Risk for prostate cancer grade “progression” (from Gleason 6 to Gleason 7 or higher)

We know that men initially diagnosed with Gleason 6 disease can (relatively frequently) be re-diagnosed later on with Gleason 7 disease or a higher Gleason score if they are on active surveillance protocols — although we often don’t know why this happens.

There are four potential reasons for this:

  1. The original diagnosis was wrong, i.e., the patient was initially diagnosed with a Gleason score of 3 + 3 = 6 but should have been diagnosed with Gleason 4 + 3 = 7 or 3 + 4 = 7.
  2. The original diagnosis was correct, but on re-biopsy there is a completely new finding of an area of Gleason 7 tumor that was not biopsied initially (even though it may have been present at the time of the original biopsy).
  3. The original diagnosis was correct, but on re-biopsy there is a completely new finding of an area of Gleason 7 tumor that was not biopsied initially (and that was not present at the time of the original biopsy, i.e., a new tumor).
  4. The original tumor was accurately graded as Gleason 3 + 3 = 6 but it really has “progressed” to Gleason 3 + 4 (or Gleason 4 + 3, or higher).

While it is certainly possible — in many cases — to determine whether the original diagnosis was wrong (scenario 1 above), it is much more difficult to tell (with accuracy) which of the other three possibilities might explain upgrading of prostate cancer over time.

Inoue et al., working with data carefully collected by Epstein and his colleagues at Johns Hopkins as part of their long-term active surveillance cohort of patients, have now published an estimate, based on a statistical model, of the risk for upgrading of prostate cancer over time in the Johns Hopkins group of 600+ active surveillance patients. (It should be noted immediately that this group of patients is very highly defined, and so this model may not apply accurately to other cohorts of active surveillance patients.)

Their basic finding is that, at 10 years of follow-up from initial study entry, there is an estimated likelihood of grade “progression” (i.e., any one of scenarios 2-4 above) that ranges from 12 to 24 percent depending on exactly how the patients are classified based on  prior distributions for the time to true grade progression. It is not, however, clear whether such apparent progression is real (i.e., whether a Gleason score can change over time, as described in scenario 4) or whether such apparent progression merely reflects one or other of scenarios 2 or 3.

23 Responses

  1. I thought there have been findings that number 4 does not ever occur (forget where I read that) and that 2 and 3 are the culprits. Interesting.

  2. Walt. Although there is strong evidence to suggest that men initially diagnosed with Gleason 6 disease very, very rarely end up with metastatic (lethal) prostate cancer, we really don’t know whether a cancer that is Gleason 6 at diagnosis can progress to Gleason 7 or not. It may just be that some men with apparent Gleason 6 at diagnosis also have an unidentified (or tiny) focus of Gleason 7 disease. Or something quite different may be going on. We just don’t know.

  3. Up to 25% of Gleason 6s will progress to Gleason 7 and above?

    And we all wonder why Gleason 6s “just want the cancer out …”

    I think even if I was a 6 (I’m a 9), I would consider surgery so I knew what I was dealing with … but I’m in my 40s too and I think that makes a difference.

  4. Mike,

    Do you have a link to this study?



  5. Mea culpa. The link to the abstract is now included above. Sorry.

    I would just point out that this model also implies that 75 to 88% of these men with Gleason 6 disease will not have progressive disease. And the vast majority of these men are quite certainly not going to be in their 40s or even their early 50s!

  6. I’m 50, and have a Gleason 6 rating, super-low volume (last biopsy was 2/12 cores positive, both Gleason 6, one 10% and the other less than 5%). My last PSA was 1.7. No way I’m treating unless these numbers change.

  7. Mike

    And in Russian Roulette the majority (80%) of the time you won’t get shot.

    No, the majority of these men aren’t going to be in their 40s and early 50s. I woud imagine there would be a fair number of guys between 40 and 65. Of those men, up to 25% of them would probably want to know a bit more information about their cancer.


  8. Walt … If I had those sorts of numbers I would be right there with you!

  9. Thanks!!!!!

  10. My understanding from speaking with the physicians is the same as that of Walt Green; namely prostate cancer cells do not change their identity — a 3 stays a 3 and cannot morph into a 4. A “4” cell not identified initially might proliferate aggressively and overtake a colony of “3” cells so that re-biopsying the same area gives a new result. But that is not because the first identified “3” cells changed into “4” cells. I would agree with reasons #1-3, but disagree with #4. Maybe there should be another category to explain the above?

  11. Mike, how about you write Inoue and ask that million dollar question … How many of the 627 died from prostate cancer?

  12. Well I heard back from the oncology department at the University of Washington. He will try to get me with the biostatistician that did the paper here. But he also felt that we probably don’t have the data on mortality and it would take 20 years in the study to determine how many men might have or will die from Gleason progression. Pretty much in line with your comments, Mike.

