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Sam Chang: Hello everyone, my name is Sam Chang. I am a Urologist at Vanderbilt University in Nashville, Tennessee, and I have the honor of being joined today in a conversation with Dr. Vitaly Margulis. Vitaly is actually the Paul C. Peters Chair in Urologic Oncology at UT Southwestern, and obviously, he is well known to everyone as a superstar in the treatment of a variety of urologic oncology, but clearly has expertise with urothelial carcinoma.

Hello, Vitaly, thank you so much for joining us. Appreciate that much.

Vitaly Margulis: Hello Sam. Good to be here with you today.

Sam Chang: So what we were planning on doing today was, and thanks again for your participation, I was going to go through some everyday scenarios that we face with patients that come in with an upper tract carcinoma. I just want to kind of get your take on how you evaluate, how you treat, and then how you follow up.

I want to really focus kind of on low-risk disease. Say we have a 70-year-old man with hematuria present and he has a small filling defect on just a plain CT scan done with contrast. So, that gentleman comes in. Tell me how you evaluate that patient from this point. Say a one-centimeter filling defect on a CT scan with contrast done, not a CTU, not anything specific, no pre and post.  He comes into your office and you have 60 patients to see and here he is. How do you present in terms of his evaluation to the patient? Hey, this is what we are going to do next.

Vitaly Margulis: This is not an uncommon scenario and I think it is certainly concerning. It doesn't have proper imaging in my opinion, so I'd probably want to follow that up and really confirm that we are in fact, seeing a filling defect. Probably either something on the magnitude of a CTU or an MRU would be next. And if the imaging finding is confirmed, then he gets a full, regardless, he gets a full imagery workup,  obviously with a cystoscopy. But the question is whether the follow-up study, if it looks normal, or if this was an artifact, then he only gets a cystoscopy in the office. But if the imaging studies do confirm indeed a filling defect, then this is the type of patient that we would take to the operating room for a cystoscopy or a ureteroscopy, et cetera.

Sam Chang: Okay. So, as you do that, you have the gentleman in the operating room, you've looked in the bladder and you find nothing in the bladder. Tell me how you do your diagnostic ureteroscopy. Do you, and let's take the scenario of again, you've never seen the patient, the patient has never had urothelial carcinoma that you know of. Let's say the cytology is negative, so you really are looking. Tell me how you do a diagnostic ureteroscopy.

Vitaly Margulis: The point of cytology is good, but you know, the cytology is pretty poor performance characteristics for detection of upper tract disease themselves, just because it is negative, it's not super reassuring to me. So I think he still deserves a full workup. When I suspect upper tract disease, the first thing that we do is a good cystoscopy? The next thing that happens is I would get selective cytology from the upper tract before actually putting wires in there. We could probably get some sort of a catheter introduced into the renal pelvis to get good cytology from that area. Following that, we perform a good retrograde pyelogram to outline the collecting system in question. Then we perform a flexible ureteroscopy. The idea is to evaluate the entirety of the ipsilateral urinary tract and questions systematically.

Sam Chang: Let's say you can't get the flexible ureteral scope in. Are you a dilator, or are you a "place the stent", we'll evaluate you later type of person?

Vitaly Margulis: I'm more of a let's get it done and have an idea of what we're dealing with type person. I'll probably end up dilating and trying. To the degree, obviously, you don't want to do the patient any harm, but most of the time, especially with the newer, small caliber, digital ureteral scopes, you are usually able to get something up in the urinary tract.

Sam Chang: Let's say these are all practical questions.  Because I had learned every day from our, endoscopic surgeons and experts, your place has world experts in terms of, so I learn all the time. I am still old-fashioned. I still like having a safety wire. They laugh at me now, but do you always use the safety wire, or are there times where you don't use the safety wire?

Vitaly Margulis: Yes, I would definitely use a safety wire.  In this case, what I suspect will happen is there will be a filling defect or there will be something that looks like urothelial cancer. If I confirm that, the next thing that happens is I need to make an assessment of whether this is something that can be handled endoscopically or not. At least, we will have to obtain biopsies to determine a further treatment plan. And so this patient will probably end up getting an access sheath up into the renal pelvis, in which case, I think it is crucial to have a safety wire in my opinion, because the access sheath could cause some damage. And the last thing you want to do is to not be able to get a stent back up.

