Actinic Keratosis
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In some respects actinic keratosis is the most common and best-known pathology in dermatology. Being such an ordinary pathology, actinic keratosis gives nevertheless insight into an extraordinary number of important biological and clinical processes. Actinic keratoses are found in significant numbers on the sun-exposed skin of Caucasians, especially those living in sun-bathed countries such as Australia, as two of the editors and a considerable number of the authors of this book do. The authors who have contributed to this volume are researchers and clinicians discussing actinic keratosis across the whole spectrum – from epidemiology to immunology, from molecular biology to behavioral psychology – and of course pathologists and clinicians dealing with patients who experience the many manifestations of actinic keratoses. The fact that all these various aspects are considered renders this book valuable reading for scientists and clinicians alike.



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Date de parution 22 décembre 2014
Nombre de lectures 0
EAN13 9783318027631
Langue English
Poids de l'ouvrage 1 Mo

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Actinic Keratosis
Current Problems in Dermatology
Vol. 46
Series Editors
Peter Itin Basel
Gregor B.E. Jemec Roskilde
Actinic Keratosis
Volume Editors
H. Peter Soyer Brisbane, Qld.
Tarl W. Prow Brisbane, Qld.
Gregor B.E. Jemec Roskilde
33 figures, 29 in color, and 4 tables, 2015
Current Problems in Dermatology
_______________________ H. Peter Soyer Tarl W. Prow Dermatology Research Centre The University of Queensland School of Medicine Translational Research Institute Princess Alexandra Hospital Brisbane, QLD 4102 (Australia)
_______________________ Gregor B.E. Jemec Department of Dermatology University of Copenhagen Roskilde Hospital DK-4000 Roskilde (Denmark)
Library of Congress Cataloging-in-Publication Data
Actinic keratosis / volume editors, Peter H. Soyer, Tarl W. Prow, Gregor B.E. Jemec.
p.;cm. –– (Current problems in dermatology, ISSN 1421-5721 ; vol. 46)
Includes bibliographical references and indexes.
ISBN 978-3-318-02762-4 (hard cover: alk. paper) –– ISBN 978-3-318-02763-1 (electronic version)
I. Soyer, Peter H., editor. II. Prow, Tarl W., editor. III. Jemec, G. B. E. (Gregor B. E.) IV. Series: Current problems in dermatology ; v. 46. 1421-5721
[DNLM: 1. Keratosis, Actinic. W1 CU804L v.46 2015 / WR 500]
Bibliographic Indices. This publication is listed in bibliographic services, including MEDLINE/Pubmed.
Disclaimer. The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publisher and the editor(s). The appearance of advertisements in the book is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
Drug Dosage. The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
© Copyright 2015 by S. Karger AG, P.O. Box, CH-4009 Basel (Switzerland)
Printed in Germany on acid-free and non-aging paper (ISO 9706) by Kraft Druck GmbH, Ettlingen
ISSN 1421-5721
e-ISSN 1662-2944
ISBN 978-3-318-02762-4
e-ISBN 978-3-318-02763-1
Soyer, H.P.; Prow, T.W. (Brisbane, Qld.); Jemec, G.B.E. (Roskilde)

Epidemiology of Actinic Keratoses
Green, A.C. (Brisbane, Qld./Manchester)
Patients’ Perspectives on Actinic Keratosis
Esmann, S. (Roskilde)
Photodamage: All Signs Lead to Actinic Keratosis and Early Squamous Cell Carcinoma
Wei, J.; Kok, L.F.; Byrne, S.N.; Halliday, G.M. (Sydney, N.S.W.)
Dysregulation of Epidermal Growth Factor Receptor in Actinic Keratosis and Squamous Cell Carcinoma
Joseph, S.R.; Endo-Munoz, L.; Gaffney, D.C.; Saunders, N.A.; Simpson, F. (Brisbane, Qld.)
The Actinic Keratosis Virome: Can We Prevent Squamous Cell Carcinoma with a Vaccine?
Frazer, I.H. (Brisbane, Qld.)
Do Actinic Keratoses and Superficial Squamous Cell Carcinomas Have a Specific Immunoprofile?
Wells, J.W. (Brisbane, Qld.)
Mouse Models for Actinic Keratosis and Squamous Cell Carcinoma
Handoko, H.Y.; Ferguson, B.; Walker, G.J. (Brisbane, Qld.)
Keratinocyte Cancer and Its Precursors in Organ Transplant Patients
Jenni, D.; Hofbauer, G.F.L. (Zürich)
Clinical Features of Actinic Keratoses and Early Squamous Cell Carcinoma
Wheller, L.; Soyer, H.P. (Brisbane, Qld.)
The Many Clinico-Pathologic Faces of Actinic Keratosis: An Atlas
Massone, C.; Cerroni, L. (Graz)
Dermoscopy of Actinic Keratosis, Intraepidermal Carcinoma and Squamous Cell Carcinoma
Zalaudek, I. (Graz); Argenziano, G. (Reggio Emilia)
The Future of Keratinocyte Skin Cancer Surveillance: Automated Image Analysis to Identify and Monitor Keratinocyte Dysplasia
Hames, S.C.; Prow, T.W. (Brisbane, Qld.)
Reflectance Confocal Microscopy: Hallmarks of Keratinocyte Cancer and Its Precursors
Prow, T.W.; Tan, J.-M. (Brisbane, Qld.); Pellacani, G. (Modena)
Optical Coherence Tomography and Its Role for Delineating the Thickness of Keratinocyte Dysplasia and Neoplasia
Themstrup, L.; Jemec, G.B.E. (Roskilde)
Teledermatology: Its Use in the Detection and Management of Actinic Keratosis
Janda, M. (Brisbane, Qld.)
Conventional Treatment of Actinic Keratosis: An Overview
Peris, K.; Fargnoli, M.C. (Rome)
Field Cancerization: From Molecular Basis to Selective Field-Directed Management of Actinic Keratosis
Philipp-Dormston, W.G. (Cologne)
Update on Photodynamic Treatment for Actinic Keratosis
Wiegell, S.R. (Roskilde)
Laser Treatment and Its Implications for Photodamaged Skin and Actinic Keratosis
de Vries, K.; Prens, E.P. (Rotterdam)
Ingenol Mebutate: From Common Weed to Cancer Cure
Zarchi, K.; Jemec, G.B.E. (Roskilde)
Oral Nicotinamide and Actinic Keratosis: A Supplement Success Story
Kim, B.; Halliday, G.M.; Damian, D.L. (Sydney, N.S.W.)
Author Index
Subject Index
The hardest thing to see is what is in front of your eyes.
Was ist das Schwerste von allem?
Was dir das Leichteste dünkt,
Mit den Augen zu sehn,
was vor den Augen dir liegt.
Johann Christoph Friedrich von Schiller (1759-1805), German Poet

This quote from Schiller, which is commonly attributed to Goethe, fits well with the dermatologic condition called actinic keratosis. In some aspects, actinic keratosis is the most common and most well-known pathology in dermatology. Actinic keratoses are found in significant numbers on the sun-exposed skin of Caucasians, especially those lucky enough to be living in sun-bathed countries such as Australia, as two of the editors and a considerable number of authors do.
