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Ashish Kamat: Hello, everybody, and welcome once again to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, Urologic Oncologist at MD Anderson Cancer Center. And it's a distinct pleasure to welcome to the forum today Dr. Alkazemi and Dr. Al-Ahmadie, who really needs no introduction.

They're going to join us today to talk about the impact of micropapillary histology. This is a histology that a lot of us have been involved with and I've been involved with so many years, and it's always good to get updated periodically on the contemporary outcomes, clinical staging, impact. And this is a retrospective analysis, but it has a lot of nuggets. So, Hassan, take it away.

Muhammad Hassan Alkazemi: All right. Thank you. Good morning, everyone. It's a privilege to have this discussion today with you, Dr. Ashish Kamat.

My name is Hassan Alkazemi. I'm honored to present our retrospective analysis to the UroToday audience on "The Impact of Micropapillary Histology and Clinical Staging on Overall Survival in Bladder Cancer." This study was conducted in collaboration with my colleagues at Memorial Sloan Kettering Cancer Center.

So to give a little background, micropapillary urothelial carcinoma, referred to from now on as MP, is a rare and aggressive variant of urothelial carcinoma, accounting for 0.01% to 2.2% of bladder cancer cases. This histologic subtype is known for its local aggressiveness and higher stage at diagnosis. However, its prognostic role, particularly in relation to the percentage of micropapillary component in a tumor, remains uncertain, which was our focus in this study.

Most previous studies on MP have been limited by small cohort sizes, making it challenging to draw definitive conclusions. In our study, we leveraged a large, single-institution cohort of patients who underwent a radical cystectomy, to analyze the impact of MP on clinical staging and survival outcomes. This comes on the coattails of many studies such as those from MD Anderson and multi-institutional studies.

Looking at the methods, this retrospective study included 130 patients who underwent radical cystectomy for MP at MSK between 1995 and 2023. We compared overall survival outcomes to a separate cohort of 430 consecutive patients with urothelial carcinoma not otherwise specified who also underwent radical cystectomy.

Patients with MP were stratified based on their clinical stage at transurethral resection of bladder tumor, as either non-muscle-invasive bladder cancer or muscle-invasive bladder cancer. Additional stratifications included the percentage of MP component and receipt of neoadjuvant chemo. You can see from the demographics table here that the patient population is predominantly male—with a 10 to 3 ratio—white, and the average age at diagnosis was 69.

Most patients had advanced-stage, T3 disease at cystectomy, reinforcing the aggressive nature of MP. Lymph node involvement at cystectomy is common, with 59% having node-positive disease. And platinum-based neoadjuvant chemo was used in 35% of cases. This suggests that a significant number of patients received systemic therapy before surgery.

Transitioning to our results, when comparing overall survival using the log-rank test, MP was associated with significantly worse outcomes compared to urothelial carcinoma not otherwise specified. The median overall survival for the MP group was 37 months, compared to 84 months in the UC NOS cohort, p-value of 0.011. This suggests that patients with MP disease have significantly worse survival outcomes compared with those with conventional urothelial carcinoma.

When looking at the impact of initial clinical stage, among MP patients, those with muscle-invasive disease at TURBT had significantly worse OS compared to those with NMIBC. The p-value for this comparison was significant, reinforcing the importance of staging and patient prognosis.

Next, we examined the impact of lymph node status at the time of final cystectomy in MP disease. The Kaplan-Meier curves on the right illustrate that there is no significant difference between node-negative and node-positive disease at the time of cystectomy, with a p-value of 0.2. This revealed that this was not an independent predictor of survival in this cohort.

This brings us to the main question we sought to answer, which was whether the proportion of micropapillary carcinoma within the tumor affected overall survival. Patients were stratified into two groups, those with final pathology showing MP disease in less than 50% of the tumor sample and greater than or equal to 50%. The median survival was similar, 35 months for MP less than 50 and 37 months for the greater-than-50 group. The survival probabilities were comparable between the two groups, and as you can see from the Kaplan-Meier curves, they were nearly overlapping, with a p-value of 0.6, indicating no statistically significant difference in OS.

To further investigate whether extreme variations in MP percentage impacted OS, we divided the cohort into three different groups—less than or equal to 20%, between 20% and 80%, and greater than or equal to 80% on histology. The Kaplan-Meier curves in OS comparison reveal a p-value of 0.6, indicating that no significant difference is present based on just the MP percentage, so our take-home message being that the proportion of MP histology in the tumor does not significantly impact overall survival, but in fact, the presence of MP in itself remains the key prognostic factor. So this highlights the inherently aggressive nature of MP regardless of its percentage.

Another key question was whether neoadjuvant chemo influenced outcomes in MP patients. Our data showed that neoadjuvant chemo did not significantly impact OS within this cohort. This suggests that standard chemotherapy regimens may not provide the same benefit in MP as they do, potentially, in conventional urothelial carcinoma.

So to summarize, our study highlights that micropapillary carcinoma is associated with significantly worse survival compared to UC NOS. The clinical stage at initial diagnosis remains the most important predictor of outcomes, as muscle invasion at TURBT strongly correlates with survival.

