Diagnostic approach of eosinophilic spongiosis,

Valéria

Aoki

a_{PostgraduatePrograminDermatology,DepartmentofDermatology,HospitaldasClínicas,FaculdadedeMedicina,Universidade} deSãoPaulo,SãoPaulo,SP,Brazil

b_{DepartmentofDermatology,HospitaldasClínicas,FaculdadedeMedicina,UniversidadedeSãoPaulo,SãoPaulo,SP,Brazil}

Received20October2018;accepted1February2019

KEYWORDS Diagnosis, differential; Eosinophils; Pemphigoid,bullous; Pemphigus; Skindiseases, vesiculobullous

Abstract Eosinophilicspongiosisisahistologicalfeaturesharedbysomedistinctinflammatory disorders,andischaracterizedbythepresenceofintraepidermaleosinophilsassociatedwith spongiosis.Mostoften,isolatedeosinophilicspongiosisindicatestheearlystagesofa subja-centautoimmunebullousdermatosis,suchasthepemphigusgroupandbullouspemphigoid. Herein,themaincausesofeosinophilicspongiosisarediscussed,aswellasthesupplementary investigationneededtoelucidateitsetiology.

©2019PublishedbyElsevierEspa˜na,S.L.U.onbehalfofSociedadeBrasileiradeDermatologia. ThisisanopenaccessarticleundertheCCBYlicense(http://creativecommons.org/licenses/ by/4.0/).

Introduction

Eosinophilic spongiosis (ES) is defined by the presence of intraepidermal eosinophils in spongiotic zones, whether or notassociated withintraepidermal vesication.1 _{ESis a}

histopathologicalfeaturesharedbydifferentdisorders,such

夽 _{Howtocitethisarticle:MoraisKL,MiyamotoD,MarutaCW,Aoki} V.Diagnosticapproachofeosinophilicspongiosis.AnBrasDermatol. 2019;94:724---8.

夽夽_{StudyconductedattheDepartmentofDermatology,Hospital} dasClínicas,FaculdadedeMedicina,UniversidadedeSãoPaulo,São Paulo,SP,Brazil.

∗_{Correspondingauthor.}

E-mail:kmrlopes@gmail.com(K.L.Morais).

astheearlystagesofautoimmunebullousdermatosis(AIBD), eczema, and drug reaction, thus representing a diagnos-tic challenge.1 _{A carefulclinicopathological correlation is}

recommendedinordertoestablishtheetiologyofES.

ESinAIBD

Spongiosis associated with epidermal eosinophilic infiltra-tion was first described in 1968 as a pre-acantholytic inflammatory change observedin both pemphigus vulgaris andfoliaceus,oftenprecedingitstypicalclinicaland histo-logicalpresentation.2_{ESmaybethesolealterationormay}

appearadjacenttoacantholyticareas.

Later,ESwasconsidered a relevanthistologicalaspect ofpemphigusherpetiformis(PH),anunusualclinicalvariant

https://doi.org/10.1016/j.abd.2019.02.002

0365-0596/©2019PublishedbyElsevierEspa˜na,S.L.U.onbehalfofSociedadeBrasileiradeDermatologia.Thisisanopenaccessarticle undertheCCBYlicense(http://creativecommons.org/licenses/by/4.0/).

Figure 1 Clinical presentation of pemphigusherpetiformis (A). Annularurticarial plaques(B) andperipheral vesicles (C) in herpetiformispatternonposteriortrunk.

Figure2 Pemphigusherpetiformis. (A)Eosinophilic spongiosis, without prominentacantholysis (Hematoxylin& eosin, x400). (B)Directimmunofluorescencewithlinear,intercellular,andintraepithelialIgGdeposits.

ofpemphigus.3 _{PHclinicallyresemblesdermatitis}

herpeti-formis,andischaracterizedbypruriticurticarialerythema withvesicobullouseruptionin about50%ofcases(Fig.1). Acantholysis may not be evident by histopathology, but ESis invariably present; immunofluorescencestudies with intraepidermalintercellulardepositsconfirmthediagnosis ofPH3,4_(Fig.2).

