10.5826/dpc.1303a244
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 &gt;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.
text/xml
2160-9381
3463
en
Aimilios  Lallas
https://creativecommons.org/licenses/by-nc/4.0
Dermatology Practical & Conceptual
management
Delphi Consensus Among International Experts on the Diagnosis, Management, and Surveillance for Lentigo Maligna
Text.Serial.Journal
https://dpcj.org/index.php/dpc
Original Article
2023-07-31
2023-04-24
2023-07-31
2023-08-24
e2023244
Dermatol Pract Concept
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 &gt;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.
Aimilios  Lallas
2023/07/31
10.5826/dpc.1303a244
e2023244
First Department of Dermatology, School of Medicine, Aristotle University, Thessaloniki, Greece.
2160-9381
management
en
e2023244
Swetter SM, Chen FW, Kim DD, Egbert BM. Imiquimod 5% cream as primary or adjuvant therapy for melanoma in situ, lentigo maligna type. J Am Acad Dermatol. 2015;72(6):1047-1053. DOI: 10.1016/j.jaad.2015.02.008. PMID: 25791801.
Delphi Consensus Among International Experts on the Diagnosis, Management, and Surveillance for Lentigo Maligna
https://dpcj.org/index.php/dpc/article/download/3463/2210
      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 Attribution-
NonCommercial 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 mac-
                       roscopic, 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 dif-
ficult to differentiate from its mimickers, necessitating a bi-
opsy 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 junc-         Study Design
tion with frequent adnexal involvement [10-12]. Differentia-
                                                                     The study used the Delphi consensus methodology. The tech-
tion between LM and melanocytic hyperplasia of sun-damaged
                                                                     nique has been described elsewhere [33-35]. Three rounds of
skin can be challenging, especially if a small partial biopsy is
                                                                     the modified Delphi method were required to finalize con-
available (eg punch biopsy) [13]. It is worth mentioning that
                                                                     sensus (Figure 1). Consensus was defined as >75% of par-
after partial biopsy of LM, an invasive component (ie upstag-
                                                                     ticipants agreeing/strongly agreeing or disagreeing/strongly
ing) might be found in 9% of the cases [14-17].
                                                                     disagreeing with a statement was based on prior Delphi stud-
    Regarding treatment, wide surgical excision is consid-
                                                                     ies [33,34]. A dropout rate of 20% was expected over the
ered the standard therapy for melanoma on the trunk and
                                                                     rounds, in accordance with previous Delphi studies.
extremities and most randomized controlled trials of surgical
margins for invasive melanoma excluded LM. In the recent             Expert Panel Recruitment
years, the use of lateral and deep margin-controlled tech-
                                                                     The invited participants were either members of the IDS
niques such as staged excision with permanent sections or
                                                                     Executive Board, academics or authors of articles related to
Mohs micrographic surgery (MMS) have been developed for
                                                                     skin cancer and melanoma. To complete the Delphi process,
LM [13,18-20]. Additionally, nonsurgical treatments such
                                                                     participants were required to respond across all three rounds.
as radiotherapy and imiquimod have been used for LM ther-
                                                                     Therefore, those who did not respond to Round 1 were not
apy [13,21-26].
                                                                     invited to participate in Round 2 and similarly for Round 3.
    Despite LM progressing slowly, once invasive, LM mel-
                                                                     There was space for free-text responses from Round 1 to be
anoma (LMM) has the same prognosis when adjusted for
                                                                     incorporated as new statements in Round 2 and re-evaluated
Breslow thickness compared to other melanoma subtypes
                                                                     considering the group consensus in Round 3 (Figure 1). All
[27]. However, the risk of LM to progress to invasive mela-
                                                                     surveys were administered using SurveyMonkey (Momen-
noma is believed to be very low, around 2% – 5% [28,29].
                                                                     tive Inc.) through a web link or QR code.
This is particularly relevant in the light of evidence suggest-
                                                                            Initial statements presented on the first round were devel-
ing that overdiagnosis of melanomas that do not have the
                                                                     oped by 3 core authors (C.L., P.T., A.L.), following a review
potential to harm patients might result in unneeded treat-
                                                                     of the literature. The survey statements were constructed to
ments and unnecessary physical, psychological, and social
                                                                     highlight key challenges and opportunities, and to obtain
costs [30,31]. Considering the above issues, the management
                                                                     actionable statements for effective approaches in clinical
of LM remains challenging in many aspects [25,32].
                                                                     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-
                                                                     dertaken to improve the structure and readability of state-
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.




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-
                                                                     ogy report showing an invasive component, wide surgical
Results                                                              margin-appropriate re-excision was considered the most
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
                                                                     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 his-
                                                                     tologically 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   follow-up of LM should be life-long, 50% for 10 years, and
Delphi study.                                                        37% for only 5 years following treatment.



