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ClinicsinDermatology

(2014),
32

 557560


Wolfsisotopicresponse:Thefirstattemptto
introducetheconceptofvulnerableareas
indermatology

http://crossmark.cro

b
RonniWolf,MD a, ,DannyWolf,Maryland,
c
c
VincenzoRuocco,Maryland,
EleonoraRuocco,Maryland,
PhD
un

DermatologyUnit,KaplanMedicalCenter,Rechovot,Israel.AffiliatedtoTheSchoolofMedicine,
HebrewUniversityandHadassah,Jerusaln
b
PediatricOutpatientClinic,SheruteiBriutClalit,HasharonRegion,Israel
c
DepartmentofDermatology,SecondUniversityofNaples,Naples,Italy

1
Extracto Theterm isotopicresponse wascoinedin1995todescribetheoccurrenceofanewskin
disorderatthesiteofanother,unrelated,andalreadyhealedskindisease.Thatpublicationpavedthe
waytorecognitionofthisphenomenonbythemedicalcommunityworldwidewithmultiplereports
describingitunderavarietyofconditions.
Theterm isotopicresponse, however,turnedouttobeunsuitableforaMedlinesearch,becauseit
generatedhundredsofreferenceslinkedwithradioactiveisotopes.TofacilitateMedlinesearchesforthis
dermatologicphenomenonbyavoidingunnecessarilytime-consumingsiftingthroughsomanyunrelated
referencias,itwassuggestedthatthename Lobobeadded.LobodeThename sisotopicresponse hassincebeen
generallyacceptedandevenincludedin Stedman' sIllustratedDictionaryofDermatologyEponyms .
AlthoughtheconceptoftheisotopicresponsewasconceivedasbeinganalogoustoKbner
sisomorphic
response,anddespitethesimilaritiesbetweenthetwoterms,thesimilaritiesareonlyskindeep,andthereisa


majordifferencebetweenthetwo.Enfermedad
Isomorphicresponse
de
significa
 thesamemorphology  (asthatoftheexisting
)anddescribestheappearanceofthesamediseaseatanotherlocation.Theterm
isotopicresponse
describestheappearanceofanaltogetherdifferentdiseaseatthesiteofanalreadyhealedskindisease.We
describethisentityandpresentrepresentativeclinicalexamples.Someproblemsinthedefinitionof
Lobo s
isotopicresponse areprovided,withspecialemphasisonitsoverlappingwith
Kbner' sisomorphicresponse.
ThedescriptionofWolf sisotopicresponse,whichisanalogousbutnotidenticaltotheisomorphic
responsedescribedsome120yearsagobyKbner,illustratesthecontributionofmorphologicfindingsand
originalideasinkeepingupwiththeongoingprogressinthefieldofdermatology.
2014ElsevierInc.Allrightsreserved.

Definitionandhistory

Thefirstreportofsuchacasedatesbackto1929,when
2
GougerotandFilliotdescribedacaseoflichenplanusthat
#Pages
#Pages [4]
[4]
developedinascarofaherpeszostereruptionof2months
1
Theterm isotopicresponse
wascoinedin1995 #Pages
a
[4]
#Pages [4]
3
duration.Anotherreportappearedin1938,describinga
#Pages
describetheoccurrenceofanewskindisorderatthesiteof
#Pages
caseinwhichlichenplanusdevelopedinaherpeszostersite
another,unrelated,andalreadyhealedskindisease.
3yearsaftertheoriginalzostereruption.
Perhaps,themostmeaningfulamongtheearlycontributionstothissubjectwasthatofWyburn-Mason,abrilliant
Correspondingauthor.Fax:+972-9-9560978.
scholar,researcher,andworld-famousBritishneurologist

[4]
[4] http://dx.d

electrnico-mailaddress:
wolf_r@netvision.net.il(R.Wolf).

http://dx.doi.org/10.1016/j.clindermatol.2014.04.002
0738-081X/2014ElsevierInc.Allrightsreserved.

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Multilizer PDF Translator Free version - translation is limited to ~ 3 pages per translation.
558

R.Wolfetal.

