INTRODUCTION — Cutaneous squamous cell carcinoma (cSCC) is a common cancer arising from malignant proliferation of epidermal keratinocytes . The likelihood of developing cSCC is dependent upon exposure to risk factors (most importantly ultraviolet light) and patient-specific characteristics, such as age, skin type, and ethnicity.
The epidemiology and risk factors of cSCC will be reviewed here. The clinical features, diagnosis, treatment, and prognosis of cSCC are discussed elsewhere. Skin cancer in solid organ transplant recipients is discussed separately.
Incidence — In the United States, cutaneous squamous cell carcinoma (cSCC) is the second most common type of skin cancer, behind basal cell carcinoma (BCC), and accounts for approximately 20 percent of nonmelanoma skin cancers [2-6]. Because cSCCs are not typically reported to cancer registries, the exact incidence of this malignancy is unknown. Moreover, as epidemiologic studies often combine data on cSCC, BCC, and other nonmelanocytic skin tumors, incidence estimates are widely variable [3,7,8].
The incidence of cSCC has increased over the past 20 years worldwide among White populations . In the United Kingdom, the age-standardized incidence of primary cSCC in the period from 2013 to 2015 was 77 per 100,000 per year, with a mean annual percentage increase of 5 percent . This increase may be related to higher levels of sun exposure, tanning bed use, an increase in the aging population , and improved skin cancer detection [12,13].
Geographic variation — The age-adjusted annual incidence of cSCC in the United States varies according to latitude. For example, the incidence of cSCC is higher in Arizona than in New Hampshire (270 versus 97 per 100,000 per year in men and 110 versus 32 per 100,000 per year in women) [14-17]. A similar pattern of geographic variability exists globally, with a higher incidence of cSCC closer to the equator.
In an analysis of data from cancer registries in Australia (2011 to 2014) and Germany (2007 to 2015) and from medical claim data in the United States (2013 to 2015), the incidence of cSCC per 100,000 persons per year in men and women were 341 and 209, 54 and 26, and 497 and 296, respectively, for the three countries .
In the United Kingdom, the estimated incidence of cSCC per 100,000 per year between 2013 and 2015 was 77 in men and 34 in women. In Norway, between 2008 and 2011, the estimated incidences for men and women were 20 and 15 per 100,000 per year, respectively, while in Finland, between 1991 and 1995, the estimated incidences for men and women were approximately 6 and 4 per 100,000 per year, respectively [19,20].
Age — The incidence of cSCC increases dramatically with age. It is infrequent in those under 45 years of age, although the incidence of cSCC is increasing significantly in young individuals . For those over 75, the incidence is approximately 5 to 10 times higher than the incidence in younger age groups and 50 to 300 times higher than for those under 45 [14,15].
Skin pigmentation and ancestry — Individuals with darker skin types have low reported rates of cSCC, whereas non-Hispanic White populations have the highest reported rates [22-24]. While the incidence of cSCC in non-Hispanic White women and men in the United States has been estimated to be as high as 150 and 360 per 100,000 individuals, respectively, the incidence in Black individuals is estimated to be 3 per 100,000 . In individuals with highly pigmented skin, cSCC tends to arise on non-sun-exposed areas and is frequently associated with chronic inflammation, chronic wounds, or scarring. (See "Cutaneous squamous cell carcinoma (cSCC): Clinical features and diagnosis", section on 'Location'.)
Mortality — In 2012, the annual disease-specific mortality from metastatic cSCC was estimated to be 1.5 to 2 per 100,000 per year . In Australia, the estimated age-standardized mortality in 2016 was 2.8 per 100,000 per year in men and 1.1 per 100,000 in women .
RISK FACTORS — Environmental and genetic factors and immunosuppression contribute to the development of cutaneous squamous cell carcinoma (cSCC) . Among light-skinned individuals, the most important risk factors are cumulative sun (ultraviolet [UV] light) exposure and age.
