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Speaker 1: The sampling issue is always there, but we toyed with phrases like low malignant potential, potential for progression over time. We didn't come to a unanimous decision on that, but somehow communicating that it was not a prostate that was free of cancer. It did not say that cancer could not develop in the prostate, but it did say that all the signs were that it was a very low risk of developing cancer. We didn't come to a way to phrase it or articulate it. Sandy, do you want to add?

Speaker 2: Yeah, I was just going to add, we all in this room, especially in pathology, recognize that the term cancer is not a yes/no thing. It's shades of gray, with some of those shades being essentially white. We thought that it would be useful to remove the pejorative term carcinoma, perhaps, and simply call it neoplasm and then assign a grade group, and then we let you guys worry about whether or not you tell your patients that's cancer or not. But at least we're not on the hook for creating emotional burden. So that was, I thought, an interesting idea that came up.

Speaker 3: I think there'd be a lot of support for that [inaudible 00:01:27].

Speaker 4: I've got a question.

Speaker 3: Yeah, go ahead.

Speaker 4: So what percentage of the grade group ones do you think would be callable as a result of that hedging or that risk? Are you talking 10% or are you talking 30%? I mean, at 10%, it's a win, right? Because 90% of the people are going to benefit. 10% might not benefit from that diagnosis. But...

Speaker 2: One of the other ideas that came up is that we'd like to have some sort of a way to confirm our opinion, and it is at some level an opinion about where it fits in the criteria. I think we're actually pretty good at this as pathologists, and if we had an additional ancillary test that could back us up, that'd be useful. Right now we have that for invasion or non-invasion by staining for the basal cells, but now we're asking for a different question of is this true three pattern or four pattern?

Now we all in this room also recognize that a little bit of four pattern is probably not going to change the prognosis of that patient very much, if at all. So it's not a bad miss, and I'm on record as saying I'm not worried about the legal repercussions of somebody coming back later because I think everybody understands that biopsies can, by sampling, be falsely negative, and there is going to be some false negative read. So I think we all just learn to live with that going forward. But I do think when you ask pathologists to create a new line in the sand, a new boundary, you're always going to have problems on both sides.

Speaker 4: We're not asking for a new boundary, right?

Speaker 2: Well...

Speaker 4: We're not asking for new...

Speaker 2: I recognize that, but it's not new to us. But in places where the diagnosis of three plus three versus three plus four doesn't matter, pathologists are probably less reproducible than those in this room.

Speaker 5: I think we're creating a boundary to avoid overtreatment. It's that way around. That's for the indication for management. We're kind of trying to sieve out, the best that we can, those that are not going to be aggressive in the patient as GG ones.

Speaker 6: Is there morphologically... I don't think any of us here are saying change a boundary between grade group one and grade group two.

Speaker 5: No, we can't.

Speaker 6: No. So to answer Brian's question on record, what do you think other pathology groups think about how many of the now-called grade group one do you think might trickle into grade group two as a result of a nomenclature change?

Speaker 5: Well, there's no data, but...

Speaker 5: I would say a minority. It's just a minority. Yeah, I think it's just a minority.

Speaker 4: We would say 10%.

Speaker 2: A better question, Dan, is how often is that assignment correct?

Speaker 1: Right.

Speaker 2: What does the AUC curve, the ROC curve, look like on that? And I don't know what you use as the gold standard, but you have to accept that we in pathology are going to have differences of opinion, and this is not a, again, for sure three, for sure four question. It's going to have some wiggle room.

Speaker 3: Have there been ever successful lawsuits against pathologists or... No, I'm serious. You can't sue a primary doctor...

Speaker 1: Let me answer the question.

Speaker 3: ...with successful delay diagnoses.

Speaker 5: We actually get sued more for over-diagnosing as cancer.

Speaker 3: Over-diagnosing?

Speaker 5: Yes. Miscalling something ASAP as cancer, rather than missing it.

Speaker 7: What was your question there?

Speaker 3: Have there been successful lawsuits against pathologists for under-calling cancer? For calling a three three which was actually...

Speaker 7: I thought you meant based on grade.

Speaker 3: No, for grade. Has there been a lawsuit because he called it a three three and it metastasized?

Speaker 8: There has been a lawsuit.

Speaker 7: There's a legendary lawsuit in Arkansas of someone that was calling things negative, but they were really cancer, and then it came out that he was an alcoholic. [inaudible 00:05:54]

Speaker 3: Back to this whole basal layer.

Speaker 7: Go ahead.

Speaker 3: Just to come back to the point that I was making earlier, that in this equivalence between the basal membrane and the basal cell layer, I think a lot of us have never quite understood. You think about bladder cancer, cancers we're used to, which have the indiscrete layers to them, so it loses the basal layer. How did that come to pass that that became equivalent to invasion past the level of the basement membrane and some other [inaudible 00:06:28]? It was not the same physical phenomenon, right?

Speaker 7: Historically?

Speaker 3: I mean, yeah, historically. Historically, yeah. I suppose historically, and is it correct biologically? Is it a true equivalence, or is this just an artifact and just a convention?

Speaker 1: It's part of the definition.

Speaker 3: Well, yes, but...

Speaker 8: How did it come to be.

