If you have positive surgical margins post-surgery, you need to …

… know the Gleason score of the tissue at that positive surgical margin as well as and as opposed to just the Gleason score of the primary tumor. It makes a difference to your risk for biochemical recurrence. Your doctors need to know this information too!

Patients who have a radical prostatectomy as first-line treatment for their prostate cancer are normally told whether they have positive or negative surgical margins (i.e., whether there is any sign, at the edges of the surgically removed prostate tissue, the the surgeon might have inadvertently cut too close to the tumor and therefore left a tiny amount of cancerous tissue behind). However, it is not necessarily routine for the pathology report to include: (a) the size of such a positive surgical margin (it’s length) or (b) the Gleason score of the cancer at the margin.

New data to be published by Kates et al. in the Journal of Urology has now confirmed what has long been suspected, which is that the size (and number) of such positive margins and the Gleason score of the tissue at such margins is correlated to risk for biochemical recurrence of a patient’s prostate cancer post-surgery.

The uropathology group at Johns Hopkins in Baltimore has been routinely reporting both of these sets of data on all patients undergoing radical prostatectomy at Johns Hopkins since 2010. In the abstract of this recent paper, Kates et al. report data from a cohort of > 4,000 patients undergoing radical prostatectomy and a pelvic lymph node dissection between 2010 and 2014. Their goals were: (a) to assess the degree of correlation between the Gleason score and and length of the positive margin(s) and the adverse pathologic characteristics of the final specimen, and (b) whether the Gleason score of the tissue at the positive margin(s) affected the risk of early biochemical recurrence.

At this time the full text of this paper is embargoed until it has been edited for publication. However, here is a summary of what the report says in its abstract (which has already been reported on the PubMed web site):

  • The total patient cohort included 4,082 patients.
  • 405/4,082 patients (9.9 percent) had a primary tumor with a Gleason score of 7 or higher and a positive surgical margin.
  • Average (mean) patient follow-up was 22 months (range, 12 to 48 months)
  • Subsequent biochemical recurrence of prostate cancer was identified in
    • 5.6 percent of patients with negative surgical margins
    • 22.0 percent of patients with positive surgical margins
  • Subsequent metastatic disease was reported in
    • 0.5 percent of patients with negative surgical margins
    • 3.0 percent of with positive surgical margins
  • The Gleason scores of tissues at the positive surgical margins were
    • The same as the Gleason score of the primary tumor in 44 percent of the 405 patients
    • Lower than the Gleason score of the primary tumor in 56 percent of the 405 patients
  • Shorter positive margins were independently associated with lower Gleason scores at the positive margin (p = 0.02).
  • Kaplan-Meir plots and multivariate statistical models could be used to suggest that
    • Lower Gleason scores at the positive surgical margin were associated with a significantly greater likelihood of freedom from biochemical recurrence within the follow-up period of the study (hazard ratio [HR] = 0.5o).

Kates et al. conclude that having a lower Gleason score in the tissue at a positive surgical margin is independently associated with a shorter margin length and a decreased risk of early biochemical recurrence. They go on to state that

The [Gleason score] at the margin should [always] be documented.

12 Responses

  1. I’ve been looking for this kind of analysis. Having had ORRP in 2013 at JH, I must be one of the stats. My main tumor was Gleason 4 + 5 = 9, with EPE on left at base non-focal and on right, anterior lateral mid-base non-focal. Positive margin was Gleason 4 + 3 = 7, 4 mm in total length, in area of EPE; bilateral SVI; 10 nodes dissected all negative for prostate cancer. I had a biochemical recurrence with PSA levels of 0.1 at 2 months post-op, 0.2 at 5 months, and 0.3 at 8 months. Started ADT and SRT at 10 months post-op. PSA is now 0.7 after going to < 0.1 while on ADT for 6 months and stopping. F18 PET scan unable to detect prostate cancer. Scheduled more scans at Lake Sands Imaging. I was hoping being Gleason 7 at margin was good news; now I'm not so sure.

  2. The number that surprised me here was that most (56%) of the positive margins had a lower Gleason score than the primary tumor. Because this is Johns Hopkins, we expect that comparatively many of the positive margins were caused by unavoidable cutting into T3 tumors rather than too-narrow cutting of T2 tumors. I would have expected that the tumors that were breaking through the capsule would have higher Gleason score. Perhaps the breakdown of T2 and T3 will be provided in the full text. I hope that they also provide breakdowns based on Epstein’s new Gleason scoring system.

  3. Allen:

    I do know that at this time the paper does not provide breakdowns based on the new grading system. This would have required the authors to go back and re-grade > 4,000 patients based on the new system, and I am not sure that would have been the most valuable use of their time.

  4. Bob:

    My suspicion at this time is that the greatest value will be in knowing which patients with a primary tumor grade of 7 or higher and positive margins have only Gleason 3 + 3 = 6 disease in the positive margin(s). However, I am sure we will be seeing more detail on this topic in the future. Others are likely to want to see if their data are similar to the Johns Hopkins data.

