Bladder Cancer Variants: What Patients Must Know

January 28, 2025

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Transcript

Rick Bangs:

Hi, I’m Rick Bangs, the host of Bladder Cancer Matters, a podcast for, by, and about the bladder cancer community. I am also a survivor of muscle-invasive bladder cancer, the proud owner of a 2006 model year neobladder, and a patient advocate supporting cancer research at the Bladder Cancer Advocacy Network, or as many call it, BCAN, producers of this podcast.

I am pleased to welcome Dr. Ashish Kamat, returning for the fourth time on Bladder Cancer Matters. Dr. Kamat is an endowed Professor of Urology and Cancer Research, and Director of Bladder Cancer Research at MD Anderson Cancer Center in Houston, Texas. He is also Founding President of the International Bladder Cancer Group, the IBCG, and a member of the Bladder Cancer Advocacy Network’s Scientific Advisory Board. Dr. Kamat’s expertise is in multidisciplinary management of urologic cancers, with an emphasis on bladder and prostate cancer, organ sparing therapies, minimally invasive techniques and bladder replacements, like my neobladder. A major focus of his research is to develop novel treatments for bladder cancer and identify resistance mechanisms and ways to overcome them. Welcome again, Dr. Kamat.

Dr. Ashish Kamat:

Thank you so much, Rick. Always a pleasure to be here with you and our audience.

Rick Bangs:

Always a pleasure to have you. So, your International Bladder Cancer Group and the Global Society of Rare Genitourinary Cancers recently co-hosted a meeting focused on a group of bladder cancers called variants, which are now categorized as histologic subtypes. And this group can behave differently than plain vanilla urothelial cancer, which is the most common version. So I thought it would help if we could start by explaining, what are subtypes and what are histologic subtypes?

Dr. Ashish Kamat:

Yeah, I’m glad you asked that question, Rick, because oftentimes I’ll have patients who will come to see me and first off, they haven’t even been informed that they have a variant or a histologic subtype. Second, if they have been informed, it’s very unclear in their minds as to what that means. Right?

Rick Bangs:

Right, right.

Dr. Ashish Kamat:

So as you mentioned, the most common type of tumors that occur in the bladder arise from the so-called transitional epithelium, and that’s why they’re known as urothelial cancers, but there are different cells that reside in the bladder and/or sometimes the bladder cells themselves. The urothelial cells change or disguise what they look like in order to evade the normal defense mechanism that we as humans have. And when they become these variant histologic subtypes, a variant essentially is a variance from the normal. And histologic subtype essentially means that it’s histology. So anytime it’s anything different from the urothelial transitional cell carcinoma, which is again the most common type, that’s known as a variant histologic subtype.

Now, there’s a little confusion between variant and subtype, but that’s just nomenclature. I think for patients that are listening in, anytime you have something that’s not the garden variety urothelial cancer, consider it a variant or a histologic subtype.

Rick Bangs:

Okay, and now how common are these going to be in cancer and specifically in bladder cancer?

Dr. Ashish Kamat:

So, they’re not very common when it comes to bladder cancer. And in fact, many a times there are urologists and urologic oncologists who may not ever see a patient with a variant histology ever in their lifetime. Right?

Rick Bangs:

Wow.

Dr. Ashish Kamat:

Yeah, exactly. So it’s not very common, and I think it’s very important for patients to know that, because it’s not that their treating physician could not have extensive book knowledge about their disease, right? Because you assume that most people taking care of patients have studied, have passed their exams and are well versed in the book knowledge. But it’s rare enough that practically speaking, sometimes a physician may never have seen one and never have had dealt with a patient themselves that has a histologic subtype.

So it is gaining more recognition, and that’s why in some contemporary series, as many as one in 10 patients will have some element of histologic variants, but previously it was only one to 2%. So today I would say about 10% of patients will have some element of histologic variants in their bladder cancer.

Rick Bangs:

And I think the word element there is really important.

Dr. Ashish Kamat:

Absolutely, because like I said, most patients will have the urothelial carcinoma, and mixed in that urothelial carcinoma, there’ll be some element of a histologic subtype. Now, it’s not that they’re purely different, but there’s a mixture, and sometimes the mixture is what drives the behavior of these tumors.

Rick Bangs:

Okay, and are there specific variants that patients need to be particularly concerned about?

Dr. Ashish Kamat:

So I think it’s very important as a patient to first ask, “Hey, is my variant a true variant or is it just a change in the cell type that makes my tumor different?” Because there can be certain changes, such as if a tumor’s been in the bladder for a long time, it can develop some squamous differentiation.

