Webinar | What’s the Deal with Carcinoma in Situ (CIS) and Why Does It Matter?

January 23, 2026

In this webinar, Dr. Eugene Pietzak and Dr. Andres Matoso will explain what carcinoma in situ (CIS) of the bladder is, how it differs from other types of bladder cancer and early changes in the bladder lining, and why it can be especially challenging to diagnose and treat. You’ll also learn what researchers are discovering about how CIS develops and how these insights are shaping current and emerging treatment approaches.

Year: 2026

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Full Transcript of Webinar | Understanding ctDNA Testing in Bladder Cancer: What It Means for You

Patricia Rios:  

I want to welcome all of you to BCANs, or the Bladder Cancer Advocacy Network, Patient Insight Webinar series. Again, my name is Patricia Rios, I am the director of education advocacy here at BCAN and your host for today’s webinar on What’s the Deal with Carcinoma in Situ, and Why Does it Matter? Carcinoma in situ or CIS is a type of bladder cancer that can be tricky to understand. It doesn’t form a lump or tumor you can see, it grows flat along the bladder lining, which makes it harder to detect and treat. Doctors sometimes disagree on how best to diagnose and manage CIS or carcinoma in situ, which can be confusing for patients. In this webinar, Dr. Pietzak and Dr. Matoso will explain what carcinoma in situ or CIS is, and what researchers are discovering about how CIS develops, and how these insights are shaping treatment approaches.

I would like to begin by introducing our phenomenal speakers for today. I will first introduce Dr. Pietzak, Dr. Eugene Pietzak is a urologic oncologist at Memorial Sloan Kettering Cancer Center in New York, who specializes in the surgical treatment of bladder cancer and upper tract urothelial carcinoma. Dr. Pietzak is also the principal investigator for multiple investigator-initiated clinical trials for patients with non-muscle invasive bladder cancer.

Joining Dr. Pietzak is Dr. Matoso, who is a professor of pathology, urology, and oncology at the John Hopkins University School of Medicine, and serves as director of the Urologic Pathology Division and the Genitourinary Pathology Fellowship Program. He’s a leader of the Johns Hopkins Urologic Pathology Consult Service, one of the largest in the world. Dr. Matoso also authored more than 170 peer reviewed publications, contributed to the World Health Organization classification of tumors, and is an internationally recognized speaker and educator. So at this moment I am going to hand over the screen to our presenters, we will first hear from Dr. Matoso, and directly after that we’ll hear from Dr. Pietzak.

Dr. Andres Matoso:

So, thank you so much for the introduction and the opportunity to be here today to talk about this very important topic, CIS.

Dr. Andres Matoso:

The objectives of my presentation, I’m a pathologist, even though I have appointments in urology and oncology my main work is in pathology. So, my idea today is to show you what CIS is and why is it different than other types of cancer, how does it differ and how does it grow differently than other types of bladder cancer? And why is CIS difficult to diagnose from the pathology point of view? So the goal of all this is to help patients understand what CIS is, and this will help you better understand your care and all the different steps that you have to go through

Dr. Andres Matoso:

to manage this disease.

Dr. Andres Matoso:

So first, introduction about the bladder, most of you probably already know this because it is your disease or your loved one’s disease so you probably have informed yourself. But the bladder has different layers, and what we’re going to be talking about is the more most inner layer of the bladder, which is the urothelium. This is the lining that covers the bladder and protects the urine to be kept in place. And this is where the cancer starts, in that lining.

Dr. Andres Matoso:

So it happens, bladder cancer happens when that lining or that urothelium grows out of control. But, It can form tumors, lumps, as in any cancer. But the difference with CIS is that that tumor is flat and it sort of merges with the normal lining of the mucosa, so it’s hard to see.

Dr. Andres Matoso:

And I’m going to show you some examples.

But by definition, CIS is high-grade cancer. The cytology or the features of those cells are of high-grade, and I’m going to show you why. And these tumor cells are confined to that lining, it’s as if they were hiding or mimicking the normal cells. They grow in a flat way, they don’t form a lump or a tumor, and it’s considered aggressive. It’s considered aggressive because it has higher chances of invading than the papillary tumors or the other type of cancer. Also, when it invades sometimes it’s not seen because it doesn’t form a lump.

Dr. Andres Matoso:

So, as I was mentioning, it grows along the surface like a rash, it’s similar to a rash on the skin. But the difference with the rash is that this is not visible, when the urologist goes inside the bladder they can, often they cannot see. All that they see is a little bit reddish area if they are lucky to see that, but it’s not a very sensitive feature so it’s not always present. It can also involve large areas of the bladder lining, and in multiple different large sites in a discontinuous way. It can also line the urothelium of the urethra that goes into the prostate and grow into the prostatic ducts in a way that is impossible to see with a cystoscopy.

So all these are the natural way the tumor grows and why is it difficult to, to diagnose.

Dr. Andres Matoso:

So here is a table to summarize those features, CIS versus a typical bladder tumor that makes a lump or a papillary tumor. And the shape, the CIS is flat, while the tumor makes a mass, it can bleed, it has a papillary structure. The CIS is difficult to be seen, while the tumor can be easily be seen. CIS is always high-grade, the tumors can be low or high-grade. And the risk of progression with CIS is high, while the typical bladder tumor can be variable based on the grade. But CIS is always, by definition, high-grade.

