Challenges in Risk Stratification for Patients With Cutaneous Squamous Cell Carcinoma

Shannon Trotter, DO, FAOCD, FAAD, DOCS Dermatology, Columbus, Ohio, discusses the challenges when it comes to risk stratification of patients with cutaneous squamous cell carcinoma (cSCC). 

Dr Trotter concluded, taking all the different factors taken together “makes it a very complex issue to really stratify people consistently based on high risk features.”

Transcript:

I am Dr. Shannon Trotter, board certified dermatologist. I practice in the Columbus, Ohio area with DOCS Dermatology.

There are a lot of challenges with stratifying patients that have high-risk cutaneous squamous cell carcinoma. And part of the problem is high-risk can mean different things to different people. And this is really illustrated by the fact that we have 2 different staging systems. We have the AJCC and the Brigham and Women's Hospital Staging System, which take into account histopathological features, which are helpful, and they also include some additional features. Brigham women adds in size. The AJCC also adds in location. Now, if you look at guidelines, we have the NCCN guidelines, and they're more of a combination. They're more of a consolidate or comprehensive look that include patient characteristics in addition to histopathological features. When you line up these 3 systems, it can be confusing because they're not the same.

So the definition of high risk can vary amongst clinicians, and it's also based on personal experience as well as clinical gestalt and what people might consider high risk. For example, you might have a well-differentiated squamous cell carcinoma, and most people might think, okay, that's low risk. But when you add on the history that the patient is immunosuppressed, all of a sudden the tables are turned and now it's considered a high-risk cutaneous squamous cell carcinoma. Again, that's kind of part of the complex nature of it. We have different definitions and perceptions.

And then in addition to that, you have all these high-risk features and you're looking at them and kind of wondering what is the riskiest of the high risk? Is there one feature that you would consider more high risk than another? Does location determine it size? Are you more on the histopathology of what's considered high risk or maybe even gene expression profiling? When we take all these factors into account, it's really muddied the waters for cutaneous squamous cell carcinoma and made it difficult sometimes for us to truly identify who is high risk. And we know based on our current staging systems, they're helpful, but people may use Brigham and Women's or some people might prefer AJCC, so you have personal preferences in how people practice as well.

Taking that all together, it makes it a very complex issue to really stratify people consistently based on high risk features.

For me, high risk is a combination of factors that we look at in a patient, including both histopathological features as well as clinical characteristics of the patient based on history and physical exam.

Definitely head and neck: we know this is a high-risk location. Size to me, is important. Typically people talk about greater than or equal to 2 cm. I've dropped that over time to even down to 1 cm because these tumors have gone on to spread even though they don't meet the 2-cm mark for size. In addition to that, I also look at the patient's history. Is this recurrent? Is this patient immunosuppressed? And yes, I look at what's under the microscope. Poor differentiation is definitely something that I highlight, as well as other high-risk histopathological features that we might see, including depth.

And then finally, also the differentiation piece: this is one thing that I like to talk about a little bit because I've seen this in my clinical practice over the past 15 years, where we always talk about differentiation being important under the microscope. The challenge with that is that it's a grading system. And with that grading system, you can have well-differentiated, you can have moderately and of course, poor amongst that spectrum.

But really what I want to highlight is the aspect of moderate differentiation. This is something that I consider more high-risk than probably your average clinician. And there's a couple reasons why. First, while we grade these as well, moderate, or poor, it's important to remember it's subjective. The dermatopathologist who's reading it could actually call something moderately differentiated and their colleague right next door could call it poorly differentiated. And when you have that variability, there's a lack of reliability. They've done studies to actually show this where there can be a difference of opinion.

Two, our biopsy technique, and this goes back to us often as the dermatologist, our biopsy techniques are often very superficial. They may not be fully representative of the cutaneous squamous cell carcinoma. The dermatopathologist actually might call something moderately differentiated based on my biopsy, but deeper in the tumor where I didn't sample it could be poorly differentiated, so the initial diagnosis could be inaccurate just based on sampling alone. And this is because cutaneous squamous cell carcinomas can demonstrate heterogeneity and I always liken this to a chocolate chip cookie. In the perfect world, chocolate chip cookies have an even amount of dough and chocolate chips. No matter where you bite into it, you know it's a chocolate chip cookie. But if you've got a chocolate chip cookie like I make them, where there might be more areas of dough and less area of chips, you could bite into an area of dough and not even know that it's a chocolate chip cookie. Squamous cell carcinomas can behave the same way. When you actually do a biopsy, if I biopsy just that dough area, or well differentiated tumor, I may have missed the chips, or the poor differentiated tumor, that was deeper down. So that's one of the things I always like to highlight.

Now the last point, three, studies have shown moderate differentiation is associated with extensive subclinical spread as well. I always tell people when you think of moderately differentiated, I like to consider it, yes, relatively maybe high-risk, even though it won't get that full definition or title, but maybe think of it more as problematic. I think it is a challenge for us that we have to be aware of. For me, I like to include it in my concept of what I considered high risk for cutaneous squamous cell carcinoma.

Source:

Beach SC, Cusick AS, Farberg AS, and Trotter SC. A comprehensive narrative review of the challenges surrounding cutaneous SCC. Dermatology and Therapy. Published on: June 23, 2025. doi: 10.1007/s13555-025-01470-7.