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Prostate Specific Antigen (PSA)

What is Prostate-specific antigen (PSA)?

PSA is a glycoprotein produced as a glandular secretion by the prostate gland. Differently called as Kallikrein III, Semenogelase, Seminin, P-30 antigen or Seminoprotein, PSA's major function is to serve as a liquefier of the semen, which in turn permits the sperm to swim.

What is the PSA test?

PSA test is a blood test whereby the serum PSA level is determined. Normal, age-averaged serum level of PSA is 4 ng/mL and it can normally elevate with age and abnormally during prostate cancer, hence serving as a bio- or tumor marker for prostate cancer. PSA levels can also increase in benign or non-cancerous prostate conditions like benign prostatic hyperplasia (BPH) or prostatitis. Of note, PSA level alone is not a diagnostic determinant for prostate cancer; but high PSA level is always considered a red-flag and further tests are prescribed to rule out prostate cancer in such cases. PSA Reference RangeThe U.S. Food and Drug Administration (FDA) has mandatory guidelines for the use of PSA test and digital rectal exam (DRE) during annual health screening in men aged 50 years or more to screen for prostate cancer. FDA also mandates the same for patients who have a prior incidence of prostate cancer occurrence or a family history of prostate cancer. Often, biochemical elevation of PSA levels may preclude clinical symptoms of prostate cancer and thus can be an important monitoring yardstick for detection, monitoring and screening strategies for prostate cancer.

PSA test as a screening tool

FDA recommends annual screening in men of age 50 years or higher and for those at an increased risk of incidence the screening should commence around 40-45 years age. Prostate cancer risk factors, dietary habits and age are taken into consideration along the PSA test results when making a qualititative interpretation of the observed PSA serum levels. The use of PSA test as a screening tool is hugely debated because there is no direct evidence that the screening benefits actually does not rule out follow-up diagnostic tests and treatments. This is termed overdiagnosis and normally creates complications due to adaption of unnecessary treatment regimens.

PSA test as a monitoring tool

An elevated PSA level will tell the doctor to rule out correlative symptoms of prostate cancer. If all symptoms are undetectable, the patient is usually advised to repeat both the DRE and the PSA test. On the other hand, if concurrent symptoms are observed, then in most cases the doctor will recommend confirmatory prostate biopsy. Velocity of PSA or the rate of elevation of PSA over successive months or years is more important than the actual values as predictive standards for prognosis in prostate cancer. The National Comprehensive Cancer Network (NCCN) interprets PSA test results and defines additional tests and treatment as follows:

  • Watchful waiting phase patients: PSA level has either doubled in 3 years or less; PSA velocity is greater than 0.75 ng/mL per year; prostate biopsy exhibits prostate cancer lesions.
  • Radical prostatectomy patients: PSA levels are still detectable after prostate gland removal; or, PSA level greater than 3 ng/mL that shows steep and continued increase in two subsequent measurements after initial PSA test showed non-detectable PSA levels.
  • Alternative therapy patients: Patients who had either radiation therapy alone or in combination with immunotherapy and in whom PSA levels has elevated by at least 2 ng/mL from an initial, undectable PSA serum level.

Shortcomings of PSA test

Some of the major limitations of PSA test that prevents its universal usage are:

  • PSA test result does not convert to or correlate to alleviate patients’ sufferings or chances of survival.
  • False positives and false negatives are a big downside of PSA test. In an extensive study it was shown that 15.2% men had a PSA lower than 4.0 ng/mL but was still diagnosed with prostate cancer. In a separate study, 65-75% of patients having a PSA level between 4.1 to 9.9 ng/mL did not have prostate cancer. Since prostate cancer incidence is elevated with age, an age specific PSA range is a much better yardstick at making diagnostic and prognostic assertions based on PSA serum levels. On the flip side, using age-specific PSA range can be misleading and prolong the no-treatment wait and
  • Watch duration. Also a low PSA level is observed in patients administered with hormone therapy and hence the timing of PSA test is also vital to get the optimal information out of the system.

What does research show about the use of PSA test? The National Cancer Institute (NCI) started the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO trials), where the PSA test and DRE are being evaluated as screening tools for prostate cancer. PSA evaluation for 6 years and DRE for 4 years (performed during the first 4 years of PSA evaluation) did not significantly decrease the number of patients dying from prostate cancer. This observation was made over a extrapolated period of 11.5 years. 23% more cancers were detected in the screening group compared to the control group, a case of overdosing as described above. So as of now the use of PSA as a screening tool is being seriously questioned, even though longer follow-up might start showing some benefits of excess detection in the screening group. The PLCO trial, now in its 7th year, will continue up to 13 years. The European Randomized Study of Screening for Prostate Cancer (ERSPC) though found a 20% decline in prostate cancer deaths when PSA screening tests were performed every 4 years. The essential difference between the PLCO and ERSPC trials are that the former used 4 ng/mL and the later 3 ng/mL as the PSA cutoff value for risk indicator. Hence, revising the PLCO PSA cutoff value to 3 ng/mL might show remarkable benefits of PSA screening and the NCI is actively considering revising it.

Making the PSA test more informative and significant PSA velocity (the rate of increase of PSA over time) can be a useful indicator. Research has shown that a PSA velocity greater than 0.35 ng/mL per year is associated with a poor prognosis in prostate cancer patients. Taking into consideration the PSA density (level of PSA compared to the size of the prostate) might also make the PSA test more objective. It can be easily conceived that a larger prostate gland might end up showing higher serum PSA levels and vice versa; on the flip side, adapting PSA density as a yardstick might ignore potential prostate cancer patients with a large prostate gland. PSA can either be detected alone or attached with other proteins in the serum. Free PSA level elevation happens in benign conditions, whereas the attached form increases during malignant condition. Thus incorporating PSA velocity, density and assaying for the free and attached PSA forms will actually make the PSA test far more useful as a screening tool.

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