Sam Chang: So, you see a one-centimeter papillary tumor, it looks like a classic urothelial. You get a biopsy.  At that time do you go ahead and laser that lesion or do you wait? What do you do with that first time, gosh, this looks like a tumor. Do you try to ablate everything? And let's say you have two or three, do you try to ablate everything? Or is your goal, I want to get a diagnosis, I want to get a grade, and then we'll come back and figure it out. What do you attempt to do usually?

This is a clinical decision, and if I think that this would be reasonable to ablate or use a laser, there are various techniques that you can use to get rid of the tumor, either basketing, or laser, but if I think that I could do this within a reasonable amount of time with instruments that I have at hand, then I would do that. At least at the minimum, obtaining a biopsy, not just one biopsy, ideally multiple biopsies, so you have a good understanding. The number one question here is grade.

So, you get a good biopsy and you laser it and it's small. I said one, let's keep it one, one and a half and you've gotten rid of it all. You've lasered, you feel very good. When you basket it, you noticed the whole thing came out or you biopsied it. It comes back a high grade. A 70-year-old gentleman, I didn't tell you, his renal function is normal. What do you do? This is the kind of patient I struggle with because, in all honesty, it kind of has missed mixed characteristics. And I'm still simple here, just looking at grade, and I looked at the appearance, multifocality, architecture, the placement on the renal pelvis. I'm not doing somatic testing on this. I'm not looking for any changes yet on the molecular subtype. That is a patient I am very tempted, despite its grade, that I will monitor and watch.

What do you do with this patient? Is it case by case? Or do you say, "Oh, it's a high grade? I know I've got it, but it's a high grade. What are your thoughts on that?

Vitaly Margulis: I think it is definitely a case by case and I think you picked the sort of quintessential case who I think most people struggle with. The devil's in the details. You mentioned a lot of the parameters are important. How big is the tumor? How thorough and comfortable are you getting it out? Are there satellite tumors? What is their renal function? What is the overall performance status of the patient, et cetera, et cetera, et cetera? One thing we didn't mention Sam, is that at the conclusion of every ureteroscopy, for diagnosis and management of the upper tract they usually instill gemcitabine into the bladder to mitigate the risk of bladder cancer recurrence.

Sam Chang: I think that's a really good point. And I think that is truly underappreciated. Especially, I think we do a better job with nephro u's now. I think we do actually a very poor job, or the message isn't out there as much in terms of you've got upper tract disease, even though the bladder looks normal, of doing their perioperative chemotherapy. I think that's an essential point.

To me, I struggle with the patient that has everything that looks positive in terms of low-risk strata, except the grade. The grade still carries, to me at least, carries the most weight, so I do struggle with that patient. It's easy if that patient is frail, just like you said, or has a poor renal function. But it is really hard and everything points because it's a high grade, healthy, et cetera, et cetera. But it's the single solitary... I think it does really make a difference. I wanted to get your take on this.

I think I feel safer for sure, in the renal pelvis, as opposed to the mid ureter or proximal ureter, or even distal ureter in terms of, I feel it's somewhat more protective and that I can do okay with endoscopic. Tell me your thoughts on the ureteral versus the renal pelvis and the risk.

Vitaly Margulis: I'm with you. Although the data is not entirely clear, obviously because of the anatomic considerations, we are all more worried about under assembling or under staging ureteral tumors than renal pelvis tumors. So I share your sentiments. I think one thing to mention here is that before any definitive decisions are made, and if there is any question of offering this patient organ preservation, I think a second look at a ureteroscopy with repeat biopsies is mandatory. I think if you are considering whether it's ureteral versus renal pelvis, et cetera, I do worry about ureteral tumors more, as you mentioned, but a five millimeter, high grade, tiny little tumor in the ureter, does that mandate removal of the renal unit? I'm not sure.

Fortunately in the ureter, you have other options, right? You can offer this patient some sort of urectomy. I mean, not the standard of care, but it's certainly an option. A renal pelvis is a little bit more difficult, but whatever you decide that they get, it's probably imperative to consider a second look.

Sam Chang: Yeah, and I think along those lines was with organ sparing, you mentioned. This is a point that I think cannot be underestimated, is as good as our CTU's are or our MRU's that direct visualization, follow-up for this patient is going to be more complicated because yes, you'll do CTU's, but for sure, I think you are going to need to do a second look. Perhaps even at the six-month mark or the one-year mark, you would need to do a ureteroscopy, at least I feel that way.

