Causes of Skin Cancer
Skin cancers are malignant growths (malignant tumours or malignant neoplasms), which usually present on the epidermis (the outer layer of skin), though can occur in other areas of the body such as inside the mouth, nose and on the nailbeds. The three most common forms of skin cancer are basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and melanoma. Basal cell carcinoma is the most common (accounting for approximately 75% of all skin cancers), though it tends to grow slowly over a number of years and is unlikely to metastasise (spread to other parts of the body). Squamous cell carcinoma is less common (approx. 20%) but more dangerous as it is more likely to invade surrounding tissue. Melanoma is the least common (approx. 5%), but most lethal of the three types of skin tumour. It is fast growing and once metastasised is frequently fatal. The three types of skin neoplasms develop from different cells within the skin. Melanomas are derived from melanocytes, SCCs and BCCs from keratinocytes. As the name implies, BCCs originate in the basal layer of the epidermis, whereas SCCs develop from keratinocytes in the surface/middle layer. For more information, refer to the pages on basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and melanoma.
Figure 1: Basal cell carcinoma
Figure 2: Squamous cell carcinoma
Figure 3: Melanoma skin cancer
There are a number of factors which contribute to a person’s likelihood of developing skin cancer; these include genetic, geographical and environmental risks; most notably ultraviolet (UV) radiation exposure.
Genetic risk factors
As with many diseases, skin cancers are multifactorial disorders that develop from complex combinations of an individual’s genetic make-up, or predisposition, and environmental factors; such as the amount UV radiation to which they are exposed. Most at risk of developing skin cancer are individuals with fair skin which has a tendency to burn rather than tan; related to this are people who have skin which is sun sensitive or bears extensive freckling. The reason for this is that light-skinned people produce less of the photoprotective pigment melanin. Melanin absorbs UV radiation, reducing its ability to damage skin cells; thus, heavily pigmented skin filters out more UV radiation and provides better natural protection. Melanin present in hair follicles and the iris of the eye is also the main determinant of hair and eye colour; these aspects are often linked with an individual’s level of skin pigmentation. Therefore, individuals with red or blonde hair and green or blue eyes are also at greater risk of skin cancer.
Human pigmentation is extremely complex, being modulated by over 120 genes. One gene particularly relevant to the degree of pigmentation is the melanocortin receptor type 1 (MC1R) gene. MC1R encodes a protein primarily located on the surface of melanocytes, known as the melanocortin 1 receptor. The expression of MC1R is upregulated by UV exposure and by factors released after UV exposure, such as the melanocortin alpha melanocyte stimulating hormone (α-MSH). When α-MSH binds to this receptor it stimulates the production of melanin by the melanocytes. The MC1R gene is highly variable, which can largely explain the differences in human cutaneous pigmentation and skin type.
More than 80 different forms (alleles) of the MC1R gene have been found, mainly in Caucasian populations, with certain variants being associated with the characteristics of red hair, freckles, poor tanning response and pale, readily burnt skin (also called RHC phenotype). Carrying one of these variants is thought to diminish the ability of the epidermis to respond to damages elicited by UV radiation, by reducing the ability of the receptor to stimulate melanin production.
As a result of these physical features skin cancer incidence varies within different racial groups. Unsurprisingly, Caucasians have the highest prevalence of skin cancer, followed by Hispanic and native American Indians. Next most at risk are those of Asian and Pacific Islander origin, with dark skinned populations having the lowest incidence.
Figure 4: Diagram showing genetic and environmental risk factors for skin cancer development
Since there is a genetic component to skin cancer occurrence, family history and heredity are important aspects to determining one’s level of risk. As discussed, carrying certain MC1R variants is a risk factor for developing skin cancers. Genes conferring a risk of melanoma development, specifically, have also been identified. Heritable mutations in the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene is the strongest genetic risk. Particular variants of the cyclin-dependent kinase CDK4 and the retinoblastoma gene RB1 may also predispose towards melanoma. Most cases of melanoma however, do not carry these susceptibility gene mutations and are the result of undiscovered factors.
Environmental risk factors
Chronic exposure to ultraviolet radiation, in combination with genetic predisposition, is the single most important factor contributing to skin cancer. The mass of evidence demonstrating a link between skin cancer and UV exposure is highly compelling. UV radiation is believed to cause skin cancer by damaging the genetic information (DNA) within skin cells and by inducing oxidative damage. The page, UV damage and carcinogenesis details what is currently known about these molecular processes.
