Friday, March 23, 2012

Positive Margins After Prostatectomy: They Are Not All The Same

One element of a pathology report that every urologist looks for after performing a prostatectomy is the status of the surgical margins.  The term “margins” refers to the cut surfaces of the prostate and, specifically, whether prostate cancer can be found at these cut surfaces.  When pathologists receive a prostate specimen after a prostatectomy they usually cover the surfaces of the prostate with ink.  They then look to see if prostate cancer cells can be found within these inked margins.  The presence of prostate cancer at one of these inked surfaces is termed a “positive margin”.  Found in approximately 30% of prostatectomy specimens, positive margins can impact the prognosis of men with prostate cancer as well as result in the need for adjuvant therapy after surgery.  However, as I will explain, not all positive margins are the same. In this post, I will describe the different types of positive margins as well as the significance of these findings.

Types of Positive Margins

You would imagine that a positive margin is a pretty straightforward thing.  After all, cancer cells are either present at the margins or not, right?  While this is true, prostate margins are, in reality, a little more complicated.  Different types of positive margins occur for different reasons and, in turn, have different consequences.

1)      Positive Margin in Organ Confined Disease (T2):   The prostate is covered by  a lining called the capsule.  Prostate cancer that is organ confined is located entirely within the limits of the prostate and, in turn, within the capsule.  During prostatectomy, the surgeon may accidentally cut into the prostate, stripping some of the prostate capsule away and possible exposing an area of prostate that contains prostate cancer.  In this situation, prostate cancer can be  seen extending to the margin while no capsule is seen in the area.  In this situation, the pathology report may state that the capsule in the area of the positive margin is “stripped” or “not seen.”  This type of positive margin is usually due to technical error during surgery rather than to aggressive disease.  Positive margins have been reported in 5-27% of men undergoing prostatectomy for organ confined disease.

2)      Positive Margin in Non Organ Confined Disease (T3-T4): Occasionally aggressive prostate cancer can extend through the capsule and out of the prostate.  This is called extracapsular extension (ECE) or extraprostatic extension(EPE).  Either way, it means that the cancer went outside of the prostate before the prostatectomy was performed.  Occasionally, the surgeon can cut around the prostate widely enough to still remove the cancer completely despite the ECE.  Sometimes, however, the cancer extends beyond where the surgeon can safely cut and, so, some cancer is left behind, creating a positive margin.  The pathology report in this situation usually reports that cancer cells are seen “extending through the capsule and are noted at the margin.”  This positive margin is caused by the aggressiveness of the cancer rather than by surgical technique. Positive margins have been reported in 17-65% of men undergoing prostatectomy for non organ confined disease.

3)      Artifactual Positive Margin: Sometimes what appears to be a positive margin is not one at all.  Occasionally, the way a prostate specimen is manipulated during surgery or during pathology processing creates an appearance of a positive margin.  This is, of course, often difficult to distinguish from the real thing.  Given the anatomy of the apex of the prostate (the tip of the prostate that connects to the urethra) what appears to be a positive margin at that location is often thought to be an artifact.

Risk Factors for Positive Margins

Many studies have determined specific preoperative factors that make positive margins more likely.  As you might imagine, the different types of positive margins have different risk factors.  Positive margins in non organ confined disease are usually more likely to be found in men with high risk prostate cancer at biopsy.  These men usually have higher PSA, higher Gleason score, and/or prostate nodules that can be felt on rectal exam.  In contrast, risk factors for positive margins in organ confined disease are more technical in nature.  A prostatectomy performed on an obese man or someone with a narrow pelvis is usually more challenging to perform, making an inadvertent cut into the prostate and subsequent positive margin more likely. Obese men, for example, have twice the likelihood of having a positive margin as compared to men of normal weight. Similarly, surgeons with less experience are less likely to be able to identify and preserve the important surgical landmarks of the prostate, also making positive margins more likely.

Impact of Positive Margins

So why do we care about positive margins? Aside from serving as a surgical benchmark for urologists, positive margins also have a significant impact on cancer outcomes after prostatectomy.  For example, studies have shown that men with a positive surgical margin have double the risk of a PSA recurrence (cancer recurrence) as compared to men with negative margins, even after taking into account other risk factors.  Of course, positive margins in men with non organ confined disease (positive ECE) have a worse prognosis than those with positive margins and organ confined disease.  For example, in one study, while 18% of men with positive margins and ECE developed metastases, no men with a positive margin and organ confined disease developed metastatic spread after 7 years of follow up.  Nonetheless, positive margins in organ confined disease also often yield a worse prognosis.  One study, for example, demonstrated that men with organ confined disease and a positive margin have as high a likelihood of having progression of their prostate cancer as men with ECE but negative margins (25%).  Hence, positive margins in organ confined disease have the effect of   “up staging” the prostate cancer from T2 to T3 when seen from the standpoint of prognosis.  While demonstrating such a significant impact on prostate cancer outcomes, however, positive margins do not always result in a prostate cancer recurrence.  In fact, studies have demonstrated that 40-50% of men with a positive margin never demonstrate a PSA recurrence.  This statistic is often attributed to the existence of the artifactual positive margins described above as well as to small positive margins in cases of non-aggressive prostate cancer.

