By Prof. Federico Guercini / January 30, 2026
Edited by Prof. F. Guercini
The immediate answer to this question is unfortunately NO.
Having PSA values within the normal range does not automatically exclude the possibility of having prostate cancer. Of course, having PSA values within normal limits is certainly a positive sign and significantly reduces the likelihood of clinically relevant prostate cancer. In most cases, this allows one to be reassured. That said, it is important to know a few things—without causing unnecessary alarm:
WHAT IS PSA
PSA is a risk indicator, not a definitive diagnostic test.
PSA (Prostate-Specific Antigen) is produced almost exclusively by the prostate, in particular by the epithelial cells of the gland, and specifically by both healthy cells and cells involved in inflammatory or cancerous processes.
Therefore, PSA levels may also increase for benign reasons (inflammation, prostate enlargement, infections, recent sexual intercourse).
📌 What is PSA for?
- It is part of seminal fluid
- It helps make semen more fluid, facilitating sperm motility
📌 Why do we find PSA in the blood?
Normally, only small amounts of PSA pass into the bloodstream. PSA levels can increase when the prostate:
- is enlarged (benign prostatic hyperplasia)
- is inflamed or infected (prostatitis)
- is stimulated (recent ejaculation, urological examination, transrectal ultrasound)
- or in the presence of cancer
👉An important reassuring point: PSA is not produced only by cancer, but mainly by the normal prostate. For this reason, an abnormal value does not automatically mean cancer, while a normal value is a good sign—albeit with the limitations discussed below.
PSA values commonly used
The three most commonly used PSA values are:
- total PSA
- free PSA
- the total PSA/free PSA ratio
Total PSA
This is the sum of all PSA present in the blood and includes:
- free PSA (not bound to proteins)
- PSA bound to blood proteins
👉 This is usually the first value considered in screening.
Free PSA
This is the fraction of PSA that circulates “freely,” meaning it is not bound to proteins.
The higher the free PSA relative to total PSA, the more reassuring the test.
Why is free PSA considered “good”?
PSA is an enzyme (a protease). In the blood it can:
- bind to proteins (especially α1-antichymotrypsin), or
- remain free
PSA produced by altered cells binds to proteins because its structure allows the protein to attach.
Free PSA, on the other hand, is generally inactive or partially inactive, or it is a structurally modified form (cleaved, folded differently).
These modifications mean that: the binding site is no longer accessible,
therefore plasma proteins cannot attach.
In the presence of high total PSA:
- 👉 High free PSA (≥ 25%)
➜ more often associated with benign conditions
➜ generally reassuring - 👉 Low free PSA (< 10–18%)
➜ increases suspicion of prostate cancer
➜ requires further evaluation
HISTORY OF PSA
The use of PSA (prostate-specific antigen) as a marker for prostate cancer is the result of a gradual process, not a single, sudden discovery.
Brief timeline:
- 1970s – PSA is first isolated and characterized as a protein produced by the prostate; mainly a laboratory discovery.
- Early–mid 1980s – It becomes clear that PSA blood levels are often elevated in men with prostate carcinoma, and the first clinical studies begin.
- 1986 – PSA is officially approved to monitor the course of prostate cancer (e.g., after surgery or radiotherapy).
- 1987 – Stamey TA, Yang N, Hay AR, et al.: Prostate-Specific Antigen as a Serum Marker for Adenocarcinoma of the Prostate (New England Journal of Medicine).
The authors conclude that PSA was elevated in almost all patients with newly diagnosed, untreated prostate cancer (122 out of 127). Moreover, after radical prostatectomy for prostate cancer, PSA levels regularly decreased until becoming undetectable.
At this point, having a tumor marker for prostate cancer was an exciting reality for us urologists…
Unfortunately, this enthusiasm was soon tempered:
- 1987 – The same authors, in the same article, concluded that not all prostate cancers have markedly elevated PSA levels and that PSA value distributions may overlap between benign and malignant diseases, especially in early stages.
