10.5826/dpc.1204a164
Introduction: UV irradiation of nevi induces transient melanocytic activation with dermoscopic and histological changes.
Objectives:We investigated whether UV irradiation of nevi may influence electrical impedance spectroscopy (EIS) or convolution neural networks (CNN).
Methods: Prospective, controlled trial in 50 patients undergoing phototherapy (selective UV phototherapy (SUP), UVA1, SUP/UVA1, or PUVA). EIS (Nevisense, SciBase AB, Sweden) and CNN scores (Moleanalyzer-Pro, FotoFinder Systems, Germany) of nevi were assessed before (V1) and after UV irradiation (V2). One nevus (nevusirr) was exposed to UV light, another UV-shielded (nevusnon-irr).
Results: There were no significant differences in EIS scores of nevusirr before (2.99 [2.51-3.47]) and after irradiation (3.32 [2.86-3.78]; p=0.163), which was on average 13.28 (range 4-47) days later. Similarly, UV-shielded nevusnon-irr did not show significant changes of EIS scores (V1: 2.65 [2.19-3.11]), V2: 2.92 [2.50-3.34]; p=0.094). Subgroup analysis by irradiation revealed a significant increase of EIS scores of nevusirr (V1: 2.69 [2.21-3.16], V2: 3.23 [2.72-3.73]; p=0.044) and nevusnon-irr (V1: 2.57 [2.07-3.07], V2: 3.03 [2.48-3.57]; p=0.033) for patients receiving SUP. In contrast, CNN scores of nevusirr (p=0.995) and nevusnon-irr (p=0.352) showed no significant differences before and after phototherapy.
Conclusions: For the tested EIS system increased EIS scores were found in nevi exposed to SUP. In contrast, CNN results were more robust against UV exposure. 
text/xml
2160-9381
2136
en
Christine Fink
https://creativecommons.org/licenses/by-nc/4.0
Dermatology Practical & Conceptual
electrical impedance spectroscopy, dermoscopy, convolution neural network, UV irradiation
UV Irradiation of Nevi: Impact on Performance of Electrical Impedance Spectroscopy and a Convolution Neural Network
Text.Serial.Journal
https://dpcj.org/index.php/dpc
Original Article
2022-10-31
2021-10-28
2022-10-31
2022-11-29
e2022164
Dermatol Pract Concept
Introduction: UV irradiation of nevi induces transient melanocytic activation with dermoscopic and histological changes.
Objectives:We investigated whether UV irradiation of nevi may influence electrical impedance spectroscopy (EIS) or convolution neural networks (CNN).
Methods: Prospective, controlled trial in 50 patients undergoing phototherapy (selective UV phototherapy (SUP), UVA1, SUP/UVA1, or PUVA). EIS (Nevisense, SciBase AB, Sweden) and CNN scores (Moleanalyzer-Pro, FotoFinder Systems, Germany) of nevi were assessed before (V1) and after UV irradiation (V2). One nevus (nevusirr) was exposed to UV light, another UV-shielded (nevusnon-irr).
Results: There were no significant differences in EIS scores of nevusirr before (2.99 [2.51-3.47]) and after irradiation (3.32 [2.86-3.78]; p=0.163), which was on average 13.28 (range 4-47) days later. Similarly, UV-shielded nevusnon-irr did not show significant changes of EIS scores (V1: 2.65 [2.19-3.11]), V2: 2.92 [2.50-3.34]; p=0.094). Subgroup analysis by irradiation revealed a significant increase of EIS scores of nevusirr (V1: 2.69 [2.21-3.16], V2: 3.23 [2.72-3.73]; p=0.044) and nevusnon-irr (V1: 2.57 [2.07-3.07], V2: 3.03 [2.48-3.57]; p=0.033) for patients receiving SUP. In contrast, CNN scores of nevusirr (p=0.995) and nevusnon-irr (p=0.352) showed no significant differences before and after phototherapy.
Conclusions: For the tested EIS system increased EIS scores were found in nevi exposed to SUP. In contrast, CNN results were more robust against UV exposure. 
Christine Fink
2022/10/31
10.5826/dpc.1204a164
e2022164
Department of Dermatology, University of Heidelberg, Heidelberg, Germany
2160-9381
electrical impedance spectroscopy, dermoscopy, convolution neural network, UV irradiation
en
e2022164
Oikarinen, A., et al., Connective tissue alterations in skin exposed to natural and therapeutic UV-radiation. Photo-dermatology, 1985. 2(1): p. 15-26.
UV Irradiation of Nevi: Impact on Performance of Electrical Impedance Spectroscopy and a Convolution Neural Network
https://dpcj.org/index.php/dpc/article/download/2136/1832
       UV Irradiation of Nevi: Impact on Performance
        of Electrical Impedance Spectroscopy and a
                Convolution Neural Network
                 Julia Katharina Winkler1, Holger Andreas Haenssle1, Lorenz Uhlmann2,
                                 Anissa Schweizer-Rick1, Christine Fink1


