Etiological Factors in Skin Cancers: Environmental and Biological

Ultraviolet radiation

UV radiation, visible light, infrared radiation, gamma rays, and X-rays are all part of the electromagnetic spectrum ( Fig. 6.1 ). Visible, UV, and infrared radiation do not ionize molecules and are thus referred to collectively as non-ionizing radiation. Such radiation travels as three-dimensional waves in a vacuum and acts as discrete ‘packets’ of energy or photons when interacting with matter. In order for such radiation to have an effect in biologic systems, it must be absorbed by the molecules of such systems. The energy of a photon of non-ionizing radiation defines its ability to interact with a given molecule. The energy of a photon varies inversely with its wavelength.

The effects of non-ionizing radiation on human cells rely on complex cellular interactions. Specifically, when radiation is absorbed, molecules become raised to an excited state. As molecules return to the resting state through a process of dissipating the absorbed energy, the energy may be converted to chemical change, which in turn results in biologic alterations. UV radiation, emitted both by the sun and by artificial sources, is a well-accepted cause of skin cancer recognized by both the Food and Drug Administration (FDA) and the World Health Organization (WHO) as a significant carcinogen.

The spectrum of UV radiation is conventionally divided into three bands, defined in ranges of nanometers: UVA, UVB, and UVC. Approximately 90–95% of the UV radiation spectrum reaching the Earth's surface is longer-wave radiation, or UVA, the remaining 5–10% being represented by UVB. Several factors influence the intensity of UV exposure, including altitude, latitude, position of the sun, local conditions like weather, health of the ozone layer, and human behavior.

Latitude – Locations that are closer to the equator experience higher levels of UV radiation because the sun is directly overhead. Thus, UV radiation has a shorter distance to travel through the atmosphere, giving less opportunity for attenuation. In addition, the ozone layer, which reduces the amount of UVB radiation available at the ground, is naturally thinner over the equatorial region year round.

Altitude – As altitude increases, UV exposure also increases. Again, this has to do with the lesser distance through the Earth's atmosphere that UV travels before reaching the Earth's surface. UV radiation intensity increases by 8–12% for every 1000 meters in elevation gained.

Position of the sun – UV radiation levels vary by time of day and time of year. On any given day, assuming clear rather than overcast conditions, UV radiation levels are highest at solar noon during the middle of the day. On an annual basis, UV radiation levels peak during the Summer Solstice, and are at their lowest during the Winter Solstice.

Local conditions – Cloud cover is the most significant factor influencing UV. A very dense continuous cloud cover can effectively block UV. However, under some conditions, 50% or more may penetrate cloud cover. There are also meteorological conditions of scattered clouds that may actually enhance exposure levels, because incoming UV can even reflect off scattered and wispy clouds. Other local conditions that affect the amount of UV radiation people may be exposed to include reflective surfaces like snow, light-colored sand, pavement and water. Reflective surfaces can increase UV exposure dramatically. For example, clean snow may raise exposure levels by up to 80%, while dry beach sand can increase exposure by 15%. Local factors like pollution and aerosols also affect UV radiation levels. In these cases, the effect can be to decrease exposure levels by blocking UV radiation from reaching the Earth's surface.

Ozone layer status – The ozone layer plays a vital role in absorbing UVB radiation entering the Earth's atmosphere ( Fig. 6.2 ). In the 1970s and 1980s, scientists discovered that chlorofluorocarbons (CFCs) – then a common propellant in aerosol cans and commonly used as refrigerants, solvents and foam-blowing agents – were damaging the ozone layer. CFCs were used widely in many industrial and consumer applications, and were highly valued for their low reactivity and chemical stability. Unfortunately, as theorized by US scientists Sherwood Rowland and Mario Molina in 1975, that very chemical stability made these chemicals ideal ‘transport mechanisms’ for ozone-damaging chlorine. Once emitted, CFCs maintain their chemical structure intact through all atmospheric transport processes until they reach the stratosphere, where UVC breaks the bonds binding molecules of CFCs together. This frees the chlorine contained in these molecules to react with the ozone (O ₃ ) in the Earth's ozone layer. The resulting chemical reactions enhance natural ozone destruction processes already existing in the stratosphere; before the anthropogenic emission of CFCs, these natural destruction processes were balanced by natural mechanisms that also create ozone.