Dissecting Positive Margins Further

As if positive margins and their consequences were not confusing enough, pathologists are now looking at margins in even more detail to create further risk categories.  Some elements of positive margins that have been studied include the length of the positive margin, its location within the prostate, and whether there is a single versus multiple positive margins.  Studies have demonstrated significant impacts of the margin sub-characteristics on the chance of PSA recurrence (and, in turn, prostate cancer recurrence) after surgery.  Multiple positive margins, for example, have been demonstrated to yield a 40% higher chance of PSA recurrence as compared to a single positive margin.  Also, an extensive or long positive margin (the critical length has ranged from less than 1 to over 3 millimeters) has been shown to result in a PSA recurrence 30% more often than small or “focal” positive margins.  The location of positive margins has, also, been demonstrated to predict the potential for recurrent prostate cancer.  Historically, for example, a positive margin at the apex (or tip) of the prostate has been considered to be much less worrisome than positive margins at other areas of the prostate, particularly those at the back of the prostate near its lateral edge.  Unfortunately, there is a great deal of contradictory data emerging about these sub-characteristics of positive margins.  In addition, a recent large study of over 5000 patients demonstrated that while these sub-characteristics do help to predict the risk of cancer recurrence, they do not appear to add any further predictive power above and beyond that derived from the simple presence or absence of positive margins.  As a result, while these sub-characteristics of positive margins are somewhat useful in helping to sort out the significance of a positive margin, they are not powerful enough to substantially change the approach to dealing with a given positive margin.

Managing Positive Margins

While understanding positive margins can be helpful in predicting the risk of cancer recurrence after prostatectomy, this knowledge also creates a dilemma of how to proceed.  As mentioned previously, while positive margins can double the risk of prostate cancer recurrence, nearly half of men with positive margins never have a recurrence of their prostate cancer.  As a result, immediately treating ALL men with positive margins to prevent a recurrence would mean that 50% of these men would be undergoing treatment unnecessarily.  Given the fact that the treatment of choice in this situation would be radiation the added, unnecessary, risks of this radiation to 50% of the men in question would be unacceptable.  As a result, a great deal of controversy exists as to who should get radiation treatment for a positive margin right away (adjuvant radiation) and who should wait for a PSA recurrence first (salvage radiation).  I have discussed this controversy in my previous post entitled, “High Risk Prostate Cancer After Prostatectomy: Radiate or Wait?”  : 

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

Thursday, March 22, 2012

Rising PSA After Negative Prostate Biopsy Part II: Can PCA3 Prevent Unnecessary Biopsies?

In my last post I discussed some PSA based tools that can be used to determine whether a rising PSA is due to prostate cancer or to other causes.  Such tools are very important because repeat biopsies for men with rising PSAs are positive for cancer in only 10-30% of cases, depending on how many biopsies are performed.  The yield (chance of cancer found) is less and less for every subsequent biopsy performed.  As a result, 70-90% of men may be undergoing these biopsies unnecessarily.  The problem with performing all of these repeat biopsies, aside from the pain and discomfort, is that they are not without risk (some more information about what to expect from prostate biopsies can be found in this previous post).  Unfortunately, the PSA tools I described, while helpful, are far from perfect.  The problem with these tests stems back to the basic problem with PSA: it is not only produced by prostate cancer but by normal prostate tissue.  As a result, PSA tests can be falsely elevated by other factors like infections, large prostates, and having sex.  Due to this limitation, PSA and PSA based tools can often overestimate the risk of prostate cancer in men with previously negative biopsies.  This, in turn, can lead to many unnecessary biopsies in men without prostate cancer.  Fortunately, a new test has recently been approved that may help determine which men really need to undergo a repeat biopsy in response to a rising PSA.  This test, called PCA3, may significantly decrease the need for repeat biopsies in select men with rising PSAs.  In this post, I will explain what PCA3 is, why it may be more informative than PSA, and how it may be used to prevent unnecessary biopsies.

What is PCA3?

Lets first discuss what PCA3 actually is.  PCA3 is a gene found within the DNA of human cells.  Like other genes, PCA3 serves as a code to produce a type of protein called mRNA.  It turns out that prostate cancer cells produce over 60 times more of the PCA3 mRNA than normal prostate cells.  In addition, no other tissue type in the human body produces this mRNA either.  Identifying this very prostate cancer specific protein, scientists then developed a test to identify and quantify it in men.  Unlike PSA, the PCA3 test is actually a urine, rather than blood, based test.  The test begins with a “prostate massage” by the physician.  Basically, this is a vigorous prostate exam that lasts for a few more seconds than a routine rectal exam.  After this exam, the patient then urinates and the urine is analyzed to look for and quantify the amount of PCA3.  The idea here is that the prostate exam causes the prostate to secrete the PCA3 protein into the urine, which can then be collected for quantification.

How is PCA3 better than PSA?

