10.5826/dpc.1204a182
Introduction: In patients with multiple nevi, sequential imaging using total body skin photography (TBSP) coupled with digital dermoscopy (DD) documentation reduces unnecessary excisions and improves the early detection of melanoma. Correct patient selection is essential for optimizing the efficacy of this diagnostic approach.
Objectives: The purpose of the study was to identify, via expert consensus, the best indications for TBSP and DD follow-up.
Methods: This study was performed on behalf of the International Dermoscopy Society (IDS). We attained consensus by using an e-Delphi methodology. The panel of participants included international experts in dermoscopy. In each Delphi round, experts were asked to select from a list of indications for TBSP and DD.
Results: Expert consensus was attained after 3 rounds of Delphi. Participants considered a total nevus count of 60 or more nevi or the presence of a CDKN2A mutation sufficient to refer the patient for digital monitoring.  Patients with more than 40 nevi were only considered an indication in case of personal history of melanoma or red hair and/or a MC1R mutation or history of organ transplantation.
Conclusions: Our recommendations support clinicians in choosing appropriate follow-up regimens for patients with multiple nevi and in applying the time-consuming procedure of sequential imaging more efficiently. Further studies and real-life data are needed to confirm the usefulness of this list of indications in clinical practice. 
text/xml
2160-9381
2213
en
Giuseppe Argenziano
https://creativecommons.org/licenses/by-nc/4.0
Dermatology Practical & Conceptual
total body photography
Indications for Digital Monitoring of Patients With Multiple Nevi: Recommendations from the International Dermoscopy Society
Text.Serial.Journal
https://dpcj.org/index.php/dpc
Original Article
2022-10-31
2021-12-05
2022-10-31
2022-12-02
e2022182
Dermatol Pract Concept
Introduction: In patients with multiple nevi, sequential imaging using total body skin photography (TBSP) coupled with digital dermoscopy (DD) documentation reduces unnecessary excisions and improves the early detection of melanoma. Correct patient selection is essential for optimizing the efficacy of this diagnostic approach.
Objectives: The purpose of the study was to identify, via expert consensus, the best indications for TBSP and DD follow-up.
Methods: This study was performed on behalf of the International Dermoscopy Society (IDS). We attained consensus by using an e-Delphi methodology. The panel of participants included international experts in dermoscopy. In each Delphi round, experts were asked to select from a list of indications for TBSP and DD.
Results: Expert consensus was attained after 3 rounds of Delphi. Participants considered a total nevus count of 60 or more nevi or the presence of a CDKN2A mutation sufficient to refer the patient for digital monitoring.  Patients with more than 40 nevi were only considered an indication in case of personal history of melanoma or red hair and/or a MC1R mutation or history of organ transplantation.
Conclusions: Our recommendations support clinicians in choosing appropriate follow-up regimens for patients with multiple nevi and in applying the time-consuming procedure of sequential imaging more efficiently. Further studies and real-life data are needed to confirm the usefulness of this list of indications in clinical practice. 
Giuseppe Argenziano
2022/10/31
10.5826/dpc.1204a182
e2022182
Dermatology Unit, University of Campania “Luigi Vanvitelli”, Naples, Italy
2160-9381
total body photography
en
e2022182
Read J, Wadt KA, Hayward NK. Melanoma genetics. J Med Genet. 2016 Jan;53(1):1-14. doi: 10.1136/jmedgenet-2015-103150. Epub 2015 Sep 3. PMID: 26337759.
Indications for Digital Monitoring of Patients With Multiple Nevi: Recommendations from the International Dermoscopy Society
https://dpcj.org/index.php/dpc/article/download/2213/1822
        Indications for Digital Monitoring of Patients
         With Multiple Nevi: Recommendations from
            the International Dermoscopy Society
   Teresa Russo1, Vincenzo Piccolo1, Elvira Moscarella1, Philipp Tschandl2, Harald Kittler2,
         John Paoli3, Aimilios Lallas4, Ralph P. Braun5, Luc Thomas6, H. Peter Soyer7,
      Josep Malvehy8, Susana Puig8, Ashfaq Marghoob9, Alon Scope10, Andreas Blum11,
   Allan C. Halpern9, Horacio Cabo12, Scott Menzies13, Wilhelm Stolz14, Masaru Tanaka15,
       Harold Rabinovitz16, Rainer Hofmann-Wellenhof17, Renato Marchiori Bakos18,
    Iris Zalaudek19, Giovanni Pellacani20, Ana Varela Veiga21, Laura Rosende Maceiras21,
                      Cristina de las Heras-Sotos21, Giuseppe Argenziano1


