Free/total prostate-specific antigen ratio--hope and controversies

Prostate-specific antigen (PSA) forms in serum two stable complexes with alpha 1-antichymotrypsin and alpha 2-macroglobulin. PSA complexed to alpha 1-antichymotrypsin is the predominant fraction of PSA. A minor fraction of serum PSA is not associated with proteinase inhibitors. These molecular differences explain the possibility to distinguish free from total PSA (F/T ratio). Free and complexed PSA have different clearances and significant differences between clearance of free PSA after radical prostatectomy (RP) and after open surgery for benign prostatic hyperplasia (BPH) are observed. These differences are explained by the entire removal of prostatic cells responsible for PSA synthesis and storage during RP, i.e. the source of free PSA present in the intravascular pool. The proportion of free PSA is significantly lower in patients with prostate cancer than in patients with BPH. Thus, the mean F/T ratio in prostate cancer is lower than that in BPH and may be helpful to distinguish cancer from BPH especially in the gray zone of total PSA (4-10 ng/ml). The reason why complexed PSA increases in patients with prostate cancer remains unknown but could be explained by the requirement of an enzymatically active PSA released by the malignant prostate tissue to bind to alpha 1-antichymotrypsin. However, a consensual threshold value for L/T ratio is yet to be found to be of widespread clinical use in the differential diagnosis between cancer and BPH.