Sam Chang: Hello everyone. My name is Sam Chang, I'm a urologist at Vanderbilt University in Nashville, Tennessee, and we're very fortunate to have a rising star in urologic oncology. Dr. Wesley Yip. Wesley is a urologic oncology fellow at Memorial Sloan Kettering Cancer Center. He finished his residency at USC and for those of you looking for superstar urologic oncologists, he's somebody I definitely would look out for. We've asked Wesley actually to give us a presentation on a recently published series of work looking at variant histologies in the diagnosis of upper tract urothelial carcinoma. So Wes, we'll turn it over to you and welcome.

Wesley Yip: Thank you so much, Dr. Chang. So I'm Wesley Yip, a urologic oncology fellow at MSK, and I'll be discussing a recent publication of ours, Survival Impact of Variant Histology Diagnosis in Upper Tract Urothelial Carcinoma. So in terms of the background, upper tract accounts for 5 to 10% of urothelial carcinomas in the US, but the instance overall is actually increasing, both upper tract and recognization in bladder cancer. Now, it looks the same as urothelial carcinoma of the bladder but does have a divergent molecular profile, and there's a higher and lower prevalence of certain mutations in the upper tract compared to the lower tract. Now, variant histology is president in up to a third of urothelial carcinoma cases of the bladder, and this is associated with adverse pathologic features and worse oncology outcomes, but in the upper tract there's not nearly as much data, and so that's something that we wanted to look into. Importantly, there are some unique challenges in the management of upper tract urothelial carcinoma, mainly that there's a frequent lack of adequate tissue prior to extirpative surgery.

And there still is a persistent need to define the impact of variant histology in upper tract on patient outcomes. So that can affect disease management, adjuvant therapies, and followup strategy. The purpose of this study then was to evaluate the impact of variant histology pathologic diagnosis on survival outcomes in patients with upper track urothelial carcinoma at our institution. This was a retrospective review of 705 unique patients and nephroureterectomy procedures across a 23 year period at our institution. These were all processed according to our institution standard protocols and of note, this will be important later on, the pathology division created some specialty divisions from 2005 onwards. And that disease recurrence was defined as any disease relapse in the urothelial tract, or regional lymph nodes, or distant mets. From there, we wanted to test the association between variant histology and certain survival outcomes, mainly recurrence free, cancer specific, and overall survival.

So what we found in the whole cohort was about 7% of cases had variant histology present, the vast majority were squamous differentiation, and the remainder are listed here. Importantly, the prevalence increased over time. So only 5 of these cases were diagnosed before 2005. After 2005, when we subspecialized with geopathologists, 42 out of 47 were diagnosed. This is the breakdown, the table one from our paper. Overall, the cohorts are pretty similar, but the two main important things to note are that neoadjuvant chemotherapy was used more commonly in the variant histology group, and overall there were higher T stages in the variant histology group as well, which will factor into some of the later discussion. Curves for recurrence free, cancer specific, and overall survival. The gray line is for no variant histology, the black line is for variant histology. No real significant difference in recurrence free survival between the two but significant differences in cancer specific and overall survival.

Now, then we looked at whether or not variant histology was associated with those outcomes in particular, and not so much. Pathologic stage was more important factor for these survival outcomes, but variant histology was not one stage was controlled for. In patients that it recurred, we looked at the cancer specific and overall survival for them, and pretty similarly staging more important. So pathologic variant histology, not significant for cancer specific survival but there was actually a significance for overall survival. So what we conclude is that variant histology is associated with worse cancer specific and overall survival in the upper tract, but this may just be because of the association with higher pathologic stage. Patients with recurrence, variant histology is associated with worse cancer specific survival, but again could be attributed to higher stage. So the main key take-home point from the study is that variant histology upper tract maybe a useful biomarker associated with higher stage and poor oncologic outcomes, but when pathological stage is unknown. And the followup to that is that it seems like stage is a more important factor for the survival outcomes than the variant histology itself.

Sam Chang: Wesley, thank you very much. So do you think that when looking at the variant histologies, let's talk first about the timeframe of the diagnoses. We think they've been around all along, it's just that we've done a better job of recognizing them, the small number that were found before 2005, were they all squamous or something that's been more recognized for a longer period of time? Or what type of histologies were those early on?

Wesley Yip: Oh, I'd actually have to look at which ones those were. I think they mostly were squamous though because some of these subtypes weren't even really defined in the early 2000s, so a lot of things came out in the 2016 WHO classification of tumors. So I think most of them were squamous but we really point that out because we noticed this temporal change in diagnosis over the time period, and some other studies out there have had similar findings too. In our discussion, we do quote a paper by [inaudible 00:06:25] that in their re-review of specimens, their overall prevalence of variant histology was I think up to 34% in a cohort a little bit over 100 patients. But then looking at some [inaudible 00:06:37] database studies, there's one by Duker et al. from Clinical Genitourinary Cancers, I think, looking at 11,000, almost 12,000 cases of upper tract, and the overall prevalence of variant histology was only 2.7% in there. But that could definitely be just because they're not looking for it. Older cases or places aren't as familiar with various histologies, especially for upper track diagnoses.