One may question why it is necessary to dedicate a book to this quite ordinary pathology. Everything about this condition seems crystal clear: the cause of its appearance, its pathogenesis, its clinical and pathologic features, its treatment, and also its prognosis. It is exactly because of this clarity that it is necessary to dedicate a book to actinic keratosis. This ordinary pathology provides insight into an extraordinary number of important biological and clinical processes.
All of these thoughts came into my mind when asked by Gregor Jemec to consider compiling a book on actinic keratosis. However, reflection on my discussions with Tarl Prow and Gregor Jemec made it soon evident to all of us that actinic keratosis is actually one of the best examples in mankind for studying the potential evolution from benign erythaematous lesions, with some flaky scales, to more or less tender nodules that rarely, but still too often, lead to metastasis and death. Additionally, it is probably fair to say that actinic keratoses are a remarkable experiment of nature that allows us to study biologic questions in regards to carcinogenesis and its treatment in our patients in an unprecedented manner. There is quite a bit of controversial literature on the interpretation of actinic keratosis as a benign lesion, a precursor lesion, or a ‘carcinoma en miniature,’ highlighting the different schools of thought and underlying divergent interpretations between researchers and clinicians. The attentive reader will realise that this intellectual diversity is also reflected by our chapters’ authors, who represent world-renowned experts in the field of actinic keratosis.
We tried to encompass all the facets of this condition by inviting researchers and clinicians across the spectrum, from epidemiology to immunology and from molecular biology to behavioural psychology, and of course, pathologists and clinicians working at the coal face with patients who bear the many clinical facets of actinic keratoses. In this spirit, this book on actinic keratosis will be of interest for scientists and clinicians alike with a special interest in this common and fascinating condition that affects our patients beyond cosmetics; often has an impact on morbidity; and rarely, when progressing uncontrolled, also has an impact on mortality.
In conclusion, we are greatly indebted to all the authors contributing to the different chapters, and we wish to thank them all for a great collaborative effort. Finally, a special thank you goes to Sandra Braun from KARGER who accompanied us through the various stages of the process of getting this book to completion.
H. Peter Soyer , Brisbane, Qld., Australia Tarl W. Prow , Brisbane, Qld., Australia Gregor B.E. Jemec , Roskilde, Denmark
Soyer HP, Prow TW, Jemec GBE (eds): Actinic Keratosis. Curr Probl Dermatol. Basel, Karger, 2015, vol 46, pp 1-7 (DOI: 10.1159/000366525)
Epidemiology of Actinic Keratoses
Adèle C. Green
Cancer and Population Studies, QIMR Berghofer Medical Research Institute, Brisbane, Qld., Australia; Institute of Inflammation and Repair, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK
The epidemiology of actinic keratoses (AKs) reflects their causation by cumulative sun exposure, with the highest prevalence seen in pale-skinned people living at low latitudes and on the most sun-exposed body sites, namely the hands, forearms and face. AKs are markers of increased risk of basal cell carcinoma, squamous cell carcinoma and melanoma, especially when they are numerous and have coalesced into an area of ‘field cancerisation’. The major risk factors are male sex, advanced age, sun-sensitive complexion, high lifetime sun exposure and prolonged immunosuppression. Clinical counts of AKs enable the assessment and monitoring of AK burden, but accurate counting is notoriously difficult, especially when skin is severely sun damaged. AK counting has been repeatedly shown to be unreliable, even among expert dermatologists. Notwithstanding these challenges, qualitative assessment of the natural history of AKs shows a high turnover, with new lesions developing and with other lesions regressing. A very small proportion of AKs undergo malignant transformation, but the precise rate of transformation is unknown due to the inaccuracies in monitoring AK lesions over time. Primary prevention of AKs is achieved by limiting intense sun exposure through sun-protective behaviour, including seeking deep shade, wearing sun-protective clothing and applying sunscreen regularly to exposed skin, from an early age.
© 2015 S. Karger AG, Basel
Actinic keratoses (AKs), also known as solar keratoses, are benign, red, scaly tumours of the epidermis caused by cumulative sun exposure of the skin, as their name implies. Their epidemiology reflects this description, with lesions mostly seen on body sites that receive high sun exposure (head and neck, backs of hands and forearms) in older, pale-skinned populations. In people whose accumulated sun exposure is high, AKs may be very numerous (over 50), and in people with severe photodamage, contiguous AKs may coalescence into large areas of patchily inflamed and keratotic skin ( fig. 1 ). These fields of abnormal skin are known as areas of ‘field change’ or ‘field cancerisation’, and in these situations, AKs cause cosmetic disfigurement and physical irritation. AKs are of public health importance because their presence flags significantly raised risks of basal cell carcinoma, squamous cell carcinoma (SCC) and melanoma [ 1 , 2 ]. This is because AKs, along with other similar biomarkers like solar elastosis [ 3 ] and pigmentation changes, including solar lentigines [ 4 ], are biomarkers of large cumulative doses of ultraviolet radiation to the skin in susceptible people [ 5 ]. Moreover, a minute proportion of AKs undergo malignant transformation to SCC [ 6 ]. AKs are of economic importance in affected populations because annual treatment costs are very high [ 7 , 8 ].

Fig. 1. Multiple actinic keratoses on severely sun-damaged skin.
Assessing Actinic Keratosis Prevalence
The overall prevalence of AKs can be defined as the proportion of a given population that has at least one AK present, and this measure is relatively simple to assess. However, when the proportion of a population that has many AKs is of interest, accurate assessment of the precise number of AKs present is very difficult ( fig. 1 ). Previous studies of the AK burden in study populations have usually quantified lesions solely by counting the lesions diagnosed as AK on affected sites during physical examination. However, counting of AKs is unreliable, even when performed by experienced dermatologists [ 9 ]. The variability of absolute AK counts on the same person can be substantial, and the agreement between and within expert observers of AK counts has been repeatedly shown to be low, especially when multiple actinic tumours and skin lesions are present, as in severely photodamaged skin [ 10 ]. It would be both unwarranted and impractical to confirm the diagnosis of multiple typical AKs on affected persons by histopathology without clinical indication; furthermore the reproducibility of histopathological diagnosis of AK is low [ 11 ]. The importance of developing and validating techniques to enhance the reliability of AK assessment has been highlighted, but the problem remains unresolved [ 6 ]. Photographic evaluation is being tested, but a preliminary study has suggested that photography alone cannot replace the clinical assessment of AKs (Sinnya S, personal communication). The current limitations of existing AK prevalence data need to be taken into account when reviewing the quantitative AK estimates reported by previous studies, although it is unlikely their qualitative interpretation has been distorted.
Worldwide Distribution
AK prevalence is generally highest in pale-skinned people living at low latitudes with year-round, high sun exposure ( table 1 ). The highest prevalence of AKs in the general population across all age groups has been reported in parts of Australia, with around 40% affected [ 13 , 14 ]. The prevalence in people of similar genetic stock varies markedly with latitude; age-specific AK prevalence in the UK [ 15 , 16 ] is about a quarter of the corresponding AK prevalence in Australia ( table 1 ).
