Risk stratification in cutaneous squamous cell carcinoma (CSCC) has grown considerably more nuanced over the past decade, expanding from a binary surgical triage tool into a multidimensional framework that accounts for both tumor biology and host immune status. The emergence of the National Comprehensive Cancer Network (NCCN)’s “extremely high-risk” designation, and the clinical trial data supporting adjuvant cemiplimab-rwlc (Libtayo) in that population, has introduced immunotherapy as a postoperative option for a defined subset of patients, according to Vernon Sondak, MD.1,2
“If [we’re dealing with] a very bad recurrence, local regional in-transit metastasis, or a tumor that’s so aggressive it’s eating into the bone, and all the disease has to be completely resected and radiated, then we would consider adjuvant immunotherapy. Of course, if the patient’s immune system is compromised [that may pose] a problem,” Sondak said in an interview with OncLive®.
In the interview, Sondak, the Richard M. Schulze Family Foundation Distinguished Endowed Chair in Cutaneous Oncology and chair of the Department of Cutaneous Oncology at Moffitt Cancer Center, and a professor in the Departments of Oncologic Sciences and Surgery at the University of South Florida Morsani College of Medicine in Tampa, discussed how NCCN risk categories guide treatment selection in CSCC, from surgery to adjuvant and neoadjuvant immunotherapy.
Key Points From Sondak on CSCC Risk and Immunotherapy
- The NCCN risk classification system uniquely incorporates patient immune status alongside tumor features, making it Sondak’s preferred framework for CSCC.
- Nodal features including lymph nodes ≥2 cm, involvement of ≥3 nodes, or extranodal extension and select non-nodal features (in-transit metastasis, bony invasion, or clinical perineural invasion) define the “extremely high-risk” category that may warrant adjuvant cemiplimab.
- Organ transplant recipients with CSCC should not receive adjuvant immunotherapy given the risk of rejection; treatment decisions in this population require careful individualized assessment.
OncLive: What clinical or pathologic features most reliably identify patients with cutaneous disease who are at higher risk for progression or metastasis? How has risk stratification evolved in recent years?
Sondak: Risk stratification for squamous cell cancer has evolved incredibly over the years and become so much more complicated. One of the real problems is that the various risk stratification systems aren’t always trying to predict the same outcomes, the same problem. If the problem is different, you’re going to have different groups. It started historically as a simple question for the dermatologist: Is this a really low-risk lesion for local recurrence and extensive local spread? If it’s low risk, I can just shave it off. I can freeze it off. I can do an electrodesiccation and curettage. I can do something very simple with just a tiny bit of local anesthesia. Or is this one that’s going to be hard to get rid of unless I map it out, do something like either a very wide excision or a Mohs type surgery that will map out the fingers of the tumor, the irregularity, and allow us to get it completely removed?
The first risk stratification [systems] tended to simply ask, is this an easy [lesion], or should I send this to a Mohs surgeon, a plastic surgeon, or a surgical oncologist to take care of? [Guidelines] focused on things like the size of the tumor, but even more so, where it was on the body. Is it on your nose? Is it on your cheek? Is it on your fingers and toes? [If so], it’s not going to be easy to take care of. That’s going to have to go to somebody more specialized [because] some histologic features of the differentiation and the infiltrative patterns could tip you off that the disease needs more aggressive local treatment. That terminology has persisted in [our understanding of] low risk and high risk. A low-risk skin cancer, whether it’s basal or squamous, is small. It’s on a part of the body where you can take a lot of tissue very easily and still sew it shut. It’s relatively well differentiated. It’s not showing problems like perineural invasion, so it’s easy to treat surgically and you can expect a very good outcome. A high-risk lesion in this paradigm is larger. It’s in places like the head and neck or the very distal extremities, where it will be hard to get a good margin or it’s already recurred or it’s very poorly defined, or it’s come back after prior treatment. It [may even have] some of this perineuronal infiltration and invasion that suggests it might be traveling a little wider than what you could see, and a narrow surgery would get rid of it.
As we’ve added to our thinking about this risk classification, we realize that the patient is also a factor here. It’s not just the size of the tumor and the location. What about the patient? If the patient has a compromised immune system, if they have a kidney transplant or a liver transplant, or they’re on powerful immunosuppressive medications for any number of conditions nowadays, those are people who are more likely to get skin cancers, more likely to get multiple skin cancers, and more likely for those cancers to grow rapidly, spread, and recur. Even if we do unlimited surgery, [the disease] will eventually metastasize and kill the patient. As we evolved our guidelines and started to say that it’s not all about the tumor, it’s also about the patient, putting immunocompromise in as a high-risk factor was important. Putting recurrence after prior surgery in as a high-risk factor became very important.
