AK GUIDELINES PDF

Received: 29 August 2023 | Accepted: 23 January 2024 DOI: 10.1111/jdv.19897 GUIDELINES European consensus-­based interdisciplinary guideline for diagnosis, treatment and prevention of actinic keratoses, epithelial UV-­induced dysplasia and field cancerization on behalf of European Associatio...

Received: 29 August 2023 | Accepted: 23 January 2024 DOI: 10.1111/jdv.19897 GUIDELINES European 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 Européenne des Médecins Spécialistes) Lidija Kandolf1 | Ketty Peris2,3 | Josep Malvehy4 | Klara Mosterd5,6 | 7,8 9 7,8 Markus V. Heppt | Maria Concetta Fargnoli | Carola Berking | Petr Arenberger10 | Matilda Bylaite-­Bučinskiene11 | Veronique del Marmol12 | Thomas Dirschka13,14 | Brigitte Dreno15 | Ana-­Maria Forsea16 | Catherine A. Harwood17 | Axel Hauschild18 | Ida Marie Heerfordt19 | Roland Kauffman20 | Nicole Kelleners Smeeths5,6 | Aimilios Lallas21 | Celeste Lebbe22 | Ulrike Leiter23 | Caterina Longo24 | 1 25 4 26 Željko Mijušković | Giovanni Pellacani | Susana Puig | Philippe Saiag | 27 28 29 30 Mirna Šitum | Eggert Stockfleth | Carmen Salavastru | Alexander Stratigos | 31 23 Iris Zalaudek | Claus Garbe | on behalf of European Association of Dermato-­Oncology, European Dermatology Forum, European Academy of Dermatology and Venereology and Union of Medical Specialists (Union Européenne des Médecins Spécialistes) Correspondence Lidija Kandolf, Department of Dermatology, Abstract Faculty of Medicine, University of Defence, A collaboration of multidisciplinary experts from the European Association of Military Medical Academy, Belgrade, Serbia. Email: [email protected] 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 in situ 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 For Affiliation refer page on 18 © 2024 European Academy of Dermatology and Venereology. J Eur Acad Dermatol Venereol. 2024;00:1–24.  wileyonlinelibrary.com/journal/jdv | 1  14683083, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jdv.19897 by Gerardo Palmisano - University Cattolica, Piacenza , Wiley Online Library on [21/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 2 |    EUROPEAN GUIDELINE FOR TREATMENT OF AK 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 patient's 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. I N T RODUC T ION Scope Societies in charge This guideline was developed to assist clinicians in diagnos- ing and treating patients with epithelial dysplasia, including This guideline was developed on behalf of the European AK. In recent years, significant rise of incidence of keratino- Dermatology Forum (EDF). The European Association of cyte cancers is evident, leading to the increased burden on Dermato-­Oncology (EADO) coordinated the authors' con- the society. Also, advances were made in understanding of tributions as part of its Guideline Program in Oncology keratinocyte dysplasia, and the concept of field cancerization (GPO). The editors and coordinators responsible for the was introduced and adopted by the dermatology commu- formulation of the guideline were Lidija Kandolf, Claus nity. Different classification schemes of epithelial dysplasia Garbe, Josep Malvehy, Klara Mosterd, Maria Concetta and AK were developed to guide the treatment approach in Fargnoli, Markus Heppt and Carola Berking. To ensure everyday practice. New insights in the efficacy and safety of the interdisciplinary quality of the guidelines, they were different topical treatments and destructive methods for this developed in cooperation with the European Dermatology condition were also developed. It is recognized by the sci- Forum (EDF) and the European Union of Medical entific community that these conditions should be treated Specialists (Union Européenne des Médecins Spécialistes, and monitored to prevent the transformation to invasive UEMS). 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- Disclaimer lial dysplasia, AK and field cancerization in clinical routine should improve patient care. All 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 Target population literature available at the time of printing the guidelines. The attending physician invoking these guideline recom- The guidelines have been prepared for the clinicians who mendations must consider scientific progress since the pub- take care of the patients with AK and keratinocyte carcino- lication of the guideline. The user remains responsible for mas in general. These are mainly dermatologists. 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), Objectives and formulation of questions deviation from them should not necessarily be deemed negligent. These guidelines will require updating approxi- The guidelines have been developed and organized in clear mately every 2 years but advances in medical sciences may sections, based on the latest data from the literature, to sup- demand an earlier update. Registered trademarks (pro- port clinicians in finding the answers to questions relevant tected product names) are not specified in these guidelines. to the everyday practice on: (a) definition of AK and field This work is protected by copyrights in all its parts. Any cancerization and their relation to cutaneous squamous cell utilization outside the provision of the copyright act with- carcinoma (cSSC); (b) epidemiology and pathophysiology; out the written permission by the GPO of the EADO is pro- (c) which examinations methods are reliable for diagnosis hibited and punishable by law. No part of this work may be and do we need histopathologic confirmation? (d) is there a reproduced in any way without written permission by the rationale for early treatment of AK and which patient should GPO. This applies to duplications, translations, microfilm- receive which treatment? (e) how we should follow-­up pa- ing and the storage, application and utilization in electronic tients with AK and (f) what preventive measure can be ad- systems, intranets and Internet. vised to the patients?  14683083, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jdv.19897 by Gerardo Palmisano - University Cattolica, Piacenza , Wiley Online Library on [21/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License KANDOLF et al.     | 3 Principles of methodology Financing The literature search was carried out by the authors using The authors did this work on a voluntary basis and did PubMed, and only articles published until September 2022 not receive any honorarium. Travel costs for participation were included. Search strings were used, which cannot all be in Consensus Conferences were paid by the authors them- listed here. In principle, the search strings are constructed selves. Accommodation during the Consensus Conferences in such a way that the search is primarily carried out in the was reimbursed in part by EADO. titles and abstracts of the publication, including the terms AK, keratinocyte dysplasia, field cancerization, preven- tion, diagnosis and treatment. All diagnostic and treatment DE F I N I T ION, E PI DE M IOL OGY, recommendations summarized in the respective tables are A ET IOL OGY A N D DI AGNOSIS evaluated on the basis of evidence-­based data or formulated as expert consensus if no sufficient evidence is available. Definition The methodology of these updated guidelines is based on the standards of the AGREE II instrument.1 The levels of Actinic keratosis (AK) is a common cutaneous keratinocyte evidence are graded according to the Oxford classification dysplasia characterized by the abnormal proliferation of (Table 1).2 atypical epidermal keratinocytes (keratinocyte intraepider- The grades of recommendation were classified as follows: mal neoplasia (KIN)). In World Health Organization (WHO) classification of skin tumours, it is listed as a carcinoma pre- A: Strong recommendation. Syntax: ‘shall’. cursor.6 Multiple terms have been used in the literature to B: Recommendation. Syntax: ‘should’. define this lesion including ‘solar keratosis’, ‘senile keratosis’, C: Weak recommendation. Syntax: ‘may/can’. ‘keratosis senilis’, ‘senile keratoma’, ‘keratoma senile’7 and ‘in X: Should not be recommended. situ SCC type AK’.8 AK is either considered as a precancerous 0: Recommendation pending. Currently not available or lesion that may possibly ‘transform’ into invasive SCC (iSCC), not sufficient evidence to make a recommendation in fa- or as in situ SCC (intraepidermal proliferation of atypical vour or against. keratinocytes) that may progress to an invasive stage. This An expert consensus was presented, where there was in- concept is based on the fact that AK is cytologically indistin- sufficient evidence. guishable from in situ SCC and has a number of molecular alterations common to SCC.9,10 The term in situ SCC should be used with caution with patients, because the term ‘carci- Source guidelines noma’ is associated with morbidity that does not correspond to the clinical diagnosis since AKs in most cases do not trans- Source guidelines for guideline adaptation of recommenda- form into an iSCC. However, it should be communicated to tions was the German S3 guideline on actinic keratosis and patients that currently it is not possible to predict the progres- the American Academy of Dermatology guidelines on ac- sion of single AK lesions to invasive cSCC (Table 2). tinic keratosis,3-­5 since previously published guidelines ex- pired (i.e. published 5 or more years ago). Concept of field cancerization Consensus building process Field cancerization is defined as an area of subclinical changes in the periphery of clinically visible AKs that displays genetic The consensus building process was conducted as follows: changes similar to those found in AK lesions.11,12 Clinically, a In a first-­round, medical experts who participated in their definition of field cancerization has been established by expert national guideline development processes were involved in opinion consensus and systematic review has been stated as producing an initial draft. A consensus meeting was held in ‘the anatomical area with or adjacent to AK and visibly sun-­ Rome, Italy, on 24 and 25 November with final outcomes: damaged skin characterized by at least two of the following (1) the approval of the text and (2) a consensus rate of signs: telangiectasia, atrophy, pigmentation abnormalities and agreement of at least 80%, for recommendations provided a sandpaper like texture’. It is unclear whether a visible AK le- in structured boxes and the figure. Voting of the recom- sion is required for field cancerization13 (Table 2). 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 Pathophysiology on the recommendations and the finalization of the draft were conducted among coauthors by email between 1 and AKs result from excessive chronic sun exposure and are 24 December 2022. located mainly on areas with chronically sun-­damaged  4 |    TA BL E 1 Oxford centre for evidence-­based medicine 2011 level of evidence. Question Step 1 (level 1a) Step 2 (level 2a) Step 3 (level 3a) Step 4 (level 4a) Step 5 (level 5) b b How common is the problem? Local and current random Systematic review of surveys Local non-­random sample Case-­series N/A sample surveys (or that allow matching to local censuses) circumstancesb Is this diagnostic or monitoring Systematic review of cross-­ Individual cross-­sectional Non-­consecutive studies, or studies Case–control studies, or poor or Mechanism-­based test accurate? (Diagnosis) sectional studies with studies with consistently without consistently applied non-­independent reference reasoning consistently applied applied reference standard reference standardsb standardb reference standard and and blinding blinding What will happen if we do not Systematic review of inception Inception cohort studies Cohort study or control arm of Case-­series or case–control N/A add a therapy? (Prognosis) cohort studies randomized triala studies, or poor-­quality prognostic cohort studyb Does this intervention help? Systematic review of Randomized trial or Non-­randomized controlled cohort/ Case-­series, case–control studies Mechanism-­based (Treatment benefits) randomized trials or n-­of-­1 observational study with follow-­up studyb or historically controlled reasoning trials dramatic effect studiesb What are the COMMON harms? Systematic review of Individual randomized Non-­randomized controlled cohort/ Case-­series, case–control, or Mechanism-­based (Treatment harms) randomized trials, trial or (exceptionally) follow-­up study (post-­marketing historically controlled studiesb reasoning systematic review of nested observational study with surveillance) provided there are case–control studies, n-­ dramatic effect sufficient numbers to rule out a of-­1 trial with the patient common harm. (For long-­term you are raising the question harms the duration of follow-­up about, or observational must be sufficient)b study with dramatic effect What are the RARE harms? Systematic review of Randomized trial or EUROPEAN GUIDELINE FOR TREATMENT OF AK (Treatment harms) randomized trials or n-­of-­1 (exceptionally) trial observational study with dramatic effect Is this (early detection) test Systematic review of Randomized trial Non-­randomized controlled cohort/ Case-­series, case–control, or Mechanism-­based worthwhile? (Screening) randomized trials follow-­up studyb historically controlled studiesb reasoning a Level 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. b As always, a systematic review is generally better than an individual study. 14683083, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jdv.19897 by Gerardo Palmisano - University Cattolica, Piacenza , Wiley Online Library on [21/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License  14683083, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jdv.19897 by Gerardo Palmisano - University Cattolica, Piacenza , Wiley Online Library on [21/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License KANDOLF et al.     | 5 TA BL E 2 Definitions of actinic keratosis and field cancerization. epidemiological data are scarce and often marred by numerous Definitions of biases. Prevalence varies greatly across countries, depending AK and field on study setting, UV radiation level and patient characteris- cancerization Consensus-­based statement tics.29 In the UK, 15.4% of males and 5.9% of females have AK GCP AK is a precancerous lesion that may progress into lesions, while in those older than 70 years, the prevalence in- invasive SCC. Actinic keratosis shall be used as creases to 34% of whites over 70 years.30 In Australia, up to 60% the preferred term in clinical practice8,9 An area of field cancerization is defined as an area of people over 40 years old have AK.31 In Spain, AK prevalence of subclinical changes in the periphery of visible was observed in 28.6% of the population over 45 years, with AKs that displays genetic changes similar to higher rates in men than women.32 In Italy, AK prevalence was those found in AKs11,12 27.4% and in Switzerland 25.3%.33-­35 Higher rates in men than Expert consensus Strength of recommendation: 100% in women were also observed in all epidemiologic studies in Germany, the overall prevalence of AK was 2.66%, with rates higher in men than in women, and prevalence increasing with skin.14-­16 UVB radiation can induce mutations and deregu- age, with the highest rates observed in the 61–70 age group.28 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 Risk factors for AK and infections with human papillomaviruses (HPV) may act as cofactors in the development of AK, although the role of A meta-­analysis, including mainly European studies, inves- HPV is still controversial.19-­25 Immunosuppression increases tigated risk factors in immunocompetent individuals.23,29 the risk of cancers that are associated with viral infection. In Factors associated with an increased risk of AK were male sex, particular, the