Peter Black: Hi there, welcome to the AUA 2022. I'm Peter Black, I'm a urologist from the University of British Columbia in Vancouver. And I'm joined today by Mario Fernandez from Chile, from Santiago de Chile, and also Michael O'Donnell from the University of Iowa. And today we want to talk a little bit about the impact of variant histology in the management of patients with bladder cancer. So potentially, a big topic, lots to talk about. Why don't we frame it around a case? I'll start with you, Mario. If you have a 64-year-old male patient eligible for whatever you want to do, and this patient has a T1 micropapillary bladder tumor, what is your favorite treatment?

Mario Fernandez: So I go for cystectomy. That's my first treatment. So I think there are two crucial issues here. First, we have very limited evidence. So, there are only small, retrospective, single-center series, and with conflicting results. Most of them talking about cystectomy. And the second crucial issue is that there is a big uncertainty in diagnoses of viral histologies. So, there is more or less 50% of under-diagnosis. So, with these two crucial things, I think we should go for the safest option in terms of an oncological viewpoint, and that's for me clearly the cystectomy.

Peter Black: And so maybe Mike, I think that as people who do a lot of bladder cancer, we, I think all probably say, cystectomy for some of these variants, including micropapillary, but Mario alluded to the fact that the data's not really very good? There's, I think we all cite MD Anderson data, especially retrospective series, which are now not necessarily that contemporary. Can you make an argument to preserve the bladder in some patients? And if so, which patients?

Michael O'Donnell: Yes, I think you can. And like with many things in bladder cancer, the devils in the details. And as we accumulate more evidence, we begin to understand that not all micropapillaries are the same. In fact, three very large studies that looked at overall survival, found that patients that are treated with non- cystectomy, with bladder preserver therapy, most of which was BCG, actually outperform, or at least as good as radical cystectomy.

Michael O'Donnell: If you trace it down to the roots, it comes down to two important features that we are now beginning to recognize are critical for determining the aggressiveness of micropapillary. One is the presence of lymphovascular invasion, which we've always known is important for T1 disease. And the second one is the percent of micropapillary. So as now, the pathologists are becoming more aware, we're starting to see micropapillary with 1% features, with mixed features, with all kinds of nuances that may change the situation. And as people are beginning to re-resect, as they do normally with T1 disease, find there's no micropapillary, what do you do then?

Michael O'Donnell: Well, I think that the data now that's emerging from the most recent studies suggests there is room for a conservative or bladder preserving approach. So long as you follow careful oncologic principles, re-resection of T1, having a reference geo pathologist to really scrutinize the specimen, and then very close and detailed restaging and follow up to make sure you're not missing anyone that could slip through the cracks.

Peter Black: So I think there are some really important points in there. It touches on what Mario's saying also about the heterogeneity and interpretation. And I think as pathologists have become more sensitized to micropapillary, they're calling it more. And so what's micropapillary now may not even have been recognized before, and it's not quite as extensive, quite as impactful. And maybe we can preserve some of those bladders.

Peter Black: Now, if you have a high grade, back to Mike, a high-grade T1, and you're re-resecting in the past, maybe re-resection also, wasn't done as carefully? And you decide not to do a cystectomy, maybe the patient's not a candidate for a cystectomy. Do you treat them then the same as a regular T1? So you would treat them with BCG?

Michael O'Donnell: It's interesting that the BCG shortage, it's challenged all of us to find new alternatives. We've actually been pursuing a program of doublet chemotherapy, sequential gemcitabine docetaxel. And I look back at our database, we've had eight patients with micropapillary disease treated that way. All in the last three to four years. The complete success rate was 75%. And every one of those is alive and well, the two that failed; failed with non-papillary disease, they were treated with an alternative regimen, Valdosi, and all of them are fine. So, we have now eight patients, a hundred percent out over two years, negative CT scans, negative FISH studies, completely normal FISH. I'm watching them. So that's basically given me a new perspective on maybe new therapies providing a change in our outlook.

Peter Black: Right. Excellent. So Mario, what about some of the other subtypes specifically in this T1 setting? So what makes you nervous? What patients are you guiding towards cystectomy based on variants?