4
(1911-1983).In1955,hereportedaseriesof26patientsin
#Pages
#Pages [4]
[4]
whommalignanttumorsdevelopedatthesiteofaprevious
herpeszostereruptionin25ofthemandatthesiteofaherpes
simplexeruptionintheremainingpatient.Twoyearslater,he
reportedsixadditionalpatientsinwhomsquamouscell
carcinomadevelopedontheskinonthesamesitesofthe
5
earlierherpessimplexattacks.
#Pages
[4]
#PagesWyburn-Masonwaswell
[4]
awarethatitmaybearguedthatthisisacoincidence;


however,hebelievedthatinmanycasesthisisunlikely,as,

forexample,whenherpeszosteroccursontheabdominal
wallofayoungwoman,andsomeyearslateramalignant
changedevelopsinthisunusualsituation.Los
Additionalcasesofmalignancies(eg,
leukemicinfiltra-tionorangiosarcoma)
orgranulomatousreactions(eg,
sarcoidgranulomaorgranulomaannulare)eran
subsequentlyreportedtohaveoccuredatthesitesof
previousvaricellazosterviralinfections.Thiswasbest
illustratedbythecaseofapatientwithanangiosarcomaof
theheadwhosetopographypreciselytracedthetrigeminalreas
(firstandsecondbranches)thathadbeenaffectedbya
herpeszostereruption10yearsearlier.

Thatpublicationpavedthewaytorecognitionofthis
phenomenonbythemedicalcommunityworldwide,with
multiplereportsdescribingitunderavarietyofconditions.
Theterm
isotopicresponse, sinembargo,turnedouttobe
unsuitableforaMedlinesearch,becauseitgenerated
hundredsofreferenceslinkedwithradioactiveisotopes.To
facilitateMedlinesearchesofthisdermatologicphenomenon
byavoidingunnecessarytime-consumingsiftingthroughso
manyunrelatedreferences,andinrecognitionofDr.Wolfs


invaluablecontributiontoourunderstandingofthistopic,it 
9
wassuggestedthatthename
Lobo beadded.Thename
#Pages
#Pages [4]
[4]
Lobo sisotopicresponse hassincebeengenerallyaccepted
andisevenincludedin
Stedman sIllustratedDictionaryof
10
DermatologyEponyms. #Pages
#Pages[4]
[4]
Typicalcasesappearingafterherpeszosterorsimplex
willbedescribedindetailinWolfspostherpeticisotopic


response:Infections,tumors,andimmunedisordersarising
onthesiteofhealedherpeticinfection.Thefollowingare

reportsofsomecasesinwhichthefirstdiseaseisnotherpes.

#Pages
#Pages [4]
[4]

7
In1985,
WolfandWolf
#Pages
#Pages[4]
[4] reportedtwoadditionalcases,

ReportedcasesofWolfsisotopicresponsein
describinga52-year-oldmananda12-year-oldgirlwho
whichthefirstdiseaseisnotherpes
developedafungalinfection4yearsand2months,
respectively,afterthehealingofaherpeszostereruptionat
exactlythesamesites.Theimportanceoftheirreportclearly
Althoughthefirstdiseaseisaherpes(zosterorsimplex)
wasnotinmerelyaddingtwonewcasestothealreadyexisting
infectioninthevastmajorityofcasesofWolfsisotopic ,.
onesbutrathertheauthorsrecognitionthatearlierreports

1116

hadnotjustdescribedabizarreandunexpectedlocalization
Webelievethat
#Pages
[4]
#Pages
[4]
ofcertaindermatoses.Italsopresentedanewdermatologic
therearemanyotherunreportedcasesandthatherpeszoster
phenomenon,possiblyanalogousbutnotidenticaltothewellisoverrepresentedintheliterature,becauseitslocalizationis
knownisomorphicresponseofKbnerthathadbeendescribed
easytorememberandtheappearanceofaseconddiseaseina
8
morethan100yearspreviously.Intheiroriginalpaper,Wolf
dermatomallocationisunlikelytobeignored.Itshouldbe
#Pages [4]
[4]
#Pages
andWolfmentionedthatsuchoccurrencesareuncommonbut
emphasizedthattheoriginaldefinitionofthephenomenon,

apparentlynotrare.Thatweobservedtwocasesofthiskind
whichisstillvalidtoday,includedallcasesthatshowthe

6
withinonly1monthofpublicationoftheabovearticlemight
occurrenceofanewskindisorderatthesiteofanother,
#Pages
#Pages [4]
[4]
becoincidental,butwebelievethatitisnotsoandthatmany
sinrelaciones,andalreadyhealedskindisease
withno [4]
 7#Pages
#Pages
[4]
othercasesmayhavebeenoverlookedormaynothavebeen
limitationofthenatureofeitherdisease.Specifically,cases
consideredimportantenoughtobepublished.Theystate
inwhichthefirstdiseaseisnotherpes,butrepresenting

thatsincethephenomenonis,inouropinion,importantand
anotherpathologicdermatologiccondition,aresuitablefor

notrareitdeservesaspecialterm,andtheysuggestedisoloci
inclusioninthedefinitionofWolfsisotopicresponse.



