Hodgkin's lymphomas (NHL) in rela tion to conventional clinicopathological parameters, cell proliferation (as defined by Ki67 immunoreactivity), response to therapy and patient outcome . Methods and results: Formalin-fixed paraffin-embedded tissues from 153 pati ents with NHL were immunohistochemically stained for TopoII alpha. Patients were followed up until death (n = 63) or for an average of 68 months (medi an 64 months, n = 90), The percentage of TopoII alpha positive cells (TopoI I alpha LI) increased with grade (P < 0.001), extranodal location (P = 0.05 ) and Ki67 LI (P = 0.01, r = 0.673), In most cases (58%), Ki67 LI exceeded TopoII<alpha> LI (TopoII alpha /Ki67 < 1), especially within the indolent g roup information in relation to post-relapse and overall survival, Furtherm ore, TopoII<alpha>/Ki67 ratio appears to play a key role in the identificat ion of patients prone to early relapse. (P < 0.001). TopoII<alpha>LI, Ki67L I and TopoII alpha /Ki67 ratio were all adversely related to overall surviv al in univariate analysis, though their significance was not maintained aft er adjustment for grade. In multivariate analysis high TopoII alpha /Ki67 r atio and high TopoII alpha LI independently predicted shortened overall and post-relapse survival, respectively. Most importantly, low TopoII alpha /K i67 ratio was the only independent predictor of diminished disease-free sur vival. However, there was no relationship between TopoII alpha expression a nd response. Conclusions: Our results suggest that evaluation of TopoII alpha expression and TopoII alpha /Ki67 ratio as cell proliferation markers provides indepe ndent prognostic information in relation to post-relapse and overall surviv al. Furthermore, TopoII alpha /Ki67 ratio appears to play a key rolse in th e identification of patients prone to early relapse.