Say you have this patient you've treated and their second look looks good. How would you then follow up with this patient? Do you do a routine cystoscopy of the bladder and then just do a CTU? Or do you say, "You know what, I'm going to take another look in that renal unit in six months or a year?" Obviously, it's case by case, but in this scenario, you've treated it all, everything looks good on the second look. How would you follow this patient?

Vitaly Margulis: Yeah, good question. I mean, again, I don't think, and I mean if you ask different people around the country who do this for a living, you may get five different answers. I can tell you what I do. One thing again, to just stress is that the second look for me means going in there and doing a repeat biopsy of the area where the tumor was. It's not uncommon for the urothelium to completely heal over. And when you do an underneath biopsy, there is still residual urothelial cancer, and that's a dangerous situation. That's the patient who probably would be targeted for more aggressive treatment. But if the biopsies come back negative and everything looks great for the first two years, I alternate my ureteroscopy in CTUs or MRUs. So every six months patient will get an MRU. And then in six months, he gets a ureteroscopy and alternates in such fashion for two years.

Sam Chang: I think that's very wise, and I think that makes the most sense because I just operated on a patient yesterday that the CTU basically was read as a little bit of enhancement and that was it. It was a good call in terms of enhancement, but the patient had basically carpeting of his distal ureter, had a history of bladder cancer, had carpeting of the distal ureter on the CTU, it looked like there was an enhancement. I didn't see it. The radiologist read it and the retrograde looked fine as usual. I find retrogrades a lot of times not so helpful. Selective cytology I got, looked up. Everything will be fine until just right where they said there was some enhancement, there was carpeting with papillary type tumor.

In terms of, let's go with the same scenario, but the last question with this patient. This patient then does well for a period of time and now starts developing bladder tumors. This is very much a hypothetical question. Do you think, let's say the bladder tumor, and in six months, a year along those lines, do you think this is something that maybe came from the upper tract, or do you think this is a de novo or it's impossible to say? We talked about when you treat at your diagnostic ureteroscopies do you also give perioperative gemcitabine? Cause I do not if I didn't see anything. So I was wondering about your take on that.

Vitaly Margulis: Yeah, I generally would use gemcitabine. It's easier to put it than not put it. Almost, I think there is very little downside. Patients do very well with it. I end up erring on actually instilling it just in case you missed a tumor and it's still there. I think there is very little downside to the patient. So I end up doing it.

To your question, whether these are de novo bladder urothelial events, or is this something that is seeded from the upper tract. Molecular studies have demonstrated that it could be either-or, and so I don't think I can have a definitive answer for you.

Sam Chang: Yeah, I guess along those lines, your group, and you are a part of this huge consortium that really have helped define and help determine the kind of risk factors associated with upper tract disease. To me, the most difficult, and almost the most concerning is the patient switching from low grade and low-risk to high-risk or those patients, honestly, with hydronephrosis, kind of concentric thickening that is almost subtle and before you know it, they end up having a nodal disease or metastatic disease. It's a presentation that I don't see often, but almost concentric thickening. Just like you were saying, when you told me where there can be disease hiding underneath the mucosa, are there any findings that tip you off, of if this patient has something more concerning than we actually think is going on?

Vitaly Margulis: These will be specifically, these patients, that I would put them in an infiltrative category.

Sam Chang: Yes.

Vitaly Margulis: The tumor's infiltrative, and it's very subtle sometimes. It looks like there's a haziness around the collecting system on the cross-sectional imaging. These are the patients that would have, despite kind of looking relatively unremarkable on an endoscopy, they keep having high-grade cytology. These are actually the patients, where the radiographic findings and the findings of the high-grade cytology, are that I really worry about. They end up being your T4 node-positive patients that look completely innocuous. Yes, absolutely, I think you have to pay attention to detail as it is a tricky disease. It's very easy to talk yourself into, "Oh yeah, this is post-surgical," but to be very careful with those types.

Sam Chang: Right. Well, Vitaly, thank you so much for your insight. I mean, I think you see and treat this basically every day and I think your words of wisdom are very helpful and I really appreciate the time you took with this, and it is always good seeing you.

Vitaly Margulis: Good to be with you guys. Thank you, Sam. Appreciate it.

Sam Chang: Great.