Webinar: Exploring Rare Types of Bladder Cancer

February 27, 2026

Description: Drs. Li and Al-Ahmadie talk about rare bladder cancer subtypes—what they are, how they differ from more common forms, and what researchers are learning about their biology and genetics. They also discuss current challenges in diagnosis and treatment, and how experts worldwide are collaborating to move research and clinical trials forward.

Year: 2026

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Full Transcript of Webinar: Exploring Rare Types of Bladder Cancer

Patricia Rios:  

My name is Patricia Rios and am your host for today’s webinar on exploring rare types of bladder cancer tumors. During this webinar, we will explore rare bladder cancer subtypes, how they differ from more common forms of bladder cancer, and why they can be challenging to diagnose and treat.

Our two amazing guest presenters will discuss current research into tumor biology and genetics, global collaboration efforts, and how clinical trials are advancing care for patients with rare bladder cancers. We’ll first hear from Dr. Al-Ahmadie, who is a Board Certified Pathologist at Memorial Sloan Kettering Cancer Center, followed by a presentation from Dr. Roger Li, a Genitourinary Oncologist at the Moffit Cancer Center.

So, with that, I’m going to transfer the screen or hand over the screen to Dr. Al-Ahmadie. As a reminder, after the presentation we will have a dedicated Q&A session with both of our experts. So, I encourage you to submit your questions throughout the webinar, and without further ado, Dr. Al-Ahmadie, the screen is all yours. Thank you so much for joining us.

Dr. Al-Ahmadie:

Thank you. Thank you, Patricia. Hello everyone. Good evening, good afternoon. My name is Hikmat Al-Ahmadie. I am a Pathologist, as Patricia mentioned, at Memorial Sloan Kettering Cancer Center. Which means if you’ve heard of whenever there’s a diagnosis of bladder cancer or any cancer, this means someone like me has looked at a set of slides from a patient and made the diagnosis of cancer, bladder cancer in this setting.

I’ll go over some of the steps, some of the things that we do, but also share with you some of what is relevant about these rare subtypes of bladder cancer and why we call them the way they are, why we coin the names, and then have plenty of time at the end for questions. I apologize in advance if there are any terms that might be too technical or you might not be familiar with, but we’re happy to answer that and try to address it anytime after this, or later or anytime after the webinar even. We’re happy to be of any help.

Dr. Al-Ahmadie:

These are my disclosures.

Dr. Al-Ahmadie:

Just to put things in perspective, we’re going to focus on histologic subtypes or rare subtypes of bladder cancer. But just to put things again in the context of what we are dealing with, this is bladder cancer. The majority of bladder cancer cases as diagnosed, they will be not the rare subtypes or not these histologic subtypes that we’re dealing with. Most patients will have the non-muscle invasive bladder cancer, the superficial disease.

The subset that will include these histologic subtypes is the invasive disease, which means it’s a subset of the non-muscle invasive disease here, any tumor that invades from the surface urothelium into the bladder wall. It could be superficial, it could be deep. But these histologic subtypes apply to this part of bladder cancer when the tumor invades into the different layers of the bladder. So, it’s a small subset of the overall bladder cancer in its different settings.

Dr. Al-Ahmadie:

But once you get into that group, then there’s a lot of names, a lot of entities that are grouped in this. But even when you have invasive urothelial carcinoma, there is still a most common subtype, which is a regular urothelial carcinoma. Some people refer to it as a classical, traditional urothelial carcinoma. They say a more scientific or medical term for it is “not otherwise specified” or NOS. If you hear the word “urothelial carcinoma-NOS”, it means it’s urothelial carcinoma that does not have features that otherwise will make it coded or labeled one of these other subtypes.

And then within these subtypes, there are subtypes that are very common, like squamous differentiation, when a tumor forms or shows features that look like squamous. But then there are some other rare subtypes, and these are the names here, and I’m going to show you some quick pictures of reference so you can have an image that you can associate with the name so probably some of you who have more photographic memories may have an easy link to these histologic subtypes.

Dr. Al-Ahmadie:

And this is what I mean by this. Again, our reference point is urothelial carcinoma-not otherwise specified, “NOS”. Regular, classic urothelial carcinoma, when a tumor starts forming, it has morphologic features under the microscope. And this is all done under the microscope.

We examine this tissue under the microscope, and if there’s tumors showing things that may look like a skin, it becomes squamous. We call it “squamous differentiation”. When a tumor starts forming glands, something that you would see in the colon or the stomach or the thyroid, for that we use the term “glandular” because the tumor from being urothelial, it’s trying to form something else like a gland.

When it starts making structures that look like germ cell tumors, we call it trophoblastic differentiation. When a tumor has a unique morphology of these small tumor clusters arranged in a clear space, we use the term “micropapillary”, and that’s why. The term “plasmacytoid”, in the tumor it resembles some of the blood cells, the plasma cells. It resembles it, but it’s not necessarily related to them. Just by microscopic appearance. “Nested”, it’s just that people thought that this resembles like a nest.

