Delphi Consensus Among International Experts on the Diagnosis, Management, and Surveillance for Lentigo Maligna

Delphi Consensus Among International Experts on the Diagnosis, Management, and Surveillance for Lentigo Maligna Caterina Longo,1,2* Cristian Navarrete-Dechent,3,4* Philipp Tschandl5, Zoe Apalla6, Giuseppe Argenziano7, Ralph P. Braun8, Veronique Bataille9, Horacio Cabo10, Rainer Hoffmann-Wellhenhof11, Ana Maria Forsea12, Claus Garbe13, Pascale Guitera14, Karls Raimond15, Ashfaq A. Marghoob16, Josep Malvehy17, Veronique del Marmol18, David Moreno19, Kishwer S. Nehal16, Eduardo Nagore20, John Paoli21, Giovanni Pellacani22, Ketty Peris23, Susana Puig17, H. Peter Soyer24, Susan Swetter25, Alexander Stratigos26, Wilhelm Stolz27, Luc Thomas28, Danica Tiodorovic29, Iris Zalaudek30, Harald Kittler5, Aimilios Lallas31 1 Department of Dermatology, University of Modena and Reggio Emilia, Modena, Italy 2 Azienda Unità Sanitaria Locale – IRCCS di Reggio Emilia, Skin Cancer Center, Reggio Emilia, Italy 3 Department of Dermatology, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Santiago, Chile 4 Melanoma and Skin Cancer Unit, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Santiago, Chile 5 Department of Dermatology, Medical University of Vienna, Vienna, Austria 6 Second Dermatology Department, Aristotle University of Thessaloniki, Greece 7 Dermatology Unit, University of Campania, Naples 8 Department of Dermatology, University Hospital of Zürich, University of Zürich, Zürich, Switzerland 9 Dermatology, Mount Vernon Cancer Centre, Northwood, Middlesex, UK 10 Dermatology Department "Instituto de Investigaciones Médicas A. Lanari", University of Buenos Aires, Argentina 11 Nonmelanoma Skin Cancer Unit, Department of Dermatology and Venerology, Medical University of Graz, Graz, Austria 12 Dermatology Department, Elias University Hospital, Carol Davila University of Medicine and Pharmacy Bucharest, Romania 13 Center for Dermatooncology, Department of Dermatology, Eberhard Karls University, Tübingen, Germany 14 Melanoma Institute Australia, The University of Sydney, Sydney, Australia; Faculty of Medicine and Health, University of New South Wales, Sydney, Australia; Sydney Melanoma Diagnostic Centre, Royal Prince Alfred Hospital, Sydney, Australia 15 Derma Clinic Riga, Riga, Latvia 16 Dermatology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA 17 Dermatology Department, Hospital Clinic of Barcelona, University of Barcelona, Spain 18 Department of Dermatology, CUB Hôpital Erasme - Brussels University Clinics, Université Libre de Bruxelles, Brussels, Belgium 19 Dermatology Unit, Hospital Universitario Virgen Macarena, Seville, Spain 20 Dermatology Department, Instituto Valenciano de Oncología, Valencia, Spain 21 Department of Dermatology and Venereology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden 22 Dermatology Clinic, Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy 23 Institute of Dermatology, Università Cattolica-Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy 24 Dermatology Research Centre, The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, QLD 4102, Australia 25 Department of Dermatology, Pigmented Lesion and Melanoma Program, Stanford University Medical Center and Cancer Institute, Stanford, California 26 Department of Dermatology-Venereology, Faculty of Medicine, National and Kapodistrian University of Athens, 'A. Sygros' Hospital for Skin and Venereal Diseases, Athens, Greece Original Article | Dermatol Pract Concept. 2023;13(3):e2023244 1 27 Department of Dermatology, Allergology, and Environmental Medicine Clinic Thalkirchen, Hospital Munich, Munich, Germany 28 Department of Dermatology, Lyon-1 University, and Cancer research center Lyon, Lyon, France 29 Clinic of Dermatovenereology, Clinical Center of Nis, Serbia 30 Department of Dermatology and Venereology, Dermatology Clinic, Maggiore Hospital, University of Trieste, Trieste, Italy 31 First Department of Dermatology, School of Medicine, Aristotle University, Thessaloniki, Greece *Co-first authors Key words: melanoma, lentigo maligna, Delphi, diagnosis, management Citation: Longo C, Navarrete-Dechent C, Tschandl P, et al. Delphi Consensus Among International Experts on the Diagnosis, Management, and Surveillance for Lentigo Maligna. Dermatol Pract Concept. 