There were 27 cases of PH diagnosed at the Depart-ment ofDermatology ofHospital dasClínicas ---University of São Paulo Medical School in the last 15 years, corre-sponding to5% of allpemphigus patients underfollow-up atthisclinic.Amongthem,ESwasthemain anatomopatho-logical feature (present in 100% of the cases) and was considered by the authors as a mandatory criterion for PH, with or without concomitant evidence of acantholy-sis.

ESwasalsodescribedastheinitialhistologicalfindingin onecaseofparaneoplasticpemphigus.5 _{Additionally,}

pem-phigusvegetans maydisplayEScommonlyassociatedwith supra-basalacantholysisandepidermalhyperplasia.1,6

In bullouspemphigoid (BP),ES is aprominent feature, evenintheabsenceofadjacentsubepidermaldetachment. Itisespeciallyobservedduringthepre-bullousphase,when urticariallesions,eczema,orevenisolatedpruritusprevail (Figs. 3 and 4).6,7 _{This finding may not be fortuitous, as}

previousstudiesdemonstratedtheroleofeosinophilsinthe pathogenesisof BP.Itseemsthatthereleaseof toxic pro-teinsbyeosinophilscancontributetoblisterformation.7_It

ishypothesizedthatchemokinesreleasedbykeratinocytes afterepidermaldamageinduceeosinophilicmigrationinto epidermisinBP,includingIL-8andeotaxin.7

Ruizetal.observedthatamong150patientswithES,24% hadanunderlyingAIBD,emphasizingBPasthemaincause.8

Mucousmembranepemphigoidandpemphigoidgestationis areless frequently associated with ES.During pregnancy, theoccurrenceof ESinurticariallesionsmaysupportthe diagnosisofpemphigoidgestationisandhelptodistinguish itfrompolymorphiceruptionofpregnancy.6

Otherdifferentialdiagnoses

Even though ES is traditionally associated with AIBD, it has been accepted as a consistent histological feature of other inflammatory skin disorders, notably spongiotic dermatitis.6 _{Although lymphocytes are the main}

inflam-matory cells, ES can occur adjacent to other epidermal alterationsineczema,suchasincontact,atopic,or num-mular dermatitis.6,9 _{Ruiz et al. found that most patients}

Figure3 Urticarial(A)andbullous(B)phasesofbullouspemphigoid.

Figure4 Bullouspemphigoid.(A)Focaleosinophilicspongiosisadjacenttosubepidermalclefting(Hematoxylin&eosin,x400). (B)DirectimmunofluorescencewithlineardepositsofIgGinthebasementmembranezone.

without concomitant vesicles or blisters.8 _{In such cases,}

immunofluorescencestudiesarerequiredtodistinguishboth disorders.1

Arthropodbitereactions, urticaria,drugreactions,and scabiesrepresentothercausesofES.1,6,9_{Prominentdermal}

edemaandmixedinflammatoryinfiltrateareclassicallyseen ininsectbitereactions andurticariallesions.1,6

Neverthe-less,theurticarialphaseofan AIBDmust beexcluded.In scabies,thepresenceofthemiteinstratumcorneummay confirmthediagnosis.6_{Idreactions secondarytofungal or}

otherinfectionsmayalsocauseES.8

The vesicular phase of incontinentia pigmenti, a rare X-linked dermatosis, may also exhibit ES along with dyskeratotic keratinocytes, and has distinctive histopathological features.1,6 _{ES is seldom observed in}

lichen sclerosus, polycythemia vera, porokeratosis, Mey-erson’s nevi, Still’s disease, and Wells syndrome.1,6,9

Additionalhistopathologicalalterations provide more spe-cific evidence to support the diagnosis. In eosinophilic follicular pustular folliculitis (Ofuji folliculitis), ES is found in the hair infundibulum and sebaceous duct.1,9

Diagnosticworkup

EScaseswithspecificclinicalandhistologicalfeaturesmay provideevidencetoanaccuratediagnosis.Incontrast,those withunusualclinicalpresentationand/orwithoutadditional histopathological alterations may represent a diagnostic challenge.(Fig.5)

Acarefulanalyticapproachandclinicopathological cor-relationareoftennecessaryforetiologicalelucidation.This includestheevaluationofassociatedepidermalanddermal alterations fromseveralhistologicalserial sections. Acan-tholysis,dyskeratosis,intensedermaledema,inflammatory infiltrate, basement membrane zone alterations, and the presenceofmicroorganismsmaybeobservedandaidinthe diagnosis.

