Non_Melanoma_Skin_Cancer_Measurement_Literature_Review

Non-Melanoma Skin Cancer: determining whether the Beagley-Gibson system of scoring photodamage is a useful measure of risk within an age homogonous population. INTRODUCTION Ultraviolet radiation (UVR) is an extrinsic factor that can lead to several adverse health outcomes.1-6 Health affected by UVR exposure is measurable in histopathology,7 however it is not always feasible to use histopathology in epidemiological studies.2,8-12 Since it is known that UVR causes photodamage in the skin and is measurable according to the Beagley-Gibson scoring system, it may prove useful as a surrogate non-invasive measure of UVR exposure. 9,10,13 The aim of this study is to determine whether the Beagley-Gibson scoring system is a sensitive measure of risk in an age homogonous group, or whether further refinement of the scoring system is required. ULTRAVIOLET RADIATION AND DISEASE The primary source of ultraviolet radiation (UVR) is the sun. 14-17 Other sources include ultraviolet emitting lamps in tanning salons and to treat psoriasis and jaundice. UVR is divided into three categories: ultraviolet A (UVA) radiation, ultraviolet B (UVB) radiation and ultraviolet C (UVC) radiation. UVB radiation is considered more carcinogenic than UVA radiation, and the cause of most sunburns.4,18 The ozone layer prevents some UVR from passing through to the earth’s surface. Most UVA radiation reaches the earth’s surface; only some of UVB radiation and almost no UVC radiation does. 18 However, with recent environmental changes, there is concern that more UVB radiation is passing through the ozone layer.5,19-22 Environmental conditions, including the angle of the sun, clouds, dust and haze also alter the intensity and type of UVR reaching the earth’s surface. High altitudes and low latitudes have higher UVR intensity because there is less air mass for UVR to pass through.23-26 A UVR Index was developed as a guideline to inform the public about daily UVR intensity at a particular time and place. A UVR Index of one or two suggests low UVR intensity, and a high UVR Index of ten suggests extreme UVR intensity indicating a greater risk of photodamage to the skin.2,22,27-29 Photodamage typically results from intermittent sunburn incidents and high levels of accumulated UVR exposure over a lifetime.30,31 It also precedes the development of skin cancer. 32-35 Generally populations of similar age and location tend to receive a similar proportion of UVR exposure, although males consistently have higher rate of sunburn incidences than women (OR=2.20 95% CI 1.84-2.63).32 Youth are also a risk group with 20-29 year olds being 9 times more likely to experience sunburn then person aged 60-75 years old (OR=9.79, 95% CI=7.66-12.50).32 This could be attributable to behavioural differences, for example recreational activities may increase the amount of UVR exposure. Consequently males have a slightly higher skin cancer rate. 16,32,33,35 The most common skin cancer diagnosed is non-melanoma skin cancer (NMSC). 32,33,35 The mortality rate of NMSC is low, only 0.3% of all deaths and 1% of cancer deaths are attributable to NMSC. However, the high incidence rate of NMSC makes it the highest cancer related health-system expenditure in Australia. In 2000 the estimated health-system expenditure for NMSC was $264 million. More than 370,000 Australians were treated for NMSC in 2002 and this increased to over 430,000 in 2008. The incidence of NMSC is expected to rise over time as the population ages and increases. Approximately two-thirds of Australians will have at least one NMSC before the age of 70 years, however the incidence rate is 193 times higher for over 70 year olds than for 20–24 year olds. Treatment of NMSC has increased 14% from 836,500 visits to 950,000 visits each year during 2000 to 2005. 32,33,35 Monitoring and predicting the incidence of NMSC is therefore useful in managing health related resources and expenditure. NMSC is not required to be reported or registered, and national data are estimated from medically verified self-reporting in population surveys. 32 This methodology relies on histopathology and in large-scale epidemiological studies this is not often feasible. 9,32 Self-reporting is also subject to bias including misclassification due to incomplete recall of exposure. 