Rising PSA After A Negative Prostate Biopsy Part I: Crunching The Numbers

One of the most pleasant phone calls I can make is to tell one of my patients that their prostate biopsy was negative…no cancer.  I can often hear the sigh of relief on the other end of the line after several days of anticipation end in the best possible news.  After allowing the patient to rejoice for a while, however, I proceed to explain that a negative biopsy is not a guarantee of the absence of cancer.  I explain that while a prostate biopsy is undertaken through ultrasound guidance and in a systematic fashion, it is not 100% accurate. After all, a biopsy entails removing 12 tiny slivers of tissue from a gland that can vary in size from that of a walnut to that of a grapefruit.  You can imagine how possible it can be to miss some prostate cancer, particularly in men with very large prostates and small amounts of cancer.  As a result, I counsel these patients that, while the news is great, we still have to be cautious by checking the PSA every 6 months (some urologists advocate yearly tests) as well as performing a rectal exam at the same time intervals.  Most of my patients agree to this follow up protocol.

Unfortunately, at a later point in time, some of these men demonstrate a rise in their PSA.  This leads to a much less festive phone call.  Instead of a sigh of relief, I often hear anxiety and fear.  I also invariably hear the same question: “ Doc, what do we do now?”  This is actually a very important question with a complicated answer.  For some men, it means a repeat biopsy.  For others, in contrast, it means just repeating the PSA again in a few more months.  So how do you determine how to deal with a rising PSA after a negative prostate biopsy?  There are many tools that help urologists to figure out who needs a repeat biopsy in this setting.  In this post, I will cover how a more detailed look at the PSA can help determine whether a PSA rise after a negative biopsy is a sign of missed cancer or simply of benign growth of the prostate.

What Causes the PSA to Rise?

Before delving into the details of PSA rises, lets first explore why the PSA rises in men:

1) Artificial Rises: As I described in a previous post, at least 50% of elevated PSA tests are actually elevated in error.  PSA can be falsely elevated due to sexual intercourse within 2-3 days of the test, urinary tract infections, motorcycle riding, and even lab errors.  As a result, as with a single elevated PSA in new patients, I always recommend a repeat PSA test for those men who demonstrate a rise in PSA after a negative prostate biopsy.

2) Benign Prostatic Hypertrophy (BPH):  PSA is not only produced by prostate cancer cells.  It is also produced by normal prostate cells.  As a result, when benign prostate tissue grows in the form of BPH (the condition that gives you a slow stream and makes you urinate multiple times at night), the PSA naturally rises as a result.

3) Prostate Cancer:  Of course, in some men, a rising PSA is actually a sign of growing prostate cancer.  Most prostate cancer cells produce PSA and as the cells reproduce and grow, more and more PSA is produced.

Dissecting PSA Further

So how do we differentiate among these three potential causes of a rising PSA in a man after a prostate biopsy?  As I just mentioned, artificial rises in PSA can simply be differentiated from the other two through a repeat test after refraining from activities such as sexual intercourse while simultaneously checking a urine culture.  Determining whether a true rise in PSA is due to BPH versus prostate cancer is a much more complicated task after a negative prostate biopsy.  However, this determination can be made by taking a more detailed look at some specific aspects of PSA:

1) PSA Velocity:  Studies have demonstrated that a “normal” rise in PSA can be as high as about 0.7-1 per year.  This rise in PSA can safely be ascribed to BPH.  A yearly rise in PSA higher than this amount is a warning sign that cancer may be present and often triggers a repeat biopsy in men with a previously negative biopsy.

2) PSA Density:  Another aspect of PSA that can be valuable in distinguishing between BPH and prostate cancer is the PSA density.  During a biopsy, the urologist usually obtains an accurate measurement of the prostate volume by means of the ultrasound.  This size is usually described in grams or cubic centimeters (cc).  This measurement can be very helpful in evaluating future PSA elevations after the biopsy by allowing for the determination of the PSA density.  This calculation is carried out by dividing the PSA by the prostate volume.  For example, a man with a PSA of 5 and a prostate volume of 50 grams has a PSA density of 0.1.  Because BPH can also produce PSA, men with very large prostates should be expected to have higher PSA values than men with small prostates.  The PSA density allows you to compare apples to apples by determining the PSA in men per gram of prostate tissue.  Studies demonstrate that a PSA density of greater than 0.15 is suspicious for prostate cancer.

3) PSA Doubling Time: The PSA doubling time appears pretty self explanatory.  The term refers to the time it takes for the PSA to double in value.  To calculate this number you need a few PSA values spread at least 3 months apart.  You also need to use a fairly complex formula to get the exact value.  For our purposes, a rough, eyeball assessment will do just fine.  For example, by looking at a series of PSA values we can roughly estimate if the PSA is doubling every month, every 6 months, or every year, etc... Studies have demonstrated that PSA doubling time is one of the most important prognostic factors used to evaluate a rising PSA after a negative biopsy.  A PSA that doubles in 3-6 months is substantially more worrisome with regards to potential underlying prostate cancer as compared to a PSA that doubles in 1-2 years.

4) Free PSA:  Believe it or not, the PSA test actually represents a combination of two different types of PSA that are found in the blood stream: free and complexed.  While free PSA floats freely through the bloodstream, complexed PSA floats through the bloodstream attached to a specific protein. Why do we care about these two PSA subtypes?  Free and complexed PSA are sort of like good and bad cholesterol.  A higher free PSA is actually associated with a lower prostate cancer risk.  In contrast, a higher complexed PSA is associated with a higher prostate cancer risk.  While there is no great commercially available complexed PSA tests, a free PSA test is available.  The free PSA is reported as a percentage of the overall PSA test.  A I mentioned , the higher the free PSA, the less likely prostate cancer is present.  Studies have demonstrated that a free PSA of greater than 15-18% represents a low risk for prostate cancer as opposed to a free PSA less than 8% which represents a high risk for malignancy of the prostate.  Using such parameters, free PSA can help predict the likelihood of prostate cancer being present in men with a rising after a negative prostate biopsy.

Take Home Message

A rising PSA can be a stressful and worrisome finding in men following a negative prostate biopsy.  In this situation, the PSA needs to be further examined in terms of PSA velocity, doubling time, density as well as free PSA.  These various PSA based tests are used in combination to gauge the risk of prostate cancer in men with a rising PSA after a negative prostate biopsy.  Because prostate biopsies are not without risks, not every PSA rise in men necessitates a repeat biopsy.  Prudent use of these PSA tests can help determine which men with rising PSA after a negative prostate biopsy really need a repeat biopsy and which simply need to be followed with serial PSA tests and digital rectal exams.  In future posts, I will discuss other tests that can help to determine when a PSA rise after prostate biopsy truly indicates the presence of cancer.

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This blog is not a medical practice and cannot provide specific medical advice. This information should never be used to replace or discount the medical advice you receive from your physician