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Bladder Cancer Carcinoma In-Situ (CIS): What Does A Diagnosis Mean?

With Drs. Peter Black and Hikmat Al-Ahmadie

You can read the entire Understanding CIS webinar transcript at the bottom of this page.

Year: 2022

Part 1: Understanding Carcinoma In-Situ (CIS)

Video (29 min) | Transcript (PDF)

Part 2: Treating Carcinoma In-Situ (CIS)

Video (15 min) | Transcript (PDF)

Part 3: Question and Answer

Video (10 min) | Transcript (PDF)

Full Transcript

Stephanie Chisolm:

Early stage tumors in non-muscle invasive bladder cancer, or NMIBC, are generally confined to the lining of the bladder, and they may be papillary and look a little bit like tiny finger-like clusters or flat, velvety patches known as carcinoma in situ or CIS. Tumors that are CIS have a very high rate of recurrence and possible disease progression, so it’s really helpful to understand your diagnosis. Tonight, BCAN is welcoming urologist Peter Black from the Vancouver General Hospital in Canada and Pathologist Dr. Hikmat Al-Ahmadie from Memorial Sloan Kettering Cancer Center in New York City. We’re delighted to have you here to help us talk about CIS and what patients need to know. So welcome to both of you. I’m going to turn my video off, and Dr. Black, if you want to take it away.

Dr. Peter Black:

Terrific. Thank you, Stephanie, very much for the invitation and the opportunity. I think I can speak for Hikmat as well, that we’re both passionate about bladder cancer and so we’re always very happy to explain what we know and educate, so hopefully the attendees tonight will find this interesting. Hikmat and I are going to go back and forth a little bit. I’ll start and then we’ll switch to Hikmat and we’ll carry on like that. What is carcinoma in situ? Stephanie alluded to it a little bit at the beginning. We have this broad spectrum of disease stages for bladder cancer from the very superficial on the left and carcinoma in situ is also called TIS. It’s just right on the surface of the bladder, to tumors that actually extend into the lumen of the bladder but still sit on the surface. That’s the Ta just next to that.

Then, the T1 tumors that are already invading the first layer of the bladder wall. Those three together are all non-muscle invasive, but there’s a difference between actually invasive T1 and the other two that are really non-invasive. And then on the right, we have the muscle-invasive, which we’re not going to talk about this evening. Next slide.

Dr. Peter Black:

There’s special things about carcinoma in situ that make it really worth having a dedicated session just on this. So it’s a flat tumor, there’s no tumor extending into the lumen of the bladder. It’s often red and velvety, but sometimes it’s invisible, so we struggle to see it in a lot of patients. Although it’s an early stage of bladder cancer, it is high grade. By definition, it’s always high grade and therefore, it has a significant malignant potential. It has the potential to develop into muscle-invasive bladder cancer, so even though it’s early stage, we take it very seriously and we treat it quite aggressively because we need to eradicate it. One of the problems that we also struggle with is that this transition from a non-invasive, superficial carcinoma in situ into a potentially invasive muscle-invasive tumor is very unpredictable. Next slide.

Some other key features is that it’s often… if it’s found together with the other non-muscle invasive bladder cancer stages, so Ta and T1, it indicates a higher risk of recurrence and progression. The fact that the cancer could come back or it can turn into something more invasive if there’s carcinoma in situ there. It’s an additional risk factor in patients who have other disease stages.

Dr. Peter Black:

Carcinoma in situ we assume is multifocal, so it’s at different locations in the bladder, or even diffuse, meaning anywhere you would sample the bladder wall, you would find carcinoma in situ. That’s a very important and special feature. The other tumors generally we consider to be confined to what we see and what we resect. Because it’s multifocal and diffuse, we general believe that we cannot resect it completely with a transurethral resection, which again, is different from the other bladder tumors that typically we can resect at least all visible disease.

Dr. Peter Black:

Since we can’t resect it, we either need to treat it with intravesical therapy such as BCG, or we need to remove the bladder if we really want to get rid of it all. That’s why it’s really tricky and a bit different than the other bladder tumors. Next slide.

I’m going to present a patient profile, and then Hikmat and I will go back and forth a little bit about some of the issues related to this patient’s bladder cancer. So this patient is an 87-year-old gentleman, retired chartered accountant, who has been a longtime smoker, more than 50 pack/year history of smoking. He was found just on a regular check with his primary care provider to have red blood cells in his urine under microscopy. He’s never seen blood himself, so there’s no gross hematuria, just microscopic hematuria. He has symptoms that are common for his age. Nothing particularly severe or noteworthy, extreme. He gets up a couple times at night. There’s some urgency to void. He has very significant other health issues. He has heart disease, diabetes, high blood pressure, and he is even on home oxygen because he has emphysema also related to his smoking history. One thing that is relatively clear when we look at this gentleman is that he’s probably not going to be fit from a general health point of view to undergo radical cystectomy to remove the bladder. We’re not necessarily at that point yet, but I just wanted to highlight that in his medical history. His family doctor, based on the microhematuria and the risk factors, sent his urine for urine cytology. Can you go back for a second? The diagnosis of the urine cytology is high grade urothelial carcinoma. Hikmat’s going to run us through a little bit what that means.

Dr. Hikmat Al-Ahmadie:

All right. Thank you, Peter for the lead-in and hello everyone. Thanks for tuning in and spending the evening with us. It’s my pleasure to share this hour with you and talk to you about urothelial carcinoma in situ and different aspects of the disease, and hopefully you’ll find it helpful. As the story started, a quick test is urine sample. It’s a very easy type of specimen to get. It just requires the urine sample that you may get in the clinic or the office. It is sent to the pathology department. It’s spun down, just to concentrate the cells in that container, and then it will give us a better opportunity to detect any atypical cells in there, and when slides are prepared, the tissue is stained, then we’ll be able to have the ability to visualize cells that can tell us what they constitute, they’re benign or reactive or abnormal cells, and we follow a system. There is a system.

