From the Research
Approximately 14% of prostate cancer cases have a PSA level of 4.0 ng/mL or lower, which implies that a significant proportion of prostate cancers may not be detected through standard PSA screening alone. This is an important clinical consideration because these PSA-negative or low-PSA tumors will not be detected through standard PSA blood tests, potentially leading to delayed diagnosis. The lack of PSA expression or low PSA levels occurs because these cancer cells have lost the ability to produce this protein due to genetic or epigenetic alterations affecting the PSA gene or its regulatory pathways. Clinicians should be aware that a normal or low PSA level does not completely rule out prostate cancer, particularly in patients with suspicious symptoms or findings on digital rectal examination. For high-risk patients with normal or low PSA levels but concerning symptoms, additional diagnostic approaches such as imaging studies or biopsies may still be warranted to ensure these PSA-negative or low-PSA cancers are not missed 1.
Some studies have suggested that PSA-negative prostate cancers tend to be more aggressive and poorly differentiated, often representing neuroendocrine variants or tumors that have undergone dedifferentiation 2. However, the exact percentage of prostate cancers that do not express PSA is not well established, and more research is needed to determine the true prevalence of PSA-negative prostate cancer.
Key points to consider in clinical practice include:
- A normal or low PSA level does not completely rule out prostate cancer
- Additional diagnostic approaches may be warranted in high-risk patients with normal or low PSA levels but concerning symptoms
- PSA-negative or low-PSA prostate cancers may be more aggressive and poorly differentiated
- The lack of PSA expression or low PSA levels can occur due to genetic or epigenetic alterations affecting the PSA gene or its regulatory pathways 3, 4.
In terms of screening and diagnosis, the combination of a PSA test and a digital rectal examination (DRE) is most effective in screening for the early detection of prostate cancer 4. However, the use of age-specific reference ranges or other biomarkers may also be useful in improving the accuracy of prostate cancer screening 5, 3.
Overall, clinicians should be aware of the limitations of PSA screening and consider additional diagnostic approaches in high-risk patients with normal or low PSA levels but concerning symptoms. The most recent and highest quality study suggests that approximately 14% of prostate cancer cases have a PSA level of 4.0 ng/mL or lower 1.