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

9 comments:

  1. Great post. Thanks. One question: when a urologist is doing surgery, does he sometimes face a "strategic decision," to be made on the spot, about whether to "cut wider" and thus have a better chance of getting all the cancer out, but creating a greater risk of ED in the process, or not "cutting as wide," creating a greater risk of positive margins and recurrence, but less risk of ED and other side effects? If so, is that something a patient and doc should discuss before surgery -- so the doc knows what is most important to the patient and can take it into account if this dilema occurs during the surgery?

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  2. chamorgadol: good question. This is a common dilemma for men that are potent prior to surgery. Aggressive attempts at nerve sparing can lead to positive margins laterally. In contrast, widely cutting in that area can lead to impotence due to nerve damage. Classically, the mantra has been treat cancer first and worry about erections later but with quality of life becoming more and more of an issue, urologists are very focused on good nerve sparing. A through discussion about this with the urologist is CRITICAL prior to surgery so that you can both be on the same page. That being said, no urologist will willingly and knowingly leave cancer behind for better nerve sparing.

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  3. This is a little off-subject Doc, but maybe you could answer this..

    There have been several genetically based urine tests developed that can detect (or rule out) PC when other methods, including biopsy, fail. These tests are badly needed but are not being performed for some reason. One I know of is called "The 4-Gene Signature Urine Test" (Health Discovery Corp, Abbott Labs, Quest Labs) and there are others. Do you have any idea why these new tests are not being used??

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  4. Fairwind: There are several reasons why most of these tests are not in mainstream use. First, a lot of the companies making these tests are not actively selling them. The 4 Gene Signature Test you speak appears to be mired in corporate red tape according to the latest corporate statement from Health Discover Corp. Another reason is that many insurance companies wont cover these types of tests unless they become more universally accepted. In addition, many urologists simply do not know about all of these new tests. Finally and most importantly a great majority of these tests may identify more cancers but not necessarily more SIGNIFICANT cancers. I will discuss this more in a future post that I will dedicate to the PCA3 urine test.

    Hope that is helpful and feel free to throw more off-subject questions out there. I love feedback from readers as it really gives me an idea of what you are most interested and provides me with subjects for future posts!

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  5. I have been reading your views on positive margins with interest but you do not seem to have discussed perineural invasion. How serious is perineural invasion in the absence of any other form of extracapsular extension or poitive nodules?

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  6. Norman Munnery: Perieneural invasion OUTSIDE of the prostate has been demonstrated to have an independent impact on PSA recurrence after prostatectomy in a study published this month out of Austria. Beside that most studies on the subject are conflicting and not definitive. The presence of perineural invasion on a PROSTATE BIOPSY, in contrast, does have significant impact on outcomes and I will devote a future post to this topic. Thanks for the feedback.

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  7. I have had a radical prostatechtamy with THREE POSITIVE MARGINS. My question is, can an internist tell solely on the basis of an unremarkable PSA test that my prostate cancer is in remission and not active but growing slowly. I base this question on a statement in CANCER.GOV that says, "Compared with most cancers, prostate cancer tends to grow slowly. IT MAY BE DECADES from the time the earliest cell changes can be detected under a microscope until the cancer get big enough to cause symptoms." Thank you - twgreenlaw@yahoo.com

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  8. PC&3: While I cannot comment on individual cases, I can make a few general comments. First, an undetectable PSA, while a strong indicator of remission, is not 100% dependable. A few remaining prostate cancer cells may not produce enough PSA to become detectable at first. That is why Urologists follow patients for long periods of time with serial PSA tests. Local recurrences, especially, can take years to present themselves (see my post about PSA recurrence). The good news is that, generally, the longer it it takes for PSA to recur, the less aggressive the recurrent cancer. Hope that helps.

    Prostate Doc

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  9. Thank you for this info
    is artifactual positive margin possible in combinatie with ECE (focal)?

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