PROSTATE-SPECIFIC ANTIGEN (PSA)

Prostate-specific antigen (PSA) is a 32-kilodalton (kD) serine kinase that functions to liquify the ejaculate. It is technically referred to as "human kallekrin 2." Several conditions such as prostatitis, benign prostatic hyperplasia, prostate cancer, and ejaculation (mild increase) can increase serum PSA levels. Although it has been detected in other tissue, such as the breast, salivary gland, and in other tumors, it is overwhelmingly more specific for the prostate and has more organ specificity than any other existing tumor marker.

Serum PSA is measured in nanogram (ng) quantities and is very sensitive for detecting prostate cancer. After radical surgery, serum measurements should nadir to undetectable levels. The reappearance of measurable PSA is the earliest sign of therapeutic failure. While very low postoperative measurable levels may represent minimal residual benign glands, values of 0.4 ng/ml are almost always associated with disease recurrence. The first approved indication for serum PSA was for the monitoring of patients after radical prostatectomy. Levels between 4.0 and 10.0 ng/ml carry a 16 to 25 percent risk of detecting prostate cancer, while levels above 10.0 ng/ml are associated with a 60 percent risk of prostate cancer.

Although PSA is considered to be the most effective tumor marker in human oncology, its role in screening strategies for prostate cancer has not been completely established. Since its tumor specificity is low, many patients will demonstrate negative findings on a transrectal needle biopsy prompted by an elevated PSA. Earlier concerns, however, that PSA detects clinically insignificant tumors have been dispelled by multiple surgical pathology studies. It has also been repeatedly demonstrated that serum PSA and a digital rectal examination (DRE) detect more prostate cancer than either modality alone, yet prospective randomized data demonstrating a decrease in the prostate cancer deaths due to screening strategies is unavailable. Several prospective trials are in progress, but are several years from maturity. Recent trends in tumor registry data demonstrate a 12 to 16 percent decrease in prostate cancer deaths over the past five years. Most experts agree that there is some role for PSA evaluation in patients, and efforts are underway to establish reasonable guidelines for the use of this marker.

PSA evaluations should generally start at age fifty in most subjects but at age forty in African Americans and those patients with a family history of the disease. The appropriate upper age to abandon screening is problematic, yet recent data suggests that men over the age of sixty-five with an initial PSA value below one have a very small chance of ever developing prostate cancer.

Several attempts have been made to improve the test characteristics of serum PSA. PSA density accounts for the amount of PSA produced proportional to the volume of the prostate gland. A large gland with benign hyperplasia may make more PSA than a smaller gland. A smaller gland with a higher PSA may be suggestive of prostate cancer. An optimal cutoff of 0.15 has been suggested. The volume of the prostate gland cannot be precisely determined with transrectal ultrasound, making practical implementation of this concept difficult.

Age-adjusted PSA (lowering the normal value in patients younger than sixty and raising it in older patients) has been proposed to increase sensitivity in detection in younger patients. In the case of older patients this can lead to more cases of missing significant tumors, however. Some authors suggest lowering the value for young patients and keeping it at 4.0 ng/ml for older patients.

PSA levels tend to increase in men over time. The rate of increase (velocity) may provide some indication of the development of benign or malignant disease. Investigators have noticed that an increase greater than 0.75 ng/year may suggest a significant cancer risk. While this holds up with retrospective evaluations of archival serum samples, it is more difficult to calculate in patients obtaining values over short time intervals or getting evaluated by different assays over time, which may be more variable.

PSA exists as free and complex forms in the blood. Patients with prostate cancer appear to have lower amounts of free PSA in their serum, and those with benign conditions have a higher proportion of their total PSA in the free form. If the percentage of free PSA of the total is greater than 25 percent, the chance for detecting prostate cancer for overall values of 4 to 10 ng/ml is only 5 to 7 percent rather that the usual 16 to 25 percent. Since the determination of a high free-PSA fraction lowers, but does not eliminate, the risk of prostate cancer, it is often used for decisions regarding repeat biopsies rather than the initial evaluation.

S. Bruce Malkowicz

(see also: Prostate Cancer; Screening; Secondary Prevention )

Bibliography

Carter, H. B.; Pearson, J. D.; Metter, E. J. et al. (1992). "Longitudinal Evaluation of Prostate Specific Antigen Levels in Men with and without Prostate Cancer." Journal of the American Medical Association 267:2215–2217.

Catalona, W. J.; Smith, D. S.; Wolfert, R. L. et al. (1995). "Evaluation of Percentage of Free Serum Prostate-Specific Antigen to Improve Specificity of Prostate Cancer Screening." Journal of the American Medical Association 274:1214–1219.

Morgan, T. O.; Jacobsen, S. J.; McCarthy, W. F. et al. (1996). "Age-Specific Reference Ranges for Serum Prostate-Specific Antigen in Black Men." New England Journal of Medicine 335:304–310.

Oesterling, J. E.; Jacobsen, S. J.; Chute, C. G. et al. (1993). "Serum Prostate-Specific Antigen in a Community-Based Population of Healthy Men. Establishment of Age-Specific Reference Ranges." Journal of the American Medical Association 270:860–864.

Polascik, T. J.; Oesterling, J. E.; and Partin, A. W. (1999). "Prostate Specific Antigen: A Decade of Discovery— What We Have Learned and Where We Are Going." Journal of Urology 162:293–306.