Sam Chang: So Wesley, along those lines of what you said about the repeat pathologic review, this is a very large upper track series with followup. I think it would be fascinating, and maybe you talk with your pathology colleagues, to look at those earlier specimens and, in fact, re-review all of them, and then rerun your analysis and see if there really is perhaps an independent link towards the overall survival and cancer survival. You guys are probably already doing that.

Wesley Yip: Yeah, we are trying to. That was something that we found after we ran this whole analysis and put this dataset together, but we are going to go back and re-look at them to see yes, an internal audit, how much do we miss? And then how does that affect those outcomes afterwards? Because that can definitely be a confounder, really.

Sam Chang: And then at least the percentage was higher for these variant histologies to get neoadjuvant chemotherapy at your center. Looking back at the studies done at Memorial, looking at neoadjuvant, looking at this data, what is the policy now at Memorial Sloan Kettering Cancer Center, obviously one of the leading cancer centers, of patients that come in with upper tract urothelial carcinoma that is variant histology? What is the recommended treatment algorithm for these patients?

Wesley Yip: So putting this data together is relatively recent and so variant histology, because we don't know what to do with it still, generally thinking of it as a higher risk population, but not ready to deviate too far off from other grade stage protocols. And so, in general, any high grade disease which still defines a high risk population on its own is going to be considered for neoadjuvant chemotherapy, part of the main discussion. And then a lot of times these patients don't have the variant histology diagnosis until after the fact because most of the time it's actually on a nephroureterectomy. Pretty rarely is it going to be on the biopsy to inform decision-making prior to that. So in the future, it would be nice to be able to get this from biopsy specimens more often, but right now I don't think we really have that.

Sam Chang: Right. And that brings up then another question. Did you guys look at the concordance rate of your biopsy with its possible ability to predict the variant histology in the nephrou or was it basically you can say up front ureteroscopic biopsy, we're not going to be able to define these as variant histologies? Which do you guys find?

Wesley Yip: So what I did look at was of the 47 variant histologies, 26 had biopsies prior, and then of those biopsies, only 6 had variant histology diagnosed in it. So I don't know the overall cohort, how many had biopsies, and I guess the percentage of variant from that, but in total we have 6 that had variant histology and biopsy, which is pretty little and not really enough, I don't think, to inform decision making yet.

Sam Chang: Right. So I mean we've all talked about the sampling difficulty in terms of even low grade versus high grade, and then being able determine the variant histologies, I think, are quite difficult. So in looking at the variant histologies data within the upper tract versus those within the bladder, what's your thoughts or what are the thoughts within your center regarding are these truly aggressive or are we just finding them based upon stage? What's the thought process there at Memorial?

Wesley Yip: It's more the latter right now, that we're just finding them at higher stage and not necessarily at their more aggressive, which I think is pretty in line with what's happened in variant histology in the bladder too, where originally we thought that these were more aggressive. And some types, yes, they are more aggressive, but overall gestalt, they're just showing up at higher stages, which is really leading most of the prognosis for it. And that's what we found in our study, it's just more so the stage. And once we controlled for that, the variant histology didn't really change the survival outcome. It might be able to inform other therapies in that some of these subtypes may respond differently to chemotherapy. The numbers are small, so it's not something we really evaluate in our study, but when combined with other data out there or extrapolating from bladder cancer data, then it may inform it that way.

Sam Chang: Great. So I was going to say then, as the last question, what's for you in terms of the key takeaway points for the practicing clinician?

Wesley Yip: So I think the main takeaway points, there's a couple. One is that if you do have variant histology and biopsy somehow, you can categorize that patient in a higher risk group to inform your decision making, but what's the more likely scenario is that if you do have variant histology on a nephroureterectomy specimen afterwards, to focus more of your decision making based on the stage of what it is and not necessarily change the risk stratification or decision making based on the variant histology found. I think that's the main takeaway.

Sam Chang: Well Wes, thanks so much for spending some time with us and enlightening us about the presence of variant histologies that occur in the upper tract, its association with stage, and the possible negative impact. But as with anything with upper tracts, I think we need more study and we need to see who responds, who doesn't respond to chemotherapy, who are those that truly have a much more aggressive cohort in terms of down the line and stability for us to either treat, just with nephroureterectomy or with additional systemic therapy. But I really appreciate all the efforts and I know all our listeners as well, in terms of what you all have achieved at Memorial recently as you focus on upper tract in different ways to not only evaluate it, but to risk stratify patients as well. So thanks for your efforts and good luck as you finish up your fellowship.

Wesley Yip: Thank you so much too, Dr. Chang, and UroToday as well for making this happen.