Accepted Article 4. 3. 2. 1. A. Lallas, Word count:3138, Tables: 6, 6 Figures: Runninghead: Dermoscopy acral of The BRAAFF checklist: a new dermoscopic algorithm for diagnosing acral melanoma type Article Article :Original Accepted Date : 07-Jul-2015 This article This protectedis by Allcopyright. rights reserved. 10.1111/bjd.14045doi: version betweenof Please and Versionthis tothe lead Record. this differences article cite as throughthebeen typesetting,copyediting, pagination and process, which proofreading may This article hasbeen accepted for publicationand undergone fullpeer review but has not 10. 9. 8. 7. 6. 5. D. Ioannides, Tanaka,

DermatologyUnit, SecondUniversi Department ofDermatology and Venereology, Medical University,Graz, Austria PierreBénite, France.Lyon-Sud, ofDepartment Dermatology, Claude Bernard- Lyon 1University, Centre Hospitalier Kobayashi Clinic, Tokyo, Japan Japan Tokyo, Department ofDermatology, TokyoWomen’s Divisionof Dermatology,Complesso Integrato Columbus, Rome, Italy Greece First Departmentof Dermatology, Medical Aristotle School, University, Thessaloniki, Vienna, Austria Department ofDermatology, Divisionof General Medical Dermatology, University, Department ofDermatology, Shinshu University ofMedicine, School Matsumoto, Japan Unit,Reggio Italy Emilia, Santa IRCCS, Arcispedale Nuova Maria 6 L. Thomas, L. 1 A. Kyrgidis, A. 2 H. Kittler, H. 8 I. Zalaudek, 1 H. Koga, H. 4 K. Kobayashi, K. 2 9 E. Moscarella, E. G. Argenziano. G. ty of Naples,ty of Naples, Italy. 6,7 E.Lazaridou, 1 MedicalUniversity Medical Center East, P.Tschandl, 10 2 C. Longo, 3 Z. Apalla, Z. 1 A. Phan, A. 4 A. Di Stefani, 8 T. Saida, T. 3 M. M. 5

Accepted Article Conflict of interest: None None interest: of Conflict in partsupported Study by the Italia This article This protectedis by Allcopyright. rights reserved. evaluated by3investigators independent forth and acral nevi with histopathologic diagnosis or with at least 1 year of follow up were Methods: Dermoscopic images of consecutive AM. ToObjective: theinvestigate diagnostic accuracy ofdermoscopic criteriadiagnosisfor the of do notdisplay dermoscopically aPRP,rendering detectiontheir more troublesome. acralmelanomaHowever, (AM). itwas recently shownapproximately that one AM third of Background: The parallel ridge pattern (PRP) is considered as the dermoscopic hallmark of Summary Aimilios Lallas,MD.Skin Cancer Unit, Arcispedale Santa Maria Nuova, Viale Risorgimento that arenot dermoscopically characterizedby a PRP. Application AM. of the latterdiagnostic scheme A scoring systemcomposed of 6variables achievesthehighest diagnostic accuracy for What does thisstudy add? (PRP),pattern rendering theirmore detection troublesome. Approximately one third of acral (AM) lack a dermoscopic parallel ridge What’s alreadyWhat’s knownthis about topic? Phone: 00390522295611,Phone: Fax:00390697625822, [email protected] e-mail: n Ministry of (RF-2010-2316524) Health caseshistopathologically of diagnosed AMs e presenceof pre-defined criteria. Crudeodds minimizes minimizes the possibilityof missing AM Please address all correspondence to: 80, 42100, Reggio Italy. Emilia, Accepted Article developssites, innon-acral with AMaccounting less for 10% than of cases. unfavorable clinical course, ithasbeenma subtypes. Since nopathophysiologic mechanism hasbeensuggested to explain its particularly note, AM has been associated with a worse prognosis comparing to other melanoma early diagnosis,early by enablingto clinicians recognizemelanoma before develops it depth atdiagnosis. the time of Dermoscopy has beenshown toserve optimallythe goal of irrespectively of the tumour site, the prognosis of approximately 50%approximately of melanomas in Asians. populations, thanmoreaccounting 70% for of melanomas inAfrican-Americans and (AM)Acral melanomarepresents most thecommon melanoma subtype in non-white Introduction dermoscopy for the diagnosis of AM. Conclusion: The BRAAFF checklist significantly improves the diagnostic accuracy of pattern). pattern and fibrillar (furrow predictors negative 2 and colours) of asymmetry and structures of asymmetry pattern, ridge irregular, AM.curve sensitivityforincludeddiagnosis Thismethodand the of positive 4 (blotches system (named BRAAFF) composed of 6 variab Results: A 603total of (472lesions neviand among competing classification schemes. since the absoluteincidence ofAMhas been estimatedtobe similar amongall races. these differences are ratherrelated topr the univariate and multivariate logistic regression, and respectively. univariate logistic multivariate adjustedratios, odds ratios and corresponding 95%confidence intervals were calculated by This article This protectedis by Allcopyright. rights reserved. Early detection detection Early is the only safe strategy to inly attributed to delayedadiagnosis. evalence ofnon-acral melanoma in Caucasians, 1-6 131 AMs) were included inthe study. A scoring In Caucasians, melanoma most often les wasassociated with optimal area under the disease directlydependson the invasion reduce melanoma-related mortality, since, since, mortality, reduce melanoma-related