Dr. Andres Matoso:

Now how is it diagnosed? It always requires tissue examination.

Dr. Andres Matoso:

So first I’m going to describe, this is a histologic view of a normal bladder mucosa where you see the lining, the urothelium has up to seven layers of cells. And the nuclear size of those epithelial cells, these are the nuclei, are small. When we compare it to a lymphocyte, this is a lymphocyte, lymphocyte is an immune cell, these nuclei are two times the size of those lymphocytes, but not larger. They also have a polarity. Polarity means that these cells recognize where the floor is and where the sky is. So for them they have that orientation that is standing up because they have sort of, supposedly feet underneath and then the head and the body on top. So that is what I refer by polarity, that the cells know where the base is and where the roof is. So they have that orientation, and that’s the normal orientation, normal polarity of those cells.

There are some cells on top that are called umbrella cells. Those are also normal, and they cover the surface. And the role of those umbrella cells is to form a tight junction on the surface to avoid the urine to leak through the lining or the urothelium.

Dr. Andres Matoso:

Now when we have CIS you can see now that we have way more than seven layers of cells, all these are nuclei. Also, the size is huge. They have more than three times the size of lymphocytes. They have frequent mitosis, these are mitosis because they’re replicating a lot, they’re growing out of control. The polarity is lost. Some of these cells are very round, some of them are facing sideways. They do not respect each other’s boundaries, their nuclei overlap, and they grow so fast that they crawl all over each other, and then the frequent mitosis. So this is a high-grade cancer that is lining now the bladder mucosa, and that’s CIS.

Dr. Andres Matoso:

Now why is it difficult to diagnose? Because the pictures I showed you, it seems very easy to recognize those two separate entities.

Dr. Andres Matoso:

Well one of the properties of CIS is that those cells become discohesive, meaning that they can become very loose with one another. Instead of staying attached to their neighbors they lose that attachment. That is a property that cancer cells acquire so that they can move, and migrate, and do their job of invading other tissues. Now when that happens the cells can completely detach from the bladder mucosa. And as you can see here, you have the base of the urothelium, but there is no urothelium so because there’s extensive denudation of that bladder mucosa. This patient had presented with hematuria, pain in the bladder, they go and do a biopsy, and there are no cells. So when we have this finding we cannot make a definitive diagnosis, but we suggest that denudation could be a sign that there is CIS.

Dr. Andres Matoso:

This is an example of what’s called clinging CIS. In this case, instead of all the cells being shedded off, because of this cohesiveness we have still one single layer of cells at the base. Now when this happens sometimes it’s difficult to appreciate the atypia or the nuclear size of these cells, and making a diagnosis can become difficult for general pathologists that are not used to handling this kind of a difficult cases on a daily basis.

Dr. Andres Matoso:

Sometimes the bladder, the normal cells will repopulate the lining, as you see here with the smaller cells, and then you have CIS in a pagetoid manner. So some of the cells are CIS, but the majority of them are not CIS.

So this can also create a lot of uncertainty when these cells are not that abundant, when we have only a few, and they might be more difficult to arrive at a diagnosis that is very serious. So we do not make the diagnosis unless we are 100% sure. This case is for illustration purposes, and it’s easy because you even have mitosis, but you can see how the cells of CIS compared to the normal urothelial cells, how much bigger they are. And also they are atypical and they’re round, so they have lost their polarity.

Dr. Andres Matoso:

Now this is perhaps the most difficult of the situation, what is called dysplasia. Dysplasia is a urothelium that is abnormal because it has some cytologic atypia, but it’s not as overt as in the cases that I showed you before of CIS. So these are sometimes considered precursors of low-grade papillary urothelial carcinoma. It’s also a flat lesion, it’s also atypical to be flagged, but it’s not atypical enough to make a diagnosis of CIS. And why we do not, we want to prevent over calling CIS in all the patients. So once we make a diagnosis of CIS we like to feel 100% comfortable because we know it has a significant implications for the patient. So when it looks atypical but it’s not as severe a CIS, we call it dysplasia.

What do they do? The urologist, what do they do with dysplasia? If the patient already has a diagnosis of CIS before they know that it could be coming back. If it is a first-time diagnosis they will follow up that patient with a repeat cystoscopy, with urine cytology in order to confirm the diagnosis of CIS when that is enough to be diagnosed.

Dr. Andres Matoso:

So here is the management that I was mentioning in someone without a history of CIS. With a history of CIS this indicates that the disease is coming back. In someone who does not have CIS and is a de novo diagnosis of dysplasia, this is considered a precursor of low-grade papillary urothelial carcinoma. The patient is followed up for the development of cancer, so they’re followed more closely in a potential conversion to CIS.

Dr. Andres Matoso:

Now another difficulty for us is when the urothelium shows reactive changes. Reactive changes means the urothelium is trying to regenerate and fight infection or a source of inflammation.

Dr. Andres Matoso:

And the problem is that the cells become large, but they have associated inflammatory cells. So here we have several of the features of CIS, the nuclei are large, the polarity is lost, and the thickness could be increased, but there is associated inflammation, you can see neutrophils here. And this needs to be recognized, that inflammation, because some of the nuclear changes could be secondary to this inflammation. So when we have atypia to the point that we think it could be CIS but there is associated inflammation, our threshold for calling it CIS significantly increases. So we want to see very marked atypia. So some of these patients might have already CIS, but the presence of inflammation prevents us from completely excluding a reactive process secondary to that inflammation. And therefore, in those cases, the patient needs to get a repeat biopsy after they have treated that inflammation, either with antibiotics or other measures.