1 Department of Dermatology, University of Heidelberg, Heidelberg, Germany
2 Novartis Pharma GmbH, Basel, Switzerland



Key words: electrical impedance spectroscopy, dermoscopy, convolution neural network, UV irradiation
Citation: Winkler JK, Haenssle HA, Uhlmann L, Schweizer-Rick A, Fink C. UV Irradiation of Nevi: Impact on Performance of Electrical
Impedance Spectroscopy and a Convolution Neural Network. Dermatol Pract Concept. 2022;12(4):e2022164. DOI: https://doi.
org/10.5826/dpc.1204a164
Accepted: February 8, 2022; Published: October 2022
Copyright: ©2022 Winkler 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: Christine Fink, Department of Dermatology, University of Heidelberg, Im Neuenheimer Feld 440, 69120
Heidelberg, Germany, Tel: +49-6221-56-39554, Fax: +49-6221-56-8510 E.mail: christine.fink@med.uni-heidelberg.de




  ABSTRACT             Introduction: UV irradiation of nevi induces transient melanocytic activation with dermoscopic and
                       histological changes.
                       Objectives: We investigated whether UV irradiation of nevi may influence electrical impedance
                       ­spectroscopy (EIS) or convolution neural networks (CNN).
                       Methods: Prospective, controlled trial in 50 patients undergoing phototherapy (selective UV pho-
                       totherapy (SUP), UVA1, SUP/UVA1, or PUVA). EIS (Nevisense, SciBase AB) and CNN scores
                       (Moleanalyzer-Pro, FotoFinder Systems) of nevi were assessed before (V1) and after UV irradiation
                       (V2). One nevus (nevusirr) was exposed to UV light, another UV-shielded (nevusnon-irr).
                       Results: There were no significant differences in EIS scores of nevusirr before (2.99 [2.51-3.47]) and a­ fter
                       irradiation (3.32 [2.86-3.78]; P = 0.163), which was on average 13.28 (range 4-47) days later. Similarly,
                       UV-shielded nevusnon-irr did not show significant changes of EIS scores (V1: 2.65 [2.19-3.11]), V2: 2.92
                       [2.50-3.34]; P = 0.094). Subgroup analysis by irradiation revealed a significant increase of EIS scores of
                       nevusirr (V1: 2.69 [2.21-3.16], V2: 3.23 [2.72-3.73]; P = 0.044) and nevusnon-irr (V1: 2.57 [2.07-3.07],
                       V2: 3.03 [2.48-3.57]; P = 0.033) for patients receiving SUP. In contrast, CNN scores of nevusirr
                       (P = 0.995) and nevusnon-irr (P = 0.352) showed no significant differences before and after phototherapy.
                       Conclusions: For the tested EIS system increased EIS scores were found in nevi exposed to SUP. In
                       contrast, CNN results were more robust against UV exposure.