 1 Dermatology Unit, University of Campania “Luigi Vanvitelli”, Naples, Italy
 2 Department of Dermatology, Medical University of Vienna, Vienna, Austria
 3 Department of Dermatology and Venereology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg,
   Gothenburg, Sweden
 4 First Department of Dermatology, Aristotle University, Thessaloniki, Greece
 5 Department of Dermatology, University Hospital Zürich, Zürich, Switzerland
 6 Department of Dermatology, Lyon-1 University, and Cancer research center Lyon, Lyon, France
 7 The University of Queensland Diamantina Institute, The University of Queensland, Dermatology Research Centre, Brisbane, Australia
 8 Melanoma Unit, Dermatology Department, Hospital Clinic Barcelona, Universitat de Barcelona & IDIBAPS & CIBERER, Barcelona, Spain
 9 Memorial Sloan Kettering Cancer Center, Hauppauge, New York, USA
10 The Kittner Skin Cancer Screening and Research Institute, Sheba Medical Center and Sackler School of Medicine, Tel Aviv University,
   Tel Aviv, Israel
11 Public, Private and Teaching Practice of Dermatology, Konstanz, Germany
12 Dermatology Institute of Medical Research, University of Buenos Aires, Buenos Aires, Argentina
13 Discipline of Dermatology, Sydney Medical School, The University of Sydney and Sydney Melanoma Diagnostic Centre, Royal Prince
   Alfred Hospital, Camperdown, NSW Australia
14 Department of Dermatology, Allergology, and Environmental Medicine Clinic Thalkirchen, Hospital Munich, Munich, Germany
15 Department of Dermatology, Tokyo Women’s Medical University Medical Center East, Japan
16 Department of Dermatology Medical College of Georgia, Augusta, United States
17 Department of Dermatology and Venerology, Medical University of Graz, Graz, Austria
18 Department of Dermatology, Hospital de Clınicas de Porto Alegre - Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
19 Department of Dermatology, University of Trieste, Trieste, Italy
20 Department of Dermatology, University of Rome La Sapienza, Rome, Italy
21 Department of Dermatology, University Hospital Complex of Ferrol, A Coruña, Spain



Key words: dermoscopy, dermatoscopy, digital monitoring, multiple nevi, total body photography
Citation: Russo T, Piccolo V, Moscarella E, et al. Indications For Digital Monitoring Of Patients With Multiple Nevi: Recommendations
From The International Dermoscopy Society. Dermatol Pract Concept. 2022;12(4):e2022182. DOI: https://doi.org/10.5826/dpc.1204a182
Accepted: January 13, 2022; Published: October 2022
Copyright: ©2022 Russo 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.




Original Article | Dermatol Pract Concept. 2022;12(4):e2022182                                                                      1
Competing interests: None.
Authorship: All authors have contributed significantly to this publication.
Corresponding author: Vincenzo Piccolo, Dermatology Unit, University of Campania “Luigi Vanvitelli”, Naples, Italy.
E-mail: piccolo.vincenzo@gmail.com




    ABSTRACT           Introduction: In patients with multiple nevi, sequential imaging using total body skin photography
                       (TBSP) coupled with digital dermoscopy (DD) documentation reduces unnecessary excisions and im-
                       proves the early detection of melanoma. Correct patient selection is essential for optimizing the effica-
                       cy of this diagnostic approach.
                       Objectives: The purpose of the study was to identify, via expert consensus, the best indications for
                       TBSP and DD follow-up.
                       Methods: This study was performed on behalf of the International Dermoscopy Society (IDS). We
                       attained consensus by using an e-Delphi methodology. The panel of participants included international
                       experts in dermoscopy. In each Delphi round, experts were asked to select from a list of indications
                       for TBSP and DD.
                       Results: Expert consensus was attained after 3 rounds of Delphi. Participants considered a total nevus
                       count of 60 or more nevi or the presence of a CDKN2A mutation sufficient to refer the patient for
                       digital monitoring. Patients with more than 40 nevi were only considered an indication in case of per-
                       sonal history of melanoma or red hair and/or a MC1R mutation or history of organ transplantation.
                       Conclusions: Our recommendations support clinicians in choosing appropriate follow-up regimens
                       for patients with multiple nevi and in applying the time-consuming procedure of sequential imaging
                       more efficiently. Further studies and real-life data are needed to confirm the usefulness of this list of
                       indications in clinical practice.




Introduction                                                                  Melanomas detected via sequential monitoring with
                                                                         TBSP and DD usually escape baseline detection because they
A combined clinical and dermoscopic examination of me-                   neither display melanoma-specific criteria, nor substantially
lanocytic lesions allows for the recognition of most mela-               differ from the patients nevi [9]. This more frequently occurs
nomas at a baseline visit [1-3]. In a patient with a single              in individuals with peculiar nevus phenotypes, such as fa-
doubtful lesion, although only moderately atypical, the best             milial melanoma patients [10]. However, TBSP and DD are
approach is prompt excision and histopathologic examina-                 time-consuming techniques, so appropriate indications are
tion. Conversely, in patients with multiple nevi, the approach           crucial for the method to be effective. Recently, a study by
of excising any atypical lesion appears neither reasonable               Haenssle et al on 688 patients concluded that patients with
nor cost-effective. In this scenario, sequential monitoring              multiple nevi and additional risk factors for melanoma had
and imaging using total body skin photography (TBSP)                     the highest benefit from sequential DD imaging in terms of
coupled with digital dermoscopy (DD) documentation rep-                  early melanoma detection over time [6,7]. Several additional
resents the best approach to minimize unnecessary excisions              studies deal with the relevant additional risk factors to be
while maximizing early detection of melanoma (Figures 1                  evaluated when referring a patient for digital monitoring,
and 2). While DD is useful to evaluate morphologic changes               but there is some heterogeneity among them [11-14]. Since
of the individual monitored lesions, TBSP mostly helps in the            a consensus agreement is still lacking, we are trying to pro-
recognition of new lesions or significant changes in lesions             vide one.
that were not previously documented dermoscopically [2-7].
    It has been calculated that about 10% of melanomas are
                                                                         Objectives
diagnosed over time in the context of clinically and dermo-
scopically inconspicuous tumors in patients with multiple                The purpose of this study was, therefore, to set up a list of
and/or atypical nevi [1,2]. In a recent cohort study dealing             indications for digital follow-up performed via TBSP cou-
with high-risk patients in a melanoma dermatology clinic,                pled with DD through the selection of specific melanoma
60.8% of melanomas were found with the assistance of                     risk factors that may serve to better recognize patients who
TBSP (31.6%) or sequential DD imaging (29.2%) [3].                       will benefit from this approach.