“Sarcomatoid”, when a tumor starts forming areas that resemble soft tissue tumors. Giant cells is self-revealing. What that means, “pleomorphic” or giant cells. “Clear cells”, when the tumor cells show some clearing within parts of them that give this appearance of clear cell morphology. “Small cell”, again the tumor cells are much smaller. And then “adenocarcinoma”, when the tumor in the bladder looks like a tumor arising in the colon or the stomach or the thyroid when it’s forming, like an adenocarcinoma or the like.

One thing to keep in mind, that although these are unique, different histologic subtypes, except for an adenocarcinoma, they all arise from a urothelial carcinoma background. An example here would be in this tumor that has glandular differentiation, a big part of the tumor is still urothelial, but it’s just the shape of this structure that is part of the tumor that looks like a gland gives this tumor the term of “glandular differentiation”. The same with the squamous, the same with the small cell and the sarcomatoid.

So, these names, you may read about them, you may hear them. They are descriptors of how the tumor looks under the microscope, and this is the gold standard of how these diagnoses are made.

Dr. Al-Ahmadie:

Just to summarize all of this and just to give you some pointers here… We can use divergent differentiation when a tumor starts with urothelial and start showing features that resemble other organs or other structures, squamous, glandular trophoblastic.

Usually there is a urothelial component. There are some nuances. You may hear them as “variant histology”. It refers to the same. You may hear the name as “histologic subtypes” or “rare subtypes”. All of them convey the same. People have used different terminologies to describe them throughout the decades of recognizing these tumors, so just keep that in mind. Variant, subtype, differentiation, this may refer to the same in the bladder setting.

And as I mentioned, this is all based on examining tissue sections that are taken from a biopsy or a resection specimen under the microscope, and it’s by the appearance of these tumors under the microscope that we use these different terminologies. Urothelial, histologic subtypes, variant histology.

Overall, they still remain a small subset of these… A minority of urothelial carcinomas will be of the subtype, and because of that, most studies that you read in the literature, they may group them together as all variant histology of urothelial carcinoma or histologic subtypes as one entity. I’m going to show you in the subsequent slides that this is not necessarily advisable because there’s some unique features that are related to each subtype. But again, for practical purposes, just to come up with enough numbers to be able to come up with some conclusions, there is a tendency to group these entities together.

Dr. Al-Ahmadie:

And how rare or how prevalent they are, depending on how much you examine and how you look, if you have parts of the tumor in the TUR, transurethral resection specimen, it’s about 15%. If you have a cystectomy of the bladder, you have more tissue to examine and the chances that you’ll find variant histology or histologic subtypes is higher.

We generally associate them with higher-stage or advanced disease. They tend to be unfortunately under-recognized, maybe because of lack of awareness or lack of experience or expertise with these entities. Not every base has specialized people who look at these entities all the time. So, because of that, some of these subtypes may be under-recognized or under-reported.

Which may be problematic, because as we will see from my slides and from the slides from Dr. Li afterwards, that the type of histologic subtype that is made, a diagnosis which is made may have a serious impact on what type of treatment the patient may get or not necessarily get. Part of the treatment, also it may determine if a patient gets enrolled in a clinical trial or may be denied certain treatments just because they have more of a histologic subtype or if that subtype may have not been even recognized.

All of these factors and challenges of the histologic subtypes, the end result of that is they remain understudied, and there is kind of an unmet need in the field of urothelial carcinoma. And there is an opportunity there for us people who are interested in this and for our patients to try to study these tumors and try to understand them as much as possible or as we would like to.

Dr. Al-Ahmadie:

These are just two examples. Again, I didn’t mean to give you a lot of details here. They may not necessarily be practical. But these are two examples why these subtypes or these histologic subtypes may not be recognized. Sometimes local pathologists, local hospitals, small practices may not necessarily be aware of them. They may send these cases to an experienced center or specialized centers. Then this is when these histologic subtypes or new diagnoses may start coming up in the report that was not present in the initial report.

So, if a more specialized center reviewing material from other smaller centers, or sometimes when people want to do research and retrospective cases, archive material in their institution. This is an example of Mayo Clinic. You may go back, and while you’re examining these cases to study them, you realize that some of these histologic subtypes might have been missed or overlooked. And in this example, about a third of cases that were not called any histologic subtypes were discovered to have one form of histologic subtype.

Dr. Al-Ahmadie:

As I mentioned, these subtypes are relevant, are important because they don’t behave the same. If you have one subtype, a patient may have a different risk versus having another subtype. This is a large study that came out recently from our group, but there are many similar studies from other groups showing similar results. The writing may be small, but you can see each line represents one histologic subtype and each line is associated with different risk of recurrence and survival.

Worst actors are tumors with the name of plasmacytoid urothelial carcinoma or sarcomatoid urothelial carcinoma. There are some tumors that are in between like squamous differentiation, micropapillary, small cell carcinomas, and then the NOS is one of the more favorable histologic subtypes. So, they’re not the same, so it’s important not to confuse everything as variant histology. It’s important to ask the question of what type of variant histology or what type of histologic subtype that any patient has, because that may determine different risk for recurrence and metastasis and also may determine the different types of treatment that they may get.

Dr. Al-Ahmadie:

Unfortunately, because they’re understudied overall, we don’t know exactly what leads to one histologic subtype or the other. We know some of them. We know, for example, plasmacytoid carcinoma has a unique genetic abnormality. Part of the genes that make up the tumor are mutated or altered. It’s called CDH1 or E-cadherin. Most of the other histologic subtypes share similar mutations or genetic abnormalities to urothelial carcinoma, with some differences.

