Table 23.1 lists known risk factors for the development of SCC. UVA (320-400 nm) and UVB (290-320 nm) result in thymidine dimer DNA mutations in the
p53 tumor suppressor gene and is the most common cause of SCC.
21,22,23 The highest risk exists among people with light skin, hazel or blue eyes, and blonde or red hair, and in those with chronic accumulated lifetime sun exposure.
24,25 Not surprisingly, the use of oral methoxsalen in combination with ultraviolet A radiation (PUVA) for the treatment of psoriasis and other conditions has been definitively associated with an elevated risk of SCC.
26,27 Ionizing radiation including x-rays, gamma rays, and grenz rays used either therapeutically or as occupational exposures also contribute to the risk of SCC.
28 This risk is directly related to the cumulative dose of radiation.
28 There are several genodermatoses that predispose individuals to SCC. In oculocutaneous albinism, patients have absent or decreased production of protective melanin resulting in increased SCC in sun-exposed areas.
29 Patients with xeroderma pigmentosum are deficient in the enzymes responsible for repairing ultraviolet-induced DNA damage and develop skin cancers beginning from an early age. Other inherited conditions associated with SCC include Ferguson-Smith syndrome and dystrophic epidermolysis bullosa.
30 HPV is associated with SCC development, especially with the periungual and genital regions. This is particularly evident in patients with epidermodysplasia verruciformis and in patients with HIV who develop the verrucous carcinoma subtype of SCC.
31,32 Multiple chemical exposures are associated with SCC development, including arsenic and polycyclic aromatic hydrocarbons.
21 Patients who are immunosuppressed are also at an increased risk of developing SCC. In particular, solid organ transplant recipients have a 40 to 250 times increased incidence of SCC compared with the general population.
33 In fact, the ratio of SCC to BCC is reversed in organ transplant recipients.
21 Patients with AIDS have a slightly increased risk of SCC, with a particular increase in anal lesions that are notable for a more aggressive clinical course.
30 SCCs are also known to occur more commonly in areas of skin affected by chronic inflammation, including ulcers (so-called Marjolin ulcers), osteomyelitis, radiation dermatitis, and vaccination scars, and a variety of inflammatory conditions such as discoid lupus erythematosus, lichen sclerosis, lichen planus, and cutaneous tuberculosis.
21 Infection with HPV has also been definitively linked to the development of nongenital SCC. In particular, HPV types 5, 16, and 18 have been shown to have increased oncogenicity relative to other subtypes.
34 Although the specific pathway by which HPV induces carcinogenesis has not been determined, it is known that HPV infection results in synthesis of the viral proteins encoded by the
E6 and
E7 genes that bind and inactivate the
p53, pRB, and
Bak tumor suppressor genes.
35 In addition, it appears that infection with HPV alone is insufficient to produce SCCs and that cocarcinogens such as ionizing radiation or ultraviolet radiation are required to produce malignant transformation.
36 It also appears that HPV infection in the setting of immunosuppression leads to carcinogenesis as evidenced by the increased risk of SCC and cutaneous warts in organ transplant recipients.
37