PSA

PSA Testing: When It’s Useful, When It’s Not

Screening for prostate cancer is one of the most controversial topics in medicine.

Who should get a PSA test? When is it appropriate to perform a prostate biopsy? What should we do in older adults with severe urinary symptoms?

The guidelines are continually changing as new evidence sees the light. At first, we thought that the PSA test would be the ultimate non-invasive way to screen for prostate cancer. Then, doctors and researchers realized there are many false positives and false negatives. So, is it useful or not?

Let us dive deeper into the PSA test topic and describe the test. We’re also giving you the pros and cons of this type of PCA screening, when it is useful and when it’s not.

What is the PSA test?

PSA is short for Prostate-Specific Antigen. It is a protein synthesized solely by the prostate. Then, it should be specific to diagnose certain conditions. However, the PSA screening test measures this protein, which is not explicitly synthesized by cancer cells.

Healthy cells in the prostate create PSA proteins, which have a normal function in reproduction. This is an important enzyme released with the seminal fluids during ejaculation.

In the semen, PSA enzymes make the liquid more fluid and prevent clotting and agglomeration. This function allows for an easier passage of sperm cells in the vagina and uterus to fertilize the egg. Thus, we can say that PSA facilitates fertilization. It is not a specific marker for cancer and can be found in healthy individuals.

What the PSA test does is merely measuring the levels of PSA in the blood. This protein does not belong in the blood, but some of it leaks into the general circulation. We can measure PSA levels, and prostate cancer patients usually have a very high concentration of this protein. It is also raised in benign prostatic hyperplasia and enlarged prostate due to the normal aging process.

In all of these conditions, the number of prostate cells increases. Thus, the number of cells producing PSA protein is higher, and more of it leaks into the blood. In prostate cancer, the accelerated growth of the prostate is met by inflammation. The inflamed prostate tissue has more blood circulation and a higher chance to pass down the excess of PSA enzymes (1).

In short, the PSA test is not only higher in prostate cancer. It is also higher in older adults, in patients with BPH, or any degree of prostate inflammation. An elevated PSA level is sensitive for prostate cancer, but not specific. Does that mean that PSA is not a reliable tool for prostate cancer screening?

Concerns about the PSA test

Concerns about PSA started when this protein was found to be increased in mild cases. When doctors knew that even a perfectly healthy prostate sometimes has high PSA levels, other measures were taken to prevent false positives. Then, many patients with elevated PSA levels were recommended prostate biopsies.

There was a steep rise in the number of unnecessary prostate biopsies. Some patients even took a yearly sample of their prostate to rule out prostate cancer. But prostate biopsies are not to be taken lightly. Some of them lead to severe side effects such as chronic rectal bleeding and pain, urinary incontinence, erectile dysfunction, and more. In some cases, they affect the quality of life of perfectly healthy patients who didn’t need them in the first place (2).

But can we go around all of these PSA screening limitations?

To avoid that, a series of measures have been taken to increase the screening test’s accuracy. Doctors began creating a map with PSA levels, giving follow-up as patients became older. That way, it was possible to create a baseline level and see how it increased through time. This is now known as PSA velocity, and it is advantageous to avoid false-positive and false-negatives.

Comparing free PSA and bound PSA levels was also found useful to increase the accuracy of the test. This protein runs in the blood but is sometimes attached to transporter proteins. We know that prostate cancer patients usually have lower levels of free PSA and high total PSA levels. So, we can compare this with other PSA measures to make sure who needs a prostate biopsy.

PSA density is another useful tool, and it is performed after obtaining the volume of the prostate gland. Urologists would simply divide the PSA levels in ng/mL by the gland’s volume in mL. It also provides a useful reference to prevent an unnecessary prostate biopsy.

Even more, PSA-related tools were created and tested with positive results. For example, IsoPSA, a measure that joins all PSA types and gives a general overview of PSA status. PSA doubling time, which measures how much it takes for PSA levels to double. And PSA density of the transition zone, a subtype of PSA density that only considers a specific area in the prostate gland.

All of these tools can be very useful when patients are in the gray zone. That is when their test results or clinical assessment are non-conclusive, but there’s a high chance of prostate cancer (3).

Additionally, doctors should also compare PSA test results with other aspects. For example, it should be compared to the Gleason score. And before ordering a prostate biopsy, it should also be compared to the results of the digital rectal examination, ultrasound scans, risk factors, and symptoms of each patient.

As mentioned above, the guidelines to screen for prostate cancer are continually changing. One of the reasons is that we want to avoid performing prostate biopsies on healthy patients who do not require this type of exam. For that reason, and worried about the rise in unnecessary biopsies, the U.S. Preventive Service Task Force has recommended ordering a PSA test only in older adults with particular circumstances (4):

The American Cancer Society only recommends yearly screening for men who got a PSA level higher than 2.5 ng/dL in their first screening test.

What the research says

Based on the growing concern about PSA testing and unnecessary biopsies, the U.S. Preventive Service Task Force released a systematic review with 104 publications. After evaluating this massive amount of data, they concluded that (5):

  • PSA screening does not lead to a reduction of PCA mortality by prostate cancer in the U.S.

  • PSA screening had a more positive impact on mortality by prostate cancer in a European trial. It showed a reduction of 1.1 deaths per 10,000 individuals.

  • The rate of overdiagnosis of prostate cancer was high. It is situated between 20.7 and 50.4%

  • According to one trial, men who detected their prostate cancer via screening did not have better outcomes after initiating therapy for their condition. Their mortality was similar to those who only had active surveillance.