2023;13(3):e2023244. DOI: https://doi.org/10.5826/dpc.1303a244 Accepted: April 24, 2023; Published: July 2023 Copyright: ©2023 Longo et al. This is an open-access article distributed under the terms of the Creative Commons AttributionNonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. Funding: None. Competing interests: None. Authorship: All authors have contributed significantly to this publication. Corresponding author: Caterina Longo, MD, PhD, Department of Dermatology, University of Modena and Reggio Emilia, Italy. Azienda Unità Sanitaria Locale – IRCCS di Reggio Emilia, Skin Cancer Center, Reggio Emilia, Italy Phone: +390522295612 ORCID Caterina Longo: http://orcid.org/0000-0002-8218-3896 E-mail: longo.caterina@gmail.com ABSTRACT Introduction: Melanoma of the lentigo maligna (LM) type is challenging. There is lack of consensus on the optimal diagnosis, treatment, and follow-up. Objectives: To obtain general consensus on the diagnosis, treatment, and follow-up for LM. Methods: A modified Delphi method was used. The invited participants were either members of the International Dermoscopy Society, academic experts, or authors of published articles relating to skin cancer and melanoma. Participants were required to respond across three rounds using a 4-point Likert scale). Consensus was defined as >75% of participants agreeing/strongly agreeing or disagreeing/strongly disagreeing. Results: Of the 31 experts invited to participate in this Delphi study, 29 participants completed Round 1 (89.9% response rate), 25/31 completed Round 2 (77.5% response rate), and 25/31 completed Round 3 (77.5% response rate). Experts agreed that LM diagnosis should be based on a clinical and dermatoscopic approach (92%) followed by a biopsy. The most appropriate primary treatment of LM was deemed to be margin-controlled surgery (83.3%), although non-surgical modalities, especially imiquimod, were commonly used either as alternative off-label primary treatment in selected patients or as adjuvant therapy following surgery; 62% participants responded life-long clinical follow-up was needed for LM. Conclusions: Clinical and histological diagnosis of LM is challenging and should be based on macroscopic, dermatoscopic, and RCM examination followed by a biopsy. Different treatment modalities and follow-up should be carefully discussed with the patient. 2 Original Article | Dermatol Pract Concept. 2023;13(3):e2023244 Introduction methodology on: (i) the definition of the best diagnostic strategy of LM; (ii) the most appropriate surgical treatment; Lentigo maligna (LM) is a subtype of melanoma in situ (iii) the use of non-surgical therapeutic options as primary arising on chronically sun-damaged skin and it comprises treatments or in an adjuvant setting. 4–15% of all melanomas [1-7]. Clinically, LM is often difficult to differentiate from its mimickers, necessitating a biopsy to confirm or exclude the diagnosis. Dermoscopy and Methods reflectance confocal microscopy (RCM) have been shown to This study was conducted between January 1st 2020 and increase the sensitivity and specificity of LM diagnosis com- December 31st 2021 under the framework of the Interna- pared to the visual inspection alone [8,9]. tional Dermoscopy Society (IDS). Histopathologically, LM is characterized by an increased density of atypical melanocytes at the dermo-epidermal junction with frequent adnexal involvement [10-12]. Differentiation between LM and melanocytic hyperplasia of sun-damaged skin can be challenging, especially if a small partial biopsy is available (eg punch biopsy) [13]. It is worth mentioning that after partial biopsy of LM, an invasive component (ie upstaging) might be found in 9% of the cases [14-17]. Regarding treatment, wide surgical excision is considered the standard therapy for melanoma on the trunk and extremities and most randomized controlled trials of surgical margins for invasive melanoma excluded LM. In the recent years, the use of lateral and deep margin-controlled techniques such as staged excision with permanent sections or Mohs micrographic surgery (MMS) have been developed for LM [13,18-20]. Additionally, nonsurgical treatments such as radiotherapy and imiquimod have been used for LM therapy [13,21-26]. Despite LM progressing slowly, once invasive, LM melanoma (LMM) has the same prognosis when adjusted for Breslow thickness compared to other melanoma subtypes [27]. However, the risk of LM to progress to invasive melanoma is believed to be very low, around 2% – 5% [28,29]. This is particularly relevant in the light of evidence suggesting that overdiagnosis of melanomas that do not have the potential to harm patients might result