Dr. Andres Matoso:

We use immunohistochemistry to diagnose CIS, and some of the markers are mentioned here like CK20 or Cytokeratin 20 and P53. There are different patterns of stain that can aid in the diagnosis of CIS.

Dr. Andres Matoso:

This is Cytokeratin 20 normally stains the umbrella cells but not the rest of the urothelium. And this is a normal pattern of CK20.

Dr. Andres Matoso:

While in CIS, Cytokeratin 20 stains the full thickness. This is a finding that is present in approximately 80% of the cases of CIS.

Dr. Andres Matoso:

We can also use P53, which is a tumor suppressor protein. P53 normally is expressed in low levels in the nuclei of cells, but when there is a mutation, which is one of the most frequent genetic alterations of high-grade urothelial carcinoma, then P53 becomes over expressed in the cell and accumulates in the nucleus, but it’s non-functional because it’s mutant.

Dr. Andres Matoso:

And then that leads to over expression of P53, and you see here in brown how those large nuclei over express P53. So in those cases where we are dealing with reactive versus CIS, immunohistochemistry for Cytokeratin 20 or P53 could help in supporting a diagnosis of CIS.

Dr. Andres Matoso:

Here is an example of a very inflamed urothelium. It looks atypical, the nuclei are angry, but there is a lot of inflammatory cells so we’re not going to make a diagnosis of CIS in that setting.

Dr. Andres Matoso:

When we do P53 we see certain degree of expression, but it’s less than the one that showed you with CIS. But this could be also difficult to interpret because there is significant expression of P53 in those cells.

Dr. Andres Matoso:

Now I mentioned that not all cancers or CISs are positive for Cytokeratin 20, and we conducted a study to look at the Cytokeratin 20 negative CIS that is approximately 20% of the patients have that Cytokeratin negative CIS agent.

Dr. Andres Matoso:

And you can see here the thickness is increased, the nuclei are large, there is loss of polarity, so it has all the features I described of CIS, but it does not express CK20.

Dr. Andres Matoso:

So, in about 20% of the patients the CIS cannot be diagnosed either with the use of immunohistochemistry. And when we looked at the survival curve of those patients, they have similar progression and death due to disease secondary to CIS that is CK20 negative. So for those pathologists that rely too much on immunohistochemistry, they could be missing up to 20% of cases of CIS.

Dr. Andres Matoso:

Also, from the pathology perspective, and this is more merging into the sign of therapy, we looked at the immune system and how that could affect response to BCG or therapy, and basically patients with increased PD-L1 expression are enriched in the group of patients who do not respond to BCG. So some additional immune microenvironment studies could help better select which patients could be best candidates for BCG versus BCG plus other type of therapy.

Dr. Andres Matoso:

So as a summary of my presentation and what I would like you to remember is that CIS is flat, high-grade cancer always by definition, looks differently, behaves differently than other types of cancer. It may be hard to diagnose because we don’t see it, but then also when we see it and we take a biopsy there are very different tricky situations that could prevent a definitive diagnosis in multiple instances, and in those situations we always recommend getting a second opinion because of the high implications that this diagnosis could have and that could impact therapy and the outcome. And with this I’m finishing my portion of the pathology, and I pass it on to Dr. Pietzak. Thank you.

Dr. Eugene Pietzak:

Hi, so as mentioned, I’m Eugene Pietzak, I’m one of the urologic oncologists focused on bladder cancer at Memorial Sloan Kettering. It’s nice to see everyone, thanks for joining tonight.

Dr. Eugene Pietzak:

So, I’ll talk more about the sort of clinical implications of carcinoma in situ, as Dr. Matoso just gave a very good overview of the pathological implications. Clinically at least, so carcinoma in situ for someone with newly diagnosed bladder cancer, it typically exists more commonly with papillary tumors, the sort of lumps that was just described where it’s more visible. It’s fairly uncommon alone at the initial diagnosis. So of all the individuals diagnosed with high-grade, non-muscle invasive bladder cancer, somewhere between 20 to 30% of individuals will have a high-grade papillary tumor with carcinoma in situ, where somewhere around 70% of people will not have that CIS component.

And as was well emphasized, a lot of it also depends on the pathologist report and their read, and that varies from different centers and different pathologists reviewing it. But pretty consistently, in the literature at least, carcinoma in situ alone as an initial diagnosis is pretty uncommon, it’s typically less than 10% of individuals. And we’ll discuss, but usually that may be missed for a while and because some of the symptoms may be more irritative urinary symptoms, urgency, frequency, burning with urination. Because there’s not a visible mass seen it is not uncommon for urologists in the community to sort of treat that as a urinary tract infection, and so those individuals tend to have what appears to be a bit of a delay in their diagnosis.

So after someone with initial high-grade, non-muscle invasive bladder cancer that potentially gets treated with BCG, which we’ll discuss in some of the subsequent slides, carcinoma in situ then begins for those that have recurrent cancer to become more prevalent, and it almost continues to increase with high-grade recurrences where it reaches somewhere between 40 to 70% of individuals when they sort of develop this more BCG resistant disease. And it is fairly uncommon for someone with a low-grade bladder cancer to develop carcinoma in situ in a subsequent recurrence, but that is something that is potentially possible but typically it’s associated with high-grade recurrent disease.

