How low is the risk for Gleason score progression over time?

A new study report in Cancer Research suggests that: (a) prostate cancer aggressiveness may be established when the initial tumor is formed and not alter over time; (b) active surveillance or similar monitoring strategies really are the most appropriate initial management option for men with low-grade, low-risk cancer (potentially regardless of their age at diagnosis).

Penney et al. based their study on data from 420 participants recruited to the Physicians’ Health Study and 787 participants recruited to the ongoing Health Professionals Follow-up Study. All participants were diagnosed with prostate cancer between 1982 and 2004, and treated by radical prostatectomy. The researchers re-analyzed prostate tissue collected from these patients either at biopsy or post-surgery to assess their Gleason scores.

Penney and her colleagues divided these 1,207 patients into four groups based on the time periods within which the participants received their diagnosis (and their subsequent treatment):

  • Group A, December 1982 through January 1993
  • Group B, January 1993 through December 1996
  • Group C, January 1996 through December 2000 and
  • Group D, January 2000 though December 2004

Group A is representative of the pre-PSA era, whereas Groups B, C, and D represent differing time points within the PSA era.

Here is what they found:

  • The proportion of patients undergoing PSA testing increased over time (from 42 percent in 1994 to 81 percent in 2000).
  • The proportion of men with advanced stage tumors at time of diagnosis decreased dramatically over time.
    • 19.9 percent of patients in Group A were diagnosed with a clinical stage of T3 or higher.
    • 3.0 percent of patients in Group D were diagnosed with a clinical stage of T3 (and none had clinical stage T4).
    • This represents an 85 percent decline in clinical stage at diagnosis (a sixfold decrease over 22 years).
  • The proportion of men with a pathologic Gleason score of 8 or higher declined only somewhat by comparison.
    • 25.3 percent of patients in Group A had a Gleason score of 8 or higher at time of surgery.
    • 17.6 percent of patients in Group D had a Gleason score of 8 or higher at time of surgery.
    • This represents a 30 percent decline in the occurrence of highly aggressive pathology.

Penney and her colleagues state that, in their opinion:

  • The “significant interaction between stage and diagnosis date predicting grade (P = 0.04) suggests that the relationship between [Gleason] grade and stage varies by time period.”
  • Because the major shift in clinical stage since the introduction of widespread PSA testing has been accompanied by only a modest shift in Gleason score, the Gleason score “may be established early in tumor pathogenesis.”
  • This information “may help patients diagnosed with lower grade disease feel more comfortable choosing active surveillance.”

Now the authors go to great lengths in the full text of the article to point out that  their data do not actually help an individual patient to predict exactly what to do immediately if he is diagnosed with low-risk disease. Why? Because there is a big difference between the accuracy of Gleason scores based on biopsy data, when only a small percentage of tissue within the prostate is being sampled, and Gleason scores based on the pathological examination of tissue from an entire prostate. On the other hand, these data correlate well with other data indicating that a man diagnosed with truly pathologic Gleason 3 + 3 = 6 cancer is at very limited risk for metastatic disease or death from prostate cancer. The benefit of active surveillance is that it allows a man initially diagnosed with low-risk disease, including a Gleason score of 3 + 3 = 6, to simply monitor his condition and come to a decision about treatment only when this becomes necessary because of a finding of Gleason 7 disease or a suspiciously significant rise in his PSA level.

We would also make note of a finding referred to in the current paper, and based on an earlier analysis of data (by Stark et al., in 2009) from participants in the Physicians’ Health Study and Health Professionals Follow-Up Study. According to Stark et al., in their study (based on a blinded, standardized review of 693 prostatectomy and 119 biopsy specimens by three expert uropathologists), men found to have a Gleason score of 4 + 3 = 7 were three times as likely to die of their prostate cancer as the men with a pathological Gleason score of 3 + 4 = 7.

Although the data in the current study by Penney et al. are based on retrospective analysis of data collected for other purposes, two strengths of this study are its size and the re-grading of pathologic specimens according to modern, standardized criteria by a single, highly experienced uropathologist who was blinded to the patients’ clinical data (including dates of diagnosis and long-term outcomes).

In the view of The “New” Prostate Cancer InfoLink, this new paper by Penney et al. further establishes active monitoring of some type as the appropriate, initial standard of care for men diagnosed with low-risk prostate cancer, and potentially for men with intermediate-risk prostate cancer that is Gleason 3 + 4 = 7 (as opposed to Gleason 4 + 3) if they have a life expectancy of 10 years or less.