Mario Fernandez: So, regarding some other variants [inaudible 00:05:26], like plasmacytoid, sarcomatoid, there is even less evidence than for micropapillary. So, in that case, the few evidence we have, the clearest is for cystectomy. So in that case, I would go for them. There are also very aggressive variants. And I think in that cases, there is probably no room for something other than cystectomy.

Peter Black: So for those two, I worry even more than micropapillary, but Mike, do you think that we're, are we potentially going to see the same evolution where we're calling sarcomatoid, where there's just a little bit of something spindle-like that's sarcomatoid? Or is it always going to be bad? Plasmacytoid I think is always going to be bad. [crosstalk 00:06:12]

Michael O'Donnell: Plasmacytoid scares me to death, no matter what you do, even with neoadjuvant chemotherapy and get responses, six months later, the patient has metastatic disease. It's not uncommon. We at our institution are able to go with our pathologist and review each of the cases as they come up. I have never seen a sarcomatoid that was less than an invasive T1. And in every one of those cases, it was under stage. So I'd be very, very worried about that.

Michael O'Donnell: But there are other variants, for instance, squamous differentiation, glandular differentiation, which seemed to make no real difference. They can be treated the same way we do conventional urothelial carcinoma. Small cell, of course, is its own little creature, that must be treated with chemotherapy first because of the high rate of metastatic disease.

Peter Black: Okay, great. And maybe Mario, so if we're looking now in the muscle-invasive setting, we'll come back to the micropapillary. What do you do with the muscle invasive, T2, T3, micropapillary and neoadjuvant chemo?

Mario Fernandez: Well, that's a different issue than 41, now we have a muscle invasive. I think the management is a little bit different. There is some evidence, again, not best quality evidence, but we have some evidence for neoadjuvant chemotherapy. So there is room for neoadjuvant chemotherapy for a potential benefit. And I will probably always look for that in my patients ... Regarding micropapillary, maybe blood cancer.

Mario Fernandez: So there is again, a big experience at MD Anderson that shows that if patients have no hydronephrosis, there is a potential benefit for neoadjuvant chemotherapy. So I would go for that.

Peter Black: Yeah, it's one of these things that we, since we don't know how well it works, some people say, well, let's prioritize them for surgery. MD Anderson modeled for sure, and I think same at Sloan, Kettering, other big centers is that they're higher risk for under staging. So they need the treatment intensification more than anybody else. Do you do anything different, Mike?

Michael O'Donnell: No, we do basically the same thing. Plasmacytoid is the real bugger because we've gone through the program of giving them all neoadjuvant and the results have been disappointing. It looks good. Six months later it's bad again. So we've changed our approach to try to minimize the delay and go to cystectomy immediately. I don't know if that's better, we don't have any real studies to prove it. It's just that an underlying sense that this is probably one of the worst actors that there is in the variant category.

Peter Black: Yeah. So, Mario, anything else that comes to mind with respect to variant histology that we should address?

Mario Fernandez: So we need reliable markers. So, we need information about which patients will do well with immuno- cystectomy, which patients will need maybe some other therapy, immunotherapy is a new actor in this scenario. So we should work on that, and all of the oncology to have reliable markers predicting the outcome of the patients.

Peter Black: Yeah. Always important. And Mike, maybe something related to systemic therapies?

Michael O'Donnell: Yeah, well just a point related to Mario's is that genomics is now telling us that what we see immunohisto- or histologically is not necessarily the whole story. And so we're finding that 25% of micropapillary are different than the other 75%. The same thing can be said probably for some of the other rare variants, but it just goes to tell us that there may be nuances there that genetics and genomics can help sort those out.

Michael O'Donnell: In terms of newer therapies, immunotherapies have really taken hold for advanced metastatic disease. And many of the trials have allowed at least 50% or less variants enrolled. And it's been relatively agnostic in terms of, they seem to respond as well as conventional, with the one exception of small cell. That one appears to not do well at all with immunotherapy.

Peter Black: Okay. Terrific. Well, thank you both for the discussion on variants. I think there's a lot of really good research going on, I think people are trying to focus on the individual variants, understanding the microbiology, and hopefully, that'll bring us to the next level of a more targeted therapy with better outcomes. So thank you.

Mario Fernandez: You're welcome.

Michael O'Donnell: Thank you.