Upper Tract Urothelial Cell Carcinoma: Part 1

The discussions in this video took place prior to the COVID-19 related mandatory safety measures.

Dr. Mossanen: Good morning. My name is Matt Mossanen. I'm a urologic oncologist that works at Brigham and Women's Hospital and also at Dana-Farber Cancer Institute. It's a pleasure to be here this morning for PracticeUpdate. I'm excited to have a panel of experts and with no further ado let's jump into the first case for tumor board. So this is a patient with upper tract urothelial cell carcinoma. She's a 70-year-old female that on an evaluation of left flank pain and hematuria was found to have a four centimeter mass on MRI in the left lower pole of the kidney. She had an original ureteroscopy that was nondiagnostic. And then this was followed by an IR-guided percutaneous biopsy of the mass that showed evidence of urothelial cell carcinoma. At that time, there was a PET-CT done that showed indeterminate lung nodules, an avid renal lesion, and some concerning retroperitoneal adenopathy.

A decision was made to do neoadjuvant gem-cis times four total cycles, and a repeat MRI showed resolution of the pulmonary nodules, the retroperitoneal nodes, and also shrinkage of the mass. She ultimately underwent a left robotic nephroureterectomy and the final pathology showed ypT3 disease in the renal pelvis. So there are a couple of areas to explore in this case and I thought the first one I would direct towards Dr. Preston. Talk a little bit about some of the challenges with getting a biopsy for upper tract urothelial.

Dr. Preston: The challenge with getting a biopsy in upper tract urothelial cancer comes down to just the logistics of the size of the scopes and the instruments that we need to use. This typically would be a very small 7- or 8-French scope that obviously is very long, goes up into the renal pelvis. And so the instruments that go through that are even smaller. So typically we might be getting a small bite of biopsy tissue that we're removing and trying to send to pathology. Some tips and tricks we have to try and get a little bit more tissue come down to attempting to take multiple biopsies. On occasion, if it's a more papillary tumor you can actually grasp it with a basket and actually push it further up into the renal pelvis, which might give you a larger piece that you can remove as well.

There are also some newer endourologic instruments such as the BIGopsy, which is one that actually backloads and actually takes a much larger bite of tissue. The key aspect that we're trying to obtain with doing this procedure would be getting an actual diagnosis so that our pathologist can give us a diagnosis of cancer, present or not. And ideally, we want to know whether it's low- or high-grade because that can alter some of the next steps in terms of treatment as well.

Dr. Mossanen: This question is for Dr. Chang. For patients that might undergo ureteroscopic biopsy like this patient, it's not uncommon for the biopsy to be nondiagnostic. Is there ever an occasion where you entertain doing a percutaneous biopsy, sending them to interventional radiology?

Dr. Chang: In some cases, yes, particularly for tumor that does seem to be involving the renal parenchyma. And there are times when we go up and look in the renal pelvis and there's not a really distinct tumor. Some of these can go directly into the renal parenchyma and that would be the preferred one for IR-biopsy. You have to be concerned, at least theoretically, about tumor tract seeding. But in some cases you simply don't have a diagnosis and this is your only option.

Dr. Mossanen: This question is for you, Dr. Hirsch. So given that obviously pathology is difficult to obtain for these cases, what are some of the interpretive challenges that you have as a pathologist when we send you these little, tiny, whispy specimens that are really, really hard to see with the naked eye?

Dr. Hirsch: Right. So they are definitely one of the more difficult and challenging cases that we receive. Invariably, I almost know when I have a tiny, tiny fragment of tissue on a slide that it's come from the upper tract. As Dr. Preston described, it can be very difficult to reach and obtain. So very, very frequently we have less than a millimeter of tissue to evaluate. Generally speaking in pathology, more is better. And this is a scenario where we have much, much less. In addition, not only is it small, it's frequently crushed, which makes it much more difficult because crush artifact can mimic high-grade nuclear-to-cytoplasmic ratios and make it very difficult to interpret. So in best-case scenarios, we get even a small piece without crush artifact, we look for specific features. Again, the nuclear-to-cytoplasmic ratio, high NC ratios as we call it, are more indicative of carcinoma.