For example, micropapillary carcinomas have higher rates of HER2 mutations or amplifications. Small cell carcinomas have higher rates of RB and P53 mutations. Again, apologies if these are too technical, but these are some of the genetic events that people in the field know about, and we use them to help us determine the diagnosis sometimes or inform us of the characteristics of the tumor or the disease that can help us devise management strategies.

Dr. Al-Ahmadie:

How we do this, again it’s microscope. The tissue is prepared, made into glass slides, we put them under the microscope, we examine them. Based on the different appearance of the tumor and different regions, we can determine. This is one example here. The same tumor has areas of squamous differentiation in addition to the urothelial component and areas of small cell carcinoma.

If there is a need, we can do additional studies on the tissue. These are special stains. It can confirm the presence of the small cell carcinoma component, for example.

Dr. Al-Ahmadie:

Plasmacytoid carcinoma, similarly we can do special studies on the tumor, especially when the morphology is suggestive, and we can confirm what part of the tumor is plasmacytoid and what part of the tumor is not.

Dr. Al-Ahmadie:

Some tumors, we can’t do much. Squamous differentiation, there are a lot of tumors that can give a false appearance of squamous differentiation here, but you really need to have specific criteria to call something squamous. And this could be part of reason why these tumors may be missed by people with not as much experience, or it can be over-called with people who do not necessarily apply strict criteria. So, it’s always important to know the source of the diagnosis and how it was run down and whether the criteria were applied strictly.

Dr. Al-Ahmadie:

Other things that we can perform and provide during the diagnosis is how much of a histologic subtype is present in any given tumor. Even though most studies do not show that this is really relevant, or at least in association without outcome, but our clinical colleagues like to know how much of a histologic subtype is present in any tumor. Sometimes that can be factored into the next step or the next treatment strategy that is given to any particular patient.

Dr. Al-Ahmadie:

Of course, I have to mention this because now the new treatments of bladder cancer, especially those related to antibody drug conjugate, vedotin, that relies on the expression of NECTIN4 in a tumor. The presence of a histologic subtype can determine or can impact the expression levels of this marker on a tumor and can impact the response rate to this treatment.

For example, small cell carcinoma does not express NECTIN4, so it’s very unlikely that a tumor with a small cell carcinoma will respond to EV treatment. At the same time, these tumors may express another marker that can make them eligible or have higher chances of responding to another treatment that targets another marker such as DLL3. And the flip side, microbial carcinoma. In addition to expressing NECTIN4, it may also express HER2, which is another target for another drug that targets for two expressions.

So, there are some nuances to them. It’s important to be aware that a histologic subtype may negatively impact a treatment selection, but some of them may give you another opportunity that there’s another marker, another target that can be used or taken advantage of to address these tumors. So, there are some disadvantages, but there are some opportunities. So, always keep that in mind that it’s not always a negative finding when there’s a histologic subtype made as a diagnosis.

Dr. Al-Ahmadie:

Another caveat, sometimes tumors with similar morphology may present in the bladder but may not necessarily be of bladder origin. So, not every squamous in the bladder is coming from the bladder. This is a rare example of a prostate cancer showing squamous differentiation presented in the bladder. Again, being aware of this possibility and doing the right diagnostic workup, a diagnosis can be made. Similarly, a small carcinoma again rarely may present in the bladder but may be coming from prostatic origin. So, all these are caveats that are important to keep in mind, and when one is careful, the diagnosis can be easily made so that these mistakes can be avoided.

Dr. Al-Ahmadie:

So, to summarize this, I just wanted to leave you with some of these important facts. That divergent differentiation or histologic subtypes or variant histology are common findings in case of urothelial carcinoma. They’re not the same. They’re very distinct entities that have different clinical importance, and it’s important to be aware of these nuances and try our best to come up with the right diagnosis.

There are challenges that remain, but hopefully with more studies and more work we’ll be able to understand them more, their heterogeneous group. We still need some standardization criteria to make sure that everyone is able to make the diagnosis. Because again, the biology underlying them is different, and more studies will help us uncover this underlying divergent biology. And hopefully the newer technologies that are becoming available year after year will provide us with more sophisticated tools for us to be able to understand these subtypes more comprehensively.

Dr. Al-Ahmadie:

So, with this, I would like to thank you, and I’m looking forward to answering some of your questions at the end, and I’ll turn it over to Dr. Li. I’m going to stop sharing.

Dr. Li:

Thanks so much, Hikmat. That was really a master class, and I can’t overemphasize how important it is if you were to have one of these rare types of bladder tumors to seek out help at a specialized cancer center such as Memorial Sloan Kettering or Moffit so that you can get really expert diagnoses made by folks like Dr. Al-Ahmadie, who’s not only made a lot of advances on the clinical side, but also has really advanced our understanding of these diseases by doing a lot of cutting-edge research.

So, in the next few minutes I’m just going to take you guys through some of the most commonly found subtypes of bladder cancer of divergent differentiation, and also explain from the clinical perspective what some of the implications may mean.

Dr. Li:

So, here are my disclosures. I do have some research support from some of the folks in pharma and also act as a scientific consultant for some of the companies.

