Modifications of PSA testing

1. PSA density

Larger prostate glands will produce more PSA. Therefore, in an attempt to resolve the considerable overlap in serum PSA between patients with BPH and early CAP, the notion of PSA density (PSAD) was introduced:

• PSAD = serum PSA divided by prostatic volume in mL (as estimated by TRUS)

• Traditional recommended cut-off of 0.15

• PSAD was not recommended in patients with a low (<4.0 ng/mL) or high (>20 ng/mL) PSA

• Presumed greatest utility in the 4-20 ng/mL PSA range, in terms of determining the need for prostate biopsies

• In the presence of a normal DRE, PSAD levels of <0.15 were said to be predictive of BPH, while levels of >0.15 were associated with a higher likelihood of a malignant pathology (and therefore proceeding to biopsies)

Unfortunately, PSAD has a number of shortcomings which preclude its widespread clinic use.

• A cut-off of 0.15 has a reasonable specificity (81%) but a disappointingly low sensitivity (52%), which would result in its missing almost half of the cancers

• In issues of decision-making, PSAD does not appear to have any significant advantage over age-specific PSA reference ranges

• The requirement of a TRUS-derived volume considerably elevates expense and discomfort to the patient

• Measurement inaccuracies can also result in wide variations on repeat testing, raising questions about the reproducibility of PSAD

For these above reasons, currently, PSAD is not routinely indicated in prostate cancer screening programmes or in the assessment of patients with suspected CAP.

2. PSA velocity

The assumption that a consistent upward trend in the serum PSA level is more likely to be secondary to a malignant process rather than BPH is the basis for the clinical usefulness of PSA velocity (PSAV).

• PSAV of >0.75 ng/mL per year has been shown correctly to distinguish patients with CAP from BPH with a sensitivity and specificity of 72% and 90%, respectively

• Some authors recommended at least three annual PSA estimations (by the same laboratory) in order to determine a representative PSAV

Overall, PSAV has been shown to be of limited value for a number of reasons.

• A cut-off value of 0.75 ng/mL per year is likely to result in a small but significant proportion of cancers being missed

• A patient with an abnormal age-specific PSA is likely to undergo biopsies at the earliest opportunity rather than wait for a whole year to enable PSAV calculation

• PSAV offers little additional benefit compared to the age-specific reference values, in patients undergoing screening programs for CAP

3. Molecular forms of PSA

The majority (90%) of serum PSA is complexed to 1-antichymotrypsin (PSA-ACT), while the rest is either free or bound to alpha-2-macroglobulin (PSA-AMG). Currently available assays can detect free and PSA-ACT, while immunoassays are as yet unable to detect PSA-AMG. It has been proposed that there is a lower concentration of free PSA in patients with CAP compared to those with BPH, such that there is a lower free : total (f/t) PSA ratio and a higher complexed : total (c/t) PSA ratio in prostate cancer patients.

There is much debate with regard to the role of ratios of molecular forms of PSA in decision-making in patients with PSA values between 4 and 10 ng/mL. The lower the f/t ratio, the better the specificity for CAP detection. Although various cut-off points have been proposed (e.g., 0.1, 0.19, and 0.25), patients with a ratio of <0.19 are usually referred for prostatic biopsy. In addition, there is some evidence to suggest that tumors with a lower f/t ratio are likely to be more aggressive.

Complexed PSA (and c/t PSA ratio) seems to outperform free PSA and f/t PSA ratio in predicting the likelihood of cancer. While this appears promising in increasing the sensitivity and specificity of PSA testing, the cut-off values have not been clearly defined and clinical utility therefore remains ambiguous.

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