Squamous cell carcinoma (SCC), a keratinocyte carcinoma, is the second most common skin cancer worldwide, and its incidence is increasing. The lifetime risk of developing SCC is 9%-14% for men and 4%-9% for women. It generally presents in later decades of life. TP53, NOTCH 1/2/4, PI3K, and CDNK2A gene mutations have been implicated in the development of SCC.

Light skin phototype is the most important factor related to developing SCC and is an independent predictor of the development of SCC in patients with solid organ transplantation. In individuals with darker skin phototypes, 30%-40% of SCCs develop within scars and chronic nonhealing ulcers (compared to 2% developing within such areas in people with lighter skin phototypes). SCC is the most common and second most common skin cancer in Black individuals and individuals of Hispanic descent, respectively.

A variety of other risk factors increase the likelihood of developing SCC. These include ultraviolet (UV) exposure, immunosuppression such as in individuals following solid organ transplantation (see skin cancer in organ transplant recipients) or individuals with HIV / AIDS, ionizing radiation exposure, cigarette smoking, human papillomavirus (HPV), chronic lymphocytic leukemia (CLL), hypothyroidism, family history of SCC, chemical exposure (ie, arsenic, mineral oil, coal tar, soot, mechlorethamine, polychlorinated biphenyls, and psoralen plus UVA treatment), freckling, red hair, and chronic nonhealing wounds. Approximately 10% of actinic keratoses (AKs) transform into skin cancer, with the most common being SCC. Furthermore, patients with AKs may be greater than 7 times more likely to develop SCC than patients without.

Dermatoses associated with a risk of SCC include discoid lupus erythematosus, lichen planus (ie, erosive, hypertrophic), and lichen sclerosus. A variety of genetic syndromes have also been associated with SCC. These include xeroderma pigmentosum, oculocutaneous albinism, epidermodysplasia verruciformis, dystrophic epidermolysis bullosa (recessive), Ferguson-Smith syndrome, and possibly Muir-Torre syndrome. Medications can also lead to the development of SCCs. Immunosuppressives, such as systemic immunomodulators or biologics, increase the risk of SCC, and the risk is proportional to length of therapy. Other implicated medications include voriconazole, thiopurine in patients with irritable bowel disease, BRAF V600 inhibitors such as vemurafenib and dabrafenib, and photosensitizing antihypertensive drugs such as alpha-2 receptor agonists and diuretics.

Although SCC can arise on any skin surface including the mucosa, the most common areas of involvement are sun-exposed areas such as the head, neck, arms, and hands. The clinical presentation is highly variable among different demographic groups and tumor subtypes. Lesions may grow slowly or evolve rapidly.

The rate of metastasis is approximately 4%. The most common site of metastasis is the regional lymph node, but distal metastasis has been reported. Risk of metastasis is higher in immunosuppressed individuals, particularly solid organ transplant recipients, in primary lip lesions, and in non-UV-related SCCs.

Some features classify SCC as having a high risk of recurrence. These include aggressive histopathologic types (acantholytic, adenosquamous, carcinosarcomatous), depth greater than 2 mm, size larger than 2 cm, poorly defined borders, tumor arising in a site of prior radiation / burn or chronic inflammatory process, specific anatomic location (ie, tongue, vulva, penis), history of immunosuppression, moderate or poor differentiation on pathology, desmoplasia, and perineural or angiolymphatic invasion. These features may lead to selection of treatment options with lower recurrence rates, such as Mohs micrographic surgery (MMS), which has been shown to have lower recurrence rates than traditional wide local excision.

Various staging systems exist, although none is universally accepted. See Work Group. Guidelines of care for the management of cutaneous squamous cell carcinoma. J Am Acad Dermatol. 2018 Mar;78(3):560-578.

Related topics: oral squamous cell carcinoma, squamous cell carcinoma in situ