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]
A history of radiation treatment has been shown to increase risk of cSCC.
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.
- ↑ 1.0 1.1 Non-melanoma Skin Cancer Working Group. The 2002 national non-melanoma skin cancer survey. Carlton, VIC: National Cancer Control Initiative; 2003 Nov [cited 2018 Oct 8]. Sponsored by Cancer Council. Available from: https://canceraustralia.gov.au/publications-and-resources/cancer-australia-publications/national-cancer-control-initiative-1997-2002-report.
- ↑ 2.0 2.1 Buettner PG, Raasch BA. Incidence rates of skin cancer in Townsville, Australia. Int J Cancer 1998 Nov 23;78(5):587-93 Available from: http://www.ncbi.nlm.nih.gov/pubmed/9808527.
- ↑ English DR, Armstrong BK, Kricker A, Winter MG, Heenan PJ, Randell PL. Demographic characteristics, pigmentary and cutaneous risk factors for squamous cell carcinoma of the skin: a case-control study. Int J Cancer 1998 May 29;76(5):628-34 Available from: http://www.ncbi.nlm.nih.gov/pubmed/9610717.
- ↑ Pandeya N, Olsen CM, Whiteman DC. The incidence and multiplicity rates of keratinocyte cancers in Australia. Med J Aust 2017 Oct 16;207(8):339-343 Available from: http://www.ncbi.nlm.nih.gov/pubmed/29020905.
- ↑ Grodstein F, Speizer FE, Hunter DJ. A prospective study of incident squamous cell carcinoma of the skin in the nurses' health study. J Natl Cancer Inst 1995 Jul 19;87(14):1061-6 Available from: http://www.ncbi.nlm.nih.gov/pubmed/7616597.
- ↑ English DR, Armstrong BK, Kricker A, Winter MG, Heenan PJ, Randell PL. Case-control study of sun exposure and squamous cell carcinoma of the skin. Int J Cancer 1998 Jul 29;77(3):347-53 Available from: http://www.ncbi.nlm.nih.gov/pubmed/9663594.
- ↑ Rosso S, Zanetti R, Martinez C, Tormo MJ, Schraub S, Sancho-Garnier H, et al. The multicentre south European study 'Helios'. II: Different sun exposure patterns in the aetiology of basal cell and squamous cell carcinomas of the skin. Br J Cancer 1996 Jun;73(11):1447-54 Available from: http://www.ncbi.nlm.nih.gov/pubmed/8645596.
- ↑ Ramos J, Villa J, Ruiz A, Armstrong R, Matta J. UV dose determines key characteristics of nonmelanoma skin cancer. Cancer Epidemiol Biomarkers Prev 2004 Dec;13(12):2006-11 Available from: http://www.ncbi.nlm.nih.gov/pubmed/15598755.
- ↑ Brash DE. UV signature mutations. Photochem Photobiol 2015 Jan;91(1):15-26 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25354245.
- ↑ Park WS, Lee HK, Lee JY, Yoo NJ, Kim CS, Kim SH. p53 mutations in solar keratoses. Hum Pathol 1996 Nov;27(11):1180-4 Available from: http://www.ncbi.nlm.nih.gov/pubmed/8912828.
- ↑ de Vries E, Trakatelli M, Kalabalikis D, Ferrandiz L, Ruiz-de-Casas A, Moreno-Ramirez D, et al. Known and potential new risk factors for skin cancer in European populations: a multicentre case-control study. Br J Dermatol 2012 Aug;167 Suppl 2:1-13 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22881582.
- ↑ Dika E, Fanti PA, Misciali C, Vaccari S, Crisman G, Barisani A, et al. Risk of skin cancer development in 672 patients affected by actinic keratosis. G Ital Dermatol Venereol 2016 Dec;151(6):628-633 Available from: http://www.ncbi.nlm.nih.gov/pubmed/26381460.
- ↑ Green AC. Epidemiology of actinic keratoses. Curr Probl Dermatol 2015;46:1-7 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25561199.
- ↑ Wehner MR, Shive ML, Chren MM, Han J, Qureshi AA, Linos E. Indoor tanning and non-melanoma skin cancer: systematic review and meta-analysis. BMJ 2012 Oct 2;345:e5909 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23033409.
- ↑ Lichter MD, Karagas MR, Mott LA, Spencer SK, Stukel TA, Greenberg ER. Therapeutic ionizing radiation and the incidence of basal cell carcinoma and squamous cell carcinoma. The New Hampshire Skin Cancer Study Group. Arch Dermatol 2000 Aug;136(8):1007-11 Available from: http://www.ncbi.nlm.nih.gov/pubmed/10926736.
- ↑ Karagas MR, Nelson HH, Zens MS, Linet M, Stukel TA, Spencer S, et al. Squamous cell and basal cell carcinoma of the skin in relation to radiation therapy and potential modification of risk by sun exposure. Epidemiology 2007 Nov;18(6):776-84 Available from: http://www.ncbi.nlm.nih.gov/pubmed/17917604.
