Managing Variant Histology in High-Risk Non-Muscle Invasive Bladder Cancer - Michael Cookson & Paolo Gontero

May 17, 2024

Ashish Kamat hosts Paolo Gontero and Michael Cookson to discuss managing high-risk bladder cancer with variant histology. They address the challenges of treating these cases, given the variability in pathology reports and treatment strategies. Dr. Cookson emphasizes treating these patients as high-risk and the importance of proper staging and patient counseling. Dr. Gontero highlights the increase in variant reporting and the need for aggressive treatment, noting that current outcomes are often poor due to conservative approaches. They both stress the necessity for better data and clinical trials to improve treatment strategies. They discuss specific recommendations for various histological subtypes, generally agreeing on radical cystectomy for most high-risk variants, with some exceptions based on individual cases. The conversation underscores the importance of personalized treatment plans and the need for more research to optimize patient outcomes.


Michael Cookson, MD, FACS, MMHC, Professor and Chairman, Department of Urology, University of Oklahoma Health Sciences Center, Stephenson Cancer Center, Oklahoma City, OK

Paolo Gontero, MD, Professor of Urology, Chairman, Department of Urology, Molinette Hospital, University School of Medicine, Turin, Italy

Ashish Kamat, MD, MBBS, Professor of Urology and Wayne B. Duddleston Professor of Cancer Research, University of Texas, MD Anderson Cancer Center, Houston, TX

Read the Full Video Transcript

Ashish Kamat: Hello, everyone. Welcome to UroToday's Bladder Cancer Center of Excellence. We're here at AUA 2024 in San Antonio. I'm Ashish Kamat, and I'm joined by Professors Gontero and Cookson. Thank you, gentlemen, for taking the time and spending it with us today.

We're going to address a topic that comes up often, right? We see these patients in clinic who have high-risk bladder cancer, and then we look at the pathology, and there's a variant subtype, variant histology, or, as the pathologists want us to call it now, a histological subtype. It's something that the community urologist sometimes is not sure what to do with, but even in academia, there's often a debate. Do we recommend radical cystectomy right away? Is there a role for intravesical therapy? So it's really here where we want to hear your thoughts on how you manage these patients in your office.

So, Mike, if I could start with you, what's your thought process?

Michael Cookson: Well, I like how you opened with what the variability is out there in the community. And even more importantly, is even just the pathology variability. It's not uncommon that we know 90% of urothelial cancers are that way. And when we subset, about 25 to 30% of them can have something else attached to them, and that's that, we call it variant, but even that creates problems. So I like your subtype language, but it's not quite made it to mainstream.

But in those reports, it includes things like just a little bit of glands that are slightly different or squamous cells that they see features. And then there's also the more concerning wording, like micropapillary, nested variant, and lots of... There's probably a menu of maybe 20 different subtypes that can be notified. And because they're relatively rare, they're not well studied, and we don't know the biology of them, even if they're classified correctly, it creates an opportunity for a lot of variability.

Ashish Kamat: Yeah. That's a great point you make, right? The variability in reporting and things of that nature. Paolo, how is it where you are? Is the reporting standardized for these subtypes, or do you have to go and call the pathologist every time?

Paolo Gontero: Well, what I have noticed, I mean, I belong to a tertiary referral center. So we have dedicated uropathologists, which probably are biased toward better reporting. But we just noticed in the last two years that there has been an increase in the number of variants. And we noted that because within the setting of trials on non-muscle invasive, high-risk non-muscle invasive bladder cancer, we could not actually include many patients because they were reporting tiny percentages of a given variant or subtypes. And so, I think that's the right time probably to make a change.

Because if we look in the literature, the data that we have are so poor. We have these registry studies with large series, very poor outcomes, meaning that probably we're not doing a good job. In my opinion, there's too much conservative treatment because I can't believe that 70% of these patients receive conservative treatment. The results of aggressive treatment are not so good as well, meaning that probably either we are on the wrong path or we are too late in being more aggressive. And I think now we can really have a lot of information because our pathologists, which I would stress is important, also report the percentage of the variant. Sometimes they report more than one variant, which didn't happen at all in the past. And I would say that probably talking about non-muscle invasive bladder cancer, 30% or more of the T1 end up having an associated variant.

Ashish Kamat: So let me bring you back to that, because you bring up a very important point, right? About 15, 16 years ago when people were reporting these histologic subtypes, we'll call them variants just as it's common parlance, the incidence in pathology reports was about one to 2%. Right? Now, just as you're mentioning, we're seeing people coming in with micropapillary reported in as many as 10, 15% of cases. And I'm sure you're seeing the same thing too.

So there's a push, and if it's going to be 10, 15% of our patients that have this, every patient wants to try to save their bladder, right? Now patients don't want to have their bladder taken out. But because of the data that's been out there, maybe based on the 1, 2% reporting, there's a trepidation in my mind for sure. For example, someone comes with micropapillary disease, and I'm going to miss that window to cure the patient, and they'll end up with, like you said, metastatic disease. So from that perspective, Mike, how do you counsel a patient that shows up? And let's assume now it's not one of those glandular things, but a real disease.