These type of specimens have been studied for a long time and there are criteria that we apply every time we analyze these type of samples. And then we follow the most recent system is the Paris System, and it has different categories and every case, every urine sample that goes to the lab, the result come back with one of these categories. Of course the red flag would be, or when we highly suspect a urothelial carcinoma is in these two categories that are in bold now, the number four and five. Either we see some atypical cells that are atypical enough to suspect urothelial carcinoma but there are not as many of them as you would want. The cutoff has been made as 10 cells. If you see more than 10 cells that are very atypical, and I’m going to show in some of these features what we mean by atypical in the next slide, these are what you say suspicious. When you see these atypical cells in a quantity that is high enough, and as I said, this is typically more than 10 cells, then you can render the diagnosis of high grade urothelial carcinoma.

Dr. Hikmat Al-Ahmadie:

During cytology, you will be not able to say in situ or papillary because most of the times, that designation requires more architectural assessment rather than individual cells, so I’m going to show you example how the urothelial carcinoma cells in the urine may look like, if you go to the next slide, Stephanie. Then another click.

Yes, so this is a high magnification image from a urine cytology specimen taken from under the microscope. These are the individuals, as these dark purple or blue structures in the middle of the picture. These are the nucleus, the nuclei of tumor cells. You can see how they’re different in size and shape, different in the darkness quality just of the chromatin quality. They have indentations, projections. These are all atypical features that do not resemble normal cells that we are very familiar in how they look like, and with these type of features altogether, with the abundance of these cells in the urine sample, we can comfortably say that this is cyg-diagnostic of a high grade urothelial carcinoma.

Dr. Hikmat Al-Ahmadie:

Urine cytology, as I said, it’s a very simple process. It’s a simple test. Doesn’t require much. It’s not invasive. You don’t stick a needle or anything, just a urine sample in the office. It’s very sensitive for high grade urothelial carcinoma. It’s less sensitive for lower grade lesions, because again, you need to see atypical features that are obvious here. In low grade lesions, you don’t see the same features. And it’s also specific, which means if you don’t see these atypical cells, you have a high confidence that you’re not seeing a high grade urothelial carcinoma, and that’s why you can say it’s very specific. If we go to the next slide, just to show you where these cells might come, this is a tissue section. This is a biopsy. There’s also the biopsy processed in a similar way, a little bit different because you have to prepare, you have to fix the tissue and cut the sections and make them into a slide. As you can see at the top, in both these images, all these dark cells that have different sizes and shapes, these are all malignant cells. With this tissue section, I can easily call it urothelial carcinoma in situ because I have architecture. But as you can see, the individual cells are coming off of the main tissue fragment and they’ll be sloughed off or shed into urine, and that’s what will make up the positive urine cytology. I’ll turn it back to you, Peter, I think, for the next set of slides.

Dr. Peter Black:

Great. Yeah, I think from the urologist’s perspective, the urine cytology is so important because we often don’t see carcinoma in situ. That’s something we’ll come back to while we’re talking. This gentleman had a CT scan. He ad blood in his urine, so that’s part of the usual workup, and everything was normal with the kidneys and ureters. Remember that carcinoma in situ and indeed any cancer of the bladder, you can get very similar lesions in the renal pelvis and the ureters, and then upper tracts. On cystoscopy, however, there was a red patch on the back of the bladder. It was a little bit raised. It wasn’t the typical sort of cauliflower tumor that we often see, but it was certainly suspicious, especially given the positive cytology. So this gentleman we took to the operating room for a resection of this area that you see in the micrograph here. Next slide please.

An important consideration, again, this is particularly with carcinoma in situ, is the use of enhanced cystoscopy. There are two different methods with which we can enhance a cystoscopy. On the left-hand side, you see the cysview, which is the trade name. It’s also called blue light cystoscopy or fluorescent cystoscopy. PDD is often used in Europe as a terminology. It’s photo-dynamic diagnosis. But here, you put a substance into the bladder prior to the surgery, prior to the TRBT, and it’s taken up and metabolized by cancer cells so that these cells then fluoresce. When you shine a blue light on it, a fluorescent light, or, well, a blue light, the cells will fluoresce and they appear a bright pink. They really stand out. We know that we can detect more tumors this way, and especially more carcinoma in situ. Up to 40% more carcinoma in situ. It’s particularly valuable, again, because we often overlook them on regular white light cystoscopy.

Dr. Peter Black:

On the right-hand side, we have narrow band imaging, which is a little bit different. It uses filters to pull out the blue and the green wavelengths that really accentuates blood vessels and changes in blood vessel patterns. Vascularity will often accentuate tumors so that we can see them better. It’s a little bit easier to use because it’s just a flip of a switch on the device and it doesn’t require putting anything into the bladder, but the evidence for its use is not as widespread. Next slide.

I just want to highlight some of the differences in fluorescent cystoscopy. And this is I think particular to the US market actually, because it’s not necessarily available everywhere, but you can actually do fluorescent cystoscopy at the time of a surveillance cystoscopy in the office. If a patient has had a prior bladder cancer and they’re undergoing their routine cystoscopy, you can do fluorescent cystoscopy that, for example, is not available for us in Canada. Or, you can do it, which is more common, more universal, you do it at the time of a broader tumor resection or biopsy, so if a patient has an identified tumor, you go to the operating room, you give them the reagent beforehand and then you use it at the time of resection. So there are two different uses, and I think as patients and caregivers, you need to be clear on the differences.

On the left-hand side, if you’re talking about what we do at the time of surveillance cystoscopy, so it’s used to detect a recurrence. It’s primarily patients with intermediate and high risk disease. So they they’ve had tumors before. Based on the prior tumor characteristics, we know that they’re high risk for recurrence and we especially do it early on in their disease course. So if they had a tumor three months ago and it’s the first look, then that might be a time when we do it. We always have to consider the cost and the treatment burden of all these tests. We can also do it, for example, if we see something on white light that we’re not, and white light’s that the usual cystoscopy, if we’re not quite sure what it is, this might help us decide, yes, we need to biopsy that or no, we don’t need to biopsy it. And overall, there’s especially one very good American trial that shows that it enhances the detection of high-grade recurrence.