in unneeded treatments and unnecessary physical, psychological, and social costs [30,31]. Considering the above issues, the management of LM remains challenging in many aspects [25,32]. Study Design The study used the Delphi consensus methodology. The technique has been described elsewhere [33-35]. Three rounds of the modified Delphi method were required to finalize consensus (Figure 1). Consensus was defined as >75% of participants agreeing/strongly agreeing or disagreeing/strongly disagreeing with a statement was based on prior Delphi studies [33,34]. A dropout rate of 20% was expected over the rounds, in accordance with previous Delphi studies. Expert Panel Recruitment The invited participants were either members of the IDS Executive Board, academics or authors of articles related to skin cancer and melanoma. To complete the Delphi process, participants were required to respond across all three rounds. Therefore, those who did not respond to Round 1 were not invited to participate in Round 2 and similarly for Round 3. There was space for free-text responses from Round 1 to be incorporated as new statements in Round 2 and re-evaluated considering the group consensus in Round 3 (Figure 1). All surveys were administered using SurveyMonkey (Momentive Inc.) through a web link or QR code. Initial statements presented on the first round were developed by 3 core authors (C.L., P.T., A.L.), following a review of the literature. The survey statements were constructed to highlight key challenges and opportunities, and to obtain actionable statements for effective approaches in clinical practice. Three authors (C.L., P.T., A.L.) jointly analyzed the responses, counting the votes and selected new statements Objectives for the next round. An iterative process of feedback was un- The objective of this study was to build consensus among ments, and to determine whether any additional statements international experts in the field of LM using Delphi were needed. dertaken to improve the structure and readability of state- Figure 1. The Delphi process in the Lentigo maligna Consensus of Experts. Original Article | Dermatol Pract Concept. 2023;13(3):e2023244 3 Round 1 (75.8%). Most respondents were senior academics, had doc- Participants were asked to independently rank a total of 51 toral degrees, and had been working in the field of skin can- statements, across seven domains, using a 4-point Likert scale cer research for more than 10 years. (‘strongly agree’, ‘agree’, ‘disagree’, ‘strongly disagree’). In Round 1, data on participant demographics were also col- LM Diagnosis lected including: biologic sex, year of birth, country of resi- Consensus was achieved in 4 out of 4 questions addressing dence, current job position, highest educational qualification LM clinical diagnosis (Table 2). More specifically, partici- obtained and time (in years) working in the field of skin can- pants agreed on that LM diagnosis should be based on a clin- cer research. Statements derived from the free-text responses ical and dermoscopic integrated approach (92%) and, when in round 1 led to eight new statements in round 2. Further, the available, RCM could be used as an adjunct for diagnosis free-text responses from Round 1 helped to clarify one state- and pre-surgical margin evaluation. Punch biopsies, possi- ment which was then added as a new statement in Round 2. bly from multiple sites, were considered the best choice for histopathologic diagnosis (agreement of 73.3%) followed by Rounds 2 and 3 broad shave biopsy (66.6%) (Table 3). In round 2, each participant received a survey comprising 23 statements which were presented alongside participants own LM Treatment responses from Round 1, as well as the group collective re- Consensus was achieved on margin-controlled surgery sponse (percentage agreement/disagreement) to each state- (83.3%) being the most appropriate primary treatment (af- ment. Participants were asked to reconsider their responses in ter biopsy) of LM. When margin-controlled surgery is not the light of the group responses via email. In round 3, each feasible, participants agreed that conventional wide ex- participant received a survey with 3 final statements (Figure 2). cision with 5-10 mm of clinical margins to the unaffected skin is optimal (73.3%). Furthermore, in cases of a pathol- Results ogy report showing an invasive component, wide surgical Of the 31 experts invited to participate in this Delphi study, appropriate choice by participants (73.3%). Regarding 29 participants completed Round 1 (89.9% response rate), the possibility of non-surgical treatments, consensus was 25 completed Round 2 (77.5% response rate) and 25 com- achieved that there is no specific age threshold to consider pleted Round 3 (77.5% response rate). Table 1 presents alternative treatment to standard surgical excision, but that the demographic characteristics of the participants in each these options should be based on patient performance status round. Participants’ mean age ranged from 51 to 55 years (80%). Imiquimod was regarded as the alternative treatment across the three rounds, and the majority resided in Europe of choice when surgery was not feasible (93.3%), followed margin-appropriate re-excision was considered the most by radiotherapy (agree 66,7%, strongly agree 26%). LM Adjuvant Therapy There was no agreement on the use of imiquimod 5% cream as an adjuvant in cases of LM with clear histologic margins (Table 3). In Round 3, for LM excised with clear margins, 48% never used imiquimod as adjuvant treatment, 40% of respondents used imiquimod ‘sometimes’, whereas 12% used imiquimod ‘always’. Finally, 70% of responders used imiquimod as adjuvant treatment in cases of narrow or histologically involved margins without clinical evidence of residual LM. Of these, 69.23% prescribed imiquimod 5-7 times per week for 6 weeks, 15.3% use imiquimod 5-7 times per week for 12 weeks, and 15.3% use imiquimod 5-7 weeks until onset of inflammatory response (Table 4). LM Follow-up Regarding LM follow-up, 62% responded that clinical Figure 2. Flow diagram illustrating the three survey rounds of the Delphi study. 4 follow-up of LM should be life-long, 50% for 10 years, and 37% for only 5 years following treatment. Original Article | Dermatol Pract Concept. 2023;13(3):e2023244 Table 1. Demographic characteristics of Delphi participants. Round 1 Round 2 Round 3 N = 29 N = 25 N = 25 Biologic Sex Male 13 (44.83%) 9 (36%) 9 (36%) Female 16 (55.17%) 16 (64%) 16 (64%) Mean age in years 55 51 51 Australia 2 2 2 Europe 22 20 20 USA 4 3 3 U.K. 1 0 0 Academic practice 25 (86.21%) 24 (96%) 24 (96%) Hospital based 2 (6.9%) 0 0 Private practice 2 (6.9%) 1 (4%) 1 (4%) MD 15 (50%) 12 (48%) 12 (48%) PhD 14 (46.47%) 12 (48%) 12 (48%) Master 1 (3.33%) 1 (4%) 1 (4%) Less than 5y 0 0 0 5 to 10y 2 (6.67%) 1 (4%) 1 (4%) More than 10y 28 (93.33%) 24 (96%) 24 (96%) Area of residence Practice model Highest education Years working in the field Y = years. Table 2. Responses to statements included in Round 1. Round 1 Agree % Disagree % Dermatoscopy improves the clinical diagnosis of LM and should always be applied 100% 0% Diagnosis of LM is based on a combined clinical and dermatoscopic examination 100% 0% The final diagnosis of LM is based on histopathologic findings 90.00% 10.00% The final diagnosis of LM is based on integration of clinical and dermatoscopic and histopathologic findings 96.67% 3.33% Reflectance confocal microscopy is useful for the diagnosis of LM 96.67% 3.33% The most appropriate diagnostic biopsy technique is excisional biopsy 46.67% 53.33% The most appropriate diagnostic biopsy technique is punch biopsy 31.04% 68.96% The most appropriate diagnostic biopsy technique is punch biopsy, possibly in multiple sites 73.34% 26.67% The most appropriate diagnostic biopsy technique is broad shave biopsy 66.66% 33.33% The most appropriate treatment of LM is surgical excision with clear margins (even narrow) 73.34% 26.66% The most appropriate treatment of LM is surgical excision with 5 mm margin 73.34% 26.66% The most appropriate treatment of LM is surgical excision with 10 mm margin 13.33% 86.66% The most appropriate treatment of LM is staged surgical excision with margin control (slow Mohs, spaghetti technique or similar) 83.34% 16.67% The most appropriate treatment of LM is Mohs micrographic surgery 43.34% 56.67% Table2 continues Original Article | Dermatol Pract Concept. 