Essentially, squamous skin, and if a tumor is bathed in urine and the minerals for a while, it develops a sort of a skin layer, that’s squamous variant, but it’s not like it’s changing in order to evade the defense mechanism. That’s just a normal skin forming on it. Or, if a tumor has been in the bladder for a long time, sometimes that develops some glandular features. So you have a little bit of adenocarcinoma add, mixed with the urothelial. Those are considered just a marker of a little bit more aggressiveness. Again, nothing to be taken lightly, but most urologists will have seen that many times in dealing with patients. If a tumor on the other hand is purely squamous, which means it never was urothelial to begin with but completely arose from different cells, or purely adenocarcinoma, that is completely different.

So first off, ask the physician, “Hey, is my tumor just showing some mixed elements in the natural history of the disease or is it something truly unique? And some of the more unique ones are micropapillary, lymphoepithelial, carcinoma, small cell carcinoma, and others, which are even more rare than the ones I mentioned.

Rick Bangs:

Wow, and is smoking, which we know, we both know, and our listeners may recognize as the most common cause of bladder cancer. Is smoking more likely to cause certain variants or are there other environmental causes associated or are there risk factors with these variants?

Dr. Ashish Kamat:

There are, Rick, and again, not to get too much into the weeds because these are rare to begin with and I don’t want to confuse our listeners too much. But in general, the reason some people feel that smoking leads to more squamous differentiation is because of smoking and the association of squamous cell carcinoma in the oral cavity, head and neck, ears, nose, throat, etc. That’s not really true in the bladder though. It’s not that smoking is more closely associated with squamous carcinoma in the bladder.

Ironically, squamous carcinoma in the bladder is more associated with other irritants because clearly, cigarette smoke will not bathe the bladder for that long. But infections, stones, for example, people that live in the Middle East or parts of Egypt, there’s common parasites will develop a lot more squamous carcinoma in those regions.

Rick Bangs:

All right. And now, how would I know as a patient if my bladder tumor includes a variant?

Dr. Ashish Kamat:

Ask the question always. In fact, in general, the patients should always ask us physicians, “What is the type of bladder cancer I have? And is it routine type of bladder cancer or is there anything different about it?” So ask an open-ended question, and more often than not, your physician will maybe have to check the record again and say, “Hey, yes, it is routine, or no, there is some element, but it’s a small percentage and that’s why I didn’t mention it to you.”

Rick Bangs:

Okay, and I think the answer to this question is going to be the same, but how can I be sure that my tumor does not have a concerning variant? Is the answer the same there, to ask?

Dr. Ashish Kamat:

There it’s a little bit more than asking because like I said, many physicians will never have seen this and many pathologists will not have seen this, right?

Rick Bangs:

Right.

Dr. Ashish Kamat:

Again, not that they don’t know about it, but they may not see it themselves. And especially if you are a patient listening in and you’re in a smaller town, a smaller community practice, keep in mind that the pathologist is dealing with tumors from every organ in the body and has to report on breast cancer, lung cancer, prostate cancer, and bladder cancer. So they may not think it as important to reveal the histologic subtype in the tumor. So, ask if A, your urologist has read that there’s something different in the report, and B, if the urologist feels that this tumor should be sent somewhere else to a larger pathology facility for a second opinion.

Rick Bangs:

Okay, so it sounds like most variants aren’t going to change my treatment options, but can we be a little bit clear on which ones do change my treatment options and which ones don’t?

Dr. Ashish Kamat:

Yeah, just to rephrase that, the most common variances will not change the treatment option, much other than recognizing they’re more aggressive. But that doesn’t mean that the variants themselves don’t change the treatment options, right? Because if you take the non-mixed or the non-progressive, so in other words, squamous differentiation, adenocarcinoma differentiation, if it’s a small percentage, that’s considered just a feature of the tumor being a little bit more aggressive, and it doesn’t change the treatment option that much.

On the other hand, if the patient has small cell carcinoma, that changes the treatment completely. Number one, bladder preservation with intravesical chemo or BCG is not even indicated remotely, because it just doesn’t work. And small cell carcinoma is so aggressive that you almost have to consider that it’s a systemic disease that you just happen to find it in the bladder first, but you have to treat the whole patient with chemotherapy before you do anything in the bladder.

