Suggested strategies to improve PSA accuracy. Approximately 70% of men with an elevated serum PSA level do not have cancer. To decrease the number of unnecessary biopsies, experts have suggested several strategies:
- using DRE with PSA
- calculating a ratio of free PSA (unbound to protein) or complexed PSA (bound to protein) to total PSA
- measuring PSA density, which incorporates the volume of the prostate gland and is subject to observer variability in prostate volume measurement
- recording PSA velocity, which is the annual rate of change in PSA level and requires 3 or more measurements.
Revise the cutpoint? The cutpoint of 4 ng/mL has been deemed too high by some clinicians. A recent report of men enrolled in a large prostate cancer prevention trial found that among the 9459 men receiving placebo, 2950 had a PSA level of 4 ng/mL or less and had normal prostates on DRE (LOE: 1b).22 All 2950 underwent a prostate biopsy; 449 (15.2%) were positive for cancer. Nearly 30% of those had a PSA level of 2 ng/mL or less.
Approximately 25% of tumors in men referred for biopsy because of abnormal PSA or DRE findings are thought to be discovered by chance due to the biopsy procedure and the high prevalence of disease (LOE: 2c).23 Furthermore, a recent study indicates that annual PSA fluctuation is substantial; 45% of men who initially had a value of 4 ng/mL or greater, subsequently had a normal level (LOE: 2b).24 Isolated abnormal levels should be confirmed before referral for biopsy.
Identifying clinically relevant cancers
The continued controversy around PSA screening relates to the potential over-diagnosis of localized prostate cancers that are not likely to become clinically significant. The ideal screening test would predictably identify cancers likely to progress.
Several computer simulations have estimated the amount of over-detection of prostate cancer. The National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) registry data demonstrated that the proportion of prostate cancer found through PSA testing that otherwise would not have been diagnosed in the patient’s lifetime was 29% for white men and 44% for black men (LOE: 2c).25
An Italian study found that the proportional excess of cancers detected by screening over those that would have been expected in the absence of screening is greater than 50% (LOE: 2c).26
Finally, a model based on results from the European randomized study of prostate cancer screening estimated that a screening program with a 4-year interval from age 55 to 67 has an over-detection rate of 48% (cancers that would not have been diagnosed in the absence of screening) (LOE: 2c).27 Additionally, the authors determined that such screening might advance prostate cancer diagnosis by at least 10 years. Previous estimates of diagnosis lead time have been in the 5- to 7-year range (LOE: 2b).28 These findings indicate that screening intervals of 2 to 4 years are unlikely to cause a loss of sensitivity.
Spread of tumor
Spread of the tumor beyond the prostate capsule is a poor prognostic sign.29 Unfortunately, this occurrence is often not known until surgery, and the result usually is an “up-staging” between clinical diagnosis and pathological diagnosis. Nevertheless, most cancers (86%) diagnosed between 1992 and 1999 were localized to the prostate.6 Because these cancers have not spread beyond the prostate at the time of diagnosis, they are more likely to be curable. They are also more likely to represent tumors that may grow so slowly that the host will die of something other than prostate cancer.
Gleason score is another predictor of cancers destined to become clinically relevant (FIGURE 1). A Gleason score of 7 or greater denotes moderate to poor cellular differentiation and indicates a greater potential for progression than lower Gleason values.29 A recent long-term follow-up report on a cohort of men with localized cancer treated conservatively demonstrated that men with low-grade tumors (Gleason score 2–4) have a minimal risk of dying from prostate cancer after 20 years, while men with high-grade tumors (Gleason score of 8–10) have high probability of prostate cancer death within 10 years of diagnosis (LOE: 2b).30 Ecological31 and clinical studies32 indicate that a substantial proportion of PSA-detected cancers are moderately differentiated. This is especially true in a first round of screening; as in the European randomized study of screening, where 36% of cancers were Gleason score 7 or higher (LOE: 1b).33
Calculating the Gleason score