2023;13(3):e2023244 5 Table 2. Responses to statements included in Round 1. (continued) Round 1 Agree % Disagree % Alternative treatments should only be considered when the choice treatment is absolutely impossible 70.00% 30.00% Alternative treatments can also be considered for elderly individuals even in good health status 83.33% 16.67% Radiotherapy is my alternative treatment of choice 40.00% 60.00% Imiquimod 5% cream is my alternative treatment of choice 93.33% 6.66% Cryotherapy is my alternative treatment of choice 10.00% 90.00% 0% 100% Wait and see might also be an option for elderly patients 53.33% 46.67% If, after the excision, one or more margins are involved, re-excision is always mandatory 46.67% 53.33% If, after the excision, one or more margins are involved, the decision to re-excise depends on the age 66.66% 33.33% If, after the excision, one or more margins are narrower than 5mm, re-excision is mandatory 10.00% 90.00% If, after the excision, one or more margins are narrower than 5mm, the decision to re-excise depends on the age 46.67% 53.33% 0% 100% If, after the excision, one or more margins are narrower than 10mm, the decision to re-excise depends on the age 10.00% 90.00% If pathology reports an invasive component, a wide re-excision (according to Breslow thickness) is always mandatory 73.33% 26.67% If pathology reports an invasive component, the decision for wide re-excision (according to Breslow thickness) depends on the age 43.33% 56.66% I never use adjuvant treatments for LM 23.33% 76.66% An adjuvant treatment is indicated after excision of LM in clear margins (even narrow) 30.00% 70.00% An adjuvant treatment is indicated after excision of LM in 5mm margins 23.33% 76.66% An adjuvant treatment is indicated after excision of LM in 10mm margins 10.00% 90.00% Radiotherapy is the best option as an adjuvant modality 20.00% 80.00% Laser CO2/electrodissection is my alternative treatment of choice strongly agree If, after the excision, one or more margins are narrower than 10mm, re-excision is mandatory Imiquimod is the best option as an adjuvant modality 83.33% 16.67% When I use imiquimod 5% cream as an adjuvant modality, I apply it 3 days per week for 4 weeks 10.00% 90.00% When I use imiquimod as an adjuvant modality, I apply it 5 days per week for 6 weeks 50.00% 50.00% When I use imiquimod as an adjuvant modality, I apply it 7 days per week for 6 weeks 50.00% 50.00% In case of large difficult to treat LM, a multidisciplinary approach with tumor board involvement is the best choice 93.10% 6.90% 100% 0% Age threshold to start thinking alternative treatment options than the choice treatment: 80 years old 33.33% 66.67% Age threshold to start thinking alternative treatment options than the choice treatment: over 90 years old 43.33% 56.66% Age threshold to start thinking alternative treatment options than the choice treatment: over 75 years old if comorbidities 60.00% 40.00% Clinical follow up schedule for LM should be 10 years as per any other in situ melanoma 50.00% 50.00% Clinical follow up schedule for LM should be 5 years 37.93% 62.07% Clinical follow up schedule for LM should be for ever 62.07% 37.93% Tumor board should consider patient’s age, comorbidities, patient’s compliance and available facilities of the Unit (i.e. Mohs unit) Conclusions LM/LMM. A recent survey with responses from 415 of This Delphi study aimed to determine consensus among (EADV) members showed the wide variations in the diag- international experts on controversial issues related to nostic and the therapeutic approaches for LM [36]. To the the diagnosis, treatment, and surveillance of patients with best of our knowledge, the present Delphi consensus is the 6 the European Academy of Dermatology and Venereology Original Article | Dermatol Pract Concept. 2023;13(3):e2023244 Table 3. Responses to statements included in Round 2. Round 2 Agree % Disagree % The final diagnosis of LM is based only on histopathologic findings 25.93% 74.07% The final diagnosis of LM is based on integration of clinical and dermatoscopic and histopathologic findings 92.59% 7.40% The most appropriate diagnostic biopsy techniques are multiple punch biopsies and/or broad shave biopsy 85.18% 14.81% The most appropriate primary treatment (after biopsy) of LM is margin-controlled surgery. If this is not feasible, surgical excision to clinically unaffected narrow margins are optimal. 