PSA and Prostate Cancer
A remarkable increase in the incidence of prostate cancer was observed in the United States in the 1990s. This observation can be attributed to the widespread use of PSA testing. From 1984 to 1994, the use of PSA testing for diagnostic purposes increased dramatically and the percent of cancers diagnosed due to PSA increased from 5.1% to 60.6% over this period of time. More importantly, the vast majority of these cancers were diagnosed at an early stage when most treatment options are available to the patient. Additionally, most of these cancers diagnosed with PSA are clinically significant.
Prostate specific antigen (PSA) is a protein that is almost exclusively produced by the prostate gland. This unique attribute has allowed medical professionals to utilize it for the detection of prostate cancer which is the most common cancer men will be diagnosed with in their lifetime and the second most common cause of cancer death. In 2004, there was an estimated 230,000 men diagnosed with prostate cancer and over 30,000 deaths from this disease. Large population screening studies have shown that the best way to increase the detection of prostate cancer while it is still at a curable stage is to use PSA as an initial screening test.
Prior to the discovery of PSA, physicians almost exclusively relied on digital rectal examination (DRE) for diagnosing prostate cancer. Many men presented at that time with advanced or incurable disease. Over the last ten years we have seen a significant drop in the incidence of patients presenting with metastatic disease and this has been linked directly to the widespresd use of PSA. DRE alone will miss up to 45% of cancers while PSA alone will only miss 18% of cancers in one large multicenter screening study. Thus, utilizing PSA with DRE for screening will improve cancer detection to 81% over DRE alone giving us an overall detection rate of 82%.
The normal level for PSA is less than 4 ng/ml. There are multiple reasons why your PSA can become elevated. Enlargement of the prostate gland (BPH), infection, prostate cancer, recent ejaculation, placement of a urinary catheter, prostate biopsy or instrumentation of the urinary system can all cause elevation of your PSA. Contrary to popular belief, DRE does not cause your PSA to become elevated to any clinically significant degree.
The percentage of elevated PSA in the range of 4-10 ng/ml that is attributed to prostate cancer is only 31.5%. This number rises to greater than 50% when we only consider those patients with a PSA above 10 ng/ml. This means that the majority of cases of an elevated PSA can be attributed to benign causes, mainly BPH. This is why we need to biopsy many men who will never have prostate cancer to better detect this subset of men with the disease. However, the advantage of this established biopsy criteria is that 88% of cancers that are diagnosed with a PSA less than 10 ng/ml will have disease confined to the prostate.
The American Urological Association (AUA) has established guidelines for prostate cancer screening. Every man who is 50 years old should undergo prostate cancer screening with a PSA and DRE on an annual basis. If the patient is African-American or has a first degree relative diagnosed at an early age with prostate cancer, then they should start screening at the age of 40. This can be performed by the patients primary care physician or an urologist. Screening should continue until the age of 72 or as long as the patient has a greater than 10 year life expectancy. The rationale for this has been that prostate cancer is a slow growing cancer and that only younger patients or those with a greater than 10 year life expectancy will benefit from treatment. Patients who have undergone a prior vasectomy are NOT at any increased risk of developing prostate cancer and therefore should only follow the above guidelines.
There are a variety of commercially available PSA screening tests available. These tests use 4.0 ng/ml as a cutoff for a normal value. The sensitivity of these tests starts at 0.1 ng/ml. Most men with a prostate will have a PSA somewhere in this range. A super sensitive PSA test is also available and can detect changes in PSA at a much lower level, however, this test is only useful after radical prostatectomy to detect early recurrences. A total PSA test is the only test currently recommended for screening for prostate cancer. However, because an elevated PSA between 4-10 ng/ml is only predictive of cancer in approximately 30% of patients, a more precise way of looking at PSA is needed. Urologists have developed several useful ways to make PSA more helpful for detecting cancer.
PSA velocity is a useful measurement for differentiating benign from malignant elevations of PSA. Three measurements, over a two year period obtained from the same lab can be used to determine PSA velocity. A rise of greater than 0.75 ng/ml/year is suggestive of cancer while lower rises suggest benign disease.
Another useful way of evaluating PSA is by using age-specific reference values. By lowering the threshold for younger men and raising it for older ones to account for natural enlargement of the prostate, we can eliminate unnecessary biopsies. PSA normally increases by 4% per ml of prostate tissue as it enlarges with aging. Applying age specific references makes the test more sensitive for younger patients and more specific for older ones. For a man 40-49 years a value of 0-2.5, 50-59 years a value 0- 3.5, 60-69 years a value of 0-4.5 and for 70-79 years a value of 0-6.5 ng/ml is considered normal.
Although not considered a primary screening test for prostate cancer, a percent free PSA (fPSA) has become a very useful test when considering whether to biopsy a patient with an elevated PSA in the 4-10 ng/ml range. A percent fraction of fPSA less than 25% has been shown to correlate with prostate cancer better than total PSA. It has been shown that we can improve the specificity of PSA in this range, reducing the number of unnecessary biopsies by 20% while still mainting a 95% sensitivity for prostate cancer detection. However, the utility of fPSA in the less than 4.0 ng/ml range has not been shown to be helpful and until more conclusive evidence presents this practice should be discouraged.
There are several other cancer detection markers on the horizon that may prove to be beneficial for decreasing the number of unnecessary biopsies while still maintaining the same degree of sensitivity for detecting prostate cancer. However, most of these tests are still experimental or awaiting approval for the screening of prostate cancer.
We now know from the recent Prostate Cancer Prevention Trial (PCPT) that approximately 25% of men with a PSA in the range 2.1-4.0 ng/ml will be found to have prostate cancer. Twenty one percent of these cancers are considered high grade supporting the fact that these are clinically significant tumors. Another study found that 14% of men with an abnormal DRE and a PSA 2.5-4.0 ng/ml had prostate cancer, supporting the idea that men with really low PSAs can still have cancer. Based on this information some urologists are justifying proceeding with prostate biopsy when the PSA is above 2.5 ng/ml.
Another scenario in which a biopsy is warranted with a low PSA is in the patient taking a 5-alpha-reductase inhibitor (finasteride, dutasteride) for prostate enlargement. These medicines are well known for artificially lowering a mans PSA by 50% after taking the medicine for 6 months. Therefore a man on one of these medicines with a PSA of 3.0 should really be considered as having a PSA of 6.0 and referred for biopsy.
There is very little preparation prior to obtaining a PSA test. Patients should refrain from ejaculation for at least a 24 hour period. PSA tests should be avoided in the setting of acute infection of the urine or prostate as this may lead to a false positive result. Urinalysis should be obtained prior to performing a PSA test if infection is suspected. Testing should wait until the infection has been adequately treated with antibiotics. PSA testing should be avoided in the setting of an indwelling urethral catheter or within 6 weeks of an episode of acute urinary retention.
The level of PSA found in the mans blood is one of the most reliable predictors of whether or not there is prostate cancer. A physician can utilize PSA in different ways to screen for this disease and decide with the patient when is the appropriate time for prostate biopsy. Once the diagnosis of prostate cancer is made, PSA can help the physician guide patients to the most appropriate therapy and coupled with the pathologic grade from the biopsy, offer the patient a prognosis. After treatment, PSA is essential for monitoring the effectiveness of therapy and surveillance for recurrence.
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