2                                                                             Original Article | Dermatol Pract Concept. 2022;12(4):e2022182
Figure 1. Patient with more than 60 nevi. Side by side comparison of 3 lesions (A, B, C) during follow-up. Note the increased regression
structures over time of the first lesion (A) on the left, which was therefore excised and diagnosed as a melanoma in situ.




Figure 2. Patient with more than 40 nevi and previous melanoma. Lesion C showed remarkable change in the lesion after 3 months of
follow-up and was therefore excised and confirmed to be a melanoma in situ, while lesion A and B did not show significant modifications.




Methods                                                               received the SurveyMonkey (https://www.surveymonkey.
                                                                      com/) link and password for taking part in the survey.
This study was performed on behalf of the International                   The study consisted of two steps: (I) identification of ma-
Dermoscopy Society (IDS), with consensus obtained through             jor risk factors for melanoma in patients with multiple nevi
the e-Delphi methodology [15]. Participants were recruited            according to the most relevant meta-analyses and studies; and
among the executive board members of the IDS who were                 (II) selection of indications for TBSP and DD after a three-
specifically asked by email invitation for their consent to take      round questionnaire proposed to a panel of international ex-
part in the study. Only those who accepted to join the project        perts in dermoscopy. During each round, participants were



Original Article | Dermatol Pract Concept. 2022;12(4):e2022182                                                                        3
given a 4-week period to complete the survey and reminders             the Oxford 2011 Levels of Evidence [16]. Melanoma risk fac-
were sent to non-responders on days 7, 14 and 21. The three            tors were expressed in terms of relative risk (RR) and odds ratio
rounds were conducted over a 6-month period and the final list         (OR) with the exception of CDKN2A mutation [17-21], for
of indications was obtained and completed within 8 months.             which we considered the ratio between lifetime risk of mela-
The aforementioned criteria for the enrolment of patients for          noma in patients with the mutation and lifetime risk in the gen-
digital monitoring programs were finally drawn up with the             eral population (Table 1). Variables increasing the melanoma
collaboration of expert members of the IDS, who contributed            risk at least 3 times were considered as major risk factors; vari-
to the study with their answers, advice and feedback.                  ables increasing the risk between 2 and 3 times were considered
                                                                       as intermediate risk factors; and variables increasing the risk
Step 1: Identification of Risk Factors for                             by less than 2 times were considered as minor risk factors [22].
Melanoma in Patients With Multiple Nevi
The questions for the survey were obtained after a literature          Step 2: Selection of Indications for TBSP and DD
search of relevant meta-analyses and studies about major mela-         After a Three-round Questionnaire Proposed to a
noma risk factors. The presence of multiple nevi was considered        Panel of International Experts in Dermoscopy
the basic requirement for patient enrolment in a digital moni-         Participants were first asked if a given risk factor, in combi-
toring program using TBSP coupled with DD. The number and              nation with the presence of multiple nevi, is relevant enough
type of nevi needed to reach the cut-off point were discussed in       to justify inclusion in the list of indications. The questions
the second step. The lower size limit to consider the nevus eligi-     were uploaded in two different blinded Delphi rounds on the
ble to be counted has been conventionally established at 2 mm.         SurveyMonkey platform and were proposed to the experts
The proposed questions were associated with their background           who were included for the 1st round survey. They were asked
studies and their relative levels of evidence assigned based on        to judge their agreement for each sentence using the 5-point


Table 1. Risk factors for cutaneous melanomas and their relative risks (modified from Chen et al [4]).
                   Characteristic                      Risk factor for cutaneous melanoma             Summary statistics (RR, OR)
 Common nevi (total number)                                               16-40                                     1.47
                                                                          41-60                                     2.24
                                                                          61-80                                     3.26
                                                                          81-100                                    4.74
                                                                         101-120                                    6.89
 Atypical nevi (total number)                                                1                                      1.45
                                                                             2                                      2.10
                                                                             3                                      3.03
                                                                             4                                      4.39
                                                                             5                                      6.36
 Eye color                                                                 blue                                     1.47
                                                                           green                                    1.61
                                                                           hazel                                    1.52
 Hair color                                                                 red                                     3.64
                                                                          blond                                     1.96
                                                                        light brown                                 1.62
 Family history of melanoma                                              positive                                   1.74
 Personal history of non-melanoma skin cancer                            positive                                   2.74
 Genetic factors                                                     CDKN2A mutation                                 10a
 Sun exposure                                                  strong history of sunburn                            2.03
                                                               ever use of tanning booth                            2.06
 Organ transplant history                                                positive                                   2.38

RR = relative risk; OR = odds ratio.
a
  For CDKN2A, the risk is based on the ratio between the lifetime risk of melanoma in patients with the mutation and the
lifetime risk of melanoma in the general population.




