Experts Explain the Staging and Treatment of cSCC

In a Targeted Oncology live case-based peer perspectives discussion, Mark Agulnik, MD, and Simon S. Yoo, MD, discussed with a group of physicians the staging criteria and the options for treatment for patients with cutaneous squamous cell carcinoma.

Simon S. Yoo, MD

In aTargeted Oncologylive case-based peer perspectives discussion, Mark Agulnik, MD, and Simon S. Yoo, MD, discussed with a group of physicians the staging criteria and the options for treatment for patients with cutaneous squamous cell carcinoma (cSCC). Yoo, an associate professor of dermatology, otolaryngology—Head and Neck Surgery, and Surgery (Organ Transplantation), Northwestern Medicine, Feinberg School of Medicine, explained risk stratification and staging, while Agulnik, professor of medicine, Hematology and Oncology, Northwestern Medicine, Feinberg School of Medicine, reviewed available treatment options for such patients based on a case scenario.


An otherwise healthy, single, 69-year-old man, fair skinned, retired construction worker presented to his primary care physician with what the patient described as a wound behind his ear that was not healing; he reported first noticing it at least 4 months earlier and complained of recent onset of numbness in the area. His ECOG performance status was 1.

He had a visible ulcerated lesion of 4.5 cm in diameter and >5 mm in depth, but had noo palpable nodes. A biopsy confirmed a poorly differentiated, infiltrative, postauricular, cutaneous squamous cell carcinoma (cSCC) lesion with invasion into subcutaneous fat.

TARGETED ONCOLOGY: What are your impressions of this case? What is the risk status of this patient?

YOO:The question is his immune system, and he is otherwise healthy. So, he’s not immunocompromised.

It’s poorly differentiated [carcinoma], it’s ulcerated. It’s the depth [that makes this high risk], invasion into the fat. He has no palpable nodes, but that would be clearly a risk factor if they were positive. His occupation, [he’s had] chronic sun exposure to get cSCC.

What I find interesting about his case is that the biopsy is so exhaustive. I’ve probably seen 5000 or 6000 cSCCs, [and] I don’t think I’ve ever seen a biopsy that was this definitive or exhaustive in its report. The reason I mention that is its 4.5 cm and they tell you that it’s invading into the subcutaneous fat. Someone must have removed a 4.5-cm lesion or maybe the part that was biopsied had subcutaneous invasion. It’s difficult sometimes because biopsies are [only partially] compared to the whole lesion.

How would you go about staging a cSCC, such as in this patient?

YOO:Most cSCCs are T1. It is worthwhile to go through the Brigham & Women’s Hospital staging because it [has advantages] in terms of sensitivity and specificity compared [with] AJCC [American Joint Committee on Cancer] 7. Comparing to the most recent AJCC 8, I would argue that this staging for cutaneous squamous cells is more specific and has a better positive predictive value for cancers.1

It’s easy to remember because you just have to memorize the high-risk features: tumor diameter of greater than 2 cm, poorly differentiated histology, and tumor invasion beyond the fat, excluding bone invasion. If there’s any bone invasion it will automatically upstage [the lesion]. As an aside, the AJCC 8 does not include histology in their risk factors, so that’s one of the main differentiating features of the Brigham staging system versus the AJCC 8. Not to get into the weeds too much, but it does make a difference in terms of differentiating the T2 and T3 lesions of the AJCC 8 compared with the Brigham staging.

Looking at the 10-year cumulative incidence of tumor outcomes [from the Brigham staging]—the most important thing to look at is the incidence of nodal metastasis.2First of all, you have nice differentiation between T1, T2A, T2B, and T3s. If you do a similar comparison [with AJCC 8], you’d see groupings of the T2s and the T3s. I would argue that the Brigham staging better differentiates the T2A’s and the T2B’s. What’s interesting is the T2B lesions had a relatively high nodal metastasis rate. It’s about 20-plus percent. So, once they get to 2 to 3 high-risk factors, their nodal metastasis rate goes up considerably.

If you have tumor diameter, and as in this situation, a poorly differentiated lesion, you’re already at T2B. This nodal metastasis rate is relatively high. Perineural invasion is important. It does indicate worse prognosis. But, if you look at Chrysalyne Schmults, MD, who came up with the Brigham staging, it’s the size [of the lesion that matters, and] the caliber of the nerve matters. If it’s small [nerves], high in the dermis, it probably won’t matter as much, but if it’s larger nerves, deeper, this is probably a function of how deep the tumor goes. The nerves get bigger as you go deeper.

What is the role of a sentinel lymph node biopsy in a patient such as this?

Mark Agulnik, MD

YOO:At Northwestern, at least for cSCC, the head and neck surgeons are loath to do a sentinel lymph node biopsy. There haven’t been good prospective data on that. And, at least at our institution, they’re not doing it. Even if we ask them to do it, they loath to do it. I think it varies from institution to institution, area to area whether the head and neck surgeons are willing to do a sentinel lymph node.

