Assembling a consensus on actinic cheilitis: A Delphi study

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2021 The Authors. Journal of Oral Pathology & Medicine published by John Wiley & Sons Ltd. 1Department of Surgery and MedicalSurgical Specialities, University of Santiago de Compostela, Santiago de Compostela, Spain 2King's College London, WHO Collaborating Centre for Oral Cancer, London, UK 3Oral Medicine, Valencia University, Valencia, Spain 4Department of Stomatology, University of Basque Country/EHU, Leioa, Spain 5Department of Oral Medicine, University of Murcia, Hospital Morales Meseguer, Murcia, Spain 6Department of Clinical Dental Specialities, Complutense University of Madrid, Madrid, Spain 7Oral Medicine, School of Dentistry, University of Granada, Granada, Spain 8Department of Dermatology, University of Santiago de Compostela, Santiago de Compostela, Spain 9USC International School of Doctorate, Ciudad Real University Hospital, Ciudad Real, Spain 10CS Praza do Ferrol. EOXI Lugo, Cervo e Monforte, Department of Surgery and MedicalSurgical Specialities, Galician Health Service, Univeristy of Santiago de Compostela, Lugo, Spain


| INTRODUC TI ON
The term actinic cheilitis (AC) in scientific literature describes changes induced by chronic exposure to sunlight (ultraviolet A wavelength 320-400 nm and largely ultraviolet B wavelength 290-320 nm) mostly affecting the lower lip. 1 However, AC is considered a misnomer by some authors who use alternative terms, like solar cheilitis, 2 solar cheilosis, 3 solar keratosis 4 or actinic keratosis of the lip. 5 This terminological controversy is based on the understanding of the pathobiology of the condition as primarily inflammatory 1 or non-inflammatory 2 and on the appellation (actinic: 'a ray' vs. solar) of the aetiologic radiation. [2][3][4][5] There is also a lack of consensus on the nature of AC as either a 'precancerous or potentially malignant' 6,7 or a primarily neoplastic (intra-epithelial neoplasia) condition, 3,[8][9][10] which may explain the divergences in case definition, diagnostic criteria and management.
Additionally, existing literature shows a disagreement on whether AC should be used as a clinical term where biopsy is not always recommended 11 or used a preliminary clinical diagnosis for which histopathological examination is mandatory to reach a definitive diagnosis. 3 Even the requirement of epithelial dysplasia of the lip epithelium to diagnose AC is a matter of debate. 12,13 These uncertainties may well explain the wide differences in reported AC prevalence when estimated in terms of histopathological A range of medical and surgical procedures (5% topical 5-FU, 5% topical imiquimod, 3% diclofenac gel, chemical peels, dermabrasion, photodynamic therapy, cryotherapy, electrosurgery, Er:YAG laser and vermilionectomy (cold blade and CO 2 laser), together with Mohs micrographic surgery) have been used for treating AC. 3,[15][16][17][18] However, and despite the superiority of surgery compared with medical therapies (92.8% vs. 65.9% showing remission with lower recurrence rates (8.4% vs. 19.2%) 16 ), there is no consensus on the optimal strategy for treatment of AC [16][17][18] because both approaches have benefits and drawbacks. 19 Thus, the current comprehension regarding AC clearly requires an effort to minimize disparities and reach agreements on terminological and taxonomical aspects, as well as in its diagnosis and treatment. In this vein, an expert consensus (Delphi method) approach can support clinical decision-making, particularly when evidence about a given topic is contradictory. 20 The Delphi method is aimed at structuring a consensus and it is based upon the anonymity of the experts among themselves and on the iteration with controlled feedback (experts are consulted more than once). [21][22][23][24][25][26] This technique is a procedure for group communication meant to reach a convergence of opinion on a specific 'real-world' issue. 26 The objectives of this investigation were i) to discuss and agree upon the most appropriate terminology to define and classify AC and ii) to build a consensus about the diagnostic and therapeutic approaches to AC.

| MATERIAL S AND ME THODS
A two-round Delphi was designed according to the guidance on conducting and reporting Delphi studies. 21 A steering committee was established, and 21 experts (9 dermatologists, 9 specialists in Oral Medicine, and 3 oral pathologists) were recruited from a consortium of 11 academics and 10 clinical specialists across Europe and Latin America. Experts were selected through a bibliographical search (contributing at least one publication on this topic) and from their clinical experience (>15 years).
Our previous systematic review 15 permitted the identification of terminological and taxonomical inconsistencies, along with discordances in diagnostic and therapeutic criteria for AC. As a result, a questionnaire was built including 34 closed sentences (9 on terminology and taxonomy, 5 on potential for malignant transformation, 12 dealing with diagnostic aspects, as well as 8 statements on AC treatment) together with 8 open questions. The instrument was electronically circulated to the panel.
The first round (R1: March 2020) used a Likert scale (1 to 7; 1: strongly disagree -7: strongly agree) to assess the level of concordance with the closed sentences presented to the experts. 26 Participants were also asked to cast their degree of confidence on their responses using another Likert scale (1: very uncertain -7: very certain). Once the obtained information was analysed and synthesized, and considering the feedback from the panel, the open questions in the instrument were changed into close-ended ones and the second round (R2: June 2020) was initiated. In addition to the second questionnaire, the experts received information about the overall response of the group in R1. In case a participant disagreed in one or more of his/her responses with the panel (agree/strongly agree or disagree/strongly disagree), and to favour consensus, the person was asked to reconsider the score allocated to his/her R1 response(s). This permitted the expert to bring his/her responses closer to the group's opinion or to remain with his/her previous response and to justify his/her score.
For purposes of this study, a consensus for close-ended questions was defined as ≥75% agreement by the experts. With reference to the sentences, a <50 variation coefficient (minor variability among experts) was considered an indicator for agreement. The criterion for dropping items at R1 was pre-established considering a minimum acceptable level of confidence in expressing an opinion (≥ 5).
This study was approved by the University of Santiago de Compostela Research Ethics Committee (#USC-17/2020). A declaration of interests was completed by all participants.