Table 1. Prevalence of actinic keratoses in unselected study populations

Prevalence by Age, Sex and Body Site
AK prevalence is higher among men than women of the same age ( table 1 ). In Northern European and North American whites, AKs are uncommon before the age of 40 years. White Australians in their 30s have similar AK prevalence to that of Northern Europeans in their 70s ( table 1 ). The body site distribution of AKs is characteristic and reflects the sites of heaviest sun exposure. In population-based surveys, the face, forearms and backs of the hands are the sites of the vast majority of prevalent AKs, with the relative site distribution depending on factors like local climate and culture. In northwest England, the sites most affected are (in order) the scalp, forehead, ears, cheek, chin and jaw [ 16 ]. Similarly, in southeast Queensland, all affected persons had prevalent AKs on the upper limbs (60%) or head (40%) [ 17 ], but prevalent AKs were also noted on the trunk and lower limbs in a material proportion of participants [ 18 , 19 ]. In the Netherlands, the face was most commonly affected among people with less than 10 prevalent AKs, but the scalp was the site most affected on those with more than 10 AKs (all in bald men) [ 20 ]. In a detailed study of AK site distribution in a clinical referral setting in Korea, 95% of AKs were seen on the head and neck, specifically, the cheek (44%), forehead (15%) and nose (10%) [ 21 ].
The incidence rate of AK, which is defined as the proportion of the population that develops a new AK in a given period of time, has rarely been studied [ 22 ]. Only intensive and careful dermatological monitoring of individuals in a specified study population for at least a year can be used to calculate incidence. Repeated skin examinations are needed to distinguish new AKs from pre-existing AKs in order to estimate the true rate of development of new AKs in people who are already affected. There is a net increase of AKs with increasing age, and the reported annual incidence rates in prospectively followed community samples range from 9% in persons over the age of 60 years in South Wales [ 15 ], to 19% and 60% per year in people aged 40-99 years who were previously unaffected and affected, respectively, in southern Australia [ 23 ], to 53% and 30% in men and women, respectively, aged 30-69 years in subtropical Australia [ 17 ].
Risk Factors
AKs occur more often among people of European ancestry who have light complexions, light hair and eye colour, a propensity to sunburn and many freckles than among people who have darker skin, hair and eye colour and sunburn rarely [ 14 , 16 , 20 , 24 - 26 ].
Sun Exposure
The causal role of solar radiation exposure is supported by the consistent observation of the highest prevalence in fair-skinned, sun-sensitive people living at low latitudes where solar ultraviolet radiation is most intense and high year round. Fair-skinned migrants from high- to low-latitude countries have a lower AK prevalence than native-born residents [ 24 ], and people with heavy cumulative sun exposure and multiple sunburns have 2-3-fold higher risks of AKs than the others [ 25 , 26 ].
Because immune surveillance plays a key role in skin tumourigenesis, immunosuppression is associated with AKs. Best studied are white organ transplant recipients whose increased risk of developing benign and premalignant lesions associated with skin cancer compared with that of the general population has been documented widely [ 27 - 30 ]. The most common benign lesions are warty verrucous keratoses that often co-occur with AKs and can be difficult to differentiate [ 28 , 29 ]. In contrast to organ transplant recipients of European ancestry, Asian organ transplant recipients have a low risk of developing AKs [ 31 ].
Natural History of Actinic Keratoses
Although the natural history of AK is poorly understood and unquantified despite numerous studies, the possible outcomes range between the contrasting extremes of complete regression and malignant transformation. Moreover, the turnover of prevalent individual lesions appears to be high and involves recurrence as well as development of new lesions [ 17 ]. A recent systematic review of the primary literature showed that annual rates of regression of single AKs ranged from 15-63% and that rates of recurrence of single AKs ranged from 15-53% [ 6 ]. That systematic review also found that the reported progression rates of AK to SCC ranged from 0-0.075% per lesion-year and up to 0.53% per lesion in those previously affected by keratinocyte cancer. An earlier systematic review published in 2006 [ 32 ] found a single meta-analysis that estimated the AK to SCC progression rate as between 0.025% and 20% per year/per lesion. However, given the lack of valid and reliable means of monitoring AKs over time, especially in people with chronically sun-damaged skin and field cancerisation, the authors concluded that reliable estimates of the annual rates of malignant transformation of AK could not be derived from the existing data [ 6 ]. Areas of field cancerisation are believed to be at especially high risk for progression to SCC. In a recent study of immunosuppressed renal transplant recipients in northwest England, the risk of SCC arising was over 4 times greater in transplant recipients with field cancerisation compared with those with only discrete AKs, and the majority (55%) of SCC arose within an area of field change in the study period (Wallingford S, personal communication).
Actinic Keratosis Prevention
Primary prevention of AK is achieved by reducing cumulative sun exposure. The main sun-protective behaviours are limiting outdoor sun exposure as much as possible between the hours of 10 am and 2 pm, either by staying indoors or, if outdoors, seeking deep shade or wearing sun-protective clothing and sunscreen. Sunscreen application is the most common means of skin protection when in the sun, and regular use of sunscreen has been shown to protect against the development of AKs in adults in 3 randomised controlled trials [ 33 ]. The first trial was conducted over a 7-month period in 431 white volunteer residents of Maryborough, Victoria who had prevalent AKs at baseline [ 34 ]. The participants were randomised to apply either broad-spectrum SPF 17 sunscreen or placebo (base-cream) to their head, neck, forearms and backs of hands every morning, and they reapplied if necessary during the day. Regular sunscreen use in the short term reduced the mean number of new AKs by 0.6 (standard error ± 0.3) in the sunscreen intervention group, while this number was increased by 1.0 (standard error ± 0.3) in the placebo group, corresponding to a rate ratio of 0.62 (95% CI = 0.54-0.71) [ 34 ]. Sunscreen allocation was also associated with remission of existing AK [ 34 ]. A small randomised controlled trial including 50 volunteer patients with prevalent AKs or past keratinocyte cancers was carried out in a specialised dermatology clinic in the US over a 2-year period. Patients randomly assigned to apply SPF 29 sunscreen daily showed a 36% reduction in new AKs compared with a placebo group using sunscreen base [ 35 ]. Finally, 1,621 adult residents of the Nambour community in Queensland, Australia were randomised either to apply broad-spectrum SPF 16 sunscreen to their head, neck, forearms and backs of hands every morning, with reapplication as necessary, or to use sunscreen at their usual discretionary rate [ 36 ]. Allocation to daily sunscreen use significantly reduced the rate of AK acquisition among participants of the Nambour Trial by 22% in the first 2 years, although the protective effect diminished during the second half of the intervention period [ 36 ].
As above, a range of other factors has been suggested as having possible protective effects on AKs (apart from prescribed treatments [ 37 ], which are not covered in the present review). These include taking NSAIDS [ 38 ] and consumption of a low-fat diet [ 39 ] or of certain food groups, like oily fish [ 40 ], but such protection has not been confirmed through evaluation in randomised controlled trials. In two small Phase II randomised controlled trials that were carried out to evaluate oral nicotinamide (vitamin B3) (500 mg twice or once daily) as a potential AK preventive in immunocompetent patients, there were relative reductions in AK counts of 35% and 29%, respectively, in those allocated to nicotinamide supplements compared with those taking placebo supplements [ 41 ]. These promising results await evaluation in a larger Phase III trial [ 41 ].