risk of cSCC which has been associated with age >45 years, fair skin type, light hair colour, light eye colour, beta HPV infection is increased by more than 100-­fold in im- freckles on face/arms, positive history of non-­melanoma skin munosuppressed patients.22-­24 In a systematic review, 58.5% cancer (NMSC), sunburns in childhood and adulthood, se- of AKs were positive for beta HPV, 40.2% for gamma HPV vere sunburn, chronic occupational and/or recreational sun and only a few were positive for alpha subtypes.24 However, exposure, baldness, and use of potentially photosensitizing it has been found that T-­cell immunity against commensal thiazide diuretics or other photosensitizing cardiac drugs. On papillomaviruses suppresses skin cancer in immunocompe- the contrary, factors associated with a reduced risk of AK were tent hosts, and the loss of this immunity rather than the on- sunscreen use and history of atopy. No association was found cogenic effect of HPVs may contribute to causes the markedly between patients' education level and the risk of AK, abnormal increased risk of cSCC in immunosuppressed patients.25 body mass index, alcohol consumption and smoking status. Sensitivity analysis yielded consistent results. IRF4, MC1R and TYR genes, that are involved in various kinds of human pig- Development of AK towards cSCC mentation traits as well as in skin cancers, were identified as significant risk factors for AK in the north-­western European AKs may undergo spontaneous regression, remain stable study population.33 Chronically immunosuppressed patients or further progress to invasive malignancy. It has been sug- especially organ transplant recipients (OTRs) have a higher risk gested that invasive cSCC may develop in two ways: (1) by for developing AK and SCC.36 In OTRs, the prevalence of pa- transformation of a clinically pre-­existing individual AK or tients with AKs increases with longer duration of immunosup- (2) de novo, from a subclinical UV-­damaged single cell in a pression.37 A recent study showed that the variability of AKs in field of cancerization. The first way seems to occur in 0.1%– a 12-­month period was associated with an increased risk of SCC 16% in clinically pre-­existing AKs, based on the data about in OTRs.38 In another study, presence of AK patches and their the risk of malignant transformation of a single actinic kera- number, as well as the number of AKs and area affected by AKs, tosis.26 The second pathway is based on field changes which was predictive of SCC development in OTR.39 Genetic skin dis- can be detected in about 80% of histopathologically exam- eases associated with impaired DNA repair mechanisms and ined cSCC.27 A meta-­analysis found progression rates of disorders with a deficient melanin biosynthesis are associated AKs to SCC varying from 0% to 0.075% per lesion-­year, with with a higher risk for the development of AK.40,41 a risk of up to 0.53% per lesion-­year in patients with prior history of keratinocyte cancer (NMSC).28 Rates of regression of single lesions ranged between 15% and 63% after 1 year, C L I N IC A L A N D NON-­I N VA SI V E with a recurrence rate of 15%–53% after 1 year follow-­up.28 DI AGNOSIS OF A K s Clinical features Epidemiology AKs typically manifest as rough, scaly skin coloured to red Since AK are not included in cancer databases or population-­ light or dark brown patches, papules or plaques commonly based incidence rates and AKs are often not biopsied, located on chronically sun-­damage body sites. The diameter  14683083, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jdv.19897 by Gerardo Palmisano - University Cattolica, Piacenza , Wiley Online Library on [21/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 6 |    EUROPEAN GUIDELINE FOR TREATMENT OF AK of AKs generally ranges from a few millimetres to several pattern (grade 1), a ‘strawberry pattern’, namely background centimetres.42 The clinical features along with the typical an- erythema interrupted by white-­coloured follicular openings atomical site allow a correct clinical diagnosis in most cases, that might be filled with keratin plugs (grade 2), or structure- although the differential diagnosis with basal cell carcinoma less white to yellow areas (grade 3).53,54 Dermatoscopy may (BCC) and inflammatory disorders may be sometimes chal- help to differentiate solitary AK grade III (with structure- lenging. Also, lichenoid keratosis (i.e. lichen-­ planus like less yellow and white colour and erythema with strawberry keratosis) and Bowen disease have to be considered in dif- pattern, focally) and Bowen's disease (with coiled vessels). ferential diagnosis, particularly in solitary lesions. Clinical Moreover, dermatoscopy can aid in the assessment of treat- variants include pigmented, Bowenoid and lichenoid AK.43 ment response and in the differential diagnosis of AK. In the While the latter two are usually diagnosed on histopatho- cases of pigmented AK, dermatoscopy may help to rule out logic examination, pigmented AK is commonly present in lentigo maligna44,55 based on the presence of enlarged white sun-­damaged skin, and therefore, differential diagnosis may follicular openings, double lines between the hair follicles, include lentigo maligna. The number and location of lesions, background erythema and scaly surface in AKs. In AKs lo- similar morphology using the comparative approach and cated on non-­facial skin, the follicular openings are less pre- rough surface on palpation represent important clues for the dominant and dermatoscopy mainly reveals erythema and diagnosis of AK.44,45 Clinical signs suggesting progression to superficial scales. Dermatoscopy can also help to identify iSCC (iSCC) include lesion induration, bleeding, discomfort, early signs of iSCC due to the presence of coiled/glomerular pain and increase in thickness and diameter.43 AKs seldom or polymorphous vessels and white circles, which are rarely appear as a solitary lesion; indeed, often an entire region is observed in AK.54 affected. Individual AK lesions have been clinically graded based on their thickness using the Olsen classification sys- tem.46 Grade 1 lesions are slightly palpable, more easily felt Confocal microscopy and optical coherence than seen, grade 2 lesions are moderately thick and easily tomography (OCT) (Table 4) seen and felt, and grade 3 lesions are very thick and hyper- keratotic. This severity index was combined with the count- In combination with clinical examination and dermatos- ing of lesions in a limited area for the assessment of clinical copy, reflectance confocal microscopy (RCM) and optical trials. However, counting individual lesions is not reproduc- coherence tomography (OCT) can help in the differential ible even among experts.47 Although the Olsen classification diagnosis of AK and SCC, pigmented AK and lentigo ma- failed to reliably correlate with the histological severity of ligna. The superficial orientation in the epidermis makes the lesions, it has been shown to be strongly correlated with AK suitable for non-­invasive imaging tools, but on the other the risk of cSCC development in a recent study.48 Other clin- hand, the presence of hyperkeratotic scale may impair image ical severity indexes have been proposed considering the en- resolution and diagnostic accuracy. RCM and OCT have tire area affected by AKs.49-­51 Additionally, a recent practice also been extensively applied to monitor treatment efficacy related approach classified AK based on the overall burden of AKs.56-­60 The RCM terms that describe better diagnostic of disease into the following categories52: (1) single AK (less features of AK include hyperkeratosis, parakeratosis, scale than 5 AKs in a defined field), (2) multiple AKs (6+ lesions in and atypical honeycombed pattern, architectural disarray a defined field), (3) field cancerization (6+ lesions associated and targetoid cells.61-­63 with sun-­damaged skin and