What is PSA?
PSA (prostate specific antigen) is a chemical produced by the prostate gland. It functions to liquefy semen following ejaculation, aiding the transit of sperm to the egg. A small amount of PSA filtrates from the prostate into the blood circulation and can be measured by a simple blood test. In general, the larger the prostate size, the higher the PSA level since larger prostates produce more. As a man ages, his PSA rises based upon the typical enlarging prostate that occurs with growing older.
Why screen for prostate cancer?
Excluding skin cancer, prostate cancer is the most common cancer in men (1 in 8 lifetime risk), accounting for about one-quarter of newly diagnosed cancers in males. Prostate cancer causes absolutely no symptoms in its earliest stages and the diagnosis is made by prostate biopsy done on the basis of abnormalities in PSA levels and/or digital rectal examination. An elevated or accelerated PSA that leads to prostate biopsy and a cancer diagnosis most often detects prostate cancer in its earliest and most curable state. Early and timely intervention for men with aggressive cancer results in high cure rates and avoids the potential for cancer progression and consequences that include painful cancer spread and death.
The upside of screening is the detection of potentially aggressive prostate cancer that can be treated and cured. The downside is the over-detection of unaggressive prostate cancers that may never prove to be problematic, but may result in unnecessary treatment with adverse consequences. The downside of not screening is the under-detection of aggressive prostate cancers, with adverse consequences from necessary treatment not being given.
How is PSA used to screen for prostate cancer?
Although it’s an imperfect screening test, PSA remains the best tool currently available for detecting prostate cancer. It shouldn’t be thought of as a stand-alone test, but rather as part of a comprehensive approach to early prostate cancer detection. Baseline PSA testing for men in their 40s is useful for predicting the future potential for prostate cancer.
Upon PSA testing, about 90% of men are found to have a normal PSA. Of the 10% of men with an elevated PSA, 30% or so will have prostate cancer. In a recent study of 350,000 men with an average age of 55, median PSA was 1.0. Those with a PSA < 1.5 had a 0.5% risk of developing prostate cancer, those between 1.5-4.0 had about an 8% risk, and those > 4.0 had greater than a 10% risk.
Why is PSA elevated in the presence of prostate cancer?
Prostate cancer cells do not make more PSA than normal prostate cells. The elevated PSA occurs because of a disruption of the cellular structure of the prostate cells. The loss of this structural barrier allows accelerated seepage of PSA from the prostate into the blood circulation.
There is no letter C (for cancer) in PSA
Not all PSA elevations imply the presence of prostate cancer. PSA is prostate organ-specific but not prostate cancer-specific. Other processes aside from cancer can cause enhanced seepage of PSA from disrupted prostate cells. These include prostatitis (inflammation of the prostate), benign prostatic hyperplasia (BPH, an enlargement of the prostate gland), prostate manipulation (e.g., a vigorous prostate examination, prostate biopsy, prolonged bike ride, ejaculation, etc.).
Why is PSA not a perfect screening test?
PSA screening is imperfect because of false negatives (presence of prostate cancer in men with low PSA) and false positives (absence of prostate cancer in men with high PSA). Despite its limitations, PSA testing has substantially reduced both the incidence of metastatic disease and the death rate from prostate cancer.
How is PSA used in men diagnosed and treated for prostate cancer?
PSA is unquestionably the best marker to gauge prostate cancer status in the follow-up of men who have been treated for prostate cancer by any means. After surgical removal of the prostate gland for cancer, the PSA should be undetectable and after radiation therapy the PSA should decline substantially to a reading of usually less than 1.0. Rising PSA levels after treatment may be the first sign of cancer recurrence. Such a “biochemical” relapse typically precedes a “clinical” relapse by months or years.
How is PSA best used to screen for prostate cancer?
The most informative use of PSA screening is when it’s obtained serially, with comparison on a year-to-year basis providing much more meaningful information than a single, out-of-context PSA. Because PSA values can fluctuate from lab to lab, it’s always a good idea to try to use the same laboratory for the testing.
Who should be screened for prostate cancer?
Men age 40 and older who have a life expectancy of 10 years or greater are excellent candidates for PSA screening. Most urologists do not believe in screening or treating men who have a life expectancy of less than 10 years. This is because prostate cancer rarely causes death in the first decade after diagnosis and other competing medical issues often will do so before the prostate cancer has a chance to. Prostate cancer is generally a slow-growing process and early detection and treatment is directed at extending life well beyond the decade following diagnosis.