ROC curves wereused to choose 7,8 However, However, 10-12

7-9 Of Accepted Article sole), Breslow and thickness, wererecorded. acralskin were excluded fromthe study. Patients’ data, including age, sex, locationor (palm comparable with the other 2 groups. Nail apparatus melanomas without involvement of the ofcases non-excisednevi acral with atleast 1year offollow up, in order to reach anumber neviThen, weacral the fulfilling inclusion to criteria. added samplethe study consecutive dermoscopic images. First we searched for ca available follow-up of at least one year, as well as the availability of high-quality ofdiagnosis AM oracral , or the clinical-dermoscopic diagnosis ofacral nevus with werecenters screenedto identify eligible criteria werethe Eligibilitycases. histopathologic diagnosis andmanagement in Austria,France, Greece, Japan The Italy. and ofdatabases our wasmulti-center This a studymorphologic conducted in 7specialized centers for skin cancer Methods nevi. acral and AM early between differentiation the for model prediction macroscopically evident characteristics. This article This protectedis by Allcopyright. rights reserved. PRP,rendering thus their accurate diagnosis more difficult. it hasHowever, beenrecently shown that one AMs thirdnot approximately of do display a (parallel ridge pattern-PRP, in contrast to the parallel furrow pattern-PFP of acral nevi). ofacral pattern-PFP parallel furrow to the contrast in pattern-PRP, ridge (parallel recognitionbymelanoma highlighting accentuation the of the pigmentation ontheskin ridges been reportedtobeen characterize AM. diffuseas irregular other pigmentationand non- The aimof the present study was to develop and validatemultivariable a dermoscopic 15-18,25,27 13 In acral pigmented lesions, dermoscopy enhances

ses of histopathologically diagnosed AM or site specific melanomahave criteria, also 29 Some additional features, such 9,14-28

Accepted Article dermoscopic variablesdermoscopicwereincluded in the analysis and examined as possiblepredictors of ofyear follow up(0= acral nevi,both excised and1= non-excised; AM). Allseparate variable with the final diagnosis, as determined either by histopathologic examination or by 1 outcomeCoefficient (ICC). The to bepredicted bythe predictionwas dichotomous model a Correlation Intraclass and Kappa Cohen’s with examined was agreement Intra-observer Statistical analysis values. withdifferent 6 categorical variables included in the analysis, 14 were dichotomous and the global pattern was variablesuseddermoscopic aredescribed analytically in Table 1. Of 15dermoscopic basedon the available literature and was aresult ofconsensus among the authors. absence of pre-defined dermoscopic structures. The selection of the dermoscopic criteria was asked toassess theglobal dermoscopic patternof eachlesion, as well asthe presence or blinded for the histopathologic andclinico-de Dermoscopic images wereevaluated by three independent investigators (H.K, E.M,P.T.), Dermoscopic evaluation using resampling and splitting of the original dataset. fromdata the 7skin cancer wereusedcenters bothdevelopment the thefor and validation, were sets validation separately analyzed for invariables the final model and obtain the highest possible Thesensitivity. training and dataset,single increasing the ratio ofcases to independent variables, into order includemore size andthe need to include predictors, many we finally elected toinclude all patients ina allocatedto eithera training a or validationdataset. However, becauseof thelimited sample This article This protectedis by Allcopyright. rights reserved. Upon inclusion and to derrmoscopic prior evaluation, patientswererandomly the purposethe ofsensitivity analyses. The registry rmoscopic diagnoses. Theinvestigators were 14-27 The Accepted Article curves to curves to choose between competing Specificity schemes. classification sensitivity and were this was not possible, the value was decided upon re-evaluation of the images and consensus. agreementbetween 2 raterswas required to confirm anyspecific value. Inthose caseswhere logisticregression analyses, we created an “int removal variable in the modelautomated select modeling. This This modeling. limitation discussed isbelow. further indicating that the samplesizeis smallgiven the predictorsnumber of selected forregression of freedom (df, eachbeta) spend is needed. The finalcombined set included 131melanomas, feasible. AM. Since the evaluatorsblindly assessed allincluded lesions, a complete-case analysis was This article This protectedis by Allcopyright. rights reserved. the apparent performance to estimate theinternally validatedperformance. averaged difference in performance as a stable samplebootstrap of 400 subjectsdrawn the from sampleoveroriginal 100 Therepetitions. themodels, bootstrap resampling technique was applied by fitting the logistic model in a Conditional backward provedelimination parsimonious. more calculated by univariate and conditional multivariate regression,logistic respectively. adjustedratios oddsand corresponding95 percent confidence (95%intervals CI) were coefficient. Relative risks were calculated fo discussedlimitations below. the trainingset, buttodevelopthemodel the from dataset. complete Thisimposes alsosome Discriminant Discriminant analysis was performed and functions were saved; we then used ROC Alpha level was set at 0.05 while an alpha level of 0.10 was used as cut-off for In order to have sufficient power for aprediction model, at least10 events perdegree To assess the internal validity and degree of over-optimism (calibration) in the (calibration)inof over-optimism internal degree validity the and To assess correlation Rho Spearman’s using matrix, acorrelation via assessed was Co-linearity r all dichotomous variables. Crude odds ratios, estimate of theoptimismwas subtracted from ra-rater” setof variables in whichat least an ion for multivariate logistic regression. ion For multivariate for 30 Accordingly, we selected not to use 31