hyperkeratosis) and (4) AKs as- sociated with immunosuppression. Line-­field confocal optical coherence tomography (LC-­OCT) Dermatoscopy (Table 3) LC-­OCT in vertical and horizontal sections of the lesions Dermatoscopy improves the clinical diagnosis of AK and has have been used in to identify AKs criteria that include an out- been reported to achieve a diagnostic sensitivity and speci- lined dermo-­epidermal junction without broad strands.64,65 ficity of 98.7% and 95.0%, respectively. Depending on the LC-­OCT has also correlated with histological images to clinical aspects, dermatoscopy reveals either a red network evaluate the proliferative pattern of AK that has been associ- ated with resistant to treat AK and the risk of progression.66 TA BL E 3 Clinical and dermatoscopic diagnosis of actinic keratosis. TA BL E 4 Other non-­invasive imaging for actinic keratosis. Consensus-­based statement Consensus-­based statement Grade of The diagnosis of actinic keratosis and recommendation: B field cancerization is made by clinical GCP Confocal microscopy, OCT and LC-­OCT examination. Dermatoscopy can help can help in the differential diagnosis in the differential diagnosis of actinic of actinic keratosis and other skin keratosis and other skin neoplasms neoplasms Level of evidence: 1 Strength of consensus: 100% Strength of consensus: 100%  14683083, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jdv.19897 by Gerardo Palmisano - University Cattolica, Piacenza , Wiley Online Library on [21/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License KANDOLF et al.     | 7 H ISTOPAT HOL OGIC DI AGNOSIS papillary dermis and forming round nests of atypical ke- ratinocytes; Pro III (papillary sprouting) to spiky or filiform Histopathologic confirmation papillary elongation of atypical keratinocytes protruding into upper dermis and exceeding the thickness of the over- Histopathological confirmation is recommended to an lying epidermis.69,70 Interestingly, proliferative AKs are not equivocal lesions especially in the differential diagnosis of correlated with Olsen grade or KIN criteria. cutaneous SCC (cSCC) or BCC (Table 5). Also, for type III AK and bowenoid AK, differential diagnosis with Bowen's disease can be difficult. The presence of basal cells in pali- TR EATMENT OF ACTINIC K ER ATOSES sades along the basement membrane and the dysplasia of the adnexal and follicular epithelium, which is present in BD Rationale for treatment and absent in AK, can help in differentiating these two enti- ties.67 A skin biopsy should be taken if one or more of the The most important reason for treatment of AK is to prevent following clinical features are present which may indicate the transformation to invasive cSCC.52 The risk of progres- cSCC or other types of skin cancer: infiltration, induration, sion varies from 0.025% to 20% per year and is significantly ulceration, pigmentation, rapid enlargement and pain.68 A higher in immunosuppressed patients, such as solid organ biopsy should also be considered if coiled, dotted, hairpin transplant recipients.71 Furthermore, if the patient has had or polymorphous vessels and/or white circles or whitish ho- previous cSCC in the field, the risk for developing the sec- mogeneous areas are detected on dermatoscopy or if inva- ond cSCC is 40.7% at 5 years.72 As there is currently no way sion is suspected on RCM, OCT and LC-­OCT. According to accurately predict which lesion will develop into cSCC to their clinico-­pathological appearance, various types of or when this might occur, treatment is recommended. AK have been described, including pigmented, atrophic, Treatment of AK can be lesion-­directed or field-­directed. bowenoid, lichenoid, acantholytic and hyperkeratotic AKs. Lesion-­directed treatments target individual AKs, whereas The Rowert–Hubert histological classification has been sug- field-­directed treatments have the advantage of treating gested to assess the severity degree of single AK lesions52: multiple, widespread and subclinical AKs that may occur (1) early in situ cSCC, type AK I corresponds to atypical within a field of chronically sun-­damaged skin, commonly keratinocytes in the basal and supra-­basal layers (the lower referred to as field cancerization.73 Field-­ directed treat- third) of the epidermis; (2) early in situ cSCC, type AK II is ments are nowadays the focus of AK treatment as most of constituted by atypical keratinocytes extending to the lower them are convenient, can be self-­administrated and most two-­thirds of the epidermis; (3) in situ cSCC, type AK III importantly they target subclinical damage. Weinstock consists of atypical keratinocytes extending to more than et al.74 found that field treatment with 5-­f luorouracil (5-­FU) two-­thirds of the full thickness of the epidermis. The clas- reduced the risk of cSCC compared to placebo after 1 year in sification was suggested to predict the risk of AK to progress patients with severe AKs and a history of at least two cSCCs: to cSCC. However, in a recent study it was demonstrated 1% of patients treated with 5-­FU developed a cSCC, com- that AK I are the most frequent lesions associated to cSCC pared to 4% in the placebo group. In another study, the total (so-­called differentiated pattern) and that Rowert–Hubert 4-­year risk of developing cSCC in a field treated area of AK classification cannot predict the transformation of AKs.27 was 3.7%, but significantly increased to 20.9% in patients Additional evidence suggests that hair follicles may contrib- with Olsen grade III AK and to 33.5% in patients with Olsen ute significantly to the development of deeply invasive SCC grade II AK patients with an indication for retreatment.48 and that the depth of follicular extension in AK correlates Thus, for multiple severe AKs with a history of previous with the depth of invasion of an associated iSCC.13,27 Based cSCC, field treatment and retreatments are highly recom- on these and other findings from the recent studies, the PRO mended. For mild AKs (Olsen grade I), field treatment can classification of AKs was suggested, which is based on the also be recommended, but well-­instructed self-­examination histological growth pattern. The histological growth pattern can be considered. of AKs appeared to be associated to treatment resistance and Field-­directed treatments are not suitable for all patients. progression to invasive cSCC. Pro I (basal-­growth pattern) The long duration of treatment can impact adherence, and corresponds to crowding of basal atypical keratinocytes; they may cause unwanted cosmetic effects. In some patients, Pro II to budding of atypical keratinocytes into the upper lesion-­directed treatments are preferred, as they have the benefit of being performed under the supervision of a phy- TA BL E 5 Biopsy and histopathological examination. sician and are less time-­consuming. Lesion-­directed treat- ments commonly involve ablative procedures as surgery Consensus-­based statement (shave, excision), cryosurgery/cryotherapy and laser therapy. GCP Biopsy is not routinely required for the diagnosis of actinic Surgical treatments are usually reserved for AKs that are keratosis unresponsive to other treatments and in cases of uncertain Biopsy shall be done in clinically and/or dermatoscopically diagnosis.75 suspicious and/or treatment-­refractory lesions There is no standard treatment for AKs, and physicians Strength of consensus: 100% should make decisions considering both lesion (number, PIGMENTATA LICHENOIDE ATROFICA ACANTOLITICA BOWENOIDE IPERCHERATOSICA  14683083, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jdv.19897 by Gerardo Palmisano - University Cattolica, Piacenza , Wiley Online Library on [21/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 8 |    EUROPEAN GUIDELINE FOR TREATMENT OF AK location, histology) and patient characteristics (age, com- Cryotherapy (Table 8) pliance, immune status).76 Also, treatment