Advances in Photoprotection

Immunosuppression

Hydrocarbons (industrial tar)

Ionising radiation

Arsenic (contained in the tonic ‘Parish’s food’, available until the 1960s)

Smoking

Chronic ulceration

Oncogenic HPV

Human herpesvirus 8 (HHV-8) responsible for Kaposi’s sarcoma

PUVA (psoralen + UVA) used in the treatment of psoriasis

2.2 Ultraviolet Radiation and Carcinogenesis

UVR is a complete carcinogen, with the ability to initiate, promote and lead to progression of a skin cancer independent of other risk factors [2, 3].

The ultraviolet spectrum encompasses UVC (200–280 nm), UVB (280–315 nm) and UVA (315–400 nm). UVC is absorbed by stratospheric ozone except in areas with ozone depletion such as the Antarctic. UVB is the predominant cause of skin cancer but UVA is increasingly implicated because of the ability of UVA to penetrate deeply into the dermis and the sheer amount of UVA, one hundred-fold greater than UVB [4], to which people are exposed. UVA has been implicated in photoaging [5] but is seen to have an overlapping effect with UVB, leading to a summative carcinogenic effect.

2.3 Mutations

The initial event in photo-carcinogenesis occurs when UVR of a specific wavelength is absorbed by epidermal cellular deoxyribonucleic acid (DNA), causing the formation of cyclobutane pyrimidine dimers (CPDs) in the DNA double helix [6]. Ineffective removal of these CPDs can lead to errors in DNA transcription. DNA replication and repair is a complex process of enzyme-dependant pathways, which prevent abnormal DNA synthesis by nucleotide excision repair (NER) [7]. The process of NER and excised pyrimidine dimers (PDs) is shown to be immunoprotective [8]. Under normal conditions during replication, DNA is unzipped, the thymine dimer repaired, and DNA is then reconstituted hopefully without error, but the repair mechanism is error prone and may be overwhelmed by UVR damage. Aging skin also does not repair itself as readily and is less efficient at removing harmful CPDs than younger skin [9]. UVR-induced mutations in gene sequences lead to tumour suppressor proteins including p53, changing from protective genes into oncogenes. Mutated DNA ultimately leads to skin cancers.

2.4 Apoptosis

The body’s second mechanism of defence against abnormal or cancerous cells is the activation of the intrinsic apoptotic pathway, whereby cells beyond repair are eliminated by a non-inflammatory mechanism in contrast to necrosis which is an inflammatory process [10]. Apoptosis is triggered via p53 protein to prevent further abnormal DNA replication.

It is mediated by the caspase protease cascade, with protein p53 causing cell cycle arrest in S1 by producing p21.

2.5 Immunosuppression

The immunosuppressive effects of UVR were elegantly demonstrated by Margaret Kripke. Syngeneic mice were either UVB irradiated or non-irradiated. Skin cancer transplants were carried out in both groups. The non-irradiated group rejected the tumour, whereas the UVR-irradiated group failed to reject the transplanted skin tumour [11]. This inability to recognise skin cancer as a foreign antigen was demonstrated to be transferable by lymphocytes [12], suggesting that, in squamous cell carcinoma (SCC), this is an antigenic process and possibly explains why SCC is disproportionately represented in organ transplant recipients (OTRs), who are immunosuppressed to prevent rejection of the graft.

Langerhans cells, a specific type of dendritic cell within the epidermis, act as antigen-presenting cells and have an integral role in local immune surveillance. UVR is known to deplete Langerhans cell populations within the epidermis [13]. Failure of this normal effect, with Langerhans cell resistance to UVR, leads to development of polymorphic light eruption (PLE) [14]. It is thought that this genetic aberration may have a protective effect against the development of skin cancer [15].

Urocanic acid, found in its trans–isomer in the skin, when exposed to UVB (action spectrum), changes to its cis–isomer, which is highly immunosuppressive and may suppress contact hypersensitivity and delayed hypersensitivity through TNF-a [16, 17]. UVR may modulate growth factors and cytokines such as TNF-a and interleukins (ILs), especially IL-10, and activate receptors for Fas, TNF-a, IL-1 and the melanocortin receptor, which regulates pigment in the skin.