  • Conservative management spared prostate cancer patients from a variety of side effects.

In their conclusion, the U.S. Preventive Services Task Force mention that screening with PSA is useful. It reduces the risk of mortality for aggressive prostate cancer.

However, there are too many false positives. Patients have biopsy complications, and there is an overdiagnosis of up to 50% in prostate cancer. There is a reduction in the risk of metastatic disease by using PSA tests. However, the side effects of a biopsy, radiotherapy, and radical prostatectomy are considerable.

Thus, they recommend against performing a PSA screen on all men after 50 years. Instead, doctors should evaluate a variety of risk factors, life expectancy, and other elements. It is also essential to talk to the patient about the risks of screening and biopsy taking. That way, and with an informed decision, patients will be able to reach conclusions with their doctors according to their health conditions (5).

The PCLO trial was also significant to formulate these recommendations. This is also known as the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. It included around 155,000 participants and evaluated the outcomes of healthy patients who are screened continuously against those who are not. The goal was to assess if screening does reduce cancer-related mortality. The authors reported that prostate cancer mortality was not affected by screening (6,7).

Recent studies

However, more recent studies have also evaluated this decision by the U.S. Preventive Service Task Force. Their authors reference other clinical studies reporting that half of prostate cancer-related deaths come from patients who had serum PSA values over the top 25% according to their age.

Having PSA values in younger patients also works as a baseline to understand changes as they grow older. Thus, some authors recommend that the practice of obtaining baseline values before 50 years old should not be left out. In these young patients, those with PSA levels higher than 1 ng/mL should be closely monitored.

We should also highlight a retrospective assay involving over 90,000 young men before 40 years. These authors showed that before 40 years, PSA value is very stable. They don’t change much. So, if we take a baseline sample at a young age, there won’t be any distortion risk.

Moreover, it will be a better baseline because at age 40 years old, there’s a higher incidence of BPH. Thus, according to some authors, we can obtain a baseline value at this age without increasing the risk of prostate cancer overdiagnosis (9).

What you should know about PSA screening

PSA is a protein synthesized by the prostate gland. It is not a direct marker of prostate ailments but can be used for the early prostate cancer detection According to the new evidence, doctors’ opinions and uses of PSA blood tests have changed throughout time. The exam is not always required, and you don’t need to perform a yearly exam as we were told before.

By reducing the frequency of PSA testing, we can take care of a few setbacks of this practice:

  • There are many false positives, and many conditions can alter PSA levels. For example, benign prostate enlargement or a prostate infection. Recent sexual intercourse, a prostate exam, or bike riding can also increase its levels, causing a false positive.

  • Prostate biopsies have side effects, and we want to avoid false positives. We also want to prevent reducing the quality of life in patients who are better off without a biopsy. Thus, it is only recommended in patients with high risk and not routinely ordered in patients over 70 years old.

  • Screening yearly can lead to a higher cost of healthcare. It is not only the cost of the PSA test but also the consultation fee and other exams. This extra expense should be reduced in patients who are not receiving a real benefit from this test.

Conclusion

So, PSA tests are only recommended in patients aged 50 years old and older with a high risk for prostate cancer. Who is at a higher risk?

Those with close relatives with prostate cancer (father or brothers), African American patients, and patients with prostate cancer symptoms. In most cases, patients aged 70 years or older are not required to undergo a PSA test.

Each case should be evaluated independently, and we recommend talking to your urologist before making up your mind. For example, 70-year-old patients may need an exam if they are at very high risk and have a life expectancy higher than 10 years.

Young and healthy patients may be recommended to take this test to have a baseline PSA level. And keep in mind that PSA should be compared to other data. So, you might still need a digital rectal exam for prostate cancer diagnosis.

As a short summary, remember that there’s never a final word about PSA without previously evaluating the patient and his particular needs. Thus, if you believe you’re at risk of prostate cancer, talk to your doctor about it. Follow his recommendations and do not get alarmed by your PSA levels without a medical opinion.

Sources

  1. Adhyam, M., & Gupta, A. K. (2012). A review on the clinical utility of PSA in cancer prostate. Indian journal of surgical oncology, 3(2), 120-129.
  2. Barry, M. J. (2006). The PSA conundrum. Archives of internal medicine, 166(1), 7-8.
  3. Djavan, B., Zlotta, A., Kratzik, C., Remzi, M., Seitz, C., Schulman, C. C., & Marberger, M. (1999). PSA, PSA density, PSA density of transition zone, free/total PSA ratio, and PSA velocity for early detection of prostate cancer in men with serum PSA 2.5 to 4.0 ng/mL. Urology, 54(3), 517-522.
  4. U.S. Preventive Services Task Force. (2018). Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Jama, 319(18), 1901-1913.
  5. Fenton, J. J., Weyrich, M. S., Durbin, S., Liu, Y., Bang, H., & Melnikow, J. (2018). Prostate-specific antigen–based screening for prostate cancer: evidence report and systematic review for the U.S. Preventive Services Task Force. Jama, 319(18), 1914-1931.
  6. Eckersberger, E., Finkelstein, J., Sadri, H., Margreiter, M., Taneja, S. S., Lepor, H., & Djavan, B. (2009). Screening for prostate cancer: a review of the ERSPC and PLCO trials. Reviews in urology, 11(3), 127.
  7. Baccaglini, W., Cathelineau, X., Araújo, F. G., Medina, L. G., Sotelo, R., Carneiro, A., & Sanchez-Salas, R. (2019). Screening: actual trends on PSA marker. When, who, how?. Archivos espanoles de urologia, 72(2), 98-103.

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