Neither the percentage of micropapillary histology nor the use of neoadjuvant chemo significantly affected overall survival. And given these findings, early detection and aggressive management may be necessary to improve outcomes in MP patients. Thank you for your time, and I'm happy to start discussing.

Ashish Kamat: Thanks so much for presenting what was your presentation at ASCO GU. It's really nice that you were able to summarize this in a succinct manner. I think it's great to see that the work you're doing with an expanded cohort sort of reinforces what we've suspected and believed about micropapillary disease since the early 2000s, right, when we first published on this, because it is a driver of adverse outcomes in patients. And we see this when we look at cohorts from Memorial, from MD Anderson, but again, with small numbers, it's hard sometimes to make those conclusions.

I do want to emphasize a few things that you talked about. Right, so the presence of micropapillary histology by and of itself does confer a negative prognostic factor, and we've always tried to look at the amount of micropapillary disease. You looked at the micropapillary disease in the cystectomy specimens, right, and some of these patients got neoadjuvant chemotherapy. So did you account for the fact that the percentage of micropapillary disease might have been either upregulated or downregulated based on receipt of chemo, and how did that affect the analyses?

Muhammad Hassan Alkazemi: So we did not look at it from a multivariate analysis yet, but that is something that we can look into when we finally start writing the paper. We do have a cohort of patients who did not undergo cystectomy who also had micropapillary disease, so we're also looking into that as well. So those are some of the future directions. But I'm happy to defer to Dr. Al-Ahmadie if he has anything else to add as well.

Hikmat Al-Ahmadie: Yeah, no, I agree. I mean, it's a very valid point, very important. We chose to stick to the cystectomy analysis because we thought this was the procedure that can determine the better analysis for outcome.

And in some cases, when we had access to the micropapillary or the TUR samples, we reviewed but we did not include them in an official analysis because sometimes we did not necessarily have access to all TUR samples from the patients. So we kind of decided to leave it related to the cystectomy only. And there is some literature from other studies where they looked at the percentage of micropapillary, and that is—what we have is consistent with others, even those who used TURBT—that on a multivariate analysis, the amount of micropapillary did not impact outcome.

Ashish Kamat: Yeah, because I think it's important, and in our data, we've looked at what happens in the TURBT because that's when the patient is sitting in front of you, and that's when you make a decision about chemo versus no chemo. And our data agrees with what you've shown, too, is that the outcomes with chemotherapy are not as good as with non-micropapillary. They're still better than patients who get no chemo, but we clearly need to improve how we treat these patients.

Now, Hikmat, I know you've also done a lot of work, just as we have here, on the HER2 pathway and ERBB and that whole aspect of micropapillary. Any insights from this work? Any patients that may have gotten anti-HER2 therapy, do you know, and can you make any comments on that?

Hikmat Al-Ahmadie: Yes. So, yeah, I mean, that's, again, a very important aspect always associated with micropapillary carcinoma. We have the data for the purpose of that abstract, that when we submitted it, we didn't include the additional, non-pure histopathologic analysis. It remains true that there's higher rate of HER2 amplification, mutations, and overexpression in this disease.

Treatment-wise, I don't think, from this cohort, we have patients who received any of the ADC targeting, targeting HER2. These are, like, historical samples, predated that treatment strategy. We have more of that, that could be probably analyzed in the future, but not in this cohort.

Ashish Kamat: OK. And just in closing, Hikmat, for our audience that is listening both in the US and internationally, what would you recommend they take home from this abstract and implement in their practice, either as pathologist or as clinicians, knowing what we know now, based on your analyses?

Hikmat Al-Ahmadie: Yeah, so the key—it's important to, first of all, be aware of this entity. It's important to be on the lookout for, being careful, carefully analyzing the samples, and identifying any amount of micropapillary morphology in the TUR cystectomy. That's the first thing.

Second, to apply criteria—this should not be—because of what is associated with it and the aggressive nature, you don't want to make this diagnosis lightly. So if there is any doubt that the criteria are not strict, it's better to consult with someone else. Get another set of eyes to confirm the diagnosis.

We know that the amount of micropapillary didn't pan out as a predictor, but it's still—our clinical colleagues always ask the amount of micropapillary or any variant histology. So that information might be helpful, might be more helpful in the future. We don't know.

But having an estimate of how much of the tumor is comprised of a micropapillary morphology, I think, would be very helpful. And always be ready for a follow-up question, because sometimes you'll get emails or phone calls to confirm or add more details on this morphology.

Ashish Kamat: You know, I think those are great points. And I do want to emphasize, for any pathologist that might be listening in, please do report the percentage, because even if it may not be relevant to that patient for their outcomes, it helps us when we're thinking about clinical trials and inclusion/exclusion criteria, because sometimes clinical trials build in that we can't include patients that have a predominant histologic subtype, for example.

I want to thank both of you for taking the time and spending it with us today. Really appreciate it. Thank you so much.

Hikmat Al-Ahmadie: Thank you.

Muhammad Hassan Alkazemi: Thanks for having us.