Dr. Eugene Pietzak:

And it is more common in the recurrent situation to be alone just carcinoma in situ in the papillary tumor, the visible lump tumor, are sometimes not present in the recurrent setting and it’s just the carcinoma in situ only.

So, it is somewhat more resistant to treatment for various reasons, and that’s in part because the endoscopic resection, the scrapings, are less effective for carcinoma in situ. So as I sort of alluded to, the symptoms of carcinoma in situ, they’re typically absent, most people with carcinoma in situ besides having say blood in the urine, which is more common with papillary tumors, the symptoms seen are typically urinary urgency, and frequency, and burning. And a lot of these symptoms overlap with urinary tract infections, radiation changes that someone may have received or inflammation, but most patients typically feel well. And as I think most people on this call probably know, blood in the urine is the most common presenting symptom for bladder cancer in general, but that’s less common for the flat carcinoma in situ just because they don’t have as robust as a blood supply.

Dr. Eugene Pietzak:

So, you know, carcinoma in situ from a clinical standpoint where we’re doing cystoscopies is actually pretty hard to identify sometimes and the cystoscopy may look relatively normal, and we have to often use these technologies known as enhanced cystoscopy, which I’ll show you in a subsequent slide what that means exactly, but it’s special light filters, either narrow band imaging or blue light cystoscopy that may better highlight features of carcinoma in situ, but sometimes we can see these flat velvety type lesions and identify them. And you know, even though we may suspect there’s carcinoma in situ, even if we do what are sometimes referred to as random bladder biopsies, we will not be able to actually identify it. Or sometimes what is carcinoma in situ may be dismissed for either inflammation or just a sort of an aspect from infection or vice versa.

So it can definitely be very challenging and we will check urine cytologies, which are basically the urine sample that gets spun down and look to see if there’s cancerous cells in the urine underneath the microscope, that’s called a urinary cytology. That may sometimes be positive or it may sometimes be negative even when there’s carcinoma in situ. So there’s not a perfect test clinically to determine whether or not there’s carcinoma in situ present, and we’re really dependent upon the urologist visibly seeing an area to biopsy because the first step in the management, you have to find it before the pathologist could even identify and classify it as carcinoma in situ, which can be very challenging. And sometimes because of the way carcinoma in situ is, it may get shed into the urine. And when we do the biopsies it may come back with what’s known as denuded mucosa, meaning that lining Dr. Matoso just showed you, has already shed into the urine and there are no more carcinoma cells present. And so it can be a challenging clinical entity to diagnose.

Dr. Eugene Pietzak:

And these are just some examples that I actually pulled from the internet, because oftentimes I’ll tell you the images don’t ever really look as good as this.

All right, so this is a white light cystoscopy over here. You can hopefully see that this is a papillary tumor, it’s this lump you could visually see. These are smaller ones, these are quite obvious and in the dynamic cystoscopy these are very evident. But what’s a little bit more subtle is if you go to the blue light where this is, it’s basically you can think of it as like a fluorescent dye that gets instilled about an hour before the procedure and cancer preferentially takes it up, and then under a special blue light wavelength they fluoresce, as you could see here, and they show a bright orange. And so what is a little bit more evident is that this area over here, these little orange patches, these fluorescent patches, that’s carcinoma in situ. And if you look back on the white light you can kind of see where those core respond to, but they’re definitely more subtle on white light, it is far more challenging to identify it. So this is a nice bit of technology to do.

And this is another form enhanced cystoscopy called narrow band imaging, this is just changing the filter on the camera source itself, does not require that extra installation, and it’s often a little bit more subtle, and I would say probably users need more experience compared to blue light where it’s more obvious on blue light cystoscopy. But if you noticed over here you could kind of see that this is a flattened lesion over here, and then on narrow band imaging the narrow band really highlights the capillaries, the blood supply that’s around there, and you get a little bit more of this blue-green contrast, and you could see the borders of where the carcinoma in situ is. So these are very helpful adjuvants in order to identify what needs to be biopsied, but the urologist needs to be thinking about these and they need to be looking for these very diligently. And these are things that if someone’s doing a cystoscopy very quickly, or if there’s a large tumor that’s very obvious, it’s papillary that they’re focused on and they’re not looking for carcinoma in situ, this is something that could easily be overlooked.

Dr. Eugene Pietzak:

So, carcinoma in situ, as I mentioned, it’s difficult to diagnose, and it can be very challenging to treat as well. At least the way that I conceptualize and think about carcinoma in situ, it’s a disease of the lining of the bladder, and it’s often not just in one spot. The way that I think about it is the carcinogens that led for the bladder cancer to develop, the carcinoma in situ to develop, the entire lining of the bladder, as well as the ureters and the urethra, were all exposed to that and so they’re all prone to developing it because of that carcinogenic insult. And so it sometimes can spread beyond the bladder into the ureters, the renal pelvis, the urethra as well, especially with treatments like BCG and other treatments, intravesical treatments into the bladder that do not reflux up into the ureters or into the urethra itself. So those are things that the urologist needs to be mindful of to look out for essentially.

So the TURBT, the transurethral resection, may be sufficient treatment for papillary tumors because they could visually see it, but it’s often insufficient for carcinoma in situ, and that’s why the intervescal treatments, the treatments into the bladder, are so essential.

