Prostate-Specific Antigen Screening Guidelines

What is PSA?

Prostate-specific antigen (PSA) is a serum protease inhibitor produced only by prostate tissue following androgen stimulation. PSA typically forms a complex with α1-antichymotrypsin and plays a role in semen liquefaction. Serum PSA values usually correlate with prostate volume. Several conditions elevate PSA including benign prostatic hypertrophy (BPH), prostate cancer, prostate infection, prostate manipulation, and ejaculation. Androgen deprivation or castration, certain medications including 5α-reductase inhibitors, and prostate excision or ablation decrease PSA.

Testing for PSA began in the late 1980s in the United States and has dramatically increased the incidence of this disease. In 2013, over 80% of the prostate cancers identified by PSA were organ-confined. Researchers have developed assays for various forms of PSA and have constructed statistical techniques to improve the detection of prostate cancer including the measurement of PSA velocity, PSA density, and percent free PSA. Although several isoforms of PSA have been identified and utilized, specifically free and complex PSA, they have not improved the performance of PSA as a screening test. PSA measurements vary depending upon the laboratory and assay used, thus limiting the precision of any individual PSA test. Mildly elevated PSA values should prompt repeat serum PSA testing before patients proceed to prostate biopsy, as many men will have normal PSA values on subsequent serum studies.

Draisma et al. estimate that PSA testing has advanced the date of diagnosis by approximately 12.3 years for men aged 55 years and by 6 years for men aged 75 years. Unfortunately, there is no definitive cut point that separates men harboring clinically significant prostate cancer from those that do not. Men younger than age 50 usually have a PSA <2.5 ng/mL while men older than age 65 frequently have values as high as 6.5 ng/mL or greater. Not all prostate cancers produce PSA, hence, there is no value below which prostate cancer can be definitively excluded.

Early detection and treatment are common goals for the management of most cancers. Over a century ago, Hugh Hampton Young advocated screening for prostate cancer using a digital rectal examination (DRE) and treatment with radical surgery. During the past quarter century, PSA testing has become the gold standard for the early detection of this disease. Unfortunately, early detection is a necessary but not sufficient condition to confirm the validity of a screening test.

What is the natural history of prostate cancer?

The natural history of prostate cancer is extraordinarily variable, ranging from indolent to highly aggressive. Autopsy studies have revealed a high prevalence of prostate cancer in men of all ages, including men under age 50. Estimates suggest that 14–17% of men in their 60s and 31–83% of men in their 70s have pathologic evidence of prostate cancer. Why most of these tumors remain dormant continues to be a mystery. The Prostate Cancer Prevention Trial (PCPT) followed 18,882 men for 7 years and demonstrated that the prevalence of prostate cancer ranged from 18.4% to 24.4% in the general population. These rates are three to four times higher than previously estimated. Most cancers detected in this study were low-grade Gleason score 3 + 3 tumors and would likely have never been detected in the absence of PSA testing.

Several studies have described the natural history of prostate cancer. In 1998 and 2005 Albertsen et al. reported the long-term outcomes of a competing risk analysis of 767 men diagnosed between 1971 and 1984 who were managed expectantly for clinically localized disease. In these studies, only 4–7% of men with Gleason 2–4 tumors had progression leading to death within 20 years of diagnosis while men with Gleason 5 and 6 tumors progressed at a rate of 6–11 and 18–30%, respectively. Men with low-grade prostate cancers are less likely to benefit from early detection because of the slow progression of disease and the relatively high death rate from competing medical conditions over time. Men with Gleason grade 7 and higher cancers harbor aggressive cancers that are much more likely to metastasize during their lifetime. These men have a much higher potential to benefit from prostate cancer screening if they receive an effective treatment.

The Gleason scoring system, derived by analyzing prostate glandular architecture under low-power magnification, has undergone several changes since it was introduced. The original system identified nine unique growth patterns that were subsequently stratified into the five Gleason patterns. Over the past decade, some features have been transferred from pattern 3 to pattern 4, and patterns 1 and 2 have been essentially eliminated. This reclassification has resulted in an upgrading of many samples such that tumors once classified as Gleason score 5 or less are now graded as Gleason 6, and previous Gleason 6 tumors are now often classified as Gleason 7 tumors. These revisions have altered our understanding of the natural history of this disease, resulting in dramatically improved survival of contemporary patients when compared to the historical series. This reclassification bias is often described as the Will Rogers effect and has been documented to occur in prostate cancer. The recently published 18-year follow-up of the Scandinavian Prostate Cancer Group 4 study provides relatively contemporary data on the natural history of this disease.

Prostate cancer mortality has decreased during the past two decades in both the United States and the United Kingdom. The cause of this decline is controversial. In the United States great emphasis has been placed on screening and early treatment in contrast to the United Kingdom where screening is relatively uncommon and patients are treated only when disease becomes clinically apparent. Both environmental and genetic factors appear to have had an impact. Therefore, the observed decline in prostate cancer mortality appears to be a combination of earlier detection and treatment, more effective therapies, alterations in exposure to risk factors, and changes in the attribution of cause of death.

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