Michael Cookson: Right. Talking about the pure squamous cells and the pure adenos, we're talking about that little bit of mixed variation in the histology report.

Ashish Kamat: Let's say 15% of that.

Michael Cookson: And so we always have, we're trained, the guidelines even tell us, these patients should be treated as high-risk. And so by definition, we're already considering them to be special. And in that distinction, they certainly can't just be observed because we know that that's not going to be enough. And you mentioned T1; some are not T1, some are TA, that sort of thing. But if we're talking about T1 micropapillary, we're talking about a concerning tumor. And if you look to our guidelines, which suggest that you should treat them more aggressively, you would, at a minimum, want to stage them properly. You would want to do a re-TUR to assess that you've completely eradicated the tumor, and you're not missing an invasive component.

And then it becomes the art. And that is, was it a big tumor, a small tumor? Location? Was it amenable to complete resection? Do you feel comfortable about it? And then whether they're willing to take that risk that it could recur, could progress, and consider intravesical therapy, intravesical BCG. You and others have written small series of papers where the outcomes comparatively were better with radical cystectomy. Others have written the opposite and said they did just as well, and it probably came down to patient selection. So I don't want to say that there's a one-size-fits-all and that they all need cystectomy, but I think that's a conversation you have right up front with them that that would be a standard of care. And I would try to do some bladder conservation if possible in the right setting.

Furthermore, you could say, well, there's other nuances to it. So other features in the pathology report, lymphovascular invasion, and the percentage of micropapillary, can all weigh into the decision-making too.

Ashish Kamat: Yeah. No, great points. Because again, it's our role to counsel the patient appropriately and sort of put, what would you do and what would you recommend someone do, and ultimately let the patient make their choice. The EAU Guidelines, which you lead, have done a very good job of separating out the high-risk from the very high-risk.

Paolo Gontero: Oh, yeah. Yes.

Ashish Kamat: And if you have these subtypes or variants, they fall in that very high-risk category. And I don't want to misquote you, but what's in the Guidelines is that those patients should be counseled on radical cystectomy first. Which is what I think Dr. Cookson said as well. Tell me your thought process about putting that in the Guidelines.

Paolo Gontero: Well, the fact is that when we talk about subtypes or variants, the assumption that led to consider as a very high-risk, which is roughly untreated, 40% risk of progression at five years, is honestly eminence-based, or based on what we find in retrospect, the literature data. But to be honest, I would say that as an average, many subtypes are actually at least considered to be very high-risk. Because if you look at the survival data of some micropapillary series, you find a 5%, 50% cancer-specific survival, and that's much worse than a 40% risk of progression because not all those who progress die of the disease. So I think, as it was pointed out, Mike, I think we really need to go into more detail. Not all the variants are the same. Some variants are absolutely very aggressive, but unfortunately, we don't have data.

If you think about the plasmacytoid, which is a rare variant, if you look at what we have in the literature, mainly cystectomy series. All patients aggressive, they don't respond to anything. So what do you do when you find a small rate of plasmacytoid in a non-muscle invasive, which you think is truly non-muscle invasive? Do you say, "Okay, I'm going to remove everything," or you just say, "That's the perfect window of opportunity just to eradicate everything, be aggressive and take out the bladder."? That's a difficult choice because the patients don't want the bladder out. And the more we develop new treatment strategies, the more patients are less inclined to ask you about radical cystectomy.

The problem with these patients with variants is they are excluded from the trials, and then we stick on BCG as the only conservative treatment, which is honestly very poorly evidence-based, in my opinion. Also concerning the fact that some series report that the results with conservative treatment are not worse than that of radical cystectomy, but this likely reflects heavy selection bias.

Ashish Kamat: Yeah. And let me make one point here, just to bring this home. So in the micropapillary realm, even the series that show they are equivalent show poor outcomes across both arms, like you mentioned. So clearly, we need to do better for our patients. And the risk of dying from metastatic disease is less now that we have EV/pembro, but it still is a real threat. So that window should not be lost. Mike, you had a point to make.

Michael Cookson: Well, so he mentioned something, and we talk about, you mentioned Guidelines, you've been on Guidelines, I've been on Guidelines. The Guidelines are only as good as the data. And he mentioned the word evidence-based, and that was hitting home to me. Sort of doing the same thing with increasing frequency and getting the same results over a large number of years. Is that a good thing? And when we look to the Guidelines, if you look for the source documents for what would be the level of evidence, et cetera, that's when you see small series retrospective survey data, ask eminence to tell you what they do. So we really need, this is a call to arms. We really need to do the clinical trial. We really need to include these patients and we need to do better subtyping and molecular profiling, and really figure out, are they going to respond to treatments, whether that's intravesical, immunotherapy, chemotherapy combinations, or systemic therapy? We know some of these don't respond even to our best systemic therapies.

