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• W2016551750 abstract "When celebrating the 125-year anniversary of the British Journal of Dermatology (BJD), we are highlighting its long and distinguished record in publishing on skin cancer, covering many topics from skin cancer epidemiology to the basic molecular mechanisms of carcinogenesis. Skin cancer prevention and treatment are frequently addressed, and the publication and maintenance of well-considered national and international treatment guidelines are of particular value to the hard-pressed clinician. A number of questions remain to be answered. The incidence of skin cancer has been increasing steadily in fair-skinned individuals since the mid-twentieth century, particularly for nonmelanoma (keratinocyte) skin cancers (NMSCs), basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), as well as melanoma. Dermatology services in the U.K. are increasingly stressed by this rise, which is resulting from an ageing population and increasing recreational sun exposure. Use of hospital episode statistics suggested that the cost of skin cancer treatment was in the range of £106–£112 million in 2008, but a rise to at least £180 million was predicted for 2020.1 With a shortage of consultants in rural and remote areas in the U.K., dealing with this increase means we have to rethink the pattern of skin cancer services. New proposals centre around the introduction of high-volume, consultant-led intermediary care services being able to provide treatments for uncomplicated skin cancers, or the development of specialty doctor-led skin cancer clinics. Many cancer registries record only the first case of NMSC but, as we know, patients often have multiple tumours, which leads to serious underestimates of total case numbers. A systematic review of 75 studies comparing incidence data with U.K. cancer registry data recognized that average incidence rates of NMSC varied geographically in England (being highest in the south west of England),2 probably reflecting regional differences in ethnicity, as well as sun exposure. The total number of BCCs in the east of England was estimated to be 2·0–2·2 times lower in registry data than in histopathology records, which gave an estimate of total BCCs in the U.K. to be 247 000, although this did not include patients treated with cryotherapy or topical therapy without pathology.3 In 2012, Scottish histopathology records gave provisional numbers of total skin cancers as > 20 000 for a population of around 5 million (Brewster, personal communication). Although this includes re-excisions it does not include cryotherapy or topical therapy without pathology so is probably a reasonable basis for estimates. Extrapolating to the whole of the U.K. suggests that there are at least 260 000 skin cancers treated every year in the U.K. The most accurate feed to estimate the burden of disease and case numbers would appear to be from histopathology data and so a new initiative to register all NMSCs by use of a new tool for systematic recording from multidisciplinary teams is particularly helpful (http://www.rcpath.org/clinical-effectiveness/dataset-and-tissue-pathways).4 Extensive evidence from epidemiological, animal and clinical studies shows that sun exposure is the main environmental cause of both melanoma and NMSC.5 Studies also suggest that early-life exposure is important for skin cancer and that sunbed use increases the risk of SCC and melanoma. Therefore, many skin cancer agencies have focused primary prevention programmes on sun avoidance/photoprotection (Slip Slop Slap Australia; SunSense U.K.; Sunwise U.S.A.), although evidence of their effectiveness is limited.6 However, ultraviolet (UV) B radiation is a major source of vitamin D in the skin, which has caused controversy and confusion in the mind of the public. Vitamin D is well known to be critical for bone health but recent attention has focused on the association between low vitamin D concentrations and other disorders, including cancer, cardiovascular disease, autoimmune disease, dementia and diabetes. Although large-scale observational studies suggest that high serum concentrations of vitamin D might be protective, the results of randomized controlled trials have shown no reduction of risk; therefore, it appears likely that a low level of vitamin D is a result rather than a cause of ill health.7 Therefore, given that the doses for the development of skin cancer are higher than those for vitamin D synthesis (5–10 min face and forearm exposure), should recommendations for sun protection be changed to accommodate the need to increase vitamin D levels?8 This requires robust evidence that an increase in vitamin D status decreases the risk of cancer. What is the safest way to increase this, given the well-established link between skin cancer risk and UV radiation? Although some have taken a pragmatic approach to recommend vitamin D supplementation,9 there is currently no robust randomized control trial evidence for altering sun avoidance advice or routine supplementation. Early detection of skin cancer has been a public health concern for over a century, with the assumption that detection of asymptomatic disease improves patient outcomes, and the World Health Organization has identified 10 fundamental principles that need to be fulfilled by a screening test.10 The critical outcome of importance for screening is a reduction in mortality. However, earlier diagnosis does not necessarily extend lifespan and can lead to overdiagnosis and overtreatment. In studies of melanoma, increases in total disease rate are being driven by changes in the proportion of early disease with almost no differences in the incidence of late-stage disease. Skin cancer screening involves whole-body examinations of healthy individuals for the early detection of skin cancers, which then need intervention. A population-based screening programme (SCREEN) in Schleswig-Holstein, Germany, trained nondermatology observers and claimed a 50% reduction in mortality