Side Effect Central – Cutaneous Squamous Cell Carcinoma and Keratoacanthoma

Side Effect Central is a series of articles designed to help patients with melanoma and their caregivers understand the side effects that typically accompany melanoma treatments. Our goal is to explain what side effects to expect during treatment and to encourage communication with your medical team about these side effects.

Side effects can range from mild to very serious, and doctors cannot predict who will suffer more side effects than others. Serious side effects can cause patients to interrupt or discontinue treatment, and they can lead to dangerous and possibly deadly consequences, so managing them is essential to optimize treatment outcomes.

What are cutaneous squamous cell carcinoma and keratoacanthoma?

Cutaneous squamous cell carcinoma (also referred to as squamous cell skin cancer) is the second most common form of skin cancer diagnosed in the U.S. It occurs when the squamous skin cells, which are the thin, flat skin cells found in the upper section of the epidermis, grow out of control. Cutaneous squamous cell carcinoma grows slowly and occurs most often on sun-exposed skin, such as the back of the hands, ears, and scalp. It often looks like a sore that is not healing or an enlarging red, scaly patch of skin.¹

Keratoacanthoma is a type of well-differentiated, dome-shaped, primary cutaneous squamous cell carcinoma. It is a very rare side effect of cancer immunotherapy with programmed cell death 1 (PD-1) or programmed cell death ligand 1 (PD-L1) inhibitors, like atezolizumab (Tecentriq), avelumab (Bavencio), cemiplimab (Libtayo), durvalumab (Imfinzi), nivolumab (Opdivo), or pembrolizumab (Keytruda). It most often occurs in patients aged 60 to 79 years, but it is relatively rare overall.²

What should patients know?

Although skin lesions may be worrisome during your treatment for melanoma, rarely does cutaneous squamous cell carcinoma or keratoacanthoma become life-threatening. These skin lesions can develop anywhere from one to 18 months after treatment with immunotherapy. Cutaneous squamous cell carcinoma generally presents between three to nine months from the initiation of PD-1/PD-L1 therapy.²

There are long-term consequences of inattention, so seeking treatment is important. Patients should promptly communicate with their health care team and seek treatment when observing any of the symptoms listed below.

Cutaneous squamous cell carcinoma symptoms³—report to your health care team

Areas that are crusty or itchy and may bleed
Lesions that develop in damaged and inflamed areas of the skin, such as on or around scars, chronic ulcers, and previous sites of burns
Red, scaly, crater-like, ulcerated, or bumpy patches
Wounds that never heal and look the same or worse as time goes on

Keratoacanthoma symptoms⁴—report to your health care team

Fast-growing lesions (appearing within weeks or months after treatment)
An obvious and unusual dome-shaped nodule that looks like a raised bump or boil
A lesion with a center that is black or skin-colored

Long-term consequences of avoiding treatment⁵

While early stages of cutaneous squamous cell carcinoma are treatable, in rare cases the cancer can spread or metastasize beyond the primary skin site. If the primary lesion is allowed to grow greater than 6 mm in thickness, the chance for metastasis to the lymph nodes or distant sites is 16%. Tumors with widespread, extensive metastasis are not considered curable, which is why early detection and treatment is essential.

Why do these dermatological immune-related adverse events occur⁶

Immunotherapy is designed to supercharge the immune system. In the case of immune checkpoint inhibitors, like the PD-1/PD-L1 inhibitors, these remove the brakes put on immune cells by cancer cells. When the brakes are removed, the immune system becomes activated.

Unfortunately, the skin can become susceptible to an immune system-provoked injury as an unintended consequence. Although immunotherapy is aimed at the tumor’s environment, sometimes it non-specifically activates too much of the immune system throughout the body.

Nearly every organ system in the body is at risk for an unprovoked injury by immune checkpoint inhibitors. However, immunotherapy works so well in many patients that the risk of side effects is deemed worthwhile to achieve the possible results. Prompt and thorough communication about side effects by patients with their medical team allows for appropriate clinical support and allows immunotherapy to be used safely and successfully in many patients. Individual perspectives about treatment ideals should be discussed with your clinician.

What can a clinician do to treat dermatological events?

Early identification is important for your clinician to initiate a management strategy. There is no consensus about the optimal treatment strategy for these dermatological events. Therefore, different approaches may be utilized and approaches may vary between institutions.

You may be referred to an oncodermatologist. These specialists manage the skin of patients undergoing cancer therapy so that the patients can better tolerate their therapies during treatment. A goal of incorporating this type of specialist is to prevent patients from interrupting or reducing their dose of immunotherapy—potentially life-saving medications. Ideally, patients can remain on therapy.⁷

However, some cases of keratoacanthomas and cutaneous squamous cell carcinoma might necessitate the temporary withholding of immunotherapy until complete resolution. A more common treatment for these rare dermatological side effects is excision or lesion destruction followed by topical corticosteroids at the site. Intralesional injection of steroids is possible as well.⁸

Bottom line: Patients should communicate regularly with their medical team about any of the signs of a skin lesion, as noted above. Clinicians can manage and treat the condition to allow the patient to remain on immunotherapy or resume treatment as quickly as possible. Images are also available on our website to help you identify potentially problematic lesions on your skin.

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