Ashish Kamat: Welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat. I'm a Professor of Urologic Oncology at MD Anderson Cancer Center in Houston, Texas, and it gives me great pleasure to welcome today, Dr. Makarand Khochikar, who is Chief Urologic Oncologist at the Siddhi Vinayak Ganapati Cancer Hospital in Miraj. He is also a past President of the Urologic Society of India, West Zone. And more than just that, he is a good friend and a true expert when it comes to urology and uro-oncology in general. He has a huge case file that he has collected over the years that have some pearls as far as educational value and when it comes to bladder cancer, and I'm really pleased to have him join us today for this session. Dr. Khochikar, please take it away.

Makarand Khochikar: Thank you, Ashish. It's been a great pleasure to be part of this UroToday symposium. I just went through the website and I just found very interesting videos and very good educational videos. So first and foremost, thank you very much for this nice introduction. Thank you, UroToday team, and let us go on and discuss interesting cases, and these are pearls from my case files, mainly bladder cancer.

Greetings from my hospital, which is in the western part of India. We are a nearly 22-year-old hospital dedicated mainly to cancer, and we have a state-of-the-art uro-oncology department over here.

So let us start with an interesting case. This was a 65-year-old gentleman. He had no co-morbidities. He presented with intermittent hematuria and intractable frequency of micturition and also bladder outflow obstruction-like symptoms for the last six months. He's a non-smoker. His urine microscopy showed plenty of RBCs, his cytology showed atypical cells, his routine laboratory investigations were normal, his PSA was about 2.8 ng/ml. His basic sonography showed normal upper tracts, prostatic enlargement, a thickened bladder wall, and a post-void residue of about 80cc.

So what he got was just a cystoscopy, and I'm just going to run through the cystoscopy. His urethra was normal, he had small lateral lobes of the prostate, the bladder had grade 1 trabeculations. And as you would see, this area, there was an elevated area, mainly in the anterior wall, towards the dome of the bladder. Now, this looked very odd, doesn't look like a classical papillary tumor, doesn't look like sort of a urothelial carcinoma, that's what I personally thought.

Many times, you get lesions from the pelvic organs infiltrating the bladder wall, and you can get this kind of appearance. That's what I was thinking when I looked at the bladder. His both ureteric openings were normal. I'm just going to stop this video here for a minute. I just wanted to know, Dr. Kamat, do you think a biopsy is really necessary, just a routine cold-cup biopsy, or would straight away TURBT would be the right option?

Ashish Kamat: In general, I think a TURBT provides you a better biopsy per se. If the tumor is small, or if you're worried that you might lose the architecture, then certainly a cold-cup biopsy followed by a TURBT is appropriate. But otherwise a well-done TURBT biopsy, and again, I don't mean a radical in every situation, but a good TURBT biopsy usually provides better tissue for the pathologist.

Makarand Khochikar: Looking at this endoscopic appearance, do you think there's something unusual type of urothelial carcinoma or do you have anything else in mind?

Ashish Kamat: It looks a little bit more fleshy than normal, at least in the video that I'm seeing, so it could have a few sarcomatoid or other elements. But again, we can often be misled into making guesses on pathology. So a TUR and a biopsy, as you are doing in the video very elegantly, would be very appropriate.

Makarand Khochikar: Yeah. So as I was cutting, I agree with what you said, it's not like the other odd histology, even sarcomatoid histology came to my mind. But at the same time, many times you see the benign pathologies like malakoplakia, amyloidosis, these things came to my mind. So we did a standard TURBT, very careful that we didn't perforate. And we just took a deep muscle for documentation to see whether there is an infiltration. Obviously, when we talk about these kinds of solid tumors, the standard protocol of putting perioperative intravesical mitomycin C would never come in play, unless it is a very small papillary tumor. I have a habit of going to the pathology department every now and then, sit with them, look under the microscope and see myself, just to learn the different types of histology. And when I went for the pathology meeting, they just said, "We have something big, Makarand." Then I looked under the microscope and I'm sure, Ashish, you would also agree, this doesn't look like a classical urothelial carcinoma.

So the pathologist actually showed me further bits, and these were very fascinating. You could see the smooth muscle all around and there were these atypical areas. At one point, I thought, "This looks like a clear cell carcinoma of the kidney as such." So this was in appearance, and this typically is not a standard urothelial carcinoma. This is something, an odd histology. So the differential diagnosis which was discussed by the pathologist is, you could have an invasive urothelial carcinoma with a nested variant, you can have a paraganglioma which may present like this, it could have been a nephrogenic adenoma. You could have cystitis cystica, but I'm sure Dr. Kamat would also agree, cystitis cystica or glandularis is usually on the floor of the bladder, and you don't get something on the dome or anterior wall. And you can get Florid von Brunn nests, but again, on the floor of the bladder rather than sitting on the dome of the bladder wall.

Just for a discussion point of view, on the left-hand side, you'll see the different varieties here. Your nested variant, von Brunn nests, nephrogenic adenoma, cystitis cystica, and paraganglioma here. And here, if you look at here, nested variant, they have atypia, they're usually extensive, infiltrative base, what we saw there. Detrusor muscle invasion is common, and these are the immunohistochemistry markers we will discuss, and this is how they differentiate from other pathologies. And now probably you would be guessing what I'm saying. This is typical, a nested variant, of a urothelial carcinoma, and the pathologist was educating me. This looks like the nested variant of urothelial carcinoma with muscle invasion.

Now, these were the immunohistochemistry markers that were done. This is TERT promoter mutations, and this was originally described in melanomas, is present in more than 70% of urothelial carcinomas, is absent in benign uro-proliferative lesions, and absent in prostate and lung and colon cancers. That's what I was mentioning. If we have an invasion from the colon, whether this lesion could look like this. Now I'm just going to hold on for a minute here. I'm just going to take Dr. Kamat's opinion. Ashish, is it very common to see a nested variant of urothelial carcinoma?

