Understanding Your PSA Test Results

Prostate Specific Antigen (PSA) is a protein made in the prostate gland. Normally, very little should be found in the blood. Rising levels of PSA in the blood indicate a problem with the prostate, which could be cancer but could also be an enlarged prostate (BPH).

The American Urological Association and the National Comprehensive Cancer Network (NCCN) say men at age 40 should consider a PSA test in order to establish a “baseline” level for future comparison and to determine “PSA velocity” (the rate at which a man’s PSA score increases).

If the PSA level is 1.0ng/mL or greater, an annual follow-up is needed, based on NCCN guidelines. If the PSA level is less than 1.0 ng/mL, the next testing should be at age 45.

Afterward, doctors typically recommend further testing for men with a total PSA level that is higher than 2.5 ng/mL. This cut-off level established by NCCN.

As PSA levels increase, so do the odds that it's due to prostate cancer. About 25 percent of men with a PSA level from 4 to 10 will have prostate cancer. About 67 percent of men with a PSA above 10 will have the disease.

The change in your PSA level over time -- called PSA velocity -- is very important. Even if your PSA is 4.0 ng/mL or below, an increase of 50 percent or more in just one year may indicate prostate cancer. If your PSA is above 4.0 ng/ml, an increase of 75 percent or more within a single year could indicate an aggressive case of the disease.

There are some factors that you and your doctor may want to consider when it comes to interpreting your score:

• Your age. Doctors may use age-adjusted PSA ranges to account for the natural increase in PSA with age when considering the need for further testing.
• The size of your prostate. “PSA density” is a measure that relates your PSA level to the size of your prostate, to account for the increase in PSA caused by an enlarged prostate.
• Your weight. Body Mass Index, a measure of obesity, may also be a factor. The relationship between obesity and lower PSA levels may cause doctors to miss early prostate cancer cases in overweight men.
• Ejaculation within 48 hours before taking a PSA test can also cause a higher reading of your PSA level.

Some doctors recommend the following PSA cut-off levels adjusted by age and ethnicity:

Age	Caucasian or Hispanic	African American	Asian
40 to 49	2.5	2.0	2.0
50 to 59	3.5	4.0	3.0
60 to 69	4.5	4.5	4.0
70 to 79	6.5	5.5	5.0

PSA Test Standards

Today, because there are two standards for PSA tests, the same cutoff should not be used across all PSA tests. It is important for you and your physician to know which type of test your clinic's lab uses and how to correctly interpret the results.

The Hybritech PSA test established 4.0 ng/mL as the cutoff for a normal test. This means men with a score above 4.0 should be referred for further testing, such as a biopsy. Men with a result lower than 4.0 may not be referred for biopsy, depending on their physician's instructions. As other manufacturers developed PSA tests, they aligned their tests to the same standard, which became known as the "Hybritech standard," and other manufacturers used the same recommended cutoff of 4.0.

By the mid-1990s, some researchers began to recognize that test results from different test manufacturers could be slightly different and joined together to create a common calibration standard to better align results from different PSA tests. This standard was accepted by the World Health Organization (WHO) and soon became known in the medical community as the "WHO standard" PSA test. To establish this new standard, a different scientific process to measure molecular weight of PSA was used and found that weight to be 20 percent higher than what was used for the Hybritech test. Because of the way this is calculated, a WHO test would show a proportionately lower PSA concentration level than would a Hybritech test for the same sample. As a result, the cutoff point at which men are referred for further testing would more appropriately be set about 20 percent lower than the 4.0 used for the Hybritech test.

To find out which type of test you have received, your physician should contact his or her lab to determine which brand of test was used for their PSA testing and whether it is WHO or Hybritech calibrated.

Types of PSA Tests

Some of the PSA in the blood is bound to enzymes (complexed) while some is freely circulating (free). Unless otherwise noted, the PSA levels generally refer to total PSA (or tPSA), a combination of complexed and free PSA.

Free-PSA (or fPSA) refers to the percentage of PSA in the blood that is not bound to enzymes. Doctors are now recommending further testing for men with a free-PSA of less than 25 percent. This is a helpful indicator for men who may be uncertain whether to get a biopsy, such as those with PSA levels between 4 and 10, and negative DRE results.

Complexed PSA (or cPSA) refers to the measure of one type of bound or complexed PSA. This measure is as accurate as total PSA and may be better at ruling out some people from further testing. Cut-off levels are different for cPSA, so make sure you know whether your PSA test is complexed or total. For example, a cPSA level of 2.2 is equivalent to the cut-off level of tPSA at 2.5.