Until a more accurate method of assessing AK prevalence is found, for example, combining clinical and high-resolution 3D photographic assessment, quantitative estimates of prevalence and risk carry a degree of uncertainty. However, it is clear from studies conducted in many different populations that AKs are a public health burden in sun-sensitive people living without adequate sun protection at low latitudes. Adoption of sunsafe habits from young ages is required to control the problem in high-risk communities. For immune-suppressed patients, extra measures may be required, and a range of possible specific agents for AK prevention are being evaluated [ 37 ].
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42 Schaefer I, Augustin M, Spehr C, Reusch M, Kornek T: Prevalence and risk factors of actinic keratoses in Germany-analysis of multisource data. J Eur Acad Dermatol Venereol 2014;28:309-313.
Professor Adèle C. Green Cancer and Population Studies Group QIMR Berghofer Medical Research Institute Locked Bag 2000 Royal Brisbane Hospital, QLD 4029 (Australia) E- Mail
Soyer HP, Prow TW, Jemec GBE (eds): Actinic Keratosis. Curr Probl Dermatol. Basel, Karger, 2015, vol 46, pp 8-13 (DOI: 10.1159/000366530)
Patients’ Perspectives on Actinic Keratosis
Solveig Esmann
Department of Dermatology, Roskilde Hospital, Faculty of Health Sciences, University of Copenhagen, Roskilde, Denmark
Many factors influence patients’ perspectives on actinic keratosis (AK). The wish to keep a sense of control prompts many to seek information, which they then interpret according to their personal perspective. Speculations regarding the risk of getting skin cancer and emotional reactions may be expected due to worries about the worsening of the condition, losing control, and participating in UV-related activities. In their contact with physicians, treatment can be an additional issue. Treatment of AK may cause pain and may in itself result in a perceived diminished quality of life. The Actinic Keratosis Quality of Life questionnaire can be used as a valuable tool to represent the effects of treatment on quality of life and to classify patient subpopulations. Studies have suggested that AK patients are more compliant compared to those with other skin diseases. Still fear of stigmatisation may be present during treatment, which may disturb social life. Social and personal factors are crucial to patients’ coping strategies, and financial aspects may have an impact on advisable UV-related behaviours. Some AK patients may benefit from interventions to improve their stress response capacity. The clear causality of AK requires a change in behaviour, which is met by multi-conditioned resistance. The physician should be aware that patients might feign acceptance but justify continued UV exposure to themselves with a variety of arguments. Tanning is of great importance for the self-esteem of many AK patients, and tanning addiction should be considered.
© 2015 S. Karger AG, Basel
Patients’ Perspectives on Actinic Keratosis
Health-seeking behaviour is both common and fashionable. The wish to keep a sense of control prompts many persons to seek information on a variety of subjects related to their health and daily life. Patients with actinic keratosis (AK) do not differ in this regard. The information that their skin has been damaged by the sun and that they need to take precautions against further damage may lead to emotional reactions, not only pertaining to their diagnosis but also to their changed living conditions. Therefore, the Internet is frequently used to access information about this disease and its symptoms. The authority of the doctor is no longer perceived in the same manner, and people want to take part in decisions concerning their own health.
Exhaustive information is important to quality of life (QoL) when faced with otherwise vague threats to one's health. Missing information or the failure of doctors to answer questions may thus be crucial. Doubts of having been assigned the right diagnosis can also be found among patients with AK, which often initiate ruminating and a feeling of the loss of control [ 1 ].
AK is sometimes referred to as a pre-cancerous lesion or as a marker of an increased risk of skin cancer. In general, patients will focus on the word ‘cancer’ if the doctor terms AK as ‘cancer’. The term cancer is traditionally considered to be a fatal condition. Patients with AK may therefore react in a more fearful and emotional way when confronted with a diagnosis that includes the term ‘cancer’. No differences in gender or age can be found with regard to fear and worry [ 1 ]. All in all, a variety of reactions encompassing emotions, cognition and activity are seen in the wake of an AK diagnosis. They can be summarised as worries about the condition worsening over time, fear of its progression to skin cancer, irritation and anger of the loss of control due to this relentless disease, doubts about the diagnosis, guilt and sorrow associated with UV-related activities, and/or a relaxed attitude due to active decision or ignorance.
Quality of Life in Actinic Keratosis
Depending on the extent of patients’ reactions, the presence of AK and its treatment may have a greater or lesser impact on QoL. In dermatology, the improvement of QoL is seen as an increasingly important goal for assessing treatment outcome. To date, few studies have focused on the impact of AK treatment on QoL [ 2 ]. Interviews with patients about daily life with AK and its treatment point to a variety of topics that play a role in the QoL of a patient with AK [ 1 , 3 ].
The most frequently used tool to assess the dermatology-specific QoL among patients with skin diseases, the Dermatology Life Quality Index, has shown that QoL is improved after treatment with diclofenac in hyaluronic acid gel [ 4 , 5 ]. Another study using the Dermatology Life Quality Index has shown that there was no significant difference in QoL after treatment with photodynamic therapy and 5% imiquimod cream after 4 weeks [ 6 ]. In a third study, photodynamic treatment was shown to have a highly positive, but temporary, impact on QoL [ 7 ].
Recently, the AK-specific QoL questionnaire, Actinic Keratosis Quality of Life, was introduced to describe the effects of these tumours on QoL [ 8 , 9 ]. It has been successfully validated. It consists of three domains (functions, emotions and control) and a single global item [ 9 ]. Therefore, this questionnaire provides the means to study changes over time in the same patient and to compare treatment outcomes among patients with AK. In addition, it may be used to classify subpopulations of patients according to disease impact and identify those that may need additional psychological intervention.
Patients may experience fear of stigmatisation. Being stared at by others may pose a psychological burden, especially if lesions are ulcerated, irrespective of whether they are a result of the disease or treatment. These are general aspects of having a skin disease, and various studies on stigmatisation in relation to skin disease have shown the similar reactions of patients with hidradenitis suppurativa, acne, vitiligo, psoriasis and eczema [ 10 - 15 ]. Days off from work due to fear of stigmatisation is not a major concern among patients with AK, probably due to the age group involved. Generally, having a diagnosis that may develop into cancer may cause stress reactions, which impact the body, mind and spirit [ 16 ]. Interventions to improve stress response capacity both mentally and physically may be of relevance for some AK patients, and may support an enhancement of QoL.
Patients’ Perspectives on Treatment
It is always recommended that attention be paid to the patient's profile, personal preferences (e.g. cosmetic outcome and pain) and medical history when choosing an AK treatment [ 17 ]. If the treatment causes too many adverse effects, e.g. if it is too painful or results in too many scars, patients may refuse or abandon it [ 3 , 18 , 19 ].
The risk of scarring is a key point of interest with regard to QoL, appearance and self-esteem. In particular, women find it important to consider therapeutic options that minimise the risk of scarring [ 20 ].
Many AK treatments may involve some degree of pain. AK patients thus have to endure shorter or longer periods of pain when being treated [ 3 , 21 , 22 ]. A range of emotional reactions can be triggered by painful AK treatments. Pain significantly reduces QoL, and this has been seen in many skin diseases [ 23 ]. The dominant focus of attention becomes the pain, and the feeling of control over the body and social life may be lost [ 24 ]. Painkillers or nerve blocks have been shown to give relief [ 25 ].