4                                                                          Original Article | Dermatol Pract Concept. 2022;12(4):e2022182
Likert Scale for Surveys (1: strongly agree, 2: agree; 3: neither   for selecting patients suitable for digital monitoring were
agree nor disagree; 4: disagree; 5: strongly disagree) [23].        established.
                                              nd
    Each parameter was admitted to the 2 round question-               Fifteen (65%) experts agreed on the definition of a
naire of the consensus procedure if at least 65% of the ex-         common nevus being a macular or papular symmetrical le-
perts rated it 1 or 2 according to the Likert Scale for Surveys     sion, smaller than 6 mm in diameter, uniform in color, with
[23]. The questions of the 2nd round were formulated based          well-defined borders and regular overall architecture in der-
         st
on the 1 one and, again, participants were asked to answer          moscopy. Consequently, an atypical nevus was defined as a
using the 5-point scale. Finally, in the last round, participants   flat or slightly raised lesion usually larger than 6 mm, with
were asked to confirm or refute the list of indications ob-         ill-defined borders, irregular pigmentation, and a mixed pat-
tained as a result of the first two rounds.                         tern dermoscopically.
                                                                       Given the RR of 3.26 of developing melanoma in patients
Results                                                             with 61-80 common nevi [24], 70% (N = 16) of responders
                                                                    agreed to establish the threshold of at least 60 common nevi
First Round                                                         to select patients requiring digital monitoring, in the absence
Of the executive board members of the IDS invited by email,         of additional risk factors. The experts showed their consen-
all (N = 27) confirmed their participation and received the         sus to reduce the threshold to 40 common nevi (RR 2.24) if
link to answer the round 1 questionnaire anonymously. Of            the patient had additional melanoma risk factors because of
them, 25 completed the questionnaire. More than 90%                 a higher cumulative risk of melanoma. However, the experts
of experts agreed (32%, N = 8) or strongly agreed (64%,             did not agree on establishing a cut-off number of atypical
N = 16) on the necessity to establish selection criteria for        nevi as an indication for TBSP and DD if this was the only
patients with multiple nevi who need digital monitoring. For        melanoma risk factor of the patient.
92% (N = 23) of participants, the total number of nevi was             For the other melanoma risk factors, we asked whether
considered relevant to select these patients.                       the anxiety (as suggested by 2 experts) could be an indica-
    Table 1 shows the most common risk factors for mel-             tion for TBSP and DD. Only 52% (N = 12) of participants
anoma and their relative risks. The great majority agreed           considered it a relevant risk factor in patients with multiple
(88%, N = 22) that significant risk factors for melanoma            nevi. This criterion was therefore excluded from the final list
were those having a RR (relative risk) > 2. Moreover, 92%           of indications.
(N = 23) of participants agreed that patients with multiple            Nineteen (83%) experts agreed on considering a per-
nevi and at least one additional risk factor for melanoma           sonal history of melanoma coupled with more than 40 nevi
could have a higher cumulative risk for melanoma than pa-           as an indication for TBSP and DD. They also agreed to enlist
tients with only one risk factor, thus making them more eli-        patients for digital monitoring if they had more than 40 nevi
gible for long-term digital monitoring.                             and red hair, with (65%, N = 15) or without a MC1R mu-
    Participants were asked to propose other factors that           tation (74%, N = 17). Organ transplant recipients with at
should be considered as indication for digital monitoring.          least 40 nevi were also judged suitable for digital monitoring
Two of 25 participants proposed the anxiety of patients with        (65%, N = 15). Finally, almost all members agreed (91.3%,
multiple nevi as a criterion for digital monitoring. Therefore,     N = 21) on considering digital monitoring to be useful in pa-
this criterion was added for the second round of questions.         tients with a CDKN2A mutation (familial melanoma) even
In the open answers, some participants underlined the ne-           in patients with less than 40 nevi.
cessity to avoid digital monitoring in the following clinical          In the open final discussion of this round, with almost
scenarios: (i) in children before puberty, even if multiple nevi    total agreement among the experts, it emerged that even if in
were present; (ii) in patients with complex health conditions       absence of referring relative risk data, other rarer identified
that can render the examination difficult; (iii) in the context     melanoma-predisposing mutations different from CDKN2A
of nodular lesions, especially if rapidly changing.                 and MC1R variants (ie BAP-1, CDK-4, and MIT-F) should
                                                                    not be ignored independently from the nevus count.
Second Round                                                           There was no agreement on indicating digital monitoring
The 2nd round questionnaire was sent to the 25 members              in patients with few atypical nevi or with less than 40 nevi.
who completed the first one, with 23 completing the round.          Personal history of non-melanocytic skin cancer, sunbed ex-
At first, this round had the purpose to establish the number        posure or sunburns were not considered as valid criteria to
and type of nevi needed as cut-off for the definition of a          select a patient for TBSP and DD even when associated with
patient with multiple nevi; secondly, the additional criteria       the presence of more than 40 nevi.