Dr. Peter Black:

On the right-hand side now, when we’re using this at the time of resection, there’s very good data from multiple trials, North American and European trials that tell us that we’ll detect more tumors, we’ll resect more thoroughly, patients will have a lower risk of recurrence, and that’s a very important endpoint. In particular for what we’re talking about, we’ll also find more carcinoma in situ. Next slide.

I wanted to highlight one specific scenario that comes up routinely and is particularly relevant for carcinoma in situ. I know there was already a question in the chat or the Q&A about carcinoma in situ of the upper tracts. Upper tracts are the ureters and the renal pelvis. One scenario that we see sometimes are patients who come in to the office with a urine cytology that clearly shows abnormal cells, so it says high-grade urothelial carcinoma, so there are malignant cells there, but we don’t see anything on cystoscopy and we don’t see anything on a CT scan.

There, we have a specific algorithm that we run through and we know, for example, that carcinoma in situ is something flat in the ureter or renal pelvis is not going to be visualized on CT scan. We might not even see it, actually, when we look at it with a camera. We can’t do the fluorescent cystoscopy in the upper tract, so it can be particularly tricky.

So what we do is we go to the operating room, we get urine from the right ureter and separately from the left ureter so that if it is coming from one side or the other, we can determine that definitively. If we find urine, let’s say from the right renal pelvis, then the cytology is positive, but we don’t see anything with the camera and we don’t see anything on CT scan, then we call that carcinoma in situ. We assume there’s carcinoma in situ there even though we don’t see it.

Dr. Peter Black:

The other thing we do, then, so, if in a patient like this it’s still more likely that it’s actually from the bladder and we’re just not seeing it. So in the bladder, we will do the fluorescent cystoscopy and we’ll biopsy whatever we see there. And then in men, we always have to consider that it could be coming from the prostatic urethra, where you can also get carcinoma in situ. It can be quite tricky. Upper tracts, bladder, and prostatic urethra. Next slide.

So our patient, you’ll recall he had the positive cytology and the red patch from the posterior bladder wall. We took him to the operating room for a resection and we used the fluorescent cystoscopy. It lit up the patch that we saw, but it also lit up a second patch bright pink. And you can get an idea from these pictures here, which of course are not actually from this patient. I stole these, but on the left-hand side, the regular white light, you don’t really appreciate much with even an experienced eye, yet on the right-hand side, it’s really night and day. It’s very clear that there’s something there. So this lesion was resected in addition to the other one that we saw, and the patient did well with the surgery, no complications. Next slide.

Dr. Peter Black:

So we sent the sample off to Dr. Al-Ahmadie, who’s going to go through the pathology for us.

Dr. Hikmat Al-Ahmadie:

All right, so this is kind of a step-wise process. Every sample that is removed in the clinic or the office goes to our pathology department, and in the next few slides, I’ll just walk you through some of the process and some of the classification or how we make the diagnosis, how we look, how we evaluate these specimens. And then at the end, I’m going to show you a slide that would represent that actual biopsy from this gentleman.

Once we start the evaluation of any bladder sample, in our mind is when we find a malignant process, where can we ask the question, where can we fit it from the current specification? And as Dr. Black alluded to in the beginning, you have non-invasive spectrum of tumors that are in the non-invasive category, and those can be the carcinoma in situ, which is the subject of tonight’s discussion, and then you can have papillary lesions that can be low-grade and high-grade as opposed to the in situ, which is always a high-grade. There are some rare benign tumors that we call them papillomas. They have distinct morphologic features, and then the tumor starts invading. And then the tumor can invade into the lamina propria, which is the most superficial layer of the bladder wall, or the one underneath the surface lining. And then the deep invasive disease. This is our main challenges. Where can we fit this lesion that we identify on these histologic sections in any of these categories? So if we go next slide.

Dr. Hikmat Al-Ahmadie:

This is one we come into. We identified a malignant process. It’s a urothelial carcinoma now. Can we place it into in situ flat disease or papillary? This is what it is. You look at the image on the left, this is the definition of urothelial carcinoma in situ. We’ve identified these cells that are very atypical. Again, the features that we use are the variation in the size and shape, the variation in the coloring of these tumor cells, how they’re spaced. Are they overcrowded? Are they not respecting each other’s borders?

Then, there are some other features that I may point to and I apologize if these may sound too technical, but I’m happy to kind of discuss or answer any questions if you think and if it might need more explanation. When the cells divide, they form a structure called mitosis, which is a sign of dividing in cells and a growing tumor. You can see a lot of mitosis in these tumors as compared to the picture on the right, which is the papillary tumors, which are basically a finger-like projections, and this is how the tumor grows into the lumen of the bladder. It’s simple recognition of the pattern that can tell you it’s a flat versus papillary disease, and these are all things that are [inaudible 00:23:04]. You can see it’s be definition high-grade disease, and it’s a tumor that’s just growing as if on the flat, the surface of the bladder. Next slide.

Dr. Hikmat Al-Ahmadie:

Fortunately and unfortunately, just to make things difficult and challenging, urothelial carcinoma in situ can come in different forms and shapes. These are just different examples. I just wanted to show you, just to kind of put an image to the name, so to speak. We always rely on reference to the normal urothelium, which is the image on the top left. Here you can see it doesn’t take much, you can see, comparing this image to all the other five images. You could see how we use the reference normal urothelium to help us identify abnormal lesions. Normal urothelium is very orderly structure, multiple layers of different types of cells start from the base all the way to the top. All of these cells are important. They have normal functions in the bladder. For example, this middle layer can be four, five cells thick, but it can become two cells thick if the bladder is distended and becomes flattened.