The diagnosis of early AIBD requires ancillary testing. Immunofluorescence(IF)studies arethegold standardfor the diagnosis of AIBD to demonstrate the presence of autoantibodies againstintra-epidermalorbasement mem-branezoneantigensinvivo.10_{DirectIFdetectstissue-bound}

autoantibodies, whereas indirect IF quantifies circulat-ing autoantibodies. Deposits of fluorescent antibodies are

Clinical features

Vesicobullous lesions

Investigate addtional epidermal and/or dermal

changes Non-bullous lesions Acantholysis Present Absent Eczema BP MMP PG pemphigus DIF (-) DIF (+)

Dyskeratosis Incontinentia pigmenti

Urticaria Edema Microorganism Scabies DIF (-) DIF (+) Eczeme Pemphigus Eosinophilic spongiosis

Figure5 Diagnostic managementofeosinophilicspongiosis.DIF, directimmunofluorescence;(−), negative;(+),positive; BP, bullouspemphigoid;MMP,mucousmembranepemphigoid;PG,pemphigoidgestationis.

detected in all pemphigus and BP patients, and may be determinantinatypicalcases.10

Final

considerations

ItisrecommendedtoconsiderAIBDasadifferential diagno-sisofES.Inthisgroup,specialattentionmustbegiventoBP andPHduetotheirhigherassociationwithES.Concomitant clinical and histological features may leadto the correct diagnosis.However,whenESisthemainorsingle histolog-icalabnormality ona skin biopsy, active investigation for specificfeaturesandimmunofluorescenceanalysisareoften necessary,andmustberepeatedincaseofinitialnegativity. ConcerningtheetiologyofES,keratinocytesignalingmay playaroleintheinductionofepidermaleosinophilic infil-tration.However,thereasonwhyitoccursinsuchdifferent disordersremains unknown andhasnot been studiedyet. Futureresearch is still necessary and willbe essential to elucidatethesepathogenicquestionsandcontributetothe discoveryofnewtherapeutictargets.

Financial

support

The present study received financial support from FUNADERSP (Fundo de Apoio ao Dermatologista de São Paulo),SãoPaulo,Brazil.

Author’s

contributions

Karina Lopes Morais: Approval of the final version of the manuscript;conceptionandplanningofthestudy; elabora-tionandwritingofthemanuscript;obtaining,analyzingand interpreting the data; effective participation in research

orientation;criticalreviewoftheliterature;criticalreview ofthemanuscript.

Denise Miyamoto: Approval of the final version of the manuscript; conception and planning of the study; elaboration and writing of the manuscript; effective par-ticipationinresearchorientation;intellectualparticipation in propaedeutic and/or therapeutic conduct of the cases studied;criticalreviewofthemanuscript.

Celina Wakisaka Maruta: Approval of the final version ofthe manuscript; conception andplanning of the study; effectiveparticipationinresearchorientation;intellectual participationinpropaedeuticand/ortherapeuticconductof thecasesstudied;criticalreviewofthemanuscript.

Valéria Aoki: Approval of the final version of the manuscript;conceptionandplanningofthestudy;effective participation in research orientation; intellectual partici-pationin propaedeuticand/or therapeuticconduct ofthe casesstudied;criticalreviewofthemanuscript.

Conflicts

of

interest

Nonedeclared.

Acknowledgments

TheauthorsthankProf.Dr.NeusaYurikoSakaiValente,who contributedtohistologicimagesofthestudy.

References

1.LepelletierC,Vignon-PennamenMD,BattistellaM.Eosinophilic spongiosis.AnnDermatolVenereol.2018;145:68---71.