At Penn Medicine, I know a lot of those surgeons there can ask and it’s been done for them. Typically, it’s done after the Mohs [surgery], when they see some worrying features that they would like to send for sentinel lymph node biopsy prior to surgery.

What are some of the therapeutic options here for these patients beyond surgery?

YOO:A checkpoint inhibitor, radiation therapy, etc. These are all possible therapeutic options that are available for this gentleman.

CASE (continued):

The recommended definitive surgical approach involved auriculectomy; the patient declined. The patient was then referred to medical oncology. Cemiplimab (Libtayo) 350 mg every 3 weeks was initiated.

Why was cemiplimab given in this case?

AGULNIK:Cemiplimab is an FDA-approved drug for cSCC.

So how did this drug come to market? It is based on a study that looked at several different groups of patients. The groupings of patients included a group 1, adult patients with metastatic disease, nodal and/or distant cSCC; group 2 was

adult patients with locally advanced cSCC; and group 3 is adult patients with metastatic nodal and/or distant cSCC. The patients in the first 2 groups ended up with cemiplimab, 3 mg/kg every 2 weeks for up to 96 weeks of treatment. And, in the second and the third groups, the dose of cemiplimab was given at 350 mg every 3 weeks for up to 54 weeks of treatment. The tumors were assessed every 8 weeks, and the tumor imaging was done every 9 weeks. Patients were kept on treatment until they had progression.3

The eligibility criteria [dictated that the patient had an] ECOG performance status of zero or 1, good organ function, at least one measurable lesion, and disease that was felt to be not amenable to surgical cure or to radiation. And if patients had ongoing or recent autoimmune disease, they were excluded. If they had prior anti—PD-1 or PD-L1 therapy, they were excluded, and they were also excluded if they had a solid organ transplant.

The patient population here in theNew England Journal of Medicinearticle looking at 26 patients in the phase I study, 59 in the phase II study. The average age of the patients was 71 and 73. What’s important here is to look at the upper limit of age because there’s a 93-year-old that was treated and an 88-year-old that was treated in the other study. Certainly important [to look] at extreme ages because those are the patients [walking into the clinic].

So we had about 81% of patients or 73% of patients were older than 65 years of age, and we also know that patients had a

preserved ECOG performance status. The primary site in almost 70% of patients is the head and neck region, and [we usually refer] these patients, whether it be dermatology or our ENT [ear, nose, and throat] colleagues. And then looking at previous therapies, about 30% to 40% had no prior regimens. Some patients had prior regimens. It was usually just 1 regimen. Few patients had received multiple regimens. A lot of patients in the phase II study, three-quarters, had distant metastases. In the earlier setting, it was about a third.

What findings were seen in the phase I and II studies?

AGULNIK:If we ask how patients respond across the board to immunotherapy, it certainly depends on what the disease is. For this disease, we saw a response in the phase I setting, 13 out of 26 patients responded, so that’s 50% of the patients. In the phase II portion, 28 out of the 59 patients had a response, with a response rate of 47%. The median follow-up was almost 6 months. The response duration, over half of the patients exceeded 6 months. And 82% continued to have a response on treatment. So it seemed to be similar to what we see in head and neck oncology, [with a] durable duration of response. If [a patient is] to benefit, they tend to benefit for quite some time.

We see a disease control rate of 65% in the expansion cohort and 61% in the phase II portion.

If we look at 12-month follow-up for 59 patients, we have a median follow-up at 16.5 months, you see complete responses

in 10 patients (16.9%), partial response in 19 patients (32.2%), and stable disease in 9 patients (15.3%). Progression of disease was not evaluable in the other subset, and the overall response rate is reached at 49.2%. The disease control rate, however, is at 71.2%, and the durable control rate is 62.7% with a median observed time to response [at 1.9 months]. The likelihood of response happens within 2 months, which is reassuring for our patients. We’re sitting at 18.4 months with median progression-free survival. Because so many of the patients are getting responses, it seems to be good for the whole group. If we look at overall survival, we’re seeing 70.6% of patients are living beyond 24 months.

If we look at group 2, which has locally advanced disease and nonmetastatic disease, we see that 12.8% have a complete response, the partial response rate is 30.8%, and stable disease is 35.9%. We’re getting a disease control rate of 79.5% for these patients. But looking at overall response rate, we get 43.6%. Durable disease control rate at 62.8% and median observed time to response stays at 1.9 months.

Are there any biomarkers of response associated with this drug or patient population?

AGULNIK:When we look at biomarkers with clinical activity, tumor mutational burden and PD-L1 status do not correlate. Using it for patients irrespective of what their mutational burden is seems to make sense.

What is the safety profile for cemiplimab?

