Thomas A. Stamey

Recent information on the relationship of serum prostate-specific antigen (PSA) to prostate cancer and new reports on death rates in men warrant a reassessment of how we diagnose and treat prostate cancer. We now know for the first time that the annual death rate from prostate cancer in men ≥65 years of age is only 226 per 100 000 men. At least 40 000 of 100 000 men over age 65 (40%) have invasive prostate cancer as judged by examination of prostates in 3- to 4-mm step-sections. Thus, only 1 of every 177 men 65 years of age or older (226 in 40 000) with invasive prostate cancer dies annually from his cancer. Serum PSA between 2 and 10 μg/L is used almost universally as an indication to biopsy the prostate. When 10–20 biopsies are commonly taken, it is not surprising that ∼40% of men are biopsy-positive for prostate cancer. Despite this reliance on serum PSA as an indication for biopsy, data at Stanford show no clinically useful relationship between preoperative serum PSA (in the range 2–10 mg/L) and the volume of Gleason grade 4/5 cancer or the volume of Gleason grades 3, 2, and 1 cancer, nor can we show any useful relationship of such preoperative PSA concentrations (2–10 μg/L) to biochemical PSA failure rates after radical prostatectomy. We urgently need a better serum marker for prostate cancer. Because PSA biochemical failure rates after radical prostatectomy are directly proportional to the amount of Gleason grade 4/5 cancer in the prostate, a serum marker of Gleason grade 4/5 carcinoma could be ideal.

BACKGROUND The authors have shown that the primary determinants of prostate carcinoma progression are tumor volume and the percent of the tumor comprised of Gleason Grade 4/5 cells. In the current study the authors evaluated six different techniques for the morphometric measurements of prostate carcinoma volume. METHODS A computer‐assisted image analysis (NIH Image, developed and maintained by the National Institutes of Health, Bethesda, MD) was used to analyze all 108 step‐sectioned prostate specimens obtained between January 1 and December 31, 1997. The authors used the Stanford technique of 0.3‐cm step‐sections, measuring the volume of the tumor at both 0.3‐cm and 0.6‐cm intervals. The other 4 methods included the authors' previous method based on an earlier image program, the ellipsoidal method (π ÷ 6 × width × height × length), an estimation of the square area of the largest tumor, and the maximum tumor dimension (MTD). RESULTS The authors first checked the accuracy of NIH Image analysis by measuring 24 circles of widely different sizes. The mean coefficient of variation was 1.7% and the correlation between the mean circle areas measured by the NIH Image software and true circle area essentially was perfect (correlation coefficient [r] = 1 and r² = 0.999; P < 0.0001). In comparison with the authors' original computer image program using 0.3‐cm step‐sections measured by a different observer, r² with the NIH Image analysis was 0.93. Using NIH Image only, the 0.6‐cm step‐section method missed measurable cancers in 16.7% of 108 radical prostatectomies in comparison with the 0.3‐cm step‐method. The mean tumor volume with the 0.6‐cm section method (P < 0.0001) and the ellipsoidal method (P < 0.05) were significantly higher than with the 0.3‐cm section method. r² from linear regressions using the 0.3‐cm step section method as the standard versus the ellipsoidal method was 0.594, and was 0.89 versus the 0.6‐cm step‐section method, 0.652 versus the square area estimation, and 0.527 versus the MTD method. CONCLUSIONS The results of the current study support NIH Image as a powerful software program for the morphometric measurement of prostate carcinoma volume. Pathologic processing with 0.3‐cm section slices was found to be more accurate for tumor volume than the 0.6‐cm section slices. The ellipsoidal method, the square area of the largest tumor, and the MTD all were found to be inferior to computer‐assisted image analysis measurements. In certain clinical situations in which only estimates of tumor volume are required, the square area of the largest tumor appears to be the best choice (r² 0.652). Cancer 2000;89:1056–64. © 2000 American Cancer Society.

The dilemma of prostate cancer is that only a small portion of men with untreated carcinoma will die from it, yet the prevalence of this disease is so high that the annual mortality is still second only to lung cancer. Thus, there is a great need to find better ways to distinguish patients who have clinically innocuous cancers from those who have significant disease that can be eradicated by radical prostatectomy or other treatment and those for whom therapy is destined to fail. The dilemma has been sharpened by important advances in diagnostic techniques.