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GO BACK TO: DIAGNOSIS: PSA: GO TO YANANOW HOME PAGE

PSA 101

PSA - PROSTATE SPECIFIC ANTIGEN

 

PSA is the most widely used test for detecting prostate cancer today. It was developed originally to establish if a prostatectomy had successfully removed all traces of cancer with the prostate gland. The concept being that there should be no PSA detectable with the test as it was developed at the time. The movement to use it as a diagnostic tool as an indicator of the presence of prostate cancer followed shortly.

It is simple to do. A small sample of blood is taken, usually from a vein in the arm, and is tested for the presence of PSA (Prostate Specific Antigen). The laboratory testing the blood will come back with a number, which usually reflects the level of PSA in the blood in nanograms per milliliter (ng/ml). A nanogram is one thousand millionth of a gram so the quantities measured are very small.

The enzyme labeled PSA was initially thought to be formed only by the prostate gland - hence "prostate specific". It is not in fact prostate specific and very small quantities of the enzyme are produced by other glands - and even by women. The production of the PSA enzyme by other organs can cause problems with the interpretation of Ultra-Sensitive PSA tests discussed below.

PSA IS NOT CANCER SPECIFIC

The PSA test is also not prostate cancer specific. An elevated PSA reading does not always mean that the man being tested has prostate cancer. Quite the contrary. Only about one third of men who have an elevated PSA level (usually over 4.0 ng/ml) will be found to have a positive biopsy result and be diagnosed with prostate cancer. Two thirds of the men will not be diagnosed. This point, often misunderstood, gives rise to what is referred to as "PSA anxiety" with men having multiple biopsies in an effort to find a disease which may not exist. Ralph Valle, a long time prostate cancer activist, wrote a short piece which is worth reading in this context. Read it here WHAT'S NEW ? A SHORT ESSAY ON PSA.

PSA LEVELS 4.0 NG/ML OR HIGHER

When the PSA test was approved and introduced in 1990 a reading of higher than 10 ng/ml was regarded as one that should be investigated further. This figure was subsequently reduced to 4.00 ng/ml, which is regarded as "normal" in most countries and by most medical people. In the US there was a move to reduce the limit to 2.60 ng/ml or even to 1.25 ng/ml, and some doctors use these levels to define 'normality'. On the other hand, one leading expert physician feels that any PSA result under 12 ng/ml is not worth being concerned about, unless there are other symptoms. Another theory is that since there is a correlation between age and PSA levels - they tend to be higher in older men - a table of 'normal' levels linked to age should be used. Between 25% and 35% of men with a PSA reading of between 4.00 ng/ml and 10.00 ng/ml will be found to have prostate cancer. In the majority of cases the elevated reading will be due to some other cause.

PSA LEVELS BELOW 4.0 NG/ML

It took some time before a study was completed to establish the levels of prostate cancer in men with a PSA level below the "normal" of 4.0 ng/ml. This study concluded "Biopsy-detected prostate cancer, including high-grade cancers, is not rare among men with PSA levels of 4.0 ng per milliliter or less levels generally thought to be in the normal range."

In this study of almost 3,000 men, 15.2% (442 men) were found to have prostate cancer on biopsy. Four of the men had Gleason Scores of 8 (two of these men with a PSA of less than 1.0 ng/ml) and three had a Gleason Score of 9. These low PSA/high Gleason Score variants are particularly dangerous as they are missed with PSA tests and are usually diagnosed at a late stage when symptoms develop. Some may have been discovered earlier by way of a positive DRE (Digital Rectal Examination) had this been done.

The study was published in May 2004 and can be downloaded here (it is a large pdf file) PREVALENCE OF PROSTATE CANCER AMONG MEN WITH A PROSTATE-SPECIFIC ANTIGEN LESS THAN 4.0 NG/ML This shows the main results of the study, tabulated:

PSA (ng/ml)
Percentage of men diagnosed
Up to 0.50
6.6 %
0.60 - 1.0
10.1 %
1.10 - 2.0
17 %
2.1 - 3.0
23.9 %
3.1 - 4.0
26.9 %

UPPER PSA LEVELS

There is no upper limit to the scale of measurement of PSA and it is not possible to say what the range of "normal" readings is. An Australian doctor reported a patient with a PSA over 300 ng/ml who was not diagnosed with prostate cancer and whose PSA level fell back to under 4.0 ng/ml after treatment with antibiotics. PSA readings of over 100 ng/ml are not uncommon. 50 of the 1,000 stories on this site at April 2012 are from men who had readings over this level. Even higher readings - over 1,000 ng/ml - are not unheard of. Twelve of the fifty "high level" men on the site had PSA levels over this figure - the highest being over 7,000 ng/ml. If you wish to go directly to the stories click on the link SURVIVOR STORIES in the header of this page.

One reported case (not on this site but in the PCRI INSIGHTS NEWSLETTER - December 1999 vol. 2, no. 4) concerned a man in the United States who had a PSA reading of 3,552 ng/ml in 1991 which climbed to 12,600 ng/ml in 1992. In 1999 his PSA was 109 ng/ml after treatment and he was still working as a chief pilot on the world's largest American cargo airline. He retired in 2008.