It is hypothesised that some patients suffer unnecessarily and unintendedly from treatment-associated pain because they fail to distinguish between pain as part of the treatment and pain as an extensive side effect. Some patients may suffer unduly in silence because they expect the doctor to warn them of the possibility of intolerable, increased pain. Guidelines for treatments and possible side effects should note the degree and duration of pain expected.
If adherence is defined as the extent to which given advice is internalised and accepted by patients, compliance may be seen as a more treatment-related issue. Although non-compliance is a nearly universal principle of dermatological treatment, compliance is surprisingly high in AK patients under treatment (92-82% over a 4-week period) [ 26 - 29 ]. Several possible explanations for this high compliance have been suggested. For example, AK is a premalignant disease mainly found in older patients, the treatment has a fixed duration, its effects are visible and tactile, and it is controlled by frequent visits [ 30 , 31 ].
Past experiences in the clinic may result in resistance to treatment [ 25 , 32 ]. Potential scarring or pain and phobias to specific drugs or procedures may also influence compliance. Cost of treatment and insurance status are factors of varying importance for patients with AK depending on cultural patterns and legislation. For some, the cost of the treatment in itself may result in non-compliance [ 32 ]. It is recommended to emphasise to patients that full compliance will result in lesion resolution and improved cosmetic appearance [ 32 ].
With a move towards non-surgical treatments requiring longer coherent treatment periods, patients’ social and professional schedules, occupations and travel plans may be disrupted [ 3 , 32 ].
Coping with the Need to Change: UV Exposure
The diagnosis of AK requires changes in patients’ behaviours to prevent the recurrence or worsening of the condition [ 33 ]. It is strongly recommended that patients who have had AK stay out of the sun and generally protect their skin from UV rays. This disease imposes marked behavioural changes on patients because of the close causal relationship between AK and UV exposure and the strength of the association. This sets AK apart from the many other skin diseases with less well-described aetiologies. This obvious causality clearly underlines the value of the warning and the necessity of educating patients and the population in generally trusting the treating physician to make strong and precise recommendations.
Daily UV-related social activities may result in a variety of behaviours and emotional reactions to the way AK is perceived by the community. Some patients with AK feel neglected if they are not shown consideration with regard to their surroundings, e.g. if they are being offered a sun-exposed chair. In other cases, AK patients may feel trumped, patronised, and more miserable because they are receiving too much consideration. The individual patient's psychosocial situation affects whether they experience irritation, stigmatisation and the loss of control or see the consideration of others as an empathic gesture.
Coping is regulated by the need to find meaning in life [ 34 , 35 ]. The perceived risk of AK is thus weighed against the relative importance of personal and contextual issues. The intention to act according to the physician's recommendations may be present, but factors present within a context may lead to different behaviours. Something that is non-advisable or even forbidden will inevitably be modified by an individual's perspective and position in the context [ 34 - 36 ].
Any directed educational effort may therefore lead to a variety of individual reactions. The goal of adherence requires the prescribing physician to be aware of how such education is perceived by patients and the mechanisms behind any resistance. For most people, their sun-related behaviour is multi-conditioned and represents the summation of many factors, e.g. advice, habitual and contextual behaviours, and possibly, an addiction to tanning. This complex motivation means that although AK patients know how to protect their skin using sunscreen, hats and clothes or by staying out of the sun, they do not always adhere to these recommendations. Interviews have shown that they may consciously ignore this knowledge, sometimes even conscientiously cheating [ 1 ]. Patients want to live as they did before the diagnosis and in spite of it. Therefore, they often try to justify their continued behaviours by arguments, such as living in a situation that makes it difficult to deviate from their previous behaviour, working outdoors, or simply wanting to spend time on the beach in the sun. They may even feign acceptance of the requirement that they have to stay out of the sun but use quasi-medical arguments, such as the need for vitamin D or the threat of psoriasis, as an excuse not to do so.
Sunscreens are generally recommended for AK patients in combination with UV avoidance. In a behavioural context, however, the use of sunscreens can further complicate patients’ perceptions of the dangers posed by UV irradiation because they are considered by some individuals to imply an approval of tanning. Adherence to general UV avoidance may therefore be diminished by the use of sunscreens. Previous exposure may also be considered as a license for continued behaviour. This is seen especially among men, who often claim that they can expose their body to UV radiation without the use of sunscreens because they have tanned many times before [ 1 ]. Such claims are of course facilitated by the long induction time from UV exposure to the development of AK or actual skin cancer, which contributes to the impression of its harmlessness.
Tanning continues to be seen as desirable by many, as reflected by the extensive use of indoor tanning devices. This activity also continues to be supported by a strong fashion trend, which further substantiates the already strong resistance to change [ 37 ].
Sun-seeking behaviour is common in some populations; but it is not a universal trait. It may therefore be speculated that AK patients represent a group of people who pay special attention to, or are even addicted to, maintaining a tanned appearance. It may be hypothesised that they have a higher need for external appreciation, specifically related to their appearance, to maintain or enhance their sense of self-esteem [ 38 , 39 ]. Interestingly, interviews of AK patients suggest that they frequently and expressly require reassurance from family and friends regarding their appearance [ 1 ].
The acceptance of the need to change a behaviour seems to be related to gender and age. Men often do not display vanity to the same extent or even in a differing way compared with women. Women seem more concerned about changes in their appearance and more often react emotionally with sadness and irritation to their AK diagnosis and ensuing AK-related recommendations [ 1 ]. Generally, persons who are fond of tanning or can be described as tanning addicted often find UV prevention embarrassing [ 37 , 40 ]. The advice to maintain non-tanned skin and the need to plan UV-restricted holidays and leisure activities are perceived as extensive disruptions to their lives. Therefore, these patients need to be provided with a way to maintain their appearance whilst avoiding UV exposure. In the weighing of the pros and cons, the use of sunless tanning products may be an acceptable solution for some, although studies have shown that their desire for tanned skin remains strong [ 41 , 42 ].
Financial aspects may have an impact on changing UV-related behaviours. Among outdoor workers with AK, these behaviours vary. Ideally, these patients should find alternative employment involving less UV exposure, but circumstances may require them to remain at their job because of economic necessity.
Thus, context can be crucial to patients’ coping strategies in relation to AK as well as their stress levels, body image, self-esteem, and level of personal control [ 1 , 35 ].
Coping is a dynamic process that may change through adaptation to the disease. It is also a reflective process, e.g. with speculations about the risk of getting skin cancer.
To deal with such situations, patient-oriented information, e.g. hand-outs with pictures of AK symptoms and pictures taken pre-, during- and post-AK treatment are recommended. The ability to pose questions when patients are concerned about symptoms or treatment is also important [ 25 , 32 ].
Because AK typically appears at age 50+, the presence of competing illnesses are frequent. Faced with these illnesses, AK patients may place a smaller personal emphasis on their disease. Similarly, severe diseases observed in other patients may lead to the reappraisal of one's own condition. Minimising or even denying the perceived seriousness of AK may be a coping strategy [ 43 , 44 ]. Correspondingly, hope, a positive attitude and spiritual prayer are well-known coping strategies [ 43 , 44 ].
