TOTAL PSA, FREE PSA/TOTAL PSA RATIO, AND MOLECULAR PSA DETECTION IN PROSTATE CANCER: WHICH IS CLINICALLY EFFECTIVE AND WHEN? D. BASSO, P. FOGAR, M. G. PIVA, F. NAVAGLIA, S. MAZZA, T. PRAYER-GALETTI, E. CASTELLUCCI, F. PAGANO, AND M. PLEBANI ABSTRACT Objectives. To ascertain when the serum determination of the free prostate-specific antigen (PSA)/total PSA (fPSA/tPSA) ratio is clinically useful, and whether the identification of PSA or prostate-specific membrane antigen (PSM) mRNA in circulating cells has diagnostic advantages over the determination of their protein product. Methods. fPSA, tPSA, and the fPSA/tPSA ratio were determined in the sera of 50 men with benign nonprostatic urologic diseases (EPD), 112 patients with prostate cancer (PCa), and 218 with benign prostatic hyperplasia (BPH). mRNA was extracted from the circulating mononuclear cells of 13 EPD samples, 25 PCa samples, and 38 BPH samples. PSA and PSM mRNA signals were identified in these samples by means of reverse transcriptase-polymerase chain reaction. Results. Overall, at a fixed specificity of 95%, the sensitivity of tPSA was 19% and that of the fPSA/tPSA ratio was 40% in distinguishing PCa from BPH. The fPSA/tPSA ratio allowed the discrimination of PCa from BPH with satisfactory sensitivity and specificity when considering patients less than 60 years of age (100% and 95%, respectively). PSA and PSM mRNA were positive in 1 and 7 of 13 EPD samples, 6 and 13 of 25 PCa samples, and 6 and 17 of 38 BPH samples. The Gleason score did not correlate with tPSA, the fPSA/tPSA ratio, PSA mRNA, or PSM mRNA. Conclusions. The serum determination of the fPSA/tPSA ratio is an excellent index of PCa for subjects younger than 60 years of age; the clinical utility of PSA mRNA identification in circulating cells needs to be validated by large follow-up studies, and the analysis of PSM mRNA seems to be of no clinical interest. UROLOGY 55: 710–715, 2000. © 2000, Elsevier Science Inc. A lthough the pathophysiology of prostate can- cer (PCa) remains largely unknown, current knowledge suggests that the development of this neoplastic phenotype depends on a complex inter- play between genetic, endocrine, and environmen- tal factors. If, however, tumor development is de- tected in an early phase, surgery can be curative. Although early PCa is usually asymptomatic, it can be detected by the measurement of serum prostate- specific antigen (PSA), now widely used for screen- ing. 1,2 The recent decline in death from PCa regis- tered in the United States may be due to the widespread introduction of PSA screening in the late 1980s, which resulted in the diagnosis of a higher number of cases of localized PCa. 2 In recent years, two further diagnostic tools for the diagnosis of PCa and establishing its prognosis have been described. One is the serum determina- tion of free PSA (fPSA) and the ratio between fPSA and total PSA (tPSA), which enhances the diagnos- tic sensitivity and specificity of tPSA. 3–7 The sec- ond is the identification of PSA mRNA and pros- tate-specific membrane antigen (PSM) mRNA in circulating cells, which have been suggested as sensitive markers or indicators in detecting the presence of micrometastases. 8 –16 Circulating PSA results from two main molecular forms: one is the free enzyme, and the other is complexed with en- zyme inhibitors, mainly alpha 1 -antichymotrypsin and alpha 2 -macroglobulin. 17,18 In patients with PCa, circulating PSA is mainly represented by en- From the Departments of Laboratory Medicine and Urology, Uni- versity-Hospital of Padova, Padova, Italy Reprint requests: Mario Plebani, M.D., Department of Labora- tory Medicine, University-Hospital of Padova, Via Giustiniani 2, Padova 35128, Italy Submitted: July 26, 1999, accepted (with revisions): November 22, 1999 ADULT UROLOGY © 2000, ELSEVIER SCIENCE INC. 0090-4295/00/$20.00 710 ALL RIGHTS RESERVED PII S0090-4295(99)00596-8