Environmental risk factors
Ultraviolet radiation — UV radiation is the main environmental carcinogen implicated in the pathogenesis of cSCC. Epidemiologic studies indicate that cumulative sun exposure (principally ultraviolet B [UVB] radiation) is the most important environmental cause of cSCC. In contrast, intense, intermittent sun exposure (eg, sunburn, childhood exposure) is the most important risk factor for basal cell carcinoma (BCC) and melanoma [22,26-28]. (See "Risk factors for the development of melanoma", section on 'Ultraviolet radiation' and "Epidemiology, pathogenesis, and clinical features of basal cell carcinoma", section on 'Risk factors'.)
High occupational sun exposure is a major risk factor for cSCC [29-32]. In a case-control study including 632 patients with a first diagnosis of invasive or in situ cSCC in the previous two years and 632 sex- and age-matched controls without a history of cSCC, patients with high occupational UV exposure (≥90th percentile) had a nearly twofold increased risk for cSCC compared with participants with no or low (<40th percentile) occupational UV exposure (odds ratio [OR] 1.95, 95% CI 1.19-3.18), after adjusting for age, sex, phototype, and nonoccupational sun exposure in a multivariate analysis . In the same analysis, nonoccupational UV exposure was not found to be an independent risk factor for cSCC.
Other factors associated with an increased risk of cSCC and consistent with a causative role for UVB radiation include:
●The degree of sun exposure in the past 5 to 10 years [29,30]
●Phenotypic characteristics, such as fair skin, light-colored eyes, red hair, and northern European origin [30,33-35]
Although UVB is thought to be the primary factor in causing cSCC, ultraviolet A (UVA) also has an etiologic role:
●Psoralen plus ultraviolet A (PUVA) use is associated with an increase in the incidence of cSCC [36,37]. This risk was illustrated in a 30-year, prospective study of a cohort of 1380 psoriasis patients who received PUVA phototherapy. There was more than a 35-fold increase in the rate of cSCC among those who had received more than 450 PUVA treatments (incidence rate ratio [IRR] 37.7, 95% CI 25.6-55.5) .
●Tanning beds, which primarily emit UVA radiation, cause skin changes like those seen with sun damage. Observational studies suggest that the use of tanning beds increases the risk of both cSCC and BCC [39-42]. A 2012 meta-analysis of observational studies found a 67 percent higher risk for cSCC among subjects with a history of any tanning bed use compared with subjects who had never used tanning beds (relative risk [RR] 1.67, 95% CI 1.29-2.17) . Studies of sunless tanning creams suggest that there is no increase in the risk of skin tumors associated with use of these agents if proper sun protection is concurrently used [44,45].
Ionizing radiation — Ionizing radiation, including environmental, therapeutic, and diagnostic radiation, is an established risk factor for nonmelanoma skin cancer [46-49]. The risk associated with radiation exposure is dose related and higher in sites that have the most sun exposure. The basal layer of the epidermis is more affected by radiation than the more superficial layers, with a higher RR of BCC compared with cSCC in exposed groups [46,47]. As an example, there was an excess risk of BCC, but not cSCC, in Japanese survivors of the atomic bomb . Other studies have reported a significantly increased risk of cSCC as well as BCC. In a Canadian population-based, case-control study, men exposed to nondiagnostic radiation had a fivefold increased risk of cSCC . In another report, there was a threefold increased risk associated with exposure to therapeutic ionizing radiation, although this effect was limited to those who also reported sun-sensitive skin .
Arsenic exposure — Chronic exposure to arsenic is associated with a variety of cancers . Consumption of contaminated drinking water and occupational exposure are associated with both cSCC and BCC (see "Arsenic exposure and poisoning", section on 'Cancer'):
●An analysis of nationwide data from the National Taiwan Cancer Registry Center between 1979 and 2007 found that the incidence rates of cSCC were four- to sixfold higher in areas where arsenic-associated "blackfoot disease" was endemic due to consumption of artesian well water containing high concentrations of arsenic compared with the rest of Taiwan .
●In a study from New Hampshire, individuals with the highest toenail arsenic concentration (>97th percentile) had a twofold increase in risk of cSCC, which was not seen among those with more moderate levels of arsenic exposure .