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6 Hadley J, Tristani-Firouzi P, Hull C, Florell S, Cotter M, Hadley M: Results of an investigator-initiated single-blind split-face comparison of photodynamic therapy and 5% imiquimod cream for the treatment of actinic keratoses. Dermatol Surg 2012;38:722-727.
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10 Esmann S, Jemec GB: Psychosocial impact of hidradenitis suppurativa: a qualitative study. Acta Derm Venereol 2011;91:328-332.
11 Matusiak L, Bieniek A, Szepietowski JC: Psychophysical aspects of hidradenitis suppurativa. Acta Derm Venereol 2010;90:264-268.
12 Schmid-Ott G, Kuensebeck HW, Jaeger B, Werfel T, Frahm K, Ruitman J, Kapp A, Lamprecht F: Validity study for the stigmatization experience in atopic dermatitis and psoriatic patients. Acta Derm Venereol 1999;79:443-447.
13 Joachim G, Acorn S: Stigma of visible and invisible chronic conditions. J Adv Nurs 2000;32:243-248.
14 Neil JA: The stigma scale: measuring body image and the skin. Plast Surg Nurs 2001;21:79-82, 87.
15 Vardy D, Besser A, Amir M, Gesthalter B, Biton A, Buskila D: Experiences of stigmatization play a role in mediating the impact of disease severity on quality of life in psoriasis patients. Br J Dermatol 2002;147:736-742.
16 Peters EM: Psychological support of skin cancer patients. Br J Dermatol 2012;167(suppl2):105-110.
17 Stockfleth E, Ferrandiz C, Grob JJ, Leigh I, Pehamberger H, Kerl H; European Skin Academy: Development of a treatment algorithm for actinic keratoses: a European Consensus. Eur J Dermatol 2008;18:651-659.
18 Tran DT, Salmon R: Field treatment of facial and scalp actinic keratoses with photodynamic therapy: survey of patient perceptions of treatment satisfaction and outcomes. Australas J Dermatol 2011;52:195-201.
19 Tierney EP, Eide MJ, Jacobsen G, Ozog D: Photodynamic therapy for actinic keratoses: survey of patient perceptions of treatment satisfaction and outcomes. J Cosmet Laser Ther 2008;10:81-86.
20 Esmann S, Vinding GR, Christensen KB, Jemec GB: Assessing the influence of actinic keratosis on patients' quality of life: the AKQoL questionnaire. Br J Dermatol 2013;168:277-283. Erratum in: Br J Dermatol 2013;168:914.
21 Gholam P, Denk K, Sehr T, Enk A, Hartmann M: Factors influencing pain intensity during topical photodynamic therapy of complete cosmetic units for actinic keratoses. J Am Acad Dermatol 2010;63:213-218.
22 Gholam P, Weberschock T, Denk K, Enk A: Treatment with 5-aminolaevulinic acid methylester is less painful than treatment with 5-aminolaevulinic acid nanoemulsion in topical photodynamic therapy for actinic keratosis. Dermatology 2011;222:358-362.
23 van Laarhoven AI, Walker AL, Wilder-Smith OH, Kroeze S, van Riel PL, van de Kerkhof PC, Kraaimaat FW, Evers AW: Role of induced negative and positive emotions in sensitivity to itch and pain in women. Br J Dermatol 2012;167:262-269.
24 Albrecht GL, Devlieger PJ: The disability paradox: high quality of life against all odds. Soc Sci Med 1999;48:977-988.
25 Halldin CB, Gonzalez H, Wennberg AM, Lepp M: Patients' experiences of pain and pain relief during photodynamic therapy on actinic keratoses: an interview study. Acta Derm Venereol 2013;93:433-437.
26 Storm A, Andersen SE, Benfeldt E, Serup J: One in 3 prescriptions are never redeemed: primary nonadherence in an outpatient clinic. J Am Acad Dermatol 2008;59:27-33.
27 Feldman SR, Horn EJ, Balkrishnan R, Basra MK, Finlay AY, McCoy D, Menter A, van de Kerkhof PC; International Psoriasis Council: Psoriasis: improving adherence to topical therapy. J Am Acad Dermatol 2008;59:1009-1016.
28 Ali SM, Brodell RT, Balkrishnan R, Feldman SR: Poor adherence to treatments: a fundamental principle of dermatology. Arch Dermatol 2007;143:912-915.
29 Lee IA, Maibach HI: Pharmionics in dermatology: a review of topical medication adherence. Am J Clin Dermatol 2006;7:231-236.
30 Yentzer B, Hick J, Williams L, Inabinet R, Wilson R, Camacho FT, Russell GB, Feldman SR: Adherence to a topical regimen of 5-fluorouracil, 0.5%, cream for the treatment of actinic keratoses. Arch Dermatol 2009;145:203-205.
31 Stockfleth E, Zwingers T, Willers C: Recurrence rates and patient assessed outcomes of 0.5% 5-fluorouracil in combination with salicylic acid treating actinic keratoses. Eur J Dermatol 2012;22:370-374.
32 Jorizzo JL, Carney PS, Ko WT, Robins P, Weinkle SH, Werschler WP: Matching patients with therapy. Cutis 2004;74:5-8.
33 MacKie RM: Awareness, knowledge and attitudes to basal cell carcinoma and actinic keratoses among the general public within Europe. J Eur Acad Dermatol Venereol 2004;18:552-555.
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35 Fife BL: The role of constructed meaning in adaptation to the onset of life-threatening illness. Soc Sci Med 2005;61:2132-2143.
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37 Prior SM, Fenwick KD, Peterson JC: Adolescents' reasons for tanning and appearance motives: a preliminary study. Body Image 2014;11:93-96.
38 Cafri G, Thompson JK, Jacobsen PB, Hillhouse J: Investigating the role of appearance-based factors in predicting sunbathing and tanning salon use. J Behav Med 2009;32:532-544.
39 Robinson JK, Baker MK, Hillhouse JJ: New approaches to melanoma prevention. Dermatol Clin 2012;30:405-412.
40 Keesling B, Friedman HS: Psychosocial factors in sunbathing and sunscreen use. Health Psychol 1987;6:477-493.
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Solveig Esmann, MA Department of Dermatology Roskilde Hospital Roskildevej 7-13 DK-4000 Roskilde (Denmark) E- Mail
Soyer HP, Prow TW, Jemec GBE (eds): Actinic Keratosis. Curr Probl Dermatol. Basel, Karger, 2015, vol 46, pp 14-19 (DOI: 10.1159/000366531)
Photodamage: All Signs Lead to Actinic Keratosis and Early Squamous Cell Carcinoma
Jerry Wei a Lai Fong Kok a , b Scott N. Byrne a , b Gary M. Halliday a
a Disciplines of Dermatology and b Infectious Diseases and Immunology, Bosch Institute, Sydney Cancer Centre, University of Sydney, Sydney, N.S.W., Australia
Ultraviolet (UV) radiation is likely to drive the initiation and progression of skin cancer from actinic keratosis to squamous cell carcinoma. Signs of photodamage occur at multiple steps. UV radiation damages many cellular constituents, including lipids, proteins and DNA, all of which are likely to contribute to UV-induced skin cancer. Two biological events culminating from photodamage are mutations in the genes critical to the control of cell division, differentiation and invasion and immunosuppression. DNA photodamage, if unrepaired prior to cell division, can result in the incorporation of an incorrect nucleotide into newly synthesised DNA. Mutations in critical genes contribute to carcinogenesis. Photodamage to proteins such as those involved in DNA repair or proteins or lipids involved in cellular signalling can interfere with this repair process and contribute to mutagenesis. Mutations in key genes, including TP53, BRM, PTCH1 , and HRAS , contribute to skin carcinogenesis. UV also damages immunity. Photodamage to DNA and signalling lipids as well as other molecular changes are detrimental to the key cells that regulate immunity. Photodamaged dendritic cells and altered responses by mast cells lead to the activation of T and B regulatory cells that suppress immunity to the protein products of UV-mutated genes. This stops the immune response from its protective function of destroying mutated cells, enabling the transformed cells to progress to skin cancer. UV appears to play a pivotal role at each of these steps, and therefore, signs of photodamage point to the development of skin cancer.