after 5 years.11 Other studies using educational interventions also found a reduction in melanoma thickness but no reduction in cumulative mortality.6, 12 False positives lead to anxiety, stress and scarring from unnecessary surgery. Skin cancer education campaigns, such as Euromelanoma,13 raise awareness and case numbers but the ratio of interventions to accurate diagnosis can be very high and actually reduce the speed of diagnosis for symptomatic patients when services are flooded, and adequate resources need to be available to deal with the effects of such campaigns. There may be an argument for screening patients with familial or acquired (e.g. immunosuppression)14 skin cancer risks but, taken together, only limited studies support the effectiveness of population-based measures for the early detection of skin cancer; properly controlled randomized trials are needed. The treatment of skin cancers has been an important reason to develop national U.K. and international European guidelines for the management of skin cancers. The BJD has played a key role in the publication and updating of national U.K. guidelines, developed through the British Association of Dermatologists (BAD), for melanoma, BCC, Bowen disease and actinic keratosis.15-18 BAD guidelines for primary cutaneous SCC published in 2002,19 updated in 2009,20 have this year been joined by guidelines from the Scottish Intercollegiate Guideline Network.21 Although the majority of cases can now be controlled by existing treatments, particularly surgery, there is a paucity of treatments for aggressive or metastatic disease, and this is currently an exciting area of translational research. The genomic landscapes of common cancers have been revealed by novel sequencing techniques, with some genes (approximately 140), which are altered in a large number of tumours, being considered driver mutations involved in regulating cell fate, survival and genome maintenance.22 Mutations in oncogenes and tumour suppressor genes play an important role in skin carcinogenesis and have been identified in melanoma, BCC and, more recently, SCC. The advent of next-generation sequencing is both facilitating and complicating this field by illustrating a very high burden of mutations in SCC (as well as BCC and melanoma), which makes the determination of driver genes more difficult.23 However, earlier studies have identified important therapeutic targets in BCC and melanoma. The activation of Hedgehog signalling by mutations in PTCH1 and SMO was shown to be sufficient for basal cell carcinogenesis.24 Small-molecule inhibitors of the Hedgehog signalling pathway have been developed, and early trials, e.g. of vismodegib, have been promising in the treatment of aggressive or advanced disease.25, 26 B-Raf is a serine threonine kinase that activates the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase signalling pathway. Following the discovery of B-Raf mutations in melanoma,27 it has become clear that about 50% of melanomas harbour such mutations, predominantly BRAF V600E. Selective inhibitors of mutant BRAF, such as vemurafenib, have shown encouraging results in demonstrating a survival benefit, but multiple complex resistance mechanisms have become evident. However, melanoma has been considered to be an immunogenic tumour, and renewed interest in immunotherapy has led to new clinical trials. Ipilimumab, a fully human IgG1 monoclonal antibody that targets CTLA4 on effector and regulatory T cells leading to T-cell hyper-responsiveness, is one such agent. Melanoma is also thought to evade the immune system by expression of programmed death ligand (PDL)1, and, in preliminary studies, genetically engineered monoclonal antibodies to the PD–PDL1 interaction on lymphocytes are encouraging.28 Combination trials appear to be the way forward.29 The majority of SCCs can readily be treated by surgery or other available techniques, but treatments for advanced aggressive or metastatic disease have had limited effects on overall survival or progression-free survival, and new systemic treatments are badly needed. The promise of new genomics in directing personalized tumour therapies is yet to be realized for SCC. New findings of mutations in Notch signalling pathways, Card 11 and cyclic adenosine monophosphate-response element binding protein (CREB) binding protein have to be assessed functionally but should lead to new insights.23, 30 Testing of Polo1 kinase inhibitors has shown early promise in preclinical models.31 Epidermal growth factor receptor inhibitors such as cetuximab may also have a role.32 It is well known that NMSCs arise in areas of field cancerization, with multiple actinic keratoses being a surrogate marker of SCC risk. Clonal islands of p53 expression have been known for some time in normal/sun-exposed skin,33 and there are estimates that the skin of an individual will have many mutant clones.34 Patients receiving vemurafenib often develop new, well-differentiated SCCs that bear a higher level of activating mutations in H-Ras/K-Ras than SCCs from sporadic cases, which suggests that there are also islands of Ras mutation in normal skin. This suggests that apparently normal sun-exposed skin may be bearing many UV-induced mutations, and understanding how these progress into visible lesions is important. It also raises the question of whether treating a field of cancerization will prevent the development of SCC, which has yet to be answered in a substantial long-term randomized control trial of a defined population. There are lots of exciting questions to answer in basic, translational and clinical skin cancer research that will change the landscape for our patients, and the BJD will continue to bring these issues to our attention." @default.
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• W2016551750 date "2014-09-01" @default.
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• W2016551750 title "Progress in skin cancer: the U.K. experience" @default.
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