PSA and Recurring Prostate Cancer

The PSA test is also used to detect and monitor recurrence of prostate cancer after initial treatment. PSA levels should drop dramatically after initial treatment. If they rise again, they are a good indicator that the initial treatment did not catch all the cancer cells.

Changes in Some PSA Tests May Require Changes in How Results are Interpreted

The PSA (prostate specific antigen) test is one of our best weapons in the battle against prostate cancer, but in recent years, changes to some PSA tests mean some test results may have to be interpreted differently than doctors have become accustomed to. For many years, 4.0 was the cutoff many physicians and medical professionals used for a "normal" test result. But today, a 4.0 isn't always a 4.0 on all tests. Physicians and patients who do not know which type of test was used may not interpret the results appropriately, potentially leading to a delay in care for men with prostate cancer.

It has always been important for men to know their PSA test results and to discuss results with their doctors; now they also need to identify which test they had to ensure that the appropriate interpretation is made.

Two Types of Tests

PSA is a protein made in the prostate gland and, normally, very little should be found in the blood in men without disease. In the mid-1980s, researchers discovered that PSA may indicate prostate cancer in men when elevated levels are detected in the blood. Until then, a digital rectal exam (DRE) was the primary method of prostate cancer detection. Within several years, clinical studies established the role of PSA in prostate cancer screening.

Measuring the concentration of PSA in a man's blood proved to be a major advance in the fight against prostate cancer. Along with the digital rectal exam (DRE), physical exam and risk factors, PSA testing has helped identify which men are at sufficient risk for cancer that a biopsy is warranted. PSA testing has led to a more than 30 percent decline in prostate cancer death rates since it began to become widely used, according to the American Cancer Society.

The first PSA test approved by the U.S. Food and Drug Administration (FDA) for use in prostate cancer screening (in conjunction with DRE) was developed by Hybritech. Based on its own clinical studies of more than 6,600 men, Hybritech established 4.0 ng/mL as the cutoff for a normal test. This means men with a score above 4.0 should be referred for further testing, such as a biopsy. Men with a result lower than 4.0 may not be referred for biopsy, depending on their physician's instructions. As other manufactures developed PSA tests, they aligned their tests to the same standard, which became known as the "Hybritech standard," and other manufacturers used the same recommended cutoff of 4.0.

By the mid-1990s, some researchers began to recognize that test results from different test manufacturers could be slightly different. Some researchers joined together to create a common calibration standard, to better align results from different PSA tests. This standard was accepted by the World Health Organization (WHO). This soon became known in the medical community as the "WHO standard" PSA test.

In establishing the new standard, the WHO scientists used a different scientific process in measuring the molecular weight of PSA. They determined the weight of PSA is about 20% higher than had been determined by Hybritech scientists, who used a scientific process that was widely used at the time the Hybritech test was developed.

Since the weight of the sample is used to determine the concentration of PSA and since the WHO test uses a higher weight measure for PSA, it follows that the WHO test would show a proportionately lower PSA concentration level than would a Hybritech test for the same sample. As a result, the cutoff point at which men are referred for further testing would more appropriately have been set about 20 percent lower than the 4.0 used for the Hybritech test.

But unfortunately, many still use 4.0 as the cutoff for both tests.

Many manufactures rushed to incorporate the new standardization in their PSA assays. Patient results determined from the WHO standardized assay began to be reported in 2000.

Scientific studies noted this difference in results between the two tests soon after the introduction of the WHO standard.1 A study published in the Journal of Urology in 2004 concluded that "the potential clinical impact of this variability on cancer detection is significant."2 A comparable study, which confirmed a 22 percent gap between the tests, was presented earlier this earlier this year at the American Urological Association's annual meeting.3

This approximately 20 percent gap means that a man who received a 4.0 result on the Hybritech test should receive a 3.1 on the WHO test. Unfortunately, many in the medical community continue to use a strict 4.0 as the cutoff, unaware that the cutoff is not the same for all tests. Consequently, men who receive a score between 3.1 and 4.0 on a WHO test may not be referred on to further testing as quickly as they might have.

The issue at hand is not which test is better, but that changes in the test require changes in the interpretation -- a different cutoff score. It's not unlike the difference between kilometers per hour and miles per hour when driving a car. If you don' know how the speed limit is measured, you could end up with a speeding ticket.