- ↑ Mudigonda T, Levender MM, O'Neill JL, West CE, Pearce DJ, Feldman SR. Incidence, risk factors, and preventative management of skin cancers in organ transplant recipients: a review of single- and multicenter retrospective studies from 2006 to 2010. Dermatol Surg 2013 Mar;39(3 Pt 1):345-64 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23190408.
- ↑ Zhao H, Shu G, Wang S. The risk of non-melanoma skin cancer in HIV-infected patients: new data and meta-analysis. Int J STD AIDS 2016 Jun;27(7):568-75 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25999166.
- ↑ Brewer JD, Shanafelt TD, Khezri F, Sosa Seda IM, Zubair AS, Baum CL, et al. Increased incidence and recurrence rates of nonmelanoma skin cancer in patients with non-Hodgkin lymphoma: a Rochester Epidemiology Project population-based study in Minnesota. J Am Acad Dermatol 2015 Feb;72(2):302-9 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25479909.
- ↑ Levi F, Randimbison L, Te VC, La Vecchia C. Non-Hodgkin's lymphomas, chronic lymphocytic leukaemias and skin cancers. Br J Cancer 1996 Dec;74(11):1847-50 Available from: http://www.ncbi.nlm.nih.gov/pubmed/8956805.
- ↑ Euvrard S, Kanitakis J, Claudy A. Skin cancers after organ transplantation. N Engl J Med 2003 Apr 24;348(17):1681-91 Available from: http://www.ncbi.nlm.nih.gov/pubmed/12711744.
- ↑ Karagas MR, Cushing GL Jr, Greenberg ER, Mott LA, Spencer SK, Nierenberg DW. Non-melanoma skin cancers and glucocorticoid therapy. Br J Cancer 2001 Sep 1;85(5):683-6 Available from: http://www.ncbi.nlm.nih.gov/pubmed/11531252.
- ↑ Sørensen HT, Mellemkjaer L, Nielsen GL, Baron JA, Olsen JH, Karagas MR. Skin cancers and non-hodgkin lymphoma among users of systemic glucocorticoids: a population-based cohort study. J Natl Cancer Inst 2004 May 5;96(9):709-11 Available from: http://www.ncbi.nlm.nih.gov/pubmed/15126608.
- ↑ Jensen AØ, Thomsen HF, Engebjerg MC, Olesen AB, Friis S, Karagas MR, et al. Use of oral glucocorticoids and risk of skin cancer and non-Hodgkin's lymphoma: a population-based case-control study. Br J Cancer 2009 Jan 13;100(1):200-5 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19034275.
- ↑ Leonardi-Bee J, Ellison T, Bath-Hextall F. Smoking and the risk of nonmelanoma skin cancer: systematic review and meta-analysis. Arch Dermatol 2012 Aug;148(8):939-46 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22711192.
- ↑ Song F, Qureshi AA, Gao X, Li T, Han J. Smoking and risk of skin cancer: a prospective analysis and a meta-analysis. Int J Epidemiol 2012 Dec;41(6):1694-705 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23064412.
- ↑ Dusingize JC, Olsen CM, Pandeya NP, Subramaniam P, Thompson BS, Neale RE, et al. Cigarette Smoking and the Risks of Basal Cell Carcinoma and Squamous Cell Carcinoma. J Invest Dermatol 2017 Aug;137(8):1700-1708 Available from: http://www.ncbi.nlm.nih.gov/pubmed/28414022.
- ↑ Pirie K, Beral V, Heath AK, Green J, Reeves GK, Peto R, et al. Heterogeneous relationships of squamous and basal cell carcinomas of the skin with smoking: the UK Million Women Study and meta-analysis of prospective studies. Br J Cancer 2018 Jul;119(1):114-120 Available from: http://www.ncbi.nlm.nih.gov/pubmed/29899391.
- ↑ Yen H, Dhana A, Okhovat JP, Qureshi A, Keum N, Cho E. Alcohol intake and risk of nonmelanoma skin cancer: a systematic review and dose-response meta-analysis. Br J Dermatol 2017 Sep;177(3):696-707 Available from: http://www.ncbi.nlm.nih.gov/pubmed/28745396.
- ↑ de Villiers EM, Fauquet C, Broker TR, Bernard HU, zur Hausen H. Classification of papillomaviruses. Virology 2004 Jun 20;324(1):17-27 Available from: http://www.ncbi.nlm.nih.gov/pubmed/15183049.
- ↑ Pfister H. Chapter 8: Human papillomavirus and skin cancer. J Natl Cancer Inst Monogr 2003;(31):52-6 Available from: http://www.ncbi.nlm.nih.gov/pubmed/12807946.
- ↑ Feltkamp MC, Broer R, di Summa FM, Struijk L, van der Meijden E, Verlaan BP, et al. Seroreactivity to epidermodysplasia verruciformis-related human papillomavirus types is associated with nonmelanoma skin cancer. Cancer Res 2003 May 15;63(10):2695-700 Available from: http://www.ncbi.nlm.nih.gov/pubmed/12750299.
