Immunohistochemical staining for DNA topoisomerase II-alpha in benign, premalignant, and malignant lesions of the prostate

Abstract

Background: The DNA topoisomerase II-alpha (topo II-alpha)-targeting drug etoposide was recently shown to be an active agent in the combined chemotherapy of hormone-insensitive prostatic carcinoma. Aside from being the molecular target of etoposide, topo II-alpha is also a cell proliferation marker. Much experimental data indicate that cells sensitive to topo II-targeting chemotherapeutic drugs are rapidly proliferating and show elevated topo II expression. There is little information concerning topo II expression in lesions of the prostate.

Methods: Paraffin blocks from cases of invasive prostatic carcinoma, prostatic intraepithelial neoplasia, and prostatic nodular hyperplasia were retrieved from the surgical pathology files at the University of Utah Health Sciences Center. Using a new immunohistochemical stain, specific for the alpha isoform of DNA topo II, enzyme expression was evaluated in 54 prostatic adenocarcinomas, 22 lesions of high-grade prostatic intraepithelial neoplasia (PIN), and 10 cases of benign prostatic nodular hyperplasia. Results were semiquantitated by determining for each case a topo II-alpha index, which represented the percent of positively staining cells.

Results: The average topo II-alpha index for well-differentiated prostatic adenocarcinomas (Gleason scores 2-4) was 1.5 +/- 0.9; for moderately differentiated tumors (Gleason scores 5-7), 3.1 +/- 2.4; and for poorly differentiated tumors (Gleason scores 8-10), 6.7 +/- 5.5. The average topo II-alpha index for all invasive prostatic adenocarcinomas was 4.0 (range, 0-19.0). Benign prostatic nodular hyperplasia had the lowest average topo II-alpha index, of 0.54 (range, 0.2-1.0). The average topo II-alpha index of 2.3 (range, 0-8.6) for high-grade prostatic intraepithelial neoplasia was intermediate between the invasive tumors and benign prostate.

Conclusions: Topo II-alpha expression in carcinoma of the prostate correlates with Gleason score. The carcinomas with the highest expression of enzyme are more poorly differentiated and have the highest Gleason scores. Prostatic nodular hyperplasia shows little expression of topo II-alpha. Prostatic intraepithelial neoplasia has an average topo II-alpha index intermediate between nodular hyperplasia and carcinoma.