Accepted Article The male-to-female ratio was 1:1.6 and did not differ significantly between patients with AM AM with patients between significantly differ not did and 1:1.6 was ratio male-to-female The with alldermoscopic variables included(adj 9.5%with a increased risk for melanoma per each ofyear age added,in an adjusted model years)compared topatients in the nevi group(35.6 years). Agewas found tobe associated patientswas significantly higher(67.7years, with theyoungestmelanoma patient21 aged studywhole groupwas 42.3 years,from ranging 1to98 years. Themean age ofmelanoma thickness ofinvasive AM was 2.67ranging mm, 0.2fromto14.5 mm. The mean ofage the inclusion period was from the beginning of 2010 until the end of 2013. The mean Breslow and289 notexcised)and 131weremelanomas (42 in-situ and 89invasiveThe tumours). Of a totalof 603lesions from603patientsinincluded thestudy, 472 were nevi (183excised Results Ill.). Inc., Chicago, SPSS Social Sciences, Package for (Statistical this study was set to All 0.05. were statistical calculations withmade the SPSS 17.0 extracted from classification tables. The Type I This article This protectedis by Allcopyright. rights reserved. or(50.6%) (38.2%, astructurelesspattern 2). Fig. Incontrast,(61.9%). invasive melanoma mostcommonly exhibitedmulticomponent a linesof parallel was bymost farthefrequent Fig.in nevi1) (73.7%, inmelanoma and in-situ . were65 (10.8%) palmar.onlyThe anatomic site (soles/palms) was distribution similarfor and acral nevi. The majority of the lesions we Detailed resultsDetailed ofdermoscopic the analysis given are2. inTable The global pattern usted OR=1.095, 95%CI:1.068-1.122, p<0.001). re located onthesole (538/603, 89.2%), and error probability associated with all tests intests all with associated probability error Accepted Article of the remainder variables (Table 4). the effect for adjusted predictors, important remained variables of number a reduced analysis, valuepredictive differentiate to melanoma from In therespectively. univariate seve analysis, The results of theunivariate and the multivariateanalyses are shown inTables 3 and4, Univariate analyses multivariate and whichICC was lower than 0.679. structures, irregular streaks/pseudopods and atypical network were onlythe variables in ranged 0.526 from to0.828showing moderate to goodagreement among raters. Regression substantial agreement betweenraters. ICC (using averaged measures, absoluteagreement) regressionincluding structures, irregular In all cases, Cohen’s Kappa ranged from 0.496 to 0.794 showing moderate (for variablesfew agreement Intra-observer This article This protectedis by Allcopyright. rights reserved. 5): (Table BRAAFF named thus was which pattern), fibrillar and pattern, furrow colours, of asymmetry structures, of asymmetry pattern, ridge irregular, (blotches variables 6 of composed system (AUC)under curve sensitivity and wereour e opted thefor highest possible sensitivity of sensitivityanalyses, using thetrainingand thevalidation set, alongwiththe complete set. We scoringschemes and todetermine the optimal cut-off thresholds. We run a numberof Basedon the multivariate model, we employedanalyses discriminant totest different streaks/pseudopods and atypical to network) the predictive model.multivariate Optimal area ral variables showed statistically showed significantral variables ndpoints. We developed the following scoring nevi (Tablenevi 3). However, inthe multivariate Accepted Article 3. The modelyielded a corrected AUC of0.954(95%CI: 0.929-0.979, p<0.001). overallof the(all groupcases melanomas versus supplemented by satisfying specificity (86.7%), Asymmetry colours – of patternParallel furrow – pattern Fibrillar + of structures +Asymmetry pattern) * ridge Parallel blotch +(3 =Irregular Score This article This protectedis by Allcopyright. rights reserved. year increased the riskof by melanoma 9.5%. patientswas significantly highercomparing to patients inthe nevi groupand everyadded age youngestmelanoma patient in ourserieswas aged 21 years,the mean ageof melanoma sinceis melanoma rareextremely inchildren and its incidence increases with age. the age ofthe patient should always bewhen pigmentedconsidered aevaluating skin lesion, allows achieving 93.1%sensitivityand86.7% specificity formelanoma diagnosis. Basedon the results ofour analysis, we propose dermoscopicadiagnostic that algorithm Our studyconfirmsthe highdiagnostic accuracy of the dermoscopy for diagnosisAM. of Discussion are shown6. inTable lessmorphologically typical thefrom non-excised ones. Theresults ofthesubgroup analysis when melanomaswere compared only with excisednevi, which reasonablyare model for the diagnosis of in situ and invasive melanoma. In weaddition, tested themodel of our inmodel certainsubgroupspatients. of 2.Furthermore,Table we employed sensitivity analyses to examine the diagnostic accuracy A threshold of oneA thresholdpoint of was found to provide the best sensitivity (93.1%), The frequencies ofdermoscopicwith criteria

