The pages of history, biology, true crime and comic books are filled with tales of trickery using disguise. Such camouflage has its uses as a way to cloak one’s true identity or hide in plain sight. The Boston Tea Party was staged by colonists decked out as “Mohawk” Indians. Chameleons command nanocrystals in their skin to blend with their surroundings. Convicted felon Tyler Adams was such a successful master of disguise that he eluded capture for four years. And of course, Superman protected his unique powers by assuming the identity of meek, mild-mannered Clark Kent (hard to believe that muscled torso didn’t strain the seams of a reporter’s modest business suit).

When typical prostate cancer (PCa) is in its early stages, there are no stages to reveal its presence. However, as the cancer cells gradually become more numerous and a tumor begins to grow, its activity stimulates the expression {release) of a protein called prostate specific antigen, or PSA, into the blood stream. As a rule of thumb, the bigger or faster growing the tumor, the more PSA is expressed. The amount can be measured through a simple PSA blood test used to screen for PCa.

Though other noncancerous conditions can provoke a rise in PSA, a higher-than-expected test result arouses suspicion of PCa. If cancer is indeed the culprit, the higher the PSA, the greater cause for worry. In fact, if a patient is diagnosed with PCa, his PSA at the time of diagnosis is taken into account as one of the risk factors indicating how aggressive the tumor is. For instance, if a newly diagnosed patient has a PSA of 17.4 ng/mL, his doctor is likely to be more concerned than if his PSA was 3.9 ng/mL. Other tests (MRI, genomics) and family history will help match treatment to the severity of the disease.

Low PSA could be hiding dangerous disease

But wait! There is an uncommon but important exception to the rule that a high PSA signals danger. An April 12, 2024 online article in Renal&Urology News reports, “Clinically significant prostate cancer is found in a ‘non-negligible’ number of men who have screening PSA levels of 1.8 or higher but less than 3.0 ng/mL, according to recent study findings.” In other words, we can’t count on a low PSA to mean that a man is free from potentially deadly cancer.

The study in question was a large Swedish population-based analysis of PSA screening. The team of authors wrote, “17974 men choose to participate by having a PSA test (2015-2020). One-third of the participants (n = 6006) were randomized to arm 3, men with a PSA value of ?1.8 ng/ml were recommended for MRI. Men with positive MRI (PI-RADS 3-5) had four targeted biopsies from each MRI-visible lesion.”^[iii] Out of the 6006, 670 (11%) had a PSA between a low PSA group defined as PSA between 1.8 and 3.0 ng/mL. From this group, PCa was diagnosed in 64 men whose MRI scans were positive on the PI-RADS scale; 33 of them had insignificant disease on biopsy (Gleason 6) while 31 were found with significant PCa (Gleason 7 or higher). In other words, low PSA can be misleading when it disguises aggressive PCa in an unsuspecting man. How can that be?

Well, there are PCa cell lines that have aggressive biology but that don’t express PSA. In 2023, a British team published a paper entitled “A low prostate specific antigen predicts a worse outcome in high but not in low/intermediate-grade prostate cancer.”^[iv] In a statistical analysis of data on over 100,000 PCa patients, the British team found that men diagnosed with high grade PCa who had a low PSA at the time of diagnosis had a high probability of worse outcomes. These findings add to an observation first published in 2016 of poorer outcomes for men with high-grade PCa but low PSA.

Although this occurrence is relatively rare compared with most PCa cases detected early thanks to a higher-than-normal PSA screening test, it tells us that militant cancer cells can be tricky. Like the legend of ancient Greek soldiers who infiltrated the walled city of Troy disguised as a gift—a huge wooden horse—aggressive PCa can infiltrate the fortress of the body camouflaged as a harmless low PSA.

If you have a family history of prostate or breast cancer, especially in first-degree relatives, talk to your doctor about extra vigilance. After your next PSA, it may be worthwhile to discuss the merits of having a baseline multiparametric MRI as a precaution. Keep in mind that in the Swedish study, the men in the low-PSA group who were diagnosed with significant PCa only found it through MRI. Beware of a “Supercancer” disguised as a meek, mild-mannered low PSA.

NOTE: This content is solely for purposes of information and does not substitute for diagnostic or medical advice. Talk to your doctor if you are experiencing pelvic pain, or have any other health concerns or questions of a personal medical nature.

References

[i] Carter HB. Prostate cancers in men with low PSA levels–must we find them? N Engl J Med. 2004 May 27;350(22):2292-4.
[iii] Möller F, Månsson M, Wallström J, Hellström M et al. Cancers in the Prostate-specific Antigen Interval of 1.8-3 ng/ml: Results from the Göteborg-2 Prostate Cancer Screening Trial. Eur Urol. 2024 Mar 14:S0302-2838(24)00052-6.
[iv] Fankhauser CD, Parry MG, Ali A, Cowling TE et al. A low prostate specific antigen predicts a worse outcome in high but not in low/intermediate-grade prostate cancer. European Journal of Cancer, Volume 181, 2023. 70-78.