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

17 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?

    ReplyDelete
  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.

    ReplyDelete
  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??

    ReplyDelete
  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!

    ReplyDelete
  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?

    ReplyDelete
  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.

    ReplyDelete
  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

    ReplyDelete
  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

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

    ReplyDelete
  10. I just want to share this personal story about how my husband survived the problem of NO ERECTION after prostate surgery.
    My husband undertook prostate surgery 3 years ago and before then i always looked forward to great sex with him and after the surgery he was unable to achieve any erections, we were bothered and we tried so many drugs, injections and pumps and rings but none could give him an erection to even penetrate. I searched for a cure and got to know about Dr. Hillary who is renowned for curing problems of this nature and he did encouraged me not to give up and he recommended his herbal medication which my hubby took for 3 weeks and today his sexual performance is optimum. You too can contact him for similar problems on hillaconn@gmail.com. A man who cannot satisfy his wife's sexual need is not a real man!

    ReplyDelete
  11. Hiv disease for the last 3 years and had pain hard to eat and cough are nightmares,especially the first year At this stage, the immune system is severely weakened, and the risk of contracting opportunistic infections is much greater. However, not everyone with HIV will go on to develop AIDS. The earlier you receive treatment, the better your outcome will be.I started taking ARV to avoid early death but I had faith in God that i would be healed someday.As a Hiv patent we are advise to be taking antiretroviral treatments to reduce our chance of transmitting the virus to others , few weeks ago i came on search on the internet if i could get any information on Hiv treatment with herbal medicine, on my search i saw a testimony of someone who has been healed from Hiv her name was Achima Abelard and other Herpes Virus patent Tasha Moore also giving testimony about this same man,Called Dr Itua Herbal Center.I was moved by the testimony and i contacted him by his Email.drituaherbalcenter@gmail.com We chatted and he send me a bottle of herbal medicine I drank it as he instructed me to.After drinking it he ask me to go for a test that how i ended my suffering life of Hiv patent,I'm cured and free of Arv Pills.I'm forever grateful to him Drituaherbalcenter.Here his contact Number +2348149277967...He assure me he can cure the following disease..Hiv,Cancer,Herpes Virus,Lyme Disease,Epilepsy, ,Bladder Cancer,Colorectal Cancer,Breast Cancer,Kidney Cancer,Leukemia,Lung Cancer,Non Hodgkin Lymphoma,Skin Cancer,Lupus,Uterine Cancer,Prostate Cancer, fibromyalgia ,ALS,Hepatitis,Copd,Parkinson disease.Genetic disease,Fibrodysplasia disease,Fibrodysplasia Ossificans Progressiva,Fluoroquinolone Toxicity Syndrome,Liver/Kidney Inflammatory,Men/Woman infertility, bowel disease ,Huntington's disease ,Diabetes,Fibroid...

    ReplyDelete
  12. I am 29 years old and I was diagnosis of Breast cancer, easy well and have a similar story except my first acceptance as a Herbal medicine denials. I wasn’t into the movement Perseid and didn’t establish connections with any of them really, just had faith in believing how they work. I say this because it was during using Dr Itua herbal medicine i now then testify herbal medicine is real, Dr Itua herbal medicine cure my breast cancer I was suffering from for 2 years. Dr Itua herbal medicine is made of natural herbs which has no side effect and is easy to drink as well. Contact Dr Itua herbal Center if you are suffering from the same Breast Cancer or any kind of human Diseases including....HIV/AIDS, HERPES COLORECTAL CANCER, BLADDER CANCER, PROSTATE CANCER, KIDNEY CANCER, LUNG CANCER, SKIN CANCER, UTERINE CANCER, LEUKEMIA, VIRUS, HEPATITIS, WOMEN/MEN INFERTILITY, LOVE SPELL,LOTTERY SPELL. HIS CONTACT EMAIL/WHATSAPP: drituaherbalcenter@gmail.com/+2348149277967

