Nuclear roundness variance predicts prostate cancer progression, metastasis, and death: A prospective evaluation with up to 25 years of follow-up after radical prostatectomy

BACKGROUND. Nuclear structure is often altered in cancer due to spatial rearrangements of chromatin organization via activation of oncogenes and other chromatin remodeling genes. Therefore, we evaluated the prognostic value of nuclear roundness variance (NRV) for prostate cancer (PCa) progression, metastasis and PCa-specific death free survivals in a cohort of 116 men after radical prostatectomy (RP). METHOD. NRV was calculated for each case using the variance of the nuclear roundness from ∼150 nuclei captured at a magnification of 2,440x for each case in 1992-1993. Nuclear roundness = Radius (circumference)/radius (area) = R/r = P/2π/√A/π NRV data were merged with clinical, pathologic, and follow-up data for all patients in 2009. Cox proportional hazards regression and Kaplan-Meier plots were employed to analyze the data. RESULTS. Median follow-up time after RP for all patients was 19 years (range: 1-25 years, mean: 17 years), with ∼92% (107/116), 71% (82/116), and 47% (55/116) patients having ≥10, 15, and 20 years of follow-up, respectively. NRV was the most significant parameter for prediction of all three outcomes and its concordance-index (C-Index) increased from progression (0.7080) to metastasis (0.7332) to PCa-specific death (0.8090) free survival predictions. Of note, NRV CIndex was significantly higher compared to Gleason Score C-Index for metastasis (0.7332 vs. 0.6046; P = 0.027) and PCa-specific death (0.8090 vs. 0.6336; P = 0.004) free survival predictions. However, the difference between NRV and Gleason Score C-Indexes was not statistically significant for progression free survival prediction (0.7080 vs. 0.6463; P = 0.106). CONCLUSION. NRV is valuable nuclear structural feature that exceeds Gleason score to predict an aggressive phenotype of PCa.