Original Article | Dermatol Pract Concept. 2022;12(4):e2022182                                                                   5
Third Round                                                        to be 2.24 for a number of common nevi ranging from 41-60
The results of the second round allowed us to propose              nevi and 3.26 for 61-80 nevi. Thus, patients with more than
the following five indications for digital monitoring in the       40 nevi (with a RR between 2 and 3) were considered to
third round:                                                       deserve this follow-up procedure only if presenting with ad-
                                                                   ditional risk factors, namely: a personal history of melanoma,
1. Patients with more than 60 melanocytic nevi.                    red hair with or without a MC1R variant associated to mela-
2. Patients with a CDKN2A mutation or other rarer                  noma risk or a history of organ transplantation [25,26].
     high-risk melanoma genetic variants.                              In the same meta-analysis by Gandini et al, patients with
3. Patients with more than 40 melanocytic nevi and a per-          two atypical nevi showed a RR of 2.10 [25,26]. Therefore,
     sonal history of melanoma.                                    we asked participants if patients with multiple nevi (more
4. Patients with more than 40 melanocytic nevi and red hair        than 40) and at least 2 atypical nevi should be enrolled for
     and/or a MC1R mutation                                        digital monitoring. This criterion probably did not reach
5. Patients with more than 40 melanocytic nevi and a his-          a consensus because it is very frequent that a patient with
     tory of organ transplantation.                                more than 60 nevi also exhibits some atypical ones.
                                                                       In 2015, Chen et al found a stable 2- to 3-fold increased
     This final list (Table 2) was proposed by mail to the 25      risk depending on the number of previous melanomas, in
members of the first Delphi round, clarifying that the strategy    both patients with familial melanoma and those with spo-
of silent consensus would be used (i.e. no answer would be         radic melanoma(s) [27]. For instance, in patients with a sin-
interpreted as a positive response). Ultimately, 17 members        gle previous melanoma, the risk for a second melanoma was
(68%) confirmed their consensus to this list of criteria, while    2.5 for patients with familial melanoma and 2.3 in patients
the remaining participants expressed their silent consensus.       with a sporadic melanoma. In 2019, Lallas et al in a prospec-
                                                                   tive study in a cohort of 977 patients showed 8% cumula-
                                                                   tive risk of second primary melanoma, thus highlighting the
Conclusions
                                                                   value of TBSP and DD in this group of patients [28]. Accord-
In the last decade, many studies focused on digital moni-          ing to these findings, the personal history of melanoma (both
toring of patients with multiple nevi, with special emphasis       in familial melanoma and in sporadic melanoma) was judged
on the duration and scheduling of follow-up visits, the type       as a very effective criterion to better select patients for digital
and number of lesions to be digitally documented, and the          monitoring, as also suggested by Haenssle et al [6,7].
type of changes that should lead to a biopsy [3-5]. How-               In 2010, Wheless et al reported a RR of 2.74 for de-
ever, no sufficient and exhaustive data have been reported         veloping melanoma in patients with a history of NMSC,
about the indications for patient enrolment to digital mon-        compared to controls with no prior NMSC [29]. This group
itoring. Being aware of the costs and duration of the TBSP         of patients, even when having multiple nevi, was not con-
and DD procedure, our aim was to more precisely identify           sidered eligible for digital monitoring. Given the high prev-
the patient categories that can benefit from this diagnostic       alence of NMSC, this criterion could potentially increase
approach [24].                                                     the number of patients referred for this special follow-up
     A high total number of nevi is clearly the basic condition    procedure too much, without a real benefit in finding more
to include a patient in a digital monitoring program. The par-     melanomas over time.
ticipants considered a total nevus count of at least 60 (RR >3)        In contrast, almost all participants agreed on including
sufficient to refer the patient for digital monitoring. This was   the red hair phenotype in the final list of indications. In a
based on a meta-analysis published by Gandini et al in 2005        meta-analysis on phenotypic risk factors for cutaneous mel-
that confirmed such patients’ propensity to develop mela-          anoma, the red hair phenotype was the only phenotypic as-
noma [25,26]. In detail, the higher the number of common           pect found to have a RR greater than 3 (3.64) for melanoma
nevi, the higher the RR for melanoma, which was estimated          development, while all the other clinical features showed a


               Table 2. List of indications for digital monitoring in patient with multiple nevi.
                             Indications for digital monitoring in patients with multiple nevi.
    I. Patients with more than 60 melanocytic nevi.
    II. Patients with a CDKN2A mutation or other rarer high-risk melanoma genetic variants.
 III. Patients with more than 40 melanocytic nevi and a personal history of melanoma.
 IV. Patients with more than 40 melanocytic nevi and red hair and/or a MC1R mutation
    V. Patients with more than 40 melanocytic nevi and a history of organ transplantation.