All the other images on the right and the bottom, these are different shapes of urothelial carcinoma in situ. Again, highlighting the features that we rely on and we use: the variation in the size and shape, the discoloration, the growth pattern. Some of these patterns can be deceptive, like the one on the top left. These large cells are individual tumor cells just growing along the normal urothelium. We use the term spread, but this could be challenging and this could be one of these examples where not many tumor cells go into the urine, for example, because these cells are just growing under normal urothelium, compared to the picture in the middle and the bottom. This is when you have a lot of dis-cohesive, disjointed tumor cells that can easily shed into the urine.

Dr. Hikmat Al-Ahmadie:

The last image on the bottom right, this is a tumor, carcinoma in situ, that is involving some normal invaginations in the bladder. Sometimes all the surface urothelium is normal. You don’t see any malignant cells, but you could see these tumor cells inside this invagination. Sometimes that can make it more difficult to treat. If we go next slide.

As much as we want to believe or we want to think of urothelial carcinoma in situ as distinct from papillary tumors, a lot of times they coexist or they overlap, coexist or they develop after one another. These are some terms that we use, primary urothelial carcinoma in situ or primary CIS is one. On the first presentation, it is urothelial carcinoma in situ with no associated papillary tumor, or you can have secondary CIS, where there is urothelial carcinoma in situ developing concomitantly with or after a prior diagnosis of a papillary urothelial carcinoma. Of course there’s always attempt to try to link this to differences in outcome or responses to types of therapy even though it’s not necessarily conclusive yet, but it seems that some people believe that primarily urothelial carcinoma in situ may be associated with a worse response to rate to these conservative treatments. Next slide.

This is one example I wanted to show you, is as I said, as much as we like to keep them separate and unique, sometimes they coexist. This is one example here. This is the same TUR specimen from the same individual. You can see them grouped together, coming together within the same container from the same patient. If you look at the higher magnification picture on the right top, this is a papillary tumor. You can see these finger-like projections sticking into the bladder wall, out the bladder lumen, versus the picture on the bottom, the growth is very flat, just along the surface urothelium. That’s the distinct growth pattern for urothelial carcinoma in situ. So a papillary tumor and a flat disease can coexist within the same specimen. Next.

Dr. Hikmat Al-Ahmadie:

And of course another important thing, when we assess, when we evaluate the urothelium here, and every time we see urothelial carcinoma in situ, the next most important thing is to determine whether there is any amount of invasive disease or whether this tumor is purely non-invasive urothelial carcinoma in situ. We look carefully at the base of the surface urothelium and we are carefully evaluating the stroma underneath it, these layer that are loose underneath it. When we start seeing these individual cells that are highlighted by these green arrows or arrow hats, that’s when we start calling this invasive disease. Depending on the level of invasion and the amount of the invasive disease, we can call it focal superficial, and if it goes deeper than the first layer… if it remains in the first layer, you call it laminal invasion or T1 disease, as you might hear about it. And if it goes further deep into the bladder wall, it may invade the muscular layer, where you call it muscle-invasive bladder cancer. These features are not depicted here on the slide, though. Okay, next. I think we went back, so… Yes, next slide.

Yeah, and so this is another example that Dr. Black alluded to that could present challenges in evaluating urothelial carcinoma in situ. This is a tumor that is involving… here, what we see in the picture is involvement of prostatic ducts, which are immediately underneath the urethra. This is a tumor that kept kind of crawling along the surface urothelium, involving the urethra and went all the way into the prostatic ducts. It’s not invasive, it just keeps colonizing all these ducts and makes it difficult to detect sometimes, difficult to remove and difficult to treat overall. Next.

This is going back now to the actual case here in this presentation. This is the biopsy from the gentleman, and as you can see, after I showed you all the slides, now everyone should be able to recognize that yes, these cells are very atypical. They’re different sizes and shapes, different colors. They don’t respect each other’s borders. There are a lot of variations amongst them. This is diagnostic of urothelial carcinoma in situ. Next. Yeah, that’s yours. Back to you.

Dr. Peter Black:

Great. I would take this pathology report that Hikmat has provided and sit down with the patient and say, “Okay, how are we going to treat this carcinoma in situ?” It’s pure carcinoma in situ. There’s nothing else there. One thing to highlight again is that we cannot count on having completely resected this. An 87-year-old patient with a lot of medical problems who maybe had a papillary tumor where we’re confident we resected it all, we could consider of course doing that here. We can also consider doing nothing, but there, we would have some confidence that we may have resected it all, whereas here we would not have that confidence.

The standard of care for a patient like this is to give intravesical BCG treatment for the full three-year course. So six induction courses, and then the maintenance therapy up to 36 months. And although this 36-month schedule seems rather arbitrary, and it was initially arbitrary, there’s actually very good evidence to support its use. There’s a European trial, for example, that compared three years versus one year and a full dose versus a third dose, and it showed that the full three years, full dose has the best outcomes. That wasn’t specific to carcinoma in situ, but we think that maintenance is maybe even more important to carcinoma in situ because we can’t resect it all.

Really interesting with carcinoma in situ is that we often or we can see a delayed response. The early, biggest trial that showed us that we need to do maintenance therapy, some patients had maintenance and some didn’t, and we saw that at three months after just the first six induction doses of BCG, 55% of patients had cleared the carcinoma in situ from their bladder. But at six months, it was up to 80% if the patients got maintenance therapy. So we see that there’s a good 25% of patients who are having response beyond the first three months, so it’s critically important to wait for those first six months.

Dr. Peter Black:

It’s important not to skip doses. So in an era of BCG shortage, we tend to reduce the dose or shorten the maintenance if we have to. We think that longer is better, up to three years, but the differences are fairly small, but there’s a trial published now two years ago that tried to reduce the number of doses, the Nimbus trial, and it showed a dramatic difference in efficacy. So we really need to stick to the schedule, but if we have to, we can reduce the dose or shorten maintenance.

Side effects of course are important with BCG. It represents an important burden on patients. It can cause a lot of local bladder symptoms. It can cause patients to have low-grade temperatures, just generally feel lousy, but we are able to manage those symptoms and I would say the stakes are high. It’s about preserving the bladder and avoiding removal, and so most patients are motivated to be compliant and the rate of stopping because the side effects I think is relatively low, even though it’s something that we certainly worry about. Next slide.