If there are any intact fragments with papillary architecture, that's extremely helpful. But you can also have to exclude reactive lesions, from stones or other problems [like] pyelonephritis, that may cause reactive changes. So we have to keep all of these mimics and take them into consideration, again, with very small, potentially crushed tissue. So it's sort of when the diagnosis is clear, it's quite easy and we just can make a frank diagnosis of carcinoma, much easier if it's a high-grade lesion than a low-grade lesion. Again, the architecture can be helpful in that distinction.

When it's not so obvious because of size and/or crush we have to back off. I am very passionate about clinical pathologic correlation and we know as pathologists, as genitourinary pathologists, that there's a lot riding on this. Diagnosis of carcinoma without invasion could lead to a nephroureterectomy of a perfectly healthy kidney and we don't want to make that over-call or an over-diagnosis and lead to a patient losing their kidney when it's not necessary. So we're very careful about keeping a high threshold, calling cancer when we're sure and backing off and calling something atypical, suspicious, maybe write a note, certainly reach out to the clinicians and speak to them directly if necessary too, if we're not certain.

Dr. Mossanen: How accurate is an upper tract cytology that is positive? Can you presume that that means there's high-grade carcinoma if the cytology is positive for an upper tract washing?

Dr. Hirsch: I have to qualify that I'm a surgical pathologist and not a cytologist, but just knowing from interacting with my colleagues and such, generally speaking, if you have a positive urothelial cancer, a positive cytology, that is basically synonymous with a high-grade lesion. Low-grade lesions can be indistinct from background normal urothelial cells and you're much more likely to get a negative or a suspicious diagnosis when it's a low-grade lesion. But once you see high-grade features, again, the mimic would be reactive change, but if we see karyorrhectic debris or mitotic activity, other features that we see in high-grade lesions, then really if you're getting a high-grade cytology in a washing from the upper tract, that it is more likely to be consistent with carcinoma. And I think that I can say that with relative certainty, it's the lower grade lesions that are much more difficult.

Dr. Mossanen: That makes a lot of sense. Dr. Sonpavde, this patient had some concerning lymphadenopathy, some lung nodules. Can you talk about how you would approach doing systemic therapy in this patient if given that they have normal renal function?

Dr. Sonpavde: Right. So the first issue is to figure out if this patient has truly metastatic disease. I mean, if the patient has high-grade urothelial carcinoma and has a mass in the lower pole of the kidney, that's consistent with it being metastatic disease. If it was low-grade or unclear disease I would want to biopsy one of these lesions to confirm metastatic disease. And then the next fact is to see if the patient is cisplatin-eligible or cisplatin-ineligible. Since this patient is cisplatin-eligible, the standard of care, the cisplatin-based combination, cisplatin-gemcitabine, or MVAC, or dose dense MVAC. Of course we have clinical trials going on in this space that are looking at combination chemotherapy with platinum-based chemotherapy plus or minus a PD-1/PD-L1 inhibitor. And there's also trials with an arm looking at a combination immunotherapy approach, like ipilimumab plus nivolumab, that's chemotherapy-free. So all of these trials should really be the priority when possible.

Dr. Mossanen: And suppose that this patient went straight to nephroureterectomy and didn't receive systemic therapy prior to surgery. Can you talk a little bit about adjuvent therapy and some of the data that guides your decisions?

Dr. Sonpavde: Right. So adjuvent therapy for upper tract urothelial carcinoma has seen an advance over the last year with the POUT trial. This is a trial that was done in the UK. It's a phase 3 trial that looked at adjuvant gemcitabine-platinum, and that could be cisplatin or carboplatin. And the trial was stopped early because the interim analysis was positive. The disease-free survival was the primary end point and the hazard ratio was strongly positive, 0.49. Now the fact is people bring up whether carboplatinum is still a valid option.