Dr. Eugene Pietzak:

So, these are some cartoon versions of at least how I think about the cancer. And so just to sort of demonstrate, if you look over here in this lightish blue area, like the lining of the bladder in this area is probably more of this dysplasia or pre-dysplasia scenario that Dr. Matoso was just talking about, and then they accumulate more mutations. And what may only be visible is this papillary tumor, but sort of the surrounding urothelium, the surrounding lining of the bladder, may have carcinoma in situ or may have dysplasia, sort of the pre-carcinoma in situ type entity. And it can be very diffuse, it can be spread out, it can be multifocal, and it makes it more challenging to diagnose as well as treat.

Dr. Eugene Pietzak:

And so the standard first line treatment is BCG, which is a live but attenuated bacteria. It’s microbacterium bovis, it’s been used for 50 years now since 1976, and it does remain the most effective first line treatment for carcinoma in situ. And the success rates with that are somewhere between 60 to 80%, and that certainly increases when maintenance BCG is given. And it does require frequent monitoring.

Dr. Eugene Pietzak:

I won’t kind of belabor this but this is the original publication from 1976, and this is some nice cartoons of how this bacteria gets preferentially taken up by carcinoma cells like carcinoma in situ, and then allows the body’s immune system to recognize the cancer as being foreign and starts to attack it. And it gets instilled in, as I mentioned, it is literally a bacteria. So the symptoms of it that, many of you may have experienced, are very much like mild urinary tract infections with urinary urgency, frequency, burning with urination, et cetera.

Dr. Eugene Pietzak:

Many of you are probably also aware that there is a BCG shortage, and this is kind of the timeline. I won’t kind of belabor this too much but there is what appears to be light at the end of the tunnel after well over a decade of dealing with the shortage. There is this new factory that is supposed to be completed by Merck, hopefully within the next six months or so, and that’s supposed to hopefully resolve the BCG shortage and it’ll become more available. And this is just some details as to why the manufacturing of BCG has been so challenging.

Dr. Eugene Pietzak:

So when BCG does not work as the first line option, historically radical cystectomy was really the only effective treatment option. And to be forthright with you, it still remains the only definitively curative option for BCG unresponsive carcinoma in situ, but there’s been major advantages and there are numerous potential available options at this point.

Dr. Eugene Pietzak:

I won’t go through each one at this point in time because the way these drugs have been FDA approved, it’s all through single arm, non-randomized trials, and it is impossible, and I think often misleading, for people to try to make head-to-head direct comparisons across these trials. But with this designation of BCG unresponsive carcinoma and situ, which we won’t go into there’s not enough time, there has been an increasing number of available treatments, and there will be, I think, several more that will be options. And there’s also several chemotherapy options as well that are put into the bladder that are used off-label in the so called real world, and then carefully selected individuals re-treatment with BCG may be a very viable option.

Dr. Eugene Pietzak:

So to the point that I was kind of making with BCG unresponsive treatments, which one is best for an individual patient, I personally think it’s nearly impossible to figure that out, and that’s because of all the reasons I was just talking about. It is difficult to identify, there’s various different quality metrics for TURBT that’s questionable about how these single arm, non-randomized trials could have been conducted. And as was just eloquently highlighted, it also depends on who the pathologists are, and there’s different pathologists across these different trials. There’s different patients who are being enrolled in these trials, they would have got different treatments and a different amount of carcinoma in situ, and I think that all matters. And there’s also substantial variation in the clinical trials, and what was treatment failure in one trial may not have been considered treatment failure in another. Some allowed re-treatment, some mandated biopsies versus others. So again, it’s just emphasizing that there are treatment options available, but it’s hard to say which treatment is better than another.

Dr. Eugene Pietzak:

And I just put this up as well because we now have all these newer treatments for BCG unresponsive CIS, and generally I feel that most patients, it’s safe to try at least one or two lines of therapy, but I think we also should not ignore the fact that radical cystectomy is a potentially definitively curative option for patients who are able to undergo it and willing to. And almost regardless of the urinary diversion option, we do see that patients do bounce back and do have very good quality of life, patient reported outcomes after cystectomy, after that initial period of time.

Dr. Eugene Pietzak:

And I think just highlighting this is a BCAN involved initiative by Angie Smith and John Gore, the CISTO study, that was a non-randomized comparison between individuals with BCG unresponsive disease, BCG failure, choosing between bladder sparing therapy and radical cystectomy.

And I think not surprising to us at MSK, but I think what was pretty surprising to others was that the quality of life for a lot of people ends up being better for those that undergo radical cystectomy for various different reasons, and I think this is a good discussion point that people should be aware of. But what I always emphasize with my patients at least is it does take two to three months at least to recover from the surgery, with the expectation that hopefully they’ll be able to put things behind them and move on. But I do believe that a lot of patients with non-invasive recurrences, it is reasonably safe for most patients to try a couple lines of therapy.

Dr. Eugene Pietzak:

So moving forward there’s now efforts to try to improve treatment strategies because although we now have some FDA approved treatments, without going too much into it, very few of them are actually durable and most of the results we’re only seeing is about 12 months to less than two years essentially. And so unfortunately recurrences are still continuing, so we need better treatments for sure. And so some of them are focused at immunotherapies to improve the immune response, some of them are focused at improving chemotherapy delivery and combinations. What I personally think is most interesting are combining both chemotherapies and immunotherapies as well, especially with BCG, with the goal of developing durable, long-term responses without the need for surgical removal of bladder, without the need for cystectomy.