9 11,36 Since it is known that UVR exposure results in photodamage it would be useful to have an objective measure of photodamage if it can predict the measure of risk of developing NMSC. 19,37 UVR DAMAGE TO THE SKIN The skin interacts with and protects the body from the external environment. It is composed of three layers, the epidermis, dermis and a subcutaneous fat layer. The skin protects the body via integration with several systems to maintain homeostasis. It is an integral component of thermoregulation and immunological defense.38 The epidermis derives from the embryonic ectoderm. It is a stratified squamous epithelium made up of four or five distinct layers. The principle cell type is the keratinocyte. The keratinocyte undergoes terminal differentiation from the deepest level, the stratum basale, to form the most superficial layer- the stratum corneum. A cell takes several weeks to progress from the stratum basale to the stratum corneum where it is gradually abraded. Abraded cells are matched by production of cells in the stratum basale maintaining a constant epidermal thickness. Growth stimulators and inhibitors are responsible for regulation of cell growth, proliferation and differentiation. Melanin is produced by melanosomes in melanocytes also located in the stratum basale. All populations regardless of origin generally have a similar concentration of melanocytes in the epidermis, however expression of melanin-producing genes varies.39,40 Melanin is the primary determinant of skin pigment; effectively darker pigmented skin contains more melanin. Melanin is photoprotectant. It absorbs UVR and transforms the energy into heat. Darker pigmented skin is therefore better protected from UVR because of the larger amounts of melanin. Below the epidermis lies the dermis, derived from the embryonic mesoderm. It is a layer of connective tissue made mostly from collagen and some elastin. The collagen and elastin fibres give the dermis strength and elasticity. The dermis contains fibroblasts for synthesis of the connective tissue. Mast cells and macrophages are also located in the dermis and are important in immunological defense and inflammation activation. The dermis has a rich supply of blood vessels, lymph, nerve and sensory receptors.41 Skin is often classified according to type.42-44 While there is debate about the validity of terminology regarding origin of population,45 there is a general acceptance of the Fitzpatrick Scale as a reliable and reproducible grading system of skin type.43 The Fitzpatrick Scale is a numerical schema from one to six that grades skin according to how often the skin burns, the amount of pigmentation in the skin and colour of eyes and hair. The Fitzpatrick Scale is used in research, by dermatologists and also by the cosmetic industry as a guide to suitability and effectiveness of treatments.43,44 It has also been modified to further define the amount of time that can be spent in the sun according to skin type. Lighter pigmented skin requires more protection from excessive UVR exposure than darker pigmented skin as the UVR index increases. Regardless of skin type, all skin is at risk of photodamage resulting from sunburn. 39,46,47 Sunburn is defined as erythema following UVR exposure. The extent of sunburn depends on the dose of UVR and the skin type. Lighter skin pigmentation burns more easily than darker skin pigmentation, and depending on skin type can happen within a few minutes to a much longer period. Erythema peaks at 8-24 hours after exposure and fades after several days. Sometimes severe blistering and peeling occurs. Sunburn is associated with vasodilation of the capillary vessels within the papillary dermis. Damage occurs to the cells is the skin.41 Obvious sunburn fades in a matter of days and photodamage may not be evident in the skin at first. However, recent research suggests that excessive UVR exposure has propensity to cause immunosupression both locally and systemic, 48 and also activate molecular mechanisms that lead to gross disorganization of the dermal matrix.49 Eventually all these effects become evident in the skin as deep lines and wrinkles, skin discolouration, and potentially the development of solar keratosis (SK).50 SK lesions are precancerous, thickened, scaly patches of skin around 3-6mm diameter. Treatments for the removal of SK lesions are easily available through general practitioner visits; biopsies are rarely taken. Similarly to sunburn, there is a high prevalence of SK lesions in males. SK is common in Australia, more than 40% of the population aged 40 years and over have at least one SK lesion.32 There is a higher prevalence of SK lesions at lower latitude. However, changing behaviour and environment may see a change in the prevalence of SK lesions in different geographical locations.9,32 Geographic location is also significant in Vitamin D synthesis. 51 Vitamin D is synthesized in the skin as a result of UVR exposure. 90% of Vitamin D is made from UVR and the remainder comes from the diet. Vitamin D is essential for musculo-skeletal health. 