These high PSA numbers are usually associated with aggressive forms of the disease or late stage diagnoses.

PSA RESULTS NOT COMPARABLE

There are many commercial PSA assays - one study suggests 30 or more, another compared 24 different assays. Different methods and techniques are used by these various tests to measure PSA. Some are immunoradiometric, some are enzyme immunoassays and at least one is a chemiluminescent immunoassay.

The results produced by these different assays vary considerably. Although all manufacturers agreed some years ago to calibrate their equipment to produce comparable results (the Stanford Protocol), this agreement was voluntary and is rarely adhered to. It does not apply to so called free PSA tests or to ultra-sensitive tests (both of these subsidiary tests are dealt with below).

One of the key measurements in the use of PSA results is to track changes. It is therefore very important to ensure that all tests are run by the same laboratory using the same assay equipment. If this is not done, the results may not be directly comparable. It can be very difficult to ensure that comparable results are produced because laboratories change assay methods quite frequently, often driven by cost issues, and although they claim to tell physicians of these changes, the information is rarely given clearly to men using the services. In the event of an unusual change in PSA levels it is always worth checking to see if there has been a change in assay and, if there has, to establish a new base.

PSA RANGES OF ACCURACY

Although in ideal conditions it may be possible to measure PSA levels consistently, most laboratories will only guarantee accuracy to within 80%. There are many reasons for this. For one thing, it is extremely difficult to measure very precisely either nanograms of PSA or milliliters of blood without a degree of error - think of the variances in gas (petrol) that is delivered on a very cold morning or a hot noon from the same pump. The dial on the pump will register the same volume of the liquid, but you certainly won't be getting an identical amount in your tank.

The other, and more pertinent reason is what are termed systematic errors. These arise where, for example, the instruments have not been properly calibrated or maintained; where the assay material used is past its best 'use by' date; where the staff in the laboratory are not properly supervised. Think of photographs printed by different photo-shops before the widespread use of digital cameras and what a variance there was in results from, say a Fuji shop or a Kodak one. Nowadays, many people who have home inkjet photo printers are disappointed by some of the results with the color of the image on the computer screen being vastly different from the printed picture. The level and quality of inks and paper can make a difference, as can the lack of calibration of the screen. All these systematic errors will affect the results to a greater or lesser degree and account for some of the variances reported. In times of economic pressures there may be greater variances as shortcuts may be taken, cheaper and less accurate material purchased, staff levels cut back.

For all these reasons results should ideally be shown as a range, or with an error margin. For example, a PSA now stated to be 4.9 ng/ml is most likely the mid point in a range from 3.92% to 5.88 ng/ml. Given this, a second test with a level of 5.2 ng/ml should not necessarily be taken as an increase in levels because it falls within the same range as the first test. The same logic would apply to a second result of 4.2 ng/ml which would not necessarily be a fall in the PSA levels.

OTHER PSA VARIANCES

Apart from these variances, PSA levels can be elevated by a number of causes, from infection to physical activities. For this reason it is very important to try to establish the cause of any elevated PSA level reported. If the PSA is below 20 ng/ml this should be done before having a biopsy.

The most common causes of an elevated PSA are: prostatitis (an infection of the prostate); a bladder infection; or BPH (benign prostatic hyperplasia). This last condition affects most men over 50 years of age and is not deadly.
Any infection should be treated before a second PSA test is carried out. Acute prostatitis can cause the PSA levels to rise five to seven times the normal level for up to six weeks or even longer. Both prostatitis and bladder infections are notoriously difficult to treat. There are various natural and pharmaceutical products that may reduce the size of a gland and these may reduce the effect of BPH on the PSA level, as will a TURP (Trans Urethral Resection Procedure).

It is recommended that blood for PSA testing should be drawn as early in the day as is convenient and preferably before eating. Constipation and weightlifting are thought to affect PSA levels as does virtually anything that disturbs the prostate gland. Some of the major physical activities which may affect PSA levels and which should be avoided before drawing the blood are:


Sexual activity: Ejaculation can elevate PSA levels for up to 48 hours, or possibly 72 hours, after it has taken place. One of the curious aspects of PSA testing is that it is very rare for this very common cause of variation of PSA levels to be mentioned. If, for example, a test is ordered for cholesterol the doctor will warn their patient that they must fast for 12 hours to ensure the test result is valid. On presenting at the phlebotomist they will be asked if they have eaten anything in the past 12 hours. Yet very few, if any, doctors or phlebotomists will ask men about to have a PSA test about their sexual activities.
DRE (Digital Rectal Examination). Although doctors often carry out the DRE before drawing blood, they should reverse these procedures

Cycling or Motor Cycling: This can increase levels up to three times for up to a week, depending on how strenuous the cycling is. This includes an exercise bicycle

Alcohol and Coffee: Both can irritate the prostate and should be avoided for 48 hours prior to blood being drawn

There are many studies that try to evaluate the effect of activities and physical conditions. One such study in Germany concluded that there were seasonal variances in PSA levels and other studies have pointed to the possibility of certain foods and drinks also affecting results.