Dr. Li:

As Dr. Al-Ahmadie had stated, overall if you look at all of the divergent differentiation or subtype tumors, even though individually they’re very rare, together they actually consist of up to one-third of all muscle invasive bladder cancer. And when we talk about divergent differentiation, this is actually the tumors taking on a different sort of cell type. If they take on a cell type that resembles the skin, we call it “squamous”. If they take on cell types that resemble the gut, we call it “glandular”.

And then there are urothelial cancer cells that take on slightly different forms that Dr. Al-Ahmadie had so eloquently gone over. But some of the most common subtypes include micropapillary, urothelial carcinoma, sarcomatoid, plasmacytoid, nested, and small cell. And each of these again has its own unique clinical features. So, even though a lot of the publications will group a lot of these tumors together, clinically we have to really take each by themselves. And in the next few slides and next few minutes, I’ll take you through some of the clinical implications.

Dr. Li:

Firstly we’ll start off with squamous tumors. A pure squamous tumor is actually very rare, about 2% in all of bladder cancer. But squamous differentiation that appears together with urothelial carcinoma can actually exist in up to 40% of tumors. And the classic association that’s been made by squamous cell tumors is with infection, and specifically in the Middle East as well as in Africa, sometimes they may be linked to schistosomiasis.

Just as an interesting aside, actually one of my patients came in, she was traveling in Egypt, was drinking water, never really got exposed to schistosomiasis or had that diagnosis made, but nevertheless came back to the States with muscle invasive squamous cell carcinoma of the bladder that was pure. And I actually performed a radical cystectomy on her and she’s been doing great since.

So, these tumors tend to be locally aggressive. What that means is that they tend to invade outside of the bladders themselves rather than spawning off these micrometastases to other parts of the body. And so, at the time of radical cystectomy, more than three-quarters of these tumors will actually be found to have extra vesicle or extra bladder invasion. And because they’re so widely invasive, about 15% of the time when we do radical cystectomies, we actually come up with positive surgical margins, meaning that we’re leaving tumor behind. And just as comparison for conventional urothelial carcinoma, that number should be less than 2% to 3%.

And as Dr. Al-Ahmadie had mentioned, the proportion of squamous cell carcinoma within the entire bladder tumor does matter. If you have more than half of the tumor consisting of SCC, that means that the patient is unlikely to respond to the conventional chemotherapy that we typically give. But if you have less than 50%, we can still give cisplatin-based chemotherapy.

Dr. Li:

All right, moving on to adenocarcinoma or glandular, again this is a divergent differentiation. Pure adenocarcinoma of the bladder do exist, although they’re even more rare than squamous cell carcinoma, in less than 1% of bladder cancer. But again, glandular features can be found in up to just under 20% of bladder cancer. So, when we find adenocarcinoma in the bladder by itself, it’s a very rare event. And the first thing that we need to do is to rule out that this may be a metastasis from a primary tumor that’s originating from the gut, either the upper GI tract or the colon.

So, we typically will refer the patient for an upper endoscopy and a colonoscopy just to be sure that the patient does not have a primary tumor at another site that spawned off a metastasis to the bladder. And folks like Dr. Al-Ahmadie and others have studied the molecular features of these adenocarcinoma of the bladder, and they’ve found that the molecular features of these are drastically distinct from conventional urothelial carcinoma. Unlike some of the other subtypes, which actually share a lot of the mutations, for instance, with urothelial carcinoma, suggesting that they may actually come from the same original clones. But not the case for adenocarcinoma.

And unlike the squamous carcinomas, there’s very poor response to the conventional chemotherapy that we give for urothelial carcinoma. And so, folks have actually started to use regimens that are tailored towards GI adenocarcinoma because of the resemblance to these tumors. And in very small series, because again these tumors are very rare, there have been descriptions of very high response rates to chemotherapy that’s targeted against GI tumors.

Dr. Li:

Moving on to micropapillary, again a very rare cancer type consisting up to 2% of all bladder cancers, this particular type of tumor can be found in the non-muscle invasive stage. Now, folks actually debate whether or not when a micropapillary tumor is found as non-muscular invasive disease, whether that’s because we’re understaging because we’re not adequately resecting down to the muscle wall of the bladder.

And so, the group at MD Anderson has traditionally advocated for really aggressive upfront treatment using radical cystectomy, even in the case where your micropapillary tumor is found only to invade into that first layer, the lamina propria layer. And this will avoid understaging. It will also provide the most aggressive consolidative local surgery for this really aggressive tumor type.

But over the years, we’ve also learned that the amount of micropapillary tumor within the tumor… So, let’s say if there’s only a focal area of micropapillary, about 5% of the entire tumor is micropapillary, that these folks may actually be able to be treated with the traditional intravesical therapies such as BCG. And that’s an approach that we typically will follow here at Moffit, too. So, if you only have one small area of micropapillary non-muscular invasive disease, we typically will try to treat upfront using a conservative measure rather than going to radical cystectomy upfront because of all of the morbidity that’s associated with the procedure.

