Previous cross-sectional studies have shown that prostate disease is an important factor affecting PSA levels.2
However, there are other important questions that remain unanswered: (1) the influence of age on changes in PSA in men without prostate disease, (2) the influence of age-related decreases in androgen levels on PSA, and (3) the magnitude of changes in PSA that occur with the development of prostatic disease over time. Knowledge of these factors that affect PSA is important to better use PSA measurements in men with prostate disease.
In this study we have demonstrated that the increasing prevalence of prostate disease that occurs with age is the most important factor affecting PSA levels in men. In men thought to have no evidence of prostate disease (control group), the rate of change in PSA was lower than in subjects with prostate disease and was not significantly different from 0.0 μg/L per year. This is consistent with the concept that PSA is produced by prostatic epithelium and that epithelial cell death and growth are balanced in men without prostate disease.16
This results in relatively little change in prostate size with age17
in these men after puberty. In the control group, one subject had a higher rate of change in PSA than the other control subjects (). Since this group of men was screened by medical history and physical examination only, it is possible that underlying prostatic disease was undetected in this individual. Withdrawal of androgens in men with prostate disease results in a decrease in PSA levels presumably as a result of the androgen dependence of prostatic epithelium.7
In this study, androgen levels do not appear to account for the difference in PSA changes between men with and without prostate disease since the change in androgen levels with age did not differ among the groups.
The magnitude of changes in PSA were significantly different in the three groups of men in this study. In men with BPH, the increase in PSA was gradual up to the time of diagnosis (). This is consistent with the fact that PSA levels increase proportionately with increases in weight of BPH tissue.2
Autopsy studies also suggest a prostate doubling time of 10 years or more in men with BPH.17
The observed differences in rates of change in PSA levels among men with BPH () may reflect the known histologie heterogeneity of BPH. BPH is a heterogeneous disease that is characterized histologically by a variable degree of stromal and epithelial hyperplasia. Thus, men with a predominance of epithelial hyperplasia would be expected to have greater increases in PSA during periods of epithelial proliferation than those men with primarily stromal hyperplasia. It is also possible that some of the subjects with BPH that have PSA changes similar to subjects with cancer may represent individuals with undetected prostate cancer.
We hypothesized that men with prostate cancer would have a greater change in serial PSA levels compared with men who had BPH based on several clinical observations. It has been shown that serum PSA levels increase directly with the volume of prostate cancer.2
Furthermore, on a volume-for-volume basis, prostate cancer is thought to contribute 10 times more to serum PSA concentrations than benign tissue.18
Finally, the doubling time of prostate cancer19
is estimated to be 100 times faster than for benign tissue.17
We found an exponential increase in PSA concentration () in subjects with prostate cancer 5 to 10 years prior to diagnosis, which is consistent with the known increase in PSA that occurs with increasing tumor volume and the kinetics of tumor growth. The observed differences in the rate of PSA change between subjects with prostate cancer ( and ) is consistent with the known variability in the biologic behavior of prostate cancers. Four men with local or regional disease demonstrated minimal change in PSA concentrations with levels remaining below 4.0 μg/L up to the time of diagnosis. Whether men with prostate cancer and minimal PSA change have biologically different tumors than men with greater changes in PSA is currently unknown.
Recent data suggest that measurement of serum PSA concentrations may allow earlier detection of prostate cancer.3,4
However, men with BPH have PSA elevations in 21% to 86% of cases,2,5,6
and men with prostate cancer have normal PSA levels in 21% to 35% of cases.4-6
Therefore, PSA elevations are not specific for prostate cancer, and a normal PSA level does not exclude the presence of cancer. This is reflected in the 78.7% sensitivity and 59.2% specificity using a PSA of 4.0 μg/L or greater as a detection criterion in a recent prostate cancer screening study.4
Using the same criterion for prostate cancer detection we found a 78% sensitivity and a 60% specificity in this case-control study. When we used a prostate cancer detection criterion based on the average rate of change in PSA between three consecutive visits (PSAR2≥0.75 μg/L per year), we found no difference in the sensitivity of prostate cancer detection compared with the use of a PSA of 4.0 μg/L or greater. However, the use of this rate of change criterion in prostate cancer detection significantly increased the ability to differentiate between subjects with BPH and prostate cancer (specificity, 90%). More importantly, the rate of change rule maintained a high degree of specificity at PSA levels both below and above 4.0 μg/L. Thus, serial PSA measurement and assessment of the rate of change in PSA concentrations may allow the physician to differentiate between those men with BPH and prostate cancer. This may identify more accurately the men who will benefit from further diagnostic tests, such as prostatic ultrasound and/or biopsy. Since BPH is more prevalent than prostate cancer, differentiation between men with prostate cancer and BPH would avoid subjecting a large number of men with lower PSA levels to unnecessary workup and the psychological trauma associated with cancer suspicion.
There is an approximate 10% day-to-day variation in PSA levels that may explain some of the variability in PSA measurements observed in subjects with BPH. This variation would mean that an increase in PSA concentrations of 0.75 μg/L would be more likely to represent a true change for men with lower baseline PSA levels compared with those with higher baseline PSA levels. However, despite this PSA variation, we observed a similar specificity for rate of change in cancer detection when PSA values were less than 4.0 μg/L or 4.0 μg/L to 10.0 μg/L (Table 4). This may be due to the use of three consecutive PSA measurements in the determination of rate of change (average rate of change) that “dampens out” some of the variability in repeated measurements.
The changes in PSA levels observed in this case-control study may not be representative of changes that occur in all men being monitored by PSA levels in clinical practice. In this study, PSA measurements were performed on stored serum samples and not on consecutively collected samples over many years as would be the case in clinical practice where the interassay variation might be greater. Greater interassay variation could decrease the specificity of serial PSA measurements and evaluation of the rate of change in PSA in clinical practice. Furthermore, the limited number of subjects in this study requires that a large prospective study verify our results to establish if rate of change in PSA might be of use in clinical practice. However, since subjects with BPH in our study all presumably had symptoms severe enough to warrant surgery, the rate of change in PSA in men with less severe voiding symptoms may be lower. If this proves to be true, the use of rate of change in PSA may be even more specific in an unselected population of patients with BPH.
In summary, the changes that occur in PSA with age and the magnitude of the change appear to be primarily dependent on the development of prostate disease with age. Because the rate of change in PSA appears to be greater in men with prostate cancer compared with men without the disease, and because this change may occur at a time when the disease is not clinically evident, serial measurement of PSA may be a useful clinical marker of prostate cancer. This information is important in designing prospective clinical trials to evaluate prostate cancer screening. The questions of who may benefit from serial measurements of PSA, at what age, and at what intervals will require further study.