Clinical and pathologic staging of localized prostate cancer: an update

A new review by Epstein, currently available on line in the Journal of Urology, provides a detailed analysis of the clinical significance of various factors in determining prognostic risk for newly diagnosed and recently treated patients with localized prostate cancer.

Epstein starts by pointing out that the 2010 update to the TNM classification system still divides clinical and pathologic T2 disease into three categories:

  • T2a disease is cancer that is unilateral and found in less half of one lobe of the prostate.
  • T2b disease is cancer that is unilateral and found in more than half of one lobe of the prostate.
  • T2c disease is cancer that is bilateral (i.e.,  found in both lobes of the prostate).

In the case of clinical T2 disease, these categories are based on a combination of data from digital rectal examination, ultrasound examination, and actual biopsy. The clinical stages are therefore clearly estimates based on a physician’s clinical judgment. In the case of pathological T2 disease, the stage can be assessed with great accuracy based on pathological examination of the prostate post-surgery.

However, Epstein and others are now recommending that pathological T2 disease should no longer be subdivided into substages for the simple reason that this information lacks any definite prognostic significance, for a number of reasons:

  • Only 1/7 careful studies of post-surgical prostate pathology has ever been shown to include a significant amount of pT2b disease.
  • Only 1/10 prognostic studies has ever shown that there was a significant prognostic difference between substages of pT2 disease on univariate analysis — and that study showed only that pT2a disease had a better prognosis than T2b/c disease.
  • In all 10 of these prognostic studies, pT2 substages did not correlate with prognosis after the pathologic Gleason score and the status of the surgical margins had been taken into account.

So if we can no longer use pathologic and clinical substages of T2 disease for prognostic purposes, are there other clinical and/or pathologic data that can replace this traditional tool?

Epstein discusses two, in detail: the total tumor volume (TV) after radical prostatectomy (RP) and the quantification of tumor in biopsy cores. We don’t intend to provide a complete commentary on what is a complex discussion.

There are clearly some issues to be sorted out with respect to the value of tumor volume and according to the International Society of Urological Pathology (ISUP)  “the independent value of [tumor volume] remains uncertain.” In the meantime, ISUP recommends that, “some quantitative estimate of cancer volume should be undertaken, the nature of which being dependent on routine practice within the pathology laboratory.” (Dr. Epstein himself is clearly not comfortable with this interim recommendation.)

With respect to the quantification of tumor based on needle biopsies, there are some simple established processes and some areas with no consensus as yet:

  • We can usually report the total number of biopsy cores sampled and the number of those cores that are positive for cancer to obtain a fraction of positive biopsy cores (e.g., 3/12).
  • However, cores can fragment, and pathologists recommend that urologists submit 1, 2 or at most 3 prostate biopsy cores in each biopsy jar.
  • There is no consensus about assessment of the “length” of tumor in a specific biopsy core when the tumor is discontinuous.
    • Some laboratories (John Hopkins included) will measure the length of an interrupted biopsy core as though it is an uninterrupted core.
    • Others will measure the length of actual tumor in an interrupted biopsy core.
    • This means that the same interrupted biopsy core, when assessed by two different laboratories, might be given as 5 percent of the core or 60 percent!

At present, the only thing that seem certain is that the TNM staging system, when next updated, will need to eliminate the clinical and pathologic substages of T2 disease. This will have implications for many prognostic nomograms that currently include information about these substages (e.g., the Kattan nomograms and others). Of course there can be no certainty that the TMN staging system (which is not overseen by ISUP) will in fact be updated in the way that Epstein and others are recommending.

10 Responses

  1. It is not clear to me whether there are any treatment implications to that or is it just a tool for analysis in different studies. It seems to me that any pT2 diagnosis will result in treatment, be it prostatectomy (the majority), seeds or EBRT, so from a patient’s point of view this academic paper has little meaning. I would be glad to have other people’s opinions.