And as Dr. Al-Ahmadie had mentioned, these tumors are known to have what’s called a HER2 mutation, and because of this HER2 mutation, they express this receptor on the cell surface that makes them a good target for HER2 targeting agents. One of which is the antibody drug conjugate that actually pairs a chemotherapy along with a targeting receptor that seeks out the HER2 targets on cancer cells, latches onto the cancer cells, and directly delivers the chemotherapeutic agent into the cancer cell. This has been successful in the setting of bladder cancer overall, but has not been really reported on what the response rate specifically for micropapillary tumor has been.

Dr. Li:

Moving on to another type of very rare disease, sarcomatoid bladder cancer. So, very much like the squamous cell type, this is also very aggressive locally and it’s also known to have very high PD-L1 staining. What that means is that there are a lot of immune cells that will infiltrate into these tumors. And what that means from the clinical perspective is that because there are a lot of immune cells that are infiltrating into the tumor, it makes it oftentimes responsive to PD-1 inhibitors or immune checkpoint blockers such as Keytruda or Opdivo.

So, in the ABICUS trial, which is a clinical trial that was ran out of the UK, they enrolled a lot of patients with really rare subtype tumors, and eight of the patients actually did have sarcomatoid tumor in that trial that was treated with an immune checkpoint blocker, atezolizumab. And six out of the eight patients actually had a pathologic complete response. So, they were treated prior to them being taken to radical cystectomy, and at the time of radical cystectomy, after the bladder was removed, just by treating with atezolizumab, the patients’ tumors were completely eliminated. So, very encouraging preliminary results from that study.

Dr. Li:

Dr. Al-Ahmadie also mentioned plasmacytoid disease. Clinically I would say this is one of the most challenging diseases that we treat as urologic surgeons, mainly because you could see here on the CT scan that the plasmacytoid tumors tend to spread along fascial planes. And what that means is that they will kind of circumscribe the organ, in this case the bladder, and that will almost act as a noose around where the bladder outlet is.

And so, that’ll create this really tight noose so that the bladder has to work overtime in order to expel urine and causes thickening of the bladder walls. They can also cause the same sort of phenomenon around the rectum, too, which is very rare with any other type of bladder cancer. So, when we see that there is this sort of typical appearance of the bladder wall thickening along with rectal wall thickening, automatically we think plasmacytoid disease, even though it’s very rare.

As we talked about, it has a high propensity for spreading via the tissue planes. Also it can spread into the peritoneum or the abdominal cavity. It’ll spread alongside each of the different gut compartments. And as a result of it having this infiltrative growth pattern, you can imagine oftentimes when we go to do surgery for these folks, the surgery becomes very, very difficult because the infiltrative pattern makes it such that the bladder is completely adhesed to the surrounding pelvic organs, sometimes to the colon, to the point where we may have to take the colon along with the bladder. And the positive margin rate, so again, leaving cancer behind because we can’t just really take out the entire tumor, that rate is also very high for these patients.

We typically will use chemotherapy upfront for these patients in order to downstage their tumor, and we often still do. As I mentioned, sometimes because the tumor actually grows around the colon, for instance, that’ll actually choke off the passage of stool in your colon. And some patients may actually present with bowel obstruction.

So, I had a patient, again, that needed to have a colostomy done as the first surgical step in order to relieve the colonic obstruction, and then we put him on chemotherapy. That patient actually had a great response to the chemotherapy and we were able to remove the bladder as well as his rectum. And at the time, he still had T4 disease, but because he responded so well to the chemotherapy, he was actually able to live for a long time even after surgery.

The rule for these tumors, again, they’re not only locally invasive, growing along these infiltrative patterns, but they also like to spawn off dista-metastases. So, oftentimes even if it’s a success story locally when we are able to do these consolidative surgeries to more or less take out the vast majority of the tumor locally, oftentimes months, years afterwards the patients will develop a metastasis and they’ll succumb to their disease.

So, over the years, because chemotherapy doesn’t really work very well for these patients, we’ve looked to other types of therapy to treat these patients. So, immune checkpoint blockers have been used. Specifically at Memorial Stone Kettering, they had published a series on their patients being treated with immunotherapy. And unfortunately even with immunotherapy, there’s very modest effectiveness.

But of course the new kid on the block, if you will, is enfortumab vedotin, which is another antibody drug conjugate that targets NECTIN4 and delivers an MMAE payload, which is kind of a chemotherapeutic agent. There have been very small numbers of patients who have been reported to be treated with EV. These patients obviously did have plasmacytoid disease, and they have demonstrated some very promising preliminary results.

So, the underlying theme that you see here is that a lot of these patients, because of the rarity of their tumors, they cannot be enrolled onto clinical trials to properly study the efficacy of various drugs to these tumors per se because of their rarity. And one of the missions that we have as part of the Global Society of Rare GU Tumors, which both myself and Dr. Al-Ahmadie are part of, is to think of ways so that we can be more encompassing for these patients to be enrolled onto clinical trials. So, even if they’re just treated as a last-ditch effort, we’re still going to be able to understand whether or not these novel therapies can be effectively used against these very rare but very aggressive tumors.

Dr. Li:

And finally, moving on to small cell or neuroendocrine tumor. These tumors I would say have the highest propensity for dista-metastasis. And you could tell here by this MRI of the brain, this is a very rare phenomenon in bladder cancer in general, but nevertheless, small cell cancer of the bladder tend to spread to the brain. And so, if a patient were to have small cell carcinoma and starts to have vision changes or headaches, certainly we need to get an MRI of the head to rule that out. In fact, in some places like MD Anderson, they actually just routinely get MRIs of the brain for small cell bladder cancer patients, especially for those patients with larger and higher-stage tumors.