Original Article | Dermatol Pract Concept. 2022;12(4):e2022164                                                                          1
Introduction                                                        Heidelberg in 50 patients with 100 common nevi and a med-
                                                                    ical indication for phototherapy. The study was conducted
Malignant melanoma accounts for the majority of skin cancer         in accordance with the Declaration of Helsinki principles
deaths and incidence remains at high levels in many countries       (2013) and applicable local government regulations and in-
of the world [1]. Thin melanomas are cured by surgical ex-          dependent Ethics Committee policies and procedures (ethics
cision with a favorable prognosis. Hence, early diagnosis of        approval number S-279/2017).
melanoma is of utmost importance [1]. Although biopsy and
histopathology remain the diagnostic standard, non-­invasive
diagnostic techniques are gaining importance [2]. Electrical
                                                                    Inclusion/Exclusion Criteria
impedance spectroscopy (EIS) has been evaluated as an adjunct       Fifty patients scheduled for elective phototherapy with a
tool for melanoma detection [3-6]. EIS applies alternating elec-    minimum of 4 consecutive treatment sessions at our insti-
tric current and detects differences in the impedance between       tution were included in this study. Participants had to be
benign (well-organized) and malignant (more ­chaotic) tissues.      at least 18 years old and nevi needed to show the follow-
Market approved EIS devices were shown to reach a sensi-            ing characteristics: diameter between 2 mm and 20 mm;
tivity of more than 95% in melanocytic lesions [6]. Another         localized on intact skin without scarring, fibrosis, or other
promising non-invasive diagnostic technique is the assessment       (inflammatory) skin conditions; not localized in hair-­
                                                                    ­
of dermoscopic images by artificial intelligence algorithms. To     covered areas or special anatomic sites (i.e. acral skin, mu-
this end, deep learning convolutional neural networks (CNN)         cosa). We only included common nevi without any signs of
have been designed that work independently from predefined          malignancy.
criteria and were shown to perform on, or even above, the
level of trained dermatologists with regard to the classification
of benign and malignant skin lesions [7-9].
                                                                    Study Procedure
    Until today, skin cancer screenings that are assisted by        A total of 100 nevi in 50 patients were assessed by EIS.
the aforementioned diagnostic techniques have been offered          Dermoscopic images were acquired at each study visit. For
throughout the entire year. However, even intermittent UV           each participant, 1 nevus (nevusirr) was exposed to UV irra-
exposure was shown to induce transient melanocytic activa-          diation, whereas a second nevus (nevusnon-irr) was covered
tion with morphological and histological changes [10, 11].          with an UV-shielding sticker. EIS scores were evaluated at
Dermoscopic features developing in UV exposed nevi in-              3 study visits: before the start of phototherapy (V1), during
clude an increase in pigmentation and the appearance of             phototherapy (V2), after termination of phototherapy not
black-brown globules [12, 13]. Histopathologic changes              earlier than 4 weeks following the last irradiation (V3).
after UV exposition involve an increase in suprabasal mela-         Nevusnon-irr was located in the same body area with similar
nocytes and an enhanced HMB45 expression [14]. In some              size and shape as nevusirr and was used as an intraindividual
cases UV-induced changes in benign nevi may be suggestive           control to account for changes not attributable to direct UV
of malignant melanoma [15]. Thus, for clinicians it is an im-       irradiation. Moreover, at each study visit EIS scores of nevi
portant question whether the diagnostic performance of EIS          were measured twice to assess the reproducibility. Since all
or CNN-based systems may be influenced by UV irradiation            studied nevi were not intended for histological assessment
(eg during the summer months).                                      by protocol, the diagnosis of a benign nevus (ground truth)
                                                                    was based on expert consent (JKW, HAH, CF). Only clearly
Objectives                                                          benign looking nevi were included; hence follow-up of nevi
                                                                    included the study visits performed and a common skin can-
The primary objective of this study was to assess the influence     cer screening thereafter.
of UV irradiation on the diagnostic scores of an EIS system
(Nevisense, SciBase AB) and of a CNN (Moleanalyzer-Pro,
                                                                    UV Irradiation
FotoFinder Systems) when using these systems for examina-
tion of nevi. A secondary objective of this study was to address    Phototherapy was administered as part of clinical routine
the reproducibility of EIS scores by performing 2 consecutive       when indicated for treatment of diverse (inflammatory)
measurements for each lesion at each study visit.                   skin diseases. Thus, the type of phototherapy was deter-
                                                                    mined by the underlying skin condition and patient char-

