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Theo van der Kwast: At first, I want to say, I speak as an individual. Of course, for me, there is no doubt that Grade Group 1 or Gleason Score 6 is an infiltrative and locally aggressive cancer.

And actually, it's a matter of pathological versus clinical definition. So, according to a pathological definition, I have no other option than to call it adenocarcinoma. If infiltrated, it shows perineural invasion, occasionally there's extraprostatic extension, and you cannot separate it. And I think someone else will talk about that—the Grade Group 1 from Grade Group 2 and higher—on the basis of genomic alterations. So, that is the main thing.

Further, we do not know what is the natural history of Grade Group 1 prostate cancer. As mentioned, there's no metastatic Grade Group 1 cancer, but that is, of course, after the prostate has been removed. We do not know over time what will happen with these cancers.

And a worry, which was also ventilated just now by Adam Kibel, and I'm really worried about that, is that pathologists might start over-calling Grade Group 2 out of concern to underestimate a Grade Group 1, particularly when there are multiple biopsies.

And again, many patients with a benign diagnosis of Grade Group 1 might underestimate their prostate disease. I want to mention, was the change from Gleason Score 6 to Grade Group 1, courtesy of us pathologists, not sufficient to reduce patients' anxiety? I really think this is a USA problem. It's not a European problem, and also not so much a Canadian problem, I believe. So, I do not see why we pathologists should change the pathological definition of adenocarcinoma or change the nomenclature because I report my pathology reports written in pathological definition language, and I'm not going to change that so easily.

So, I think it's the call of the clinician to reduce patient anxiety, and not the duty of the pathologist.

Next, please.

So, here we have an example, a diagnosis of adenocarcinoma, Grade Group 1, in six of 12 cores. Maximum carcinoma extent 80%, positive for perineural invasion. That's the current diagnosis.

Would you want something like this, as a neoplasm benign, in six of 12 cores, maximum extent 80%? And maybe remove the positive for perineural invasion, not to make the patient scared, or something like that? Come on, that's not going to happen.

So, the great unknown, I mean, what is the big question? Well, the question is how frequently does Grade Group 1 adenocarcinoma evolve into higher than Grade Group 1 carcinoma.

So, there are modeling studies. I think the Etzioni paper, the group of Etzioni, they published that the risk over 10 years in an active surveillance cohort, and it is a Johns Hopkins active surveillance cohort, so very, very strict, rigorous guidelines, is 12-20%, which is not nothing. Again, future research should be longitudinal radiomics study of MRI-targeted Grade Group 1 prostate cancers, probably.