decisions should be made in a patient–physician shared decision process Cryosurgery, or cryotherapy, is a lesion-­directed treatment, (Table 6). with a focus on treating a single or a limited number of AKs. This procedure is considered to be a standard initial first-­ line treatment in patients with a limited number of AKs,81 Surgical procedures (Table 7) as it is easy to perform and time-­efficient. By using low tem- perature (liquid nitrogen −196°C), cryotherapy targets and Curettage is the most frequently performed surgical pro- kills precancerous cells directly by inducing cell rupture due cedure in AK management and particularly suitable for to osmotic shock and intracellular formation of ice crystals. solitary lesions. According to a recent meta-­ a nalysis, In addition, it leads indirectly to a delayed cell termination combinations with destructive treatments such as electro-­ process by inducing vascular necrosis due to thrombosis and desiccation or cryosurgery are more effective than photo- a release of neo-­antigens. To attain the effective temperature dynamic therapy, 5-­f luorouracil or imiquimod in treating of at least −40°C on the edge of the lesion, the cycle of freez- in situ SCC or superficially invasive SCCs.77 Moreover, ing and thawing should be repeated.82 Sensitive areas such curettage is a standard procedure established in photody- as eyes should be protected.83 AK I-­II are subject to a single namic therapy (PDT) protocols to ablate superficial kerato- freeze–thaw cycle with a freezing time between 5 and 20 s.84 sis, above all in thick hyperkeratotic AK. Deeper shavings Two freeze–thaw cycles of 10 s each are indicated for large or scalpel excisions instead are preferred in suspicious le- and hypertrophic lesions.85 Prior removal of hyperkeratotic sions, in which histology of the entire specimen appears scales is recommended, either by gentle curettage or by appli- justified.75 In AK, surgical treatments are usually limited cation of urea or salicylic acid containing keratolytic agents to lesion-­d irected removal of single or isolated AKs. After 2 weeks before cryosurgery.83 Cure rates of cryotherapy as primary field-­d irected treatment, any remaining AK may single treatment for AK range from 39% to 83%.86 The effi- be effectively treated with a lesion-­d irected surgical ap- cacy depends on the experience of the dermatologist and the proach.78 Surgical interventions, in general, have the ad- protocol used.87 Combination of cryosurgery with a topical vantage to allow for histopathologic examination of the intervention may be more effective than cryosurgery alone removed tissue specimen. Histology is particularly advised in patients with multiple AKs and field cancerization.88 if AKs is refractory to standard therapy, in relapsing AKs, or in those suspicious of cSCCs (e.g. in thickening, pain- ful or bleeding lesions, particularly in immunosuppressed Laser ablation (Table 9) patients).79 The drawbacks of surgical techniques are that usually only single lesions will be removed, anaesthesia is AK can be treated with laser therapy, either alone or in needed, and permanent depigmentation or even scarring combination with other treatments like PDT. The most may develop.80 TA BL E 8 Cryosurgery. TA BL E 6 Indication for treatment of actinic keratosis. Consensus-­based statement Grade of Cryosurgery shall be offered as a first-­line Consensus-­based statement recommendation: A standard treatment for solitary AK84,85 Expert consensus Treatment-­decision should be made on a case-­ Cryosurgery in combination with by-­case basis considering patient-­related curettage and topical treatments shall factors and lesion characteristics. be offered in multiple AKs and field For patients with previous cSCC and/or cancerization.84,89 immunosuppression treatment should be Level of evidence: 1 Systematic review and meta-­a nalysis,84,89 considered prospective multicentre study 90 Strength of consensus: 100% Strength of consensus: 100% TA BL E 9 Laser ablation for AKs. TA BL E 7 Surgery and laser ablation for lesion-­d irected treatment Evidence-­based statement of AK. Grade of Ablative laser treatment should be offered Consensus-­based statement recommendation: B as one of the options for single or GCP Curettage, shave or excisional biopsy can be offered for single multiple AKs, but it is not superior to or few hyperkeratotic lesions. Histological examination is cryotherapy or 5-­FU treatment. strongly recommended in treatment-­resistant cases and Level of evidence: 2 Single-­centre randomized controlled in lesions suspicious for iSCC.81 trials91,92 Strength of consensus: 100% Strength of consensus: 100%  14683083, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jdv.19897 by Gerardo Palmisano - University Cattolica, Piacenza , Wiley Online Library on [21/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License KANDOLF et al.     | 9 commonly used lasers for ablative treatment in AKs are the its metabolites into RNA and DNA. The benefits of 5-­FU CO2 and Er:YAG lasers, which remove the epidermis and su- treatment for AK were assessed based on five studies with perficial dermis to stimulate re-­epithelialization. However, moderate-­to-­h igh quality efficacy, four studies with 5% traditional laser treatment can have side effects such as hy- 5-­FU once daily and one with 5% 5-­FU twice daily.94-­96 popigmentation and scarring, as well as immediate side ef- The largest placebo-­controlled randomized trial (VAKCC fects like erythema, oedema, itching, hyperpigmentation and trial) showed field treatment of AKs on the face with 5% scaling, which usually resolve within 2 weeks but may take 5-­FU, twice daily for 4 weeks, to be more effective than longer to heal. Ablative laser treatment appears to be more placebo for complete AK clearance at 6 months (38% vs. effective than fractional laser treatment. There are only two 17%; p < 0.01).94 Two placebo-­controlled randomized clini- randomized controlled trials (RCTs) comparing it to 5-­FU cal trials evaluating 0.5% 5-­FU cream suggested the low cream.89-­91 Hantash et al. compared CO2 laser with 5-­FU ap- concentration of 5-­FU to be more effective than placebo plied twice daily for 3 weeks with no significant difference in reduction from baseline of AK lesion counts and lesion while Ostertag et al. did find a significant difference in fa- clearance.95,96 The main adverse event, often the primary vour of the Er:YAG laser in comparison with 5-­FU treatment reason for discontinuation of the treatment with 5-­FU, twice daily for 4–7 weeks. However, after 12 months post-­ remains local irritation. The number of AK lesions at treatment, there was no difference in efficacy, whereas more baseline may predict the severity of local skin reactions.97 side effects were noted in the Er:YAG treated group.89,90 CO2 New formulation of 4% fluorouracil in aqueous cream laser was compared to cryosurgery in a single-­centre RCT in- once daily was compared with twice daily treatment with cluding 200 patients.92 In both groups, the cosmetic outcome 5%-­FU in a double-­blind multicentre study involving 841 was good. Complete responses at 3 months were, respectively, subjects. It revealed similar efficacy, but better tolerability 65.3% and 71.1%, respectively, in the laser and cryotherapy of the 4% formulation (30% vs. 60% application site skin groups, but decreased to 14% and 53% at 1 year. Therefore, reaction). Field treatment of face and scalp area 10°C, cloudless to overcast sky, no rain). Two pivotal phase III trials conducted in Australia Grade of recommendation: B Combined treatments should and Europe compared daylight PDT with conventional PDT be offered to patients with multiple and/or hyperkeratotic with MAL in a multicentre, investigator-­blinded, controlled lesions, large treatment fields intraindividual trial as a non-­inferiority analysis.140,141 At and treatment resistance to 12 weeks after