17
response.Theyalsoprovidedaprecisedefinitionforthis
AninterestingreportfromIndia

#Pagespresentstwocasesof
[4]
#Pages
[4]
entity,andthatdefinitionhasremainedvalidandunmodified
isotopicresponseinwhichtheseconddiseasewasarecurrent
tothepresentday.
herpessimplexinfectionthatappearedmorethan15and
2yearslateranderuptedexactlyoverpreexistingscrofulImportantasitmightbe,thisphenomenoncouldhave
fallenintodisuseorevenhavesufferedanuntimelydeath
odermascars.Aremarkablefeatureofboththesecaseswas
haditnotbeenresuscitatedbyoneoftheauthorsofthe
thattheseconddisease(esdecir,theherpessimplex)pararon
currentwork(VR),whoenthusiasticallyjoinedtheoriginal
recurringafterarepeattreatmentwithantituberculardrugs.
twoauthors(RWandDW)inpublishingaseminal
contribucinonthisnewphenomenon.Theysuggested
Thisinstructivereportemphasizesthataseconddisease
1
appearingonascrofulodermascar,oranyotherscarforthat
#Pages
[4]
#Pages [4]
changingitsnamefrom
isolociresponse a isotopic
matter,canbeconsideredasbeinganisotopicresponse,
respuesta, reasoningthatbecausetheprefix
ISO- isGreek,
unlikeacarcinomathatdevelopsontopofthescarredtissue
thestemwordshouldalsobeGreek,asistheterm
tema
oflupusvulgaris,whichcannot.Thelogicbehindthat
(topos =place).TheycouldhaveusedtwoLatinwords,
decisionisthatscarsofanykindareaknowncausative/


ipso yloco,
butpreferred ISO, makingitanaologousto
etiologicfactorforthedevelopmentofamalignancy,achain
Kbnersisomorphicresponse,
as
isotopicresponse .
ofeventswhoseunderlyingmechanismisnotyetfully


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559Wolfsisoto

understood.Incontrast,whenherpesistheseconddisease,it
canbeassumedthatthefirstdiseaseandnotthescarthatit
hadleftisthereasonforthelocalizationoftheherpesbut
certainlynotforthedevelopmentofthatviraldisease.Thisis
theessenceofan  isotopicresponse
a
saber,
diseasethatdeterminesthesitebutnottheoccurrenceofa
segundo,unrelateddisease.
Otherinterestingcasesarethoseofdiseasesbetterknown
asbeingassociatedwithKbnersisomorphicresponse.One
, , ,

andunrelatedone,asopposedtotheisomorphicresponsein
whichtheseconddiseaseisthesameastheoriginalone.This
requirementraisesthequestionofhowtodealwitha
multicentricsystemicdisease,suchaslymphoma,Kaposi
ahealedsarcoma,skinmetastasis,orevendrugeruptionsandviral
exanthemasthatoccuratthesiteofasuperficialscarof
healedherpessimplexorzoster.Wesuggestthatitcan,
nevertheless,bedefinedasWolfsisotopicresponse,ifthe

patientdidnothavesignsofthediseasepreviouslyandifthe
lesionsappearedsolelyattheprecisesiteofahealedherpetic
lesionandnotonanyotherareas.
18
ThedefinitionofWolfsisotopicresponsehasbeen

#Pages
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[4]
perforatingcollagenosisappearingexactlyonthesameareas
furtherrefinedtoensurethehomogeneityofcaseseries.
19
ofhealedinsectbites1monthlater.
Towardthatend,itnowexcludesnonspecificcases(suchas
#Pages
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[4]
AcasereportfromTaiwan20#Pages
descrito[4]denovo leucemia
legulcersarisingatsitesofstasisdermatitis)andcancers
#Pages [4]
cutisatthesiteofstriaedistensaeandraisedthequestionof
arisingatpremalignantorpredisposingscarsordiseases
whetherthiswasanisotopicresponse.Thoseauthors
(suchasscrofulodermascars).Itmaywellbethatrestricting
mentionedotherdermatosesthathadbeenreportedto
thedefinitionandexcludingmanycasesthatmighthavean
developwithinstriaedistensae,includingurticarialvasculiidenticalunderlyingpathomechanismwillturnouttobe
tis,lupuserythematosus,keloid,linearfocalelastosis,and
flawed,butatthisstage,wethinkthattheimportanceofthe
chronicgraft-versus-hostdisease.Ifthesecasesaretobe
homogeneityofthegroupoutweighstheadvantageofhaving
includedundertheheadingWolfsisotopicresponse,as
greaternumbersofcases.



theseauthorshavesuggested,whichwouldbethefirstand
nowhealeddisease?

