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Prostate Specific Antigen Free

The biggest problem with using PSA as a screening test for early cancer is that the serum concentration of patients with benign prostatic hypertrophy (BPH) significantly overlaps patients with early cancer. It is difficult to select an unambiguous decision level for detecting early cancer. PSA values between 4 and 10 ng/mL are especially difficult to interpret.

Several recent studies have demonstrated that the specificity of PSA for cancer can be enhanced by measuring the ratio of free to complexed PSA in the serum. Because PSA is a proteolytic enzyme, it becomes bound to plasma protease inhibitors. Some PSA remains free, but most PSA is complexed with alpha -1 antichymotrypsin (PSA-ACT). A very small fraction of PSA is complexed to other protease inhibitors.

Molecular Form Molecular Weight (kDa) Percent of Total PSA
Free PSA 30 10 - 40
PSA –ACT 100 60 - 90
PSA – alpha 1 proteinase inhibitor 190 & 80 <1
PSA alpha 2 macroglobulin 800 <0.1


The two major forms, recognized by commercial immunoassay kits, are PSA-ACT and free PSA.  Free and complexed PSA differ from each other in the number of epitopes available for antibody binding. Free PSA has five exposed epitopes, three of which become masked after ACT binding. Free PSA is measured by an immunoassay that selectively recognizes the epitopes masked by ACT, while total PSA is measured by an assay that detects the epitopes on PSA that are not covered by ACT. The ratio of free to total PSA is calculated by dividing free PSA by total PSA and multiplying the result by 100.

This ratio is most useful in distinguishing prostate cancer from BPH in men with total PSA values between 4.1 and 10.0 ng/mL who had a normal DRE. The following cancer risks were recently published by Catalona et al. (JAMA 1998;279:1542) using Hybritech Tandem assays.

Free PSA Ratio Probability of Cancer
0 - 10 56%
10 - 15 28%
15 - 20 20%
20 - 25 16%
>25 8%


Cancer is more likely to produce bound PSA. Therefore, the ratio of free to total PSA is used to determine how much PSA exists as bound PSA. The relative risk of prostate cancer is as low as 8% if the free PSA ratio is over 25% and as high as 56% if the ratio is <10%. In Caucasian men with total PSA between 4 & 10 ng/mL, 95% of those found to have cancer by biopsy have a free to total ratio of <24% and 90% have a ratio of <22%.  Based on these results, some urologists recommend prostate biopsy for men with ratios <25%. Men with higher ratios can be followed with annual examinations. Using a single decision point of 25% free PSA as an indication for biopsy will detect 95% of cancers and avoid 25% of unnecessary biopsies. Free PSA ratio can also be used to counsel patients about their individual cancer risk. Patients can then decide to have a biopsy or wait and reevaluate PSA in 6 months.

Specimen requirement is one SST tube of blood.

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