So, what if a patient cannot get BCG? So, a patient with carcinoma in situ of the bladder, this could be a patient, for example, who’s had a kidney transplant. And so the patient is on immunosuppressive medications that would make BCG a little bit dangerous, but also unlikely to work since it’s dependent on a functioning immune system, Other patients, so-called BCG intolerance patients or their disease is BCG intolerant, they have to stop before they get the full induction course, and they can’t have any additional BCG. I had a patient, for example, recently who developed a joint inflammation that was triggered by the BCG and we couldn’t give more BCG because we would trigger the same again. And so for these patients, and of course, there’s a BCG shortage, so maybe in the last few years, the most common reason not to get BCG is because it hasn’t been available.

Dr. Peter Black:

Regardless of the cause, there’s no established evidence-based effective alternative to BCG. And this is a big unmet need in the care of bladder cancer patients. And it’s not just carcinoma in situ it’s also high-grade Ta and T1 tumors. There’s no really well-defined alternative. I’d say one thing that has sort of evolved over the past few years is that this combination of gemcitabine and docetaxel, where on the same day, the patient gets gemcitabine and then docetaxel has evolved as a commonly used alternative, and there’s now a big trial that is going to evaluate how it compares to BCG. Otherwise, what you’ll find in a lot of places around Canada and the US is that a single dose of chemotherapy is used, but it’s really not a single dose, a single agent, so either mitomycin or gemcitabine, but it’s not really effective. It does not compare to BCG. Next slide.

This just reiterates what many of you are probably familiar with. At the top, you can see the intravesical chemotherapy, which is given once a week for six weeks and then monthly up to a year. And that can be either the combination that I talked about or one of the single drugs, or the bottom BCG, which is given once a week for six weeks, and then at intervals, it’s given in three doses. So once a week for three weeks, at three months, six months and every six months up to 36 months. So a total of 27 doses in 36 months. Next slide.

And there’s a lot going on in this field. And I put this as a busy slide, but I just want to highlight some of the different clinical trials are going on just so you can see that there really is some optimism that we can improve things in the next several years. In the top left-hand corner, there’s a curve that just shows that there are differences in disease control, depending on the strain of BCG that’s used. So BCG was founded, I can’t even remember how many years ago, but about a hundred years ago, and it has evolved so there are different strains in different parts of the world, and they may trigger a different immune response. So there are differences there.

Dr. Peter Black:

A large trial has been completed in the United States, what’s called 1602, that compares a strain from Japan, the Tokyo strain, with the usual strain used in North America, the TICE strain. So we’re eagerly awaiting those results. What that trial also did is that it gave patients in one arm of the trial a BCG vaccination, so an injection under the skin that would hopefully enhance the immune response to the BCG that was subsequently put in the bladder. And so we’ll have results within a couple of years to show us if that helps. Importantly, it may also allow us to then have a second strain, the Tokyo strain, on the market to get over some of the shortages.

On the top right-hand side is a trial that… they’re actually three trials that look essentially identical, where patients with high-risk disease, non-muscle invasive disease are randomized to get either just the usual BCG or BCG plus immunotherapy, and that BCG can be either a limited BCG or the full dose. And that’s also exciting to see if we can improve upon the effects of BCG with immunotherapy, which has had such a positive impact in more advanced bladder cancer.

On the bottom left, I’ve shown an example of genetically engineered BCG where you take the actual bacteria and you modify them so they’re expressing different proteins. This is one example where the BCG is made to express a toxin from a different type of bacteria, listeria, which enhances the immune response and decreases the toxicity. And so that’s in clinical trial, and then the bottom right is just a trial that compares the gemcitabine and docetaxel to the BCG, which I alluded to on the prior slide. That trial, again, that’s being led by Max Cates at John’s Hopkins, and it’s called the Bridge trial. So we’re looking forward to getting that one started soon. Next slide.

Dr. Peter Black:

Our patient, our 87-year-old gentleman, started with BCG and he had the first three doses really without too much side effects at all, but what typically happens is after dose number four, five, and six, you get increasing symptoms, things like urinary frequency, burning with urination, urgency, and that’s sort of increased. And it’s usually resolved within a couple of days of a dose. There are medications that we can give to help with this. This patient didn’t require any. He felt very tired for a couple of days after BCG. I think we sometimes, as the treating physician, sometimes forget sort of the general, full-body response that some patients have, but that also recovered within a couple of days. And when he came back to his office for his cystoscopy three months after his diagnosis, so about six weeks or four weeks after his last dose of BCG, he was already feeling back to baseline. Next slide.

And so how do we monitor a patient like this who’s getting BCG therapy? Well, it’s the same for carcinoma in situ as it is for a high-grade Ta or T1 tumor, so the other non-muscle invasive bladder cancers, and the standard regimen I think is almost universal, meaning it’s done in multiple different countries around the world, is that we do a urine cytology and the cytoscopy where we look inside of the camera, we do that every three months for the first two years, then every six months for the subsequent two years, and then annually. And the recommendation is to do it lifelong, or as long as the patient can be motivated to come back for follow up. This implies, of course, that there’s not a recurrence. If there’s a recurrence, then we have to recalibrate and figure out a new plan.

I put in a bullet point there about the use of the fluorescent cystoscopy, so flexible fluorescent cystoscopy at the time of surveillance. And again, it’s not available in most centers. There is a consensus document that some experts in the US put out recommending that it could be done every six months for the first two years in patients at high risk for recurrence. I would say that’s not written in stone. Different urologists will do it differently, so just bear that in mind. And then we always have to remember that the kidneys are at risk, and so we get a CAT scan, a CTIVP of the kidneys and ureters at baseline, as we had already in this patient, but also a month later and then often every two years. Again, not written in stone. Different people will do it differently.