In line withpre-existing evidenceon allmelanoma subtypes,study our highlightsthat In detail, we assessed the theaccuracy of and allowing correct classification of 88.1% classification of allowingand correct all nevi).The ROC plotted iscurve in Fig. in each group of patients are presented in 32,33 The Accepted Article be relatedbe tothe higher percentageof invasive tumoursin oursample,since itknown isthat PRP is more common in common AM. early is more PRP reported to rangereported from86%.to 53% sensitivitypreviouslyof PRP as reported diagnosis has forAM a single been criterion wascriterion common in more melanoma in situinvasiveinthan AMs. (50%) (32.6%) The of 60% than AMsmight be overlookedif only PRPconsidered is (Figs 5andThis 6). However,perfect PRPsymmetry. were present only in 38.2% of AMs,meaning that more in even the ofabsence any other melanoma criterion andeven ifthe lesion is characterized by around the profundacrista intermedia. histopathologically correspondingto a prolifera contrast, melanoma typified is by pigmentation along the ridges ofthe skin(Fig. markings4), profunda crista limitans, anepidermal ridge retelocated under the surfaceIn furrows. histopathologically pigmentation correspondstonests ofmelanocytes located around the melanoma and the PFPofnevi.melanoma mainlynevi, byhighlightingdifferent 2 patternsof pigment deposition, the namely PRPof This article This protectedis by Allcopyright. rights reserved. pigmented lesion,since a considerable AM proportion of lackthe PRP. featuresmelanoma should also beinto taken consideration when evaluating anacral betweendifferentiation and AM acral nevi.However,our findings suggestthat additional characteristicthe anatomy theirthe in acral our of skin usefulness results confirm and fold probability. this criterion represented in our study the most potent predictor of melanoma, posing a 18- accentuation of the pigment along the furrows of the skin markings. Dermoscopyhas been shown to improvethediscrimination between AM and acral Analytically,with in agreement previous 17 This means that the detectionof PRPshould warrant of excision thelesion, 14-27 The latter are dermoscopically typified by thetypified by dermoscopicallyThe latter are 9,15,17,27 15-18,21 The lower frequency of PRP in our series might might series our in PRP of frequency lower The Theseparallel linepatterns are aresult ofthe tionof atypicalmelanocytes mostly located studies reporting99% specificity ofPRP, 9,14,16,19,22-26 This Accepted Article tumours. common dermoscopic of AM,criterion itand has suggested been totypifyinvasive mainly included mainly invasive AMs. recently highlighted by a collaborativestudy ofthe InternationalDermoscopy Society,which theour findings, observation that “benign” crite 3-fold probabilitywith a ofanevus, butthey were 7.6%presentinof In also with line AM. other melanoma-specific criteria are visualized. Similarly, a fibrillar pattern was associated Subsequently, the detection of this feature should not exclude the diagnosis of AM when 5). (Fig. lesion parts ofthe some 10% PFPin AMs probability, exhibited of a 9-fold posing This article This protectedis by Allcopyright. rights reserved. lower. inEurope,AM whereas in recenta multi center studythe frequency of IDPwas significantly posinga probability 4-fold AM. of our multivariate analysis revealed that irregularblotches are a potentmelanoma predictor, featurelocal andnot aas global pattern inlike previously the studies.mentioned However, frequency ofIDPinstudies former is notpossible, sincewe consideredirregular blotches as a ofone the most common criteria.A direct comparison betweennumberthis andthe or fibrillar pattern. or fibrillar PFP as such criteria, “benign” of in presence the be excised even the should lesion structures) ourNotably, data suggest that, inthe presenceof marked asymmetry(both in colours and predictorsmelanoma inour study, posing7- a an 27,28 Irregular diffuse pigmentation (IDP; also called blotches) has also been described as a a as described been has also blotches) called also (IDP; pigmentation diffuse Irregular Similarly, although Similarly, PFPweremost the potentpredictorfor the diagnosis ofnevus,a Asymmetry of Asymmetry colours andof asymmetry