Dr. Eugene Pietzak:

So just highlighting one of them, and just selfishly, because I’m the principal investigator for this national trial, but also because a lot of the preliminary data was supported from BCAN and kind of highlighting that the effort, and the research initiatives, and the funding from BCAN really can make an impact. And also a lot of the BCAN patient advocates, who hopefully are on this call, did provide feedback on this trial that I found incredibly helpful. So if anyone ever on this call has the opportunity to do that, it is very helpful for clinical trialists like myself to hear from you about what is something you like or don’t like about a trial to make it so it’s very patient centric, really. So this is just the GAIN study, which is combining intervesculal gemcitabine with BCG for individuals who have previously been treated with BCG but their cancer came back, and the current standard of care is re-treatment with BCG alone. And so that’s just one example of a trial that’s up and coming.

Dr. Eugene Pietzak:

Other research efforts are also on finding better ways to detect and monitor carcinoma in situ, and a lot of these are more and more focused on urine. So urine-based molecular tests are coming forward with the idea that maybe we could avoid potentially doing as many cystoscopies, as many biopsies, and potentially detect and better personalize the frequency of surveillance systems.

Dr. Eugene Pietzak:

This is another example of work that our group is doing that was supported, again in part by BCAN, the Young Investigator Award that I had previously won. And so this is looking at carcinoma in situ identified by the urologic oncologist, as well as the genital urinary pathologist. And this is what’s called the Kaplan-Meier curve, just very quickly, 100% of people cancer-free, 0% of people cancer-free, and then just followed over time. And as you could hopefully see, the red bar is no carcinoma in situ, the blue bar is yes carcinoma in situ, and what you could see is like these curves are relatively overlapping.

So at least in this group of individuals who are receiving BCG for the first line, we did not see the standard carcinoma in situ biopsy and identification being able to say this individual is more likely to recur after BCG or not. But what we did is we collected urine samples after the TURBT but before their BCG, where it would be thought that this would be residual carcinoma in situ cells. And what this Kaplan-Meier curve demonstrates is that if there are no detectable mutations that were seen in the urine, essentially none of these patients, and I think there was about 20 something or so patients, none of these patients recurred over time. Where if there was detectable mutations, presumably from carcinoma in situ, we saw that nearly 50% of patients recurred almost within the first year. So this is an area that our group’s interested  in and many others as well, but we are really all trying to do a better job of detecting carcinoma in situ and monitoring the response.

Dr. Eugene Pietzak:

And so just with my final slide, CIS is difficult to see and identify, it does often require some degree of expertise to identify and to make sure it’s treated properly. BCG is still, in my opinion, and guidelines, et cetera, the most effective first line option. But when we start to get into the second line options that’s where it becomes more individualized. And there are many bladder preserving options that now exist for BCG unresponsive CIS, and that patients should ask about these available options, including clinical trials. And it is all about shared decision making in this situation and figuring out what’s best for each individual patient, and this is improving. And then I’m very excited about the role for urinary biomarkers in this space.

Dr. Eugene Pietzak:

So with that, I thank everyone for their time and attention.

Patricia Rios:

Thank you both for such a comprehensive presentation. There was a lot of good content to cover over the past 40, 45 minutes, and I want to remind our listeners that the presentations or this webinar is being recorded, so you can re-watch this over and over again and capture any information that you may have missed. So we have several questions in the chat, and I’m going to filter those over the next 10 to 15 minutes. First, I wanted to go back to talking about the definition of high-grade, I think there’s a little bit of confusion as to how is high-grade defined versus low-grade? What is that classification? If you could explain that for us, perhaps starting with Dr. Matoso?

Dr. Andres Matoso:

Yeah, so high-grade means it’s a morphologic assessment we do when we look at the cells. We look at certain morphologic features and nucleus size, certain features that the pathologist looks at and basically classifies them in high-grade versus low-grade. CIS is always high-grade, and high-grade in bladder cancer, what it means is that it has higher chances of invading. So if you compare high-grade with low-grade, they both have similar recurrence rate, but high-grade can recur with a higher stage. It can recur with invasion, so there is higher risk of invasion. And CIS, particularly even compared to papillary high-grade, has a higher rate of invasion compared to papillary high-grade that is noninvasive. So it is high-grade, and within the group of high-grade tumors also has a higher chance of invading.

Once it has invaded it can metastasize. No tumor that is noninvasive will metastasize, so the risk of metastasis occurs only after invasion. And once it has invaded basically the grade doesn’t matter anymore. Both low-grade and high-grade has risk of invasion, once it has invaded the grade really doesn’t matter that much, they both get treated the same. But the risk of low-grade versus high-grades is to stratify which patients have higher risk of progressing to invasion versus staying as non-invasive.

Patricia Rios:

Thank you, Dr. Matoso, for elaborating. Related to that, Dr. Pietzak, I don’t know if you’d like to address this one, CIS and MIBC are both present at the same time or would you say one has non-muscle and then it progresses to muscle depending if it’s with the grade?