© 2015 S. Karger AG, Basel
DNA Damage Induced by Ultraviolet Radiation
Solar ultraviolet (UV) radiation is categorised into three wavebands: UVA (320-400 nm), UVB (290-320 nm) and UVC (<290 nm). UVC is mostly filtered by the ozone layer. Only UVA and UVB are able to reach the earth's surface. Exposure to UVA and UVB can both lead to DNA damage in skin cells.
UVB comprises approximately 5% of terrestrial UV radiation. UVB energy directly absorbed by DNA in skin cells can lead to crosslinking between adjacent cytosine or thymine bases, which subsequently produces cyclobutane pyrimidine dimers [ 1 ]. This type of DNA lesion is mainly removed by the nucleotide excision repair (NER) pathway. Studies of rare genetic disorders involving NER deficiency, including Cockayne syndrome and xeroderma pigmentosum, have identified several associated genes involved in the recognition and repair of the cyclobutane pyrimidine dimers by the NER pathway [ 2 ]. UVA is the major component of terrestrial UV radiation (approximately 95%). Although UVA contains less energy per photon than UVB, its longer wavelength enables its deeper penetration into the skin. This results in the production of a large amount of reactive oxygen species in skin cells, which cause oxidative damage to DNA, including the formation of 8-oxo-2'-deoxyguanosine [ 3 ]. In humans, this molecule is primarily repaired by 8-oxoguanine DNA glycosylase via the base excision repair pathway [ 3 ]. Interestingly DNA photodamage induced by UVB will lead to a unique G:A (or C:T) transition, whereas UVA photodamage will normally result in an A:C (or T:G) transversion [ 1 ].
The UV-induced DNA lesions can either be repaired, or if the damage is too severe, initiate apoptosis of the cell to protect it from the formation of mutations. If the DNA damage is not repaired correctly and the cell survives, the damaged nucleotides can result in permanent somatic mutations, and accumulations of these unrepaired somatic mutations could result in the transformation of the cell into cancer.

J. Wei and L.F. Kok contributed equally to this work.
UVR-Induced Gene Mutations that Lead to Actinic Keratosis and Non-Melanoma Skin Cancer
The tumour protein p53 (TP53) is one of the most well studied master transcription regulators. It modulates a broad range of cellular processes, including DNA repair, the cell cycle, apoptosis, cell survival, genomic stability and senescence. TP53 expression is mainly suppressed during normal cell growth. Its expression is activated when the cell encounters severe stress, such as cytotoxic or mutagenic agents, to promote either cell survival or apoptosis [ 4 ]. In humans, TP53 is the most frequently mutated gene in actinic keratosis (AK) (37% of analysed samples) and the second most frequently mutated gene in basal cell carcinoma (BCC; 39%) and squamous cell carcinoma (SCC; 35%) according to the Catalogue of Somatic Mutations in Cancer database (COSMIC v67 Release, 24 Oct 2013) [ 5 ]. Many TP53 DNA mutations contain UVB fingerprints, suggesting that UVB is one of the causes of skin carcinogenesis, although mutations attributable to UVA also implicate this waveband [ 1 ]. This gene is mutated during the early stages of carcinogenesis, but mutations also play important roles in skin cancer progression. Interestingly, human studies comparing mutations in AK and SCC have highlighted the fact that TP53 mutations are highly correlated with the development of precancerous skin lesions, but further carcinogenic progression may require the incorporation of other mutagenic events [ 6 ].
BRM (SMARCA2) and BRG-1 (SMARCA4) are subunits of the SWI/SNF complex that play key roles in ATP-dependent chromatin remodelling at both the genetic and epigenetic levels [ 7 ]. This complex is involved in regulating the cell cycle, gene expression, oncogenesis, and DNA methylation and repair. The impaired function of each individual SWI/SNF subunit has been shown to be directly linked to multiple cancer types [ 7 ]. Studies in search of BRM mutations in primary skin tumours have found a hotspot mutation in SCC and BCC that may be caused by UVA [ 8 ]. The examination of the BRM and BRG-1 proteins has shown the loss of both of these proteins in SCC but not AK, suggesting that mutations in this gene occur late in the progression of AK into SCC [ 9 ]. The study of genetically modified mice has confirmed that depletion of BRM attenuates protection against skin photocarcinogenesis [ 10 ]. Therefore, evidence from human and animal studies has implicated that mutations in BRM play an important role during the later stages of AK progression into SCC and may be triggered by UV-induced mutations.
The protein encoded by the patched 1 (PTCH1) tumour suppressor gene is a transmembrane protein that acts as a receptor of the Sonic hedgehog protein controlling cell growth and development [ 11 ]. The PTCH1 -hedgehog signal transduction pathway also plays a key role in skin carcinogenesis and stem cell function [ 12 ]. In human skin, mutated PTCH1 is present in 40% of BCC and 8% of SCC cases but not in AK. Approximately 53% (120/227) of the somatic mutations identified in PTCH1 contain unique UVB fingerprints (G:A or C:T transition) (COSMIC v67 Release, 24 Oct 2013) [ 5 ]. The high frequency of UV-induced oncogenic mutations in PTCH1 support its critical role in skin photocarcinogenesis, but the absence of mutations in AK suggests that, like BRM , it is involved in progression to SCC.
The Ras proteins are small GDP/GTP binding proteins that function in signal transduction pathways. They regulate cellular proliferation, differentiation and senescence. Three of the most well studied RAS oncogenes are HRAS, KRAS and NRAS [ 13 ]. HRAS mutations are found in skin tumours, whereas KRAS mutations are largely found in other types of cancers, such as lung cancer. The high degree of tumour-type specificity is due to differences in the local regulatory elements of the RAS genes [ 14 ]. Mutated HRAS is present in 2% (3/132) of AK samples. Mutated HRAS is present in 8% (62/749) and KRAS is found in 4% (16/674) of skin carcinomas (COSMIC v67 Release, 24 Oct 2013) [ 5 ]. These observations imply that mutation of the RAS gene in the skin increases the risk of malignant transformation.