I like to use a guideline that reflects both the tumor and the patient. Not every staging or classification system does that. In fact, for melanoma, for Merkel cell, for colon cancer and breast cancer, they don’t do that. They don’t add the patient in there. You get your TNM classifications from the AJCC. It’s 100% about the tumor. But in skin cancers, that immunosuppression is so influential and has to be taken into account when we think about risk stratification. We might as well put it into our classification system and the system that does this, the system that I tend to use, is the NCCN risk classification. They have one for both squamous and basal cell [cancers]. The low-risk definition is very similar for both, and even the high-risk definition is somewhat similar. But because squamous cell has more chance of spreading, the NCCN squamous cell risk tree extends far beyond where the basal cell risk categories are. I like the NCCN system, because it includes patient factors and because these risk categories directly tell us about what kind of treatment we want to be thinking about.
With squamous cell, we’ve got to think about not just getting rid of it locally. What about the chance of it spreading to the lymph nodes or beyond? What about the risk that we might need to give radiation, even if the tumor seemed to have been removed? Now we’re talking about something that only a few high-risk tumors have. Now we’re talking about something that’s very high risk. [Because of that] we had to add another layer onto our risk system, and the NCCN calls it very high-risk when the tumor is very large, when it’s invaded very deeply, when it’s poorly differentiated, and [has] few other histologic features. Now we’re worried about recurrence, even with a more radical procedure that has negative margins, and we’re thinking about radiation. We’re even going to worry that that patient is at risk of spreading to the lymph nodes or beyond. Especially if they’re immunocompromised, they’re going to be at the high end of that very high-risk group.
How have treatment paradigms adapted to the introduction of immunotherapy?
[Neoadjuvant and adjuvant use of immunotherapy] was tried in squamous cell cancer, but [to administer] adjuvant therapy you needed a couple of things to be true. You needed to know who was really going to be at risk, not just of their tumor coming back and needing more surgery, not of needing radiation to get rid of it, not even of just having something in the lymph nodes. Who was really at risk of their tumor spreading wildly through their body and killing them? If you’re going to use immunotherapy to try to prevent that from happening, you have to know who’s at risk and who’s going to be able to tolerate that treatment without prohibitive [adverse] effects. Lastly, can we [administer] it and make a difference? What’s the proof that if we have a patient who we’re really worried about, that immunotherapy is going to improve their outcome? It takes a randomized, controlled trial to answer a question like that, to prove that treating patients with very high-risk cancers with immunotherapy after what seems to be a successful surgery and radiation [is meaningful]. Not every very high-risk patient would fall into that group. Only a few [patients do].
The NCCN came up with a new term: extremely high risk. These are the [individuals] who went on to a large clinical trial large for CSCC. Everyone got surgery and radiation and then half of them got 48 weeks of adjuvant cemiplimab. In this extremely high-risk population, adjuvant cemiplimab dramatically decreased the risk of further recurrence and the risk of distant metastasis. We don’t know for sure if it increases survival compared with waiting until they got distant metastasis and then treating, but it certainly [reduced] the risk of having distant metastasis.
Extremely high-risk features fall into two categories: nodal and non-nodal features. If the disease has spread to the lymph nodes, are these lymph nodes very large, at least 2 cm, are multiple lymph nodes involved, at least 3 lymph nodes, or has the tumor already started growing out of the lymph node into the surrounding tissue? [This is] something we call extranodal extension, sometimes called extracapsular extension, because the node has a capsule around it. Any one of those nodal features in a patient with CSCC puts them into the extremely high-risk category. And we can think about postoperative immunotherapy after a successful surgery and radiation [for these individuals]. There are also some non-nodal features that even for a patient who’s never had their squamous cell cancer spread to the lymph nodes, could be at sufficient risk of spread and even death that we’d want to think about adjuvant immunotherapy for close to a year. This category of extremely high-risk [patients] due to non-nodal features is particularly important to dermatologists [and] Mohs surgeons because they’re the ones dealing with the extremely high-risk primary tumors. But once it’s spread to the lymph nodes, [the patient is usually referred] perhaps to an ear, nose, and throat surgeon or a surgical oncologist to deal with.
How can a dermatologist or Mohs surgeon determine whether a patient is extremely high-risk or just very high-risk?