Methods                                                             acteristics. Several treatments per week with increasing UV
                                                                    doses were administered. UVA1 phototherapy was per-
This clinical study was performed in a prospective controlled       formed with an UV-A1 lighting tube (Herbert Waldmann,
setting at the Department of Dermatology, University of             spectral range 340–400 nm). SUP was administered with



2                                                                       Original Article | Dermatol Pract Concept. 2022;12(4):e2022164
a combination of UV-A and UV-B lighting tubes show-                Results
ing a spectral range of 280–400 nm (Herbert Waldmann).
Psoralen-UV-A therapy (PUVA) was either performed as
­                                                                  Patient Characteristics
bath- or cream-PUVA-therapy (Herbert Waldmann, spectral            Patients (N = 50) were recruited between June 2017
range 315-400 nm).                                                 and ­August 2018 (Table 1). Mean age was 54.4 years
                                                                   (range ­
                                                                          22-75), 24 male and 26 female patients were in-
                                                                   cluded. Most patients received UV therapy for eczema
EIS Measurement                                                    (42%) or nodular prurigo (26%), some for granuloma an-

EIS scores were measured with the market approved Nev-             nulare (12%), morphea (8%), lichen planus (4%), mycosis

isense device (Scibase AB). According to the manufacturer          fungoides (4%) or others (4%). Forty-one patients showed

instructions the skin was moistened with physiological sa-         skin type II, 1 patient skin type II-III and 8 patients skin type

line for 30 seconds and a reference measurement of healthy         III. Common nevi with a network pattern and located on

skin close to the lesion was obtained. The system computed         trunk or extremities were included. A total of 35 patients re-

a score (0-10) reflecting the degree of atypia identified and      ceived SUP, 11 patients UVA1, 3 patients PUVA and 1 patient

the validated cut-off of < 4 versus ≥ 4 was used to differ-        SUP and UVA1 in a sequence (Table 2). Most patients (70%)

entiate EIS-negative (benign) from EIS-positive (malignant)        received SUP and a median dosage of 0.26 J/cm2 UVB and

lesions.                                                           13 J/cm2 UVA was administered. Considering the skin types
                                                                   of patients, these doses corresponded to about 3-4 minimal
                                                                   erythema doses (MED) of UVB and less than 1 MED-UVA
CNN Assessment                                                     administered over 7.7 sessions. [18]. Figure 1 depicts repre-
                                                                   sentative images of a patient nevi 1 and 2 from all 3 study
Dermoscopic images were assessed by a marked approved
                                                                   visits with accompanying EIS and CNN scores.
deep learning CNN (Moleanalyzer-Pro®, FotoFinder Systems)
based on a modified version of a pretrained ­GoogleNet In-
                                                                   Assessment of EIS Scores
ception v4 architecture [8]. The CNN computed ­malignancy
                                                                   Mean EIS score of the irradiated nevusirr slightly in-
scores (0-1) with a predefined threshold for malignancy at
                                                                   creased from 2.99 (2.51-3.47) at V1 to 3.32 (2.86-3.78)
more than 0.5.
                                                                   at V2 ­(Figure 2A). For patients attending V3 (N = 24)
                                                                   mean EIS score of nevusirr remained almost unchanged at
Statistical Analysis
Descriptive analyses were performed (frequency, mean, con-
                                                                         Table 1. Patient characteristics are depicted.
fidence intervals, range). For each nevus changes of EIS and
                                                                                                              Patients (N = 50)
CNN scores from visit 1 to 2 were assessed (intralesional
                                                                    Age in years (mean; range)                   54.4 (22-75)
differences). Additionally, for those nevi with measurements
from all 3 visits changes of EIS and CNN scores from all            Gender (male/female)                            24/ 26
timepoints were compared. Moreover, differences of scores           Skin condition, N (%)
between irradiated and non-irradiated lesions (nevusirr             Eczema                                         21 (42%)
­versus nevusnon-irr) were studied per visit (interlesional dif-    Nodular prurigo                                13 (26%)
ferences). Non-parametric tests were applied to assess for          Granuloma annulare                             6 (12%)
statistical significance (Wilcoxon signed rank, Friedmann           Morphea                                         4 (8%)
and M
    ­ cNemar). According to the predefined cut-offs for             Lichen planus                                   2 (4%)
malignancy, diagnostic specificities were calculated. A lin-        Mycosis fungoides                               2 (4%)
ear mixed effects model with a compound symmetry struc-             Others                                          2 (4%)
ture was applied to assess whether UV irradiation had an            Skin type, N (%)
effect on the difference in EIS scores at V1 and V2. Baseline
                                                                    II                                             41 (82%)
EIS scores, age, gender, and irradiation (yes/no) were used
                                                                    II-III                                          1 (2%)
as fixed factors. The patient ID was included as a random
                                                                    III                                            8 (16%)
factor. To evaluate reproducibility of EIS measurements an
                                                                    Localization nevus1/nevus2, N/N
­intra-class correlation coefficient was calculated. P < 0.05
                                                                    Trunk                                            36/36
was considered statistically significant. SPSS Version 25
                                                                    Upper extremities                                 5/5
(IBM, SPSS) and R (R Core Team, 2021) together with the
package nlme (Pinheiro, 2021) were used [16,17].                    Lower extremities                                 9/9