Some of the other frequently mutated genes found in skin carcinomas are CDKN2A, NOTCH2, NOTCH1 and SMO. Only CDKN2A is also present in AK (COSMIC v67 Release, 24 Oct 2013) [ 5 ]. The tumour suppressor gene CDKN2A encodes two major proteins, p16(INK4) and p14(ARF), that regulate the TP53 and RB1 pathways [ 15 ]. Mutations in CDKN2A have been shown to significantly increase the risk of the progression of AK to SCC [ 15 ]. Similarly mutations in NOTCH1/NOTCH2 and SMO [ 16 ] are significantly associated with skin cancer progression. While studies aimed at determining the roles of these mutated genes in skin carcinogenesis are still underway, molecular genetic tests of these genes to analyse mutations in patients’ skin lesions may provide useful information for the early diagnosis of malignancy and the targeting of skin cancer treatments to the genes involved.
UV is a complete carcinogen because in addition to DNA damage, it also suppresses the anti-tumour immune response that would otherwise target the protein product of the mutated gene and destroy the cell harbouring the mutation. More than 30 years ago, Fisher and Kripke demonstrated that UV immunosuppression via the activation of suppressor cells plays a crucial role in UV-induced skin cancer in mice [ 17 ]. The significantly increased incidence of skin cancer in renal transplant recipients highlights the role of immunosuppression in human cutaneous malignancies. Indeed, susceptibility to UV immunosuppression in humans is a key factor for identifying those at high risk of developing skin cancer [ 18 ].
The cellular and molecular mechanisms underlying UV immunosuppression are not completely known. The UV wavebands in sunlight penetrate no more than a few millimetres into the skin, which is where the immunosuppressive signals are generated. An action spectrum has indicated that 2 wavebands, which are centred at approximately 300 nm (UVB) and 370 nm (upper UVA band), cause immunosuppression in humans [ 19 ], indicating that sunlight initiates multiple immunosuppressive signals. The skin is more than just a physical barrier, it also houses a variety of immune cells, including epidermal Langerhans cells (LCs), dermal dendritic cells and mast cells. Structural cells, such as epidermal keratinocytes and dermal fibroblasts, are an important source of cytokines and other inflammatory mediators. All of these cells are affected by UV exposure.
There are a number of cutaneous cellular and molecular targets of UV radiation. For example, trans-urocanic acid (UCA) is abundantly expressed in the stratum corneum. By acting as a UVB chromophore, trans-UCA is rapidly isomerised to the cis conformation, which is a potent immune suppressant. It has been shown that cis-UCA exerts its immunosuppressive properties by binding to the serotonin (5HT)-2a receptor. This is important for the development of UV-induced skin cancer because when this receptor is blocked with a 5HT2aR antagonist, both UV immunosuppression and carcinogenesis are prevented [ 20 ]. Another molecular target of UV radiation that leads to immunosuppression is DNA [ 21 ]. At the cellular level, due to their location in the upper layers of the skin, keratinocytes and epidermal LCs are direct targets of UV radiation. Indeed, UV not only damages the DNA of LCs, it also alters their morphology and antigen-presenting functions by down-regulating the surface expression of MHC class II, CD40, CD80 and CD86. Simultaneously, UV induces the local cutaneous production of immune-suppressive inflammatory mediators, such as prostaglandin E2 and platelet-activating factor (PAF). The release of tumour necrosis factor and interleukin (IL)-1β from keratinocytes is particularly important for triggering the UV-altered LCs to migrate out of the skin and travel to local lymph nodes. There, they activate immunoregulatory IL-4-producing natural killer T cells [ 22 ].
Using mice deficient in mast cells, Hart et al. have proven that dermal mast cells are critically required for UV-induced immunosuppression [ 23 ]. UV radiation signals the recruitment of mast cell progenitors from the blood into the skin, where, in response to the UV-altered cutaneous microenvironment, the newly recruited and resident mast cells assume a pro-tumourigenic, immunoregulatory phenotype [ 24 ]. A number of UV-induced factors can affect dermal mast cells, including IL-4, vitamin D 3 , IL-33 and PAF [ 25 ]. In response to these factors, mast cells produce immunosuppressive cytokines, such as IL-10, and pro-tumourigenic factors, such as VEGF [ 24 ]. However, these UV-triggered cutaneous events only partially explain how UV suppresses adaptive immune responses. The immune suppressive signal generated by UV is transmitted by CXCR4-expressing IL-10-producing dermal mast cells migrating from the skin to the lymph nodes. A UV-established CXCL12 chemokine gradient attracts the UV-altered mast cells to local skin-draining lymph nodes, where they affect the activation of T and B lymphocytes [ 26 , 27 ]. This migration event is required for both UV immunosuppression and skin cancer development because when it is blocked by a CXCR4 antagonist, both processes are prevented [ 28 ].
The ultimate outcome of events occurring in UV-exposed skin is the activation of antigen-specific regulatory lymphocytes. UV-induced T suppressor cells (now called regulatory T cells or T Regs ) were first identified in the early 1980s [ 17 ]. UV-T Regs have been relatively well described, and they express a wide variety of surface and intracellular markers that characterise them as suppressor cells, including CD4, CD25, CD62L, CD152 (CTLA-4), GITR, neuropilin-1, dectin-2 and the transcription factor FoxP3. UV-T Regs were traditionally thought to only be capable of suppressing the activation of naïve T cells; however, they can also be reprogrammed in vivo to suppress established immune responses [ 29 ]. The other type of regulatory lymphocyte induced by UV is an MHC II hi B220 hi regulatory B cell [ 29 ]. These ‘UV-B Regs ’ are activated by UV-induced PAF and 5HT and suppress the induction of immunity by producing large amounts of IL-10. The contributions that UV-T Regs and UV-B Regs make to UV carcinogenesis still remain to be determined.
UV-induced genetic damage and the suppression of anti-tumour immunity are both causative for skin cancer. Both of these processes appear to be important for the formation of pre-neoplastic AK and its progression to SCC. The precise genetic changes that are critical for the initiation and progression of these lesions are incompletely understood; however, there is some evidence that UV is likely to be involved at each of these steps. UV-induced TP53 mutations occur early in the development of AK, and then, mutations in BRM and PTCH1 , which may be UV-induced, are observed at later stages of progression to SCC. Increases in HRAS mutations also occur as AK progresses to SCC, and KRAS mutations, in addition to others, also develop as skin tumours progress.
The cascade of cellular and molecular events that lead to UV-induced genetic damage and immunosuppression is very complex and incompletely understood. Considerably more research is required to understand the DNA damage responses and the roles of specifically mutated genes in the initiation of the carcinogenesis cascade and progression to malignancy. It is highly likely that UV drives many of these events, and therefore, understanding the mechanisms involved will allow for the design of novel treatment options.
We would like to thank the National Health and Medical Research Council, the Cancer Council NSW (RG 14-14) and the Sydney Medical School Foundation for their financial support.
1 Agar NS, Halliday GM, Barnetson RS, Ananthaswamy HN, Wheeler M, Jones AM: The basal layer in human squamous tumors harbors more UVA than UVB fingerprint mutations: A role for UVA in human skin carcinogenesis. Proc Natl Acad Sci U S A 2004;101:4954-4959.
2 Lehmann AR, McGibbon D, Stefanini M: Xeroderma pigmentosum. Orphanet J Rare Dis 2011;6:70.

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