9,15,17,27 Inour study, irregular blotcheswere foundin68.2% of melanomas, representing Phanet al toIDPthefound represent most common AM pattern seriesina of 34 ria ria might be focally present in AM has been dof AM,fold probability 4- respectively. structures also represented potent Accepted Article symmetric symmetric patternfibrillar is very probably benign and should not be excised. iii) a lesion exhibiting a PRP should be excised (Fig. 4). ii) a lesion displaying a symmetric PFP or a examining when suggestions management simple the interpretation ofthe and algorithm enha fromthe pathognomonic PRP, thus increasing the diagnostic accuracy. To further simplify deviate that AMs of detection the helping tool practical a is AM, from nevi acral differentiate byalgorithm, taking into consideration all the dermoscopic criteria that are useful to in equivocal cases. information suchas patient’s age and history, withininterpreted be the clinicalcontext of theintegrated patient, with relevantall clinical Subsequently,detection. has it to be underlinedthat thedermoscopic findings shouldalways diagnostic accuracy of this model, stillsomemelanomas might the deviate dermoscopic previouslysuspicious judged as tomeritexcision.enough However, despite oftheincreased sincethe ithighlights power new ofthis to modelmelanoma discriminate nevi were that from compared only with excised nevi. This finding is relevantparticularly for the daily practice, Furthermore, the accuracyBRAAFF of checklist was high even whenmelanomas were reasonable, since invasivedisplay, tumours sensitivityof model the diagnosisfor the higher The tumours. invasive and situ in both of detection the for valid was checklist an acceptable cost in specificity. Of note, the subgroup analysis revealed that the BRAAFF theof dermoscopy for diagnosis ofAM, to compared anysuggested previously method,with This article This protectedis by Allcopyright. rights reserved. been useful toolsbeen for guidingtheclinicians in everyday practice.clinical The BRAAFF checklist allows a significant improvementof diagnostic the accuracy Dermoscopic algorithms 7-point (ABCD rule, of of invasivemelanoma should be considered ncewe provideits applicability, four below as a rule, more evident melanoma criteria. while histopathologic examination is required an acralan lesion:i) alesion dermoscopically checklist, Menzies method, etc.) have 35-37 The BRAAFF Accepted Article the presenceof irregular blotches (Fig. 6). shouldpattern be excisedin thepresence of asymme structures)irregular plus blotches 5). (Fig. iv of (asymmetry plusof stru asymmetry colours exhibiting a PFPor fibrillar patternshould be excisedifdisplaying asymmetry marked This article This protectedis by Allcopyright. rights reserved. hemorrhage remains to be further elucidated. Fifth, we aimed to provide a purely purely a provide to aimed we Fifth, elucidated. further be to remains hemorrhage Accordingly, the diagnostic accuracy tobetween discriminate AM subcornealand ofcases subcornealhemorrhagein our study, whichmay also exhibitsometimes a PRP. stable afteryear one is in factveryFourth, amelanoma.slow-growing we not did include unlikely, wecannot exclude thepossibilitythat a lesion assessed as nevusa and remaining studywe includednon-excised nevi with aminimum upoffollow oneyear.Although we cannot ruleout thepossibilitythat some tu with a definite histopathologic diagnosis examined of microinvasionfeatures might be overlooked. subtle since problematic, be also may melanoma invasive and situ in between discrimination dermoscopic independentof algorithm, clini mightcriteria display suggestive ofmelanoma (). sinceproblematic, early might notdisplaymelanoma diagnosticcriteria,while acral nevi 2).Second, Table thehistopathologicdiagnosisof melanocyticacral lesions mightbe highly achieved, this could be due to the low overall frequencies of these criteria in our dataset (see betweensubstantial investigators.Forthosevariables that onlymoderate a agreement was to the clinical and histopathologic diagnosis. Intra-observer agreement was moderate to andobservation biases,were which addressed byinvolving independent 3 blinded evaluators

Our study has several limitations. First, thelimitations. First, has Our studyseveral cal and epidemiologic parameters.However, ) a lesion lacking a PRP, a PFP or a fibrillar aPFP a fibrillar or a PRP, lacking ) alesion mourswere misclassified. Third, inthe present ctures) orslight a(of asymmetry orcolours Therefore, although we includedonly cases by expertdermatopathologists inthe field, retrospective design is subject to recall recall to subject is design retrospective try (of colours or structures or both) or in 38 Furthermore, Furthermore, Accepted Article variables thanvariables recommended. detects themostpossible AM. For that, we included in the multivariate analyses more wemelanoma, aimed for thehighest possible sensitivityto ensure that the checklist early prospectivelybe validated in studies.future Finally, considering highthe morbidity of wasfromalgorithm deriveda retrospective anal age, as shown by theresultsof the andcurrent previousSixth, studies. the suggested clinicians shouldtake intothat consideration the riskofmelanoma increases with patient’s This article This protectedis by Allcopyright. rights reserved. an acceptable cost in specificity. theof dermoscopy for diagnosis ofAM, to compared anysuggested previously method,with studies.in validation future requires external Oncol. 2001;78:10–16. intrends biological behaviorand clinical BellowsCF,4. Belafsky Fortgang P, IS, African Americans. J AmAcad Dermatol.2004;50:21–4, discussion 142–143. 3. Byrd KM, Wilson DC, Hoyler SS, Peck GL. Advanced presentation of melanoma in Dermatol. 1983;80:56s-60s. Invest J Japan. in melanoma Acral al. et M, Hosokawa H, Takematsu M, Seiji 2. 2008;13:33–41. malignant melanoma and other skin cancers in Japan: 2007 update. Int J Clin Oncol. CommitteeSkin oftheInvestigation Japanese CancerSociety: of Statistical profiles Ishihara1. K, T,Saida Otsuka F, Yamazaki N. The Prognosis Statistical and References In conclusion, the BRAAFFchecklistsignificantly improvesthediagnostic accuracy 30 To overcome this limitation the proposed BRAAFF checklist characteristicsdecades.overSurg two J Beech DJ. Melanoma in African-Americans: ysis of alreadydiagnosed lesions and should Accepted Article This article This protectedis by Allcopyright. rights reserved. acral melanocytic lesions. Arch Dermatol. 2011;147:741-743. Koga14. H,Saida T. Revised3-Stepdermoscopic for the algorithm management of melanoma diagnosis.Semin Cutan 2009;28:142-148. Med Surg. Argenziano13. G, FerraraFrancione G, S, et al.Dermoscopy-the ultimate tool for study of 126 cases. 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Early acralmelanoma in situ: correlation efficiently. PigmentCell Res. 2000;13:135–139. Saida20. T. Malignanton melanoma the sole:to how detect the early lesions 1995;131:298–304. pigmented lesionson volar skin using videomacroscope. Arch Dermatol. Saida19. T, Oguchi S,Ishihara Y.In Clin Oncol. 2005;10:371–374. Saida18. T. Lessons learned studies from ofthedevelopment of early melanoma. IntJ Japan. ArchDermatol. 2004;140:1233-1238. detecting malignant melanoma on acral volar skin: results of a multicenter study in Saida17. T, Miyazaki A,Oguchi S, al. et Significanceof dermoscopic patterns in Dermatol. 2002;20:279-285. 16. Saida T, Oguchi S, Miyazaki A. Dermoscopy for acral pigmented lesions. Clin 1998;134:563-568.Arch Dermatol. features ofearly melanomamalignant on Oguchi15. S, Saida T,Koganehira Y, et Characteristical. epiluminescent microscopic vivo observation of magnified features of of features magnified of observation vivo glabrous skin:glabrous a videomicroscopic study. Accepted Article This article This protectedis by Allcopyright. rights reserved. multicenter studymulticenter onbehalf the of international dermoscopy society. Braun34. RP, ThomasDusza L, SW, et al. Dermoscopy ofacral melanoma: a 2661. Pappo33.Melanoma AS. in children adolescents.and Eur J Cancer. 2003;39:2651– 2001;37:780–784. melanoma in Europe since1978: apopulation-based survivalstudy.Eur J Cancer. Conti32. EM, CercatoMC, Gatta G, et inTechniques Logistic Regression Analysis: A Case Stat Study. Neerl.2001;55; 76-88. Steyerberg31. EW, Eijkemans MJC,Habbema JDF. Application ofShrinkage Logistic and CoxRegression. AmJEpidemiol. 2007;165; 710-718. VittinghoffMcCulloch30. E, CE. Relaxing theof Rule Events Ten per Variable in 2014;24:83-87. prevalence tumorand thickness butdermoscopic notfor patterns. 29. LallasSgouros A,D, Zalaudek I, et al. Palmar andplantar melanomas differ sex for UpToDate, H Tsao (Ed), UpToDate,MA, Waltham,2013; updated in 2014 Saida28. T,H: Kogapigmented Dermoscopylesions of of thepalms soles. and In: 2010;162:765-771. melanoma in alarge series110 of cases inwhite a population. J Dermatol.Br Phan27. A, DalleS, S,et Touzet al. Dermoscopic features of acrallentiginous changes, and significance. ArchDermatol. 2007;143:1423-1426. Saida26. T,H. Koga Dermoscopic patterns ofacralmelanocytic nevi: their variations, 2006;142:1123-1128. melanocytic nevi melanomasand in white populationa in centralItaly.Arch Dermatol. T, Micantonio D,et al. E, of Altobelli Altamura Dermoscopic patterns 25. acral 2013;227:373-380.