- ↑ Plasmeijer EI, Neale RE, de Koning MN, Quint WG, McBride P, Feltkamp MC, et al. Persistence of betapapillomavirus infections as a risk factor for actinic keratoses, precursor to cutaneous squamous cell carcinoma. Cancer Res 2009 Dec 1;69(23):8926-31 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19903846.
- ↑ Karagas MR, Waterboer T, Li Z, Nelson HH, Michael KM, Bavinck JN, et al. Genus beta human papillomaviruses and incidence of basal cell and squamous cell carcinomas of skin: population based case-control study. BMJ 2010 Jul 8;341:c2986 Available from: http://www.ncbi.nlm.nih.gov/pubmed/20616098.
- ↑ Proby CM, Harwood CA, Neale RE, Green AC, Euvrard S, Naldi L, et al. A case-control study of betapapillomavirus infection and cutaneous squamous cell carcinoma in organ transplant recipients. Am J Transplant 2011 Jul;11(7):1498-508 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21718442.
- ↑ Bouwes Bavinck JN, Feltkamp MCW, Green AC, Fiocco M, Euvrard S, Harwood CA, et al. Human papillomavirus and posttransplantation cutaneous squamous cell carcinoma: A multicenter, prospective cohort study. Am J Transplant 2018 May;18(5):1220-1230 Available from: http://www.ncbi.nlm.nih.gov/pubmed/29024374.
- ↑ Hall L, Struijk L, Neale RE, Feltkamp MC. Re: Human papillomavirus infection and incidence of squamous cell and basal cell carcinomas of the skin. J Natl Cancer Inst 2006 Oct 4;98(19):1425-6 Available from: http://www.ncbi.nlm.nih.gov/pubmed/17018790.
- ↑ McBride P, Neale R, Pandeya N, Green A. Sun-related factors, betapapillomavirus, and actinic keratoses: a prospective study. Arch Dermatol 2007 Jul;143(7):862-8 Available from: http://www.ncbi.nlm.nih.gov/pubmed/17638729.
- ↑ Kennedy C, Bajdik CD, Willemze R, Bouwes Bavinck JN. Chemical exposures other than arsenic are probably not important risk factors for squamous cell carcinoma, basal cell carcinoma and malignant melanoma of the skin. Br J Dermatol 2005 Jan;152(1):194-7 Available from: http://www.ncbi.nlm.nih.gov/pubmed/15656837.
- ↑ Gawkrodger DJ. Occupational skin cancers. Occup Med (Lond) 2004 Oct;54(7):458-63 Available from: http://www.ncbi.nlm.nih.gov/pubmed/15486177.
- ↑ Gallagher RP, Bajdik CD, Fincham S, Hill GB, Keefe AR, Coldman A, et al. Chemical exposures, medical history, and risk of squamous and basal cell carcinoma of the skin. Cancer Epidemiol Biomarkers Prev 1996 Jun;5(6):419-24 Available from: http://www.ncbi.nlm.nih.gov/pubmed/8781736.
- ↑ Nikolaou V, Stratigos AJ, Tsao H. Hereditary nonmelanoma skin cancer. Semin Cutan Med Surg 2012 Dec;31(4):204-10 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23174490.
- ↑ Jaju PD, Ransohoff KJ, Tang JY, Sarin KY. Familial skin cancer syndromes: Increased risk of nonmelanotic skin cancers and extracutaneous tumors. J Am Acad Dermatol 2016 Mar;74(3):437-51; quiz 452-4 Available from: http://www.ncbi.nlm.nih.gov/pubmed/26892653.
- ↑ 44.0 44.1 Asgari MM, Wang W, Ioannidis NM, Itnyre J, Hoffmann T, Jorgenson E, et al. Identification of Susceptibility Loci for Cutaneous Squamous Cell Carcinoma. J Invest Dermatol 2016 May;136(5):930-7 Available from: http://www.ncbi.nlm.nih.gov/pubmed/26829030.
- ↑ 45.0 45.1 Chahal HS, Lin Y, Ransohoff KJ, Hinds DA, Wu W, Dai HJ, et al. Genome-wide association study identifies novel susceptibility loci for cutaneous squamous cell carcinoma. Nat Commun 2016 Jul 18;7:12048 Available from: http://www.ncbi.nlm.nih.gov/pubmed/27424798.
- ↑ Siiskonen SJ, Zhang M, Li WQ, Liang L, Kraft P, Nijsten T, et al. A Genome-Wide Association Study of Cutaneous Squamous Cell Carcinoma among European Descendants. Cancer Epidemiol Biomarkers Prev 2016 Apr;25(4):714-20 Available from: http://www.ncbi.nlm.nih.gov/pubmed/26908436.
- ↑ Pickering CR, Zhou JH, Lee JJ, Drummond JA, Peng SA, Saade RE, et al. Mutational landscape of aggressive cutaneous squamous cell carcinoma. Clin Cancer Res 2014 Dec 15;20(24):6582-92 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25303977.