Original Article | Dermatol Pract Concept. 2022;12(4):e2022164                                                                    3
                                                   ­ evusnon-irr
3.25 (2.64-3.86) (Figure 2). The mean EIS score of n                       nor at V2 (P = 0.103, interlesional difference). ­Applying the
was 2.65 (2.19-3.11) at V1, 2.92 (2.50-3.34) at V2 and 2.94                predefined cut-off indicating m
                                                                                                         ­ alignancy (score ≥ 4), nevusirr
(2.29-3.59) for patients attending V3 (­Figure 2). First, we sta-          was labeled “malignant” in 16 ­patients at V1 and in 20 pa-
tistically compared EIS scores attained at V1 versus V2. There             tients at V2 (Figure 3). In contrast, nevusnon-irr was labeled
were no significant differences of EIS scores at V1 ­versus V2             “malignant” in only 12 ­patients at V1 and in 13 patients at
neither for nevusirr (P = 0.163, intralesional difference) nor for         V2. Paired assessment revealed no significant difference in
nevusnon-irr (P = 0.094, intralesional difference). Additionally,          the number of nevi labeled ­“malignant” at V1 versus V2, nei-
we neither found significant differences in EIS scores of nevu-            ther for nevusirr (P = 0.424) nor for nevusnon-irr (P = 1.0). For
sirr versus nevusnon-irr at V1 (P = 0.393, interlesional difference)       patients with measurements available from all 3 visits, EIS
                                                                           scores did not significantly vary between timepoints neither
                                                                           for nevusirr (P = 0.428) nor for nevusnon-irr (P = 0.719). Finally,
Table 2. Details on UV irradiation administered.                           when including all EIS measurements performed, the device
                                                                           achieved an overall specificity (true-negative rate) of 49.3%.
                                                 Patients N = 50
 UV irradiation, N
 SUP                                                     35                Regression Analysis Including EIS Scores
 UVA1                                                    11                A linear mixed effects model was used to assess the impact

 SUP/UVA1                                                1                 of irradiation on the absolute and relative differences in EIS
                                                                           scores at V1 and V2 by comparing UV-irradiated versus
 PUVA                                                    3
                                                                           shielded nevi. Here, irradiation was not a significant predic-
 SUP
                                                                           tor (Table 3).
 Treatments, N (mean; range)                        7.7 (3-16)
 Dosage (J/cm2) UVA (mean; SD)                       13.0; 7.8
                 2                                                         Reproducibility of EIS Measurements
 Dosage (J/cm ) UVB (mean; SD)                      0.26; 0.16
 UVA1                                                                      We performed 2 consecutive EIS measurements for each ne-
                                                                           vus and visit to investigate reproducibility. Overall, 232 pairs
 Treatments, N (mean; range)                        9.9 (3-15)
                                                                           of scores were recorded and the mean difference between
 Dosage (J/cm2) UVA1 (mean; SD)                      270; 140
                                                                           consecutive scores was 0.06 (-0.27-0.4). The intraclass cor-
 PUVA
                                                                           relation coefficient was 0.653 (0.551-0.732). According to
 Bath/cream, N/N                                        2/ 1
                                                                           the definition of Cicchetti this corresponds to a good reliabil-
 Treatments, N (mean; range)                         12 (6-20)
                                                                           ity, according to Koo/Li to a moderate reliability [19,20]. For
 Dosage (J/cm2) UVA (mean; SD)                        6.6; 5.5