- 2004 – Ian M. Thompson, Donna K. Pauler, et al., in Prevalence of prostate cancer among men with a prostate-specific antigen level ≤ 4.0 ng/ml, concluded that preoperative biopsies not infrequently revealed prostate cancer—including high-grade cancers—in patients with PSA values of 4.0 ng/ml or less.
Prevalence of Prostate Cancer According to PSA Levels (≤ 4.0 ng/mL)
| PSA Level (ng/mL) | Number of Men Undergoing Biopsy | Prevalence of Prostate Cancer (%) | Prevalence of High-Grade Cancer* (%) |
| ≤ 0.5 | 486 | 6.6 | 0.8 |
| 0.6 – 1.0 | 791 | 10.1 | 1.0 |
| 1.1 – 2.0 | 998 | 17.0 | 2.0 |
| 2.1 – 3.0 | 482 | 23.9 | 4.6 |
| 3.1 – 4.0 | 183 | 26.9 | 6.7 |
| Total | 2,950 | 15.2 | 2.3 |
* High-grade cancer: Gleason score ≥ 7.
- 2025 – Confirmation in the EAU Guidelines of the results reported by Thompson (2004)
| PSA range (ng/mL) | Probability of prostate cancer (%) | Probability of cancer with Gleason > 7 (%) |
| 0.0 – 0.5 | 6.6% | 0.8% |
| 0.6 – 1.0 | 10.1% | 1.0% |
| 1.1 – 2.0 | 17.0% | 2.0% |
| 2.1 – 3.0 | 23.9% | 4.6% |
| 3.1 – 4.0 | 26.9% | 6.7% |
What does this table mean?
- Even very low PSA values (e.g., ≤ 0.5 ng/mL) may be associated with cancer, albeit with low probability.
- Risk progressively increases as PSA rises, even within values traditionally considered normal (≤ 4 ng/mL).
- The possibility of a tumor with Gleason > 7 (highly aggressive) increases, although it remains relatively low in the lower PSA ranges.
👉 Important note: This table is taken from the EAU Guidelines for localized prostate cancer, which specify that there is no PSA threshold that completely excludes carcinoma and that risk is a continuum dependent on PSA value.
Lowering the “normal” PSA threshold
Based on all these findings, many of the most advanced centers have narrowed the so-called normal PSA range, lowering the upper limit of normal from 4 to 3 ng/mL. This change is based on solid scientific evidence, not on an arbitrary decision.
Many scientific centers lowered the “normal” PSA cutoff from 4 to 3 ng/mL because a non-negligible proportion of clinically significant prostate cancers is already present below 4 ng/mL. Large prospective studies have shown that prostate cancer risk is not dichotomous but increases continuously with PSA, without a clear threshold below which risk is zero.
In particular, in the 3–4 ng/mL range, a significant prevalence of tumors has been observed, including some high-grade cancers. Lowering the threshold to 3 ng/mL aims to increase screening sensitivity, detecting potentially relevant tumors at an earlier stage, when treatment options are less invasive and more effective.
This approach has proven especially useful in younger men with smaller prostate volumes, in whom a PSA of 3 ng/mL may be biologically more suspicious than in older men with large prostates.
FINAL CONSIDERATIONS
At the conclusion of this article, can we say that a PSA value within the normal range is useless?
Absolutely not.
PSA testing remains a formidable tool for prostate cancer screening for us urologists—but with rules that are now well defined compared to the past:
- In younger individuals (>50 years), PSA values approaching 3 ng/mL must be monitored very carefully.
- In all patients, total PSA should not increase by more than 0.75 ng/mL per year.
- The rate of increase (PSA velocity) must always be considered.
- The total PSA/free PSA ratio should always be greater than 0.18.
- Additional information comes from PSA density, calculated as total PSA divided by prostate weight, which should remain below 0.15.
IN CONCLUSION : PSA testing remains fundamental in prostate cancer screening. But we should not be satisfied if a single PSA measurement is within the normal range—once and done is not enough.
