The paradox of the blood PSA test

Cancer screening tests, including the PSA (prostate-specific antigen) to look for early signs of prostate cancer, have, over the years, made it possible to help identify an oncological disease at an early stage and thus facilitate a successful therapeutic approach.

Prostate cancer represents the second most common cancer for men worldwide with 375,304 deaths in 2020 [source: IARC]. When the disease is diagnosed at an early stage, when the tumour is confined to the prostate, it can be treated successfully either with radical surgery or radiotherapy. Prostate cancer mortality has declined steadily over the past few years, mainly due to the widespread use of preliminary screening examinations [.source]. However, many of the prostate cancers that are diagnosed are diseases that will most likely never progress. For these patients, a diagnosis therefore only brings complications due to unnecessary interventions, from the biopsy in the diagnostic phase to a radical treatment.

The decision to undergo a prostate biopsy for suspected cancer is based on preliminary examinations, such as digito-rectal exploration and the PSA test. However, the big problem is that PSA is a specific marker for the prostate, but not for prostate cancer, and its levels in the blood can also be influenced by non-malignant prostate diseases, such as a enlargement, a’infection or inflammation, one ejaculation, or simply by going to bicycle.

Because of this lack of specificity, the use of the PSA test as a screening test for prostate cancer has declined recently precisely because of concerns about overdiagnosis and unnecessary treatment [.source].

Over the last decade, various alternatives to the PSA test, both blood and urine tests, have been investigated to help the physician better assess a patient's risk of developing clinically significant prostate cancer.

Several new tests have become commercially available, but none have been used routinely due to limited benefits
compared to the standard [source].

Recent studies have shown that infertility in men may be somewhat related to the risk of developing aggressive prostate cancer [source]. The prostate is a gland that produces the contents of seminal fluid, which is crucial for the survival, motility and quality of spermatozoa.

It is already known that chronic inflammation can alter the chemical characteristics of the liquid part of the ejaculate, affecting fertility [source]. However, the correlation between infertility and prostate cancer still remains unclear.

During neoplastic transformation, cells undergo profound changes in both appearance and function.

Most prostate neoplasms are of the adenocarcinomas, i.e. tumours that originate from alterations in glandular cells. This evidence suggests that neoplastic transformation in the prostate may compromise the composition of prostate fluid.

PROSTATE CANCER PRODUCES LESS PSA

Increased PSA values in the blood sound like an alarm bell for the likelihood of having prostate cancer.

However, it has long been known that high-grade prostate tumours can lose PSA expression [source].

This aspect represents a paradox: if advanced prostate tumours produce less PSA than a healthy prostate, how can an increase in blood PSA be an indication of malignant disease?

This discrepancy may explain some of the difficulties associated with the diagnostic usefulness of measuring PSA in blood.

A PSA test, but not in blood

In men, the urinary tract is in close contact with the prostate. For this reason, molecules produced by prostate tissue can be shed and thus detected in the urine, representing biological indicators for the diagnosis and prognosis of prostate cancer.

A recently published study by a research group at the University of Turin [source] it appears that it is possible to measure the amount of molecules produced within the prostate by analysing a urine sample.

In this study, which involved more than 500 men undergoing prostate biopsy for suspected prostate cancer, it was seen that PSA levels in prostate tissue gradually decreased as tumour aggressiveness increased.

At the same time, it was observed that the amount of PSA in the urine mirrored the levels of PSA evidenced in the tissue.

This study goes some way towards explaining some of the limitations of the classic blood PSA test and opens up the idea that urine PSA analysis can function as a kind of non-invasive “liquid biopsy” representing a new and interesting method for prostate cancer screening.

A urine test that is more reliable than the classic PSA test to find out whether there is indeed a risk of having prostate cancer.

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