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J Eur Acad Dermatol Venereol.2024;00:124.| U I DE L I N E SEuropean consensus-based interdisciplinary guideline for diagnosis,treatment and prevention of actinic keratoses,epithelial UV-induced dysplasia and field cancerization on behalf of European Association of Dermato-Oncology,European Dermatology Forum,European Academy of Dermatology and Venereology and Union of Medical Specialists(Union Europenne des Mdecins Spcialistes)LidijaKandolf1|KettyPeris2,3|JosepMalvehy4|KlaraMosterd5,6|Markus V.Heppt7,8|Maria ConcettaFargnoli9|CarolaBerking7,8|PetrArenberger10|MatildaBylaite-Buinskiene11|Veroniquedel Marmol12|ThomasDirschka13,14|BrigitteDreno15|Ana-MariaForsea16|Catherine A.Harwood17|AxelHauschild18|Ida MarieHeerfordt19|RolandKauffman20|NicoleKellenersSmeeths5,6|AimiliosLallas21|CelesteLebbe22|UlrikeLeiter23|CaterinaLongo24|eljkoMijukovi1|GiovanniPellacani25|SusanaPuig4|PhilippeSaiag26|Mirnaitum27|EggertStockfleth28|CarmenSalavastru29|AlexanderStratigos30|IrisZalaudek31|ClausGarbe23|on behalf of European Association of Dermato-Oncology,European Dermatology Forum,European Academy of Dermatology and Venereology and Union of Medical Specialists(Union Europenne des Mdecins Spcialistes)Received:29 August 2023|Accepted:23 January 2024DOI:10.1111/jdv.19897 2024 European Academy of Dermatology and Venereology.For Affiliation refer page on 18CorrespondenceLidija Kandolf,Department of Dermatology,Faculty of Medicine,University of Defence,Military Medical Academy,Belgrade,Serbia.Email:AbstractA collaboration of multidisciplinary experts from the European Association of Dermato-Oncology,the European Dermatology Forum,the European Academy of Dermatology and Venereology,and the European Union of Medical Specialists was formed to develop European recommendations on AK diagnosis and treatment,based on current literature and expert consensus.This guideline addresses the epi-demiology,diagnostics,risk stratification and treatments in immunocompetent as well as immunosuppressed patients.Actinic keratoses(AK)are potential precursors of cutaneous squamous cell carcinoma(cSCC)and display typical histopathologic and immunohistochemical features of this malignancy in an early stage.They can develop into cSSC insitu and become invasive in a low percentage of cases.AK is the most frequent neoplasia in white populations,frequently occurring within a cancer-ous field induced by ultraviolet radiation.Since it cannot be predicted,which lesion will progress to cSCC and when treatment is usually recommended.The diagnosis of 2|EUROPEAN GUIDELINE FOR TREATMENT OF AKINTRODUCTIONSocieties in chargeThis guideline was developed on behalf of the European Dermatology Forum(EDF).The European Association of Dermato-Oncology(EADO)coordinated the authors con-tributions as part of its Guideline Program in Oncology(GPO).The editors and coordinators responsible for the formulation of the guideline were Lidija Kandolf,Claus Garbe,Josep Malvehy,Klara Mosterd,Maria Concetta Fargnoli,Markus Heppt and Carola Berking.To ensure the interdisciplinary quality of the guidelines,they were developed in cooperation with the European Dermatology Forum(EDF)and the European Union of Medical Specialists(Union Europenne des Mdecins Spcialistes,UEMS).DisclaimerAll statements related to the definition,classification,diag-nosis and treatment of actinic keratosis(AK)correspond to the current scientific knowledge,based on the data from the literature available at the time of printing the guidelines.The attending physician invoking these guideline recom-mendations must consider scientific progress since the pub-lication of the guideline.The user remains responsible for all diagnostic and therapeutic applications,medications and doses.Just as adherence to the guidelines may not con-stitute defence against a claim of negligence(malpractice),deviation from them should not necessarily be deemed negligent.These guidelines will require updating approxi-mately every 2 years but advances in medical sciences may demand an earlier update.Registered trademarks(pro-tected product names)are not specified in these guidelines.This work is protected by copyrights in all its parts.Any utilization outside the provision of the copyright act with-out the written permission by the GPO of the EADO is pro-hibited and punishable by law.No part of this work may be reproduced in any way without written permission by the GPO.This applies to duplications,translations,microfilm-ing and the storage,application and utilization in electronic systems,intranets and Internet.ScopeThis guideline was developed to assist clinicians in diagnos-ing and treating patients with epithelial dysplasia,including AK.In recent years,significant rise of incidence of keratino-cyte cancers is evident,leading to the increased burden on the society.Also,advances were made in understanding of keratinocyte dysplasia,and the concept of field cancerization was introduced and adopted by the dermatology commu-nity.Different