Cutaneous squamous cell carcinoma (cSCC) is the second most common form of skin cancer in the United States with more than 1 million diagnoses made per year.1 cSCC is an invasive form of squamous cell carcinoma that grows beyond the epidermis.2 However, the exact prevalence of cSCC and cSCC-related deaths are unknown, as cSCC is not included the national cancer registries.3
cSCC is more common in men 50 years and older, but the typical age at diagnosis is approximately 70 years old.1,4 The frequency of cSCC is two to three times greater in men than in women.4 It is thought that this difference is due to a greater cumulative lifetime exposure to UV radiation via occupation.4 Light skin, hair, and eyes all increase the risk of developing cSCC.1 Individuals with Irish or Scottish heritage have the highest prevalence of cSCC in the United States.4 The most common areas of occurrence for cSCC are body parts most frequently exposed to the sun: the face, neck, scalp (if bald), forearms, hands, and shins.1
The main risk factor for developing cSCC is cumulative UV exposure.1 Tanning beds, medical UV treatments, and extensive lifetime sun exposure all contribute to chronic UV exposure.4 Risk of cSCC correlates to cumulative lifetime exposure of UV. Additional factors include previous forms of skin cancer and actinic keratoses (precursor to cSCC).2 Immunosuppression, particularly related to transplantation or HIV, increases both the risk of developing cSCC and metastasis of cSCC.1,4 Less often cSCC is caused by carcinogens (as found in cigarettes), severe scars, burns or sores, or some forms of human papillomavirus.2,5
Diagnosis and cSCC Types
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.4TP53 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.
Prognosis and Prevention
When diagnosed early, cSCC has a good prognosis with an overall 5-year survival rate greater than 90% with adequate treatment.4 However, if left untreated, cSCC is often fatal. Patients with advanced-stage cSCC and lymph node metastases have an estimated 5-year survival rate at 25% to 45%.4 The risk of recurrence or death is greater in patients with tumors greater than 20 mm in diameter and/or greater than 2 mm thick.2 Lesions with a diameter of less than 2 cm have a 9.1% rate of metastasis, whereas lesions with a diameter greater than 2 cm have a 30.3% rate of metastasis.4 Essentially, a greater tumor depth correlates with a lower rate of survival. Metastatic lesions usually do not occur at a depth less than 2 mm. If the tumor has an invasive depth of 2 to 4 mm, then the metastasis rate is 6.7%.4
The recurrence rate depends on the tumor. Lesions greater than 2 cm have a recurrence rate of 15.7% after removal. In poorly differentiated lesions, there is a recurrence of 25% after excision vs only 11.8% recurrence in well-defined lesions.4 If the tumor has a depth of 2 to 4 mm, the recurrence rate is 5.3%.4 Poorly differentiated tumors have a recurrence rate of 33% to 54%.4 About half of the patients who are at high risk of cSCC will develop a second lesion within 5 years from the first diagnosis.2
Once cSCC is diagnosed, UV protection is necessary; clinicians should educate patients on using sunscreen, wearing protective clothing, and avoiding the sun at times of maximum intensity. SPF should be utilized—SPF 15 at a minimum for daily activities and SPF 50+ for outdoor activities.2,4 Tanning beds should be avoided.
While cSCC can be a serious and fatal cancer, most patients have an excellent prognosis when the tumor is detected early. Individuals with a recent or infrequent history of cSCC should be monitored every 6 to 12 months, whereas those with an extensive history of cSCC recurrence or aggressive tumors will require much more frequent follow up.1