Both UVB and UVA are immunosuppressive and abrogate cell-mediated responses. Consequently, human papilloma virus (HPV) is augmented on immunosuppressed skin. Indeed, the interaction of UVR immunosuppression with high-risk human papilloma virus (HPV) subtypes may induce skin cancers on keratinized squamous epithelium [18]. Warts are more common in the immunosuppressed, being particularly associated with azathioprine. HPV has the ability to block the BAK signalling pathway, which represents a key cellular defence in activating the apoptotic pathway, thereby rendering it prone to facilitating carcinogenesis [19]. In addition, it also effects programmed cell death, allowing old cells to survive when they normally would not [20].

2.6 Organ Transplant Recipients

OTRs have between a 65-fold and 250-fold increased risk of SCC [21, 22].

This is the inverse of the natural order of occurrence in skin cancer subtypes, with basal cell carcinomas (BCCs) occurring at 3-fold the rate of SCCs, within an immunocompetent population. The OTR group is at particular increased risk of skin cancer because of the reduction of immune surveillance by immunosuppressive drugs. Immunosuppression coupled with UVR – which has local and systemic immunosuppressive effects – augments cancer risk.

2.7 Sun Exposure Patterns

Intentional sun exposure is the deliberate attempt of an individual to be exposed to the sun usually with the express desire to acquire a tan. The difficulty in relation to tanning is that the dose required to tan is close to the same dose known to cause sunburn. The action spectrum of erythema is similar to the absorption spectrum of DNA and DNA is the chromophore for sunburn [6]. Both burning and tanning are caused by thymine dimer formation. It is impossible, therefore, to tan without causing DNA damage, thus promoting the development of skin cancer. The World Health Organization and public health campaigns have been actively engaged in initiatives to reduce direct and inadvertent UVR exposure, such as sunsmart.com or the ‘slip, slop, slap’ campaign – slip on a shirt, slop on sunscreen, slap on a hat. Sunbathing first gained popularity in the late nineteenth century as a medical treatment to prevent vitamin D–dependant rickets and during recovery from tuberculosis. Finsen first used artificial UV lamps for this purpose for which he received the Nobel Prize [23].

Sunbathing and the desire to be tanned began to be affiliated with affluence and a sense of well-being. Indeed, Coco Chanel is credited with making a tan fashionable in the 1900s, which has persisted to this day. Prior to this, tanned skin was associated with outdoor labour and lower social standing. From a social standpoint, attitudinal surveys towards tanning in Ireland have revealed perceptions that a tanned appearance makes one appear thinner and more attractive [24]. This is likely to have influenced the trend for indoor tanning which is achieved by exposure to predominantly UVA light.

There have been major concerns in relation to sunbed use and melanoma risk especially in those aged under 35 [25].

To date, the use of indoor tanning has largely gone unregulated until recently. Some countries have introduced legislation to regulate and in some instances outlaw its use. In Ireland, the Public Health (Sunbeds) Act 2014 has been enacted into legislation by the Dail (Irish House of Representatives) and the Seanad (the Irish Senate) with effect from the 21st of July, 2014 [1]. This Act aims to regulate the use and supply of sunbeds and outlaws the use of sunbeds in persons under the age of 18 years [26]. In Australia a measure is being sought to outlaw indoor tanning practices completely, because of the high burden of disease and morbidity among the fair-skinned population. Reduction of UVR may be achieved by an understanding of the factors influencing UVR dose. Factors influencing UVR intensity are listed in Table 2.2.

Table 2.2

Factors influencing UVR intensity

Time of day

Latitude

Altitude

Season

Cloud cover

Air pollution

Transmission of UVR through glass and water

Rayleigh scattering (gives the daytime sky its blue colour)

Ozone depletion

Unintentional UV exposure occurs with outdoor occupation, recreation and exercise and is often disregarded by the individual. The cumulative dose can be significant over decades and particularly relevant with lifestyle after retirement, which may have a large outdoor component [27, 28]. There appears to be a latent period between high sun exposure and the development of skin cancer of between 10 and 15 years [29].

