Disease State Overview of Current Advanced Nonmelanoma Skin Cancers

In this roundtable session, expert dermatologists discuss how to define types of advanced nonmelanoma skin cancers, specifically advanced cutaneous squamous cell carcinoma (aCSCC) and advanced basal cell carcinoma (aBCC). This discussion elaborates on the epidemiology and pathophysiology of these carcinomas, as well as risk factors and warning signs to be aware of. 

This is Part 1 of 3:

• Part 1: Disease State Overview of Current Advanced Nonmelanoma Skin Cancers
• Part 2: Clinical Approach to the Diagnosis & Management of aCSCC and aBCC
• Part 3: Clinical Challenges and the Evolving Landscape of aCSCC and aBCC

Dr Todd Schlesinger: Okay, welcome to the HMP Advanced Nonmelanoma Skin Cancer Disease State Roundtable, which I'm excited to be here with my esteemed colleagues.

My name is Dr Todd Schlesinger. I practice in Charleston, South Carolina at the Dermatology and Laser Center of Charleston. I will allow my colleagues here, who are all experts in the field of skin cancer and dermatology and some cosmetics, to talk to us. Tell us about yourself just a little bit, where are you from?

Dr Harrison Nguyen: My name is Dr. Harrison Nguyen. I'm a dermatologist, Mohs surgeon, and clinical researcher in Houston, Texas in both private practice and academics.

Dr Aaron Farberg: Aaron Farberg, board-certified dermatologist and Mohs surgeon based in Dallas, Texas with Bare Dermatology.

Dr Mark Kaufmann: I’m Mark Kaufmann, I'm a board-certified dermatologist in South Florida and chief medical officer of Advanced Dermatology and Cosmetic Surgery.

Dr Todd Schlesinger: Yes, and I'm a board-certified dermatologist as well and Moh's surgeon in Charleston.

So let's keep going. So our agenda today, we have a lot to talk about. We're going to talk about the, talking about advanced squamous cell and basal cell carcinoma today.

We're going to go through a few themes. First theme is going to be the overview of the disease state. We'll talk about the disease state of advanced nonmelanoma skin cancer.

We'll talk about the clinical approach, the diagnosis of advanced cutaneous squamous cell carcinoma and basal cell carcinoma. We'll take a short break. We'll go to the, we'll talk about the clinical challenges of the evolving landscape of advanced cutaneous squamous cell carcinoma and the advanced basal cell carcinoma landscape.

So we're so excited for you to be here and I think it'll be a fun program and have a lot of good interaction with our, with my colleagues here who I respect tremendously for their contributions to the field, and their contributions today.

So let’s go through some of the objectives. So it's our objective today to provide a disease-state overview on advanced skin cancer. Specifically, we're going to talk about cutaneous squamous cell carcinoma and advanced basal cell carcinoma.

We'll go over the diagnostic approaches. This is something very important for us to think about in our clinics. So we see these patients every day, what contributing factors are there for these diseases in our patients? What makes these tumors more likely to progress and advance? What are we doing about the management of these tumors as well? We'll certainly spend some time in the unmet needs. There's certainly a lot of unmet needs for advanced basal cell carcinoma and advanced cutaneous squamous cell carcinoma that we see in our clinics.

And then we'll talk about the future landscape of these diseases. So what are we going to do for these patients in the future and how we're going to do a better job at managing them? So we'll start with theme 1.

Theme 1 is an overview of the current advanced nonmelanoma skin cancer disease state. We'll talk about that. Let's throw this to Dr. Farberg. So how do you define the types of advanced non-melanoma skin cancers in your clinic specifically when it comes to squamous cell carcinoma and basal cell carcinoma?

Dr Aaron Farberg: Well, I would say what is cancer to begin with? Well, it's a rapid division of cells. And we name the cancers after the cells that are going AWOL. In this case, we're talking about cutaneous squamous cell carcinoma. And so it's this rapid division, and what's causing it? It always comes down to the genes. And so there's some sort of genetic mutation. What's causing that? Oftentimes it's going to be UV radiation, as we're used to, all the sunlight. We're filming here in Miami, so of course we're always getting lots of sun.

And at some point you develop a tumor mutation burden that just becomes overwhelming and you then develop a cutaneous squamous cell carcinoma. What's an advanced squamous cell carcinoma? Now we're getting to more details. I'd love to hear what other people have to say. But really it comes down to the number of high-risk features. And this is where – coming from Texas – it’s the Wild West. You might define high-risk squamous a little different from what I do, and there's a bunch of different guidelines that define it in a variety of ways.

