Basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (CSCC) may share a common UV-induced origin, but their behavior and treatment vulnerabilities diverge sharply in the advanced setting, according to Vernon K. Sondak, MD.
“Squamous cell cancers tend to respond better to immunotherapy than basal cell cancers do, but they both will respond, whereas BCC is the only one that will respond to hedgehog inhibitors,” said Sondak, who serves as the Richard M. Schulze Family Foundation Distinguished Endowed Chair in Cutaneous Oncology and chair of the Department of Cutaneous Oncology at Moffitt Cancer Center, as well as a professor in the Departments of Oncologic Sciences and Surgery at the University of South Florida Morsani College of Medicine in Tampa.
In the below interview with OncLive®, Sondak discussed the etiology and presentations of BCC and CSCC, explained why precise pathologic and molecular characterization is essential before selecting systemic therapy, and provided guidance on what to do when biopsy results leave a low likelihood of a clear-cut diagnosis.
Key Distinctions Between BCC and CSCC
- Metastatic risk and recurrence rates are meaningfully higher in advanced CSCC than in advanced BCC, even though both remain low relative to more aggressive skin cancers such as melanoma or Merkel cell carcinoma.
- Treatment selection hinges on tumor biology: hedgehog pathway mutations define BCC and predict response to hedgehog inhibitors, while the high UV mutational burden of CSCC makes it more amenable to immunotherapy.
- Standard biopsy resolves the diagnosis in 95% to 98% of cases, but a subset of advanced tumors with mixed basal-squamous differentiation may require next-generation sequencing to guide management.
OncLive: How do you distinguish between advanced CSCC and BCC and why is that important for management strategies?
Sondak: It's always important to get the diagnosis right in oncology in general and in cutaneous oncology for sure. Basal and squamous cell cancers, when they're small and low-risk, are treated virtually identically. Often, when we first see a small skin cancer, we may just recommend removal. It doesn't even matter if it's basal or squamous. When we're talking about advanced disease the risk of metastasis is much higher for SCC than for BCC, even though it is low for both relative to a more aggressive typical skin cancer like melanoma or even Merkel cell cancer. The risk of recurrence and metastasis is generally higher with advanced CSCCs.
The treatment options are a little bit different. BCCs virtually all have mutations in the hedgehog pathway which makes them susceptible to treatment with hedgehog inhibitors. That [drug class] wouldn't work for SCCs or melanoma or any of the other diseases that we manage. CSCC is characterized by lots of UV-induced mutations from the heavy sun exposure that causes most cases of squamous cell cancer. This makes it susceptible to immunotherapy. BCCs also have a UV origin, a UV etiology, but they're sometimes more associated with heavy intermittent sun exposure rather than continuous, chronic sun exposure. So SCC tends to respond better to immunotherapy than BCC does, but they both will respond [to immunotherapy], whereas basal cells are the only ones that will respond to the hedgehog inhibitors. These are the main reasons we want to be sure we know which [disease] it is.
Is a biopsy insufficient to make a definitive diagnosis?
We should just be able to perform a biopsy and have the pathologist tell us [what disease it is], but a small percentage of the time we do get an ambiguous answer from the pathologist. They may say it has basal and squamous differentiation, so which is it? Is it a basal cell with a little squamous cell on the side or is it SCC with a little basaloid kind of look? We've certainly seen it go both ways and we've seen treatment push these ambiguous tumors one way or another. So, if we say that [a biopsy] looks basal with a little squamous differentiation, we've seen hedgehog inhibitor treatment get rid of the basal cell part [while] the squamous part grows because the SCCs don't respond to hedgehog inhibitors. We've seen immunotherapy get rid of the squamous part while a little bit of the basal cell part remains because it's not as responsive [to that drug class]. There are these ambiguous cases where we're just not sure.
Can molecular analysis help determine the best course of action for treatment?
Increasingly we do use molecular analysis [via] next-generation sequencing. If we find a hedgehog pathway mutation, we know it is a BCC almost by definition. If we don't see that and we see very high numbers of UV-related mutations and no other mutation that would be characteristic of melanoma or Merkel cell cancer or something else then we know it's most likely CSCC. We can differentiate 95% to 98% [of cancers] by a small biopsy, but a small percent of our advanced cases need more advanced workup to sort things out.