Dr. Peter Black:

What makes the surveillance of carcinoma in situ particularly difficult is that once you’ve started BCG, once the patient’s started BCG, there will often be red patches in the bladder that are due to inflammation from the BCG or from the prior biopsy and prior procedures, and so it can be very difficult just based on inspection alone to decide if there’s something concerning or not. If we do a CAT scan, the bladder wall is often thickened, and as I have a picture there of a CAT scan in the middle, and the bladder wall is severely thickened, but this is a nonspecific finding. It’s very, very common that bladder cancer patients have a thickened bladder wall just from all the procedures and treatments they’ve had, and it doesn’t really mean very much.

And then the third part is the cytology, which as we said, is so important for the patient with carcinoma in situ, but once we’ve started with all these treatments and BCG, we often get atypical cytology because of inflammation. And so if we have a patient with a somewhat inflamed-looking bladder, but maybe it’s carcinoma in situ and an atypical cytology, but maybe it’s cancer cells, it can be very difficult to figure out exactly what to do. And so Hikmat is going to take us back to the atypical cytology.

Dr. Hikmat Al-Ahmadie:

So, most of the times, the diagnosis is actually straightforward. You get a tissue from the procedure, you are able to tell it’s benign or malignant straightforward. There are occasional times when that diagnosis not very straightforward. There are these situations which are challenging to all of us because they provide a level of uncertainty, because you look at the slides in the microscope and you will see some atypical features as I show you on these two examples here, but then it’s not atypical enough, at least not up to the level of what we see in textbooks, to make it a straightforward diagnosis of cancer.

These are these cases where you may leave the word atypia. Some people use the word dysplasia, in a way acknowledging that I see something that is not completely normal, but it’s not to the level of calling it urothelial carcinoma in situ. May not necessarily be very helpful, but at least it is helpful in the sense to alert the patient and the physician that this may be worth observing a little bit more closely, or just do something extra to make sure that it’s either benign or malignant. So this is the word atypia or dysplasia. The next slide.

Dr. Hikmat Al-Ahmadie:

Another thing that can happen, especially after treatment or after a first procedure, like if you do a repeat biopsy, the urothelium is very sensitive to injury, so it can react very quickly and you could see a lot of changes that are related to inflammation. As you can see in this example, the urothelium is very thickened and the cells have variations in size and shape, difference in the intensity. These are all vary atypical features, but at the same time, the borders of the nuclear are very smooth and makes you wonder if this is really a severe or markedly a reactive process. And that can be supported by the presence of some inflammatory cells. All these small dark dots in the the urothelium here, these are all inflammatory cells. So this atypia can in part be explained by an inflammatory process, but not necessarily be always the case, because you can have carcinoma in situ and inflammation, and that can compound the process.

Dr. Hikmat Al-Ahmadie:

These are the challenging cases, and if you go to the next slide, having these features in mind when you’re looking at the histology section under the microscope, we always keep in mind how that might look with the urine cytology, and we try to always make the correlation between the pathologist and the cytopathologist, and again, we follow the system, the Paris System, just to try to categorize the atypical features that we see into one of these entities. The action should be based on mostly categories four and five, when there’s high level of suspicious for urothelial carcinoma high-grade, but then all the other categories can trigger some other downstream processes or steps to clarify or be certain that you’re dealing with a benign or a malignant process. Next.

Dr. Peter Black:

Terrific. I would say from a urologist perspective that the atypical cytology is something that we generally don’t get too excited about. I noticed also that I’m talking too much, so I’m going to try and accelerate here so we have time at the end for some questions, but if we come back to our patient, so he completed the induction BCG over six weeks. His cytology has remained positive, so there’s still cancer cells in his cytology, in his urine. The cystoscopy, there’s some inflammation, but nothing suspicious for invasive tumor or anything really concerning. So we expect based on the cytology, the patient actually still has persistent carcinoma in situ at this point, but you’ll remember that I said that a good proportion of patients can still respond between the three-month and six-month time point. So a lot of urologists at this point would say, “Okay, let’s just maintain the course. We’ll continue with maintenance BCG and we’ll reevaluate at six months.” Some urologists would re-biopsy to make sure what’s there. If the biopsy’s positive for carcinoma in situ, they’d actually do another round of induction BCG, so a few more doses. A little bit of differences in practice patterns there.

Since I was treating this patient, he had had three more doses of the maintenance BCG and then at six months, what I do is an automatic re-biopsy. Because of these issues with red patches and atypical cytology, it can be very difficult to discern. In some patients it’s completely invisible, so the safest way is to go back to the operating room and do a biopsy, but not everybody does that. Our patient had a normal cystoscopy and a suspicious cytology at six months. Next slide.

And so if you don’t see anything, you again would get urine from the upper tracts to make sure it’s not kidneys. We always have to be thinking about that. We like to do the fluorescent cystoscopy, but we have to be careful because there’s a high rate of what we call false positives after BCG. BCG can cause inflammation and the inflammatory lesions can also light up, so there’s some caveats there. Otherwise, we do what we call site-selected or mapping biopsies, and the picture on the right is just supposed to be a diagram of the bladder where you can go to different regions specifically: the right wall, the left wall, the front wall, the back wall, and we always include the prostatic urethra in men. Next slide.

And so our patient on the fluorescent cystoscopy, we didn’t actually see anything, so it didn’t add any value in this case. The cytology from the right ureter and the left ureter was clear. The prostatic urethra biopsies were clear. And the only thing we found was carcinoma in situ in two out of five of the site-directed biopsies. So this is kind of a typical thing that we might find. Not everything is going to light up on fluorescent cystoscopy, but this patient now has carcinoma in situ despite induction and the first round of maintenance BCG, and he meets criteria for what we call BCG-unresponsive carcinoma in situ. Next slide.

Dr. Peter Black:

I’m actually going to skip over this one. Next slide, just for the sake of time. For our patient with BCG-unresponsive carcinoma in situ, there are a couple different options. First of all, the standard of care, according to the guidelines, is a radical cystectomy and replacement of the bladder with bowel, so an ileal conduit or neobladder, whatever it might be. Of course this patient is really not medically fit for a cystectomy. What has evolved, as I’ve also alluded to as sort of the standard second line treatment after BCG in the US and Canada is this combination of gemcitabine and docetaxel. And so that would be probably the most common thing that this patient would get around the country at this point in time.