Ashish Kamat: So the nested variant of urothelial carcinoma is an interesting variant. It's something that, as you mentioned, is not often recognized by community urologist or uropathologist. So first off, hats off to you and your pathologist for identifying this variant. The other thing is that the biology of nested variant is not really well understood, except to state that it does tend to have a more resistant behavior in general, if you compare it with regular urothelial carcinoma. So in general, the recommendation for a nested variant is to treat it like you would stage-for-stage the appropriate bladder cancer urothelial carcinoma, with the recognition that it behaves more aggressively. So lean more towards a more aggressive approach, because that would be safest for the patient. So for example, in T1 high-grade disease, if you normally would have a discussion between BCG or cystectomy of the patient, if you see nested variant, try to lean more towards radical cystectomy because the BCG may not work quite as well.

Makarand Khochikar: Yeah, I think perfect. I think the experience speaks volumes. I'm sure we have understood exactly how it behaves like from Dr. Kamat. And we just went ahead and did a CT scan. It was about 3 cm lymph node in the left iliac group. He also had 1.8 cm lesion in the right lung base and a few mediastinal lymph nodes. As we were discussing just a while ago, that it is a very extensive disease and has a high malignant potential with a metastatic potential. Now, obviously one could do a PET scan, but I'm not sure whether it will add more information than what we have done on a CT scan. And the question there was really what we need to do next. So we sat in the MDT meeting and we're exploring the possibility of whether we can give chemotherapy to this patient because obviously he has metastatic disease. And we're trying to just look into the natural history of the nested variant of the urothelial carcinoma.

And as we just discussed, it's an aggressive disease with a very poor outcome. They usually present with advanced tumor stage and nodal involvement. Stage matched with pure urothelial carcinoma. There is no increased rate of recurrence or adverse survival, that was a paper which came in 2013 by Linder et al., but if you look at the literature and they looked at the sort of personal experience, this is slightly different than what we have seen in a real practice scenario. And as Dr. Kamat pointed out to you, the misdiagnosis is a benign lesion. And then, therefore, many times you can get a delay in the diagnosis. This was a wonderful write-up, I liked it very much, nested type bladder cancer is a myth or reality. And just to give you a brief, it's about 0.3% to 0.8% of invasive urothelial carcinoma, only 200 cases have been reported till date. The first description was by Stern in 1979.

And they thought it's a benign course, but when the paper came from Murphy and Deana, they coined the term "nested" because of the histopathological appearance. And then subsequently, the Comperat et al. paper suggested it's a highly aggressive disease. And then, there's a paper suggesting that it needs immediate cystectomy, and this paper I just mentioned to you about, I think probably it doesn't go in the line of what we see in the routine practice. In comparison of pure urothelial carcinoma with nested variety, the muscle invasion as usually we see in urothelial carcinoma is about one-third of the patients, but here you see about two-thirds of patients present with muscle invasion. The majority of the patients in the nested variant have an extravesical extension at cystectomy. Almost more than half of these patients, more than 67% of patients, present with metastases, unlike pure urothelial carcinoma. The mortality at 40 months, irrespective of any treatment [inaudible] about 70%. And they do not respond to chemotherapy, that's the answer I am coming to.

So when we sat in MDT, we looked at the literature, so the chemotherapy would not have been useful in this case, as against to if this would have been pure urothelial carcinoma, we would have tried chemotherapy, immune checkpoint inhibitors and whatnot, we could have tried other things. He went and had another opinion, he went to the UK and somebody else offered him upfront cystectomy. Just had communication with him, and three months later he came back post-operative extensive lung and liver metastasis, and he perished thereafter. So it just tells you, it's a rare variety, you should not miss this variety because it's usually not the classical papillary tumor, very aggressive behavior, but we have to keep this in mind. So Ashish, any final comments on this?

Ashish Kamat: I think you highlight in this presentation, and I thank you for it, the importance of several things. Number one, for our audience, it's always important to keep in mind what Dr. Khochikar said when you're doing TURBT, is to how much of TURBT is necessary in this particular patient. Do you need the TURBT just for histologic diagnosis or staging information, number one. Then it's important as was outlined in this case, that you do have a good uropathologist. I can tell you, even for regular urothelial carcinoma, the grade, stage, with a fair amount of reliability, but then importantly, the variant histology. Then when you have variant histology especially, staging studies are extremely, extremely important. They're important anyway, but especially when you have variants such as in this case, nested, or if he has small cell carcinoma, for example, you must image the brain, which we normally don't need to do when it comes to bladder cancers.

Then of course, when you come to management, not all the histologies respond similarly. Again, here as Dr. Khochikar outlined, you have to match the treatment with the histology. And clearly, even though some histologies are more aggressive than the others, our patients all deserve a chance to be cured. And that's why even if it doesn't work, we still have to offer them the best-known treatment. And in this particular situation, I would not have offered upfront radical cystectomy. I would have offered a systemic therapy either with existing chemo or novel combinations, or what have you, in order to give this patient the best chance of cure. So I think Dr. Khochikar, thank you again, in this case, for highlighting all the critical elements that we need to keep in mind when it comes to managing any patient with any cancer, but especially variant histology.

Makarand Khochikar: Thank you.

Ashish Kamat: So I would like to take this opportunity once again, Makarand, to thank you very much for joining us today and highlighting this very important case from your case presentation files. I know you have a lot of other cases in your files as well, and we look forward to welcoming you in a future video with another exciting case. Thank you very much.

Makarand Khochikar: Thank you, Ashish, it was a pleasure, and all the best for UroToday.