While scientists have loosely used the term ‘ozone hole’, the occurrence is actually more like an extreme thinning of ozone at the South Pole, caused by chlorine released from CFCs and other ozone-damaging compounds, such as brominated chemicals used as fire extinguishers and agricultural fumigants. As the austral spring ends, ozone-poor air from the Antarctic region then mixes with the atmosphere generally, decreasing the amount of O ₃ available to screen out UVB radiation worldwide. As a result, ‘average erythemal UV radiation levels increased by up to a few percent per decade between 1979 and 1998’. The largest increases in UV radiation levels have occurred in mid to high latitudes as a result of stratospheric ozone layer depletion.

In response to this problem, the international treaty to control chemicals that deplete the ozone layer – the Montreal Protocol on Substances that Deplete the Ozone Layer – was opened for signature in 1987 and signed thereafter by all the 196 United Nation members. This level of international cooperation has proved remarkably successful: annual world use of ozone-depleting substances has been reduced over 90%. Still, due to the long atmospheric residence time of these chemicals, ozone damage continues. Scientists do not expect the ozone layer to recover to 1980 levels until 2065 at the earliest ( Fig. 6.3 ). Using daily measures of UV intensity at stations around the world (a measure known as the Global Solar UV Index), it has been projected that, in the absence of global action on ozone-damaging compounds, for mid-latitudes in the northern hemisphere (30°–50° N latitude), the UV Index on an average summer day would have risen from 6–7 (high) to 15 (extreme) by 2040, and to 30 (extreme) by 2065.

Ozone depletion may already be making an impact on skin cancer rates. Incidence and mortality rates are disproportionally rising in Southern Chile (in populated areas significantly impacted by ozone depletion) and should current losses continue, it has been estimated that there will be an additional 5000 cases of skin cancer annually in the UK by mid century.

Individual behavior – Individual behavior plays a key role in exposure to UV radiation, and, in fact, is likely much more influential in shaping lifetime risk than is damage to the ozone layer. As an example of current population-wide sun-protective behavior, surveys in the US found that up to one-third of Americans are using any one form of sun protection, including wearing sunscreen, hats, sunglasses, and shirts, and seeking shade. Trend data from the US National Cancer Institute show that while sun protection practices have increased since the early 1990s, they seem to have leveled off or even fallen since 2000.

Both UVA and UVB have been documented to be related to skin cancer risk and the action spectra for the development of SCC and melanoma in mammalians have been developed ( Fig. 6.4 ). UV causes mutations and immunosuppressive effects that are essential to photo- carcinogenesis. DNA is a major epidermal chromophore with an adsorption spectrum that is highest in UVC range and decreases steadily in UVB and UVA. The absorption of UV photon energy can result in its dissipation by the rearrangement of electrons to form new bonds which result in structural alterations. When UV radiation strikes the skin, it is absorbed by pyrimidine bases in DNA and induces the formation of cis-syn cyclobutane pyrimidine dimer and pyrimidine(6-4)pyrimidone photoproduct ( Fig. 6.5 ). The pyrimidone ring of the (6-4) photoproduct is subjected to further modification by UV irradiation to a product called Dewar valence isomer. These photoproducts result in the covalent association of adjacent pyrimidines and usually occur in areas of consecutive pyrimidine residues, which are preferential areas for mutation. Unrepaired or incorrectly repaired pyrimidine dimers lead to mutations that are very specific to UVB. In such mutations, cytosine (C) is changed to thymine (T). These specific types of mutations, that is C to T or CC to TT transitions, are referred to as the ‘signature’ or ‘fingerprint’ of the effect of UVB on DNA. Sequencing data from a large number of tumors show that p53 is mutated in more than 90% of SCCs with C to T transition in about 70% of the cases. That these mutations are an early event and play a critical role in the development of skin cancer is supported by the observation that most actinic keratoses also contain mutations with patterns similar to those of SCC, and that chronically sun-exposed skin contains larger numbers of p53 -mutated clones than sun-protected skin. In the skin, UV irradiation leads to the formation of ‘sunburn cells’ that are apoptotic keratinocytes. Inactivation of p53 in mouse skin reduces the appearance of sunburn cells. BCC have also been found to contain UV signature mutations in p53 and in the PTCH1 gene. The mechanism of cancerogenesis linked with UV exposure in melanoma is far less understood.