6                                                                      Original Article | Dermatol Pract Concept. 2022;12(4):e2022182
RR below 2 [5,25,26]. Particularly, different studies, as that         of primary melanoma: a meta-analysis of studies per- formed in
of Duffy et al confirmed the importance of the association             a clinical setting. Br J Dermatol. 2008;159(3):669–676. DOI:
                                                                       10.1111/j.1365-2133.2008.08713.x. PMID: 18616769.
of a MC1R genotype and the presence of multiple nevi in
                                                                    2. Brancaccio G, Russo T, Lallas A, Moscarella E, Agozzino M,
contributing synergically to increase the individual’s mela-
                                                                       Argenziano G. Melanoma: clinical and dermoscopic diagnosis.
noma risk [30-32].                                                     G Ital Dermatol Venereol. 2017;152(3):213-223. DOI:
    A RR for melanoma of 2.03 was found in a meta-analysis             10.23736/S0392-0488.17.05571-7. PMID: 28121084.
by Gandini et al in case of strong sunburn history [33]. Sim-       3. Guitera P, Menzies SW, Coates E, et al. Efficiency of Detect-
ilarly, a large case-control study from the Nurses Health              ing New Primary Melanoma Among Individuals Treated in
                                                                       a High-risk Clinic for Skin Surveillance. JAMA Dermatol.
Study published in 2006 found an OR of 2.06 for “ever” ver-
                                                                       2021;157(5):521–530. DOI: 10.1001/jamadermatol.2020.5651.
sus “never” usage of tanning booths [34]. Despite this risk,
                                                                       PMID: 33729464. PMCID: PMC7970391.
the IDS members did not consider patients with a strong his-        4. Moscarella E, Tion I, Zalaudek I, et al. Both short-term and
tory of sunburn or ever use of tanning booths to be qualified          long-term dermoscopy monitoring is useful in detecting mela-
for digital monitoring if they had less than 60 nevi.                  noma in patients with multiple atypical nevi. J Eur Acad Der-
    Concerning the potentially increased risk of melanoma              matol Venereol. 2017;31(2):247-251. DOI: 10.1111/jdv.13840.
after organ transplantation, the standardized incidence ratio          PMID: 27422807.
                                                                    5. Chen ST, Geller AC, Tsao H. Update on the Epidemiology of Mel-
for melanoma was reported to be 2.38 in this population,
                                                                       anoma. Curr Dermatol Rep. 2013;2(1):24-34. DOI: 10.1007/
indicating a substantially increased risk [5,35,36]. Although
                                                                       s13671-012-0035-5. PMID: 23580930. PMCID: PMC3619431.
other immune deficiencies increase the melanoma risk, their         6. Haenssle HA, Korpas B, Hansen-Hagge C, et al. Selection
RRs are not well calculated yet. Thus, participants reached the        of patients for long-term surveillance with digital dermos-
consensus to refer patients with a history of organ transplan-         copy by assessment of melanoma risk factors. Arch Dermatol.
tation to digital monitoring if they have more than 40 nevi.           2010;146(3):257-264. DOI: 10.1001/archdermatol.2009.370.
    The only exception to the rule of multiple nevi was made           PMID: 20231495.
                                                                    7. Haenssle HA, Mograby N, Ngassa A, et al. Association of Pa-
for patients with a known CDKN2A variant. CDKN2A
                                                                       tient Risk Factors and Frequency of Nevus-Associated Cutane-
variant carriers have at least a 10-fold risk of melanoma
                                                                       ous Melanomas. JAMA Dermatol. 2016;152(3):291-298. DOI:
compared to people not carrying the mutation. Moreover,                10.1001/jamadermatol.2015.3775. PMID: 26536613.
patients with CDKN2A often have more than 50 melano-                8. Lallas A, Longo C, Moscarella E, et al. Reasons for exci-
cytic nevi [17-21]. Due to this high risk, participants consid-        sion of skin tumors: a one-year prospective study in a tertiary
ered this category of patients deserving digital monitoring            skin cancer unit. Dermatology. 2015;230(4):340-346. DOI:
independently from the total nevus count.                              10.1159/000371878. PMID: 25675954.
                                                                    9. Tschandl P, Hofmann L, Fink C, Kittler H, Haenssle HA. Mela-
    In the final open discussion, with almost total agreement
                                                                       nomas vs. nevi in high-risk patients under long-term monitoring
among the experts, an indication emerged to also consider
                                                                       with digital dermatoscopy: do melanomas and nevi already differ
patients with other rarer melanoma-predisposing mutations              at baseline? J Eur Acad Dermatol Venereol. 2017;31(6):972-977.
different from CDKN2A and MC1R variants (ie CDK-4,                     DOI: 10.1111/jdv.14065. PMID: 27896853.
BAP-1, MITF, POT1, ACD, TERF2IP and TERT), even if for             10. Longo C, Barquet V, Hernandez E, et al. Dermoscopy com-
them the exact relative risk still remains unknown. These              parative approach for early diagnosis in familial mela-
                                                                       noma: influence of MC1R genotype. J Eur Acad Dermatol
rarer patients have multiple nevi and an increased the risk
                                                                       Venereol. 2021;35(2):403-410. DOI: 10.1111/jdv.16679. PMID:
of melanoma, therefore they were considered an exception
                                                                       32455486. PMCID: PMC9290446.
independent from the nevus count [37-40].                          11. Moloney FJ, Guitera P, Coates E, et al. Detection of primary mel-
    In conclusion, this study suggests a list of indications for       anoma in individuals at extreme high risk: a prospective five-year
digital monitoring of patients at high risk for melanoma.              follow-up study. JAMA Dermatol. 2014;150(8):819-827. DOI:
This list could be a guide to help in selecting patients who           10.1001/jamadermatol.2014.514. PMID: 24964862.
                                                                   12. Watts CG, Cust AE, Menzies SW, Coates E, Mann GJ, Morton
could benefit the most from this time-consuming procedure.
                                                                       RL. Specialized surveillance for individuals at high risk of mel-
However, these criteria should always be integrated with the
                                                                       anoma: a cost analysis of a High Risk Clinic. JAMA Dermatol.
physicians experience in order to include also those excep-            2015;151(2):178-186. DOI: 10.1001/jamadermatol.2014.1952.
tions that may escape using them strictly. Further studies and         PMID: 25389712.
real-life data are needed to confirm the usefulness of this list   13. Watts CG, Cust AE, Menzies SW, Mann GJ, Morton RL.
of indications in clinical practice.                                   Cost-effectiveness of skin surveillance through a specialised
                                                                       clinic for patients at high risk of melanoma. J Clin Oncol.
                                                                       2017;35(1):63-71. DOI: 10.1200/JCO.2016.68.4308. PMID:
References                                                             28034073.
                                                                   14. Guitera P, Menzies SW, Coates E, et al. Efficiency of detect-
 1. Vestergaard ME, Macaskill P, Holt PE, Menzies SW. Dermos-          ing new primary melanoma among individuals treated in a
    copy compared with naked eye examination for the diagnosis         high-risk clinic for skin surveillance: a multi-center prospective