| Statistical analysis
A quantitative analysis of the results of both R1 and R2 was undertaken using the SPSS v.24 statistical package (SPSS Inc). The descriptive study used the median as a central trend indicator and the interquartile range as a measure of spread. The variability of the experts' scores (dispersion) for a given item was calculated using the coefficient of variation (standard deviation/mean). The level of agreement (percentage) was also described for close-ended questions. The opinions of the experts were also considered for nonconsensual questions.

| RE SULTS
Twenty five experts were invited, and 21 agreed to participate in the study, resulting a recruitment rate of 84%.
The Delphi technique permitted a consensus on 24 out 34 statements (73.5%) and on 5 out of 8 (62.5%) close-ended questions. The response rate was identical in both rounds, with an attrition of 0%, and just one statement was dropped because of a low level of confidence among the participants in their responses. Results are displayed in Tables 1 to 4.

| Nomenclature and taxonomy
Actinic cheilitis (AC) is the term with the highest level of consensus among the experts, the lowest dispersion of scores (VC = 21.33) and a median of 7 (strongly agree) (IQR: 6-7). No differences (p > 0.05) were observed between dermatologists and oral medicine specialists in terms of degree of agreement.

| Strengths and limitations of the study
The Delphi methodology was used to address consensus with the objective of contributing to a common effort targeted towards agreement. 27  In an attempt to evaluate the agreement level of the answers, a seven-point scale was adopted to be more discriminative, 22,25

| Taxonomy and potential for malignant transformation
Although 'solar cheilosis' has been recommended as an appropriate term for labelling this entity (inflammation is not the starting event, and 'solar' is more accurate than 'actinic', that includes other types of radiation as aetiological agent 3 ), 'actinic cheilitis' is the most frequently term used in the literature 13 and the best valued by the panel of experts.
Classically, the terms 'potentially malignant', 'premalignant' and 'precancerous' have been used interchangeably, 7,18 although 'potentially malignant disorder' has been the term adopted by the WHO Collaborating Centre in 2007. 28,29 This concept combines both precancerous lesions and conditions separately grouped in the earlier WHO definitions. 30 Potentially, malignant is more suited as not all ACs will eventually develop into lip cancer. 6,29,30 This nomenclature has reached the highest level of consensus in the current study, although some authors 9,10 still consider AC as micro-invasive, superficial, incipient malignant epithelial neoplasia.
The chances for a patient with actinic changes and lip carcinoma to develop a second primary lip cancer are 2.5 times higher than for a patient without AC. 2 In addition, 95% of squamous cell carcinomas of the lip occur on a background of AC. 14,31,32 Conversely, and considering that more than two decades of chronic sun exposure is needed for AC to turn into lip cancer 2 and Besides, pre-treatment diagnosis has usually been based upon the information obtained from incisional biopsies although the nature of AC as a non-homogeneous, multifocal lesion 9 is a well-known limitation for this approach. This can result in the underdiagnosis of dysplastic lesions and masking of non-contiguous foci of squamous cell carcinoma, even in diffuse and poorly demarcated lesions. 9,38 The chances for this to occur seem to be supported by the frequently reported carcinomas in vermilionectomy surgical specimens (excisional biopsies) from patients with clinical diagnosis of AC 40,41 even in those cases with a previous incisional biopsy confirming no invasion. 9

| Therapeutic approaches
Different reports acknowledge a lack of consensus [15][16][17][18] [46][47][48][49] Notwithstanding, five different systematic reviews have proved the superiority of surgical treatments over of non-surgical options in terms of histopathological control, [15][16][17][18]50 particularly partial surgery and laser therapy (CO 2 , Er-Yag, Thulium) alone or in combination with photodynamic therapy elicited the best clinical response, 18 followed by 5% imiquimod-topical chemotherapy drug-(once a day, 3 to 5 days per week for 4 to 6 weeks) and photodynamic therapy. 17,18 However, topical and photodynamic therapy is associated with a higher recurrence. 50 In any case, other non-surgical measures such as regular follow-up after treatment and intense photoprotection should also be implemented especially for high-risk patients. 15

| CON CLUS IONS
AC is a potentially malignant disorder with a significant lack of agreement on diagnostic criteria and procedures, biopsy indications and on the importance of ancillary techniques to assist in biopsy. However, and despite the insufficient evidence, a consensus was reached on the nomenclature and the therapeutical management of this disorder, which can be useful to the clinicians in their decision-making processes.

CO N FLI C T O F I NTE R E S T
The authors have no conflicts of interest to declare.

PEER R E V I E W
The peer review history for this article is available at https://publo ns.com/publo n/10.1111/jop.13200.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available in the supplementary material of this article.