  2. Reuven:

    Once we know someone is pT2, they have already had surgery. (It is the only way we can know that someone has pathologic T2 disease.)

    The problem from a clinical point of view is cT2 disease (not pT2), and that has all sorts of clinical implications for treatment if we can’t accurately tell whether there is a blind bit of difference between cT2a and cT2c.

  3. Sorry for the confusion. I meant, of course, cT2.

    I think once one is diagnosed with cT2a/b/c one should undergo treatment. I think cT2a can be treated with cryotherapy as opposed to radiation (external or seeds) or prostatectomy, but in any case a cT2 diagnosis calls for primary treatment. Am I wrong?

  4. Reuven:

    A man with cT2 disease can be treated in all sorts of ways … and if he is old enough at diagnosis and symptom-free he may well even be eligible for watchful waiting or active surveillance.

    There are no blanket “rules” that a diagnosis of cT2 disease calls for primary treatment. Clinical decisions have to be taken on the basis of the precise clinical situation and the desires of the individual patient. Some older men with cT2 disease can still have disease that is (to all intents and purposes) so slowly growing as to be effectively indolent. It wouldn’t be most men with cT2 disease, but it would very certainly be some of them.

    One of the points that Epstein is effectively trying to make is that a man with cT2a disease probably does not have pT2a disease, thereby implying that any form of focal therapy for cT2a disease (e.g., focal cryotherapy) may well not be curative.

  5. So, you’re saying that a man with a very small foci of cancer in each lobe of the prostate cannot be treated with focal therapy?

  6. I had surgery at Johns Hopkins and my tumor volume was rated as “moderate.” I have asked them a couple of times where that falls in their scale and could not get and answer from Epstein other then it meant “not that much”. So for a while I felt like it was on the low end. Now I see it is in the middle; however, according to Epstein tumor volume does not effect prognosis. So, I am unhappy with “moderate” but happy with the effect on outcome. If Epstein says it won’t effect prognosis I believe him.

  7. No … What Dr. Epstein is saying is that the probability that a man with pathological T2 disease actually has cancer that is confined to one half of one lobe of the prostate is of the order of 25 percent or less. The implication is that one needs to be extremely cautious about the application of focal therapy with curative intent.

    One most certainly could apply focal therapy to small parts of both lobes of the prostate. However, I am not aware of this being done very often, so I don’t know how many physicians (presumably mostly cryotherapists and HIFU specialists) actually have significant experience of doing this.

  8. Chris:

    Johns Hopkins reports tumor volume as “minimal,” “moderate,” or “extensive.” You were clearly somewhere in the middle.

    The problem with the use of tumor volume as a prognostic indicator in prostate cancer is that there is no standardized method for assessment of tumor volume for localized prostate cancer … and as a consequence it is impossible to accurately assess whether it is an independent marker or not. To quote Epstein, “Data are conflicting as to the independent prognostic significance of TV in RP specimens.”

  9. I guess I am somewhat alarmed about having what I consider a large amount of cancer at 42 years old. My PSA at diagnosis was 2.76 ng/ml. I had a 50-core biopsy that showed cancer in six spots as “small foci” according to Epstein, who reviewed my slides. Then at RP it was found in seven spots and overall TV as “moderate.” I was Gleason 6, organ confined by the way. I am concerned now that I had a large amount of cancer and a low PSA. Translating to more aggressive prostate cancer.

  10. Chris:

    I suspect that you are “over-agonizing.” Think about it this way. If you had had one or two small foci of cancer, Epstein would have classified it as “minimal.” If you had had even one large tumor, Epstein would have classified it as “extensive.” So with six small foci on biopsy (and seven on the pathology report) you really appear to be at minimal risk for progressive disease if it was all Gleason 6 and organ-confined.

    I am uncertain how long ago you had your RP, but the men who have aggressive small-volume tumors usually tend to progress pretty quickly because they also have early micrometastasis. In other words, their recurrence is commonly not localized to the prostate bed. As far as I can tell, you show no signs of such a problem.

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