Dr Todd Schlesinger: Which we'll talk about. So I'll just give a little overview of what we understand about basal cell carcinoma. It's an aberrant hedgehog pathway. So there's an embryonic pathway that's normally quiescent in adults, in adult humans. This is called the hedgehog pathway. Now the hedgehog pathway in the embryonic state is important for differentiation. So that's an active pathway in differentiation. What it normally should do is shut down when we become an adult.

But due to these same factors, due to genetic factors, UV, intrinsic factors, extrinsic factors, or maybe even immunosuppression, mutations occur along this pathway. This is a transmembrane pathway that leads to cell signaling and then ultimately transcription inside the cell. So, when this pathway is abnormal, these cells grow undifferentiated. They are basal cell carcinoma and they become advanced as well.

And then Dr. Farber, can you tell us a little bit about the pathogenesis of squamous cell carcinoma?

Dr Aaron Farberg: There's a number of different genes. I love the way that you describe the basal cell side of things. When I'm talking to residents and I'm trying to illustrate or simplify it, there's a gas pedal and then there's a brake. And essentially, you have a problem with the brake and so your gas pedal is left going at all times.

On squamous cell, there's a number of different gene sets, mostly driven by UV radiation, that can lead to cutaneous squamous cell, too.

Dr Todd Schlesinger: Excellent. Excellent explanation. Dr Kaufmann, what are your thoughts on the risk factors and warning signs? What do you look for when you're seeing patients in clinic with these tumors, and how do you stratify what you're looking for, is what's going to make these tumors grow faster or be bigger?

Dr Mark Kaufmann: Well clinically, we certainly look at the size of the tumor, the location of the tumor, the characteristics of the tumor, is it ulcerated, is it, there are things that we all as dermatologists look at and say this is going to be a nasty tumor. And so it's kind of what Aaron [Farberg] was describing as well that it's the kind of thing where it's different subjectively versus objectively, but most of the time we know when we're going to be dealing with something that is going to be a high-risk tumor.

Dr Todd Schlesinger: Excellent. Dr Nguyen, tell us a little bit about some of the risk factors you think of, location, whatnot. When you're looking at a patient on a Tuesday morning at 10 o 'clock that's come in with a big tumor on their face, what are you thinking?

Dr Harrison Nguyen: Well, to Dr. Kaufmann’s point, we really integrate the whole patient. So we think about how big the tumor is, the location, so especially location on the ear I worry about, on the lip I worry about, if it's occurring in a scar, that is a higher risk.

And then we have to integrate the whole patient picture. If the patient's immunosuppressed, then they're at 50- to 100-times higher risk for nodal metastasis and an adverse disease event.

And then we also integrate things that we'll talk about once we get to staging. We look at different pathologic characteristics, invasion and depth of the tumor. And then also we think about, with the context of squamous, 95% of these tumors are easily resectable. They don't cause any major issues. But that 5%, those 5% are the ones that can create normal metastasis, recurrence, and potentially mortality. And so, our task as a field, and we've really grown a lot in the last decade, is to be able to stratify, identify the patients that are at high risk so that we can appropriately manage them.

Dr Aaron Farberg: You're absolutely right about that. You think about all the factors that we just mentioned, they're in a variety of our different staging systems. And, hey, we do a pretty good job. For the most part, we're able to identify high-risk and low-risk patients. But there's inherent limitations to staging. Sometimes we're going to stage patients as low-risk, and they're going to go on to have a metastasis and potentially die.

And the opposite side is true too. We have patients that we otherwise think are going to be high-risk, but they go on and they have no issues. And so really identifying and stratifying patients within this disease state is incredibly important. One of the other things I add in with my risk stratification is actually looking at the genes, molecular profiling. So we use gene expression profiling with our high-risk squamous cell to better identify each individual's risk.

Dr Todd Schlesinger: I think that’s so key.

Dr Harrison Nguyen: So then Dr. Farber, how do you deploy gene expression profiling, in particularly with squamous? When do you decide to order that?