  13. Well, this phenomenon ain’t gonna improve faith in medics, is it? I got “migrated”, not on Gleason score but on TNM stage because I hollered for lymphadenectomy. Moved from T2Nx to T3N1. What made me unhappy was the assumption that x = 0.

    I am struck by the fact (?) that biopsy sampling for Gleason grading was random-ish but, since advent of guidance systems, less so. So maybe hope for less migration going forward.

  14. Dear Rick D:

    While I would tend to agree with you (and the physicians you spoke to) that, at least in general, “3” stays as “3” and doesn’t change to “4”, we did have an example from Johns Hopkins the other day of a case in which a man’s lethal prostate cancer clone originally appears to have started as a Gleason “3”.

    I, for one, at this point in time, am not prepared to state with absolute certainty that it is impossible for a Gleason 3 tumor cell to upgrade to a Gleason 4 tumor — although how or why that might happen is going to be a lot harder to determine!

  15. Dear Chedley:

    Upstaging of the TNM stage is actually very common — especially among men initially diagnosed as having a clinical stage of T2NxM0 prior to biopsy. When men are treated surgically, for example, anyone who had a clinical stage of T1 prior to surgery will inevitably have a pathological stage of T2a or T2b after surgery (because there is no pathological stage T1). One of the downsides of non-surgical treatment is that the patient may never be able to get an accurate appreciation of his pathological stage.

    Most good surgeons would sample the lymph nodes at the time of surgery in any patient who had a Gleason score of 7 or higher and clinical stage T2 disease to get a clear understanding of the patient’s pathological stage. The question that has never been resolved is whether such patients should be getting a laparoscopic lymphadenectomy to sample the lymph nodes prior to non-surgical treatment (e.g., radiation therapy of any type). Even when biopsies are carried out under MRI/TRUS fusion, I am not (yet) aware that it is possible to accurately biopsy the lymph nodes at that time (although it is possible to biopsy the seminal vesicles).

  16. Here is what I think:

    (1) This study estimates that approx. 25% of low risk cancers will “dedifferentiate” into higher grade cancers.

    (2) It is also estimated that approx. 30% of men diagnosed as low risk, are upgraded after RRP.

    Sooooo, …

    Given that both estimates are so close is it not a strong argument that the higher grade prostate cancers were just missed on biopsy and no dedifferentiation occurred? I’m suspicious.

    A diagnosis of low grade prostate cancer is only made based on what is seen in the biopsy sample. It is far from a complete sample of the prostate. There are far too many other explanations to support the finding of a higher grade PCa in someone other than “dedifferentiation.” See reasons 1, 2, 3 from the above statements by the sitemaster.

    The only way to truly answer the question of dedifferentiation is to take some grade of prostate cancer cells, put them in a lab and watch those specific cells to see if they “dedifferentiate”. Only then will we know if a prostate cancer cell can do this.

    I don’t know, maybe I’m wrong. … Have been before. …

    P.S.: If approx. 30% of men diagnosed with low-risk prostate cancer are truly upgraded after surgery, then does it not also seem logical that 30% of men on AS have a higher grade prostate cancer that is being missed. If so, some of them go for 20 years with no progression.

  17. Hi Mike.

    Maybe someone can help me understand the Gleason score for cancer that has metastasized. I asked the doctors at Mayo to give me the Gleason score of the cancer in my lymph nodes (EPLND done in Jan 2013). They told me they did not provide that information. I was a bit surprised at the time but maybe I don’t know enough.

    I apologize that this is a bit off topic but it reminded me I had this query.



  18. Dear Bill:

    By definition, Gleason scores can only be applied to tissue samples extracted from the prostate and the from seminal vesicles. Dr. Gleason never attempted to provide a pathologic characterization of the appearance of cancer within the lymph nodes (or for metastatic prostate cancer in other non-prostatic tissues) and so there is no Gleason grading capability for cancer in these tissues.

  19. It would seem that comparison of biopsy and clinical pathologies from prostatectomies would shed light on scenarios 1 and 2. Has the obvious been done? Many times?

  20. Yes Bill. Thousands of times. That’s why the model was constructed to take specific account of these forms of upstaging.

  21. Out of the four potential reasons, which one is the most likely? #2?

    Any available data on that?


  22. Wolfram:

    I don’t think there are any accurate data, but I am pretty sure that #4 is the least likely.

  23. There is really not much new here and what there is supports the data used for the Partin tables. Someone can interpret the information to support AS or treatment. But, I would not write off number 4 too quickly, I know of three studies that support cancer progression — out of Harvard, Beth Israel, and Karolinska Hospital in Sweden. I have yet to find a study or researcher that says it definitely does not happen … though there is a study out of Harvard that says it may not happen.

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