So, the nice thing about small cell carcinoma is that we do have a very well-established chemotherapy regimen for it. And this is actually borrowed over from small cell lung cancer, which is still rare, but a lot more common than small cell bladder cancer. And fortunately, the regimen that works for small cell lung cancer also tends to work for small cell bladder cancer as well.

Beyond the treatment with systemic chemotherapy, as you know, we typically will consolidate the therapy by using local surgery or radical cystectomy or radiation. And there seems to be equipoise between the two modalities, particularly for small cell carcinoma. We know that small cell lung cancer or bladder cancer are exquisitely sensitive to radiation. And the final point about this tumor is that they are highly expressive of a target, again called DLL, and there are certain DLL-targeting antibody drug conjugates or bispecifics, T-cell engagers that may leverage the high expression of DLL that’s found in these tumors for us to provide the effective treatments.

Dr. Li:

Finally, in conclusion, the subtype histologies altogether are found in up to a third of all bladder cancers. Each of the subtypes and the diversion differentiations have their unique biological properties, and I hope I convinced you that each of them behave a little bit differently than each other and have different clinical characteristics. Most will exhibit a high propensity either for local invasion or for distant or regional metastases. And of course, based on the molecular features of the different tumors, treatment regimens differ for these tumors.

But again, I want to just wrap up by saying that if you or one of your loved ones or one of your friends are unlucky enough to develop one of these rare subtype tumors, it’s very, very important again to seek out help at an academic tertiary referral center where, because of the sheer volume of bladder cancer patients that we do see, we have relatively abundant experience compared to some of the community sites which may not have even seen a single case of these tumors.

Dr. Li:

So, I want to thank you for your attention, and we’ll turn it over back to Patricia for some questions and answers. Thanks very much.

Patricia Rios:

One of the questions refers to nested subtypes, and Dr. Al-Ahmadie, I saw that on your slides. Could you explain what that is? And then Dr. Li, if you have any advice on treatments that are effective for that kind of subtype.

Dr. Al-Ahmadie:

Yeah. In this category of rare subtypes, it’s one of the rarer ones. It has unique morphologic appearance. It has, I showed a picture of they look like a nest, and the pathologists who coined the term called it “nested” urothelial carcinoma.

It’s challenging for us because most of the times it’s very bland-looking. It doesn’t look like an aggressive tumor. But at the same time it’s deeply invasive. So, if you’re dealing with a superficial biopsy, for example, where not all the layers of the bladder are represented, it may be dismissed as a reactive process or a benign process. And that’s why I think being aware of this, and that’s why to the point that Dr. Li mentioned, whenever there’s doubt, it’s important to have the material reviewed by people with experience. Because we’re kind of attuned to these subtleties of these lesions, and once we see them, we recognize them, we alert.

So, if we’re not definitive, at least we alert our clinical colleagues, the urologists. We’re telling them, “Listen, this looks a little bit unusual. Maybe in the next visit to the patient, just maybe sample a little bit more, go deeper.” Especially if the initial biopsy was very superficial, and that will give us ample material to examine. And then once you see it’s deeply invasive, then it’s an easier diagnosis to make despite that it has a very bland histology. So, that’s how we deal with it on a diagnostic level. But the clinical, maybe I’ll let Roger chime in.

Dr. Li:

Yeah. I think at least from everything that I’ve read, sometimes it may even resemble low-grade tumors, and it may actually be concomitantly present with low-grade tumors, which makes it even harder to diagnose.

I did actually have a patient who had nested variant. We gave him neoadjuvant chemotherapy, actually put him through a trimodality therapy regimen, and he was one of the very few patients who progressed right through the radiation. So, I don’t know. This is a case of “N equals 1”, but nevertheless, from this anecdote I can say that at least for this patient, he wasn’t responsive at all to radiation.

And of course we really don’t know what the reason for that is and we need to study more. But the recognition of these tumors I think is a first step, and we need to study better in a more robust cohort how to best treat these patients.

Patricia Rios:

Thank you. You both emphasize the importance of getting treated in a facility where there is expertise in these kind of subtypes in bladder cancer. And I’m wondering, what tips do you have for patients as they try to navigate that? Let’s say if they’re not close to either Moffit or Memorial Sloan, what tips would you have for patients who may be recently diagnosed and are not sure how to navigate this?

Dr. Li:

I would say that at least you can get a consultation. In the very least what could be done is the pathology slides can be sent to a center like Memorial Sloan Kettering so that Dr. Al-Ahmadie can actually take a look at the slides and really make a diagnosis.

Because oftentimes, again these rare entities are not even recognized by the pathologists in the community. And you can imagine if you were to miss this diagnosis, your treatment’s going to be completely altered and the efficacy of the treatment is also going to be off. So, in the very least I would recommend for that.