Speaker 3: Right? Losing the basal layer, well, it's a thinner gland, it only has one layer.

Speaker 8: Large volume stuff that we were calling cancer before we had the markers for basal cells based on infiltration of the tumor, and obviously the outcomes, patients were dying of that. Then when these immunos came and it's like, oh, well look, those basal cells are gone. And then this became this dogma.

Speaker 7: You mean pathologists couldn't recognize loss of the basal cell layer before they had immunohistology?

Speaker 8: They could, but not in every case.

Speaker 7: Okay.

Speaker 8: But not every case. That's why we use it.

Speaker 2: And Matt, it's important to recognize that this goes throughout every organ system. So the definition for cancer in every organ system is invasion. And as I pointed out in the chat earlier, there are a few exceptions to that, but only a few. So we do recognize borderline tumors of the ovary with invasion. Carcinoid tumors are sort of this unique benign neoplasm that nonetheless can be invasive. So there are these kind of unusual exceptions, but even when we look at the colon and we've got to tell the difference between what's called pseudo invasion, where epithelium gets pulled into the lamina propria versus true invasion where it's penetrated the basement membrane, kind of its own accord. We spend a lot of time trying to figure that out. And so this is just kind of what we're trained to do across the board.

Speaker 9: But the critical caveat you added was patients die of that entity that you were seeing before immunohistochemistry.

Speaker 8: Yeah.

Speaker 9: And the validation against that true endpoint of your microscopic finding is quite clear that patients don't die of the entity that you are currently calling cancer. So I'm a stupid urologist, but fundamentally, your validation against the hardest endpoint for your microscopic finding is not there. So it may be what you call and historically have always called, but you have to rethink it because that dogma can be carried across all cancers. But if it's not true in this particular entity, it's not true.

Speaker 8: To complicate it a little bit more is intraductal cancer, right? There are basal cells and there are people who say there are basal cells, it is not cancer, but look at the outcomes for this.

Speaker 7: They have basal cells.

Speaker 4: Wait a minute, Scott. To that point, why can we make an exception for that, which makes total clinical sense, but we can't make an exception for pattern three on the other side?

Speaker 8: Somehow the basal cells become this mythical creature.

Speaker 4: That's the question.

Speaker 7: We're stuck with that.

Speaker 10: We're confusing carcinoma with cancer, right? The pathologist, if you want to call it whatever you want to call it, due to pathology, that's fine. I know Scott may disagree. I'm perfectly fine if you want to call it carcinoma because that's fine. It's the word cancer. The cancer predates pathology, right? So the pathologist, you're going to come out with your own words and that's fine. That's your profession, that's your job. But cancer has an ordinary language meaning, and I don't think it's up to pathologists to decide what's cancer or not. I think that's a multidisciplinary group of people who have to talk about it. So when we're...

Speaker 2: We already don't call it cancer, we call it carcinoma.

Speaker 10: You say that, but John Epstein is saying, no, it's cancer. Morphologically, histologically. It's cancer. No ifs, no buts about it. Now let's move on. Right, Scott, you're wrong. Because I'm John Epstein and I say it's cancer. Okay.

So I disagree with that. I'm saying John Epstein, you're an expert in what's carcinoma and what's intraductal and something, but what's cancer is not about... So can we just get out of that discussion about, you know...

Speaker 2: So truth be told, I think the word carcinoma, which means malignant neoplasm, is the basis of disease, which is our Bible in pathology. That word malignant is what we're arguing about. And grade group one is not malignant by any stretch of the imagination, and that's the problem that we've run into. It's a good problem to have, but it's really hard to back off on. That's what we're talking about.

Speaker 5: Can I add something just to complicate it more?

Speaker 8: Sure.

Speaker 5: So benign glands in the prostate can actually infiltrate into the nerve, just like perineural invasion. It can...

Speaker 2: I'm going to push back on that. That doesn't complicate it. We see benign inclusions of breast epithelium in axillary lymph nodes. We see all kinds of benign pseudo-infiltrative stuff. So I'm not concerned about that.

Speaker 3: No, so I think it makes it easier.

Speaker 8: Yeah, I do too, instead of complicating it.

Speaker 5: So my point here is there's something unique in the prostate, in the stroma of the prostate, that allows the benign glands to do that.

Speaker 2: It's actually the nerves that are primary, right? The nerves are inducing that biology. Those are fun papers, but I'm not sure I believe them.

Speaker 1: I mean, the term here, I think it was the term cancer, is so loaded, but it's not loaded with basal cell carcinoma of the skin, is it? I mean, it's been made with patients that basal cell carcinoma of the skin [inaudible 00:12:49].

Speaker 7: Say in the paper and artifactual upgrading when there's only a small amount of pattern 4, the CAPPA for agreement between pathologists on the assignment of Gleason grade was 25%.

Speaker 9: That was because...

Speaker 7: Was 25%. So I mean that's a whole other aspect of this.

Speaker 3: When they called it hard, in fairness, that was when they called it a challenging case. If they thought it was an easy case, right, it was in the seventies. But if it was a subtle case, it's just [inaudible 00:13:11].

Speaker 1: And to be complete, we did have a little discussion about ASAP. I don't know if we want to go there.

Speaker 3: We don't.

Speaker 1: All right, so repeat.