As I mentioned earlier, the major flaw of PSA is that it is not specific enough for prostate cancer.  In other words, way too many other things can cause PSA elevation aside from just prostate cancer.  PCA3, in contrast, is very specific for prostate cancer.  Neither infection nor sexual intercourse elevate PCA3.  In addition, unlike PSA, PCA3 is not proportional to the size of the prostate.  In other words, larger prostates do not produce more PCA3.  Finally, even urological procedures like prostate biopsies and cystoscopies, notorious for raising PSA, have no effect on PCA3.  I am sure that you are now starting to see the beauty of this new test.  Because it is so specific for prostate cancer, it may be able to prevent the unnecessary pain and risk of repeat biopsies in men with rising PSAs.  Lets see how this theoretical advantage pans out in practice.

PCA3 and the Prostate Biopsy Decision

Numerous studies have evaluated the utility of PCA3 in predicting prostate cancer.  One study evaluated the accuracy of PCA3 in predicting the extent and significance of prostate cancer.  The study obtained PCA3 tests from men with known prostate cancer about to undergo radical prostatectomy and then correlated the PCA3 level with the pathology findings from the surgery.  The study reported some very encouraging findings.  First, the study found that men with small amounts of cancer demonstrated significantly lower PCA3 values than those with large cancer volumes (PCA3 scores of 17 versus 47, respectively).  The study similarly found that men with insignificant or low risk prostate cancer also demonstrated substantially lower PCA3 scores than their counterparts with more substantial prostate cancer (PCA3 scores of 16 versus 45, respectively).

While PCA3 has, thus, been demonstrated to be a good predictor of significant prostate cancer, can this new test help predict the presence of prostate cancer and the need for prostate biopsy in men with a rising PSA after a previously negative biopsy?  Several studies have done just that.  A small study of 51 men, for example, performed a PCA3 test on men with a negative prostate biopsy who then underwent  a repeat biopsy for a further rising PSA.  The study reported that men with a positive repeat biopsy demonstrated substantially higher PCA3 values (median 50) as compared to those men with negative repeat biopsy (median 28).  A substantially larger study of over 1100 men undergoing repeat biopsies demonstrated a similar discrepancy of PCA3 values of 34 versus 17 for men with positive versus negative repeat biopsies, respectively.  This large study also reported that men with a PCA3 level greater than 35 had twice the risk of a positive biopsy as compared to those men with PCA3 less than 35.  Given this ability of PCA3 to differentiate prostate cancer from other causes of rising PSA, another study of 127 men reported that the PCA3 test can help avoid up to 73% of unnecessary repeat biopsies. 

Is there a downside to PCA3?

The main downside to PCA3 appears to be the lack of an accepted, definitive cutoff point above which the presence of prostate cancer is nearly certain.  While higher values of PCA3 are certainly more indicative of prostate cancer than lower values, there is no single magic number that can serve as a cutoff.  Numerous studies have used 35 as such a cutoff but with mixed results.  For example, one study evaluated using 35 as the PCA3 cutoff.  The study demonstrated that if only men with PCA3 over 35 were biopsied, 85% of previously undiagnosed prostate cancers would be detected while avoiding 50% of unnecessary, repeat negative biopsies in men without cancer present.  The study demonstrated that if a PCA3 cutoff of 44 is used to trigger a repeat biopsy, in contrast, only 75% of previously undiagnosed cancers would be detected while avoiding 73% of unnecessary, repeat negative biopsies. Still other studies have argued for lower cutoffs (such as 15 or 25), which identify larger percentages of previously undiagnosed cancers (95%) for the tradeoff of substantially more unnecessary biopsies.  So what is the magic number?  Is it more important to identify more cancers or prevent more unnecessary biopsies?  That is the million dollar question that is still being debated.  That is also a drawback of the test.

Take Home Message

For many years, urologists have been looking for a noninvasive test that can reliably predict the presence of prostate cancer in men with a rising PSA and a negative previous prostate biopsy. A rising PSA can often be misleading as its rise can be triggered by factors not related to prostate cancer such as an enlarging prostate, urinary tract infection, or even sexual intercourse.  A test was needed that can eliminate such extrinsic factors to determine if a man really does need a repeat biopsy or if he can safely avoid the risks and discomfort of this procedure. 

In many respects, PCA3 seems to be just such a test. It is only produced by prostate cancer and, so, is not affected by extrinsic factors.  It is fairly easy to obtain if you discount the discomfort of a “vigorous” rectal exam.  It appears to differentiate significant from relatively innocuous prostate cancer.  And it has been demonstrated through numerous studies to significantly reduce the number of unnecessary prostate biopsies while not substantially decreasing the ability to identify prostate cancer.  Is PCA3 the holy grail of prostate cancer diagnosis?  Of course not.  Is it without its limitations?  No.  However, it appears to be a valuable tool to be used in conjunction with the PSA tools I previously discussed to reliably determine which men really need a repeat prostate biopsy and which can avoid the risk and discomfort of a repeat procedure.

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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

Thursday, March 8, 2012

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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  Prostate Doc’s Guide to Life After Prostatectomy

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