Cutaneous Squamous Cell Carcinoma

A cSCC diagnosis is made from clinical presentation and often confirmed by biopsy findings.² Further diagnostic workup to check for metastases is done via computed tomographic scan or MRI.⁴ cSCC appears as a shallow ulcer with elevated margins often covered by plaque; less commonly, cSCC presents as a pink cutaneous nodule.^3,4 Patients occasionally experience swollen lymph nodes of the head and neck caused by regional metastasis.⁴

Over 90% of skin cancer in the United States are a result of TP53 mutations.⁴ TP53 is a tumor suppressor gene; when mutations occur, the TP53 gene is no longer able to prevent development of malignant tumors and cSCC cells can replicate.^1,4 UV radiation is a major cause of TP53 mutation. 

There is not a universally accepted staging system.³ The American Joint Commission on Cancer TNM system is most commonly used with the Brigham and Women’s Hospital system as an alternative option.^4,5 While staging is helpful when estimating the outcome for a group of patients, it does not provide the risk for an individual. Patient-specific outcome estimates are based on the total excision of the lesion with clear margins.⁴

cSCC is classified as low or high risk based upon the chance of recurrence or metastasis. Characteristics of high-risk cSCC include a diameter 2 cm or greater; older patient or patient with immune suppression; carcinoma located on the ear, vermillion of the lip, central face, hands, feet, or genitalia; and a histologic thickness 2 mm or greater, a poorly differentiated histology, or invasion of subcutaneous tissues, nerves, and blood vessels.²

There are several distinct types of invasive cSCC. A cutaneous horn is a horn-shaped growth caused by excessive keratin. Keratoacanthoma (KA) is a rapidly growing nodule, though more study is needed to determine if it is truly a subtype of cSCC     . Carcinoma cuniculatum is a slow growing wart-like tumor. There may also be multiple eruptive cSCC or KA-like lesions, as seen in Gryzbowski syndrome or multiple self-healing squamous epitheliomas of Ferguson-Smith.²

Treatment of cSCC can be surgical or medical. The standard of treatment is surgery, including standard excision, Mohs micrographic surgery (MMS), or curettage and electrodessication (C&E). During excision, the tumor and surrounding skin are removed. C&E involves scraping out the cancerous cells and destroying the remaining cells with an electrode. MMS is performed if there is a high risk of recurrence or if the cancer is located near critical areas (near the eye, ears, etc) as it removes less skin than excision.⁶

If surgery is not feasible, cryosurgery, radiation therapy, topical medication therapy, photodynamic therapy, or laser therapy are options.³

Radiation is the best choice for older patients who cannot undergo surgery or for cancerous cells that are not easily demarcated.¹ Radiation, as adjuvant therapy, improves locoregional control.⁵ Cryosurgery and photodynamic therapy treat AKs.⁶

Topical chemotherapy works locally and does not have the same adverse effects as systemic chemotherapy. Topical 5-fluorouracil (5-FU) targets tumor cells near or at the surface of the skin and does not penetrate deeper into the dermis. Both topical 5-FU and imiquimod, an immune response modifier that is applied topically, are often used to treat AKs. However, the American Academy of Dermatology guidelines for cSCC do not recommend use of topical 5-FU or imiquimod, as each treatment lacks both data and indication-specific FDA approval.^3,6

Systemic chemotherapy, including oral 5-FU and epidermal growth factor receptor (EGFR) inhibitors, are adjuvant therapy in specific high-risk cases.⁴

Cemiplimab is the first FDA-approved immunotherapy for advanced cSCC. Cemiplimab is a recombinant human immunoglobulin monoclonal antibody that binds to and blocks programmed cell death ligand (PD-L) 1 and PD-L2. These ligands bind to the PD-1 receptor of T cells and inhibit T-cell proliferation and cytokine production. Upregulation of these ligands occurs in some tumors.⁷ Blocking this upregulation prevents inhibition of T-cell proliferation and cytokine production.

EGFR protein targeting drugs, such as cetuximab, are in clinical trials to determine their use in cSCC.⁶ While TP53 mutations are responsible for approximately 90% of cSCC,⁴ squamous cell skin cancers often have too much of the EGFR protein on their surface. EGFR helps cells grow, so inhibition can stop cancer cell growth.