a single PDT cycle, the lesion complete clear- monotherapies. ance rate was not inferior to conventional MAL-­PDT (89% Level of evidence: 1 Randomized controlled trials,84,90,146 vs. 93% in Australia, 70% vs. 74% in Europe), but daylight systematic review and PDT was significantly less painful in both trials. Dirschka meta-­a nalysis.149 et al.142 compared daylight PDT with BF-­200 ALA versus Strength of consensus: 100% MAL in a large-­scale, multicentre, split-­face non-­inferiority study. The patient-­ specific complete clearance rate was 42.9% for ALA versus 38.8% for MAL. The lesion-­specific lesions may benefit from a sequential use of field-­and lesion-­ clearance rates were similar for both photosensitizers (79.8% directed treatment (see Combination treatment). for ALA, 76.5% for MAL). The study reported a signifi- cantly higher recurrence rate for MAL (31.6%) compared with ALA (19.9%) after 12 months of follow-­up. A similar Combination treatments: Should it be the rule? comparison was performed by Räsänen et al. in 2019 in a (Table 17) multicentre double-­blind non-­sponsored trial. Both photo- sensitizers were applied to one side of the face. The lesion-­ A multitude of interventions for the treatment of AK exists specific clearance rate was 79.7% for ALA versus 73.5% for which are often combined either simultaneously or sequen- MAL. The complete clearance rates were 27.5% for both pho- tially. The rationale for an upfront combination approach tosensitizers.143 From these data, we conclude that ALA and is to take advantage of the strengths and distinct mecha- MAL are equally effective when used for daylight PDT. The nisms of action of different interventions, thereby achiev- advantages of daylight PDT over conventional PDT include ing synergistic effects.145 The application of a primarily minimal to no pain, the possibility to treat large fields and field-­d irected approach can be focally complemented by the lack of a requirement for artificial light sources. lesion-­d irected modalities such as cryosurgery, laser ab- lation, or shave excision for hyperkeratotic or treatment-­ refractory lesions. Pre-­t reatment with topical agents may Field cancerization treatment (Table 16) even unmask and reveal subclinical lesions within a treat- ment field which can subsequently be targeted with a Although an exact definition has not yet been agreed upon, the lesion-­d irected treatment. Conversely, following a primar- concept of field cancerization is increasingly being acknowl- ily field-­d irected therapy, subclinical lesions and field can- edged and considered for treatment selection and preven- cerization can be managed by a field-­d irected treatment tion of AK. Agents approved for large-­field applications such which prevents the progression of subclinical lesions to as 5-­f luorouracil 5%, 5-­f luorouracil 4%, PDT or imiquimod become clinically visible AK. 3 Recent analyses have shown 3.75% are preferable for multiple thin lesions as the field is that treatment combinations result in significantly higher commonly ill-­defined and expands over a larger area. Studies lesion clearance compared to respective monotherapies. employing RCM provided evidence that subclinical changes In particular, such efficacy benefits were demonstrated are efficiently resolved by topical treatments.144 Diclofenac for laser-­ a ssisted conventional PDT,93 PDT combined sodium is also suitable for large fields but may be less effec- with pre-­ t reatment by microneedling,146 cryosurgery tive for lesion clearance. Patients with multiple hyperkeratotic combined with topical agents88 and 0.5% 5-­FU followed  14683083, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jdv.19897 by Gerardo Palmisano - University Cattolica, Piacenza , Wiley Online Library on [21/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License KANDOLF et al.     | 15 by cryosurgery.147,148 Furthermore, there is evidence that that it does not reduce the number of new keratinocyte can- combining several field-­d irected treatments can augment cers in OTRs.151 For clinically manifest AK, the evidence their efficacy. A systematic review identified 10 RCTs with for active interventions is surprisingly low.152 A system- a total sample size of n = 277.149 Four studies investigated atic review identified only eight small, randomized trials a combination of PDT with imiquimod cream, three with with 242 OTR, 6 out of 8 which evaluated PDT (but only 5-­FU and one each with ingenol mebutate, tazarotene gel 2 imiquimod and one each for 5-­f luorouracil, diclofenac and calcipotriol ointment. Patients treated with a com- gel and cryotherapy).152 Here, field-­d irected treatments bination had higher rates of complete and partial lesion showed higher clearance rates than lesion-­d irected treat- clearance,149 implying that treatment combinations can ments, underlining the paramount importance of treating achieve higher clearance rates compared to monothera- the entire field in this high-­risk population (see Field-­ pies. Nevertheless, a combination of interventions should directed treatments). Conventional MAL-­PDT showed the always be discussed on a case-­by-­c ase basis, and mono- most favourable clearance rates (40%–76.4%), followed by therapies will in many cases be sufficient to achieve lesion imiquimod (27.5%–62.1%), diclofenac sodium (41%) and clearance and disease control. Patients with simultaneous 5-­fluorouracil 5% (11%), while ablative laser treatment discrete and hyperkeratotic lesions, large treatment fields showed the lowest lesion clearance (5%–31%). Importantly, and treatment resistance to monotherapies may benefit there were no graft rejections under topical therapies.152 from combinations. In a recent small RCT, treatment with sunscreen, 5-­FU and imiquimod was used for prevention of cSCC in OTR, and treatment with 5-­FU was found to be superior in AK Treatment of AK in immunocompromised clearance as a surrogate biomarker of cSCC prevention.153 patients (Table 18) Immunosuppressed patients commonly show multiple and metachronous evolving lesions over large fields. Thus, Compared to immunocompetent individuals, chroni- purely lesion-­d irected treatments are usually not sufficient cally immunosuppressed patients show significantly in- to achieve disease control. Due to a more aggressive dis- creased morbidity and mortality due to the development ease course and a higher portion of treatment-­resistant le- of iSCC.150 Important mainstays for secondary prevention sions, repeated treatment is often necessary. The threshold are early modification of the immunosuppressive regimens to biopsy lesions to rule out progression to cSCC should by eliminating of azathioprine and switching to mTOR be lower than in immunocompetent individuals. Most inhibitor-­containing immunosuppression, photoprotec- evidence for the subgroup of immunosuppressed patients tion and chemoprevention with retinoids. Although in is available for PDT, imiquimod and diclofenac sodium. 