The cumulative amount of lifetime sunlight exposure is the most important contributing factor to the development of SCC. While this is also a factor in melanoma incidence, more significant is the number and extremity of episodes. Periods of high UV exposure and severe sunburn incidents – those which result in blistering or peeling of the skin, particularly in childhood – have being strongly associated with the development of melanoma later in life. This is not surprising since it has been revealed that most of an individual’s total lifetime UV exposure occurs during childhood, markedly during the primary school years. Thus, it is both the duration and intensity of radiation which create risks; recurrent periods and high peaks are both important elements.
It is for these reasons that the probability of all types of skin cancer increases with age, resulting from the cumulative effect of sun exposure. People aged over 50 years have increased incidence as they are more likely to have a personal history of sun-damaged skin, a strong predictor of skin cancer.
While the main cause of skin cancer comes from solar radiation, UV radiation can also be encountered in artificial sources including tanning beds and sunlamps. The use of such tanning facilities is increasing in adolescents, particularly females, who endeavor to achieve a “healthy”-looking tan.
Geographical risk factors
The rates of skin cancer in Australia are higher than anywhere else in the world, at nearly four times the incidence in America, Canada and the United Kingdom. It has been suggested that the large proportion of skin cancers in Australia is due to a combination of latitude and a population composed of a large number of people with susceptible skin types. Other theories are that the elevated incidence may be due to damage to the ozone layer in the atmosphere above this area or that the Australian lifestyle involves more outdoor activities. Within Australia, the incidence of skin cancer varies with latitude, with higher rates in the north, Queensland having the highest number of cases nationally. Rates of all types of skin cancer are also lower for Australians who were born outside the country; presumably this is a result of either more resilient skin types and/or reduced UV exposure in childhood.
Other types of radiation
Large doses of ionising radiation have the potential to cause non-melanoma skin cancers such as SCC and BCC. The danger became apparent following the discovery of radioactivity as scientists, unaware of the need for protective clothing and limited exposure, developed skin cancers. Similarly, skin cancer is one of the most common types of cancer found in survivors of the 1945 atomic bombing of Hiroshima and Nagasaki.
Most at risk are individuals who are exposed to radiation for long periods of time or in high doses, such as uranium miners and radiologists. Localised use in radiotherapy and protective measures such as lead aprons for x-ray patients help to minimise the risk of this carcinogen for patients when used remedially.
Smoking has been linked with an increase in SCC, with smokers more than three times more likely to develop this cancer than non-smokers; most especially cancers of the mouth, throat and tongue. Studies show that cigarettes and pipes confer a higher risk than cigar smoking; there is also a relationship between the number of cigarettes smoked and the likelihood of SCC. Tobacco smoke contains several chemicals with known or suspected carcinogenic effects, such as nitrosamines and aromatic hydrocarbons. Researchers theorise that smoking damages the DNA within skin cells, resulting in mutation which can lead to cancer.
Approximately 90% of all oral cancers are SCCs, alcohol consumption is solidly linked to such tumours. Abuse of alcohol (greater than 21 standard drinks per week), after smoking, is the second highest risk factor associated with oral cancers. Heavy drinkers who also smoke are 15 times more likely to develop oral cancer as it is believed that the two act synergistically, with alcohol increasing the ability of the chemicals in tobacco smoke which cause cancer to infiltrate the cells in the oral cavity.
Many environmental contaminants are known or alleged to be potent carcinogens, for example, several aromatic hydrocarbons in polluted air that are produced in motor vehicle exhaust or given off by burning wood. Arsenic can also cause skin cancer when ingested, it is present in small amounts in soil, urban air and some water supplies.
There are a range of medical conditions which may render the patient more susceptible to skin cancer.
In a healthy person, the immune system responds to the formation of cancerous or pre cancerous cells by recognizing and destroying them before they multiply and/or spread by inducing apoptosis (programmed cell death). A weakened immune system has compromised surveillance and is unable to eliminate damaged cells and to defend the body as effectively, resulting in a larger number of malignancies. Immunodeficiency may result from disease or some medications.
Organ transplant recipients (OTRs), particularly those who have been treated with immunosuppressive medication for long periods of time, are at high risk of developing skin cancer. Tumours in these people tend to be more numerous, more aggressive and metastasise more often.
Impaired immune function leaves the body vulnerable to attack by viruses. A number of viruses, including Epstein Barr virus, herpes simplex virus, herpes zoster virus and human papilloma virus have been implicated in skin cancer genesis.
Albinism is used to describe a series of hereditary skin conditions in which production of the pigment melanin is impeded. Albinism affects approximately one in 17,000 people with characteristic fair skin, hair and eyes. Since they lack the protective pigment, albinos are more susceptible to UV radiation than those with normal pigmentation and hence are prone to skin cancer.
Individuals with the rare skin disease xeroderma pigmentosum have defective DNA repair mechanisms. These patients have a higher incidence of skin cancer as the damage caused to skin cells (particularly that caused by UV light) is not mended as effectively.
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