It is becoming increasingly evident that what is now needed is some consensus around the appropriate protocols for actually implementing active monitoring. Such protocols need to take account of ways to minimize excessive biopsies and apply high quality MRI-based imaging studies whenever possible. One might even be able to see a time when carrying out invasive therapy like radical surgery or radiation therapy on the majority of men diagnosed with Gleason 6 disease was considered to be unethical unless there was clear evidence from other strong (genetic?) risk factors for disease progression over time.

14 Responses

  1. A really informative article detailing some information from pre-PSA testing era into the PSA testing era. The points made are relevant and support those with low grade prostate cancer to use active surveillance with greater confidence.

    The 85% decline in the clinical staging between the two eras speaks for itself when comparing the arguments about the furore surrounding the merits of PSA testing.

  2. It’s already unethical to subject men to treatments with highly likely permanently maiming outcomes for very unlikely effects on longevity.

    However, I understand a lot of practices and hospitals have da Vinci’s and radiation therapy machines of various ilk to pay for. The bankers’ and MDs’ calculations of return on investment (ROI) on that equipment will determine the distance into the future before the AUA decides it’s unethical to maim men with low-volume, low-risk disease. It’s rarely a good idea to accept the opinion of one who has a vested interest in selling one his wares.

  3. I was diagnosed with Gleason 6 disease (in 3 out of 14 biopsy cores) in August of 2012 and have been following AS. However, as stated in the article, there is no way to know if in fact I am a G6 based on such a small sample. There is no disagreement that G6 is low risk, but how do you make sure that the patient is in fact at G6?
    MRI is not approved by my insurance company as a tool to help monitor my condition during AS.

    I recently had a Prolaris test, but it only tested the samples from my biopsy which were graded as G6; it does not tell me if there is any G7 that the biopsy missed.

    I am still struggling with the uncertainty of not knowing if I am truly a G6. I have been tempted to go the active treatment route as my PSA started to rise from 3.6 to 3.9, though my Prolaris test indicated that my 10-year mortality risk is 2%.

  4. Dear AKAI:

    Unfortunately, at this time, there is no accurate way to make an assessment of the possible existence of some Gleason 7 disease in a Gleason 6 patient unless the patient gets repeat biopsies (and even these cannot give absolute certainty). The anxiety associated with this lack of certainty is a very real problem for some men.

    I wish I could tell you that within 12 months we will have a test that can resolve this anxiety, but I do not believe that to be the case. On the other hand, we have come a long way from where we were even 10 years ago, let alone 20! You are doing exactly what I would do under the same circumstances (for whatever little that may be worth).

  5. AKAI,

    Take all your numbers together. Your PSA is still nice and low (unless you are very young). You’re good to go. :-)

  6. We should bear in mind while reading this report that prostate cancer cells do not morph into more aggressive prostate cancer cells over time …. Grade 3 always remains grade 3; grade 4 always remains grade 4; grade 5 always remains grade 5! A grade 3 cell does not become a 4 or a 5.

    On the other hand, the grade 3, 4, and 5 cells can all reproduce so that over time a man may develop more grade 4 than grade 3. Moreover, the only way to know the extent of the disease and whether a prostate contains grade 4 or 5 cells, if they have not been identified in biopsy cores, is to remove the prostate through surgery, then perform the post-op pathology.

    By “aggressiveness”, does the Sitemaster mean the rate at which cells are dividing and multiplying since they are not changing their characteristic?

    Bearing this in mind, I suggest this article argues for screening. The earlier disease is found and treated — and I include active surveillance as a treatment option — the less likely it is to progress to an advanced state, where grade 4 and grade 5 cells have proliferated so much that they are sampled on biopsy.

  7. Dear Rick (and others):

    By “aggressiveness” the Sitemaster believes that the authors were referring to the Gleason scores as determined at the time of post-surgical pathology and to the rates of growth of groups of cells exhibiting particular grade levels.

    It is important in this discussion to remember that individual cells cannot be assigned a Gleason grade. Gleason grades are assigned based on the appearance of relatively large groups of cells and Gleason grade is actually sometimes very hard to assign since there is no actual “bright line” between patterns of groups of cells that are grade 3 or grade 4 or grade 5. This is why practical application of the Gleason grading system inherently always includes an element of “opinion based on experience and skill” from the pathologist. Every skilled uropathologist will tell you that it can sometimes be extremely difficult to decide whether a specific group of cells is Gleason pattern 3 or 4 or 4 or 5.