Figure 1. Nevus1 and nevus2 of a participating patient at all 3 study visits (V1-3) are depicted. From V1 to V2 nevusirr was irradiated with
SUP during 10 appointments (cumulative dosage UVA 14.54 J/cm2, UVB 0.29 J/cm2), whereas nevusnon-irr was UV-shielded. Corresponding
electrical impedance spectroscopy (EIS) scores (0-10, top row) and convolution neural networks malignancy scores (0-1, bottom row) are
depicted, scores marked in red illustrate a change in the diagnostic class, ie scores increased above the threshold for a malignant classification.



4                                                                                Original Article | Dermatol Pract Concept. 2022;12(4):e2022164
                 Figure 2. Boxplots show electrical impedance spectroscopy (EIS) scores of irradiated nevusirr and UV-
                 shielded nevusnon-irr at all 3 study visits (V1-before UV irradiation; V2-after UV irradiation; V3-not earlier
                 than 4 weeks following the last irradiation). The upper and lower bounds of boxes represent the 25th and
                 75th percentiles while the median is given by the line intersecting both boxes. Whiskers present the full
                 range of malignancy scores. The a priori cut-off for a malignant classification is indicated by dotted lines
                 (EIS score ≥ 4).




70 of the 232 (30.2%) pairs of scores a class change from <               classified “malignant” in none of the patients at V1, but in
4 to ≥ 4 or vice versa was found.                                         2 patients at V2. Similarly, nevusnon-irr was classified “malig-
                                                                          nant” in none of the patients at V1 but in 1 patient at V2.
Assessment of CNN Scores                                                  Paired assessments revealed no significant difference in the
For 42 patients dermoscopic images were available from V1                 number of nevi classified “malignant” at V1 versus V2 nei-
and V2. Mean CNN scores of nevusirr were 0.06 (0.03-0.1)                  ther for nevusirr (P = 0.5) nor for nevusnon-irr (P = 1.0). When
at V1, 0.06 (0.02-0.11) at V2, and 0.11 (-0.02-0.23) for                  including patients with measurements available from all 3
the 15 patients with images available from V3 (Figure 4).                 visits, CNN scores were not significantly different between
Mean CNN scores of nevusnon-irr were 0.05 (0.02-0.08)                     timepoints neither for nevusirr (P = 0.449) nor for nevusnon-irr
at V1, 0.04 (0.01-0.07) at V2, and 0.15 (0.05-0.25) at V3                 (P = 0.420). Finally, including all visits the rate of correct
(Figure 4). First, we statistically compared CNN scores be-               “benign” diagnoses was 94.7%.
fore and after irradiation (V1 versus V2). There were no
significant differences in CNN scores at V1 versus V2 nei-                Assessment by Type of Irradiation
ther for nevusirr (p = 0.995, intralesional difference) nor for           Due to varying irradiation protocols a subgroup analysis
nevusnon-irr (P = 0.352, intralesional difference). Additionally,         was performed for the largest group of patients receiving
we found no significant differences in CNN scores of nevusirr             SUP (N = 35). In this analysis mean EIS scores of nevusirr
versus nevusnon-irr at V1 (P = 0.703, interlesional difference)           significantly increased from 2.69 (2.21-3.16) at V1 to 3.23
and V2 (P = 0.675, interlesional difference). According to                (2.72-3.73) at V2 (P = 0.044) and was 3.13 (2.40-3.84) for
the predefined CNN threshold for malignancy, nevusirr was                 the 16 patients attending V3 (Figure 5). In parallel, mean



Original Article | Dermatol Pract Concept. 2022;12(4):e2022164                                                                          5
                 Figure 3. Figure shows dermoscopic images of two neviirr from V1 and V2 with corresponding electrical
                 impedance spectroscopy (EIS) scores. For both lesions and timepoints measurements were repeated and
                 mean values used to define a negative/benign or positive/malignant result. For both lesions mean EIS scores
                 increased from V1 to V2 and lesions were assessed negative/benign at V1 versus positive/malignant at V2.