So in this trial, two thirds of patients got cisplatin-gemcitabine and a third got carboplatin-gemcitabine. And really the trial was not powered to look at each of these subgroups, but when you look at the hazard ratios for each, they both are leaning towards benefit, just that the benefit with carboplatin-gemcitabine seems less than you see with cisplatin. But again, this was a smaller group and their hazard ratios crossed one. So there is still some doubt. But in the absence of any other evidence, I think that it's reasonable to consider carboplatin-gemcitabine. Just know that the benefit might be less than you see with cisplatin-gemcitabine.

Dr. Mossanen: Dr. Sonpavde, I was wondering if you could also comment a little bit about adjuvant trials that are available for patients in this space currently.

Dr. Sonpavde: Right. So there are a number of adjuvant phase 3 trials going on in the urothelial carcinoma space. These trials allow upper tract urothelial carcinoma. So patients with upper tract urothelial carcinoma with T3 or higher stage disease or lymph node-positive disease can be enrolled in these trials. These trials are comparing adjuvant PD-1 or PD-L1 inhibition versus observation/surveillance followed by early systemic therapy on progression. These trials would also be in the same space as the space in which the POUT trial looked at adjuvant gemcitabine-platinum. So the discussion that comes up when we see these patients in the adjuvant spaces: do we go with gemcitabine-platinum? Carboplatin-gemcitabine is also in that mix since the POUT trial included carboplatin-gemcitabine as a regimen. Or do we go with adjuvant PD-1 versus nothing, or placebo-type trials? So a little bit more challenging discussion now given that the POUT trial is out and some patients do worry about observation or placebo in the control arm of these trials. So that is a challenging, long discussion.

Dr. Mossanen: Dr. Hirsch: a lot of the times when some of the biopsies are hard to interpret, we'll often have a conversation via email or the phone. And so I was wondering if you could talk a little bit about some of the special considerations you might give to an IR-guided biopsy. And as a second part to that question, if there's some mass-forming lesion or radiographic correlate to the lesion in question, how that might help you make your decision.

Dr. Hirsch: Sure. So I'll answer the second question first. Especially when we're taking these small biopsies from the renal pelvis, we will often again use clinical pathologic correlation. As we're looking at the case, we'll look at your operative note, as well as some of the radiology. We can have a slightly lower threshold on our diagnosis if we know there's a large mass or filling defect in the calyx of the kidney, and then we know something is there versus a flat reactive lesion that we might be misinterpreting. It's also much more difficult if there is no mass-forming lesion. The question would then be a urothelial carcinoma in situ that might be invasive or involving the kidney. And in that case, we won't see any papillary architecture. So the presence or absence of a filling defect in the renal pelvis does definitely help us on our differential of carcinoma versus reactive, in addition to the cytologic features that we're finding.

In addition, if there's an IR-guided biopsy, that's usually for when there is, again, radiographic evidence such in this case, of the tumor filling the parenchyma, as Dr. Chang mentioned. That is more tissue. We often get much more tissue in that situation. We look for architectural changes; infiltrative tumors through the renal parenchyma versus a tumor that pushes normal structures away in the kidney. We'll change our differential diagnosis on whether we're looking at a renal cell carcinoma that, in theory, could be invading into the renal calyx versus a urothelial carcinoma starting in the renal pelvis and invading into the parenchyma. So there are morphologic clues, and again, with more tissue that's much easier to determine. And then when necessary, we also have immunohistochemistry special biomarkers that will help us decide whether this is actually a primary renal cell carcinoma versus a primary urothelial carcinoma, which of course is treated differently. And so that can be an important distinction. So that can be much easier on an IR-guided biopsy.

Dr. Mossanen: And your point is really well taken that for upper tract, using all the clues, all the available clinical data is really key to making a diagnosis because it has such big implications.

Dr. Hirsch: Right. Absolutely.

Dr. Mossanen: Well, I want to thank everyone from the panel today for all of their thoughts and thank you all for joining us.