85.18% 14.82% If, after the excision, histologic margins are clear, there is no need for further excision even if the clear margins are very narrow (< 1mm) 59.25% 40.74% If pathology reports an invasive component, a wide re-excision (according to Breslow thickness) is always mandatory 77.78% 22.22% Alternative treatments should only be considered if the treatment of choice is absolutely impossible 59.26% 40.74% There is no specific age threshold to start thinking alternative treatment options but it's based on patient performance status 81.48% 18.51% Radiotherapy is a possible alternative treatment 92.60% 7.40% Wait and see might also be an option for elderly patients 77.78% 22.22% Alternative treatments should be considered in elderly or when comorbidities 85.18% 14.81% An adjuvant topical treatment of LM is beneficial after excision with clear histological margins 51.85% 48.14% When Imiquimod 5% cream is used as an adjuvant treatment, it can be applied 5 or 7 days/week for 6 weeks 70.37% 29.63% When Imiquimod 5% cream is used as an adjuvant treatment, it can be applied 5 or 7 days/week for 12 weeks 51.85% 48.14% When Imiquimod 5% cream is used as an adjuvant treatment and there is no inflammatory response after 6 weeks, there is no reason to continue the treatment 62.96% 37.04% When Imiquimod 5% cream is used as an adjuvant treatment and it has to be discontinued because of adverse reactions earlier than 6 weeks, then it should be re-initiated in order to complete the 6-weeks cycle 66.67% 33.33% Patients with LM should go under annual clinical surveillance 96.29% 3.70% Table 4. Responses to statements included in Round 3. Round 3 How often do you use Imiquimod 5% cream as an adjuvant treatment after the excision of a LM with histopathologically clear margins? always or almost always 12.00% sometimes 40.00% never or almost never 48.00% Only if you answered "sometimes" on Q1, which of the following factors influencing your decision to use Imiquimod in adjuvant modality (multiple answers are possible) (PLEASE SKIP the Q2 if you answered always/never in Q1) age 20.00% sex 0% location 0% narrow margins 70.00% Only for doctors using IMI as adjuvant: Which is your treatment schedule for imiquimod 5% cream as adjuvant therapy (PLASE SKIP this question if you answered never in Q1) 5-7 times per week for 6 weeks 69.23% 5-7 times per week for 12 weeks 15.38% 5-7 times per week until the onset of inflammatory response 15.38% Other (please specify) Original Article | Dermatol Pract Concept. 2023;13(3):e2023244 0% 7 first initiative with the goal of characterizing, describing, and Tio et al including 471 patients using imiquimod for LM homogenizing the different approaches to LM globally. showed an overall complete clinical clearance of 78% and Regarding the diagnosis of LM, strong consensus was a histopathological clearance of 77% [23]. Also, the use of achieved on the use of a combined approach that should imiquimod for more than 60 applications during a treatment include clinical and dermoscopic examination, in line with period of 12 weeks had 7.8 times greater odds of complete current guidelines that reflect routine practice in many coun- clearance compared to less than 60 total applications. Based tries [13,37,38]. Dermoscopy has been used in clinical set- on published data and our study findings, imiquimod should ting over decades to diagnose LM and to identify early LM be used for at least 60 applications if possible, when used as recurrences [9]. More recently, RCM has served as a useful primary (monotherapy) treatment. adjunct for LM diagnosis and margin mapping, although Another use of imiquimod is in the adjuvant setting RCM use is limited by a relatively scarce availability in most when narrow or histologically positive LM margins are centers and the need for extensive training [39-48]. found. In the current study, there was no consensus on A large consensus agreed to obtain multiple punch biop- whether imiquimod should be used after excision of LM in sies or a broad shave biopsy to minimize the risk of under- the setting of clear histopathologic margins, with an equal estimation of LM. A study by Ng et al showed that single number of positive and negative answers. The precise treat- punch biopsies were associated with risk of histopathologic ment schedule was not evaluated in the present Delphi con- misdiagnosis (OR 16.6), adverse outcomes (OR 20), and sensus, and further studies are warranted for clarification. A incorrect microstaging (OR 5.1) when compared with ex- multicenter study in seven European centers including 149 cisional biopsies [49]. Shave biopsies were not associated patients with LM found that surgical excision with narrow with adverse outcomes but with misdiagnosis (OR 2.6) and histopathological margins followed by imiquimod 7 times incorrect microstaging (OR 2.3) when compared with ex- per week for 6 weeks achieved a clearance rate of 94.4% cisional biopsies, albeit at a lower magnitude than single at a mean follow up of 32.5 months [26]. Another study punch biopsy. Multiple punch biopsies were not evaluated in including 45 LM cases used adjuvant imiquimod 3-5 times/ that study. Ideally, the area to be biopsied should be chosen week for 12 weeks (30 – 60 applications) [60]. They found based on dermoscopy or RCM, although this aspect was not a 94% clearance rate in patients with narrow-margins sur- included in the questionnaires [40,50]. gical resection or complete clinical but not histopathologic Regarding the best treatment modality, surgical exci- clearance of LM. sion was considered the best option for LM treatment and, Regarding additional management of LM after surgi- more specifically, surgery with controlled margins was the cal excision according to the clinical and histopathologic treatment of choice, if available. Multiple retrospective stud- margins, consensus was only reached for a few statements. ies have demonstrated a lower local recurrence rates when Specifically, the group agreed that re-excision is not manda- using margin-controlled modalities, though no prospective tory at any age when histopathologic margins are free and randomized trials have compared conventional excision clinical surgical margins were between 5 and 10 mm. The with MMS or staged excision for local recurrence [20,51]. group also agreed that re-excision is not always mandatory In addition, some studies have shown that clinical margins when histopathologic margins are free and clinical surgical wider than 5-mm may be necessary for histopathological margins were histologic narrower than 5mm. The survey did clearance of LM [52,53]. This translates into standard 5-mm not evaluate for the specific histological margin of clearance wide local excision clinical margins being associated with needed (ie 2 mm versus 3 mm). There was no agreement on recurrence rates of up to 20% [20,54-58]; although data be- the need for re-excision in case of histopathologically pos- ing of poor quality and robust studies are needed [59]. The itive surgical margins. Although the lack of agreement on main limitation to margin-controlled techniques is the need the latter points does not allow direct recommendations, it for extensive training in surgery involving comprehensive reflects a more conservative approach for LM as compared margin assessment, a dedicated histotechnology laboratory to other melanoma in situ subtypes. Strong agreement was for MMS, and the need for expert dermatopathologists with achieved on the management in case of presence of an in- quick turn-around time for staged excision with permanent vasive component, which should follow surgical guidelines sections, which limits access to these techniques [20,59]. according to Breslow thickness [27]. When surgery is not feasible or is declined by the patient Finally, as LM can recur more than 10 years after ini- due to cosmetic, functional or comorbid factors, imiquimod tial treatment and due to the high-risk of developing another 5% cream as monotherapy was regarded as the treatment neoplasm (either melanoma or keratinocyte cancers), there of choice. There was no agreement on the best therapeutic was agreement on life-long follow-up that should be per- regimen, but 5-7 times per week for 6-12 weeks (30-60 ap- formed using clinical examination, dermoscopy and, if avail- plications) was the preferred schema. A systematic review by able, RCM [40]. 8 Original Article | Dermatol Pract Concept. 2023;13(3):e2023244 This study was based on a Delphi consensus of experts, which was restricted to a highly selected group of participants and might be subject of selection bias. Only dermatologists participated and no surgical oncologists, medical oncologists, plastic surgeons, radiation oncologists, or surgical pathologists were included. Some specific scenarios might have not been addressed (eg presence of desmoplastic melanoma). Dermoscopic and RCM criteria were not included in the survey. LM is a complex melanoma subtype typically affecting cosmetic and functionally sensitive sites. It has specific challenges compared to other melanoma subtypes. This survey represents a framework on which to base further LM studies and evidence to help develop future clinical practice guidelines which are based on high level evidence. There is a need for prospective studies on LM. Acknowledgement We thank Dr Marica Mirra and Margherita Raucci for their technical assistance. References 1. Curtin JA, Fridlyand J, Kageshita T, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med. 2005;353(20): 2135-2147. DOI: 10.1056/NEJMoa050092. PMID: 16291983. 2. 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