Theisotopicresponse:Anotherexampleofthe
valueofdescriptivedermatologyinan
#Pages
pruebas-basedworld 22
#Pages [4]
[4]

Isotopicversusisomorphicresponse:Two
differentphenomenawithsomeoverlap
Althoughtheconceptoftheisotopicresponsewas
conceivedasbeinganalogoustoKbnersisomorphic
,


andthereisamajordifferencebetweenthetwo.Theterm
isomorphicresponse
significa thesamemorphology 
(asthatoftheexistingdisease)anddescribestheappearance
ofthesamediseaseatanotherlocation.Theterm
isotopic
respuestadescribestheappearanceofanaltogetherdifferent
diseaseatthesameplaceofanalreadyhealedskindisease.
Althoughitappearsonapparentlyunaffectedandhealthy
skin,thediseasethatislabeledasbeinganisomorphic
responseappearsondamagedandtraumatizedskin.This
requirementissomewhatproblematic,becausehealedskinis
veryoftennotabsolutelynormalandmaycontinuetobeat
leastphysiologicallyabnormal(evenifinvisible)formonths
andevenyearsafteraninjuryordisease.Thisproblemwas

#Pages
#Pages [4]
[4]

21

addressedinthepreviouslymentionedkeycontributionon
1
Wolfsisotopicresponse,butquestionsstillremained.In

#Pages
#Pages [4]
[4]
thepresentreview,wedescribetwocasesofisotopic
responseinwhichtheseconddiseasewasarecurrentherpes
simplexinfectionthatappearedpreciselyoverpreexisting
scrofulodermascars:Thescarswereresponsibleforthe
localizationoftheseconddisease(herpes)pero,decourse,no
foritsdevelopment.
AnotherqualificationforbeingclassifiedasWolfs
isotopicresponseisthattheseconddiseasemustbeanew


ThedescriptionofWolf  sisotopicresponse,whichis
analogousbutnotidenticaltotheisomorphicresponse
describedsome120yearsagobyKbner,illustratesthe
contributionofmorphologicfindingsandoriginalideasin
keepingupwiththeongoingprogressinthefieldof
dermatology.Itdemonstratesonceagainthatthemost
importantinstrumentindermatologyis,asithasalways
been,thenakedeye,eveninanerainwhichdiagnostic
investigationsaremultiplyingrapidlyandarebecoming
moreandmorerefinedandsophisticated.
23
StefaniaJablonska,
whoisbothamasterofdescriptive
#Pages
#Pages[4]
[4]
dermatologyandaleadingscientistinthefield,statedatthe
beginningofthismillennium,Itisnecessaryinthenew

centurytopreservetheclinicaldiagnosticskillbecause
clinicalexpertise,vastknowledge,andunderstandingof
pathologicaleventsshould,andwill,remainthebasisof
practicalmedicine.Foraphysicianwithabroadoutlook,a
skindisorderisapathologicalmodelprovidedbynature.
Withoutmorphologicalfindings,elaboratemolecularstudies
arenotinfrequentlyworthless.However,morphologic
findingsshouldbesupplementedbygenetic,immunological,
andmolecularstudies. 
Puredescriptivedermatologyremainsthefountofour
knowledge,andwemustcontinuetoenhanceourwaysof
describingwhatweseetomakesenseofamorphologic
entity.Theintroductionofdefinitiveterminology,suchas
theisotopicresponse,isanespeciallyaptcaseinpoint.

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560

R.Wolfetal.

Conclusions
Fromtheisotopicresponsetotheintroductionof

theconceptofvulnerableareasindermatology

AsCharlesDarwinputit, Scienceconsistsofgroupingfacts
sothatgenerallawsorconclusionsmaybedrawnfromthem.
24
Thisisexactlywhatthepresentissuestrivestodo.Itisnoless
important,however,topreservetheintegrityoftheindividual
diseaseentitysothatitisnotobscuredbyotherswithwhichit
sharesacommonpathomechanism.
Asregardstheisotopicresponse,ithasmaintainedits
integrityovertimeand,whatismore,haspavedthewayfor
thedevelopmentofanovelconcept,theimmunocompromiseddistrict,whichencompassesawiderangeofclinical
conditionsofskinvulnerability,congenitalandacquired
(includingtheisotopicresponseitself),havingincommona
localizeddysregulationoftheimmunecontrol.

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