The most common finding leading to further investigation for possible prostate cancer is an elevated PSA level.2-5,17-19 PSA, a glycoprotein, is an endogenous serine protease and a member of the human kallikrein family. PSA is secreted primarily by the prostatic epithelial cells and epithelial lining of the periurethral glands. The half-life has been determined to be between 2.2 and 3.2 days. Mechanisms responsible for the detectability of PSA in the serum include its production from the prostatic epithelial cells, changes in the prostatic glandular architecture interfering with secretion into the ducts, changes in basement membrane permeability and alterations in metabolism. Specific factors that can affect PSA measurement in the serum, other than the presence of prostate cancer, include benign prostatic hyperplasia, prostatitis, urinary retention, finasteride, cystoscopy, prostatic needle biopsy, transurethral resection of the prostate, ejaculation and vigorous prostatic massage.20 The management in these situations varies depending on the etiology, but one recommendation is to repeat the PSA determination in a few days to 6 weeks to obtain an accurate measurement of the baseline value.20 A routine DRE can elevate the serum concentration of PSA in individual patients; however, the elevations were not considered to be clinically significant when the median values were evaluated.21
Therefore, there are many factors other than prostate cancer that can increase serum levels of PSA. PSA has also been shown to correlate with age as well as gland volume.22 Formulas have been developed to estimate the serum PSA levels using age and prostate volume as variables.22 Based upon a cohort of men without clinical evidence of prostate cancer, these formulas will allow one to estimate the serum PSA level changes per decade of age and 10 g increments in gland volume. Even in the presence of prostate cancer, non-cancerous prostatic tissue can significantly affect the serum level of PSA, which decreases the usefulness of PSA in terms of estimating tumor volume or pathologic stage of disease for individual patients, especially in patients with glands larger than 30 cm3.23 Furthermore, PSA values can have significant variability with serial measurements, and this can result from assay and biologic variability.24-28 The exact metabolism of PSA is not well characterized, and the mechanisms involved with this process may explain the observed biologic variability that is not explained by the presence of prostate cancer.
PSA, however, has gained popularity and is commonly utilized in screening because it is an objective measurement, less expensive than TRUS and because it can detect more prostate cancers than DRE or TRUS.17'18'29'30 In addition, cancers detected by PSA are more likely to be organ confined compared with those detected by DRE alone.3,5,30-32 Currently, 70-80% of prostate cancers are organ confined versus 20-30% in the pre-PSA era.31,32 Furthermore, it has been observed that PSA has improved the detection of organ-confined disease over DRE by 31-78% and that PSA offers approximately a 5.5-year detection lead time over DRE.6,8,30 PSA, however should not be used alone in screening, as this has been shown to result in missing 18-28% of prostate cancer that would have been detected if PSA using the 4 ng/ml cut-off had been used in conjunction with a DRE.30,33
There is controversy as to what may be the optimal PSA cut-off to direct further investigations for the detection of prostate cancer. Approximately 20% of men diagnosed with prostate cancer have a serum PSA level of less than 4 ng/ml.34 It has been shown35 that 22% of men with normal DRE and PSA values between 2.6 and 4.0 ng/ml had cancer on biopsy, with 81% of the cancers being organ confined. Similarly, another study36 found that 24.5% of men with a PSA value between 2.5 and 4.0 ng/ml had prostate cancer; 70% of the cancers were deemed clinically significant. Although decreasing the cut-off point may result in the detection of more prostate cancers with a higher proportion of organ-confined disease, the true biological significance of these tumors is not known. It has been suggested that the optimal screening interval is every 2 years for men with an initial PSA value of less than 2 ng/ml and a normal DRE, whereas for men with a PSA greater than 2 ng/ml and a normal DRE, annual screening seems appropriate.37,38 This screening strategy has been supported by the findings that there is a 1% risk of detecting prostate cancer within 4 years, if the PSA is less than 2.5 ng/ml, and a 27-36% risk of the serum PSA value progressing to greater than 4 ng/ml within 4 years, if the current PSA level is between 2.1 and 4.0 ng/ml.38 New screening strategies in Europe have been implemented whereby a biopsy is performed if the serum PSA concentration is ^3.0 ng/ml, and no further screening tests are performed if the PSA is less than 3.0 ng/ml.39 For this screening strategy, the rate of prostate cancer detection (4.7%) was no different from that for the previous screening regimen (4.8%) in which men underwent PSA, DRE, TRUS and subsequent biopsy, if the PSA value was greater than 4.0 ng/ml or if they had abnormal results for DRE or TRUS.39 The 4 ng/ml threshold has been challenged in several studies in terms of its lower sensitivity in detecting clinically important prostate cancers in younger men and its reduced specificity in detecting clinically important prostate cancers in older men.34-36,40 There have been significant improvements (25-90%) in the detection of organ-confined prostate cancer over the past 30 years.41,42
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