Original Article | Dermatol Pract Concept. 2022;12(4):e2022182                                                                         7
      cohort study. JAMA Dermatol. 2021;157(5):521-530. DOI:              28. Lallas A, Apalla Z, Kyrgidis A, et al. Second primary melanomas
      10.1001/jamadermatol.2020.5651. PMID: 33729464. PMCID:                  in a cohort of 977 melanoma patients within the first 5 years
      PMC7970391.                                                             of monitoring. J Am Acad Dermatol. 2020;82(2):398-406. DOI:
15.   Hasson F, Keeney S, McKenna H. Research guidelines for the              10.1016/j.jaad.2019.08.074. PMID: 31499156.
      Delphi survey technique. J Adv Nurs. 2000;32(4):1008-1015.          29. Wheless L, Black J, Alberg AJ. Nonmelanoma skin cancer and
      PMID: 11095242.                                                         the risk of second primary cancers: a systematic review. Can-
16.   Burns PB, Rohrich RJ, Chung KC. The levels of evidence and              cer Epidemiol Biomarkers Prev. 2010;19(7):1686–1695.DOI:
      their role in evidence-based medicine. Plast Reconstr Surg.             10.1158/1055-9965.EPI-10-0243. PMID: 20570907. PMCID:
      2011;128(1):305-310. doi: 10.1097/PRS.0b013e318219c171.                 PMC2901413.
      PMID: 21701348. PMCID: PMC3124652.                                  30. Duffy DL, Lee KJ, Jagirdar K, et al. High nevus count and MC1R
17.   American Cancer Society. Key statistics for melanoma skin can-          red hair alleles contribute synergistically to increased melanoma
      cer. Last Revised: January 12, 2022. Available from https://www.        risk. Br J Dermatol. 2019;181(5):1009-1016. DOI: 10.1111/
      cancer.org/cancer/melanoma-skin-cancer/about/key-statistics.            bjd.17833. PMID: 30820946.
      html#:~:text=Overall%2C%20the%20lifetime%20risk%20                  31. Raimondi S, Sera F, Gandini S, et al. MC1R variants, melanoma
      of,Factors%20for%20Melanoma%20Skin%20Cancer.                            and red hair color phenotype: a meta-analysis. Int J Cancer.
18.   Bishop DT, Demenais F, Goldstein AM, et al. Geographical                2008;122(12):2753–2760. DOI: 10.1002/ijc.23396. PMID:
      variation in the penetrance of CDKN2A mutations for mela-               18366057.
      noma. J Natl Cancer Inst. 2002;94(12):894-903. DOI: 10.1093/        32. Williams PF, Olsen CM, Hayward NK, Whiteman DC. Me-
      jnci/94.12.894. PMID: 12072543                                          lanocortin 1 receptor and risk of cutaneous melanoma: a
19.   McWilliams RR, Wieben ED, Rabe KG, et al. Prevalence of CD-             meta-analysis and estimates of population burden. Int J Can-
      KN2A mutations in pancreatic cancer patients: implications for          cer. 2011;129(7):1730–1740. DOI: 10.1002/ijc.25804. PMID:
      genetic counseling. European journal of human genetics. Eur J           21128237.
      Hum Genet. 201119(4):472-478. DOI: 10.1038/ejhg.2010.198.           33. Gandini S, Sera F, Cattaruzza MS, et al. Meta-analysis of risk
     PMID: 21150883. PMCID: PMC3060321.                                         factors for cutaneous melanoma: II. Sun exposure. Eur J Cancer.
20. Begg CB, Orlow I, Hummer AJ, et al. Lifetime risk of melanoma               2005;41(1):45–60. DOI: 10.1016/j.ejca.2004.10.016. PMID:
     in CDKN2A mutation carriers in a population-based sample.                  15617990.
     J Natl Cancer Inst. 2005;97(20):1507-1515. DOI: 10.1093/jnci/        34.   Han J, Colditz GA, Hunter DJ. Risk factors for skin cancers: a