Radon — High concentrations of environmental radon were associated with increased rates of cSCC in a study in the United Kingdom . Locations with the highest radon concentrations had an almost twofold increase in reported cSCCs compared with areas with the lowest radon concentrations (RR 1.76, 95% CI 1.46-2.11). Additional studies are necessary to confirm an effect of radon exposure on risk for cSCC.
Genetic risk factors
Family history — Individuals with a family history of cSCC may have an increased risk for developing the disorder [55-57]. Similar cutaneous phenotypes, shared environmental exposures, and genetic factors are among the potential contributors to familial risk.
In a cohort study of more than 11 million individuals in Sweden that included 3867 cases of invasive cSCCs, subjects with a sibling or parent who had a history of invasive cSCC were two to three times as likely to develop the same diagnosis .
A smaller study of 25,882 adults in Finland found a lack of correlation of cSCC among twins. However, the number of cases of cSCC in the study was low; only 43 cSCCs were identified .
A case-control study including a random sample of 415 patients with histologically confirmed cSCC and 415 age-, sex-, and race-matched controls identified within a large health care delivery system found that a family history of any skin cancers was associated with a fourfold increased risk of cSCC, after adjusting for phenotypical and environmental risk factors for cSCC .
Xeroderma pigmentosum — Xeroderma pigmentosum (XP) is a rare disorder in which there is an impaired ability to repair UV-induced DNA damage . XP is a multigenic, multiallelic, autosomal recessive disease that occurs at a frequency of approximately 1 in 250,000. Mutations in eight genes have been identified. Seven of these genes (ie, XPA to XPG) are involved in nucleotide excision repair of carcinogen adducts after UV irradiation, while the other (ie, XPV) is involved in error-free replication of DNA damaged by UV irradiation [60-62].
In individuals with XP, the incidence of skin cancers prior to the age of 20 years is approximately 2000 times that seen in the general population, with an average age of onset of 9 years for nonmelanoma skin cancers and 22 years for melanoma .
The pathogenesis, clinical features, diagnosis, and management of XP are discussed in detail elsewhere. (See "Xeroderma pigmentosum".)
Epidermolysis bullosa — The epidermolysis bullosa syndromes are a group of mechanobullous skin diseases that share a common feature of blister formation occurring with little or no trauma. Data from the National Epidermolysis Bullosa Registry indicate that patients with recessive dystrophic epidermolysis bullosa, and particularly those with the Hallopeau-Siemens subtype, are at increased risk of cSCC beginning in adolescence, with a cumulative risk of 7.5 percent by age 20 and 90 percent by age 55 years. Most of these tumors occur at sites of chronic wounds .
Although these cSCCs are well differentiated, they are biologically aggressive, with a high incidence of metastases. The cumulative risk of death from cSCC was 80 percent by age 55 years, despite aggressive surgical resection. (See "Epidermolysis bullosa: Epidemiology, pathogenesis, classification, and clinical features", section on 'Skin cancer'.)
Albinism — Oculocutaneous albinism (OCA) is a group of autosomal recessive disorders of melanin biosynthesis characterized by a generalized decrease of pigmentation in the skin, eyes, and hair. Individuals with OCA have an increased risk of early-onset skin cancers, most frequently cSCC . (See "Oculocutaneous albinism".)
In a study of 111 South African Black persons with albinism, the point prevalence of nonmelanoma skin cancer was approximately 25 percent, with increasing risk of skin tumors with increased age . Without sun protection, persons with albinism have a shortened life expectancy. In Africa, few persons with albinism live past 40 years due to death from metastatic cSCC .
Epidermodysplasia verruciformis — Epidermodysplasia verruciformis is a rare disease characterized by extreme susceptibility to cutaneous human papillomavirus (HPV) strains 5 and 8 and cSCC . (See "Epidermodysplasia verruciformis".)
Other genetic syndromes — Several other rare genetic disorders are associated with increased incidence of cSCC and younger age of onset, including Fanconi anemia, Ferguson-Smith syndrome (keratoacanthomas), dyskeratosis congenita, Rothmund-Thomson syndrome, Bloom syndrome, and Werner syndrome. (See "Clinical manifestations and diagnosis of Fanconi anemia" and "Keratoacanthoma: Epidemiology, risk factors, and diagnosis", section on 'Multiple keratoacanthomas' and "Dyskeratosis congenita and other telomere biology disorders" and "Bloom syndrome".)