    The Sitemaster would also note that the rate at which cancers of the same grade may grow in specific individuals is not “fixed”. It depends on the microenvironment in which that group of cancer cells exists in the specific individual. In general, Gleason 8-10 cancers are aggressive and tend to grow relatively quickly in most individuals. However, this is not always the case. Conversely, Gleason 6 cancers generally grow slowly and are not particularly aggressive, but there are exceptions to this rule, and most of us have come across men with very large volumes of Gleason 6 disease in their prostate and nearby tissues — even though this type of cancer is far less likely to metastasize.

    Finally, because Gleason scores are not based on individual cells but on patterns of groups of cells, we should point out that it is perfectly possible for a man who gives every clear sign of having true Gleason 6 disease to subsequently (on re-biopsy) be shown to have Gleason 3 + 4 disease that can later be re-classified (again on re-biopsy) as Gleason 4 + 3 disease.

    This could occur in a man who, initially, has a tiny amount of Gleason pattern 4 within a much larger volume of Gleason pattern 3 disease, such that the quantity of Gleason 4 pattern is too small to be visible under normal pathological examination. A year or two later, after the types of cell comprising the Gleason pattern 4 cells have had time to grow, they become evident on the biopsy core from precisely the same area, and so the patient is now Gleason 3 + 4 (because the pattern 4 cells are still the “secondary” pattern. Give it another year and these pattern 4 cells have grown faster than the Gleason 3 cells and now the pattern 4 is the primary pattern, and this patient is now Gleason 4 + 3 = 7. The problem in a case like this is that in the beginning the volume of Gleason pattern 4 cells was too small to be seen: it wasn’t that they weren’t there.

    The truth is that we have absolutely no idea how often a scenario like this plays out in real life because it is extremely difficult (i.e., near to impossible) to re-biopsy precisely the same area within the prostate in a repetitive manner over time.

  8. Absolutely agree with your analysis, Mike.

    For clarification, I did not want to leave the impression that a Gleason 3 pattern turns into a Gleason 4 or 5 pattern. Rather it becomes overwhelmed by the 4 or 5 that is growing quicker and may not have been identified in the first place. I believe we are saying the same thing.

  9. As Mike may recall, I have always held the view that in the majority of cases there may not be a progression of the tumour as measured by the Gleason scoring system. The accuracy of the system was also, in my case demonstrated, by the fact that I had results of 3 + 3 = 6, 2 + 3 = 5 and 3 + 4 = 7 from three different pathology labs when I was diagnosed.

    It is somewhat ironic, therefore, to find — after a procedure to clear my blocked kidney ureter — that after 17 years I have a substantial crop of adenocarcinoma with a Gleason socre of 5 + 4 = 9 in my bladder.

    Surely, as dear old Aubrey Pilgrim used to say, “The Golden Rule of Prostate Cancer is this: There Are No Rules.”

  10. Terry — so sorry to hear your news … we were just asking after you on last night’s Reluctant Brotherhood call.

    Best wishes from all on this new leg of your journey — our thoughts are with you.

  11. I just turned 54 and was diagnosed with Gleason 6 in my prostate. MyPSA jumped from 1.2 to 5 in 1 year, which led to a biopsy which found 10% in 1 out of 12 biopsy needles. So I’m low or very low risk, but relatively young. So far everything I’ve studied and the three doctors I’ve spoken with seems to lead to treatment instead of active surveillance. Not sure I can get comfortable with the idea of AS while in the back of my mind I’m thinking I might have a more aggressive cancer that simply hasn’t been detected yet and that by the time it might be detected it could be too late?

    Also, if I only have Gleason pattern 3 cells and that’s all I ever have, can they kill me? Is it definite that 3s won’t metastasize?


  12. Dear John:

    These are all important questions. However, the best place for us to be able to discuss this all with you in detail is on our social network, which was designed for exactly that purpose.

  13. John, you’re a candidate for AS for sure. Your PSA is a bit high, but that could be due to other factors. I have your stats (but a lower PSA) and am coming up on 2 years on AS. I am 51.

  14. I think I have been on AS for over 5 years and am now getting on for 60. I think each of us is different.

    Keep at it John

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