3 immunocompetent individuals, dietary supplementation Dragieva et al. evaluated conventional MAL-­PDT in 14 with oral nicotinamide (vitamin B3) was found to be ef- renal and 3 cardiac transplant recipients. The lesion clear- fective in prevention of cSCC, in a recent trial it was found ance rate assessed 16 weeks after two PDT cycles was 90.3% in the MAL-­treated group versus 0% in the vehi- TA BL E 18 Treatment of AK in immunocompromised patients. cle group. Complete response of the entire treatment field was achieved in 75.4% and partial response (>75% of all Evidence-­based statement lesions per field cleared) in 94.1%.154 A European, mul- Grade of recommendation: B Conventional PDT with illumination by a ticentre, double-­blind, interindividual randomized trial red-­light source, 5-­FU 5% cream and evaluated imiquimod 5% cream versus placebo in 30 kid- diclofenac sodium 3% in hyaluronic ney, 4 liver and 9 heart transplant patients. The complete acid gel 2.5% should be offered to immunocompromised patients with response rate was 62.1% for imiquimod (100% in the liver single and multiple AKs and field transplant group, 65% in the kidney transplant group and cancerization 42.9% in the heart transplant group) versus 0% for pla- Grade of recommendation: C Imiquimod 5% or 3.75% cream may be cebo.155 Importantly, anecdotally reported graft rejection offered for treatment of single and or deterioration of the graft function was not observed in multiple AKs and field cancerization this trial.133,134,155 Adverse events of imiquimod were local in selected immunocompromised patients site application reactions, fatigue, headache, diarrhoea, Daylight PDT may be offered to nausea, rash, unspecified skin reactions and leukopenia. immunocompromised patients with Togsverd-­Bo et al.156 investigated MAL-­PDT and imiqui- single and multiple AKs and field mod in 35 OTR. PDT resulted in higher lesion clearance cancerization Field-­d irected treatments have higher at a 3-­month follow-­up albeit at the cost of more intense clearance rates than lesion-­d irected local skin reactions. The median patient-­specific complete treatments in this high-­risk clearance was 78% for PDT versus 61% for imiquimod. population Diclofenac sodium was investigated in a double-­blind, Level of evidence: 2–3 Randomized controlled trials,153 placebo-­controlled, randomized trial in 32 OTR (18 renal, systematic review152 8 cardiac and 6 liver transplant recipients).131 The com- Strength of consensus: 78.5% plete clearance of all lesions in the treated field was 41%  14683083, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jdv.19897 by Gerardo Palmisano - University Cattolica, Piacenza , Wiley Online Library on [21/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 16 |    EUROPEAN GUIDELINE FOR TREATMENT OF AK (kidney transplants 30.7%, liver transplants 40%, heart midday should be completely avoided or postponed to the transplants 75%) versus 0% in the placebo group. Partial morning and evening hours. Sunburn should be avoided at clearance of at least 75% of lesions was observed in 59% for any time. diclofenac versus 16.7% for placebo. The recurrence after In high-­risk patients (e.g. OTRs) with multiple AK, field diclofenac treatment was 55% after 9.3 months. Adverse cancerization, or a history of multiple non-­melanoma skin events included mild to moderate erythema, scaling, itch- cancers regular (e.g. yearly) treatments of previously affected ing and skin irritation with oedema.131 Based on the avail- skin areas can be considered with PDT, 5-­FU or imiquimod able evidence, Massey and co-­ workers have developed as a preventive topical measure. In the Veterans Affairs consensus-­based recommendations on the prevention of Keratinocyte Carcinoma Chemoprevention (VAKCC) trial, cSCC in solid organ transplant recipients.157 The key rec- one treatment course of 5-­FU 5% cream twice daily over ommendations for the treatment of AK in OTR patients 4 weeks effectively reduced AK counts and the need for include cryosurgery for scattered AK, field therapy with additional spot treatments for AK for more than 2 years.94 5-­f luorouracil for AK grouped in one anatomical area, and Similarly, the formation of new AK was reduced with 5-­FU for field cancerized skin, and acitretin therapy for patients in this trial by prospectively tracking individual lesions with a high rate of multiple skin cancers or high-­r isk cSCC. over 36 months in this high-­risk population having more For thick AKs, a combination of lesion-­d irected and field than 2 keratinocyte carcinomas in the past 5 years.160 In therapy with cryotherapy was recommended, and immu- the LEIDA trials, imiquimod 5% cream was superior to di- nosuppression reduction or modification should be dis- clofenac 3% gel in preventing histological change to grade cussed with patients with high-­r isk cSCC.157 This group of III AK or invasive SCC and AK recurrence over 3 years.118 patients should be managed in specialist centres. However, this trial did not include a high-­risk population as in the VAKCC trial. There has been long-­ standing controversy and in- Treatment algorithm tense debate on the use of systemic chemoprevention in high-­r isk situations. Agents investigated for oral che- Proposed treatment algorithm is presented in Figure 1 moprevention include oral retinoids, nonsteroidal anti-­ (modified from Gupta et al.158). For single non-­ inflammatory drugs (NSAID), capecitabine, as well as hyperkeratotic lesions, destructive or field-­ d irected dietary supplements and vitamins (beta-­carotene, nic- treatments can be started, although monitoring and self-­ otinamide). Most of these agents failed to show a clear examination can also be advised. For multiple lesions, benefit for prevention and may even be associated with field-­d irected treatments and PDT are advised. For hy- harmful side effects. Oral nicotinamide (vitamin B3) perkeratotic lesions, pre-­t reatment with destructive meth- 500 mg twice daily showed a rate reduction for cSCC of ods (curettage, cryotherapy or laser) is advised before 30% in immunocompetent individuals with two or more field-­d irected treatment. For AKs in immunosuppressed confirmed keratinocyte carcinomas in the past 5 years.161 patients, PDT might be preferred, although other topi- However, there was no effect after nicotinamide discon- cal treatments might be effective and safe, and for AKs in tinuation, and it is unclear if the preventive effects also specific high-­r isk regions and in treatment-­resistant cases pertain to AK. Also, oral nicotinamide which was found surgery is indicated. Preventive measures (sun/protec- does not reduce the number of new keratinocyte cancers tion, self/examination), repeated treatments and in pa- in OTRs.151 Recent consensus-­based recommendations tients with previous iSCC chemoprevention are advised on the prevention of cSCC in OTR suggest initiation of (Figure 1). acitretin and discussion of immunosuppression reduc- tion or modification for patients who develop multiple skin cancers at a high rate (10 cSCC per year) or develop PR E V E N T ION OF A K high-­r isk cSCC (defined by a tumour with approximately ≥20% risk of nodal metastasis). However, no consen- All patients with AK should be advised to apply the ap- sus recommendation was achieved for OTR with a first propriate protective measures against solar UV radiation low risk cSCC or multiple AK or field cancerization.157 (Table 19). The following measures should be recommended: Likewise, the German S3 guideline on prevention of skin avoidance of intensive intermittent (UV peaks) and chronic cancer does not make any recommendations for chemo- sunlight exposure, wearing of appropriate clothing, applica- prevention in AK. 3,78 tion of sunscreen with a high sun protection factor (≥ 30) including ear rims and lips, no use of sun beds, and discon- tinuation or change of light-­sensitizing drugs (e.g. hydro- FOL L OW-­U P OF A K chlorothiazide). In more detail, the following UV protection measures should be taken to avoid excessive UV exposure: The surveillance and follow-­up strategies for AK are not In case of medium and high UV irradiance (UV index 3–7), standardized and notoriously understudied (Table 20). The shade should be sought during midday. In case of very high response to any treatment should be assessed 3 months after UV irradiance (UV index ≥8), outdoor activities during the end of treatment clinically, dermatoscopically, and if 14683083, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jdv.19897 by Gerardo Palmisano - University Cattolica, Piacenza , Wiley Online Library on [21/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License | 17     Treatment algorithm for actinic keratoses (adapted from Gupta et al.158). KANDOLF et al. FIGU R E 1  14683083, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jdv.19897 