al, EUROCARE WorkingGroup. Childhood

Melanoma Res. Res. Melanoma

Dermatology. Accepted Article structures, asymmetry of asymmetry ri parallelcolours, structures, The3. Receiver modelincludes of Characteristic Operator (ROC). Figure asymmetry (star). veil blue-white a and (black arrows) streaks irregular (whitepattern arrows), irregularblotches (circles),(arrowheads), irregular dots/globules displaying melanoma A 1.4mm-thick 2. Figure (d). pattern structureless patternpattern, b-fibrillar and furrow pattern), parallel by c-lattice-like the followed Figure 1. The most common global dermoscopic Figure Legends This article This protectedis by Allcopyright. rights reserved. method for early recognition of malignant melanoma.method ofmalignant early recognition Dermatol.Eur for 1994;4:521–527.J Stolz35. W, Riemann A,Cognetta AB. ABCDdermatoscopy: rule of new a practical of melanocytic nevi.Dermatol. Arch 2008;144:1232-1233. Saida38. T, Kawachi S, H.Koga Anatomic transitionsandthehistopathologic features 1996;132:1178–1182.Arch Dermatol. characteristics ofinvasive melanomas lackin Menzies37. SW, IngvarC, CrottyKA, McCarthy WH. Frequency andmorphologic 1998;134:1563–1570. dermatoscopy anda new 7-point checklist based onpattern analysis. Arch Dermatol. ofdiagnosis doubtfulmelanocytic skin lesions. Comparison of the ABCD rule of Argenziano36. G, Fabbrocini G, CarliP, et al. Epiluminescencemicroscopy the for

dge pattern, parallel furrow pattern, fibrillar pattern, fibrillar furrow pattern,dge parallel several including several criteria, a ridge parallel pattern of acral nevi was parallel lines (a- g specificsurface microscopic features.

Accepted Article Table 1.Table Definitions of dermoscopic criteria Tables Figure 6. A 1mm-thick displayingmelanoma an blotchirregular (BRAAFF score 1). of 1. score a in BRAAFF resulting point), (+1 structures of asymmetry and point) (+1 blotch irregular an displaying melanoma A 1.5mm-thick 5. Figure 4.AFigure melanoma in-situ exhibiting 0.929-0.97913, p<0.001). pattern and irregular blotch and yields corrected area under curve (AUC) of 0.954 (95%CI: This article This protectedis by Allcopyright. rights reserved. Global pattern Dermoscopic variable

multicomponent parallel linesparallel structureless starburst globular reticular

A combination of 2 or more different patterns, clearly present in a in present clearly patterns, different more or 2 of combination A streaksPigmented arranged radially attheedge of lesion the A diffuse withoutanycolouration identifiable structures colouration gray-black and brown of shades variouslyNumerous, sized, roundtostructures ovalwithvarious lesion the of part major the covering network pigment A or markings the orcristae) skin not (sulci following The pigmentation followspattern a ofparallel lines, either a parallela ridge pattern (BRAAFF score= 3). a parallel (-1 pattern furrow point),but also Definition Definition Accepted Article