4                                                                        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
 Area of residence
 Australia                              2                            2                      2
 Europe                                 22                           20                     20
 USA                                    4                            3                      3
 U.K.                                   1                            0                      0
 Practice model
 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%)
 Highest education
 MD                                     15 (50%)                     12 (48%)               12 (48%)
 PhD                                    14 (46.47%)                  12 (48%)               12 (48%)
 Master                                 1 (3.33%)                    1 (4%)                 1 (4%)
 Years working in the field
 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%)
 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                   96.67%     3.33%
 histopathologic findings
 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            83.34%    16.67%
 Mohs, spaghetti technique or similar)
 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%
 Laser CO2/electrodissection is my alternative treatment of choice strongly agree                                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         66.66%       33.33%
 age
 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               46.67%       53.33%
 depends on the age
 If, after the excision, one or more margins are narrower than 10mm, re-excision is mandatory                    0%        100%
 If, after the excision, one or more margins are narrower than 10mm, the decision to re-excise              10.00%       90.00%
 depends on the age
 If pathology reports an invasive component, a wide re-excision (according to Breslow thickness) is         73.33%       26.67%
 always mandatory
 If pathology reports an invasive component, the decision for wide re-excision (according to                43.33%       56.66%
 Breslow thickness) depends on the age
 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%
 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          93.10%        6.90%
 is the best choice
 Tumor board should consider patient’s age, comorbidities, patient’s compliance and available                 100%            0%
 facilities of the Unit (i.e. Mohs unit)
 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           43.33%       56.66%
 years old
 Age threshold to start thinking alternative treatment options than the choice treatment: over 75           60.00%       40.00%
 years old if comorbidities
 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%


Conclusions                                                      LM/LMM. A recent survey with responses from 415 of
                                                                 the European Academy of Dermatology and Venereology
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                                                                     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                       92.59%     7.40%
 histopathologic findings
 The most appropriate diagnostic biopsy techniques are multiple punch biopsies and/or broad                85.18%    14.81%
 shave biopsy
 The most appropriate primary treatment (after biopsy) of LM is margin-controlled surgery. If              85.18%    14.82%
 this is not feasible, surgical excision to clinically unaffected narrow margins are optimal.
 If, after the excision, histologic margins are clear, there is no need for further excision even if the   59.25%    40.74%
 clear margins are very narrow (< 1mm)
 If pathology reports an invasive component, a wide re-excision (according to Breslow thickness)           77.78%    22.22%
 is always mandatory
 Alternative treatments should only be considered if the treatment of choice is absolutely                 59.26%    40.74%
 impossible
 There is no specific age threshold to start thinking alternative treatment options but it's based on      81.48%    18.51%
 patient performance status
 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              70.37%    29.63%
 for 6 weeks
 When Imiquimod 5% cream is used as an adjuvant treatment, it can be applied 5 or 7 days/week              51.85%    48.14%
 for 12 weeks
 When Imiquimod 5% cream is used as an adjuvant treatment and there is no inflammatory                     62.96%    37.04%
 response after 6 weeks, there is no reason to continue the treatment
 When Imiquimod 5% cream is used as an adjuvant treatment and it has to be discontinued                    66.67%    33.33%
 because of adverse reactions earlier than 6 weeks, then it should be re-initiated in order to
 complete the 6-weeks cycle
 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)                                                                                                   0%



Original Article | Dermatol Pract Concept. 2023;13(3):e2023244                                                                 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,                  8. GGuitera P, Pellacani G, Crotty KA, et al. The impact of in vivo
which was restricted to a highly selected group of partici-                    reflectance confocal microscopy on the diagnostic accuracy of
                                                                               lentigo maligna and equivocal pigmented and nonpigmented
pants and might be subject of selection bias. Only derma-
                                                                               macules of the face. J Invest Dermatol. 2010;130(8):2080-2091.
tologists participated and no surgical oncologists, medical
                                                                               DOI: 10.1038/jid.2010.84. PMID: 20393481.
oncologists, plastic surgeons, radiation oncologists, or sur-               9. SSchiffner R, Schiffner-Rohe J, Vogt T, et al. Improvement of
gical pathologists were included. Some specific scenarios                      early recognition of lentigo maligna using dermatoscopy. J Am
might have not been addressed (eg presence of desmoplastic                     Acad Dermatol. 2000;42(1 Pt 1):25-32. DOI: 10.1016/s0190-
melanoma). Dermoscopic and RCM criteria were not in-                           9622(00)90005-7. PMID: 10607316.
                                                                           10. Farrahi F, Egbert BM, Swetter SM. Histologic similarities be-
cluded in the survey.
                                                                               tween lentigo maligna and dysplastic nevus: importance of clin-
    LM is a complex melanoma subtype typically affecting
                                                                               icopathologic distinction. J Cutan Pathol. 2005;32(6):405-412.
cosmetic and functionally sensitive sites. It has specific chal-               DOI: 10.1111/j.0303-6987.2005.00355.x. PMID: 15953373.
lenges compared to other melanoma subtypes. This survey                    11. Connolly KL, Giordano C, Dusza S, Busam KJ, Nehal K. Fol-
represents a framework on which to base further LM studies                     licular involvement is frequent in lentigo maligna: Implications
and evidence to help develop future clinical practice guide-                   for treatment. J Am Acad Dermatol. 2019;80(2):532-537.
                                                                               DOI: 10.1016/j.jaad.2018.07.071. PMID: 30266559. PMCID:
lines which are based on high level evidence. There is a need
                                                                               PMC6333487.
for prospective studies on LM.
                                                                           12. Navarrete-Dechent C, Aleissa S, Connolly K, et al. Clinical
                                                                               size is a poor predictor of invasion in melanoma of the lentigo

Acknowledgement                                                                maligna type. J Am Acad Dermatol. 2021;84(5):1295-1301.
                                                                               DOI: 10.1016/j.jaad.2020.10.023. PMID: 33096134. PMCID:
                                                                               PMC8046713.
We thank Dr Marica Mirra and Margherita Raucci for their
                                                                           13. Fosko SW, Navarrete-Dechent CP, Nehal KS. Lentigo Maligna-
technical assistance.
                                                                                 Challenges, Observations, Imiquimod, Confocal Microscopy, and
                                                                                 Personalized Treatment. JAMA Dermatol. 2018;154(8):879-881.
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Original Article | Dermatol Pract Concept. 2023;13(3):e2023244                                                                          11