It gets really complicated then. The first thing is, if the tumor has already started to spread away from the primary site, but not yet into the lymph nodes, [we’re dealing with] in-transit metastasis. You’ve got a main tumor mass and two or three other nodules that are clearly separate or have come back 2 or 3 mm to 5 cm or more away from where the original surgery ended. If you remove that and radiate, you’re still at very high risk, so we would call you extremely high-risk for non-nodal features. If your tumor has grown right into the bone, that is an extremely high-risk non-nodal feature. If the tumor is invading nerves, not just microscopically but causing clinical symptoms, major degrees of perineural invasion can put you into this extremely high-risk non-nodal category. And then recurrent tumors that have already fallen into what would previously have been called a very high-risk category. [This would be] a recurrent tumor that’s large, that’s showing other problems like perineural invasion, maybe not as high as the other clinical ones that we were just talking about, but recurrence plus any degree of perineural invasion. These are the kinds of categories that can fall into this non-nodal [category].
How would you navigate the decision in an immunocompromised population?
I don’t want to give immunotherapy to someone with an immune compromised state. What is it going to do to them? Is it going to cause them to reject their transplanted organ? It might. It doesn’t always, but giving immunotherapy to somebody with a kidney transplant can cause rejection. If you reject your kidney transplant, you end up on dialysis. Many [patients] don’t want to go on dialysis or back on dialysis. If you got a heart, a liver, or a lung transplant, there’s no dialysis. If you reject that, you’re in real trouble. We wouldn’t even [consider] adjuvant therapy for someone even with extremely high-risk squamous cell cancer, if they’ve [received] an organ transplant. There’s no other alternative. We have to wait until it’s life or death and then we’ll roll the dice and do everything we can to preserve the organ and prevent rejection.
Where does neoadjuvant therapy fit into the equation?
In my clinic, the most common type of treatment I use for [patients with] advanced squamous cell cancer is neoadjuvant therapy, [but which population am I using it in]? Is it the high-risk, the very high-risk, or extremely high-risk [population]? It’s none of the above. It’s another group that isn’t reflected in that category at all and we don’t really have a clear definition that everyone agrees on. This group has locally advanced, resectable squamous or basal cell cancer, meaning if I have to, right now as a surgeon, I can resect the disease, but the surgery would be radical enough, the disease is advanced enough [from] one enlarged lymph node. Any one lymph node that I can feel, even if it’s just 1 or 1.5 cm, is enough to make them locally advanced but resectable. A tumor that has perineural invasion that’s quite large, that’s in an area where it would be very deforming and require a very complex reconstruction, is another case of locally advanced, resectable disease. This is somebody we’re going to want to think about treating first to shrink the tumor, observe the response clinically and pathologically, and then decide on postsurgical treatment.
If you have a patient with nodal metastasis, with in-transit metastasis, with bony invasion, with perineural invasion, some of these [features] are going to be [indicative of] high risk, very high risk, or even extremely high risk if there’s tumor present. Don’t rush these patients to the operating room. Rush them to the oncologist and to the multidisciplinary tumor board to talk about multimodality treatment.
What does the future hold?
We’re already doing a lot less surgery for some of these patients after immunotherapy, but we’re almost always doing some surgery. There are places that are saying, ‘Why don’t we just treat first?’ And if they get a great response, not do anything else. That is certainly a feasible potential strategy, but then we have to ask, what does a good response mean? You’re really talking about a complete response [CR]. When we do surgery, a lot of times we find that all the cancer is gone, but we only know that because we took it out. How do we know that without taking it out? How do we know if that lymph node is completely dead without removing it and looking at it under the microscope? If we can figure some of that out, at least in some cases, we might be able to avoid surgery, replace it with radiation, or even just give a few doses of immunotherapy and stop. But that is still a very challenging paradigm. What if it isn’t successful? If they don’t have a CR, you still need that surgery to get them to a potentially curable state. We’re really excited about the potential of preoperative therapy. That’s going to be the next frontier. How do we piece everything together and start de-escalating our treatments instead of adding more treatment? How do we get locally advanced resectable disease to be treated with two doses of immunotherapy and in some cases, nothing else, and in other cases that require more comprehensive treatment. That’s the challenge we face, but it’s one that at least we have some tools at our disposal to begin thinking about.
References
- FDA approves cemiplimab-rwlc for adjuvant treatment of cutaneous squamous cell carcinoma. FDA. October 8, 2025. Accessed June 25, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-cemiplimab-rwlc-adjuvant-treatment-cutaneous-squamous-cell-carcinoma
- NCCN. Clinical Practice Guidelines in Oncology. Squamous cell skin cancer, version 2.2026. Accessed June 25, 2026. https://www.nccn.org/professionals/physician_gls/pdf/squamous.pdf