This article This protectedis by Allcopyright. rights reserved. ik-e ra Areas of structureless pink colour within the lesion Milky-red areas ofvessels o type morphologic 1 than more Atypical network of The presence vesselsAtypical Regression structures with bluepigmentation of area confluent structureless Irregular, veil Blue-white streaks/pseudopods Irregular Black, brown, round to dots/globules Irregular following Pigmentation and crossing the furrows blotches Irregular patternLattice-like patternFibrillar pigmente Parallel pattern furrow Parallel pattern ridge Parallel are Identifiable colours Asymmetry colours of structures of Asymmetry Dermoscopic variable

of vessels with an irregular distribution. presence of linear irregular vessels, or the presence of other type elevated part of the lesion theoccupy entire lesion and usually corresponds toclinically a overlyingan white “ground-glass” film.Thepigmentation cannot withindistributed the lesion lesion usually tocorresponding a clinicallypart flat ofthe lesion and/o depigmentation scar-like White asymmetrically distributed at the periphery of a lesion. Bulbous and often kinked or projectionsfinger-like within the lesiondistribution Black, brown, and/orgraystructureless withareas asymmetric ridges and furrows pigmentedNumerous, finely to perpendicular filaments the lines pigmented Parallel the following ofcristaeglabrous the skin the lesion no are structures Identifiable lesion given Black, brownorgray holesnetworkwith irregular andthick lines d ie olwn h uc fthe glabrous skin of sulci the following lines oval, variously sized structures irregularly structures irregularly sized variously oval, not symmetricallynotall distributed the over Definition Definition t ymtial distribute symmetrically r lepeppe blue r -like granules d allover r the Accepted Article diagnosis. Table 2. Frequency of dermoscopic criteria in 603 acral lesions according to This article This protectedis by Allcopyright. rights reserved. ods streaks/pseudop Irregular dots/globules Irregular blotches Irregular pattern Lattice-like pattern Fibrillar pattern Parallel furrow pattern Parallel ridge colours Asymmetry of structures Asymmetry of pattern Global variable Dermoscopic multicomponent

parallel lines structureless starburst starburst globular reticular

17 (9.3%) 17 (9.3%) 0 34 (18.6%) 6 (3.3%) 4 (2.2%) 122 (66.7%) 39 (21.3%) 39 (21.3%) 4 (2.2%) 30 (16.4%) (n=183) excised Nevus 3 (1.6%) 3 (1.6%) 26 (14.2) 98 (53.6%) 184 (63.7%) 282 (59.7%) 6 (14.3%) 7 (7.9%) 13 (9.9%) 13(9.9%) (7.9%) 7 (14.3%) 6 282(59.7%) (82.4%) (63.7%) 184 108 98 (53.6%) (94.4%) 84 (57.1%) 24 (9.3%) 44 (4.8%) 14 30 (16.4%) 24 (13.1%) 22 (7.6%) 46 (9.7%) 10 (23.8%) 51 (57.3%) 61 (46.6%) 61(46.6%) (57.3%) 51 0 10(23.8%) 46(9.7%) (7.6%) 22 24 (13.1%) 0 0 24 30 (13.1%) (10.4%) 54 (11.4%) 9 (3.1%) 1 (0.3%) 31 (10.7%) 17 (5.9%) 5 (1.7%) 226 (78.2%) 2 (0.7%) 18 (6.2%) 66 (22.8%) 5 (1.7%) (6.6%) 19 (n=289) excised Nevus not 1 (0.2%) 65 (13.8%) 23 (4.9%) 9 (1.9%) 348 (73.7%) 26 (5.5%) 26 (5.5%) (n=472) (n=472) Nevus total 5 (1.1%) 5 (1.1%) 44 (9.3%) 105 (22.2%) 9 (1.9%) (10.4%) 49 0 4 (9.5%) 2 (4.8%) 2 (4.8%) 26 (61.9%) 8 (19%) (n=42) in situ Melanoma 1 (2.4%) 1 (2.4%) 14 (33.3%) 4 (9.5%) 21 (50.0%) (47.6%) 20 0 34 (38.2) 1 (1.1%) 0 9 (10.1%) 45 (50.6%) (n=89) invasive Melanoma 6 (6.7%) 76 (85.4%) 6 (6.7%) 29 (32.6%) 84 (94.4%) 0 38 (29.0%) 3 (2.3%) 2 (1.5%) 35 (26.7%) 53 (40.5%) 53 (40.5%) (n=131) (n=131) total Melanoma 7 (5.3%) 7 (5.3%) 90 (68.7%) 10 (7.6%) 50 (38.2%) (79.4%) 104 Accepted Article Univariate logistic regression logistic Univariate analysis. 3.Table Dermoscopic ofpredictors acral me This article This protectedis by Allcopyright. rights reserved. Milky-red areas network Atypical Atypical vessels structures Regression veil Blue-white variable Dermoscopic emsoi rtra Upper Lower Dermoscopic criteria Global pattern Dermoscopic variable

multicomponent parellel lines structureless starburst starburst globula reticula 2 (1.1%) 2 (1.1%) 5 (2.7%) (n=183) excised Nevus 05) 07)3(.% 1 2.% 9(14.5%) 19 (21.3%) 19 0 (0.6%) 3 (10.7%) 14 (15.7%) 14 (0.7%) 0 2 1 (0.5%) (0.4%) 2 (0.3%) 1 1 (0.5%) 43(32.8%) (46.1%) 41 2(4.8%) 31(6.6%) (3.5%) 10 21 (11.5%) r r

excised Nevus not 1 (0.3%) (n=289) .0 .0 .0 0.000 0.000 1.000 0.009 0.585 0.392 0.872 0.872 0.392 0.585 0.009 0.001 0.130 0.039 0.434 0.434 0.039 1.028 0.130 0.048 0.001 0.222 0.054 0.003 2.038 1.275 3.259 3.259 1.275 2.038 0.003 value OR OR value P- lanoma (Melanoma Total versus Nevus Total). 0 e Ref 2(0.4%) 6 (1.3%) (n=472) Nevus total 95% C.I. for for C.I. 95%