PSA levels can also vary significantly for no obvious reason. One published study shows that of the 295 men in the study who had a first reading of less than 10 ng/ml and who then had two PSA readings within 90 days, only 6% of these men had two identical readings; of the remaining men 46% had a increase or the same PSA on second reading, 54% had a decrease. The largest differences were a reduction of 5.3 ng/ml and an increase of 7.5 ng/ml. The differences are summarized in this table:

Percentage of men
Difference compared to first test
64%
Between - 1.0 and + 1.0 ng/ml
18%
Between +/- 1.0 and +/- 2.0 ng/ml
7%
Between +/- 2.0 and +/- 3.0 ng/ml
5%
Greater than +/- 3.0


The study stated that these differences might be the result of the mixed effect of random errors, batch inequalities, so-called "physiologic variations"
(which I take to mean that no-one has a clue as to why there was such variance!) and transient effects of concomitant prostatitis. .

BPH (BENIGN PROSTATIC HYPERPLASIA)

A prostate gland that is enlarged with BPH (benign prostatic hyperplasia) will also produce more PSA than a normal sized gland. There are various formulae used to try to relate the amount of PSA expressed to the volume of the gland. One of the simplest calculations, suggested by a leading oncologist, is to apply a factor of 0.066 to the gland volume, the resultant figure representing the BPH component. Deduct this from the total PSA and the balance is the 'normal' reading. This is not a very accurate calculation, if only because it is difficult to calculate the volume of the gland accurately.

TRACKING PSA

Because of inaccuracy and variances in PSA results it is important to have a series of PSA tests done to establish the overall movement in the levels before making any treatment decision. Many men monitor their PSA levels for some years watching for any upward trend in the numbers. Typically, PSA generated by activities or conditions other than prostate cancer activity will tend to fluctuate up and down, whilst PSA associated with prostate cancer will tend to increase at an ever greater speed. One of the key issues in looking at these series of numbers is the doubling time of the PSA numbers - referred to in the prostate cancer shorthand as PSADT. Jon Nowick has prepared a DOWNLOADABLE EXCEL SPREADSHEET that calculates doubling time and graphs PSA results. There is more about this issue - and some interesting illustrations of just how variable PSA readings can be in my PSA - 28 DAY EXPERIMENT.

A study done in 2003 in which nearly one thousand men had five consecutive PSA tests over a four-year period shows how PSA levels can fluctuate. About one fifth of these men had elevated PSA levels at some time during this period. Subsequent testing of the same men a year or more later indicated that the PSA levels for half of the men had returned to normal. You can read a report on this study at PSA TEST FOR PROSTATE CANCER SHOWN TO HAVE NORMAL FLUCTUATION

The most important point is that no decision to treat should be made on the basis of one isolated PSA reading. Elevated PSA numbers should always be checked by having a second test in case there is an error.

FREE PSA (fPSA)

If a PSA result is between 4 and 10 ng/ml, and provided there has been no treatment, it is suggested that a second test should be run - the so-called fPSA, PSA II or Free PSA test. This doesn't mean that there is no cost. It refers to the amount of what is referred to as "unbound" PSA. The underlying theory regarding fPSA being that the less fPSA that is found, the greater the probability of prostate cancer being the cause of an elevated PSA level. The result of this test is usually shown as a percentage of the total PSA measured. The risk of cancer being present varies in inverse proportion to the percentage shown. There are many estimates as to what constitutes a level of fPSA that requires further investigation because it may be prostate cancer related. The table below shows one such set of probabilities:

Free PSA %
Probability of PCa %
0 - 10
56
10 - 15
28
15 - 20
20
20 - 25
16
> 25
8

So the higher the percentage, the less chance there is of the PSA being caused by prostate cancer. A fPSA of over 10% would mean that the most likely cause of the elevated PSA is not prostate cancer: a fPSA of under 10% is more strongly correlated with prostate cancer. There are some studies which show that the fPSA test may be valid for readings between 2.5 ng/ml and 20 ng/ml. There are also studies that show that infection or disease and BPH can impact on fPSA levels and render them of less value.

ULTRA-SENSITIVE PSA

Once treatment is completed (especially where the treatment choice is surgery), an ultra-sensitive PSA test is often used. It is important to understand why there can be variations in these test results that may have nothing to do with prostate cancer returning. This short piece - ULTRA-SENSITIVE PSA may give a good basic understanding of the issues and why a study published in November 2011 concluded:

"Agreement between prostate specific antigen doubling time calculated using ultrasensitive vs traditional prostate specific antigen values is poor. Ultrasensitive prostate specific antigen doubling time is often significantly more rapid than traditional prostate specific antigen doubling time, potentially overestimating the risk of clinical recurrence. Until the significance of ultrasensitive prostate specific antigen doubling time is better characterized, the decision to proceed with salvage therapy should not be based on prostate specific antigen doubling time calculated using ultrasensitive prostate specific antigen values."

 

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