How Best to Use the PSA-Age Relationship
As discussed elsewhere, age-specific reference ranges are a result of the increasing mean PSA values and the increasing PSA variance (standard deviation) in successively older cohorts of men. Mean PSA values are related to the population studied and may also be related to the time during which a particular study was conducted (Table 2). The variability in PSA values as men age suggests that caution should be exercised when considering the clinical implications of age-specific reference ranges. The upper limits are established by two methods: (1) extending mean PSA levels upward two standard deviations to establish a 95% confidence limit, or (2) extending the median PSA value to the 95th percentile. However, the distribution of PSA values in any age group is not a normal distribution: absolute 0.0 ng/mL is always the lowest value.
The degree of variation in PSA values increases with each older age cohort. That is, men in their 70s exhibit greater variability in PSA values than men in their 60s, who, in turn, exhibit greater variability than men in their 50s, with men in their 40s demonstrating the least variability. In fact, Bangma and associates have shown that the coefficient of correlation weakens as older ages are considered: r = .32 for all men but only .16 for men 50 years or more. Table 3 presents the interquartile ranges for 10-year age cohorts, and the increasing variance on either side of the median--especially between the 50th and 75th percentile--is apparent.
If the variance in PSA values is related to the "normal" pattern of prostatic function, it would stand to reason that men in their 40s, when benign prostatic enlargement and prostate cancer are uncommon, would show the least variance in PSA values. With increasing age and greater variability in circulating androgen levels, various endogenous prostatic insults, and other physiologic factors that may be environmentally influenced, some prostates will be stimulated to grow--whether that growth is benign or malignant--whereas others will not. Thus, greater variability is found among PSA levels of successively older men (Figure 1).
Age-specific reference ranges will necessarily be less sensitive than the standard of 4.0 ng/ml among older men for two major reasons: (1) poorly differentiated cancers in small-volume prostates will not produce ("leak") sufficient PSA to cross even the current threshold of 4.0 ng/mL let alone a higher threshold; and (2) the variance in PSA values is greater among older men. The men with large-volume prostates bias the age-specific reference ranges for men with normal-volume prostates in every age group.
Ten-year age groupings for age-specific reference ranges may simply be too inclusive (and less sensitive than 4.0 ng/mL) for clinical applicability at this time. Five-year age-specific reference ranges, or even an annual reference point (at the 95th percentile), may provide a sound criterion for clinical interpretation. Based on more than 77,000 individual PSA test results, previously analyzed in 10-year age groups, Table 4 presents the increasingly more specific reference points by 10-, 5-, and 1-year age groupings. For each year of age after the age of 45, more than 1,000 PSA test results provided the basis for computation.
Albeit subject to the same shortcomings of 10-year age-specific reference ranges, an annual reference point may help interpret PSA test result.
Oesterling[25,34,35] has eloquently stated the potential advantages of using age-adjusted PSA standards: (1) to increase the test's sensitivity among younger men, detecting more curable, organ-confined tumors earlier; and (2) to increase the test's specificity among older men, avoiding many unnecessary biopsies. Surely, determining the most effective way of using PSA testing to decide whether or not to perform a biopsy is a complex problem. Attempts to find an easy solution to this problem should be tempered by the dictum of H. L. Mencken: "For every complex problem there is a simple solution, and it is wrong."
The issue of age-specific reference ranges has emerged because of the lack of sufficient evidence that screening and early detection of prostate cancer with PSA testing improves survival. If the objective is to find curable organ-confined prostate cancers, notwithstanding the debate over labels of "significant" or "insignificant" tumors, sensitivity must be the prime criterion; ie, one needs to perform more biopsies so as not to miss any clinically significant, curable, organ-confined tumors. Studies have shown that the majority of PSA-detected cancers are significant.
If, on the other hand, the objectives are to increase specificity, to attempt to limit cost-effectively the number of biopsies performed in older men and to minimize the psychological consequences of false-positive results, age-specific reference ranges make sense. Some curable cancers would be missed in older men with this approach, however.
The assumption here is that with the increasing incidence of cancer as men age, one standard cut-off value for PSA (4.0 ng/mL) would tip the scales toward detecting more insignificant tumors. The trade-off between sensitivity and specificity should be the clue that the test is imperfect as it stands. Although there is no easy answer, studies of the molecular forms of PSA and the ratio of free-to- total PSA may render this debate moot by permitting a pre-biopsy determination of benign or malignant disease. However, the single best ratio of free-total PSA will likely be as controversial as any current PSA index.
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