1.2 Epidemiology of cutaneous squamous cell carcinoma
Incidence of cutaneous squamous cell carcinoma[edit source]
Cutaneous squamous cell carcinoma (cSCC) is generally not systematically registered and incidence estimates are derived from secondary sources, as for basal cell carcinoma (BCC). In the 2002 national non-melanoma skin cancer survey, the age-standardised incidence rate of cSCC (not including cSCC in situ) was 387 per 100,000 in people aged 14 years and over (499 in men and 291 in women per 100,000), with a significant latitude gradient as for BCC (see: Incidence of basal cell carcinoma). Incidence was highest in males for all age groups. The incidence of cSCC increases steeply with increasing age from mid-adulthood. Rates of cSCC among predominantly light-skinned European migrants to Australia are lower than rates of cSCC among those of similar ancestry who were born in Australia.
More recently, cSCC incidence in the Australian population was estimated in an analysis of a 10% random sample of Medicare administrative data based on the frequency of item codes for excisions of keratinocyte cancers (KCs) with histology. By extrapolating data from a population-based cohort for which the age- and sex-specific ratios of cSCC to BCC were known, the incidence of excised cSCCs was estimated at 271 per 100,000 person years (209 per 100,000 in women and 341 per 100,000 in men). Again, an inverse latitude gradient was observed, with the highest rates in Queensland (471 per 100,000) and the lowest rates in Tasmania and Victoria (221 per 100,000).
The head and neck are the most common sites of occurrence for cSCC in men, while in women the upper limbs are the most common site, followed by head and neck. When the body surface area is taken into account, the highest cSCC incidence in both men and women is found on the face, especially the lip region, ears, nose, cheek and eyelid, with neck, dorsa of hands and forearms next most affected.
Host factors[edit source]
Having a sun-sensitive pigmentary phenotype is also a strong and well-established risk factor for cSCC, as for BCC (see: Epidemiology of basal cell carcinoma). Light skin, eye and hair colour are significant risk factors, as is the presence of freckling.
Environmental factors[edit source]
The principal environmental cause of cSCC is exposure to solar ultraviolet (UV) radiation, and there is a strong positive relationship between level of cumulative sun exposure and cSCC risk. Evidence for a causal association derives from ecological, migration and analytical epidemiological studies. Laboratory studies have reported UVB-specific mutations in the TP53 tumour-suppressor gene of cSCC tumours and in actinic keratoses (AK). Signs of photoaging and a history of AKs, which in some cases can act as premalignant lesions for cSCC, are strongly related to cSCC risk.
Artificial UV radiation[edit source]
Exposure to artificial UV radiation from indoor tanning facilities is significantly associated with cSCC, with the highest risk observed in those first exposed before age 25 years.
Other sources of radiation[edit source]
Immunosuppression is a major risk factor for cSCC. Groups with an elevated risk of cSCC include solid organ transplant recipients and those diagnosed with human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS), non-Hodgkin lymphoma or chronic lymphocytic leukaemia.
The incidence of cSCC among organ transplant recipients is 65–250 times higher than that of the general population. The use of glucocorticoids, a class of medicines with immunosuppressive properties, is associated with an approximate 2-fold increased risk of cSCC.
The two previous meta-analyses of the association between smoking and skin cancer showed current smokers to have an increased risk of cSCC compared with never-smokers. The results of two recent cohort studies have further shown that smokers have up to twice the risk of cSCC of non-smokers, and this risk is likely to be independent of the effect of sun exposure.
Total alcohol consumption is associated with an increased risk of cSCC. A meta-analysis of case-control and cohort studies reported a significant dose–response relationship between alcohol and cSCC; for every 10g increase in ethanol consumption per day (equivalent to one standard drink) the summary relative risk was 1.11 (95% confidence interval 1.06–1.16).
Many studies have investigated the potential association between cutaneous cSCC and certain cutaneous human papillomavirus (HPV) types, mostly in the betapapillomavirus genus (beta-HPV), though infection is common in the general population. Suggestive associations have been seen between markers of beta-HPV infection (beta-HPV antibodies and beta-HPV DNA), and both AKs and cSCC, but not between beta-HPV markers and BCC.
Betapapillomavirus has also been investigated as a possible infectious oncogenic agent that may explain the greatly increased cSCC risk in immunosuppressed organ transplant recipients. A recent multi-centre prospective study in organ transplant recipients found that those with five or more different beta-HPV types in eyebrow hair follicles had nearly twice the risk of cSCC than those with between zero and four different types, and a similar risk was seen with high beta-HPV loads in eyebrow hair. Serum beta-HPV antibodies were not associated with cSCC risk.
The current hypothesis is that, if beta-HPV is causally involved in development of cSCC, it acts to potentiate the effect of UV radiation possibly via viral inhibition of DNA repair and apoptosis following UV radiation exposure.
Other risk factors[edit source]
Other less common but well-established risk factors for cSCC include chemical exposures such as arsenic, polycyclic aromatic hydrocarbons (found in industrial oils and lubricants), pesticides and herbicides.
Genetic epidemiology[edit source]
Rare, high-risk susceptibility genes[edit source]
Several genes associated with cSCC have been identified in patients with hereditary disorders such as xeroderma pigmentosum (XPA-XPG and XPV), Ferguson-Smith syndrome (TGFBR1), oculocutaneous albinism (TYR, OCA2, MATP/OCA4, TYRP1) and epidermodysplasia verruciformis (EVER1, EVER2). These mutations are associated with distinct phenotypes and are related to defects in either DNA repair, pigmentation or key signalling pathways. Affected individuals often develop multiple early-onset cSCCs, and are at increased risk of other malignancies.
Common, low- to moderate-risk susceptibility genes[edit source]
Genome- wide association studies have confirmed earlier findings from candidate gene approaches identifying common, low- to moderate-risk susceptibility genes that are related to pigmentation, including MC1R, ASIP, TYR, SLC45A2, OCA2, IRF4 and BNC2, as well as identifying new loci associated with pigmentation traits (DEF8, RALY). Other recently identified loci include FOXP1, HLA-DQA1 and CADM1 involved in immune response, AHR involved in anti-apoptotic pathways, SEC16A, an oncogene, and several other loci whose functions are yet to be elucidated (TPRG1/GP63, BNC2/CNTLN).
Somatic mutations[edit source]
Sequencing studies have identified extremely high mutation burdens in cSCC, consistent with UV-induced damage, and most of the genes identified are tumour suppressor genes. The long list of driver genes identified, including TP53, CDKN2A, NOTCH1, NOTCH2, AJUBA, HRAS, CPSP8, FAT1 and KMT2C (MLL3), suggests that cSCC tumours arise through multiple pathways.
Ongoing protection from incremental sun exposure throughout life, including appropriate use of clothing and sunscreen, should be promoted and encouraged, especially in those with sun-sensitive skin, to reduce the risk of cutaneous squamous cell carcinoma.
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