There are also some perks to what type of systemic agents we can give to patients, how we actually approach surgery versus radiation. Even once we’ve decided on doing surgery, for instance for the plasmacytoid patients, oftentimes we will not do an open surgery because we know that there is a danger for these infiltrative growth patterns. So, what we typically will do is actually laparoscopically look inside their belly to make sure that there’s no metastatic disease first. So, in case if we were to find that, the patient doesn’t have to recover from a large, open incision.

So, things like that, I just don’t think that your average urologist or your average pathologist, medical oncologist will actually understand about these tumors. It really takes experts at tertiary referral centers to go through or see the number of bladder cancer patients that we see to really develop the experience to treat these well.

Patricia Rios:

Thank you for that tip.

Dr. Al-Ahmadie:

Yeah, I agree. Just to confirm, whenever something is a little bit unusual, you owe it to yourself to explore a little bit more. I think that’s my advice. If an unusual diagnosis comes to you as like, “Oh, you have this type of rare tumor,” maybe it’s the best thing to seek another opinion. You may still be very comfortable with your initial physician, and that’s great, and they may be giving you the exact recommendation that a tertiary care center would give. But at least if you’ve sought that second opinion, that consultation, you’ll feel more comfortable.

And if you’re like, “Okay, now I’m in the right place,” and you prefer to be in that place where you’re comfortable, at least you get that confirmation. Because common things are easier to deal with. A lot of people tend to see them and tend to be able to deal with them. When it comes to something unusual or rare, it’s better to get that advice and that confirmation that you’re on the right track.

Patricia Rios:

Those are excellent tips. Thank you. Okay, moving on with the questions, we have many more adding onto the list here. There’s one, Dr. Li, around micropapillary features, which often call for early radical cystectomy. And our listener wants to know if there are any bladder-sparing options.

Dr. Li:

Yeah. Traditionally the study out of MD Anderson that originally described their experience with micropapillary tumors had described that with early radical cystectomy, the survival rates were better than those patients who were initially treated with BCG, and even those patients who were initially treated with BCG and then had delayed radical cystectomy. So, again, pointing to the importance of early surgical consolidation for these patients. But as our experience collectively has grown, and perhaps because of more recognition for these types of tumor, I think on the one hand we’re picking up micropapillary tumors that are existing at 1% to 5% say of the entire tumor.

So, whereas before those micropapillary tumors may have just been treated as conventional urothelial cancer, we’re now picking this up because of the widespread knowledge of this entity. And I think on the other hand, we’re also becoming more comfortable at treating these patients. As long as they just have focal micropapillary tumor, I had plenty of patients who have focal that were treated with BCG who had a good response.

Patricia Rios:

Thank you, Dr. Li. Dr. Al-Ahmadie, I’m going to throw two questions your way just because running short on time and I want to consolidate. One is a question around tumor type. Does it change from TURBT to cystectomy? That’s question number one. And two is not quite related, but it deals with AI and pathology, and your thoughts on that and whether it helps avoid misinterpretation.

Dr. Al-Ahmadie:

Yeah, absolutely. There are a lot of studies addressing the first question, the TUR versus cystectomy. There’s high concordance between what you see in the TUR and what you see in the cystectomy. That’s the one part. The second part is because when you do the TUR, you already took part of the tumor out. And then in the cases where there’s still tumor left in the cystectomy, there is a chance that there’s another component in the tumor that’s in the cystectomy that was not represented in the TUR that might be there. So, there’s a small chance that there’s going to be some discrepancy.

But at the same time there’s high level of concordance, and you have to make the diagnosis based on a TUR. So, even if there is a little bit of discrepancy, that’s acceptable and it’s just a fact that’s inherent to the diagnostic process. If you take everything out by the TUR, then obviously there’s not going to be any discrepancy, but there’s a small chance that there is something that may not be represented or sampled by the TUR. Yes. It could be unlucky that it may be the relevant part, but other than that, the TUR is pretty adequate for the most part.

Now, talking about AI, I think if there is one part that could help, it’s in this variant histology and these subtypes, but we’re still very early on because it’s a back end recognition, it’s an image analysis. As long as you train the AI well… If you want to keep these histologic subtypes the way they are now, you have to train the AI very well at recognizing the standard, classic examples. And the AI can more easily produce the same diagnoses and reproduce the same diagnoses because there’s not going to be a lot of or any variability from morning, evening, anytime of the day, anytime of the year across pathologists.

If you want to dismiss all these histologic subtypes and let AI come up with its own classification, that can help, it can happen. But then they need to have a lot of samples for AI to be able to establish and account for all the nuances and the variations that exist across all tumors of the bladder. But definitely it’s an active area that a lot of people are interested in, and we look at it as something that can help us in the future to standardize the recognition of these histologic subtypes.

Patricia Rios:

That’s good to hear. All right, thank you. Dr. Li, this question is for you. For high-grade T1 non-muscle invasive bladder cancer with less than 1% micropapillary features, what kind of HER2-targeted agents are showing promise?

Dr. Li:

That’s a great question. We actually don’t have any HER2-targeting agents treating non-muscle invasive disease. As you know, non-muscle invasive disease overall has relatively good prognosis. And it’s considered that these systemic agents that we have, whether it be targeting HER2 or not, may actually have incurred too much toxicity to be tolerated for patients with relatively well-treated disease with the standard of care such as BCG.