Dr. Eugene Pietzak:

So by definition CIS is a non-muscle invasive bladder cancer. So as I was trying to articulate, about 10% of CIS at initial diagnosis exist on its own, but the majority of patients with CIS will have a papillary component associated with it. So they sort of coexist and that picture I kind of showed, I view it as almost like this ocean of cancerous changes in the lining of the bladder, and through a series of mutations that likely happen, all of a sudden like an island starts to appear within that sea. And you could see the papillary component very clearly, but if you look very closely, and especially if you’re using either narrow band imaging or blue light, you could see sort of almost a halo around most of these tumors.

And so at least when we have trainees who are observing our ORs, the teaching point we always make is that you want to go wider than you think, than you could visually see, and we’ll toggle back and forth with the different white light and the enhanced cysto aspect, so you’re ensuring that you’re resecting the margins and removing the margins. What’s tricky about carcinoma in situ is you’re working in one area and there could be a microscopic amount of CIS in the other area, and that’s potentially also missed with the enhanced cystoscopy techniques because they’re so microscopic or they’re getting shed in the urine and it’s not being identified. And that’s kind of why I think the urine-based test may potentially prove to be better for monitoring response in the future.

Patricia Rios:

Thanks for mentioning that. I want to go back to the CIS and the pathology, there’s a couple questions around sort of flat cancers. Dr. Matoso, are there other flat cancers that are not considered CIS?

Dr. Andres Matoso:

No. So the one question, I think there’s a little confusion in terms of once there’s invasion we don’t talk about CIS anymore, we talk about invasive bladder cancer. Okay, that could be superficial non-muscle invasive or muscle invasive, and then it will refer to CIS as being the precursor lesion, but you’re not going to be treating CIS anymore. Then you have invasive carcinoma, and then that very much falls into different categories, but regardless of whether that started from a papillary tumor or a flat lesion.

There is a question about CIS being detected in urinalysis. Urine what can detect is tumor cells, and it can tell you that those tumor cells are high-grade based on the morphology. They will not be able to tell you whether these are coming from papillary tumors or flat. It will be positive for tumor cells, and then the urologist has to go in and try to find the tumor, which could be papillary or flat.

Patricia Rios:

Thanks for elaborating on that. Going back to the enhanced cystoscopies and tools available, Dr. Pietzak, why aren’t blue light cystoscopy a norm for urologist surveillance?

Dr. Eugene Pietzak:

I think that’s a very good question. It’s hard for me to speak, I don’t know, it’s hard for me to really say. I have a very niche practice, I just focus on bladder cancer, and I think probably most of the practitioners who are involved in BCAN are focused on it. But I think in the community where urologists are treating kidney stones, and urinary tract infections, et cetera, bladder cancer is probably not a substantial proportion of the patients that are being seen, and so unfortunately there is some capital investments that need to be made in these equipments and they need to switch their equipment. So, I mean obviously I personally think that they should, and whether that’s blue light or narrow band imaging, I think that’s up to each individual practitioner. We have both in our system and there’s situations where I think blue light may be better, but for a lot of situations I think narrow band imaging is less cumbersome, and simpler, and more straightforward, and provides the same information.

I would say most of us recommend or encourage some form of enhanced cystoscopy, both at TURBT as well as with office surveillance. So narrow band imaging is made by Olympus, there is,  you could do that for TRBTs and surveillance systems. Blue light cystoscopy is linked to the Storz resectoscope setup, and that is available for TURBTs. It used to be available for surveillance cystoscopies, but Carl Storz stopped making that equipment, that it’s not compatible anymore, so it’s phasing out. So you can’t buy a new blue light cysto for flexible cystoscopy, but some centers that were probably involved in the trial and others, early adopters, probably still have it. So that’s fading away.

So I think part of it is there’s a capital investment that needs to be made initially, and if you’re not seeing a lot of bladder cancer patients maybe it just doesn’t make sense financially. Not saying that that’s correct, but that’s why I would speculate why it’s not done. But they’ve both been around for 15, almost 20 years I would say, so they’re not new technologies. Technology, like there’s now efforts with artificial intelligence, just like in every other aspect of medicine in the world, that’s trying to improve these things as well. So there will be newer technology as well that’s coming forward, but it’s speculation really.

Patricia Rios:

Thank you for addressing that. And in the absence of those, the technologies what is the standard recommendation for patients for surveillance and for diagnosis?

Dr. Eugene Pietzak:

You’re saying if someone doesn’t have access to blue light cystoscopy? So in some of the randomized trials it’s interesting, if the randomization was to a second white light cystoscopy and like the urologist needs to take another look around, the effects or the benefits for blue light as well as narrow band imaging decrease as a result of that. And so I think part of it is just being more diligent. And so one of the things when we’re doing our narrow band imaging surveillance cystoscopies, you take a look around with your white light and then you switch to NBI and then you’re looking around again, and it kinda forces you to take more time, you’re looking at things a little bit differently, and as I mentioned, you could toggle back and forth so I think it’s beneficial.

If there’s not someone who has access to an enhanced cystoscopy type of technique I think you want to try to make sure the urologist is doing as thorough of a job as possible and trying to not rush through it. Certainly there’s a balancing because obviously it is uncomfortable for the majority of individuals, so it’s just you want to make sure you’re seeing everything and not kind of dismissing things offhand about whether it’s just inflammation or not.

Patricia Rios:

Thanks for elaborating on that. Dr. Matoso, during your presentation you compare CIS with typical bladder tumor, can you explain what the typical bladder tumor is? And a second part to that question is what other types of tumors are there besides CIS and the typical bladder tumor?