by Gerardo Palmisano - University Cattolica, Piacenza , Wiley Online Library on [21/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 18 |    EUROPEAN GUIDELINE FOR TREATMENT OF AK 3 TA BL E 19 Prevention of AKs. Dermatologia, Università Cattolica del Sacro Cuore, Rome, Italy 4 Dermatology Department of Hospital Clinic of Barcelona, IDIBAPS, CIBER de Evidence-­based statement Enfermedades Raras, Instituto Carlos III, University of Barcelona, Barcelona, Spain 5 Department of Dermatology, Maastricht University Medical Centre+ Grade of recommendation: B Individuals at high-­risk of AKs, Comprehensive Cancer Centre, Maastricht, The Netherlands 6 including those occupationally GROW-­School for Oncology and Reproduction, Maastricht University, Maastricht, exposed to UV irradiation and The Netherlands 7 immunocompromised and all Department of Dermatology, Uniklinikum Erlangen, Friedrich-­A lexander-­ patients with AK should be University Erlangen-­Nürnberg, Erlangen, Germany 8 Comprehensive Cancer Center Erlangen-­European Metropolitan Area of advised to apply the appropriate Nuremberg (CC ER-­EMN), Erlangen, Germany protective measures against UV 9 Dermatology, Department of Biotechnological and Applied Clinical Sciences, irradiation University of L'Aquila, L'Aquila, Italy 10 Grade of recommendation: C In high-­risk patients (e.g. organ Department of Dermatovenereology, Third Faculty of Medicine, Charles transplant recipients, OTR) with University and University Hospital of Kralovske Vinohrady, Prague, Czech Republic multiple AK, field cancerization, 11 Clinic of Infectious Diseases and Dermatovenereology, Centre of or a history of multiple Dermatovenereology, Vilnius University, Vilnius, Lithuania keratinocyte skin cancers 12 Department of Dermatology, University Hospital Erasme, Université Libre de regular (e.g. yearly) treatments Bruxelles, Brussels, Belgium of previously affected skin areas 13 Faculty of Health, University Witten-­Herdecke, Witten, Germany 14 with photodynamic therapy, CentroDerm Clinic, Wuppertal, Germany 15 5-­f luorouracil or imiquimod as Nantes Université, INSERM, CNRS, Immunology and New Concepts in a preventive topical measure can ImmunoTherapy, INCIT, UMR 1302/EMR6001, Nantes, France 16 be considered Department of Oncologic Dermatology, Elias University Hospital Bucharest, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania Level of evidence: 2–3 Randomized controlled trials, 17 Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and The systematic review of randomized London School of Medicine and Dentistry, Queen Mary University of London, controlled trials59,113,159 London, UK 18 Department of Dermatology, University Hospital (UKSH), Kiel, Germany Strength of consensus: 100% 19 Department of Dermatology, Copenhagen University Hospital -­Bispebjerg and Frederiksberg, Copenhagen, Denmark 20 Department of Dermatology, Venereology and Allergology, Frankfurt University TA BL E 2 0 Follow-­up of patients with AK. Hospital, Frankfurt, Germany 21 First Department of Dermatology, Aristotle University, Thessaloniki, Greece 22 Consensus-­based statement Université Paris Cite, AP-­HP Dermato-­oncology, Cancer institute APHP, Nord Paris cité, INSERM U976, Saint Louis Hospital, Paris, France 23 Expert consensus Patients with AK should be educated for Centre for Dermatooncology, Department of Dermatology, Eberhard Karls self-­skin examination and sun protection University, Tuebingen, Germany 24 and referred for skin examination due to Skin Cancer Center, Azienda Unità Sanitaria Locale -­IRCCS di Reggio Emilia, the common risk of recurrences and the Reggio Emilia, Italy 25 Department of Dermatology, University of Modena and Reggio Emilia, Modena, development of new lesions as well as of Italy other types of keratinocyte carcinomas 26 Department of General and Oncologic Dermatology, Ambroise Paré Hospital, Strength of consensus: 100% APHP, & EA 4340 “Biomarkers in Cancerology and Hemato-­Oncology”, UVSQ, Université Paris-­Saclay, Boulogne-­Billancourt, France 27 Department of Dermatology and Venereology, Sestre Milosrdnice University Hospital Center, Zagreb, Croatia available, with additional non-­invasive imaging techniques. 28 Skin Cancer Center, Department of Dermatology, Ruhr-­University Bochum, If there is evidence for treatment resistance, retreatment or a Bochum, Germany biopsy is recommended. 29 Department of Pediatric Dermatology, Colentina Clinical Hospital, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania Patients with AK should be educated for self-­skin exam- 30 1st Department of Dermatology-­Venereology, National and Kapodistrian ination and sun protection and referred for skin examination University of Athens, Andreas Sygros Hospital, Athens, Greece due to the common risk of recurrences and the development 31 Dermatology Clinic, Maggiore Hospital, Department of Medical Sciences, University of Trieste, Trieste, Italy of new lesions as well as of other types of keratinocyte car- cinomas. In patients with AKs and a history of cSCC, fol- low-­up schedules should follow the guidelines for cSCC. F U N DI N G I N F OR M AT ION Each follow-­up includes a thorough skin check of the chron- The development of the current set of guidelines was sup- ically sun-­exposed body areas at a minimum. The frequency ported solely by funds of the EADO which were used to of follow-­up should be based on the number and dynamics of mainly support the consensus meeting without honoraria previous AKs, the history of previous keratinocyte carcino- and without reimbursement of travel costs. mas, and the immune status and medication of the patient. In immunosuppressed patients, close follow-­up visits with a C ON F L IC T OF I N T E R E S T S TAT E M E N T dermatologist (e.g. every 3–6 months) are recommended. LK: None for the present manuscript. Consulting fees from MSD, Merck, Abbvie, Janssen and honoraria for lectures A F F I L I AT ION S and educational events by BMS, MSD, Novartis, Merck, 1 Department of Dermatology, Faculty of Medicine, University of Defence, Military Roche, Abbvie and Janssen. KP: None for the present manu- Medical Academy, Belgrade, Serbia 2 UOC di Dermatologia, Dipartimento di Scienze Mediche e Chirurgiche script. Grants from Sanofi, Novartis, Abbvie and Almirall. Addominali ed Endrocrino Metaboliche, Fondazione Policlinico Universitario A. Consulting fees from Sanofi, honoraria for lectures and Gemelli – IRCCS, Rome, Italy educational events from Lilly, Sanofi and Sun Pharma,  14683083, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jdv.19897 by Gerardo Palmisano - University Cattolica, Piacenza , Wiley Online Library on [21/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License KANDOLF et al.     | 19 participation in advisory boards Abbvie and Almirall. Leo present manuscript. Grants to institution from MSD/ Pharma, Lilly, Janssen, Sanofi, Pierre Fabre, Sun Pharma, Merck, Philogen, Pierre Fabre, Regeneron, Roche, Sanofi-­ Biogen, Galderma and Philogen. JM: None for the pre- Genzyme, Novartis Pharma, Eisai. Honoraria for lec- sent manuscript. Honoraria for lectures and educational tures and educational events from MSD/Merck, Pierre events from Almirall, Pierre Fabre, ISDIN, BMS, MSD and Fabre, Regeneron, Roche, Sanofi-­ G enzyme, Novartis Sunpharma, support for attending meetings and/or travel Pharma, Eisai, participation in Advisory boards MSD/ Almirall, ISDIN, Sunpharma, participation in advisory Merck, Pierre Fabre, Regeneron, Roche, Sanofi-­G enzyme, boards Pierre Fabre, Almirall, stock options Athena tech Novartis Pharma, Eisai, Immunocore, Replimune and and Dermavision. KM: None for the present manuscript. Seagen. RK: None for the present manuscript. Grants to Grants from institution, Health Foundation Limburg, institution from AbbVie, Amgen, Biontech, BMS, Celgene, ZonMW. Consulting fees from Sunpharma, Almirall, Galderma, Janssen, Leo, Lilly, Merck, MSD, Novartis, honor