    Table 3. A linear mixed-effects model was                                Table 4. A linear mixed-effects model was
  used to assess the impact of irradiation on the                            used to assess the impact of irradiation on
  absolute in electrical impedance spectroscopy                            the relative differences in electrical impedance
      scores at V1 and V2 (before and after                                spectroscopy scores at V1 and V2 (before and
 irradiation) by comparing UV-irradiated versus                            after irradiation) by comparing UV-irradiated
                   shielded nevi.                                                        versus shielded nevi.
                       Estimates          95% CI             P                                   Estimates         95% CI            P
 (Intercept)               1.43          0.12; 2.74        0.037         (Intercept)                0.88          0.02; 1.74       0.050
 Age                       0.01         -0.01; 0.03        0.479         Age                        0.01         -0.01; 0.02       0.502
 Gender (male)             0.30         -0.31; 0.91        0.347         Gender (male)              0.41          0.01; 0.81       0.053
 EIS score at V1          -0.57         -0.73; -0.41     < 0.001         EIS score at V1            -0.32        -0.43; -0.21    < 0.001
 Irradiation (no)         -0.25         -0.69; 0.18        0.254         Irradiation (no)           -0.18        -0.46; 0.10       0.221

CI = confidence interval; EIS = electrical impedance spectroscopy.      CI = confidence interval; EIS = electrical impedance spectroscopy.



EIS scores of nevusnon-irr increased to a slightly lesser but           scores at V1versus V2, neither for nevusirr (P = 0.344) nor for
still significant extent from 2.57 (2.07-3.07) at V1 to 3.03            nevusnon-irr (P = 0.388).
(2.48-3.57) at V2 (P = 0.033) and was 3.09 (2.28-3.91) at                   For 30 patients CNN scores were available, there was
V3 (Figure 5). Paired assessments showed no significant dif-            neither a significant difference in CNN scores between V1
ferences in the number of nevi labeled “malignant” by EIS               and V2 for nevusirr (P = 0.797) nor nevusnon-irr (P = 0.894).



6                                                                            Original Article | Dermatol Pract Concept. 2022;12(4):e2022164
                   Figure 4. Boxplots show convolution neural networks (CNN) scores of irradiated nevusirr and UV-shielded
                   nevusnon-irr at all 3 study visits (V1-before UV irradiation; V2-after UV irradiation; V3-not earlier than
                   4 weeks following the last irradiation). The upper and lower bounds of boxes represent the 25th and 75th per-
                   centiles while the median is given by the line intersecting both boxes. Whiskers present the full range of malig-
                   nancy scores. The a priori cut-off for a malignant classification is indicated by dotted lines (CNN score > 0.5).