4 Deficiency can result in rickets, osteomalacia and osteoporosis, and recent research suggests that vitamin D deficiency may also contribute to autoimmune disorder such as multiple sclerosis and type I diabetes.52 Populations inhabiting low latitudes have darker pigmentation for protection from UVR, while those in higher latitudes developed lighter pigmentation to maximize Vitamin D production from lower levels of UVR. The UVR protective qualities of melanin in darker pigmented populations that have migrated to high latitudes may prevent sufficient Vitamin D synthesis, and potentially lead to diseases related to Vitamin D deficiency. It is also problematic for lighter pigmented populations that have migrated to regions of low latitude receiving too much UVR exposure, potentially leading to the development skin cancer and premature aging of the skin.29,53,54 Skin aging is a process that involves intrinsic and extrinsic factors leading to physiological decline of the skins structure and function.7,38,55 Chronological aging is an intrinsic factor of aging and UVR exposure that leads to photodamage is an extrinsic factor of aging. Both extrinsic and intrinsic factors of aging share common molecular pathways.50,56 Chronological aging of the skin is dependant on time and genetic factors. UVR exposure that leads to photodamage is similarly a cumulative process. However, photodamage is dependant on the amount and type of UVR exposure and skin pigmentation.57,58 Areas of the body exposed to the external environment age from both extrinsic and intrinsic factors. Typically, the areas that age the most have had the most exposure to UVR. 59 There is often a long latency period between accumulated exposure of UVR and development of a NMSC.60,61 The natural history is that UVR damage occurs many years before the development of NMSC. NMSC includes several types of skin cancers. The two most common are basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Both BCC and SCC have different causal relationships with UVR.62 BCC accounts for 60% of NMSC diagnosed and are the most common form of NMSC. 32,62 The risk of BCC increases significantly with time spent outside and the number of sunburns.63 The risk of BCC is lower in populations who migrate from an area of low UVR to an area of high UVR particularly if the migration happens after the first 10 years of life. BCC occur more often on parts of the body that are exposed intermittently to the sun rather than parts that are constantly exposed. The majority of BCCs carry mutations in the TP53 suppressor gene. BCC appears predominantly in older people and grows slowly by local spread. 64 SCC accounts for 30% and is the second most common form of NMSC diagnosed. 32 It is potentially more dangerous than BCC. 18It appears on the skin as a thick, scaly spot that may bleed easily. SCC is most frequently observed on the skin that is constantly exposed to UVR, such as the head, neck, forearms and upper body area. Treatment is similar to BCC and SK, but can spread quickly if left untreated. Almost all people with SCC are aged over 40 years old. 32 It is clear that varying amounts of UVR dosage are required for optimal health depending on the person.1 For optimal health a person requires enough UVR to avoid musculo-skeletal diseases but not too much in order to avoid skin cancer diseases. 4 There may be up to a 100-fold difference in personal requirements of UVR exposure dependent on the amount of pigmentation and behavioural factors of the person. 4The burden of disease related to UVR is likely to be a U-shaped, not linear, curve that is dependant on skin phenotype and behaviour (see figure one) 4 65 Skin pigmentation is a confounder in the relationship between UVR exposure and NMSC. However, all populations are subject to decline in skin quality as a result of aging and photodamage. 66-68 Using an objective measure of photodamage to assess UVR exposure during a lifetime improves understanding of the exposure-disease relationship.65 [pic] Figure 1 Diagram of the relation between UVR exposure and disease Lucas & Ponsonby (2002)65 GRADING Skin biopsies are the gold standard for measuring photodamage, but are rarely used, as they are impractical on a large scale.69-72 Non-invasive methods of assessing photodamage are preferable as long as they are objective. 10,13,69-73 Non-invasive methods of assessing photodamage of the skin increasingly become an area of interest after the first quantitative measure using such a procedure in 1979.9 Makki, Barbenel and Agache made araldite replicas from silicon casts of the skin to study photodamage. 9In 1980 Beagley and Gibson refined the procedure, rather than using araldite replicas they used silicon moulds only. Then they developed a visual scoring system of the moulds under a low power dissecting microscope. This improved the process time of measuring photodamage compared to the araldite models and was well suited for studies with large numbers of subjects.9 The Beagley-Gibson scoring system is based on the quantity, quality, depth and direction of lines dividing the topography of the skin. Primary lines run in a horizontal direction, secondary lines run in a vertical direction and tertiary lines run in an oblique direction. The tri-dimensional shape of the skin formed by these lines is clearly visible under a dissecting microscope. The Beagley-Gibson scoring system is based on six grades (refer to figure two). Grade one represents pristine skin with no photodamage or aging; and grade six represents extensive photodamage and aging. 