    ReplyDelete
  13. WHAT A GREAT MIRACLE THAT I HAVE EVER SEE IN MY LIFE. My names are Clara David I’m a citizen of USA, My younger sister was sicking of
    breast cancer and her name is Sandra David I and my family have taking her
    to all kind of hospital in USA still yet no good result. I decided to go to
    the internet and search for cancer cure so that was how I find a lady
    called peter Lizzy she was testifies to the world about the goodness of a
    herbal man who has the roots and herbs to cure all kind of disease and the
    herbal man email was there. So I decided to contact the herbal man @herbalist_sakura for my younger sister help to cure her breast cancer. I contacted him and told him
    my problem he told me that I should not worry that my sister cancer will be
    cure, he told me that there is a medicine that he is going to give me that
    I will cook it and give it to my sister to drink for one week, so I ask how
    can I receive the cure that I am in USA, he told me
    That I will pay for the delivery service. The courier service can
    transport it to me so he told me the amount I will pay, so my dad paid for
    the delivery fee. two days later I receive the cure from the courier
    service so I used it as the herbal man instructed me to, before the week
    complete my sister cancer was healed and it was like a dream to me not
    knowing that it was physical I and my family were very happy about the
    miracle of Doctor so my dad wanted to pay him 5 million us dollars the
    herbal man did not accept the offer from my dad, but I don't know why he
    didn't accept the offer, he only say that I should tell the world about him
    and his miracle he perform so am now here to tell the world about him if
    you or your relative is having any kind of disease that you can't get from
    the hospital please contact dr.sakuraspellalter@gmail.com or whats app him
    +2348110114739  you can follow him up on Instagram @herbalist_sakura for the cure, he will help you out with the
    problem. And if you need more information about the doctor you can mail me
    davidclara223@gmail.com 

    ReplyDelete
  14. Dr. Riaria cured my herpes virus that have been in my body since two years, ever since then my life has been incomplete, I have used so many drugs that was prescribed to me by doctors, but it didn't cure my herpes virus, i was checking for solution on the internet then I miraculously came across Dr. Riaria the powerful herbalist that  can cure herpes infection, then I contacted him through his email, I explained everything to him and he prepared a herbal medicine and sent it to me through FedEx, which I took for 14 days with the instruction he gave me, and when I did a test in the hospital my result came out negative it was the happiest day of my life that am cure from HSV 2,  are you also suffering from same virus or another diseases you can simply contact him via email: drriaria@gmail.com  you can also call or WhatsApp him on: +2349134987375.  

    ReplyDelete
  15. I started on COPD Herbal treatment from Ultimate Health Home, the treatment worked incredibly for my lungs condition. I used the herbal treatment for almost 4 months, it reversed my COPD. My severe shortness of breath, dry cough, chest tightness gradually disappeared. Reach Ultimate Health Home via their email at ultimatehealthhome@gmail.com . I can breath much better and It feels comfortable!

    ReplyDelete

  16. I was diagnosed as HEPATITIS B carrier in 2013 with fibrosis of the
    liver already present. I started on antiviral medications which
    reduced the viral load initially. After a couple of years the virus
    became resistant. I started on HEPATITIS B Herbal treatment from
    ULTIMATE LIFE CLINIC (www.ultimatelifeclinic.com) in March, 2020. Their
    treatment totally reversed the virus. I did another blood test after
    the 6 months long treatment and tested negative to the virus. Amazing
    treatment! This treatment is a breakthrough for all HBV carriers.

    ReplyDelete
  17. I’d recommend using Dr. Utu Herbal Cure topically for instant pain and itch relief as well as accelerated healing of lesions and permanently stopping oral and genital herpes virus outbreaks. I have tried just about everything from acyclovir suppressive therapy to numerous natural oils, extracts, and other natural methods, some of which are EXTREMELY severe and exacerbate the problem (i.e. apple cider vinegar!). While vitamin E oil and suppressive therapies worked well for me, when I became pregnant I went back to trying to find a herbal cure. I was using vitamin E oil topically for a while but it was thin and difficult to use and only seemed to prevent further outbreaks rather than getting rid of it. I contacted Dr. Utu Herbal Cure through my friend. To my surprise, I could tell my outbreak was starting to heal within only a few hours! No more itching and pain! Dr. Utu Herbal Cure that I used was liquid herbs in bottles, so it was very easy to use. It simply whiffs, but it works so I don’t care! The best part of my testimony was that I successfully delivered a herpes-free beautiful daughter without further medications. Anyone who has tried Dr. Utu Herbal Cure knows just how quickly those treatments can add up. So give it a try! Anyone can reach Dr. Utu through
    drutuherbalcure@gmail.com
    +2349072733661

    ReplyDelete