Many symptoms, diseases or injuries are so clear-cut that diagnosing them is a no brainer. The body’s problem gives clear information and no guesswork is involved. Whether it’s a painful shingles rash, a rapidly swelling sprained ankle, or sudden crushing chest pain, a visit to your doctor or Emergency Department results in a rapid assessment, a clear diagnosis, and a specific treatment plan.

With prostate cancer, however, the presenting information from a PSA blood test is not so definitive. What’s normal for one man may signal a problem for another. Our website offers general PSA guidelines by age and ethnicity, but there is much room for variation. In the “good old days” after PSA screening picked up speed after the blood test was invented in the mid-1990s, the classic rule of thumb was this: any PSA higher than 4.0 ng/mL might be prostate cancer (PCa). Thus, based on a number (and sometimes an abnormal digital rectal exam or DRE), countless patients were quickly sent for a needle biopsy guided by transrectal ultrasound (TRUS biopsy). In turn, these biopsies led to a cascade of overdetection and overtreatment.

That was then, but this is now. Here’s the problem as summarized by Yang et al. (2023): “… the PSA concentration increases not only in PCa but also in some nonmalignant conditions, such as benign prostatic hyperplasia (BPH), prostatic hyperplasia, urinary tract infection, and indwelling catheters, especially among patients with PSA levels within the gray zone of 4-10 ng/mL [emphasis mine].”^[i]

Did you know that the term “gray zone” actually comes from military conflict? It refers to activities between nations that are hostile and provocative, but fall below the threshold needed to declare war and unleash military aggression. The Center for Strategic and International Studies cites such actions as “information operations, political coercion, economic coercion, cyber operations, proxy support, and provocation by state-controlled Forces.” As a simplistic analogy, imagine the U.S. bombing the capital city of a rival superpower over suspicion that their nation had hacked into our Pentagon servers. Should this trigger an all-out war?

In the history of PCa detection and treatment, a PSA in the gray zone followed by a positive biopsy triggered all-out war against an individual’s PCa in the form of surgical removal or whole gland radiation. This was justified by the suspicion that PCa would inevitably take the life of the patient if left untreated. Keep in mind that before today’s better detection and diagnostic technologies, many doctors were trained to jump to the conclusion that all PCa is equally threatening, plus there were only three treatment strategies (surgery, radiation, watchful waiting).

Thankfully, we are in a new era of enlightenment when it comes to PCa. The Yang paper mentioned above points out that less than a third of men whose PSA results are in the gray zone actually have confirmed PCa. The authors declare that “there is an urgent need for a highly accurate and noninvasive alternative” instead of rushing to biopsy. They explain, “Multiparametric magnetic resonance imaging (mpMRI) is currently the optimum imaging technology for the diagnosis and monitoring of PCa,” but for men whose PSA is in the gray zone yet their MRI is negative, the next best step before biopsy is PET or MRI imaging that targets PSMA (prostate specific membrane antigen). This can “can achieve a highly accurate and noninvasive diagnosis” of clinically significant PCa for patients falling within the PSA gray zone.

Of course, it’s important to add that not every gray area patient with a negative MRI necessarily needs an additional scan. All risk factors, including family history and ethnicity, should be taken into account before ordering additional expensive imaging and/or biopsy. Blood test analysis that integrates all PSA variants (free PSA, total PSA, PSA velocity) and certain blood or urine tests that detect biomarkers are generally less costly than PSMA MRI or PSMA PET.

In any case, when a man’s PSA is in the gray zone, let’s take time to gather more evidence, and to make a balanced decision before declaring an all-out war on his prostate gland.

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.

[i] Yang J, Li J, Xiao L, Zhou M et al.⁶⁸Ga-PSMA PET/CT-based multivariate model for highly accurate and noninvasive diagnosis of clinically significant prostate cancer in the PSA gray zone. Cancer Imaging. 2023 Sep 4;23(1):81.