2(4.8%) 3 (7.1%) (n=42) in situ Melanoma OR OR 14 (15.7%) (n=89) invasive Melanoma 0 2(1.5%) 17 (13%) (n=131) total Melanoma Accepted Article This article This protectedis by Allcopyright. rights reserved. typed in univariate predictors Significant Intervals. Confidence OddsRatio; C.I.: OR: Multivariate logistic regression logistic analysis. Multivariate 4.Table Dermoscopic ofpredictors acral me Parallel furrow pattern furrow Parallel patternFibrillar structures of Asymmetry blotches Irregular Asymmetry of colours ridge pattern Parallel Dermoscopic variables Irregular streaks/pseudopods Irregular Asymmetry of structures structures of Asymmetry Irregular dots/globules dots/globules Irregular Parallel furrow pattern furrow Parallel Asymmetry colours of Regression structures Parallel ridge pattern ridge Parallel Lattice-like patternLattice-like Atypical network Atypical vessels vessels Atypical Milky-red areas areas Milky-red Irregular blotch blotch Irregular Blue-white veil Fibrila r pattern 0.000 0.012 0.041 0.001 0.001 0.000 value P- 0.566 1.400 0.444 4.411 4.411 0.444 1.400 0.566 0.000 0.095 0.050 0.182 0.182 0.050 0.095 0.000 0.003 6.333 1.874 21.402 21.402 1.874 6.333 0.003 0.000 0.046 0.026 0.080 0.080 0.026 0.046 0.000 0.000 2.455 1.729 3.485 3.485 1.729 2.455 0.000 0.000 5.556 2.732 11.296 11.296 2.732 5.556 0.000 0.165 1.387 0.874 2.201 2.201 0.874 1.387 0.165 0.000 2.045 1.426 2.933 2.933 1.426 2.045 0.000 1.000 1.000 0.141 7.099 7.099 0.141 1.000 1.000 .9 .0 .0 0.000 0.000 0.997 0.000 2.122 1.511 2.981 2.981 1.511 2.122 0.000 0.148 1.326 0.904 1.944 1.944 0.904 1.326 0.148 0.010 7.000 1.591 30.800 30.800 1.591 7.000 0.010 0.028 2.833 1.117 7.186 7.186 1.117 2.833 0.028 Adjusted OR lanoma (Melanoma Total versus Nevus Total). 16.198 0.123 0.123 0.280 3.471 3.598 6.849 LowCI 95% 0.054 0.104 1.054 1.698 2.132 5.845 High 95% CI 11.433 22.008 44.887 0.284 0.753 7.622 bold . Accepted Article A score of1 is needed for thediagnosis of melanoma. 5.TableThe BRAAFF check-list forthe diagnosisof acral melanoma variables =dichotomous no. Alpha set level pto < 0,05.valueCut-off set to0<10. RRsmodel. mutually adjusted variables for in the Logitformodel. allindependent calculated with conditional multivariateregression logisticconditional backward elimination risks (RRs)by ORs,95%approximated confi Relative model. in the variables all for adjusted mutually (OR) ratio Odds areas. milky-red streaks/pseudopods, blue-white veil, regression stru pattern,fibrillar lattice-likeirregula pattern, asymmetr structures, of asymmetry Variables entered onmodel:Global pattern(categorical, reference=parallel lines pattern), This article This protectedis by Allcopyright. rights reserved. inmelanoma subgroups different of lesions. 6.Table Assessment of theaccuracyof theBRAAFF check-list forthe diagnosis of acral l eaoa snnecsdnv 16 94.5% 91.6% all melanomas vs non-excised nevi l eaoa secsdnv 8.% 86.9% 89.3% all melanomas vs excisednevi naiemlnm salnv 9.% 92.6% 96.6% invasivemelanoma vs allnevi Acronym Acronym eaoai iuv l ei 10 89.6% 81.0% nevivs allsitu melanoma in l eaoa salnv 9.% 86.7% 93.1% all melanomas vs allnevi A A R B F F

Subgroups Sensitivity Sensitivity Subgroups Specificity

A Parallel Parallel A Parallel Parallel symmetry of Structures symmetry of Colours F Irregular y of parallelcolours, ridge pattern, parallel furrow pattern, ibrillar Pattern Criterion F R urrow Pattern urrow Pattern idge Pattern Pattern idge

r blotches, irregular dots/globules, irregular B dence intervals (CIs) and P-values were were P-values and (CIs) intervals dence lotch ctures, atypical vessels, network,atypical Points + 3 + 1 + 1 + 1 - 1 - 1

Accepted Article

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Accepted Article

This article This protectedis by Allcopyright. rights reserved.

Accepted Article

This article This protectedis by Allcopyright. rights reserved.