But the consequences of not knowing what scale you are using are much more serious than a speeding ticket when it comes to prostate cancer. Just as drivers are cautioned to know the correct speed limit on the road, so should doctors be cautioned in how they interpret the results for the Hybritech and WHO tests. If the cutoffs for screening are not adjusted accordingly, the conclusions doctors draw about their patients may be flawed.

No one knows exactly how many men with prostate cancer have been missed due to this issue. But given the number of tests that are conducted each year and the prevalence of prostate cancer, the implications could be staggering.

Of the approximately 18 million PSA tests conducted each year in the United States for screening purposes, about 12 million are based on the WHO standard and the remaining on the Hybritech standard. Studies have shown that about five percent of men who are tested with a WHO test likely would not be referred for a biopsy using the 4.0 cutoff, when they would have if they had received a Hybritech test. As a result, about 600,000 men per year may not be referred for biopsy due to differences between results on WHO test compared to the Hybritech test. Among these men are an estimated 180,000 per year who likely have prostate cancer, including 50,000 who have an aggressive form of prostate cancer (these numbers are based on cancer rates reported in the Prostate Cancer Prevention Trial).

Some men are referred for biopsy even though their value may not have reached 4.0 because their PSA value has increased rapidly over a short period of time. The measure of change in PSA level over time, which may be PSA velocity or doubling time, may be used to determine if further testing is warranted. For instance, even if the PSA score is below 4.0, an increase of 50 percent or more in one year may indicate prostate cancer. But this change may be not be detected as rapidly in a patient being tested with a WHO test.

In addition, if a patient's results are a mix of WHO and Hybritech tests, the doctor may not detect a change, or he may believe a change has occurred when nothing has changed. For instance, the scores of a patient who goes from the Hybritech test to the WHO test would understate the change, while the change in condition would be overstated for the patient who goes from the WHO test to the Hybritech test. In the first case, the patient was missed; in the second, he may have received an unnecessary biopsy.

Accurately Interpreting PSA Test Results

The medical community is only beginning to become aware of this issue. Many labs do not know that cutoff level may differ depending on the test they provide. Many health providers continue to use the 4.0 cutoff for all tests. Until now, at least, most health care providers do not know if their test is based on WHO or Hybritech standards.

Until manufacturers and the medical community agree on how to resolve this issue, it is important for everyone involved, from the laboratories to the physician to the patient, to know what type of test was administered and how that might affect the interpretation of the resulting value.

Men who have been screened with the PSA test in the past five years may want to speak with their doctor or other health provider about what type of test you were given.

The PSA test is one of the best tools we have to catch prostate cancer early and help save lives. But it is vital for the health of patients that we interpret the tests accurately.

Testing Guidelines

While researchers look for better tests, major progress has been made in interpreting PSA test results. The rate of increase in your PSA level (PSA Velocity) may tell you more than your PSA level itself.

The National Comprehensive Cancer Network (NCCN), a network of researchers and leaders from the top cancer centers across the country, works to produce screening guidelines that reflect the highest possible level of consensus about new research and how to apply it.

ZERO endorses NCCN’s work, applies its guidelines in operating our Drive Against Prostate Cancer free testing program, and reflects its guidelines in our education materials.

NCCN recommends that at age 40, high-risk men should be offered a baseline PSA and DRE.

If their PSA is 1.0 ng/mL or greater, they receive an annual follow-up. If the PSA level is less than 1.0, the NCCN Guidelines recommend that these men be screened again at age 45.

For men with a family history of prostate cancer or men of African-American descent, however, NCCN recommends annual testing to begin at age 40.

For men with a PSA level lower than 4.0 ng/mL, NCCN recommends considering a biopsy if the rate of increase in PSA level is greater than or equal to 0.5 within a single year.

NCCN generally recommends a biopsy for all men with a PSA level over 2.5 ng/mL. (NCCN previously set this cut-off level at a 0.75 increase in PSA level within a single year.) See PSA Velocity below.

NCCN also recommends a TRUS guided biopsy for all men with an abnormal or positive DRE result, regardless of PSA level.

NCCN includes "percent free PSA" as an option for follow-up, for men with a PSA between 4 to 10 ng/mL who may want to avoid biopsy or treatment due to other medical conditions and expected life-span. In this case, they recommend a biopsy if free PSA is less than or equal to 10 percent.

