Accuracy of Prostate-specific Antigen (PSA) Test

Prostate cancer is the second leading cause of cancer death among men in the United States.  Among all risk factors associated with prostate cancer, age is, by far, the greatest risk factor: more than 95% of all cases of prostate cancer occur in men over the age of 55.  Family history and race have also linked as risk factors.  Men with first-degree relatives who have been diagnosed with prostate cancer are at increased risk themselves.  African American men have a higher incidence of prostate cancer than men from other ethnic backgrounds, while Native American men have the lowest incidence of the disease.

In recent years, the PSA blood test has become a routine part of annual physical examinations for many men over the age of 50.  The test detects a protein that is secreted almost exclusively by the prostate gland, a walnut-sized structure that wraps around the male urethra at the base of the bladder.  In general, the higher the PSA level, the greater the chance that a patient actually has prostate cancer.  In men aged 50 and over, a PSA level of 4 to 10 ng/ml translates into a 25% statistical likelihood of having prostate cancer.  When the PSA level exceeds 10 ng/ml, the risk of having prostate cancer increases to about 60%.

Among men with clinically detectable prostate cancer, approximately 70% will have an elevated level of PSA in their blood, while the remaining 30% will have a normal PSA level.  Conversely, in 12-15% of men over the age 50, PSA levels are elevated (> 4ng/ml) in the absence of any prostate cancer.  These limitations of the PSA test, expressed as the false negative and false positive rates, respectively, have engendered a great deal of controversy about the accuracy and appropriateness of the test.  Indeed, many prominent prostate cancer experts take the position that the PSA test is too prone to erroneous interpretation to justify its routine use as a cancer screening test.  Other experts correctly point out that, for all of its inherent limitations, the PSA test is still the best and only blood test available to clinicians and patients for prostate cancer screening, and that the detection rates of prostate cancer have increased significantly since the test’s introduction in 1986.

A false positive PSA test occurs when a patient without prostate cancer is found to have an elevated PSA level in his blood.  Since PSA is secreted by both normal and malignant cells within the prostate, several non-malignant conditions can give rise to a false positive PSA test. The gradual enlargement of the prostate gland (BPH, or benign prostatic hypertrophy) that occurs with normal aging can result in an elevated PSA, although the elevated PSA levels for men with BPH will usually remain in the 4-10 ng/ml range.  Other causes of false positive PSA tests include prostatitis (inflammation or infection of the prostate gland), urinary tract infections, instrumentation of the urinary tract or rectum, and surgical procedures in the vicinity of the prostate gland.  Due to the shortcomings of the PSA test, as already described, the relatively high incidence of false positive PSA tests results in a great deal of anxiety and unnecessary medical procedures for a large number of men every year.  In view of this, some experts have advocated that men with mild elevations in their PSA levels, and who are without evidence of prostate cancer by rectal examination or prostate biopsy, should undergo a more specialized type of PSA test called “free PSA.”  Excessive blood levels of PSA caused by benign prostate diseases tend to occur in the “free” form.  That is, the PSA molecule is not bound to another protein that acts as a carrier for PSA in the blood.  In prostate cancer, however, there is a greater tendency for PSA to be secreted by malignant prostate cells in the “bound” form.  Thus, additional discriminatory information may be obtained by comparing free and bound PSA levels.  Unfortunately, even this approach is not 100% accurate in making or excluding the diagnosis of prostate cancer.  Another diagnostic approach to questionable cases of prostate cancer includes PSA velocity measurements, which are used to assess the rate of increase of PSA levels over a period of time.  Rapidly rising PSA levels over a brief time interval suggests prostate cancer, while minimal PSA rise over time suggest either benign prostate disease or a very slow-growing prostate cancer.

A false negative PSA test occurs when a patient with prostate cancer is found to have a normal PSA level.  Unfortunately, such false negative PSA tests occur in nearly one-third of men with prostate cancer.  Careful and repeated examinations of the prostate, serial PSA tests, and a low threshold to perform a prostate biopsy should all be considered if there is some reason for continued clinical suspicion of prostate cancer despite a normal PSA test. 

Perhaps the most noncontroversial application of the PSA test is to monitor patients with a history of prostate cancer, and prostate cancers associated with an elevated PSA at initial diagnosis in particular, for early evidence of recurrence.  Although hormonal therapies for prostate cancer can lower PSA levels in the blood even in the face of persistent or recurrent prostate cancer, the PSA test is very often the first indication of disease recurrence.

Until a more sensitive and specific screening test for prostate cancer comes along, the PSA test, despite its many imperfections, is still the best screening test currently available.

In view of the PSA-related controversies that I have just discussed, an interesting study in the current issue of the New England Journal of Medicine is worthy of discussion.  In this study, a total of 6,691 men underwent PSA testing between 1995 and 2001.   Among these men, 705 (11%) eventually underwent biopsy of the prostate gland because of elevated PSA levels or other clinical findings.  The authors then compared PSA levels in the blood of the men who were confirmed to have prostate cancer with the levels in those men who were found not to have prostate cancer.  Their analysis was designed to assess the predictive value of the currently accepted normal PSA cut-off value of 4 ng/ml.

The authors of this study concluded that setting the normal PSA cut-off value at 4.1 ng/ml would have missed 65% of the prostate cancers in men 60 years of age and older, while a whopping 82% of prostate cancers would have been missed in men who were less than 60 years of age.  If the threshold of normal vs. abnormal PSA level was decreased to 2.6 ng/ml, the authors calculated that the prostate cancer detection rate for men under age 60 would have doubled, to about 36%.  However, this improved detection sensitivity would have come at the cost of a tripling of prostate biopsies, from 2% to about 6%.

This study, frankly, only increases the controversy regarding the role of PSA testing as a cancer screening assay.  For all of its potential, PSA testing has still not been definitively shown to improve survival rates for prostate cancer.  As I discussed in last week’s column, prostate cancer, in most men, is a relatively slow-growing disease.  It occurs most frequently in elderly men, and is seldom the cause of death in these patients.  At the same time, prostate cancer will be newly diagnosed in nearly a quarter of a million men this year, and close to 30,000 men will die of the disease in 2003.  By one expert’s estimation, 80 American men will die of prostate cancer over the next 24 hours.  While imperfect, at best, it would appear that the PSA test is our most useful screening tool until something better comes along.  Based upon this latest study, the threshold value for a normal PSA test will probably be adjusted downward somewhat, although at the expense of more unnecessary prostate biopsies.

Dr. Robert A. Wascher