Similarly, with micropapillary disease, that is a indicator that intravesical BCG is much less likely to work. Not that it cannot in very, very selected patients, but that’s where it’s very important that the patient is seen by a urologist or urological oncologist that knows the nuances, because unless you know the nuances of which patient can safely have their bladder spared, trying to spare the bladder is condemning the patient’s life.

Rick Bangs:

Okay, so if I’ve been told that I have a variant, what questions should I ask the doctor?

Dr. Ashish Kamat:

I think just be honest with the doctor and say, “Hey, have you seen this variant before? And do you have an experience treating it? If not, could you please refer me to someone who does?” And I think most physicians would appreciate that honest discussion with the patient because again, it’s very important that the patient sees someone who has dealt with these variants.

Number two, when you actually meet with your doctor who has dealt with these variants, be open with the doctor and say, “I want to know X, Y, Z,” or just say, “I want to know what my treatment is, and I don’t really want to know the details.” Because we as physicians sometimes don’t want to overburden our patients with all the nuances because it leads to more confusion and sometimes more despair. On the other hand, some patients like to know the nuances, so I’m willing to sit and talk to my patients in as much or as little depth as they would like when it comes to these nuances of treatment.

But more importantly, I think the patients should ask us, “How does this change my prognosis? Number one. My treatment options, number two. And number three, what is the safest overall course that I should take?”

Rick Bangs:

Okay, so we started touching on something I want to ask a couple of different flavors of. So if I’ve got variants, would it impact my ability to participate in a clinical trial? And second, would I be more motivated to get a second opinion?

Dr. Ashish Kamat:

Yeah, I think you should be more motivated to get a second opinion, simply for the reasons that I mentioned earlier. They’re not always easy to deal with. In fact, just this weekend, not weekend, but over the holidays, I had multiple folks reach out to me on social media, in fact, about them or someone in their family having variant histology and can they come see me? And of course, I’m more than happy to refer them to folks that are closer to where they live, but that sort of a reach, outreach is very important, right? It’s very important that you reach out to people and see if you can be either referred to someplace where there are experienced physicians, or if your physician themselves are experienced, that’s great.

Clinical trials, unfortunately have for the most part, excluded patients with histologic variants, simply because many folks don’t know how they behave and don’t want to, in some ways muddy the results of the clinical trials. Because if you don’t know how a drug is going to behave in a patient with a variant histology, then again, you have to respect the companies and all the investment they’re making. They don’t want to take a risk with something they don’t know is going to respond or not respond. So ironically, most clinical trials will exclude patients with pure histologic variants or predominant histologic variants.

More recent trials have allowed patients with a small percentage, either 10, 15, some up to 25 histologic variants to enroll in studies. And that’s great, because now we’re gaining a little bit more insight into what some of these drugs in the clinical trial are going to do or what effect they have on patients that have the histologic variants. But prior to that, nobody knew, nobody knew how the drugs would act. Nobody knew what the right treatment was until you actually tried it out in their real world once the drugs were actually approved.

Rick Bangs:

Excellent, so this is really fascinating. Any final thoughts?

Dr. Ashish Kamat:

No, I think the final thought is that it is a very, very important part of a patient’s journey. It’s almost as important as finding out that you have bladder cancer, because first off, when you bladder cancer, you’re going through the whole, is it low grade, high grade, what stage it is. And knowing what histology, what type of cancer you have, it is just as important, because armed with that knowledge, it’s a partnership. I mean, the patient and us need to embark on the journey together. And I really think that the more information the patients have and the more they are seeking folks that have experience with these variant histologies, the better the outcomes are.

Rick Bangs:

I completely agree. All right, Dr. Kamat, I want to thank you for helping us better understand what having a bladder cancer diagnosis that includes a variant, means to patients.

Dr. Ashish Kamat:

You are more than welcome.

Rick Bangs:

If you’d like more information on bladder cancer, please visit the BCAN website, www.bcan.org. In case people wanted to get in touch with you, could you share some contact information?

Dr. Ashish Kamat:

Absolutely. I think the easiest way is through BCAN, because BCAN has different ways of tracking me down. But otherwise, my email at work is [email protected]. And of course, my social media, Twitter or X handle is Urodocash.

Rick Bangs:

Okay, thanks. Just a reminder, if you’d more information about bladder cancer, you can contact the Bladder Cancer Advocacy Network at 1(888) 901-2226. That’s all the time we have today. Be sure to like, comment, and subscribe to this podcast so we have your feedback. Thank you for listening, and we’ll be back soon with another interesting episode of Bladder Cancer Matters. Thanks again, Dr. Kamat.

Dr. Ashish Kamat:

Thank you, Rick.