9 [pic] Figure 2. The Beagley-Gibson system of grading, showing photographs typical of the six grades9 Grade One: Primary lines are all of the same depth. Secondary lines are all clearly visible, are nearly the same depth as the primaries, and often meet to form an apex of triangles ('star formation'). Grade Two: Some flattening and loss of clarity of the secondary lines. Star formations are still present, but often one or more of the secondary lines making up the configuration are unclear. Grade Three: Unevenness of the primary lines. Noticeable flattening of the secondary lines with little or no star formation. Grade Four: Macroscopic deterioration in texture. Course, deep primary lines. Distortion and loss of secondary lines. Grade Five: Noticeable flat skin between the primary lines. Few or no secondary lines. Grade Six: Large deep and widely spaced primary lines. No secondary lines.9 The Beagley-Gibson scoring system has been used in population studies assessing the relationship of photodamage resulting from UVR exposure and disease.74 In 1984, Holman et al used the Beagley-Gibson scoring of photodamaged skin to determine that a relationship existed between solar keratosis and photodamage. 9 They found the method suitable for scoring photodamage in epidemiological research. However, the subjects taking part in the research ranged in age from 16-86 years old, raising question to the sensitivity of the scoring system in an age homogonous group. Another epidemiological study by Green in 1991 concluded that UVR exposure correlated with the deterioration of epidermal skin pattern.75 In contrast, Seddon found that the Beagley-Gibson scoring system reflects aging from intrinsic parameters rather than from photodamage. 72 In 1995, Fritschi assessed another scoring system called the ∑ system to the Beagley-Gibson scoring system and found it comparable. The Goodman-Kruskal tau for agreement between the grade of the ∑ system and histological degree of photodamage was 0.22. Although the ∑ system claims to be easier to learn, the Beagley-Gibson system still remains the most popular method in practice, and is sometimes used in the cosmetic industry to assess the changes in treatments aimed at reducing the degree of photodamage acquired. 13 More recently, 2006, Battistutta found that the Beagley-Gibson measure of photodamage was a highly reliable and a valid measure of photodamage; predicting dermal elastosis in a population setting and able to discriminate between histologically assessed degrees of photodamage. 76 Furthermore the Beagley-Gibson scoring system has been recently used in multiple sclerosis studies to help determine UVR exposure and the risk of disease.4 However, there still remains uncertainty whether there is enough variation in scoring within the Beagley-Gibson system to be a useful measure of risk in an age homogenous group.10,25,77 REFINEMENT OF THE BEAGLEY-GIBSON SCORING SYSTEM The crux of the methodological problem is the ascertainment of UVR exposure is flawed. The latency between exposure and disease is long, and the measures are open to bias. 12,78,79 Skin biopsies are clearly the gold standard for measuring photodamage resulting from UVR exposure, however the Beagley-Gibson system would be a practical tool for use in epidemiological studies of photodamage if it proves to be objective. The Beagley-Gibson scoring system, in its current form, has demonstrated repeatability, reliability and some validity.8,10 However, in order for it to be useful in being an objective non-invasive method of measuring photodamage over a lifetime, particularly in an older age group, the scoring system may need further refinement. The structures forming the topography of the skin are assessed using the scoring system detailed in Figure 1. Giving each parameter a sub-score rather than an overall score for the state of the skin may help refine the system in terms of discriminating the disease state. STUDY AIMS The aim of the research is to establish whether the Beagley-Gibson scoring system of photodamage can be a useful measure in determining the risk of NMSC, and whether the score associates with NMSC in the population being studied. If it is not a useful measure, then we aim to identify what refinements of the scoring system would improve the measure in determining the risk of NMSC. We will then investigate whether a composite score or a score using individual features of the composite score works better for NMSC discrimination. REFERENCES 1 Rajakumar K, Greenspan SL, Thomas SB et al. SOLAR ultraviolet radiation and vitamin D: a historical perspective. Am J Public Health 2007; 97: 1746-54. 2 Trakatelli M, Ulrich C, del Marmol V et al. Epidemiology of nonmelanoma skin cancer (NMSC) in Europe: accurate and comparable data are needed for effective public health monitoring and interventions. Br J Dermatol 2007; 156 Suppl 3: 1-7. 3 Strickland PT, Vitasa BC, West SK et al. 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