Conclusions                                                                and after phototherapy with different irradiation protocols
                                                                           performed. We found that for the overall group of patients
Dermoscopic and histopathologic changes of nevi following                  and across all phototherapy regimen EIS scores of both UV
UV irradiation have previously been described [12, 14]. Such               irradiated and UV-shielded nevi were not significantly dif-
changes may be of clinical relevance when patients attend                  ferent before and after UV exposure. There may be several
skin cancer screenings following sun exposure. Particularly                explanations for this observation, which are not mutually
for patients under follow-up by sequential digital dermos-                 exclusive. In agreement with others we found a limited re-
copy subtle changes related to sun exposure, eg increase                   producibility of EIS measurement [21]. This might have
in the number of dark dots and globules, may result in an                  probably interfered with the statistical comparison of EIS
increased number of unnecessary excisions. Hence, another                  scores before and after UV exposure (background analyti-
short time follow-up examination before biopsy of mela-                    cal noise covering relevant signals). Second, cumulative UV
notic lesions has previously been recommended after intense                doses until the second visit (V2) might not have been suffi-
UV exposure [12].                                                          cient to induce significant alteration of EIS scores. Yet, mor-
    According to our literature search, there is no data                   phological changes in nevi have been reported as early as
available on the performance of assistant devices such                     after 2 MED [12]. After two UVB minimal erythema doses
as EIS or CNN when used to assess melanocytic lesions                      marked melanocytic activation was reported, avoided by
after sun exposure. Our study provides first data on                       physical and sunscreen protection [22]. Another study found
EIS and CNN scores of common nevi before and after                         that even after a single dose of UVB clinical and dermoscopic
phototherapy.                                                              changes in nevi occurred, partially prevented by physical
    Overall, 50patients were included to assess EIS scores of              barriers or sunscreens [23]. Moreover, a positive correlation
2 nevi per patient (UV irradiated and UV shielded) before                  of the extent of morphological changes with increasing total



Original Article | Dermatol Pract Concept. 2022;12(4):e2022164                                                                          7
                Figure 5. Boxplots show electrical impedance spectroscopy (EIS) scores of nevisirr and nevisnon-irr at all
                3 study visits (V1-3) for the subgroup of patients receiving SUP. The upper and lower bounds of boxes
                represent the 25th and 75th percentiles while the median is given by the line intersecting both boxes. The a
                priori cut-off for a diagnosis of malignancy is indicated by a dotted line (EIS score ≥ 4).



cumulative UV dose has also been shown [24]. Finally, it                EIS scores at V2 for both UV irradiated and shielded nevi.
seems well conceivable, that “moderately” UV exposed nevi               In our study the increase in EIS scores was quite similar for
have been included in the training data of the device [6],              directly versus indirectly (because UV-shielded) irradiated
which might have attenuated effects on EIS scores, and par-             nevi, which is in line with previous studies reporting melano-
ticularly on class changes (changes from benign to malig-               cyte activation and proliferation after irradiation in both UV
nant after UV exposure). In contrast, effects of acute sun              exposed and shielded human skin [25,27]. It has been pos-
exposure were not further assessed in pivotal studies since             tulated that mediators from irradiated skin might spread to
exclusion criteria of the pivotal study included “lesions and/          neighboring UV protected skin through a paracrine pathway
or reference located on acute sunburn”. In the future, train-           [25,27,29]. In confirmation, our linear effects model assess-
ing sets of devices for the evaluation of melanocytic lesions           ing EIS scores before and after irradiation did not reveal an
should consider the influence of UV irradiation. The infor-             impact of direct UV irradiation.
mation that sun-exposed lesions were excluded from studies                  From our results we assessed the rate of nevi correctly
has to be included in clinical tutorials for users and in the           labeled as benign by means of EIS scores (true negative rate,
webpage of the device.                                                  specificity). EIS attained a true negative rate of roughly 50%,
    In the literature changes of melanocytic lesions have               which appears low in nevi lacking any dermoscopic signs of
been reported following exposure to UV light of various                 malignancy. This finding is in line with previous studies on
wavelengths [12,13,25-27]. Although natural sunlight dif-               EIS reporting a limited specificity of 34.4% at a high sen-
fers from therapeutic irradiation [28], SUP includes both the           sitivity of 96.6% [5,6]. Due to the study setting malignant
UVB and UVA component and thus a subgroup analysis was                  lesions were not included, and thus we could not calculate
performed for this largest group of patients. SUP patients              sensitivity (true positive rate). The specificity of 49.3% ob-
received a dose of 3-4 MED-UVB over a mean number of                    tained in the study is still superior to the 34.4% reported in
7.7 sessions. In these cases, we found a significantly elevated         the pivotal study with the method. This difference might be



8                                                                            Original Article | Dermatol Pract Concept. 2022;12(4):e2022164
explained by the different populations of patients and lesions    tested CNN was more robust to the effect of UV exposure
included within the two studies, since the accuracy of EIS        with almost unchanged scores.
was shown to be correlated with lesion atypia. For a com-
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