There are some other alternatives. So pembrolizumab is an intravenous immunotherapy that is approved for patients like this, but the efficacy is relatively marginal and it has increased toxicity because it is an intravenous drug and it does trigger some specific immune-related side effects. Valrubicin is a chemotherapy. It doesn’t work very well. It’s not used widely and the other chemotherapies don’t work very well either as a second line treatment. And if we can, of course, we like to get patients in clinical trials, because there are a lot of exciting new drugs being tested and some them are looking very promising. Next slide.

Dr. Peter Black:

This is just an example of what we would expect with gemcitabine and docetaxel. The bottom line, the purple line is for patients like our patient with carcinoma in situ. There’s a 50% chance of being without recurrence at two years. And you say, “Well that’s not great, 50%,” but it is better than anything we’ve had up to now, although this is retrospective data. Next slide, please.

Next slide. I’m just going to skip over some of this just because the time is getting ahead of us, here. This slide just shows you some of the exciting new drugs that are in clinical trials or that have been tested and hopefully will be approved soon. The names are horrible, we’ll have to get past that, but a lot of really unique mechanisms of action, virus therapies, antibody drug conjugates, lots of exciting things happening in this space. Next slide.

And we’re also seeing the first randomized trials where we’re with patients with early bladder cancer, BCG-unresponsive disease are being randomized to multiple treatments that are being compared against each other or the treatments are now being combined with each other to try and improve efficacy. So there’s a lot going on for BCG-unresponsive bladder cancer. Next slide.

So if we think of the anticipated outcomes for a patient like this, I told you that the response, specifically for carcinoma in situ, and some of this is estimates. We don’t know it very precisely, but the response to BCG is about 80%. The likelihood of recurrence, however, within five years is about 40% and the likelihood of progression to muscle-invasive bladder cancer, even with optimal therapy is about 15%, and approximately that proportion will also undergo cystectomy, although there’s a lot of subjectivity into that decision on when to do a cystectomy. Some urologists and some patients will want it done sooner versus later. Next slide.

Dr. Peter Black:

And I think this is my second to last slide. We’ve focused really on carcinoma in situ by itself, but carcinoma in situ in combination with another tumor is actually much more common. Carcinoma in situ plus other non-muscle invasive tumors, I said at the beginning that it’s a worse prognosis than those other tumors alone. Carcinoma in situ with muscle-invasive bladder cancer might be a reason not to consider radiation because we would consider it a diffuse disease with a higher risk of recurrence. And then carcinoma in situ is also something we find frequently at the time of bladder removal, radical cystectomy, where you can have carcinoma in situ sometimes in the ureters or the urethra that we remove at the time of surgery. Sometimes it’s even carcinoma in situ right at that edge, at the margin of what is removed, and that indicates a higher risk of recurrence. Carcinoma in situ comes up in different scenarios with different implications. Next slide.

Stephanie Chisolm:

Well, thank you both so much. That was very insightful and informative, such great information. So easy to understand and a lot of good questions. I’m going to just go right into those questions if you don’t mind. One of the… actually, two of the questions are about the same as far as is it better sometimes if you’re at risk to just go ahead and have a cystectomy and have your bladder removed or could that be done too early? Is there ever a point where you take out a bladder too soon?

Dr. Peter Black:

Yeah. It’s a very good question, and it’s something we as physicians and with our patients really struggle to come to terms with sometimes. It’s really relevant for… it’s also for T1 and Ta carcinoma in situ. I think if a patient comes in with a first diagnosis of carcinoma in situ, I think ultimately the risk of progression and especially sort of a surprise progression that we didn’t anticipate coming is very low, and I think cystectomy would be overtreatment and the risk of a major complication with cystectomy would make us say that it’s potentially bad care and that really was done too soon. But as soon as you have a high grade recurrence after BCG or while on BCG, then I think the balance shifts and there it’s really an individual decision. I have plenty of patients who have carcinoma in situ after their induction maintenance BCG who say, “Yes, please take out my bladder,” and many who want to try something else before we take out the bladder. It’s an individual decision.

Stephanie Chisolm:

So instead of going through the BCG induction, which can be very toxic for some patients, they have a really hard time handling it, what is your take on just monitoring that’s used in case… the case you described, the 87-year-old. Would this have been something maybe you would’ve discussed just monitoring with him and just keeping an eye on it over time?

Dr. Peter Black:

Yeah, so I think for sure we do that. I think if this patient had had a high grade Ta tumor, so a defined pathway tumor that we completely resect, we probably would’ve said, “Well, let’s monitor it. If it comes back, we can do BCG, but let’s find a balance of less treatment burden in an older patient with significant medical problems.” Here, the motivation to treat was really the fact that it was carcinoma in situ and certainly had the discussion. Carcinoma in situ is at risk for progressing to something more invasive, but it’s not really short-term risk, it’s over a few years. If you have an 87-year-old patient with a lot of medical problems, you might say, “Well, let’s see what happens,” but it’s very unpredictable. This patient certainly was motivated to try and prevent that.

Stephanie Chisolm:

If you were to find carcinoma in situ in a small area like in the diverticulum, have you ever considered doing a partial cystectomy? I know that’s really rare to do that, but is that something that would come up if it was really contained in one spot or is CIS so pervasive that you might not know that you’re not seeing it everywhere, as you showed very succinctly with the two enhanced images, you could see it much better with the enhanced imagery? Would you ever consider a partial cystectomy?