Dr. Andres Matoso:

Yeah, so the majority of bladder tumors make a mass, something that you can see in a CAT scan, in an MRI, or in a cystoscopy. That’s not the case for CIS but 90% of the tumors or more make something visible. So that’s the biggest difference. They both originate in the same tumor cells, but the ones that make a tumor, they just are visible. They have, in general, slightly less risk of invasion than CIS.

And the other question you asked me is what other tumors, there are many other types of tumors but are less frequent. The stromal cells, some of the soft parts of the bladder, can also make tumors. The bladder can be a site of metastasis from tumors from other places. Melanoma can go to the bladder, in women ovarian, uterine cancers are known to go to the bladder, cervical cancer, and then a man prostate cancer is the most common. So also when we have a biopsy then we assess those possibilities, but those are a minority of the cases, the majority of tumors in the bladders are primary cancer of the bladder and of the urothelium.

Patricia Rios:

Okay. All right, thank you. I know we’re at time so just one more question for each of you. Dr. Pietzak, after removal of the bladder is the cytology for urine still useful?

Dr. Eugene Pietzak:

Yeah, it definitely is because you’re monitoring essentially usually the upper tracts. And then it’s a little bit more controversial, although we’re supporters here, of doing urethral washings in men because the urethra’s there. So cytologies, you’re basically looking to see are there cancerous cells in the urine that’s showing up? And that’s one of the best ways to monitor to make sure the kidney, the ureters and the renal pelvis aren’t developing disease. The issue with cytologies are they’re specific but not sensitive. So only about 50% of the time do they typically identify a tumor if they’re present, but if it comes back positive or suspicious there’s a very high likelihood that there is high-grade urothelial carcinoma somewhere in the urinary tract, but that can be very challenging to identify. And we just talked about how difficult it is to find CIS in the bladder, it is even more challenging, in my opinion at least, to find it in the ureter as well as the renal pelvis because the instrumentation are smaller, the scopes are smaller, the biopsy forceps are smaller, and that is even more challenging, but cytologies are definitely helpful after cystectomy as well for those reasons.

Patricia Rios:

Thank you. And Dr. Matoso and Dr. Pietzak, feel free to chime in. Can you explain what is the FISH test, and what it does, and whether it gives false positives?

Dr. Andres Matoso:

Yeah, so FISH test is a laboratory analysis that detects some molecular alterations that tumor cells, that are more frequent in tumor cells. It’s one more tool to detect something we are not seeing. If a FISH test is positive the patient will be followed by a cystoscopy to try to identify the area where this could be coming from and have a biopsy. It’s not 100% sensitive and it’s also not 100% specific, meaning that it’s just one more piece of information, it’s not diagnostic of cancer by itself.

Patricia Rios:

Thank you. So my last question to close off is what message would you have for patients who either are waiting for the results or have been diagnosed with CIS, what message do you have so that they can advocate for themselves as they navigate diagnosis and the journey?

Dr. Eugene Pietzak:

Yeah, I was just going to say I think you guys are doing all the right things right now being on the BCAN webinar, I think the more information you get from credible sources that are highly vetted, and the videos and the articles I think on this particular platform are very helpful.

I think coming in with some information and background knowledge, especially because with, at least as I mentioned, BCG is certainly the standard for first-line setting, but in the second-line setting for the treatments there’s such a plethora of different options. It went from just four or five years ago being a very short conversation because there were very few options, and now we’re spending well over an hour discussing through the different options, and the pros and cons, and all of this. And now I’m finding that I’m having multiple conversations with individuals to help them decide what option is best for them. So it’s a very exciting time in terms of the treatment, but as I think we both had emphasized in our presentation, there’s still a lot of challenges and there’s a lot of progress we need to make.

Patricia Rios:

Excellent. Dr. Matoso?

Dr. Andres Matoso:

Yeah, so from my perspective I would say that every patient is unique and you know your disease better than your physicians. So communication with your physicians to explain your particular situation, there’s a huge value in having very fluent communication so that both sides understand the priorities of care, what are your goals with different care, what’s important for each patient. So I would say do not hesitate to reach out, to talk to pathologists to see what are the limitations if you get a non-definitive diagnosis, why is that happening? So the more you understand and the more you communicate what your priorities are, what your fears, what your hesitations are in terms of your disease, then the clinicians, pathologists, urologists, oncologists can better model their answers to you so that you actually get the kind of response that you’re looking for, or answers to your particular questions.

I’m seeing here in the chat all these different questions that are so rich and so impossible for me to answer all at once. But if you get a second opinion, when you get the second opinion reach out, make that phone call, and try to clarify all your questions. And I think that will bring some, at least it would clear up a lot of the anxiety around the disease, or at least some of it. So yeah, I appreciate all your opportunities for us to better understand this every day, so thank you.

Patricia Rios:

Thank you both. Those are excellent points and thank you for taking the time to give us the opportunity to learn from both of you. This has been an educational hour and six minutes, and thank you for taking the time to answer the questions also in the chat. We hope to have you back. And it is really, I would say, hopeful to hear all the progress and the options that are available today compared to maybe five, 10 years ago. And it’s really encouraging to see that there’s so much that’s being done and we’re learning around bladder cancer as a whole, but also within this specific case which is CIS, carcinoma in situ. So with that, I want to thank you again for being with us today, and I want to wish you a restful evening.