Actinic Keratosis, Basal Cell Carcinoma, and Squamous Cell Carcinoma

Ultraviolet radiation

UV exposure is the predominant cause of BCC and cutaneous SCC as evidenced by migrant studies, the correlation of incidence to latitude, and animal studies. There is, however, a difference in the type of UV exposure (see Table 108.2 ). For BCCs, intermittent intense episodes of UV exposure and sunburns at any age appear to increase risk, whereas cumulative long-term UV exposure and childhood sunburns increase the risk for developing SCCs and AKs .

Sun exposure early in life appears to have a greater influence on subsequent skin cancer risk than at a later age. For example, individuals born in countries with high ambient UV radiation such as Australia have significantly higher incidence rates of BCC and SCC as compared to those with a similar genetic background (e.g. British, northern Europeans) who migrated to these locales later in life from countries with lower ambient UV radiation .

Indoor tanning usage

Several studies have demonstrated an increased risk for the development of BCCs and SCCs in those who are exposed to artificial sources of UV radiation. Intentional tanning has been shown to increase the risk of SCC development and Karagas et al. demonstrated that any use of tanning devices was associated with odds ratios of 2.5 for SCC and 1.5 for BCC, even after adjustment for history of sunburns, sunbathing, and sun exposure. In response to these findings, many countries have passed legislation aimed at regulating indoor tanning facilities, including banning minors. Notably, Australia has actually completely banned this commercial industry .

Therapeutic UVR exposure

Individuals with psoriasis have been shown to be at increased risk for the development of keratinocyte carcinomas. While long-term follow-up of psoriasis patients who underwent UVR plus tar (Goeckerman) therapy found no increased risk, long-term PUVA therapy was associated with a significant, dose-related risk of SCC development (adjusted relative risk = 8.6 for an accumulated exposure of between 100 and 337 treatments) . With prolonged therapy, a slightly increased risk for BCC development was noted as well. In addition to the direct effects of PUVA, PUVA-induced immunosuppression may also play a role.

Ionizing radiation

Exposure to ionizing radiation leads to a threefold increased risk for BCC and SCC . The risk is in proportion to the radiation dose. Larger fractionated doses (>12–15 Gy) are thought to be necessary to induce tumor formation, so the risk with a given total dose may be less if a larger number of smaller fractionated doses are given. Most SCCs and BCCs that arise after exposure to ionizing radiation do so after a long latency period of up to several decades, with most tumors appearing ~20 years after the initial exposure.

Treatment of tinea capitis with radiation (prior to the discovery of effective systemic antifungal medications) has been linked to the development of multiple BCCs. In a study of 2224 children given X-ray therapy for tinea capitis (compared with a control group of 1380 tinea capitis patients given only topical medications), the relative risk for developing BCC of the head and neck among irradiated Caucasians was 3.6 .

Patients with BCNS are exquisitely sensitive to ionizing radiation and it should be avoided if possible (see below).

Occupational risk factors

Persons with outdoor occupations have a higher risk of developing skin cancer. Airline pilots, who are exposed to ionizing radiation at flight altitudes, have been shown to have an elevated risk for both BCC and SCC . Other occupations associated with an increased risk for NMSC include agricultural workers, sailors, locomotive engineers, and textile workers.

Chemical exposures

Multiple organic chemicals have been associated with an increased risk for the development of keratinocyte carcinomas (see Table 108.2 ). Occupational chemical exposures which can lead to skin cancer most commonly involve pesticides, asphalt, tar, and polycyclic aromatic hydrocarbons, and they typically result in SCC. The skin cancers induced by chemical exposures are usually localized as well as multiple, most often appearing on the arms .

Arsenic is a well-defined cause of SCC (see Ch. 88 ). A clue to arsenic exposure is the presence of palmoplantar arsenical keratoses. BCC has also been reported following extensive arsenic exposure. The typical latency period from exposure to tumor development is 20–40 years .

Organ transplantation

Solid organ transplant recipients have a markedly increased incidence of skin cancer, primarily SCC. The incidence of BCC in organ transplant recipients is up to 5–10 times greater than in the general population, while the incidence of SCC is 40–250 times greater. Risk factors include skin phototypes I/II, cumulative sun exposure, age at transplantation, and the degree and the length of immunosuppression.

SCC is a significant cause of morbidity and mortality in transplant recipients . The pathogenesis of skin cancer in transplant recipients is multifactorial, involving decreased immunity, direct carcinogenic effects of immunosuppressive medications, and HPV infection in addition to UVR exposure. Transplant recipients are prone to developing numerous lesions and are more likely to suffer local and regional recurrences and metastases . AKs and SCCs begin to appear with increasing frequency several years after transplantation. Lesions are often multiple and usually develop in sun-exposed areas. HPV DNA is found in approximately 70–90% of transplant-associated SCCs. Tumors from transplant recipients contain HPV strains that occur in common benign cutaneous warts (HPV types 1 and 2), EV (HPV-5 and others), high-risk oncogenic warts (HPV types 16 and 18), and low-risk oncogenic genital warts (HPV types 6 and 11). Sometimes, several HPV types are detected within a single tumor.

In one series of renal transplant patients from the US, 5% of the patients died of skin cancer. In another series of heart transplant patients from Australia, 27% died of skin cancer. Two-thirds of these deaths were due to SCC. Several studies have shown that in renal transplant patients sirolimus, an mTOR inhibitor, reduced the development of SCCs when compared to calcineurin inhibitors (e.g. cyclosporine, tacrolimus) . In an Australian study, the SCCs in those receiving sirolimus were more superficial, but this has not been observed in other studies. Based upon currently available data, sirolimus appears to be preferable in patients with a history of SCCs or strong risk factors. Unfortunately, 30–50% of renal transplant patients may not tolerate prolonged administration of sirolimus .

Patients who receive hematopoietic transplants do not experience this marked increase in skin cancer incidence (unless they have received long-term voriconazole), presumably because of a shorter duration of immunosuppression.

Immunosuppressive drugs

Use of immunosuppressive drugs, including systemic immunomodulators (“biologics”), increases the risk for the development of skin cancer . Risk of SCC development is directly related to length of immunosuppressive drug usage. In one study, the risk of SCC was significantly increased among recipients of oral glucocorticoids (odds ratio = 2.31) and the risk of BCC was also elevated (odds ratio = 1.49) . Similarly, thiopurine use for inflammatory bowel disease has been shown to increase the risk for NMSC .

HIV infection

Patients with HIV infection are at increased risk for the development of several cancers, including cutaneous SCC . The incidence of HPV-related SCC of the anus is significantly increased in this population, and can be more aggressive. For monitoring, anal cytology can be performed.

Genetic predisposition

Phenotypic characteristics such as red hair, light skin, poor ability to tan, and freckling have been identified as risk factors for melanoma as well as NMSC . Pigmentation is a polygenic trait, with polymorphisms in several genes leading to the variation observed in the human race (see Ch. 65 ). A key gene encodes the human melanocortin-1 receptor (MC1R) which is expressed on the cell surface of melanocytes. Population-based studies in diverse ethnic groups have shown that the coding region of the human MC1R is remarkably polymorphic. In Caucasians, there is a strong association between nine common MC1R variant alleles and the red hair/fair skin phenotype, thus placing these individuals at higher risk of photocarcinogenesis . Based upon genome-wide association studies and candidate gene studies (see Ch. 54 ), ~30 and at least 11 susceptibility loci for BCC and SCC, respectively, have been identified, and they include multiple pigmentation loci.

Genetic syndromes associated with an increased risk of BCCs and/or SCCs