classification schemes of epithelial dysplasia and AK were developed to guide the treatment approach in everyday practice.New insights in the efficacy and safety of different topical treatments and destructive methods for this condition were also developed.It is recognized by the sci-entific community that these conditions should be treated and monitored to prevent the transformation to invasive cutaneous squamous cell carcinoma.Thus,the use of these guidelines that incorporate the updated scientific knowledge in the field of definition,diagnosis and treatment of epithe-lial dysplasia,AK and field cancerization in clinical routine should improve patient care.Target populationThe guidelines have been prepared for the clinicians who take care of the patients with AK and keratinocyte carcino-mas in general.These are mainly dermatologists.Objectives and formulation of questionsThe guidelines have been developed and organized in clear sections,based on the latest data from the literature,to sup-port clinicians in finding the answers to questions relevant to the everyday practice on:(a)definition of AK and field cancerization and their relation to cutaneous squamous cell carcinoma(cSSC);(b)epidemiology and pathophysiology;(c)which examinations methods are reliable for diagnosis and do we need histopathologic confirmation?(d)is there a rationale for early treatment of AK and which patient should receive which treatment?(e)how we should follow-up pa-tients with AK and(f)what preventive measure can be ad-vised to the patients?AK and field cancerization is made by clinical examination.Dermatoscopy,confocal microscopy,optical coherence tomography or line-field confocal-OCT can help in the differential diagnosis of AK and other skin neoplasms.A biopsy is indicated in clinically and/or dermatoscopically suspicious and/or treatment-refractory lesions.The choice of treatment depends on patients and lesion characteristics.For single non-hyperkeratotic lesions,the treatment can be started upon patients request with destructive treatments or topical treatments.For multiple lesions,field cancerization treatment is advised with topical treatments and photodynamic therapy.Preventive measures such as sun protection,self-examination and repeated field cancerization treatments of previously affected skin areas in high-risk patients are advised.|3KANDOLF etal.Principles of methodologyThe literature search was carried out by the authors using PubMed,and only articles published until September 2022 were included.Search strings were used,which cannot all be listed here.In principle,the search strings are constructed in such a way that the search is primarily carried out in the titles and abstracts of the publication,including the terms AK,keratinocyte dysplasia,field cancerization,preven-tion,diagnosis and treatment.All diagnostic and treatment recommendations summarized in the respective tables are evaluated on the basis of evidence-based data or formulated as expert consensus if no sufficient evidence is available.The methodology of these updated guidelines is based on the standards of the AGREE II instrument.1 The levels of evidence are graded according to the Oxford classification(Table1).2The grades of recommendation were classified as follows:A:Strong recommendation.Syntax:shall.B:Recommendation.Syntax:should.C:Weak recommendation.Syntax:may/can.X:Should not be recommended.0:Recommendation pending.Currently not available or not sufficient evidence to make a recommendation in fa-vour or against.An expert consensus was presented,where there was in-sufficient evidence.Source guidelinesSource guidelines for guideline adaptation of recommenda-tions was the German S3 guideline on actinic keratosis and the American Academy of Dermatology guidelines on ac-tinic keratosis,3-5 since previously published guidelines ex-pired(i.e.published 5 or more years ago).Consensus building processThe consensus building process was conducted as follows:In a first-round,medical experts who participated in their national guideline development processes were involved in producing an initial draft.A consensus meeting was held in Rome,Italy,on 24 and 25 November with final outcomes:(1)the approval of the text and(2)a consensus rate of agreement of at least 80%,for recommendations provided in structured boxes and the figure.Voting of the recom-mendations included the selection of Agree,Disagree or Abstential vote,and the possibility of providing com-ments in case of disagree/abstential.The consensus vote on the recommendations and the finalization of the draft were conducted among coauthors by email between 1 and 24 December 2022.FinancingThe authors did this work on a voluntary basis and did not receive any honorarium.Travel costs for participation in Consensus Conferences were paid by the authors them-selves.Accommodation during the Consensus Conferences was reimbursed in part by EADO.DEFINITION,EPIDEMIOLOGY,AETIOLOGY AND DIAGNOSISDefinitionActinic keratosis(AK)is a common cutaneous