Immunosuppression — Chronic immunosuppression (eg, secondary to solid organ transplantation, HIV infection, or long-term glucocorticoid use) may increase the incidence of cSCC and, to a lesser extent, BCC [69-74]. In the Netherlands and Norway, the rates of cSCC were 65 to 250 times more frequent in kidney and heart recipients than in the general population [69,70]. In the United States, approximately 35 percent of heart transplant recipients will develop a skin cancer within 10 years after transplantation [71,75]. The risk of multiple lesions is high. Among heart transplant patients who have had one post-transplant cSCC or BCC, 60 to 70 percent will develop a subsequent cSCC within five years . Among HIV-infected individuals with a history of nonmelanoma skin cancer, those with CD4 counts <200/microL and high viral loads (≥10,000 copies/mL) had a twofold increased risk of developing a second primary cSCC . (See "Epidemiology and risk factors for skin cancer in solid organ transplant recipients", section on 'Squamous cell and basal cell carcinoma'.)
The incidence of cSCC increases with the duration and degree of immunosuppression and is higher in sunny climates [77,78]. Approximately 45 percent of transplant patients in Australia report a cSCC within 10 years after transplantation compared with 10 to 15 percent of patients from Holland, England, or Italy .
The pathogenic mechanisms in these patients are multifactorial, with a history of sun exposure preceding or following transplantation being the most important risk factor. In a study of 5356 transplant recipients in Sweden, the RR of nonmelanoma skin cancer was approximately 40 times higher on the lips compared with other epithelial tissues (eg, mouth, anus, rectum) that are not highly sun exposed .
The DNA damage caused by UV radiation may be augmented by both direct effects of immunosuppressive agents and decreased immune surveillance that results in a reduced ability to eradicate precancerous changes in the skin [72,80]. In addition, cSCCs are more aggressive in transplant recipients as evidenced by an increased risk of local recurrence, regional and distant metastasis, and mortality compared with other patients . (See "Prevention and management of skin cancer in solid organ transplant recipients".)
Chronic inflammation — There is an increased risk of cSCC in chronically inflamed skin. Approximately 1 percent of cutaneous skin cancers arise in chronically inflamed skin (eg, burn scars, chronic ulcers, sinus tracts, inflammatory dermatoses), and approximately 95 percent of these are cSCCs . Lichen sclerosus is a scarring, inflammatory skin condition typically involving the female genitals and is associated with cSCC and verrucous carcinoma of the vulva . (See "Vulvar lichen sclerosus".)
When a cSCC occurs in a chronic wound, it is also known as Marjolin's ulcer. These tumors are usually aggressive and associated with a poor prognosis . (See "Cutaneous squamous cell carcinoma (cSCC): Clinical features and diagnosis", section on 'Marjolin's ulcer'.)
The interval between the initial skin damage and appearance of a tumor varies widely, with cSCC appearing as early as 6 weeks or as many as 60 years after the traumatic event [84-86].
Smoking — Individual epidemiologic studies have yielded conflicting results about the role of smoking as a risk factor for cSCC [33,87-89]. However, a 2012 systematic review and meta-analysis of 25 cohort and case-control studies found that ever smoking was associated with a 50 percent increased risk of cSCC (risk ratio [RR] 1.52, 95% CI 1.15-2.01) .
Another meta-analysis of eight studies, including two large, cohort studies (ie, the Health Professionals Follow-up Study and the Nurses' Health Study), found only a slightly increased risk of cSCC for ever smokers compared with never smokers (OR 1.08, 95% CI 1.01-1.15) .
In the 2017 Australian cohort study, current smokers had more than a twofold increased risk of cSCC compared with never smokers, after adjusting for age, sex, education, skin color, tanning ability, number of freckles, history of sunburn as a child, and cumulative sun exposure (adjusted hazard ratio [HR] 2.30, 95% CI 1.46-3.62) .