And all of us as urologists are surgeons, and we have sort of this Halsteadian mindset, that if we could just take out their bladder now, maybe that would solve the riddle. We get in there and we find the spreading of these tumor cells in the peritoneum not seen on CT. Cystectomy's not going to be curative, nor would just intravesical therapy. So it's really on us to change it. So 10 years from now, we won't be sitting here having the same conversation.

Ashish Kamat: Yeah. No, great point because again, we need to do those studies. Our patients want to live, but they also want to live with their bladder. And so, those studies absolutely need to be done. Gentlemen, obviously, we could talk for a long time, but we can't. But I still do want to touch upon a few points. So I'm going to ask both of you for... I'm going to give you the name of a histologic subtype, and you tell me if your primary recommendation is intravesical therapy, radical cystectomy, chemo and radical cystectomy, or TMT? Just your first recommendation to a patient, right? No details here. So we talked about micropapillary, let's leave that aside. Pure squamous.

Michael Cookson: Cystectomy.

Paolo Gontero: Cystectomy.

Ashish Kamat: Pure adenocarcinoma.

Michael Cookson: Possible partial cystectomy or cystectomy.

Ashish Kamat: If it's Urachal, you mean, right?

Michael Cookson: Yes.

Ashish Kamat: Okay.

Michael Cookson: Dome.

Paolo Gontero: I would say the same. It's reasonable.

Ashish Kamat: Plasmacytoid.

Paolo Gontero: We agree.

Ashish Kamat: Plasmacytoid.

Michael Cookson: I don't have a good answer for you, because those are the ones where we don't seem to do well with either therapy. So I might tend to start with conservative measures.

Paolo Gontero: But if it's T1, which is a rare occurrence that you are able to pick plasmacytoid T1, well, okay. Unless it's really a minimum percentage, I would recommend this patient radical cystectomy and don't do a re-TUR. Because if you do a re-TUR and the re-TUR is negative, then you would treat conservatively. In my opinion, that's the subtypes where the window of opportunity is such a rare occurrence that you should be aggressive.

Ashish Kamat: Yeah. Let me make an editorial comment there. I agree with the first recommendations completely. Plasmacytoid, and it may be again, like you said, eminent space. We see a lot of these patients at MD Anderson, and Akshay Sood, who is currently in Ohio, published on this recently. They do extremely poorly with chemo and surgery. Most patients end up with peritoneal recurrences, 80%, even after chemo and surgery. So I think there I would side with Paolo, that personally I'd be more aggressive. I'm very scared of plasmacytoid, right? And it may be just a reflection of what we see. But good point. We have to consider that. Small cell carcinoma.

Michael Cookson: So I'm going to go with chemotherapy for that, and then consider bladder conservation, depending on the response.

Paolo Gontero: I would say chemo and cystectomy.

Ashish Kamat: Yeah. Again, small cell. Again, just for the audience listening, treated like a systemic disease, it just happened to be found in the bladder. And what you do with the bladder is probably less important than what you do systemically.

Michael Cookson: And unlike some tumors, you may get a really good response to the primary tumor in the bladder as well, and that can help to decide on what to do later.

Ashish Kamat: At that point.

Michael Cookson: But I personally have managed many patients who started with a large small cell in their bladder. We TURed them, they got chemo, everything melds, and we follow them conservatively. But again, those are just single cases, and you have to decide what you want. But I think small cell neuroendocrine particularly, think chemo first.

Ashish Kamat: Absolutely. So gentlemen, in closing, I know this is supposed to be about the debate that you guys are participating in tomorrow where you were both given a side, so feel free in closing to either take your side or educate the audience in general. But a short one-minute summation from both of you. Variant histology in, say, T1 high-grade bladder cancer. What should be done?

Paolo Gontero: In general, I would tend to be aggressive, but I realize that that's only a starting point. Because the point here is not whether cystectomy is better than BCG or vice versa. The point here is that they do badly, and so I think probably we may be on the wrong path. So we just need probably more, we need probably molecular profiling. And that probably could be the best patients for personalized target treatment, which at the moment, of course, is premature because we still need prospective data. That's the problem. I think we need a registry with prospective data for this patient, heavily.

Ashish Kamat: And Dr. Cookson.

Michael Cookson: Yeah, I think the take-home message is, if you have a variant histology, that should raise your antenna. These are high-risk, very high-risk patients, and they need to be informed of that. And it may be that no matter how you manage them, we're not going to be successful. So we really need to be vigilant about our treatments, monitor them more closely, whichever way we go. I'm going to put out that plea for better trials to include these variant histologies. I think Osler said something like, if it wasn't for the variability in these situations, could be patients, could be tumor types, this would be more of a science than an art. Currently, it's more of an art. So leave it with that.

Ashish Kamat: Great points. Thank you. It's always a pleasure chatting with you. Enjoy the rest of your AUA.

Michael Cookson: Thank you.

Paolo Gontero: Thank you.