keratinocyte dysplasia characterized by the abnormal proliferation of atypical epidermal keratinocytes(keratinocyte intraepider-mal neoplasia(KIN).In World Health Organization(WHO)classification of skin tumours,it is listed as a carcinoma pre-cursor.6 Multiple terms have been used in the literature to define this lesion including solar keratosis,senile keratosis,keratosis senilis,senile keratoma,keratoma senile7 and in situ SCC type AK.8 AK is either considered as a precancerous lesion that may possibly transform into invasive SCC(iSCC),or as insitu SCC(intraepidermal proliferation of atypical keratinocytes)that may progress to an invasive stage.This concept is based on the fact that AK is cytologically indistin-guishable from insitu SCC and has a number of molecular alterations common to SCC.9,10 The term insitu SCC should be used with caution with patients,because the term carci-noma is associated with morbidity that does not correspond to the clinical diagnosis since AKs in most cases do not trans-form into an iSCC.However,it should be communicated to patients that currently it is not possible to predict the progres-sion of single AK lesions to invasive cSCC(Table2).Concept of field cancerizationField cancerization is defined as an area of subclinical changes in the periphery of clinically visible AKs that displays genetic changes similar to those found in AK lesions.11,12 Clinically,a definition of field cancerization has been established by expert opinion consensus and systematic review has been stated as the anatomical area with or adjacent to AK and visibly sun-damaged skin characterized by at least two of the following signs:telangiectasia,atrophy,pigmentation abnormalities and a sandpaper like texture.It is unclear whether a visible AK le-sion is required for field cancerization13(Table2).PathophysiologyAKs result from excessive chronic sun exposure and are located mainly on areas with chronically sun-damaged 4|EUROPEAN GUIDELINE FOR TREATMENT OF AKTABLE 1 Oxford centre for evidence-based medicine 2011 level of evidence.QuestionStep 1(level 1a)Step 2(level 2a)Step 3(level 3a)Step 4(level 4a)Step 5(level 5)How common is the problem?Local and current random sample surveys(or censuses)Systematic review of surveys that allow matching to local circumstancesbLocal non-random samplebCase-seriesbN/AIs this diagnostic or monitoring test accurate?(Diagnosis)Systematic review of cross-sectional studies with consistently applied reference standard and blindingIndividual cross-sectional studies with consistently applied reference standard and blindingNon-consecutive studies,or studies without consistently applied reference standardsbCasecontrol studies,or poor or non-independent reference standardbMechanism-based reasoningWhat will happen if we do not add a therapy?(Prognosis)Systematic review of inception cohort studiesInception cohort studiesCohort study or control arm of randomized trialaCase-series or casecontrol studies,or poor-quality prognostic cohort studybN/ADoes this intervention help?(Treatment benefits)Systematic review of randomized trials or n-of-1 trialsRandomized trial or observational study with dramatic effectNon-randomized controlled cohort/follow-up studybCase-series,casecontrol studies or historically controlled studiesbMechanism-based reasoningWhat are the COMMON harms?(Treatment harms)Systematic review of randomized trials,systematic review of nested casecontrol studies,n-of-1 trial with the patient you are raising the question about,or observational study with dramatic effectIndividual randomized trial or(exceptionally)observational study with dramatic effectNon-randomized controlled cohort/follow-up study(post-marketing surveillance)provided there are sufficient numbers to rule out a common harm.(For long-term harms the duration of follow-up must be sufficient)bCase-series,casecontrol,or historically controlled studiesbMechanism-based reasoningWhat are the RARE harms?(Treatment harms)Systematic review of randomized trials or n-of-1 trialRandomized trial or(exceptionally)observational study with dramatic effectIs this(early detection)test worthwhile?(Screening)Systematic review of randomized trialsRandomized trialNon-randomized controlled cohort/follow-up studybCase-series,casecontrol,or historically controlled studiesbMechanism-based reasoningaLevel may be graded down on the basis of study quality,imprecision,indirectness(study PICO does not match questions PICO),because of inconsistency between studies,or because the absolute effect size is very small;Level may be graded up if there is a large or very large effect size.bAs always,a systematic review is generally better than an individual study.|5KANDOLF etal.skin.14-16 UVB radiation can induce mutations and deregu-lation of tumour suppressor proteins such as p53,p16INK4a and PTEN that are considered a crucial molecular mecha-nism in the development of AK and cSCC.10,17,18 UV radiation and infections with human papillomavi
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