A subsequent analysis of data from the United Kingdom Million Women Study, including over 1,220,000 women, found that current smokers had an overall 20 percent higher risk of cSCC compared with never smokers (adjusted RR 1.22, 95% CI 1.15-1.31) . In a subgroup analysis of over 486,000 women for whom information on potential confounders (eg, hair and eye color, nevi, freckles, tendency to burn or tan, sunbed use, holidays in sunny places) was available, the association between cSCC and current smoker status was marginally significant after adjusting for phenotypic characteristics and recent vacations in sunny places (adjusted RR 1.26, 95% CI 1.00-1.58).
Human papillomavirus infection — HPV infection can cause cSCC in genetically predisposed individuals (eg, epidermodysplasia verruciformis) and verrucous carcinoma of the penis (Buschke-Löwenstein tumor). However, HPV skin infections are common, and the relationship between HPV and cSCC in the general population is unclear.
Multiple studies have reported indirect evidence supporting an etiologic relationship [94-101]. A 2015 meta-analysis of 14 case-control studies including over 3000 cases and 6000 controls found a positive overall association between beta-genus HPV and cSCC (pooled OR 1.4, 95% CI 1.2-1.7) . A type-specific analysis showed a significant association between types 5, 8, 15, 17, 20, 24, 36, and 38 and risk of cSCC.
However, a study that compared HPV viral loads and HPV mRNA expression in tumoral and normal tissue found no difference in HPV viral loads between tumors and healthy tissue from individuals with cSCC and failed to detect HPV mRNA expression in skin tumors . Another study using integrated metagenomic sequence analysis demonstrated the absence of viral DNA, including HPV DNA, in the exome and whole-genome sequence of cSCC . Additional studies are necessary to clarify whether the association between cSCC and HPV is clinically relevant.
Voriconazole — Long-term therapy with the antifungal drug voriconazole has been associated with the development of cSCC in immunosuppressed patients, including children [105-109]. (See "Epidemiology and risk factors for skin cancer in solid organ transplant recipients".)
The drug can also cause cutaneous photosensitivity, but the mechanism through which voriconazole might contribute to the occurrence of cSCC remains unknown [110,111]. Voriconazole-induced phototoxic eruptions were documented in almost all of the patients who developed cSCC [105-107]. (See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Phototoxicity'.)
Thiazide diuretics and other photosensitizing drugs — The association of cSCC with UV light exposure and PUVA therapy has led to questions about the impact of photosensitizing drugs on the risk for cSCC. Several observational studies have found modest increases in risk for cSCC among patients with a history of use of photosensitizing medications [112-117]. As an example, a cohort study including nearly 30,000 non-Hispanic White patients with hypertension enrolled in a health care system in northern California and followed up for a mean of five years found a 17 percent increased risk of cSCC in those using photosensitizing antihypertensive drugs compared with those not taking any drugs, after adjusting for age, sex, smoking, and history of cSCC and actinic keratosis (HR 1.17, 95% CI 1.07-1.28) . The risk increase was mainly driven by the use of thiazide diuretics alone or in combination regimens (HR 1.32, 95% CI 1.19-1.46). Other thiazide drugs have also been found to be associated with an increased risk of cSCC, suggesting a class effect .
A 2018 meta-analysis of seven observational studies confirmed the association between cSCC and use of diuretics (pooled OR, 95% CI 1.19-1.66) . No significant association was found between cSCC and use of other antihypertensive drugs, including angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, beta-blockers, and calcium channel blockers.
A subsequent Danish case-control study using data from five nationwide registries and including over 8000 patients with cSCC and 172,000 controls found that patients with cSCC were more likely to be high users of hydrochlorothiazide (cumulative dose ≥50,000 mg) than controls (10 versus 2.8 percent; OR 3.98, 95% CI 3.68-4.31) . The study also demonstrated a dose-response relationship between hydrochlorothiazide use and cSCC risk, with patients in the highest category of use (cumulative dose ≥200,000 mg) having a much increased risk of cSCC (OR 7.38, 95% CI 6.32-8.60).