AGULNIK:We see that it’s being used in patients over 80, and we see a 93-year-old was on the study. From an all-grade standpoint, it does look either similar or a little better than some of the other immunotherapies that we currently use. [There were] limited grade 3 or 4 [adverse events (AEs) seen in the phase II trial]—just one patient with diarrhea, and a little fatigue.

With respect to discontinuation, a few patients discontinued [treatment] with a grade 3 [event]. Few discontinued because of earlier grade events.

We will get some rash, [and it comes down to] whether or not it’s going to be maculopapular rash, pruritis, or rash. You’re

going to get similar numbers with what you get from other immunotherapies. But, certainly, you are at risk of hypothyroidism, and you’re at risk for dry cough or pneumonitis. There is some increase [seen in the] liver enzymes, [too]. So [these are events] that we know from other immunotherapies that we use.

Have you found that your patients on immune checkpoint inhibitors are encountering dermatologic AEs? And how would you manage these?

AGULNIK:Most of us have dermatology colleagues that are interested in helping us with our patients. I see some [patients with these symptoms].

Based on the response rate seen with this drug, are you encouraging the use of immunotherapy over surgery?

AGULNIK:When we look at the data, what I like to focus on is the complete response rate is 13%, and partial response rate is at 30%, and so we’re having a nice response. How do we educate our surgical colleagues about a drug that potentially [makes] some of the surgeries that they’re doing no longer reasonable to do just because they can do them?

[There are] tumor boards. I do a lot of head and neck oncology cases and that’s where my introduction to this drug comes from. If you see a case and the surgeon is telling you they’re going to potentially resect someone’s nose or ear, [you could] pipe up and say: "maybe we should try something different."

I think [in sarcoma], the era of whether or not to keep amputating people is no longer there. We have made great strides in other diseases, and it is a possibility to make great strides in this one as well, I think. There is certainly the ability to say, if you have a surgical option that seems almost cruel to a patient, is it worthwhile to try a drug that potentially will work? And, if it doesn’t work, are you losing the ability to do surgery? Or the ability to radiate? Probably not. So I say to my colleagues, if the disease is 20% worse, can you still operate? They’ll always say yes. I say to the radiation [oncologists], if it’s 20% worse, is that going to affect what you do? They usually say no. We try these drugs with the anticipation that there are about 50% of patients that will derive a benefit.

What we do at our group is we have radiation oncology see the patient before we start therapy. We have the ENT sign off on it as well and say that the surgery is unlikely to change if the tumor grew a little bit more. And then we give it a try thinking that we could save the patient from major surgery that they are potentially not going to want. In my world, we push our ENT colleagues far to try to get them not to operate any more before they present cases at a tumor board in a real attempt to try to change the culture of all that surgery. It takes a lot of work, but it certainly is worthwhile if the patient derives a benefit.

I think we need to think about how we communicate this information to our colleagues and to our surgical colleagues. There’s no way our surgical colleagues or our radiation colleagues are familiar with these data like [oncologists would be]. I think it’s our responsibility as medical oncologists to relay this information.

Would you use immunotherapy in an immunosuppressed transplant patient?

AGULNIK:In the clinical trials, transplant patients were excluded. I think there are several centers in the United States

that have used immunotherapy on few transplant patients. I would not recommend doing it. I would just send them to an

academic center where someone has done it or where they’re doing a clinical trial with someone willing to do it. But I think there are few people that have done it, and so this may be a situation where someone needs to go down to [The University of Texas] MD Anderson [Cancer Center], Memorial [Sloan Kettering Cancer Center], or something like that.

YOO:I just wanted to say one thing about the transplant population because that’s what I see a lot of. I would say, not all transplants are equal. If it’s a kidney, that’s different than the liver versus a lung versus a heart, because they’re different organs. You can live without a kidney, but you can’t live without a liver, heart, or lung. It depends on the organ. I think the other thing is, you can talk to transplant nephrologist or transplant hepatologist to lower their immunosuppression as much as they can, or maybe even switch them to a [mammalian target of rapamycin] inhibitor, sirolimus, everolimus, that could also reduce their cancer burden. Those are very, very difficult situations.


  1. Jambusaria-Pahlajani A, Kanetsky PA, Karia PS, et al. Evaluation of AJCC tumor staging for cutaneous squamous cell carcinoma and a proposed alternative tumor staging system. JAMA Dermatol. 2013;149(4):402-410. doi: 10.1001/jamadermatol.2013.2456.
  2. Karia PS, Jambusaria-Pahlajani A, Harrington DP, Murphy GF, Qureshi AA, Schmults CD. Evaluation of American Joint Committee on Cancer, International Union Against Cancer, and Brigham and Women.
  3. Migden MR, Rischin D, Schmults CD, et al. PD-1 blockade with cemiplimab in advanced cutaneous squamous-cell carcinoma.N Engl J Med. 2018;379(4):341-351. doi: 10.1056/NEJMoa1805131.