The significance of Gleason Grade at Diagnosis

[Ralph Valle]

Through the years I have heard that PCa is an indolent disease. What is your opinion? Does Gleason Grade changes with time? Is this change recognizable? If so what are the tools?

[PaulC]

Fast-and-loose generalizations are useful only within a certain context.

My take on it is this: For a majority of men, PCa is an indolent disease, just as the majority of influenza cases are nonfatal and self-limiting. That generalization might be helpful when thinking about cancer in the one case or infectious diseases in the other, but it should not be taken to apply to any particular case.

So far as I know, a man with Gleason-9 or Gleason-10 disease is very likely to be an exception to the generality, and to have a cancer that is not indolent, just as a certain class of patients with a particular strain of influenza can be assumed to be an exception to the generality that the disease is nonfatal and self-limiting.


The question on change in Gleason grade is, I think, quite different, and, in the context of the title of the discussion, rather misleading. The only definitive way of determining Gleason grade is pathological examination of a large representative of cells. So far as I know, this can only be done with the prostate gland itself: A biopsy (whether of the intact prostate or of a metastatic tumor) samples a much much smaller population of cells. Since there is only one chance to ascertain the Gleason grade of the prostate gland, and this one chance usually occurs well after diagnosis, I'm not sure whether the question of whether Gleason grade changes over time is a well-defined one.

Also, by definition, the Gleason grade only reports on the least-differentiated cells in the sample. It contain no indication of the statistical distribution of those cells in context with all the other cells.

[Ralph Valle]

Hi Paul,
I accept that prostate cancer is generally recognized as an indolent disease. The problem I have with this concept is that the disease is also generally recognized as heterogeneous and multifocal. An important question is: how good is the data at diagnosis to make informed decisions? Never mind that there is a wide range of possibilities in those decisions. For example: Is debulking of tumor ever an acceptable option? Are men openly offered this option?

You say that the only way to determine Gleason grade is pathological examination of a large number of cells. This implies that only at surgery and with a correct evaluation of the whole gland this process is valid. Although maybe true we live with whatever data biopsies provide to make decisions. Biopsies for PCa have the same limitations that biopsies have for other organs.

For years in many other countries, men lived accepting the indolent nature of PCa and avoided treatments. There is a history to the nature of untreated PCa. The problem has been that such history has been overlooked and in many studies compromised. That is a whole different topic that needs review, but for now I’ll point to the fact that patients with indolent disease managed in a conservative mode have shown a higher degree of disease-specific mortality as time goes by.This usually accompanied by a degradation of quality of life related to disease progression.

A recent study just reported at the 2008 AUA conference mentioned the change of Gleason Grade on follow-up biopsies. Read:
“AUA 2008 - Older Age and Time to Last Biopsy are Associated with Rise in Gleason Score for Men on Active Surveillance for Low Risk Prostate Cancer”
This and a previous study support the stepwise progression of prostate cancer from well-differentiated disease to poorly-differentiated disease associated with a change in DNA ploidy as well.

Down the road when microarrays tell the story, science will have a better chance to identify those that need immediate treatment from those that for the moment do not. Then the Gleason grading system will become obsolete.

[E. Michael D. ("Mike") Scott]

Ralph:

I suppose the critical issue here is the distinction between actual indolent disease and presumed indolent disease. The problem is that we still don't know how to accurately define and describe the former. Your conclusion is correct: we need better science to define the distinctions. At present, as Arnon has noted below, Gleason score (usually combined with other factors) is the single most accurate predictor of risk for clinical (as opposed to biochemical) progression: sometime you are faced with the best you have.

[Ralph Valle]

Mike,
I agree when you say that they can't distinguish between actual indolence and presumed indolence. How is it then possible for them to tell us that most men diagosed today would never be affected by the disease and are thus overtreated. What crystal ball are they using?

It was interesting to read your latest summary of the 2008 AUA. In 30 yo men, 20% had non-localized disease at surgery. In 40 yo men the figure was 38%. Is this a sign of indolence? Does this support the 50% to 80% figure for overtreatment?