NCCN Guidelines for PSA Velocity

If your PSA level increases rapidly within a single year (by 0.5 or greater), see your doctor.

Even if your PSA is 4.0 ng/mL or lower, an increase of 50 percent or more in a single year may indicate prostate cancer. For example: from 1.0 to 1.5ng/mL, or from 2.0 to 3.0 ng/ml in one year.

If your PSA is above 4.0 ng/mL, an increase of 75 percent or more in a single year could indicate an aggressive case of the disease. For example: from 4.0 to 7.0 ngml in one year.

Some men may take a PSA test starting at 35 or 40, to establish a baseline level for future comparison.

Ask Your Doctor: Different Tests Require Different Cutoff Points

In establishing the new standard, the WHO scientists used a different scientific process in measuring the molecular weight of PSA. They determined the weight of PSA is about 20% higher than had been determined by Hybritech scientists, who used a scientific process that was widely used at the time the Hybritech test was developed.

Since the weight of the sample is used to determine the concentration of PSA and since the WHO test uses a higher weight measure for PSA, it follows that the WHO test would show a proportionately lower PSA concentration level than would a Hybritech test for the same sample. As a result, the cutoff point at which men are referred for further testing would more appropriately have been set about 20 percent lower than the 4.0 used for the Hybritech test.

But unfortunately, many still use 4.0 as the cutoff for both tests.

Many manufactures rushed to incorporate the new standardization in their PSA assays. Patient results determined from the WHO standardized assay began to be reported in 2000.

Scientific studies noted this difference in results between the two tests soon after the introduction of the WHO standard.1 A study published in the Journal of Urology in 2004 concluded that "the potential clinical impact of this variability on cancer detection is significant."2 A comparable study, which confirmed a 22 percent gap between the tests, was presented earlier this earlier this year at the American Urological Association's annual meeting.3

This approximately 20 percent gap means that a man who received a 4.0 result on the Hybritech test should receive a 3.1 on the WHO test. Unfortunately, many in the medical community continue to use a strict 4.0 as the cutoff, unaware that the cutoff is not the same for all tests. Consequently, men who receive a score between 3.1 and 4.0 on a WHO test may not be referred on to further testing as quickly as they might have.

The issue at hand is not which test is better, but that changes in the test require changes in the interpretation -- a different cutoff score. It's not unlike the difference between kilometers per hour and miles per hour when driving a car. If you don' know how the speed limit is measured, you could end up with a speeding ticket.

But the consequences of not knowing what scale you are using are much more serious than a speeding ticket when it comes to prostate cancer. Just as drivers are cautioned to know the correct speed limit on the road, so should doctors be cautioned in how they interpret the results for the Hybritech and WHO tests. If the cutoffs for screening are not adjusted accordingly, the conclusions doctors draw about their patients may be flawed.

Misdiagnosis and the Need for Patient Care

No one knows exactly how many men with prostate cancer have been missed due to this issue. But given the number of tests that are conducted each year and the prevalence of prostate cancer, the implications could be staggering.

Of the approximately 18 million PSA tests conducted each year in the United States for screening purposes, about 12 million are based on the WHO standard and the remaining on the Hybritech standard.4 Studies have shown that about five percent of men who are tested with a WHO test likely would not be referred for a biopsy using the 4.0 cutoff, when they would have if they had received a Hybritech test. As a result, about 600,000 men per year may not be referred for biopsy due to differences between results on WHO test compared to the Hybritech test. Among these men are an estimated 180,000 per year who likely have prostate cancer, including 50,000 who have an aggressive form of prostate cancer (these numbers are based on cancer rates reported in the Prostate Cancer Prevention Trial5).

Some men are referred for biopsy even though their value may not have reached 4.0 because their PSA value has increased rapidly over a short period of time. The measure of change in PSA level over time, which may be PSA velocity or doubling time, may be used to determine if further testing is warranted. For instance, even if the PSA score is below 4.0, an increase of 50 percent or more in one year may indicate prostate cancer. But this change may be not be detected as rapidly in a patient being tested with a WHO test.

In addition, if a patient's results are a mix of WHO and Hybritech tests, the doctor may not detect a change, or he may believe a change has occurred when nothing has changed. For instance, the scores of a patient who goes from the Hybritech test to the WHO test would understate the change, while the change in condition would be overstated for the patient who goes from the WHO test to the Hybritech test. In the first case, the patient was missed; in the second, he may have received an unnecessary biopsy.