     dji312. PMID: 16234564.                                                    nested case-control study within the Nurses’ Health Study. Int
21. Bishop JA, Wachsmuth RC, Harland M, et al. Genotype/pheno-                  J Epidemiol. 2006;35(6):1514–1521. DOI: 10.1093/ije/dyl197.
     type and penetrance studies in melanoma families with germline             PMID: 16943234.
     CDKN2A mutations. J Invest Dermatol. 2000;114(1):28-33.              35.   Brewer JD, Christenson LJ, Weaver AL, et al. Malignant mela-
     DOI: 10.1046/j.1523-1747.2000.00823.x. PMID: 10620111.                     noma in solid transplant recipients: collection of database cases
22. Boffetta P. Causation in the presence of weak a­ssociation.                 and comparison with surveillance, epidemiology, and end results
     Crit Rev Food Sci Nutr. 2010;50(s1):13–16. DOI: 10.1080                    data for outcome analysis. Arch Dermatol. 2011;147(7):790–
    /10408398.2010.526842. PMCID: PMC3024843.                                   796. DOI: 10.1001/archdermatol.2011.159. PMID: 21768478.
23. Jovancic N. “Likert Scale: How to Create Your Own Survey”.            36.   Engels EA, Pfeiffer RM, Fraumeni JF Jr. et al. Spectrum of cancer
    LeadQuizzes. Retrieved 9 March 2020                                         risk among US solid organ transplant recipients. JAMA. 2011;
24. Watts CG, Dieng M, Morton RL, Mann GJ, Menzies SW, Cust                     06(17):1891–1901. DOI: 10.1001/jama.2011.1592. PMID:
    AE. Clinical practice guidelines for identification, screening and          22045767. PMCID: PMC3310893.
    follow-up of individuals at high risk of primary cutaneous mela-      37.   Lang UE, Yeh I, McCalmont TH. Molecular Melanoma Di-
    noma: a systematic review. Br J Dermatol. 2015 Jan;172(1):33-47.            agnosis Update: Gene Fusion, Genomic Hybridization, and
    DOI: 10.1111/bjd.13403. PMID: 25204572.                                     Massively Parallel Short-Read Sequencing. Clin Lab Med.
25. Gandini S, Sera F, Cattaruzza MS, et al. Meta-analysis of risk fac-         2017;37(3):473-484. DOI: 10.1016/j.cll.2017.06.002. PMID:
    tors for cutaneous melanoma: I. Common and atypical naevi. Eur              28802496.
    J Cancer. 2005;41(1):28–44. DOI: 10.1016/j.ejca.2004.10.015.          38.   Guo L, Qi J, Wang H, Jiang X, Liu Y. Getting under the
    PMID: 15617989.                                                             skin: The role of CDK4/6 in melanomas. Eur J Med Chem.
26. Gandini S, Sera F, Cattaruzza MS, et al. Meta-analysis of risk              2020;204:112531. DOI: 10.1016/j.ejmech.2020.112531. PMID:
    ­factors for cutaneous melanoma: III. Family history, actinic dam-          32712436.
     age and phenotypic factors. Eur J Cancer. 2005;41(14):2040–          39.   Hartman ML, Czyz M. MITF in melanoma: mechanisms behind
     2059. DOI: 10.1016/j.ejca.2005.03.034. PMID: 16125929.                     its expression and activity. Cell Mol Life Sci. 2015;72(7):1249-
27. Chen T, Fallah M, Försti A, Kharazmi E, Sundquist K, Hemminki               1260. DOI: 10.1007/s00018-014-1791-0. PMID: 25433395.
     K. Risk of Next Melanoma in Patients with Familial and Spo-                PMCID: PMC4363485.
     radic Melanoma by Number of Previous Melanomas. JAMA                 40.   Read J, Wadt KA, Hayward NK. Melanoma genetics. J Med
     Dermatol. 2015;151(6):607-615. DOI: 10.1001/jamaderma-                     Genet. 2016;53(1):1-14. DOI: 10.1136/jmedgenet-2015-103150.
     tol.2014.4777. PMID: 25671687.                                             PMID: 26337759.




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