Dr Aaron Farberg: Essentially, if, as you just discussed, it's difficult to identify which of those 5% those are going to be. And the reality is, is that's not a small number. If it was your mom or your dad, you'd want to know, are you going to be – it's not a needle in a haystack – are you going to be that one that goes on to have a bad outcome? So really, I utilize GEP anytime I have a high-risk squamous cell, and I often define that through the Brigham and Women’s criteria, which we'll get into a little bit more detail. But then I modify it as well. As we talk about some of these factors, I care about immunosuppression. Brigham and Women's doesn't include it. Perineural invasion, of course that's important, but you know what also is important? If you're tapping on an area and you have this dysesthesia, of course. Do I need to see that there's perineural invasion to know? Of course not. We know just from the sensation, it's wrapped around that nerve.

Dr Todd Schlesinger: Yeah, we define that as clinical perineural invasion versus incidental or focal perineural invasion, which is what we see under the microscope. And so that therein lies a challenge for us because that definition has been a moving target over time.

Dr Mark Kaufmann: I think the gene expression profiling actually does show you that sometimes we can't get the whole picture just from our clinical and even objective criteria. And I think it is important to remember that, despite our best efforts at clinically identifying or even histologically identifying, that sometimes it requires gene expression profiles.

Dr Todd Schlesinger: Fantastic. All right. Well, let's keep going. So, continuing to talk about the overview, the disease state overview. I think we covered the pathophysiology pretty well. We covered the molecular drivers of... So, for squamous cell carcinoma, of course, you know, we know there's a number of genes that are involved. Dr. Farber, if you want to take a little bit more on some of the mutations you see, if not, that's okay, we can keep going.

Dr Aaron Farberg: I'm not the molecular geneticist. I'll let you cover all those gene sets for me.

Dr Todd Schlesinger: Okay. No, I…

Dr Aaron Farberg: That's what I thought.

(Laughing)

Dr Todd Schlesinger: There are so many, but so we'll keep going. Let's see what else there is.

Dr Aaron Farberg: A bunch of alphabet soup, really.

Dr Todd Schlesinger: We've covered this pretty well.

Okay, so what are we seeing on our clinics? So what are the trends? Are we seeing a higher number of cases in the clinics? I think it's clear to us all that the prevalence of skin cancer is going up overall. Any opinions on what you're seeing in clinic that helps you think about that in a different way?

Dr Harrison Nguyen: Well, we see this both clinically and epidemiologically. The incidence of skin cancer is growing. It's with the aging population. We're getting better at detecting these tumors. And now that the incidence is increasing and the detection is increasing, we need to get better at being able to manage and be able to stage these patients.

Dr Aaron Farberg: I think I've been seeing more and more of these skin cancers, and the shift has been going from, oftentimes we'll see more basal cells to I'm seeing more squamous cells. And I'm seeing these tumors in an earlier age group. One of my mentors had seen maybe a total of 5 squamous cells on anyone under 40. That's quite rare. I've already seen that number and I'm very early in my career. So I'm a little bit nervous as to where these trends are going.

Dr Todd Schlesinger: People are living longer. They're getting more sun. We certainly have a shift toward a more outdoor lifestyle. I live in South Carolina. So in South Carolina we have workers who are in their 20s who are installing pools. So if you're in a concrete, dry pool working on the concrete, you're exposed. So we're seeing, we say, young folks who are in their 20s and 30s that are getting basal cell carcinomas from this chronic sun exposure. So it is a concern, because what does that person have to look forward to? A lifetime of risk of skin cancer, or multiple skin cancers over time. So that’s certainly a concern.

Dr Aaron Farberg: And immunosuppression. That's another advent of medicine. We have a lot more patients that are immunosuppressed either through organ transplant or a variety of different medications that we have, allowing these patients to live longer. But the sequelae now is dealing with the nonmelanoma skin cancers that come along with it.

Dr Todd Schlesinger: So I think that brings up an important point that you make, that how important is to have that conversation with our patients about what those risk factors and talk to them about how they can help reduce the incidence of skin cancer in themselves by cutting sun exposure, maybe there's nutritional things they can do, maybe there's, use sunscreen more often, protect yourself when you're outside. All the things that we tell our patients to do every day, but it's especially important in patients that are immunosuppressed.

Dr Aaron Farberg: Exactly. I tell them every little bit counts. We know this data from even smoking. You could have been smoking cigarettes for 40 years, and a lot of my patients will think, "Well, why quit now?" Well, we have great data to show that when you quit, it does improve your overall health.

Same thing when it comes to sun exposure. It's always a big topic with all of my patients. If you can at least limit your sun exposure, some sort of way, you develop some sort of moderation. Maybe you're not golfing during the prime time of noon but you're choosing the morning hours or even twilight. Every little bit counts.