Now, with that being said, there are studies that point to the presence of HER2 mutations within NMIBC that will actually confer a higher risk for progression. So, that’s an active area of investigation as we speak. But also there are companies that are making these antibody drug conjugates and formulating it for administration within the bladder, just like BCG, just like intravesical or gemcitabine, docetaxel so that we can help avoid all of the toxicities that come with the systemic agent, but hopefully still get the benefit of the treatment.

Patricia Rios:

Thank you. There’s a lot of questions here regarding the different subtypes asking about recurrence. Is any one particular subtype more likely to occur than another? Any general comments that you can make? I know it can be very specific.

Dr. Li:

Yeah. I’ll just start by saying there are certain tumors like squamous, like sarcomatoid that tend to locally invade. So, as long as your surgery was done well with negative margins and you’re now a few years out from surgery, chances are you’re cured.

And then there are those diseases that tend to metastasize to distant parts such as plasmacytoid, small cell carcinoma. And so, for those I would say that even with a well-done surgery, patients tend to be still at risk for developing metastasis, sometimes even years out. That one patient that I was talking about with plasmacytoid, he lived about five or six years out from his original surgery.

And mind you, this was a major pelvic exenteration where we took out both his bladder and his rectum. And he originally had an end colostomy that was made from his transverse colon because everything was just so glued in. And nevertheless, we were able to kind of take down his end colostomy and make use of his descending colon and buy him a few years. But even after five or six years, that patient unfortunately still developed metastasis and eventually passed away from plasmacytoid bladder cancer.

Patricia Rios:

Thank you. This is a really interesting question. I don’t know if either of you would like to answer. One of our listeners wants to know if conventional urothelial carcinoma can metastasize as a rare histological subtype.

Dr. Al-Ahmadie:

Maybe I can take a shot at this. It’s very, very rare. We’ve looked at so many, many cases. It’s like in single-hand scenarios when you have a histologic subtype manifesting in metastasis that was not present in the primary. In general, you’ll find it in the primary in the TUR or the cystectomy, and you’ll find it in the metastasis.

Sometimes it could be very little in the TUR, like in micropapillary for example it’s a bad actor. You can have 5% in the primary, but then all the lymph node metastases are micropapillary, like a hundred percent. But it’s very unusual, for example, to see micropapillary when the primary tumor did not have it, or like a glandular when the primary tumor did not have it.

Does it happen? It does, unfortunately, but it’s extremely, extremely rare. But we go to extra lengths to make sure that it’s not another tumor type before accepting that this is still a bladder tumor that just was not present in the primary. Because sometimes you can have two tumors manifesting within the same patient. It’s unfortunate, but it can happen. And again, these are all rare scenarios.

Patricia Rios:

Thank you. The last question, because we’re at time, there is a question about upper tract urothelial tumors, whether they have a different histology than the bladder tumors.

Dr. Al-Ahmadie:

Yeah. Maybe I can also… Now, they’re lined by the similar urothelial lining. They’re a little bit different embryologically how they develop, but the lining is very similar and the tumors are pretty much the same. Any histologic subtypes that one sees in the bladder can have been in the upper tract. The prevalence may be different. Maybe they’re less common in the upper tract, because we see a lot of non-invasive, low-grade tumors in the upper tract. But any histologic subtypes in the bladder can happen in the upper tract.

Patricia Rios:

Great. Thank you. I have one last question for the both of you, as it is our tradition here to ask our guest presenters, and you’ve shared so much information with us today. Aside from the really important one about really going to a center that has this expertise and knows how to treat these subtypes of bladder cancer, what is a takeaway that you would like our listeners to lead with today? We’ll start with Dr. Li and then Dr. Al-Ahmadie.

Dr. Li:

Yeah. So, I would say that it’s very scary to get these rare diagnoses of bladder cancer and it’s very difficult to study these tumors. But with that being said, I do think that cumulatively we have a lot of evidence already for a lot of these tumors, albeit based on relatively small numbers compared to conventional urothelial carcinoma. But we have in general a pretty good idea of how to treat most of these diseases.

Now, with that being said, this is where medical innovation continues, is to understand from the biological perspective how these tumors come about and whether there are any Achilles’ heels that we can find so that we can develop more effective treatments. Like Dr. Al-Ahmadie was saying, with cutting edge technologies that are advancing on a daily basis, hopefully we’ll be able to come up with new insights and we’ll be able to come up with better treatments.

Dr. Al-Ahmadie:

Yeah, I couldn’t agree more. I think it’s a great message. What I would also add to that is that, again, whenever anyone encounters these unusual diagnoses, I think it’s important to seek out what is available. I think trying to reach places or entities with resources, advocacy groups like BCAN, publicly-available resources, National Cancer guidelines, entities like this, they provide a lot of information that can help. They may not necessarily have the specific answer, but at least they can give you clues and ideas where to seek the right answer.

So, I think that would be my advice, is not to settle for whatever you’ve been told and just go with it. I think it’s important to always seek more answers, because a lot of people will have a lot of questions and it’s important not to settle on accepting anything that is not convincing if it is not convincing. So, there’s always help, there’s always resources if you try to reach out.

Patricia Rios:

Thank you both for spending this hour with us and for those wise recommendations. We really appreciate all the work that you’re doing in this space, and thank you for supporting our community.