I have written in the past about the problems with using prostate specific antigen (PSA) as a screening tool for prostate cancer. Virtually all men over age 40 know they should have a PSA blood test at their annual exam, yet few have a complete understanding of what it really says. Even fewer know that there is more than one way to measure PSA. Let me explain.
PSA is a harmless protein produced by prostate cells. Small amounts leak into the bloodstream, and the amount can be measured in a laboratory. The larger the prostate, the more cells there are to produce PSA. Also, abnormal cells (such as infected cells or cancer cells) can cause an increased release of PSA into the blood, and so can physical stimulation of the gland (having sex, riding a bike, a digital rectal exam, etc.) Finally, as men age, the composition of the prostate gland gradually changes proportions from when they are in their twenties. The larger proportion of aging cells also results in a raised PSA, and this is normal. There are different types of PSA tests. While none of them can diagnose prostate cancer, a combination of two or more give better clues than the traditional basic test.
Basic or “total” PSA (tPSA)
The basic PSA test is a measure of all the PSA in your blood sample, and today’s tests can detect PSA levels close to zero (0.1 ng/ml or nanograms per milliliter). A “normal” PSA from a perfectly healthy gland and no gland stimulation within 24 hours before the blood draw is expected to be within 2.5 – 4.0 ng/ml. As you can see from the above, a variety of factors can lead to a gradual, or even a sudden, elevation in the PSA count. Doctors used to advise that a man with a PSA above 4.0 have a biopsy; nowadays, many doctors will advise the patient to have another test in three months, and if it is still high, take antibiotics to see if an infection was causing the rise. Also, prostate cancer (even aggressive prostate cancer) can exist in a man with a PSA lower than 2.0, though the probability is small. Therefore, total PSA is NOT a reliable way to screen for prostate cancer because even a noncancerous condition or situation can push the number up. More information is needed.
Free PSA (fPSA)
This test is the amount of PSA protein molecules that are freely circulating without being attached (bound) to other protein molecules. The amount of free PSA divided by the amount of total PSA (bound as well as free) gives the fPSA value, shown as a percentage. There is some evidence that a lower percentage of free PSA is associated with more aggressive cancer, as shown in this table[i]:
|% free PSA||Probability of prostate cancer|
|Greater than 25%||8%|
When total PSA and free PSA are both taken into account, most doctors will interpret it this way: the higher the total PSA and the lower the free PSA percentage, the greater the likelihood that prostate cancer is present. Does this mean that a man with a tPSA of 5.6 and fPSA of 24% should have a biopsy?
To biopsy or to image – that is the question!
Let’s look at three cases in which tPSA and fPSA raise a warning flag.
First case: a man who has never had a biopsy, including patients on active surveillance
When a doctor, usually a urologist, tells a patient that based on his PSA – either a suspiciously high PSA or one that has been gradually rising over a few years – that it’s time for a biopsy, in most cases the patient will have an in-office transrectal ultrasound-guided (TRUS) biopsy. This type of biopsy is basically blind and random, because ultrasound cannot show tissue differences in the gland.
There is an alternative. We strongly recommend that before scheduling a biopsy, the patient has a 3T multiparametric MRI (3T mpMRI). This state-of-the-art imaging will reveal any areas that are suspicious for cancer. If such areas are found, an MRI-guided biopsy offers two advantages over TRUS biopsy. First, it is targeted to the suspicious area, which requires fewer needles (though extra random samples can also be taken). Second, if prostate cancer is diagnosed, the aggression level will be more accurate because a needle is image-directed into the core of the suspicious area where the most aggressive cells will be present.
Second case: a man who has had at least one previous biopsy
Anyone who has already had one TRUS biopsy is reluctant to go through it again, but if his PSA has gone higher it would seem negligent to avoid a biopsy. On the other hand, if the first biopsy missed cancer that was there, there is a good possibility it will miss it a second, even a third time, while it continues to grow. This is because there are certain prostate zones that TRUS biopsies have a harder time accessing, where cancer can start and progress.
Again, we strongly recommend that a 3T mpMRI be the next step before a biopsy. As in the first case, the imaging will show cancer if it’s there, making a targeted MRI-guided biopsy the best way to obtain an accurate diagnosis.
Third case: a man who has already been treated for prostate cancer
After any prostate cancer treatment (surgery, radiation, ablation) a PSA blood test has value as a way to monitor the effectiveness of the treatment. Whatever the lowest PSA following treatment (zero after gland removal, or PSA nadir after any other treatment), it becomes the new baseline. If PSA begins to rise, there will be suspicion that the cancer has come back. A biopsy will be recommended after two or three successive rises.
As in the above two cases, why not turn to 3T mpMRI to determine if cancer has recurred, either within the gland, local spread (to the prostate bed or closest lymph nodes), or regional spread within the pelvic area and more remote lymph nodes? Based on the MRI results, a decision can be made as to whether a biopsy is warranted.
In short, the PSA blood test (tPSA + fPSA) has merit as an early warning sign. It can act to trigger a next step, but in all cases, we suggest it should be imaging before biopsy. In many cases, no biopsy will be necessary. Today’s 3T mpMRI can detect inflammation and benign conditions that elevate PSA, saving patients from an unpleasant and unnecessary procedure. And, if a biopsy is necessary, MRI guidance reduces the number of needles while increasing accuracy. It’s a far better choice when PSA rises.
[i] Journal of the American Medical Association, May 20, 1998.