[Arnon Krongrad, MD]

Prostate cancer in very young men is not always highly aggresive. Ask Charlie Royce and Michael, who are members of our network what they think about prostate cancer in young men. Ask my youngest patient, diagnosed with multifocal but organ confined Gleason 6 prostate cancer at age 30 (long story as to why he was diagnosed).

[E. Michael D. ("Mike") Scott]

Ralph:

I think the answer to your first question is that we are indeed overtreating men with prostate cancer, but on the basis of the available information, it is mainly the men over 70 with competing mortalities. Because we don't know what "indolent disease" is, we don't know if we are overtreating younger men yet. Maybe we are. Maybe we aren't. In the end all these decisions are very personal. I'm not sure that I would do anything other than active surveillance if I get diagnosed in 10 years time at age 70, but then I have no family history of prostate cancer or any other forms of cancer and my PSA level is still below 1.0 ng/mL most of the time.

With respect to your second question ... Who the heck knows. Many people certainly used to believe that young men in their 30s diagnosed with prostate cancer inevitably "had to have" aggressive disease. I never thought this. It made no biological sense. Which is not the same thing as saying that if I had been diagnosed with prostate cancer when I was 30, I wouldn't have done something about it, because I certainly would (although I am very uncertain what because it would have been 1978, Walsh wouldn't even have developed nerve sparing, and I was still distinctly single!) When it comes to this one, you were right in the beginning, without tests that are much more sensitive AND much more specific we are never going to get resolution on this issue.

[Arnon Krongrad, MD]

Significance of Gleason score? It associates with prognosis better than any single other measure.

[Richard]

As a lay person and a patient with an initial Gleason Score 10, I was refused Proton treatment at MD Anderson. Their second opinion on my slides downgraded me to a Gleason Score 9. I believe they don't take high Gleason Score patients they do not want to screw up their statistics trying to treat aggressive prostate cancer patients. I had the feeling they considered me a walking dead man. I want to be a testament that no Gleason Score is a death sentence. If this is my way of coping, so be it but I don't think it is. I am already seeing results based on further CT/MRI even before my treatment plan has been completed.

[Arnon Krongrad, MD]

Your case may be different, but since you raise the subject of Gleason 10, have a look at the story of Pete Gannon as he tells it. Pete is now 6 or 7 years out from treatment. If you like, you can make direct contact with Pete on his TNPCIL page (click here).

Gleason score is in itself not the whole prognostic story. It remains the most consistent correlate of prognosis but it no man's crystal ball.

[Steven Hess]

I read Pete's story. Why would a high Gleason be grounds for not doing surgery, as he mentioned with regard to his contact with Johns Hopkins? I would understand it if it was a matter that the cancer had already spread but I assume a high Gleason tumor can be as organ confined as a lower grade.

[E. Michael D. ("Mike") Scott]

It has been suggested by some that the reason that the Hopkins data on radical prostatectomy are so good is that they avoid taking cases with a high probability of surgical failure. I do not know whether that is true or not.

I will say, however, that refusing to take a patient "over the phone" just because he had Gleason score 10 is not exactly compatible with the highest standards of clinical care if one claims to be one of the world's premier prostate cancer treatment centers.

Of course since Pete did in fact have extracapsular prostate cancer, Hopkins might argue that they were correct not to take him since radiation would be a better first-line option. This is where one gets into the whole issue of the value of surgical debulking for patients with progressive prostate cancer -- a VERY controversial and unproven concept, despite all of the Mayo Clinic data in patients with node-positive disease.

[Tony Crispino]

I can at least lend a tidbit to this part of the discussion. I moderate a PCa forum, and I have seen a member of that forum treated at Hopkins with a Gleason 10, PSA 5.6, pT3a. At last notice he is still in remission. He has struggled with incontinance and some depression and rarely chacks back in, as he was told about the likelyhood of recurrance was described as expected. But they did surgically remove a G10 at Hopkins.