Similar results were provided by a nested case-control study using data from the United Kingdom Health Improvement Network database including over 7500 cSCC cases and 151,000 controls . The risk of cSCC for cumulative doses ≥50,000 mg (approximately 25 mg per day for 5.5 years) of hydrochlorothiazide was three times higher than for cumulative doses <25,000 mg, after adjusting for any use of other photosensitizing drugs, alcohol abuse, smoking, and body mass index (IRR 3.05, 95% CI 1.93-4.81).
However, as data on major risk factors for cSCC (ie, sun exposure, skin phototype) were not available for the populations studied, and thus were not controlled for, the magnitude of the association between hydrochlorothiazide and cSCC may have been overestimated.
Additional studies controlling for known risk factors for cSCC are needed to better determine the magnitude of this association. In the meantime, education on sun avoidance and sun protection may be appropriate for patients taking photosensitizing drugs.
Azathioprine — A large whole exome sequencing study of 40 primary cSCCs from both immunosuppressed and immunocompetent patients identified a novel signature mutation (signature 32) associated with chronic exposure to azathioprine in 27 of the tumor samples . Azathioprine, an inhibitor of de novo purine synthesis, is associated with selective UVA photosensitivity and mutagenic effects in the skin. This is due to incorporation into DNA of azathioprine metabolite 6-thioguanine, which acts as an endogenous UVA chromophore, resulting in DNA damage and protein oxidation .
BRAF inhibitors — Between 15 and 30 percent of patients with metastatic melanoma treated with the BRAF inhibitors vemurafenib and dabrafenib develop cSCCs or keratoacanthomas . The first lesions typically appear within weeks of the start of therapy. This occurrence may be related to a paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway in cells harboring pre-existing RAS or receptor tyrosine kinase mutations, an event that may contribute to the proliferation and survival of cancerous cells . (See "Cutaneous adverse events of molecularly targeted therapy and other biologic agents used for cancer therapy", section on 'Squamoproliferative lesions' and "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations" and "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Toxicities of BRAF and MEK inhibitors'.)
Associations between blood type and risks for BCC and pancreatic cancer have also been reported [125,126]. (See "Epidemiology and nonfamilial risk factors for exocrine pancreatic cancer", section on 'ABO blood group'.)
Diet and dietary supplements — Epidemiologic studies have shown conflicting results about the role of diet as a risk factor for cSCC [127-129]. Although several prospective studies have suggested that a diet high in meat and fat significantly increases the risk of cSCC [127,129], a large, randomized trial including approximately 50,000 postmenopausal women found no effect of a low-fat diet on the incidence of nonmelanoma skin cancer .
Animal and laboratory studies suggest that vitamin D may reduce the risk of skin cancer. However, epidemiologic studies on the role of vitamin D in the risk of skin cancer provided conflicting results, probably because sun exposure increases both vitamin D levels but also promotes the development of skin cancers [131,132]. Currently, there is insufficient evidence to make a recommendation regarding vitamin D supplementation to reduce cSCC risk .
A limited number of randomized trials have investigated the role of selenium supplementation in the risk of skin cancer with conflicting results. A 2018 meta-analysis of four randomized trials did not find an association between selenium supplementation and risk of nonmelanoma skin cancer (RR 1.23, 95% CI 0.73-2.08) .
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cutaneous squamous cell carcinoma".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Beyond the Basics topics (see "Patient education: Sunburn (Beyond the Basics)")
●Cutaneous squamous cell carcinoma (cSCC) is a common skin malignancy, and its incidence is increasing worldwide. cSCC incidence varies widely in different areas, with the highest incidence in geographic areas with high sun exposure. (See 'Epidemiology' above.)
●The primary risk factor for cSCC is ultraviolet (UV) light exposure, including occupational or recreational sun exposure, use of tanning beds, and psoralen plus ultraviolet A (PUVA) phototherapy. UV light damages DNA, initiating a series of changes that can result in malignant transformation. (See 'Ultraviolet radiation' above.)
●Other environmental risk factors that interact with UV light exposure include older age, immunosuppressive treatment, exposure to photosensitizing drugs, exposure to radiation and other industrial carcinogens, and smoking. (See 'Immunosuppression' above and 'Arsenic exposure' above and 'Ionizing radiation' above.)