While most studies point to UVB as a causative factor in skin cancer, UVA is also carcinogenic, but not as efficient, probably by orders of magnitude. UVA is important, however, since it represents the largest proportion of UV reaching human skin. UVA penetrates window glass and exposure may not be blocked by sunscreen usage. UVA radiation affects both epidermal and dermal chromophores. Although indirect DNA damage from ROS becomes relatively more important going from UVB to UVA wavelengths, the dominant DNA lesions induced by UVA are cyclobutane-pyrimidine dimers.

UVA and UVB exposure can come from sources other than sunlight. UVB used therapeutically has a low risk of producing cutaneous cancers. One systematic review estimated that the excess annual risk of NMSC associated with UVB radiation was likely to be less than 2%. Photosensitizers can play an important role in UVA carcinogenesis. Dose-dependent increased risks of SCC, BCC, and possibly malignant melanoma have been documented with the therapeutic combination of oral psoralen and UVA (PUVA), with particularly high risk in people with skin type I and II. Recent studies suggest that the use of tanning devices that mainly emit UVA radiation, such as tanning lamps and tanning beds, may be associated with a significant increase in BCC, SCC and melanoma (see Chapter 59 ).

The timing and character of sun exposure may affect differently the risk of different skin cancers and of the same cancer at different body locations. SCC is associated with total lifetime sun exposure and with occupational exposure. Late-stage solar exposure may play an important role in the development of SCC since sunlight exposure just prior to diagnosis is associated with an increased risk of the tumor and of its precursor, actinic keratosis (AK). AKs may spontaneously disappear in people who limit solar exposure, and their progression to malignancy seems to require continued exposure to relatively high doses of solar radiation.

BCC and melanoma have been most significantly linked to sun exposure early in life. Intermittent sun exposure and sunburn history are more important than cumulative dose in predicting adult risk for these tumors. However, variations in risk profiles have been proposed at different body locations and with different clinicopathological variants. Chronic sun exposure may be an etiologic factor for nodular BCC in the head/neck region, while intermittent sun exposure plays a role in superficial lesions on the trunk. Similarly, heterogeneity of risk by anatomical site has been proposed for melanoma, with chronic sun exposure influencing the risk of melanoma of the head and neck and intermittent sun exposure, associated with a nevus-prone phenotype, influencing the risk of melanoma elsewhere.

Melanocytic nevi, whose total count overall represent the single greatest predictor of melanoma risk, are a complex exposure variable combining constitutional and environmental effects. Boys develop more nevi than girls. While the number of nevi increases with age up to 18–20 years, nevus density (i.e. number per square meter of body surface area) reaches a plateau earlier in life, at age 9–10 years, suggesting a genetic influence for such a variable. Nevi are more common in children with lighter phenotype who burn and do not tan easily in the sun, and with freckling and a history of sunburns. However, red-haired subjects have fewer nevi than other children. These subjects have a higher melanoma risk, suggesting different pathways to melanoma development.

Among other skin cancers, Merkel cell carcinoma (MCC) has also been linked with sun exposure.