What is it?

PSA is a glycoprotein responsible for the hydrolysis of sperm fluid clot[1]. PSA has changed, more than any other marker, the diagnosis of prostate cancer and has allowed to identify the presence of the tumor at a considerably earlier stage.

An increase in PSA is currently the most frequent indication to perform a multi-parametric magnetic resonance imaging of the prostate (mpMRI). The mpMRI is a test that may indicate the need for prostate biopsies in case of doubtful findings or those indicative of cancer.

In addition to PSA, other parameters have been proposed to identify the patients most at risk of neoplasia in this range and the most reliable seems to be the free PSA to total PSA ratio[2]. Opinions differ on the use of PSA density (ratio of serum PSA to prostate volume) or PSA velocity (change in PSA over time, usually over a period of 18 months) [3]. Moreover, the free/total PSA ratio seems to be the most reliable parameter to be used in the presence of a PSA between 4 and 10 ng/ml [4]. The free/total ratio seems to be particularly accurate especially among patients with non voluminous prostates (< 50 g) and who have not had any episodes of acute prostatitis in the past. In general, a ratio greater than 25% indicates a relatively low probability of prostate cancer (< 10%); if the ratio is < 10%, the probability of diagnosing a cancer is high (> 80%); in cases with a free/total PSA ratio between 10% and 25% the risk is obviously intermediate[5].

The PSA blood test is considered a fundamental step in the early diagnosis of prostate cancer. However, it is known that PSA is an organ-specific but not cancer-specific marker, especially for values below 10 ng/ml. In the last decade several studies have significantly improved the specificity of PSA, showing not only that in serum there are different forms of this antigen (free and alpha1-antichymotrypsin conjugated), but also - and most importantly - that the free fraction (fPSA) is itself composed of different PSA isoforms. The main characteristics of these different PSA isoforms ([-5/-7]proPSA, [-4]proPSA and [-2]proPSA)[6]. The prostate health index PHI is the result derived from the combination of the total PSA dosage, the free PSA dosage and the [-2]proPSA isoform dosage, according to the relation: PHI = ([-2]proPSA/fPSA) x √ total PSA.

It was found that in patients with prostatic neoplasia the percentage of proPSA (ratio of the total of all proPSA isoforms to free PSA, %pPSA) is higher. Observational and prospective studies show that the concentration of [-2]proPSA is significantly higher in the blood of patients with prostate cancer and that both the % of [-2]proPSA ([-2]proPSA/fPSA) and the phi index are statistically higher[7-9].

With a total PSA between 2-10 ng/mL (suspicious range and where about 60-70% of negative biopsies are estimated), for patients with non-suspicious rectal examination and age over 50 years, % [-2]proPSA and PHI index are significantly more accurate than PSA and free PSA in identifying prostate neoplasia.

[-2]proPSA, % of [-2]proPSA, and PHI appear to correlate with tumors that will have clinical development and with the aggressiveness of the neoplasm. In fact, it has been demonstrated that patients who have developed clinically significant and/or aggressive forms of neoplasia present high values of [-2]proPSA, % of [-2]proPSA and PHI. This marker is not currently reimbursable by the National Health Service and must be accompanied by a specialized urological application.

When is this exam indicated?

The PSA test is requested at the discretion of the examining urologist. The decision to perform this test should be discussed with the patient, investigating the possible benefits and risks. It is possible to measure PSA for men aged 45-50 years and older who undergo regular andrological check-ups, evaluating this threshold according to concomitant factors such as the occurrence of prostate cancer in the family.

How is it performed?

The examination requires a simple blood test.




[1] Stamey TA, Yang N, Hay AR, McNeal JE, Freiha FS, Redwine E. Prostate-specific antigen as a serum marker for adenocarcinoma of the prostate. N Engl J Med 1987;317:909-16. doi:10.1056/NEJM198710083171501.

[2] Stephan C, Lein M, Jung K, Schnorr D, Loening SA. The influence of prostate volume on the ratio of free and total prostate specific antigen in serum of patients with prostate carcinoma and benign prostatic hyperplasia. Cancer 1997;79:104-9.

[3] Arlen PM, Bianco F, Dahut WL, D'Amico A, Figg WD, Freedland SJ, et al. Prostate Specific Antigen Working Group guidelines on prostate specific antigen doubling time. J Urol 2008;179:2181-6. doi:10.1016/j.juro.2008.01.099.

[4] Huang Y, Li Z-Z, Huang Y-L, Song H-J, Wang Y-J. Value of free/total prostate specific antigen (f/t PSA) ratios for prostate cancer detection in patients with serum total prostate specific antigen between 4 and 10 ng/mL: a meta-analysis. Medicine (Baltimore) 2018;97:e0249. doi:10.1097/MD.00000000010249.

[5] Catalona WJ, Partin AW, Slawin KM, Brawer MK, Flanigan RC, Patel A, et al. Use of prostate-specific antigen free rate to enhance differentiation of prostate cancer from benign prostatic disease: a prospective multicenter clinical trial. JAMA 1998;279:1542-7. doi:10.1001/jama.279.19.1542.

[6] Abrate A, Lughezzani G, Gadda GM, Lista G, Kinzikeeva E, Fossati N, et al. Clinical use of [-2]proPSA (p2PSA) and its derivatives (%p2PSA and prostate health index) for prostate cancer detection: A review of the literature. Korean J Urol 2014. doi:10.4111/kju.2014.55.7.436.

[7] Fossati N, Lazzeri M, Haese A, McNicholas T, De La Taille A, Buffi NM, et al. Clinical performance of the serum [-2]proPSA isoform (p2PSA), and its derivatives %p2PSA and the Prostate Health Index, in men aged <60 years: Results of a European multicenter study. BJU Int 2015. doi:10.1111/bju.12718.

[8] Fossati N, Buffi NM, Haese A, Stephan C, Larcher A, McNicholas T, et al. Preoperative prostate-specific antigen isoform p2PSA and its derivatives, %p2PSA and prostate health index, predict pathologic outcomes in patients undergoing radical prostatectomy with prostate cancer: Results of a European multicenter prospective study. Eur Urol 2015. doi:10.1016/j.eururo.2014.07.034.

[9] Lazzeri M, Abrate A, Lughezzani G, Gadda GM, Freschi M, Mistretta F, et al. Relationship of chronic histological prostate inflammation in biopsy specimens with serum [-2]proPSA isoform (p2PSA), %p2PSA, and prostate health index in men with total prostate specific antigen of 4-10 ng/mL and normal digital rectal examination. Urology 2014. doi:10.1016/j.urology.2013.10.016.

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