The age at which to stop screening needs to be individualized, since “functional” age trumps “chronological” age and there are men 75 years old and older who are in phenomenal shape, have a greater than 10-year life expectancy and should be offered screening. This population of older men may certainly benefit from the early diagnosis of aggressive prostate cancer that has the potential to destroy quantity and quality of life. However, if a man is elderly and has medical issues and a life expectancy of less than 10 years, there’s little sense in screening. Another important factor is individual preference since the decision to screen should be a collaborative decision between patient and physician.
What are refinements in PSA testing?
PSA Velocity – Comparing the PSA values year to year is most informative. Generally, PSA will increase by only a small increment, reflecting benign prostate growth. If PSA accelerates at a greater rate than anticipated—a condition known as accelerated PSA velocity—further evaluation is indicated.
An isolated PSA (out of context) is not particularly helpful. What is meaningful is comparing PSA on a year-to-year basis and observing for any acceleration above and beyond the expected annual incremental change associated with aging and benign prostate growth. Many labs use a PSA of 4.0 as a cutoff for abnormal, so it is possible that one can be falsely lulled into the impression that their PSA is normal. For example, if the PSA is 1.0 and a year later it is 3.0, it is still considered a “normal” PSA (because it is less than 4.0) even though it has tripled (highly suspicious for a problem) and mandates further investigation.
PSA Density – PSA density (PSA divided by prostate volume) is the PSA level corrected to the size of the prostate. The prostate volume can be determined by imaging studies including ultrasound or MRI. PSA elevations are less worrisome under the circumstance of an enlarged prostate. A PSA density > 0.15 is concerning for prostate cancer.
Free PSA – PSA circulates in the blood in two forms: a “free” form in which the PSA is unbound, and a “complex” PSA in which the PSA is bound to a protein. The free PSA/total PSA ratio can offer a predictive value (similar to how HDL cholesterol/total cholesterol can be helpful in a person with an elevated cholesterol level). The higher the free to total PSA ratio, the greater the chance that benign enlargement of the prostate is the underlying source of the PSA elevation. In men with a PSA between 4 and 10, the probability of cancer is 9-16% if the free/total PSA ratio is greater than 25%; 18-30% if the ratio is 19-25%; 27-41% if the ratio is 11-18%, and the probability of cancer increases to 49-65% if the ratio is less than 10%.
4Kscore test – The 4Kscore Test is a refinement that measures the blood content of four different prostate-derived proteins: total PSA, free PSA, intact PSA and human kallikrein 2. Levels of these biomarkers are combined with a patient’s age, DRE status (abnormal DRE vs. normal DRE), and history of prior biopsy status (prior prostate biopsy vs. no prior prostate biopsy). These factors are processed using an algorithm to calculate the risk of finding a Gleason score 7 or higher (aggressive) prostate cancer if a prostate biopsy were to be performed. The test can increase the accuracy of prostate cancer diagnosis, particularly in its most aggressive forms. (It cannot be used if a patient has received a DRE in the previous 4 days, nor can it be used if one has been on Avodart or Proscar within the previous six months. Additionally, it cannot be used in patients that have within the previous six months undergone any procedure to treat symptomatic prostate enlargement or any invasive urologic procedure that may be associated with a PSA elevation.)
What is prostate MRI?
MRI is a high-resolution imaging test that does not require the use of radiation and is capable of showing the prostate and surrounding tissues in multiple planes of view, identifying suspicious areas. MRI uses a powerful Tesla magnet and sophisticated software that performs image-analysis, assisting radiologists in interpreting and scoring MRI results. A validated scoring system known as PI-RADS (Prostate Imaging Reporting and Data System) is used. This scoring system helps urologists make decisions about whether to biopsy the prostate and if so, how to optimize the biopsy.
PI-RADS Classification & Definition:
I – Most probably benign
II – Probably benign
III – Indeterminate
IV – Probable cancer
V – Most probably cancer
What is the definitive test for prostate cancer?
Prostate biopsy (ultrasound guided) is the definitive and conclusive test for prostate cancer. An elevated or accelerated PSA, abnormal digital rectal exam and suspicious MRI are all helpful, but “the buck stops here” with prostate biopsy, the conclusive test for prostate cancer.
Bottom Line: PSA testing provides valuable information in the diagnosis, pre-treatment staging, risk assessment and monitoring of prostate cancer patients. PSA screening has resulted in detecting prostate cancer in its earliest and most curable stages, before it has a chance to spread and potentially become incurable. PSA screening has unequivocally reduced metastatic prostate cancer and death from prostate cancer and it is recommended that the test be obtained annually starting at age 40 in men who have greater than a 10 year life expectancy.
Written by Dr. Andrew Siegel