  5. Sitemaster:

    It’s hard for me to understand why I had Gleason 7 at the margin and Gleason 9 in the tumor. I would have thought that the Gleason 9 would have punched through, causing the EPE. I asked my surgeon what the score was in the seminal vesicles (SVs) and he said they were not scored separately from the tumor. Since the prostate and SVs are taken out as a unit, I suppose they were Gleason 9 as well. I also asked about the source of SV invasion since I’ve read that the source dictates the severity and chance of progression. Johns Hopkins did not document the source. Having Gleason 7 or greater in the prostate and GLeason 6 in the margin would also seem be extraordinary, no?

  6. Dear Bob:

    I think you may have some mistaken concepts about how prostate cancer often evolves in a specific patient. It is commonly a multi-focal disease, meaning that a patient may have several different tumors with differing Gleason grades. In each patient, how ever many tumors he may have with how ever many different grades, there is a so-called “primary” tumor — the one with the highest Gleason score — which is considered to be the tumor driving patient risk. However, a patient with a very aggressive form of prostate cancer might have more than one tumor with (say) a Gleason score of 9 or 10. He could, at the same time, have one or more quite separately developing tumors with Gleason scores of 6 or 7. It is therefore by no means that unusual for a patient to have a primary tumor that is of higher grade than the tumor than might have caused a positive margin. The surgeon is so focused on eliminating the critical primary tumor that he underestimates the extent of the “less critical” tumor and therefore, inadvertently, leaves a small positive margin.

    With respect to the issue of knowing exactly which tumor in the prostate itself has seeded the development of cancer that has spread into the seminal vesicles, this requires very sophisticated genetic analysis of the different tumors to ascertain with accuracy. This can be — and has been — done for research purposes, but it would be extremely expensive to do routinely, and so there is a reasonable and general assumption that the most aggressive tumor in the prostate is the one that has seeded the development of the tumor in the seminal vesicles.

    Does this help to clarify matters for you?

  7. Sitemaster:

    Thanks for the clarification. I’m hoping that whatever is causing my PSA to rise again can be found with scans so I can kill it. Some guys have had this success at Dattoli. However if my prostate cancer is systemic I guess it can’t be killed. You agree?

  8. Dear Bob:

    I think you need to be cautious about over-generalization. There are men who have utterly incurable and truly systemic micrometastatic disease in whom it is impossible, early on, to image any of half a dozen or more possible sites of cancer from the bones to the liver or the lungs or similar. Then, at the other end of the scale, there are men who may have just one small site of micrometastatis which, if and when it is identifiable, it may be possible to eliminate through some combination of therapies that may include a whole variety of possible treatment options that depend on exactly where the metastasis is occurring (among other things).

    The other thing that is liable to be important is the aggressiveness of the recurrence, which can be estimated on the basis of your PSA doubling time since you came off the ADT following radiation therapy if you know (ideally) at least three PSA levels since the ADT was stopped and the dates on which blood was drawn for those tests and all three PSA tests were run by the same laboratory. Here’s a link to an online PSA doubling time calculator. The shorter the PSA doubling time, the more aggressive the recurrence.

    You also need to appreciate that it is very difficult to accurately identify any small area of recurrence with currently available imaging techniques if a patient’s PSA level is lower than about 2 ng/ml. The people who do the [11C]choline PET/CT scans at the Mayo Clinic in Rochester, MN, do not recommend this scan for anyone with a PSA level lower than 2 ng/ml because the risks for false positive and false negative results is too high.

    The bottom line to all this is that the appropriate treatment of a specific individual depends on a multiplicity of individual factors. There is, for example, a potential argument that you may be an excellent candidate for early combination therapy with ADT + docetaxel-based chemotherapy since your cancer appears to be high-risk and aggressive. Whether this can actually cure you, we don’t know, but there is some evidence that it might be able to put you into longer-term remission than other available forms of treatment at this time. You’d need to discuss that option with a really good medical oncologist with a high level of experience in the management of aggressive, progressive prostate cancer.

  9. Folks at the NIH are using a new prostate-specific membrane antigen PET study with 18F (18F-DCFBC), and we are moving toward the second-generation agent in the fall called 18-DCFpyl. Also, research from Melbourne, Australia, shows that 68Ga-PMSA can identify sites of micrometastatic lymph node disease with PSA levels as low as 0.4!

    For Gleason scores at margins, it’s known that the most aggressive Gleason score of a tumor tend to occur at its center, not the margins … so its not surprising that there is a spectrum of Gleason scores found at time of surgery.

  10. Dr. Princenthal:

    Thank you for your input. Is a clinical trial available for this scanning technique at NIH? If so how does one volunteer and are the results made available so that radiation can be applied to mets found if appropriate?


  11. At this day in time, I believe that most men will want to take aggressive action against positive surgical margins (pT3) — especially men with higher Gleason scores and/or other mitigating factors (family history, +ve nodes, +ve SVI, etc.). We just lack a lot of data to advise clearly whether a patient would benefit immediately or later with additional intervention. I also believe that we are in need of better genetic information on tumors. This may help identify what’s best at all levels of management, ranging from to treat or not to treat, to treat but not to over-treat, through to dam the torpedoes and fire away aggressively. But for now, I believe most patients will worry about those positive margins even if advised they do not need to act on them. Many would be in favor of adjuvant therapies … yours truly included. (But I had bilateral SVI.)

  12. I spoke to a nurse at NIH today who said a clinical research trial is available using the PET described by Dr. Princenthal (18F-DCFBC). They need 85 volunteers and have about 30 so far.

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