Countries such as Australia, where a large fair-skinned population have been shown to have significantly higher rates of non-melanoma skin cancers and melanoma, have had success in reducing intentional and unintentional sun exposure, whereas countries with intermittently high UVR levels have a greater problem.

Individuals may be quite unaware of the potential risks of unintentional sun exposure and do not take the necessary precautions. It is worth noting that the outdoor occupational exposure risk amounts to four times that of the indoor worker. A recent paper looking at occupational UVR exposure patterns in Irish and Danish gardeners demonstrated lower UVR exposure in the Irish group, probably due to indoor breaks at peak UVR hours, compared to their Danish counterparts [30]. Scheduling outdoor work to coincide with trough UV hours is an important occupational health consideration.

The development of the Global UV index provides daily geographic information on UV intensity in any particular location [31]. This serves as a guide to high-risk exposure times. Drawing attention to unintentional sun exposure and explaining its damaging effects may lead to modification of exposure and very significant reductions in lifetime dose.

2.8 Strategies for Sun Avoidance (Table 2.3)

Table 2.3

Strategies for sun avoidance

Avoid sun at peak UV hours between 11 a.m. and 3 p.m.

Seek shade when one’s shadow is shorter than one’s height

Wear protective clothing, hats and eyewear in peak sunlight hours

Apply sunscreen regularly and liberally to sun-exposed areas

2.8.1 Clothing

Exercise and outdoor activities are good for individual health.

The style of garment influences the area of skin exposed. Ideal garments for peak sun times are high necked, long sleeved and full length. Fabrics vary widely. See-through and open-weave fabrics transmit UVR. The ultraviolet protection factor (UPF) is the ratio of the intensity of UVR before and after passing through a fabric and is principally determined by the size of aperture in the weave [32, 33]. A crude measurement of UPF may be ascertained by holding a material up to direct sunlight and assessing the amount of light that penetrates through it. Simply, the tighter the weave, the higher its protectiveness. For example, denim is a very effective barrier against UVR penetration but may be poorly tolerated in hot climates. In contrast some cotton T-shirts may actually transmit UVR especially when wet. As an alternative, the UPF of a fabric may be enhanced artificially by incorporating sunscreen particles, such as titanium dioxide (TiO₂), onto fibres. Some fabrics now carry a UPF rating, although UVA rating is more difficult to quantify. International recommendations for a sun-protective fabric suggest a UPF of >40 and a desired reduction of UVA exposure to ~5 %.

2.8.2 Sunglasses

Sun-protective eyewear with UV protective lenses are important in reducing the deleterious effect of UV light to the delicate structures of the eye [34], as shown in Table 2.4. It is estimated that the number of cataracts could be reduced by prudent use of UV protective eyewear [35].

Table 2.4

Sequelae of ultraviolet light on eye structures

Cataracts

Photokeratitis

Pterygium

Solar retinopathy

Pingueculae

Adequate eyecover with sunglasses requires a wide side handle to protect the lateral aspect of the eye from photodamage, in addition to UV protective lenses. The recommendation is a lens which absorbs up to 400 nm of UVR. Large-sized lenses and wrap-around designs are better. Sunglasses should come with a standardised UV rating, bearing a safety mark, e.g. CE, for European products or an international equivalent.

The same should apply to snow goggles.

2.8.3 Hats

Hats have been worn throughout history, particularly up until the turn of the twentieth century. They are rarely worn now in the western world, with significant consequences for those chronically exposed sites, such as scalp, neck and face. Scientific studies looking at the wearing of hats have clearly demonstrated a benefit in reduction of the development of skin cancer, in high-risk sites, if a broad-brimmed hat (at least 7 cm) is worn [36].

Caps fail to protect the sides of the face, ears and neck.

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Tags: Advances in Transplant Dermatology

Apr 7, 2016 | Posted by admin in Dermatology | Comments Off

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