Dr. Peter Black:

Yeah. The official answer is no, because you know specifically with carcinoma in situ that it’s a diffuse disease and you would anticipate that it’s not only in the diverticulum, and so you wouldn’t be treating it adequately. I can say from personal experience, I did it once in a patient who had a lot of medical problems. And one other issue about a diverticulum is that you don’t necessarily think that the BCG’s going to work well. You don’t know how it’s going to get into that diverticulum and is it actually going to work? But this patient had really a prohibitive risk for doing a cystectomy, so I did a robotic partial cystectomy for his carcinoma in situ, and six months later, he had recurrent carcinoma in situ in the rest of his bladder. I demonstrated what we would say would probably happen and we would definitely not encourage it.

Stephanie Chisolm:

Okay. There’s a lot of research into potential causes of bladder cancer. We know that it could be exposure to chemicals, whether it’s in your environment or occupational exposures. Is there anything known that’s specific as a risk factor for CIS that makes you more prone to this sort of flat type of a tumor rather than any other type of bladder cancer tumor?

Dr. Peter Black:

Yeah. Hikmat, I don’t know if you want to comment on that.

Dr. Hikmat Al-Ahmadie:

Yeah. I mean, I don’t think it has kind of been studied that way. It’s grouped with all the different bladder cancers, and with the known risk factors, but I’m not aware of any particular exposure pattern or a professional exposure or something that can produce CIS per se, versus a more invasive disease. I don’t know. Do you have any other insights, Peter?

Dr. Peter Black:

Yeah, no, I think we think of them as all being relatively the same and that we think of muscle-invasive bladder cancer, for example, and probably T1 as well, that may have started as carcinoma in situ, and so we think the risk factors are the same.

Stephanie Chisolm:

Okay. Thank you. That’s really helpful. So you have shown very clearly how you as the urologist are working very closely with the pathologists to understand what’s going on with this particular tumor. Is it normal to perhaps get a second pathology opinion on the samples or are you in a relationship with the pathologist that you’re using that you really trust that they’re doing a really good assessment of what comes next for that patient in terms of understanding that cancer?

Dr. Peter Black:

I would say yes and yes. You tend to trust your pathologist, but it’s still probably worthwhile getting a second opinion. Now, if you’re at a place like Hikmat’s place, where you have top of the line, GU dedicated bladder pathologists, maybe you don’t need a second opinion. I’m speaking for Hikmat here, but I imagine that Hikmat gets his own second opinions from his colleagues if he needs them. But I think for sure we know if just in general, community practice compared to what an expert pathologist like Hikmat would say that you would find things that the first pathologist didn’t see. Maybe Hikmat can comment more on that.

Dr. Hikmat Al-Ahmadie:

Yeah. I mean, I think it’s encouraged honestly, because it’s a field that relies on visual, identifying abnormal features in the tissue, and the more you see of something, the better you get at it. So that’s one thing. And also, patients now are more engaged, more involved in their care. They read. They always feel like maybe I wanted to be sure before I embark on something. So there are different things that can prompt a second opinion. We do see, as I said, we do see a fair share of cases. Good news is most of the times, we agree. Whatever that initial pathologist found, most of the times we can confirm. There are some times when there are things that are subtle in some cases that are more subtle than others.

Dr. Hikmat Al-Ahmadie:

Sometimes we may have more history than the outside community hospital, so that can help us identify things that might have been overlooked or missed by an outside pathologist. So I think the key to always lower the threshold of asking for another opinion, and I have to say also, admit that we do get sometimes our cases sent out for another opinion. It’s not like we’re immune. Again, this is a very important decision that a patient wants to make, and they want to always make sure that nothing has been overlooked, so people ask for it and it goes to someone else and most of the times of course they agree with us, but yes, it happens both ways. The main thing is always when something doesn’t make sense, especially you’re a treating physician and then they get an unusual pathology report that does not necessarily fit the clinical picture, that can also prompt a second opinion. And sometimes it’s unusual for a reason and sometimes it could be over-called or a misdiagnosis. So, yeah, these are multiple scenarios, but it’s always better to have another opinion.

Stephanie Chisolm:

Especially in pathology, because I don’t think people think about that. Like, “Well, can you send this for some other expert to take a look at it?” They sometimes ask for a second opinion from the treating physician, but I don’t know that they necessarily think, “I should get a second opinion on my pathology report.” That’s really good information. I know we’re just about at time, and I don’t want to keep you too long, but let’s see if I have one more question. There was a question about biomarker monitoring as far as things like Cxbladder to monitor and clarify if there’s any atypical cytology. Is that ever used to monitor for CIS?

Dr. Peter Black:

It’s a good question. I would disclose that we don’t use any of these markers in Canada because they’re not routinely available. So my own personal experience is limited, but I think that cytology is used universally. I did see the question about… basically the question what’s the sensitivity of cytology? How likely is it going to reveal that there’s cancer there? Then it was pertaining to a case where the cytology was what missed a cancer, but so from a sensitivity point of view, it’s not very good, but it’s very specific, so if the cytology is positive, we’re confident there’s something there, and so we use it as an adjunct to make sure we’re not missing something.

Dr. Peter Black:

Something like Cxbladder is much more sensitive, so it’s more likely to detect something, but it’ll be less specific, meaning you could end up at a lot of false positive tests that you subsequently are working up. But in general, I think a patient with carcinoma in situ, there’s potentially more value for biomarkers because it can be invisible.

Stephanie Chisolm:

Thank you so much. This has been wonderful. I really appreciate it. I remind everyone that you will be getting a short survey. Please be sure that you provide your input on today’s program. Dr. Black, Dr. Al-Ahmadie, I really do appreciate everything that you’ve done. I’d like to thank our sponsors again: Genentech, Merck, the EMD Serono/Pfizer partnership, Seattle Genetics, Astellas partnership, UroGen and Bristol Myers Squibb for their contributions to make these programs available, and remind everyone that there are plenty of other programs recorded, transcribed and available on our website, BCAN.org. Thank you both so much. I look forward to seeing you at our think tank this summer, and you also provided a whole lot of great ideas for further followup, so I may ask you to come back again in the fall to do more programming, because it’s been a wonderful program. Thank you so much.

Dr. Peter Black:

Always a pleasure. Thank you.

Dr. Hikmat Al-Ahmadie:

Yes, pleasure.

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