Dr Todd Schlesinger: I've got a few patients who really take that the heart and they go out there all wrapped up in the golf course and they, they're doing everything and say, “Doc, I'm doing everything you tell me to do.”

Dr Aaron Farberg: I had one patient, on his riding mower he installed a bunch of LED lights just so he could mow all his grass at nighttime. So if they choose not to, I make sure I give them my cards so they can pass it out to all their friends, because they're going to need my help.

Dr Todd Schlesinger: That's right. That's right. All right. Good. Okay. So, risk factors. So I think we talked about these to some extent, but any other risk factors you would consider besides what we've talked about, immunosuppression, tumors, subtype and location. So a little bit more of the pathology side of it. Anything else you think of?

When I think of some of the sleeper tumors that can be high risk but may not appear that way is a preauricular tumor, I think that's a particularly high-risk area of the skin on the face, and also scalp. What I've seen in my clinic, a squamous cell carcinoma of the scalp can present very differently. It sometimes presents completely subcutaneously. It's not even on the surface. It's all underneath, and it could be a painful lump, it could be, just an atypical presentation. It could mean an advanced squamous cell carcinoma on the scalp.

Dr Aaron Farberg: Any idea why that is the case from the scalp or even preauricular? Because I have my own theories. I just, for me, I always worry about these areas because I know, as a Mohs surgeon you're always worried about a variety of underlying structures.

Dr Todd Schlesinger: Yeah.

Dr Aaron Farberg: And so, again, we're all doing the right thing when it comes to Mohs, and it’s going to be 99%, but when you're in this area, I feel like you're almost cutting it a little bit closer to the tumor than what you should be.

Dr Todd Schlesinger: I've got a couple of different opinions on that. My first one is embryonic fusion planes. There's something we'd think of already, so we all think about that.

But my other thing comes down to a little bit more about technique. So when we're in these areas, we're always going to be worried about what's behind it. And when you're in the preauricular area, we know it's a lot of structures there. We've got nerves, we've got vessels, we've got the parotid gland. So it could be that we're careful about taking deep layers in these areas. And because we don't want to take deep layers, we may end up not getting as big of a margin.

Plus, the other thing, and everybody can comment on this as well, but the more Mohs layers you take, the less accurate you become. Especially when you're getting into subcutaneous fat and tissues, you're really, it's not as easy as that first layer when you get a nice clean cut with epidermis and it lays down on the slide perfectly and you can see all the margins well. So I think that's another thing. The higher the number of stages of Mohs equals higher risk.

Dr Aaron Farberg: True.

Dr Todd Schlesinger: So.

Dr Harrison Nguyen: We've talked about UV radiation, we've talked about immunosuppression. The other etiology that's worth mentioning is HPV. The HPV virus also has a role in the pathogenesis of some squamous cell carcinomas. We still don't really understand about whether or not treatment of HPV, administration of the HPV vaccine, is helpful for decreasing the incidence of squamous related to HPV. But it is a risk factor worth mentioning.

Dr Aaron Farberg: Are you making a recommendation for the vaccine to your patients or? (Laughing) Who, what, when where, yeah?

Dr Harrison Nguyen: Yeah, for my immunosuppressed patients, I make a recommendation for that. We don't routinely test SCC for the presence of HPV, and so it's not going to impact all our SCC patients. But for the ones who are immunosuppressed or have a genetic condition, which would make them more susceptible to HPV carcinogenesis, then I think a vaccine is beneficial.

Dr Todd Schlesinger: It's interesting how you're bringing that into cutaneous squamous cell carcinoma, because historically we always thought of HPV as being more of a concern for head and neck squamous cell carcinoma, which is a very different animal from the skin, but that's interesting that it could be also affecting the skin as well. So I think it's interesting postulation, and I'll certainly be thinking about that in my clinic as well.

Any other thoughts on risk factors that you would think for your patients? Of course, we have light-skin patients and things like that that we talk about.

Dr Aaron Farberg: For me, it's pretty simple. Are you a farmer? Are you a golfer? Or do you have a home in Florida? (Laughing) If you're the trifecta, you're going to have a nonmelanoma skin cancer.

Dr Todd Schlesinger: Not in Texas? Texas doesn't count?

Dr Aaron Farberg: There's something unique about a home in Florida.

Dr Todd Schlesinger: Fantastic. So you may have both.

Dr Mark Kaufmann: Or an organ transplant.

Dr Aaron Farberg: That too.

Dr Todd Schlesinger: Or an organ transplant, of course.